(2) robert w. schrier - atlas of diseases of the kidney volume 03 (pdf)

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Series Editor Robert W. Schrier Professor and Chairman Department of Medicine University of Colorado School of Medicine Denver, Colorado

Table of Contents

VOLUME ONE VOLUME TWO VOLUME THREE VOLUME FOUR VOLUME FIVE

VOLUME THREE Edited by Christopher S. Wilcox

Contents CHAPTER 1 THE KIDNEY IN BLOOD PRESSURE REGULATION L. Gabriel Navar and L. Lee Hamm

CHAPTER 2 RENAL PARENCHYMAL DISEASE AND HYPERTENSION Stephen C. Textor

CHAPTER 3 RENOVASCULAR HYPERTENSION AND ISCHEMIC NEPHROPATHY Marc A. Pohl

CHAPTER 4 ADRENAL CAUSES OF HYPERTENSION Myron H. Weinberger

http://www.kidneyatlas.org/toc.htm





http://www.kidneyatlas.org/book3/adk3-03.QXD.pdf


CHAPTER 5 INSULIN RESISTANCE AND HYPERTENSION Theodore A. Kotchen

CHAPTER 6 THE ROLE OF HYPERTENSION IN PROGRESSION OF CHRONIC RENAL DISEASE Lance D. Dworkin and Douglas G. Shemin

CHAPTER 7 PHARMACOLOGIC TREATMENT OF HYPERTENSION Garry P. Reams and John H. Bauer

CHAPTER 8 HYPERTENSIVE CRISES Charles R. Nolan





1

The Kidney in BloodPressure Regulation

Despite extensive animal and clinical experimentation, themechanisms responsible for the normal regulation of arterialpressure and development of essential or primary hyperten-

sion remain unclear. One basic concept was championed by Guytonand other authors [1–4]: the long-term regulation of arterial pressureis intimately linked to the ability of the kidneys to excrete sufficientsodium chloride to maintain normal sodium balance, extracellular fluidvolume, and blood volume at normotensive arterial pressures.Therefore, it is not surprising that renal disease is the most commoncause of secondary hypertension. Furthermore, derangements in renalfunction from subtle to overt are probably involved in the pathogenesisof most if not all cases of essential hypertension [5]. Evidence of gener-alized microvascular disease may be causative of both hypertension andprogressive renal insufficiency [5,6]. The interactions are complexbecause the kidneys are a major target for the detrimental consequencesof uncontrolled hypertension. When hypertension is left untreated, pos-itive feedback interactions may occur that lead progressively to greaterhypertension and additional renal injury. These interactions culminatein malignant hypertension, stroke, other sequelae, and death [7].

In normal persons, an increased intake of sodium chloride leads toappropriate adjustments in the activity of various humoral, neural,and paracrine mechanisms. These mechanisms alter systemic andrenal hemodynamics and increase sodium excretion without increasingarterial pressure [3,8]. Regardless of the initiating factor, decreases insodium excretory capability in the face of normal or increased sodiumintake lead to chronic increases in extracellular fluid volume andblood volume. These increases can result in hypertension. When thederangements also include increased levels of humoral or neural factorsthat directly cause vascular smooth muscle constriction, these effectsincrease peripheral vascular resistance or decrease vascular capacitance.Under these conditions the effects of subtle increases in blood volumeare compounded because of increases in the blood volume relative to

L. Gabriel Navar L. Lee Hamm

C H A P T E R

1.2 Hypertension and the Kidney

the capacitance, often referred to as the effective blood volume.Through the mechanism of pressure natriuresis, however, theincreases in arterial pressure increase renal sodium excretion,allowing restoration of sodium balance but at the expense ofpersistent elevations in arterial pressure [9]. In support of thisoverall concept, various studies have demonstrated strong relationships between kidney disease and the incidence ofhypertension. In addition, transplantation studies have shownthat normotensive recipients from genetically hypertensivedonors have a higher likelihood of developing hypertensionafter transplantation [10].

This unifying concept has helped delineate the cardinal roleof the kidneys in the normal regulation of arterial pressure aswell as in the pathophysiology of hypertension. Many different

extrinsic influences and intrarenal derangements can lead toreduced sodium excretory capability. Many factors also existthat alter cardiac output, total peripheral resistance, and cardio-vascular capacitance. Accordingly, hypertension is a multifactorialdysfunctional process that can be caused by a myriad of differentconditions. These conditions range from stimulatory influencesthat inappropriately enhance tubular sodium reabsorption toovert renal pathology, involving severe reductions in filteringcapacity by the renal glomeruli and associated marked reduc-tions in sodium excretory capability. An understanding of thenormal mechanisms regulating sodium balance and howderangements lead to altered sodium homeostasis and hyperten-sion provides the basis for a rational approach to the treatmentof hypertension.

400

0

80

120

160 Isolated systolic hypertension(61 y)

Normotensive(56 y)

Aor

tic

pres

sure

, m

m H

gA

orti

c bl

ood

flow

, mL/

s

A

40

20

500

C AB

PP = 72 mm Hg

PP = 40 mm Hg

PP = 30 mm Hg

600 800 900700Arterial volume, mL

6080

100

120

140160

180200

Art

eria

l pre

ssur

e, m

m H

g

B

FIGURE 1-1

Aortic distensibility. The cyclical pumping nature of the heart places a heavy demand onthe distensible characteristics of the aortic tree. A, During systole, the aortic tree is rapidlyfilled in a fraction of a second, distending it and increasing the hydraulic pressure. B, The distensibility characteristics of the arterial tree determine the pulse pressure (PP) in response toa specific stroke volume. The normal relationship is shown in curve A, and arrows designatethe PP. A highly distensible arterial tree, as depicted in curve B, can accommodate the strokevolume with a smaller PP. Pathophysiologic processes and aging lead to decreases in aortic dis-tensibility. These decreases lead to marked increases in PP and overall mean arterial pressurefor any given arterial volume, as shown in curve C. Decreased distensibility is partly responsi-ble for the isolated systolic hypertension often found in elderly persons. Recordings of actualaortic pressure and flow profiles in persons with normotension and systolic hypertension areshown in panel A [11,12]. (Panel B Adapted from Vari and Navar [4] and Panel A fromNichols et al. [12].)

HEMODYNAMIC DETERMINANTS

For any vascular bed:

Blood flow =Arterial pressure gradient

Vascular resistance

For total circulation averaged over time:

Blood flow = cardiac output

Therefore,

Cardiac output =Arterial pressure - right atrial pressure

Total peripheral resistance

and:

Mean arterial pressure = Cardiac output � total peripheral resistance

FIGURE 1-2

Hemodynamic determinants of arterialpressure. During the diastolic phase of thecardiac cycle, the elastic recoil characteris-tics of the arterial tree provide the kineticenergy that allows a continuous delivery ofblood flow to the tissues. Blood flow isdependent on the arterial pressure gradientand total peripheral resistance. Under nor-mal conditions the right atrial pressure isnear zero, and thus the arterial pressure isthe pressure gradient. These relationshipsapply for any instant in time and to time-integrated averages when the mean pressureis used. The time-integrated average bloodflow is the cardiac output that is normally5 to 6 L/min for an adult of average weight(70 to 75 kg).

1.3The Kidney in Blood Pressure Regulation

Arterialpressure

Neurohumoralsystems

Total peripheralresistance

(Autoregulation)

Net sodium andfluid balance

Dietaryintake

Cardiacoutput

Bloodvolume

Venousreturn

Interstitialfluid volume

Cardiovascularcapacitance

Mean circulatorypressure

Heart rate andcontractility

+

Urinaryexcretion

–

Insensible losses(skin, respiration, fecal)

–

ECF volume

Arterial baroreflexesAtrial reflexesRenin-angiotensin-aldosteroneAdrenal catecholaminesVasopressinNatriuretic peptidesEndothelial factors: nitric oxide, endothelin kallikrein-kinin systemProstaglandins and other eicosanoids

FIGURE 1-3

Volume determinants of arterial pressure.The two major determinants of arterialpressure, cardiac output and total peripheralresistance, are regulated by a combinationof short- and long-term mechanisms. Rapidlyadjusting mechanisms regulate peripheralvascular resistance, cardiovascular capacitance,and cardiac performance. These mechanismsinclude the neural and humoral mechanismslisted. On a long-term basis, cardiac outputis determined by venous return, which isregulated primarily by the mean circulatorypressure. The mean circulatory pressuredepends on blood volume and overall cardio-vascular capacitance. Blood volume is closelylinked to extracellular fluid (ECF) volumeand sodium balance, which are dependenton the integration of net intake and netlosses [13]. (Adapted from Navar [3].)

Concentrated urine: Increased free water reabsorption

Antidiuretic hormone release

Thirst:Increased water intake

Decreased water intake Increased salt intake

Dilute urine:Increased solute-free water excretion

If increased

Na+ and Cl–

concentrations in ECF volume

Extracellularfluid volume

Quantity of NaCl in ECF

NaClintake

NaCl losses(urine

insensible)

If decreased

Antidiuretic hormone inhibition

=÷

+

–

A201510

Extracellular fluid volume, L

2

0

3

4

5

6Edema

Bloo

d vo

lum

e, L

B

FIGURE 1-4

A, Relationship between net sodium balance and extracellular fluid(ECF) volume. Sodium balance is intimately linked to volume balancebecause of powerful mechanisms that tightly regulate plasma andECF osmolality. Sodium and its accompanying anions constitute themajor contributors to ECF osmolality. The integration of sodiumintake and losses establishes the net amount of sodium in the body,which is compartmentalized primarily in the ECF volume. The quotientof these two parameters (sodium and volume) determines the sodiumconcentration and, thus, the osmolality. Osmolality is subject to verytight regulation by vasopressin and other mechanisms. In particular,vasopressin is a very powerful regulator of plasma osmolality; how-ever, it achieves this regulation primarily by regulating the relativesolute-free water retention or excretion by the kidney [13–15]. Theimportant point is that the osmolality is rapidly regulated by adjustingthe ECF volume to the total solute present. Corrections of excessesin extracellular fluid volume involve more complex interactions thatregulate the sodium excretion rate.

B, Relationship between the ECF volume and blood volume. Undernormal conditions a consistent relationship exists between the totalECF volume and blood volume. This relationship is consistent aslong as the plasma protein concentration and, thus, the colloidosmotic pressure are regulated appropriately and the microvasculaturemaintains its integrity in limiting protein leak into the interstitialcompartment. The shaded area represents the normal operatingrange [13]. A chronic increase in the total quantity of sodium chloridein the body leads to a chronic increase in ECF volume, part ofwhich is proportionately distributed to the blood volume compartment.When accumulation is excessive, disproportionate distribution tothe interstitium may lead to edema. Chronic increases in blood volume increase mean circulatory pressure (see Fig. 1-3) and leadto an increase in arterial pressure. Therefore, the mechanisms regulating sodium balance are primarily responsible for thechronic regulation of arterial pressure. (Panel B adapted fromGuyton and Hall [13].)


20014060 100 120 18016080Renal arterial pressure, mm Hg

2

1

0

3

4

5

6

5

3

1

2 4

A

B

C

Elevatedsodium intake

High sodium intakeNormal sodium intakeLow sodium intake

Normalsodium intakeReduced

Sodi

um e

xcre

tion

,

norm

al �

reductions in arterial pressure cause antinatriuresis [9]. This phenome-non of pressure natriuresis serves a critical role linking arterialpressure to sodium balance. Representative relationships betweenarterial pressure and sodium excretion under conditions of normal,high, and low sodium intake are shown. When renal function isnormal and responsive to sodium regulatory mechanisms, steadystate sodium excretion rates are adjusted to match the intakes.These adjustments occur with minimal alterations in arterial pressure,as exemplified by going from point 1 on curve A to point 2 oncurve B. Similarly, reductions in sodium intake stimulate sodium-retaining mechanisms that prevent serious losses, as exemplified bypoint 3 on curve C. When the regulatory mechanisms are operatingappropriately, the kidneys have a large capability to rapidly adjustthe slope of the pressure natriuresis relationship. In doing so, thekidneys readily handle sodium challenges with minimal long-termchanges in extracellular fluid (ECF) volume or arterial pressure. Incontrast, when the kidney cannot readjust its pressure natriuresiscurve or when it inadequately resets the relationship, the results aresodium retention, expansion of ECF volume, and increased arterialpressure. Failure to appropriately reset the pressure natriuresis isillustrated by point 4 on curve A and point 5 on curve C. Whenthis occurs the increased arterial pressure directly influences sodiumexcretion, allowing balance between intake and excretion to bereestablished but at higher arterial pressures. (Adapted from Navar [3].)

Intrarenal Mechanisms Regulating Sodium Balance

FIGURE 1-5

Arterial pressure and sodium excretion. In principle, sodium balancecan be regulated by altering sodium intake or excretion by the kidney.However, intake is dependent on dietary preferences and usually isexcessive because of the abundant salt content of most foods. There-fore, regulation of sodium balance is achieved primarily by alteringurinary sodium excretion. It is therefore of major significance that,for any given set of conditions and neurohumoral environment,acute elevations in arterial pressure produce natriuresis, whereas

15075 100 125 175Renal arterial pressure, mm Hg

0

0

50

100

150

LowNormalHigh

Filt

ered

sod

ium

load

, µm

ol/m

in/g

Frac

tion

al s

odiu

m

reab

sorp

tion

, %Fr

acti

onal

sod

ium

ex

cret

ion,

%

94

92

96

98

100

2

4

6

8

FIGURE 1-6

Intrarenal responses to changes in arterial pressure at different levels of sodium intake.The renal autoregulation mechanism maintains the glomerular filtration rate (GFR) duringchanges in arterial pressure, GFR, and filtered sodium load. These values do not changesignificantly during changes in arterial pressure or sodium intake [3,16]. Therefore, thechanges in sodium excretion in response to arterial pressure alterations are due primarilyto changes in tubular fractional reabsorption. Normal fractional sodium reabsorption isvery high, ranging from 98% to 99%; however, it is reduced by increased sodium chlorideintake to effect the large increases in the sodium excretion rate. These responses demon-strate the importance of tubular reabsorptive mechanisms in modulating the slope of thepressure natriuresis relationship. (Adapted from Navar and Majid [9].)


Renal arterial pressure, mm Hg

0

0.2

0.4

0.6

Glo

mer

ular

filt

rati

on ra

te,

mL/

min

•g

RE

RA

0

5

10

15

20

Vas

cula

r res

ista

nce,

m

m H

g•m

in•g

/mL

1500 50 100 200

0

1

2

3

4

5

Rena

l blo

od fl

ow,

mL/

min

•g

RA

RE R

V

GFR=Kf• EFP

Tubular reabsorption

EFP=9

PCU=Kr• ERP

πc=37

πi=8

πga

=25 πB<1

πge

=37

Pc=20

Pi=6

Pg=60

PB=20

25

15

of the glomerular capillaries as protein-freefluid is filtered such that filtration is greatest inthe early segments of the glomerular capillar-ies, as designated by the large arrow. Theglomerular forces, EFP, and blood flow areregulated by mechanisms that control the vas-cular smooth muscle tone of the afferent andefferent arterioles and of the intraglomerularmesangial cells. The filtration coefficient alsois subject to regulation by neural, humoral,and paracrine influences [17]. Changes intubular reabsorption can result from alter-ations of various processes governing bothactive and passive transport along thenephron segments. Peritubular capillaryuptake (PCU) of the tubular reabsorbate ismediated by the net colloid osmotic pressuregradient (πc - πi). As a result of the filtrationof protein-free filtrate, the plasma colloidosmotic pressure entering the peritubular capil-laries is markedly increased. Thus, the colloidosmotic gradient exceeds the outwardlydirected hydrostatic pressure gradient (Pc - Pi).Appropriate responses of one or more ofthese modulating mechanisms allow the kid-neys to respond rapidly and efficiently tochanges in sodium chloride intake [3,17].πB—colloid osmotic pressure in Bowman’sspace; πga—colloid osmotic pressure in initialparts of glomerular cappillaries; πge—colloidosmotic pressure in terminal segments ofglomerular capillaries; RA—resistance of preglomerular arterioles; RE—efferent resistance; RV—venous resistance. (Adapted from Navar [3].)

FIGURE 1-7

Hemodynamic mechanisms regulating sodium excretion. Many different neurohumoralmechanisms, paracrine factors, and drugs exist that can influence sodium excretion and thepressure natriuresis relationship. These modulators may influence sodium excretion by alter-ing changes in filtered load or changes in tubular reabsorption. Filtered load depends primar-ily on hemodynamic mechanisms that regulate the forces operating at the glomerulus. Asshown, the glomerular filtration rate (GFR) is determined by the filtration coefficient (Kf)and the effective filtration pressure (EFP). The EFP is a distributed force determined by theglomerular pressure (Pg), the pressure in Bowman’s space (PB), and the plasma colloid osmot-ic pressure within the glomerular capillaries (πg). The πg increases progressively along the length

FIGURE 1-8

Renal autoregulatory mechanism. Because the glomerular filtration rate (GFR) is soresponsive to changes in the glomerular forces, highly efficient mechanisms have beendeveloped to maintain a stable intrarenal hemodynamic environment [16]. These powerfulmechanisms adjust vascular smooth muscle tone in response to various extrinsic disturbances.During changes in arterial pressure, renal blood flow and the GFR are autoregulated withhigh efficiency as a consequence of adjustments in the vascular resistance of the preglomerulararterioles. Although efferent resistance also can be regulated by other mechanisms, it doesnot participate significantly over most of the autoregulatory range. The GFR, filtered sodiumload, and the intrarenal pressures are maintained stable in the face of various extrarenaldisturbances by the autoregulatory mechanism. (Adapted from Navar [3].)


A

Preglomerularresistance

Vascular effector(afferent arteriole)

Macula densa:Sensor mechanism

Transmitter

Early distal tubule:flow-related changesin fluid composition

Proximal todistal tubule

flow

Glomerulotubularbalance

Proximal tubularand loop of Henle

reabsorption

Plasma colloidosmotic pressure

Arterialpressure

Glomerularfiltration

rate

Glomerularpressure and plasma flow

Late proximal perfusion rate, nL/minC4030

High sodium intake,ECF volume expansion

Low sodium intakeDecreased ECF volume

Normal

20100

40

30

20

10

0

Sin

gle

nep

hro

n G

FR, n

L/m

in

B

ProximaltubuleDistal

tubule

Collectionpipette

Perfusionpipette

Wax blockingpipette

Maculadensa

vasoconstriction, whereas decreases in flow cause afferent vasodilation[16,18,19]. Blocking flow to the distal tubule or interrupting the feed-back loop attenuates the autoregulatory efficiency of the glomerularfiltration rate (GFR), glomerular pressure, and renal blood flow. B, Individual tubules can be blocked and perfused downstream,while collections are made or pressure measured in an early tubularsegment. C, When the tubule is perfused at increased flows, theglomerular pressure and GFR of that nephron decrease. The shadedarea in the normal relationship represents the normal operatinglevel of the TGF mechanism. This mechanism helps stabilize the filtered load and the solute and sodium load to the distal nephronsegment. The responsiveness of the TGF mechanism is modulatedby changes in sodium intake and in extracellular fluid (ECF) volumestatus. At high sodium intake and ECF volume expansion the sensi-tivity of the TGF mechanism is low, thus allowing greater spilloverof salt to the distal nephron. During low sodium intake and otherconditions associated with ECF volume contraction, the sensitivityof the TGF mechanism is markedly increased to minimize spilloverinto the distal nephron and maximize sodium retention. The hor-monal and paracrine mechanisms responsible for regulating TGFsensitivity are discussed subsequently.

The myogenic mechanism is intrinsic to the vessel wall andresponds to changes in wall tension to regulate vascular smoothmuscle tone. Preglomerular arteries and afferent arterioles but notefferent arterioles exhibit myogenic responses to changes in walltension [16,20]. The residual autoregulatory capacity that existsduring blockade of the tubuloglomerular feedback mechanism indicates that the myogenic mechanism contributes about half tothe autoregulatory efficiency of the renal vasculature. (Figureadapted from Navar [3].)

FIGURE 1-9

Tubuloglomerular feedback (TGF) and myogenic mechanisms. Twomechanisms are responsible for efficient renal autoregulation: theTGF and myogenic mechanisms. The TGF mechanism is explainedhere. A, Increases in distal tubular flow past the macula densa generatesignals from the macula densa cells to the afferent arterioles to elicit


K+

Na+

Ca2+Ca2+

Ca2+

Ca2+

PhosphorylatedMLC

Phosphorylated MLCK(inactive)

Tensiondevelopment

PKA

PKC

cAMP

cAMP R

Calmodulin

Phosphoinositides

PLC

Receptor-operatedchannel

Voltage-operatedchannel

Chloridechannel

MLC Actin

Ca2+-Cal Active MLCK

MLCK

Ca2+

SR

Smooth muscle cell

Gi Gs

Ad Cy

Agents that increase cAMP (or cGMP):Epinephrine (β), PTH, PGI2,PGE2, ANP, dopamine, nitric oxide,adenosine (A2)

Calcium-activatedpotassium channel

+

–

Cl_

Agents that increase cytosolic calcium:Angiotensin II, vasopressin, epinephrine (α),TXA2, leukotrienes, adenosine (A1),ATP, norepinephrine, endothelin

DAG + IP3

Ca2+

R

Gq

FIGURE 1-10

Cellular mechanisms of vascular smooth muscle contrac-tion. The vascular resistances of different arteriolarsegments are ultimately regulated by the contractiletone of the corresponding vascular smooth musclecells. Shown are the various membrane activationmechanisms and signal transduction events leading toa change in cytosolic calcium ions (Ca2+), cyclic AMP(cAMP), and phosphorylation of myosin light chainkinase. Many of the circulating hormones and paracrinefactors that increase or decrease vascular smooth muscle

tone are identified. Ad Cy—adenylate cyclase; ANP—atrial natriuretic protein; Cal—calmodulin;cGMP—cyclic GMP; DAG—1,2-diacylglycerol; Gq, Gi, Gs—G proteins; IP3—inositol 1,4,5-triphosphate;MLC—myosin light chain; MLCK—myosin light chainkinase; PGE2—prostaglandin E2; PGI2—prostaglandinI2; PKA—protein kinase A; PKC—protein kinase C;PLC—phospholipase C; PTH—parathyroid hormone;R—receptor; SR—sarcoplasmic reticulum; TXA2 —thromboxane A2. (Adapted from Navar et al. [16].)

FIGURE 1-11

Differential activating mechanisms in afferent and efferent arterioles.The relative contributions of the activation pathways are differentin afferent and efferent arterioles. Increases in cytosolic Ca2+ inafferent arterioles appear to be primarily by calcium ion (Ca2+)entry by way of receptor- and voltage-dependent Ca2+ channels.The efferent arterioles are less dependent on voltage-dependentCa2+ channels. These differential mechanisms in the renal vasculatureare exemplified by comparing the afferent and efferent arteriolarresponses to angiotensin II before and after treatment with Ca2+

channel blockers. A, These experiments were done using the juxtamedullary nephron preparation that allows direct visualizationof the renal microcirculation [21]. AA—afferent arteriole; ArA—arcuate artery; PC—peritubular capillaries; V—vein; VR—vasa recta.

(Continued on next page)

A


Angiotensin IIControl

15

10

20

25

30Afferent arteriole

ControlCa

2+ channel blockers

0.1 nM 10 nM

Dia

met

er, µ

B Angiotensin IIControl

Efferent arteriole

0.1 nM 10 nM

FIGURE 1-11 (Continued)

B, Both afferent and efferent arterioles constrict in response toangiotensin II [22]. Ca2+ channel blockers, dilate only the afferentarterioles and prevents the afferent vasoconstriction responses toangiotensin II. In contrast, Ca2+ channel blockers do not signifi-cantly vasodilate efferent arterioles and do not block the vasocon-strictor effects of angiotensin II. Thus, afferent and efferent arteri-oles can be differentially regulated by various hormones andparacrine agents. (Panel A from Casellas and Navar [21]; panel Bfrom Navar et al. [23].)

ACE

Smooth muscle cell

Vasodilation Vasoconstriction

Endothelial cell

EDHF NO PGI2PGF2α

Relaxing factors Constricting factors

TXA2

Endothelin

EDCF

Shearstress

Plateletactivating

factor

BradykininThrombin Insulin

SerotoninHistamine

AcetylcholineLeukotrienes

ATP-ADP

Angiotensin II

Angiotensin I

paracrine agents that alter vascular smoothmuscle tone and influence tubular transportfunction. (Examples are shown.) Angiotensin-converting enzyme (ACE) is present onendothelial cells and converts angiotensin Ito angiotensin II. Nitric oxide is formed bynitric oxide synthase, which cleaves nitricoxide from L-arginine. Nitric oxide diffusesfrom the endothelial cells to activate solubleguanylate cyclase and increases cyclic GMP (cGMP) levels in vascular smoothmuscle cells, thus causing vasodilation.Agents that can stimulate nitric oxide are shown. The relative amounts of the various factors released by endothelial cells depend on the physiologic circum-stances and pathophysiologic status. Thus, endothelial cells can exert vasodilatoror vasoconstrictor effects. At least onemajor influence participating in the normalregulation of vascular tone is nitric oxide.EDCF—endothelial derived constrictor factor; EDHF—endothelial derived hyper-polarizing factor; PGF2�—prostaglandinF2�; PGI2—prostaglandin I2; TXA2—thromboxane A2. (Adapted from Navar et al. [16].)

FIGURE 1-12

Endothelial-derived factors. In addition to serving as a diffusion barrier, the endothelialcells lining the vasculature participate actively in the regulation of vascular function. Theydo so by responding to various circulating hormones and physical stimuli and releasing

50 75 100 125 150

2

1

3

Control

NOS inhibition

Sodi

um e

xcre

tion,

norm

al

Renalarterial

pressure

Shearstress

Endothelialnitric oxide

release

Diffusion totubules

EpithelialcGMP

Decreased sodiumreabsorption

Sodiumexcretion

Vascular dilationbut counteracted by autoregulation

Renal arterial pressure, mm Hg

�

FIGURE 1-13

Nitric oxide in mediation of pressure natriuresis. Several recent studieshave demonstrated that nitric oxide also directly affects tubular sodi-um transport and may be an important mediator of the changesinduced by arterial pressure in sodium excretion, as described in Figure1-5 [9,24]. Increases in arteriolar shear stress caused by increases inarterial pressure stimulate production of nitric oxide. Nitric oxide mayexert direct effects to inhibit tubule sodium reabsorptive mechanismsand may elicit vasodilatory actions. Nitric oxide increases intracellularcyclic GMP (cGMP) in tubular cells, which leads to a reduced reab-sorption rate through cGMP-sensitive sodium entry pathways [24,25].When formation of nitric oxide is blocked by agents that prevent nitricoxide synthase activity, sodium excretion is reduced and the pressurenatriuresis relationship is markedly suppressed. Thus, nitric oxide mayexert a critical role in the regulation of arterial pressure by influencingvascular tone throughout the cardiovascular system and by serving asa mediator of the changes induced by the arterial pressure in tubularsodium reabsorption. (Adapted from Navar [3].)


ALH

DLH

PCT

PST

DCT

Filtered NA+ load = Plasma Na × Glomerular filtration rate= 140 mEq/L × 0.120 L/min= 16.8 mEq/min × 1440 min/d= 24,192 mEq/min

Urinary Na+ excretion = 200 mEq/dFractional Na excretion = 0.83%Fractional Na reabsorption = 99.17%

< 1%

7%

30%TALH

60%

CCD

OMCD

IMCD

2% –3%

FIGURE 1-14

Tubular transport processes. Sodium excretion is the differencebetween the very high filtered load and net tubular reabsorptionrate such that, under normal conditions less than 1% of the filteredsodium load is excreted. The percentage of reabsorption of the filteredload occurring in each nephron segment is shown. The end result isthat normally less than 1% of the filtered load is excreted; however,the exact excretion rate can be changed by many mechanisms. Despitethe lesser absolute sodium reabsorption in the distal nephron seg-ments, the latter segments are critical for final regulation of sodiumexcretion. Therefore, any factor that changes the delicate balanceexisting between the hemodynamically determined filtered load andthe tubular reabsorption rate can lead to marked alterations insodium excretion. ALH—thin ascending limb of the loop of Henle;CCD—cortical collecting duct; DCT—distal convoluted tubule;DLH—thin descending limb of the loop of Henle; IMCD—innermedullary collecting duct; OMCD—outer medullary collectingduct; PCT—proximal convoluted tubule; PST—proximal straighttubule; TALH—thick ascending limb of the loop of Henle.

[Na+]

Na+

Na

[K+]

K

Tubule lumen

Peritubular capillary

Active transcellular

Paracellular(passive)

Lateral intercellular

space∆P

∆π

K

K

Na

Na

(–)

(–)Cells

FIGURE 1-15

Proximal tubule reabsorptive mechanisms. The proximal tubule isresponsible for reabsorption of 60% to 70% of the filtered load ofsodium. Reabsorption is accomplished by a combination of bothactive and passive transport mechanisms that reabsorb sodium andother solutes from the lumen into the lateral spaces and interstitialcompartment. The major driving force for this reabsorption is thebasolateral sodium-potassium ATPase (Na+-K+ ATPase) that transportsNa+ out of the proximal tubule cells in exchange for K+. As in mostcells, this maintains a low intracellular Na+ concentration and ahigh intracellular K+ concentration. The low intracellular Na+

concentration, along with the negative intracellular electricalpotential, creates the electrochemical gradient that drives most ofthe apical transport mechanisms. In the late proximal tubule, a lumento interstitial chloride concentration gradient drives additional netsolute transport. The net solute transport establishes a smallosmotic imbalance that drives transtubular water flow throughboth transcellular and paracellular pathways. In the tubule, waterand solutes are reabsorbed isotonically (water and solute in equivalentproportions). The reabsorbed solutes and water are then furtherreabsorbed from the lateral and interstitial spaces into the peritubularcapillaries by the colloid osmotic pressure, which establishes a predominant reabsorptive force as discussed in Figure 1-7. �P—transcapillary hydrostatic pressure gradient; �π—transcapillarycolloid osmotic pressure gradient.


_

Cell

3Na+

CI_

2 K+

ATP

ADP

Lumen

Na+

K+

H+

Regulation of reabsorbtionStimulation Antidiuretic hormone β-adrenergic agents Mineralocorticoids

Inhibition Hypertonicity Prostaglandin E2

Acidosis Calcium

Thick ascending limb cells

Furosemide

2Cl-Na

K+

orNH4

+

+10mv

FIGURE 1-17

Sodium transport mechanisms in the thick ascending limb of theloop of Henle. The major sodium chloride reabsorptive mechanismin the thick ascending limb at the apical membrane is the sodium-potassium-chloride cotransporter. This electroneutral transporter isinhibited by furosemide and other loop diuretics and is stimulated by a variety of factors. Potassium is recycled across the apical membrane into the lumen, creating a positive voltage in the lumen.An apical sodium-hydrogen exchanger also exists that may functionto reabsorb some sodium bicarbonate. The sodium-potassiumATPase (Na+-K+ ATPase) at the basolateral membrane again is thedriving force. The basolateral chloride channel and possibly otherchloride cotransporters are important in mediating chloride effluxacross the basolateral membrane. Sodium and chloride are reab-sorbed without water in this segment because water is impermeableacross the apical membrane of the thick ascending limb. Thus, thetubular fluid osmolality in this nephron segment is hypotonic.

HCO3_

Cl_

CO3

Anion_

Na+

Na+

Na+

H+

Ca2+

3Na+

_

_

Regulation of reabsorption

StimulationAngiotensin IIAdrenergic agents or increased renal nerve activityIncreased luminal flow or solute deliveryIncreased filtration fraction

InhibitionVolume expansion (via increased backleak)Atrial natriuretic peptideDopamineIncreased interstitial pressure

Glucose

Lumen

3Na+

2 K+

ATP

ADP

Proximal tubule cells

pathways across the apical membrane mayinclude a coupled sodium chloride entrystep or chloride anion exchange that is coupled with sodium-hydrogen exchange.Major transport pathways at the basolateralmembrane include the ubiquitous and preeminent sodium-potassium ATPase (Na+-K+ ATPase) that creates the major driving force. The other major pathway is a sodium-bicarbonate transport systemthat transports the equivalent of one sodiumion coupled with the equivalent of threebicarbonate ions (HCO-

3). Because thistransporter transports two net charges out the electrically negative cell, membranevoltage partially drives this transport pathway. A basolateral sodium-calciumexchanger is important in regulating cell calcium. Not shown are several other pathways that predominantly transportprotons or other ions and organic sub-strates. Several major regulatory factors are listed.

FIGURE 1-16

Major transport pathways across proximal tubule cells. At the apical membrane, sodium istransported in conjunction with organic solutes (such as glucose, amino acids, and citrate)and inorganic anions (such as phosphate and sulfate). The major mechanism for sodiumentry into the cells is sodium-hydrogen exchange (the isoform NHE3). Chloride transport


_

Cell

3Na+

2CI_

2 K+

ATP

ADP

Lumen

Na+

Na+

K+

(IMCD)

K+

Regulation of reabsorbtionStimulation Aldosterone Antidiuretic hormone

Inhibition Prostaglandins Nitric oxide Atrial natriuretic peptide Bradykinin

Collecting duct principal cell

Amiloride

_

_

3Na+

2 K+

ATP

ADPNa+

Na

Cl_

Na+

H+

Am

ilori

de

Thiazides

Distal tubule andconnecting tubule cells

FIGURE 1-18

Mechanisms of sodium chloride reabsorption in the distal tubule. The distal convolutedtubule and subsequent connecting tubule have a variety of sodium transport mechanisms.The distal tubule has predominantly a sodium chloride cotransporter, which is inhibited by thiazide diuretics. In the connecting tubule, sodium channels and a sodium-hydrogenexchange mechanism also are present. Amiloride inhibits sodium channel activity. Againthe sodium-potassium ATPase (Na+-K+ ATPase) on the basolateral membrane providesmost of the driving force for sodium reabsorption.

FIGURE 1-19

Mechanism of sodium chloride reabsorption in collecting duct cells.Sodium transport in the collecting duct is mainly via amiloride-sensitive sodium channels in the apical membrane. Some evidence forother mechanisms such as an electroneutral sodium-chloride cotrans-port mechanism and a different sodium channel also has been reported. Again, the basolateral sodium-potassium ATPase (Na+-K+

ATPase) creates the driving force for overall sodium transport. There are some differences between the cortical collecting duct andthe deeper inner medullary collecting duct (IMCD). In the cortical collecting duct, sodium transport occurs in the predominant principalcell type interspersed between acid-base transporting intercalatedcells. The principal cell also is an important site of potassium secretion by way of apical potassium channels and water transportvia antidiuretic sensitive water channels. Regulation of sodium channels may involve either insertion (from subapical compartments)or activation of preexisting sodium channels.


Glossopharyngealnerve

Afferents

Carotidsinus

Arterialpressure

Atrialreceptors

Arterial pressure, mm Hg

Bar

ore

cep

tor

firi

ng

rate

, im

pulse

s/s

↓ RBF↓ GFR

↑Reabsorption↓Na+ excretion

Vascular smoothmuscle

TPR

Kidney

Heartrate

Aorticarch

Postganglionic

Sympathetics Adrenalmedulla

Efferents Bulbospinalpathway epinephrine

Preganglionicsympathetics

(acetylcholine)

Normal

Resetting

NTS

Norepinephrine

Epinephrine

Medulla

100

∆I

∆P

NADN –

Vagusnerve

Systemic Factors Regulating Arterial Pressure and Sodium Excretion

FIGURE 1-20

Neural and sympathetic influences. The neural reflexes serve as theprincipal mechanisms for the rapid regulation of arterial pressure.The neural reflexes also exert a long-term role by influencing sodiumexcretion. The pathways and effectors of the arterial baroreflexand atrial pressure-volume reflex are depicted. The arrows indicateincreased or decreased activity in response to an acute reduction inarterial pressure which is sensed by the baroreceptors in the aorticarch and carotid sinus.

The insert depicts the relationship between the arterial bloodpressure and baroreflex primary afferent firing rate. At the normallevel of mean arterial pressure of approximately 100 mm Hg, thesensitivity (�I/�P) is set at the maximum level. After chronic resettingof the baroreceptors, the peak sensitivity and threshold of activationare shifted to a higher level of arterial pressure.

The cardiovascular reflexes involve high-pressure arterial recep-tors in the aortic arch and carotid sinus and low-pressure atrialreceptors. In response to decreases in arterial pressure or vascularvolume, increased sympathetic stimulation participates in short-term control of arterial pressure. This increased stimulation does

so by enhancing cardiac performance and stimulating vascularsmooth muscle tone, leading to increased total peripheral resis-tance and decreased capacitance. The direct effects of the sympa-thetic nervous system on kidney function lead to decreased sodiumexcretion caused by decreases in filtered load and increases intubular reabsorption [26].

The decreases in the glomerular filtration rate (GFR) and filtered sodium load are due to increases in both afferent andefferent arteriolar resistances and to decreases in the filtrationcoefficient (see Fig. 1-7). Sympathetic activation also enhancesproximal sodium reabsorption by stimulating the sodium-hydrogen(Na+-H+) exchanger mechanism (see Fig. 1-16) and by increasingthe net chloride reabsorption by the thick ascending limb of theloop of Henle. The indirect effects include stimulation of reninsecretion and angiotensin II formation, which, as discussed next, also stimulates tubular reabsorption. �I—change in impulse firing;�P—change in pressure; DN—dorsal motor nucleus; NA—nucleusambiguous; NTS—nucleus tractus solitarii; RBF—renal blood flow;TPR—total peripheral resistance. (Adapted from Vari and Navar [4].)


Arterialpressure

NaClintake

Stresstrauma

Angiotensinogen

Angiotensin I

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Val-Tyr-Ser-R

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu

Angiotensin II

Angiotensin- converting enzyme, chymase (heart)

Angiotensinases

Metabolites

Inactive fragments

Angiotensin (1–7)Angiotensin (2–8)Angiotensin (3–8)

AT1, AT

2, AT

?Receptor binding andBiologic actions

Renin

release

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe

ECFvolume

Macula densa mechanismBaroreceptor mechanism

Sympathetic nervous system

Juxtaglomerular apparatusCytosolic Ca2+

cAMP

Renin

FIGURE 1-21

Renin-angiotensin system. The renin-angio-tensin system serves as one of the mostpowerful regulators of arterial pressure and sodium balance. In response to variousstimuli that compromise blood volume,extracellular fluid (ECF) volume, or arterialpressure—or those associated with stressand trauma—three major mechanisms areactivated. These mechanisms stimulate reninrelease by the cells of the juxtaglomerularapparatus that act on angiotensinogen toform angiotensin I. Angiotensinogen is an�2 globulin formed primarily in the liverand to a lesser extent by the kidney. Angio-tensin I is a decapeptide that is rapidly converted by angiotensin-convertingenzyme (ACE) and to a lesser extent bychymase (in the heart) to angiotensin II, anoctapeptide. Recent studies have indicatedthat other angiotensin metabolites such asangiotensin (2–8), angiotensin (1–7), andangiotensin (3–8) have biologic actions.

Adrenalcortex

Vasoconstrictiontransport effects

Proximal and distal sodium + water

Reabsorption byintestine

Central nervous system

Distalnephron

reabsorption

Growthfactors

Sympatheticdischarge

Adrenergicfacilitation

Kidney Heart

Contractility

Vasoconstriction

Proliferation

Hypertrophy

Vasopressin release

Thirst, salt appetite

Water reabsorption

Peripheral nervoussystem

Vascular smoothmuscle

Intestine

Aldosterone

Cardiacoutput

Total peripheralresistance

Maintain or increaseextracellular fluid volume

Angiotensin II and/or active metabolites

FIGURE 1-22

Multiple actions of angiotensin. Angiotensin II andsome of the other angiotensin II metabolites have amyriad of actions on many different vascular bedsand organ systems. Angiotensin II exerts short- andlong-term actions, including vasoconstriction andstimulation of aldosterone release. Angiotensin II also

interacts with the sympathetic nervous system byfacilitating adrenergic transmission and has long-termactions on vascular smooth muscle proliferation byinteracting with growth factors. Angiotensin II exertsseveral important effects on the kidney that contributeto sodium conservation. (Adapted from Navar [3].)


Enhance proximaltubular reabsorption

Decrease Kf

Inhibit renin release

PT

BS

GC

Afferent arteriolarvasoconstriction

Efferentarteriolar

vasoconstriction

Increased sensitivity

of TGF mechanism

TAL

AA

EA

PC

HCO3_

Na+Na+

Na+

H+

__+

+

K+

G

PLA

AngiotensinAngiotensin

cAMPTubulelumen

FIGURE 1-23

Angiotensin II actions on renal hemodynamics. Systemic andintrarenal angiotensin II exert powerful vasoconstrictive actions onthe kidney to decrease renal blood flow and sodium excretion. Atthe level of the glomerulus, angiotensin II is a vasoconstrictor ofboth afferent (AA) and efferent arterioles (EA) and decreases thefiltration coefficient Kf. Angiotensin II also directly inhibits reninrelease by the juxtaglomerular apparatus. Increased intrarenalangiotensin II also is responsible for the increased sensitivity of thetubuloglomerular feedback mechanism that occurs with decreasedsodium chloride intake (see Fig. 1-9) [17,27,28]. BS—Bowman’sspace; GC—glomerular capillaries; PC—peritubular capillaries;PT—proximal tubule; TAL—thick ascending limb; TGF—tubu-loglomerular feedback mechanism. (Adapted from Arendshorst andNavar [17].)

FIGURE 1-24

Angiotensin II actions on tubular transport. Angiotensin II receptorsare located on both the luminal and basolateral membranes of theproximal and distal nephron segments. The proximal effect hasbeen studied most extensively. Activation of angiotensin II-AT1receptors leads to increased activities of the sodium-hydrogen (Na+-H+) exchanger and the sodium-bicarbonate (Na+-HCO-

3)cotransporter. These increased activities lead to augmented volumereabsorption. Higher angiotensin II concentrations can inhibit thetubular sodium reabsorption rate; however, the main physiologicrole of angiotensin II is to enhance the reabsorption rate [28].cAMP—cyclic AMP; G—G protein; PLA—phospholipase A.(Adapted from Mitchell and Navar [28].)


A. SYNERGISTIC RENAL ACTIONS OF ANGIOTENSIN II

Enhancement of proximal reabsorption rate

Stimulation of apical amiloride-sensitive Na-H exchanger

Stimulation of basolateral Na-HCO3 cotransporter

Sustained changes in distal volume and sodium delivery

Increased sensitivity of afferent arteriole to signals from macula densa cells

60

55

50

45

40

35

300 10 20 30 40

End proximal fluid flow, nL/min

Glo

mer

ula

r p

ress

ure

, mm

Hg

ProximalReabsorption

Distaldelivery

SNGFR

B60

55

50

45

40

35

300 10 20 30 40

End proximal fluid flow, nL/min

Glo

mer

ula

r p

ress

ure

, mm

Hg

Proximal reabsorption

Distaldelivery

SNGFR

C

FIGURE 1-25

A–C, Synergistic effects of angiotensin II on proximal reabsorptionand tubuloglomerular feedback mechanisms. The actions ofangiotensin II on proximal nephron reabsorption and the ability of angiotensin II to enhance the sensitivity of the tubuloglomerularfeedback (TGF) mechanism prevent a compensatory increase inglomerular filtration rate caused by the reduced distal tubular flow.These actions allow elevated angiotensin II levels to exert a sustained reduction in sodium delivery to the distal nephron segment. This effect is shown here by the shift of operating levelsto a lower proximal fluid flow under the influence of elevatedangiotensin II [27]. The effects of angiotensin II to enhance TGFsensitivity allow the glomerular pressure (GP) and nephron filtra-tion rate to be maintained at a reduced distal volume delivery ratethat would occur as a consequence of the angiotensin II effects onreabsorption. SNGFR—single nephron glomerular filtration rate.(Panels B and C adapted from Mitchell et al. [27].)

Principal cell

Mitochondria

Proteins

MRNucleus

3Na+

2 K+

ATP

ADP

Na+

A

Aldosterone

Spironolactone

mRNA

K+

_

LumenFIGURE 1-26

Effects of aldosterone on distal nephron sodium reabsorption. A, Mechanism of action of aldosterone. Angiotensin II also is a very powerful regulator of aldosterone release by the adrenalgland. The increased aldosterone levels synergize with the directeffects of angiotensin II to enhance distal tubule sodium reabsorp-tion. Aldosterone increases sodium reabsorption and potassiumsecretion in the distal segments of the nephron by binding to thecytoplasmic mineralocorticoid receptor (MR). On binding, thereceptor complex migrates to the nucleus where it induces transcription of a variety of messenger RNAs (mRNAs). ThemRNAs encode for proteins that stimulate sodium reabsorption by increasing sodium-potassium ATPase (Na+-K+ ATPase) proteinand activity at basolateral membranes, increasing mitochondrialATP formation, and increasing the sodium and potassium channelsat the luminal membrane [29]. Growing evidence also exists fornongenomic actions of aldosterone to activate sodium entry pathways such as the amiloride-sensitive sodium channel [30].



14

12

10

8

6

4

2

0

Filt

ered

so

diu

m r

emai

nin

g, %

0 20 40 60 80 100

Normal

Aldosterone blockade

Distal nephron length, %B

Principal cell

Mitochondria

Proteins

MR

Nucleus

3Na+

2 K+

ATP

ADP

Aldosterone

Lumen

Cortisone

II-β_OHSD defect orglycyrrhizic acid or

carbenoxolone

Na+

K+

mRNA

Cortisol

Principal cell Lumen

Mitochondria

Proteins

MRNucleus

3Na+

2K+

ATP

ADP Primary hyperaldosteronismAdrenal enzymatic disorderAdenomaGlucorticoid-remediablealdosteronism

Na+

K+

Aldosterone

mRNA


B, The net effect of aldosterone is to stimulate sodium reabsorptionalong the distal nephron segment, decreasing the remaining sodiumto only 2% or 3% of the filtered load. The direct action of aldosteronecan be blocked by drugs such as spironolactone that bind directlyto the mineralocorticoid receptor.

FIGURE 1-27

Syndrome of apparent mineralocorticoid excess and hypertension.Aldosterone increases sodium reabsorption and potassium secretionin the distal segments of the nephron by binding to the cytoplasmicmineralocorticoid receptor (MR). Cortisol, the glucocorticoid thatcirculates in plasma at much higher concentrations than does aldos-terone, also binds to MR. However, cortisol normally is preventedfrom this by the action of 11-�-hydroxysteroid dehydrogenase (11-�-OHSD), which metabolizes cortisol to cortisone in mineralocorti-coid-sensitive cells. A deficiency or defect in this enzyme has beenfound to be responsible for a rare form of hypertension in personswith the hereditary syndrome of apparent mineralocorticoid excess.In these persons, cortisol binds to the MR receptor, causing sodiumretention and hypertension [31]. This enzyme also is blocked by gly-cyrrhizic acid (in some forms of licorice) and carbenoxolone. Thediuretic spironolactone acting by way of inhibition of MR is able toblock this excessive action of cortisol on the MR receptor.

FIGURE 1-28

Hyperaldosteronism and glucocorticoid-remediable aldosteronism.Hypertension can result from increased aldosterone or fromincreases in other closely related steroids derived from abnormaladrenal metabolism (11-�-hydroxylase deficiency and 17-�-hydroxylase deficiency). The most common cause is an aldos-terone-producing adenoma; bilateral hyperplasia of the adrenalzona glomerulosa is the next most common cause. In glucocorti-coid-remediable aldosteronism, a DNA crossover mutation resultsin a chimeric gene in which aldosterone production is regulated byadrenocorticotropic hormone (ACTH). Increases in aldosteronealso can result secondarily from any state of increased renin suchas renal artery stenosis, which leads to increased circulating con-centrations of angiotensin II and stimulation of aldosterone release[31]. MR—mineralocorticoid receptor; mRNA—messenger RNA.


3Na+

2 K+

ATP

ADP

Na+

K+

CellLumenLiddle's

syndrome

Liddle'ssyndrome

ppp p

p p

δβ

β

δ

αα

Atrial stretchreceptors

Atrial natriuretic peptide

Intrathoracicblood volume

AldosteroneReninTubular sodium reabsorption

Vasodilation

Sodiumexcretion

Vascularresistance

Extracellular fluid volumeBlood volume

Gitleman'ssyndrome

Pseudohypoaldosteronism

Bartter'ssyndrome

Na+

LB

Cl_

K+ K+

Na+

2Cl-

Na Cl

FIGURE 1-29

Excess epithelial sodium channel activity in Liddle’s syndrome. Theepithelial sodium channel responsible for sodium reabsorption inmuch of the distal portions of the nephron is a complex of threehomologous subunits, �, �, and � each with two membrane-span-ning domains. Liddle’s syndrome, an autosomal dominant disordercausing low renin-aldosterone hypertension often with hypokalemia,results from mutated � or � subunits. These mutations increase thesodium reabsorptive rate by way of these channels by keeping themopen longer, increasing sodium channel density on the membranes,or both. The specific problem appears to reside with proline (P)-richdomains in the carboxyl terminal region of � or � that are involvedin regulation of the channel membrane localization or activity. Thenet result is excess sodium reabsorption and a reduced capability toincrease sodium excretion in response to volume expansion [31,32].

FIGURE 1-30

Syndromes of diminished sodium reabsorption and hypotension.Recently, a variety of syndromes associated with salt wasting, andusually hypotension, have been attributed to specific moleculardefects in the distal nephron. Bartter’s syndrome, which usually isaccompanied by metabolic alkalosis and hypokalemia, has beenfound to be associated with at least three separate defects (the threetransporters shown) in the thick ascending limb. These defects areat the level of the sodium-potassium-2chloride (Na+-K+-2Cl-)cotransporter, apical potassium channel, and basolateral chloridechannel (see Fig. 1-17). Malfunction in any of these three proteinsresults in diminished sodium chloride reabsorption similar to thatoccurring with administration of loop diuretics. Gitelman’s syndrome,which was originally described as a variant of Bartter’s syndrome,represents a defect in the sodium chloride cotransport mechanismin the distal tubule. Pseudohypoaldosteronism results from a defectin the apical sodium channels in the collecting ducts. In contrast toBartter’s and Gitelman’s syndromes, hyperkalemia may be present.These rare disorders illustrate that defects in sodium chloride reab-sorptive mechanisms can result in abnormally low blood pressureas a consequence of excessive sodium excretion in the urine. Althoughthese conditions are rare, similar but more subtle defects of the heterozygous state may contribute to protection from hypertension in some persons [31]. B—basolateral side; L—lumen of tubule.

FIGURE 1-31

Atrial natriuretic peptide (ANP). In response to increased intravas-cular volume, atrial distention stimulates the release of ANP fromthe atrial granules where the precursor is stored. Extracellular fluidvolume expansion is associated with increased ANP levels, whereasreductions in vascular volume and dehydration elicit decreases inplasma ANP levels. ANP participates in arterial pressure regulationby sensing the degree of vascular volume expansion and exertingdirect vasodilator actions and natriuretic effects. ANP has beenshown to markedly increase the slope of the pressure natriuresisrelationship (see Figs. 1-5 and 1-6). The vasorelaxant and transportactions are mediated by stimulation of membrane-bound guanylatecyclase, leading to increased cyclic GMP levels. ANP also inhibitsrenin release, which reduces circulating angiotensin II levels[33–35]. Related peptides, such as brain natriuretic peptides, havesimilar effects on sodium excretion and renin release [36].


Cytochrome P450monooxygenases

Leukotrienes(vasoconstriction)

HETEs(vasoconstriction)

TXA2/PGH

2(vasoconstriction)

EETs(vasodilation )

PGI2/PGE

2(vasodilation,

natriuresis)

Membrane phospholipids

Phospholipase A2

Cyclooxygenase Lipoxygenases

Endoperoxides HPETEs

HETEs

Lipoxins

COOH

Arachidonic acid

States of volume depletion and hypoperfu-sion stimulate prostaglandin synthesis[16,17,38].

The vasodilator prostaglandins attenuatethe influence of vasoconstrictor substancesduring activation of the renin-angiotensinsystem, sympathetic nervous system, or both[33]. These prostaglandins also have trans-port effects on renal tubules through activa-tion of distinct prostaglandin receptors[40]. In some pathophysiologic conditions,enhanced production of TXA2 and othervasoconstrictor prostanoids may occur. Thevasoconstriction induced by TXA2 appearsto be mediated primarily by calcium influx[17,40].

Leukotrienes are hydroperoxy fatty acidproducts of 5-hydroperoxyeicosatetraenoicacid (HPETE) that are synthesized by way ofthe lipoxygenase pathway. Leukotrienes arereleased in inflammatory and immunologicreactions and have been shown to stimulaterenin release. The cytochrome P450 mono-oxygenases produce several vasoactiveagents [16,37,41,42] usually referred to asEETs and hydroxy-eicosatetraenoic acids(HETEs). These substances exert actions on vascular smooth muscle and epithelialtissues [16,41,42]. (Adapted from Navar [3].)

FIGURE 1-32

Arachidonic acid metabolites. Several eicosanoids (arachidonic acid metabolites) arereleased locally and exert both vasoconstrictor and vasodilator effects as well as effects ontubular transport [16,37]. Phospholipase A2 catalyzes formation of arachidonic acid (anunsaturated 20-carbon fatty acid) from membrane phospholipids. The cyclooxygenase path-way and various prostaglandin synthetases are responsible for the formation of endoperox-ides (PGH2), prostaglandins E2 (PGE2) and I2 (PGI2), and thromboxane (TXA2) [38,39].

Bradykinin

Kallikrein-kinin system

B2-receptor

B1-receptor

Endothelium-dependent

Nitric oxidePGE

2

Nitric oxidePGE

2

Vasodilation natriuresis

Low molecular weight kininogen High molecular weight kininogen

Des Arg-bradykinin Kinin degradation products

Plasma kallikreinTissue kallikrein

Kininase II (ACE)NEP

Kininase I

FIGURE 1-33

Kallikrein-kinin system. Plasma and tissue kallikreins are function-ally different serine protease enzymes that act on kininogens (inac-tive �2 glycoproteins) to form the biologically active kinins(bradykinin and lysyl-bradykinin [kallidin]). Kidney kallikrein andkininogen are localized in the distal convoluted and cortical collect-ing tubules. Release of kallikrein into the tubular fluid and intersti-tium can be stimulated by prostaglandins, mineralocorticoids,angiotensin II, and diuretics. B1 and B2 are the two majorbradykinin receptors that exert most of the vascular actions.Although glomerulus and distal nephron segments contain both B1and B2 receptors, most of the renal vascular and tubular effectsappear to be mediated by B2-receptor activation [16,17,43,44].Bradykinin and kallidin elicit vasodilation and stimulate nitricoxide, prostaglandin E2 (PGE2) and I2 (PGI2), and renin release[45,46]. Kinins are inactivated by the same enzyme that convertsangiotensin I to angiotensin II, angiotensin-converting enzyme(ACE). The kallikrein-kinin system is stimulated by sodium deple-tion, indicating it serves as a mechanism to dampen or offset theeffects of enhanced angiotensin II levels [47,48]. Des Arg—bradykinin; NEP—neutral endopeptidase.


260 280 300 320 340Plasma osmolality, mOsm/kg

2

0

4

6

10

8Decreased

ECF volume

NormalECF

volume

IncreasedECF

volume

Plas

ma

vaso

pres

sin,

pg/

mL

FIGURE 1-34

Vasopressin. Vasopressin is synthesized by the paraventricular and supraoptic nuclei of the hypothalamus. Vasopressin is stored in the posterior pituitary gland and released inresponse to osmotic or volume-dependent baroreceptor stimuli, or both. Atrial fillinginhibits vasopressin release. Increases in plasma osmolality increase vasopressin release;however, the relationship is shifted by the status of extracellular fluid (ECF) volume, withdecreases in the ECF volume increasing the sensitivity of the relationship. Stress and traumaalso increase vasopressin release [15]. Therefore, when ECF volume and blood volume arediminished, vasopressin is released to help guard against additional losses of body fluids.(Adapted from Navar [8].)

Tubulelumen

ATP

Collecting ductprincipal cell

Adenylatecyclase

GTP

G

G

Gα

Gα

GTP

GDP

V2

Protein kinase A

Circulating vasopressin

Plasma membrane

H2OAquaporin 2

waterchannels

cAMP + PPi

Aquaporin 2

FIGURE 1-35

Vasopressin receptors. Vasopressin exerts its cellular actions throughtwo major receptors. Activation of V1 receptors leads to vascularsmooth muscle constriction and increases peripheral resistance.Vasopressin stimulates inositol 1,4,5-triphosphate and calcium ion(Ca2+) mobilization from cytosolic stores and also increases Ca2+

entry from extracellular stores as shown in Figure 1-10. The vaso-constrictive action of vasopressin helps increase total peripheralresistance and reduces medullary blood flow, which enhances theconcentrating ability of the kidney. V2 receptors are located pri-marily on the basolateral side of the principal cells in the collectingduct segment. Vasopressin activates heterotrimeric G proteins thatactivate adenylate cyclase, thus increasing cyclic AMP levels. CyclicAMP (cAMP) activates protein kinase A, which increases the densityof water channels in the luminal membrane. Water channels (aqua-porin proteins) reside in subapical vesicles and on activation fusewith the apical membrane. Thus, vasopressin markedly increasesthe water permeability of the collecting duct and allows conservationof fluid and excretion of a concentrated urine. An intact vasopressinsystem is essential for the normal regulation of urine concentrationby the kidney that, in turn, is the major mechanism for couplingthe solute to solvent ratio (osmolality) of the extracellular fluid. As discussed in Figure 1-4, this tight coupling allows the conflu-ence of homeostatic mechanisms regulating sodium balance with those regulating extracellular fluid volume. G� and G—proteins; PPi— inorganic pyrophosphate. (Adapted fromVari and Navar [4].)


Initial increase invascular resistance

Initial increase in volume

VolumeNeurogenic orhumoral stimuli

Autoregulatoryresistance

adjustments

Increased arterialblood pressure

Cardiac output

Tissue blood flow

Increased vascular resistance

Effective bloodvolume

Renal volumeretention

Vasoconstrictoreffects

Capacitance

either one or more of the physiologic mechanisms described inthis chapter fails to respond appropriately to intravascular expan-sion or some pathophysiologic process causes excess production ofone or more sodium-retaining factors such as mineralocorticoids orangiotensin II [51,52]. Through mechanisms delineated earlier,overexpansion leads to increased cardiac output that results in over-perfusion of tissues; the resultant autoregulatory-induced increasesin peripheral resistance contribute further to an increase in totalperipheral resistance and elevated arterial pressure [2,53,54].

Hypertension also can be initiated by excess vasoconstrictorinfluences that directly increase peripheral resistance, decrease cardiovascular capacitance, or both. Examples of this type ofhypertension are enhanced activation of the sympathetic nervoussystem and overproduction of catecholamines such as that occurringwith a pheochromocytoma [45,54,55]. When hypertension causedby a vasoconstrictor influence persists, however, it must also exertsignificant renal vasoconstrictor and sodium-retaining actions.Without a renal effect the elevated arterial pressure would causepressure natriuresis, leading to a compensatory reduction in extra-cellular fluid volume and intravascular volume. Thus, the elevatedsystemic arterial pressure would not be sustained [2,8,54]. Derange-ments that activate both a vasoconstrictor system and producesodium-retaining effects, such as inappropriate elevations in theactivity of the renin-angiotensin-aldosterone system, lead to aneven more powerful hypertensinogenic mechanism that is not easilycounteracted [27]. These dual mechanisms are why the renin-angiotensin system has such a critical role in the cause of manyforms of hypertension, leaving only the option to increase arterialpressure and elicit a pressure natriuresis. (Adapted from Navar [3].)

Hypertensinogenic Process

FIGURE 1-36

Overview of mechanisms mediating hypertension. From a patho-physiologic perspective, the development of hypertension requireseither a sustained absolute or relative overexpansion of the bloodvolume, reduction of the capacitance of the cardiovascular system,or both [4,49,50]. One type of hypertension is due primarily tooverexpansion of either the actual or the effective blood volumecompartment. In such a condition of volume-dependent hypertension,

Reduced renal pressure, d

80

100

120

140

Reduce renal perfusion pressure

Renal perfusion pressure

Aldosterone

Angiotensin II + Aldosterone160

180

Mea

n ar

teria

l pre

ssur

e,

mm

Hg

0

0 1 2 3 4 5

246

Aldosterone

Angiotensin II + Aldosterone

81012

14

Cum

ulat

ive

sodi

um b

alan

ce,

mm

ol/k

g BW

FIGURE 1-37

Predominance of the renin-angiotensin-aldosterone mechanisms. Collectively, the variousmechanisms discussed provide overlapping influences responsible for the highly efficientregulation of sodium balance, extracellular fluid (ECF) volume, blood volume, and arterialpressure. Nevertheless, the synergistic actions of the renin-angiotensin-aldosterone systemon both vasoconstrictor as well as sodium-retaining mechanisms exert a particularly pow-erful influence that is not easily counteracted. In a recent study by Seeliger and coworkers[56], renal perfusion pressure was lowered to 90 to 95 mm Hg. The angiotensin II andaldosterone levels were not allowed to decrease and were fixed at normal levels by contin-uous infusions. The results demonstrated that all compensatory mechanisms (such asincreased release of atrial natriuretic peptide and reduced activity of the sympathetic sys-tem) could not overcome the hypertensinogenic influence of maintained aldosterone oraldosterone plus angiotensin II as long as renal perfusion pressure was not allowed toincrease. Thus, under conditions of increased activity of the renin-angiotensin system, anincreased renal arterial pressure seems essential to reestablish sodium balance.In conclusion, regardless of the specific intrarenal mechanism involved, the net effect of along-term hypertensinogenic derangement is a reduced capability for sodium excretion atnormotensive arterial pressures that cannot be completely compensated by other neural,humoral, or paracrine mechanisms, leaving only the option to increase arterial pressureand elicit a pressure natriuresis. (Adapted from Seeliger et al. [56].)


References

1. Guyton AC: Blood pressure control: special role of the kidneys andbody fluids. Science 1991, 252:1813–1816.

2. Cowley AW Jr: Long-term control of arterial blood pressure. PhysiolRev 1992, 72:231–300.

3. Navar LG: The kidney in blood pressure regulation and developmentof hypertension. Med Clin North Am 1997, 81:1165–1198.

4. Vari RC, Navar LG: Normal regulation of arterial pressure. InPrinciples and Practice of Nephrology, edn 2. Edited by Jacobson HR,Striker GE, Klahr GE. St. Louis: Mosby-Yearbook; 1995:354–361.

5. Luke RG: Essential hypertension: a renal disease? A review andupdate of the evidence. Hypertension 1993, 21:380–390.

6. Freedman BI, Iskandar SS, Appel RG: The link between hypertensionand nephrosclerosis. Am J Kidney Dis 1995, 25:207–221.

7. Tepel M, Zidek W: Hypertensive crisis: pathophysiology, treatmentand handling of complications. Kidney Int 1998, 53(suppl 64):S-2–S-5.

8. Navar LG: Regulation of body fluid balance. In Edema. Edited byStaub NC, Taylor AE. New York: Raven Press; 1984:319–352.

9. Navar LG, Majid DSA: Interactions between arterial pressure andsodium excretion. Curr Opin Nephrol Hypertens 1996, 5:64–71.

10. Rettig R, Schmitt B, Pelzl B, Speck T: The kidney and primary hyper-tension: contributions from renal transplantation studies in animalsand humans. J Hypertens 1993, 11:883–891.

11. Folkow B: Pathophysiology of hypertension: differences betweenyoung and elderly. J Hypertens 1993, 11(suppl 4):S21–S24.

12. Nichols WW, Nicolini FA, Pepine CJ: Determinants of isolated systolichypertension in the elderly. J Hypertens 1992, 10(suppl 6):S73–S77.

13. Guyton AC, Hall JE: Integration of renal mechanisms for control ofblood volume and extracellular fluid volume. In Textbook of MedicalPhysiology, edn 9. Philadelphia: WB Saunders; 1994:367–383.

14. Bankir L, Bouby N, Trinh-Trang-Tan M-M: The role of the kidney inthe maintenance of water balance. In Bailliere’s Clinical Endocrinologyand Metabolism. Water and Salt Homeostasis in Health and Disease.Edited by Baylis PH. London: Bailliere; 1989:249–311.

15. Baylis PH: Regulation of vasopressin secretion. In Bailliere’s ClinicalEndocrinology and Metabolism: International Practice and Research.Edited by Baylis PH. London: Bailliere Tindall; 1989:313–330.

16. Navar LG, Inscho EW, Majid DSA, et al.: Paracrine regulation of therenal microcirculation. Physiol Rev 1996, 76:425–536.

17. Arendshorst WJ, Navar LG: Renal circulation and glomerular hemo-dynamics. In Diseases of the Kidney, edn 6. Edited by Schrier RW,Gottschalk CW. Boston: Little-Brown; 1997:59–106.

18. Braam B, Mitchell KD, Koomans HA: Navar LG: Relevance of thetubuloglomerular feedback mechanism in pathophysiology. J Am SocNephrol 1993, 4:1257–1274.

19. Briggs JP, Schnermann J: Control of renin release and glomerular vascular tone by the juxtaglomerular apparatus. InHypertension:Pathophysiology, Diagnosis, and Management, edn 2. Edited byLaragh JH, Brenner BM. New York: Raven Press, 1995:1359–1385.

20. Carmines PK, Inscho EW, Gensure RC: Arterial pressure effects onpreglomerular microvasculature of juxtamedullary nephrons. Am JPhysiol (Renal Fluid Electrolyte Physiol 27) 1990, 258:F94–F102.

21. Casellas D, Navar LG: In vitro perfusion of juxtamedullary nephronsin rats. Am J Physiol (Renal Fluid Electrolyte Physiol 15) 1984,246:F349–F358.

22. Carmines PK, Navar LG: Disparate effects of Ca channel blockade onafferent and efferent arteriolar responses to ANG II. Am J Physiol(Renal Fluid Electrolyte Physiol 25) 1989, 256:F1015–F1020.

23. Navar LG, Inscho EW, Imig JD, Mitchell KD: Heterogenous activa-tion mechanisms in the renal microvasculature. Kidney Int 1998,54(suppl 67):S17–S21.

24. Stoos BA, Garcia NH, Garvin JL: Nitric oxide inhibits sodium reab-sorption in the isolated perfused cortical collecting duct. J Am SocNephrol 1995, 6:89–94.

25. Stoos BA, Carretero OA, Garvin JL: Endothelial-derived nitric oxideinhibits sodium transport by affecting apical membrane channels incultured collecting duct cells.J Am Soc Nephrol 1994, 4:1855–1860.

26. DiBona GF, Kopp UC: Neural control of renal function.Physiol Rev1997, 77:75–197.

27. Mitchell KD, Braam B: Navar LG: Hypertensinogenic mechanismsmediated by renal actions of renin-angiotensin system. Hypertension1992, 19(suppl I):I-18–I-27.

28. Mitchell KD, Navar LG: Intrarenal actions of angiotensin II in thepathogenesis of experimental hypertension. In Hypertension:Pathophysiology, Diagnosis, and Management, edn 2. Edited byLaragh JH, Brenner BM. New York: Raven Press; 1995:1437–1450.

29. O’Neil RG: Aldosterone regulation of sodium and potassium trans-port in the cortical collecting duct. Sem Nephrol 1990, 10:365–374.

30. Wehling M, Eisen C, Christ M: Membrane receptors for aldosterone:a new concept of nongenomic mineralocorticoid action. NIPS 1993,8:241–244.

31. Lifton RP: Molecular genetics of human blood pressure variation.Science 1996, 272:676–680.

32. Warnock DG: Liddle syndrome: an autosomal dominant form ofhuman hypertension. Kidney Int 1998, 53:18–24.

33. Jamison RL, Canaan-Kuhl S, Pratt R: The natriuretic peptides andtheir receptors. Am J Kidney Dis 1992, 20:519–530.

34. Paul RV, Kirk KA, Navar LG: Renal autoregulation and pressure natri-uresis during ANF-induced diuresis. Am J Physiol 1987, 253:F424–F431.

35. Knepper MA, Lankford SP, Terada Y: Renal tubular actions of ANF.Can J Physiol Pharmacol 1991, 69:1537–1545.

36. Jensen KT, Carstens J, Pedersen EB: Effect of BNP on renal hemody-namics, tubular function and vasoactive hormones in humans. Am JPhysiol (Renal Fluid Electrolyte Physiol 43) 1998, 274:F63–F72.

37. Capdevila JH, Falck JR, Estabrook RW: Cytochrome P450 and thearachidonate cascade. FASEB J 1992, 6:731–736.

38. Smith WL: Prostanoid biosynthesis and mechanisms of action. Am JPhysiol (Renal Fluid Electrolyte Physiol 32) 1992, 263:F181–F191.

39. Frazier LW, Yorio T: Eicosanoids: their function in renal epithelia iontransport. Proceedings of the Society for Experimental Biology andMedicine 1992, 201:229–243.

40. Breyer MD, Jacobson HR, Breyer RM: Functional and molecular aspectsof renal prostaglandin receptors. J Am Soc Nephrol 1996, 7:8–17.

41. McGiff JC: Cytochrome P-450 metabolism of arachidonic acid. AnnRev Pharmacol Toxicol 1991, 31:339–369.

42. Imig JD, Zou A-P, Stec DE, et al.: Formation and actions of 20-hydroxyeicosatetraenoic acid in rat renal arterioles. Am J Physiol(Regulat Integrative Comp Physiol 39) 1996, 270:R217–R227.

43. Bhoola KD, Figueroa CD, Worthy K: Bioregulation of kinins:kallikreins, kininogens, and kininases. Pharmacol Rev 1992, 44:1–80.

44. El-Dahr SS: Development biology of the renal kallikrein-kinin system.Pediatr Nephrol 1994, 8:624–631.

45. Carretero OA, Scicli AG: Local hormonal factors (intracrine,autocrine, and paracrine) in hypertension. Hypertension 1991, 18(suppl I):I-58–I-69.

46. Siragy HM, Jaffa AA, Margolius HS: Bradykinin B2 receptor modulatesrenal prostaglandin E2 and nitric oxide. Hypertension 1997, 29:757–762.

47. Margolius HS: Kallikreins and kinins: molecular characteristics andcellular and tissue responses. Diabetes 1996, 45:S14–S19.


48. Siragy HM: Evidence that intrarenal bradykinin plays a role in regula-tion of renal function. Am J Physiol (Endocrinol Metab28) 1993,265:E648–E654.

49. Ploth DW, Navar LG: Physiologic control of arterial blood pressureand mechanisms of hypertension. In Clinical Approaches to HighBlood Pressure in the Young. Edited by Kotchen TA, Kotchen JM.Boston: John Wright, PSG; 1983:23–78.

50. Guyton AC, Manning RA, Normon RA, et al.: Current concepts andperspectives of renal volume regulation in relationship to hyperten-sion. J Hypertens 1986, 4(suppl 4):S49–S56.

51. DeWardener HE: The primary role of the kidney and salt intake in theaetiology of essential hypertension: part II. Clin Sci 1990, 79:289–297.

52. Hamlyn JM, Blaustein MP: Sodium chloride, extracellular fluid vol-ume, and blood pressure regulation. Am J Physiol (Renal FluidElectrolyte Physiol 20) 1986, 251:F563–F575.

53. Coleman TG, Guyton AC: Hypertension caused by salt loading in thedog. Circ Res 1969, XXV:153–160.

54. Guyton AC, Hall JE, Coleman TG, et al.: The dominant role of thekidneys in long-term arterial pressure regulation in normal and hyper-tensive states. In Hypertension: Pathophysiology, Diagnosis, andManagement, edn 2. Edited by Laragh JH, Brenner BM. New York:Raven Press; 1995, 78:1311–1326.

55. Julius S, Nesbitt S: Sympathetic overactivity in hypertension: a movingtarget. Am J Hypertens 1996, 9:113S–120S.

56. Seeliger E, Boemke W, Corea M, et al.: Mechanisms compensating Naand water retention induced by long-term reduction of renal perfusionpressure. Am J Physiol (Regulat Integrative Comp Physiol 42) 1997,273:R646–R654.

2

Renal Parenchymal Diseaseand Hypertension

Hypertension and parenchymal disease of the kidney are closelyinterrelated. Most primary renal diseases eventually disturbsodium and volume control sufficiently to produce clinical

hypertension. Both on theoretical and practical grounds, many authorsargue that any sustained elevation of blood pressure depends ultimatelyon disturbed renal sodium excretion, ie, altered pressure natriuresis.Hence, some investigators argue that a clinical state of hypertensionrepresents de facto evidence of disturbed (or “reset”) renal functioneven before changes in glomerular filtration can be measured.

Many renal insults further induce inappropriate activation of vasoactivesystems such as the renin-angiotensin system, adrenergic sympatheticnerve traffic, and endothelin. These mechanisms may both enhancevasoconstriction and act as mediators of additional tissue injury byaltering the activity of inflammatory cytokines and promoters of inter-stitial fibrosis.

Arterial hypertension itself accelerates many forms of renal diseaseand hastens the progression to advanced renal failure. Recent studieshave firmly established the importance of blood pressure reduction asa means to slow the progression of many forms of renal parenchymalinjury, particularly those characterized by massive proteinuria. Overthe long term, damage to the heart and cardiovascular system resultingfrom hypertension represents the major causes of morbidity and mor-tality for patients with end-stage renal disease.

Here are illustrated the roles of renal parenchymal disease in sustaininghypertension and of arterial pressure reduction in slowing the progressionof renal injury. As discussed, parenchymal renal disease may refer toeither unilateral (uncommon) or bilateral conditions.

Stephen C. Textor

C H A P T E R


FORMS OF UNILATERAL RENALPARENCHYMAL DISEASE RELATEDTO HYPERTENSION

Renal artery stenosisAtherosclerosis and fibromuscular lesions (Chapter X)

Small vessel diseaseVasculitisAtheroembolic renal infarctionThrombosis and infarction

Traumatic injury Renal fracturePerirenal fibrosis (“Page” kidney) Radiation injury

Arteriovenous malformation or fistulasOther diseases

Renal carcinomaEnlarging renal cystMultiple renal cysts

Renin-secreting tumors (rare)

FIGURE 2-1

Forms of unilateral renal parenchymal diseases related to hypertension. Many unilateralabnormalities, such as congenital malformations, renal agenesis, reflux nephropathy, andstone disease, do not commonly produce hypertension. However, some unilateral lesionscan produce blood pressure elevation. Data for each of these are based primarily ondemonstrating unilateral secretion of renin and resolution with unilateral nephrectomy. Itshould be emphasized that unilateral renal disease does not reduce the overall glomerularfiltration rate beyond that expected in patients with a solitary kidney. It follows that addi-tional reductions in the glomerular filtration rate must reflect bilateral renal injury.

FIGURE 2-2

Angiogram and nephrogram of a persistent fractured kidney. The kidney damage shown hereproduced hypertension in a young woman 2 years after a motor vehicle accident. Measurementof renal vein renins confirmed unilateral production of renin from the affected side. Bloodpressure control was achieved with blockade of the renin-angiotensin system using anangiotensin II receptor antagonist (losartan). Many traumatic injuries to the kidney producetemporary hypertension when a border of viable but underperfused renal tissue remains.

20

50

60

70

80

40

0

Pre

vale

nce

of h

yper

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sio

n, %

APKDCIN IgAMCN DN MPGN FSGNMGN

10

30

Prevalence of Hypertension in Chronic Renal Disease

FIGURE 2-3

Prevalence of hypertension in chronic renal parenchymal disease.Most forms of renal disease are associated with hypertension. Thisassociation is most evident with glomerular diseases, including diabeticnephropathy (DN) and membranoproliferative glomerulonephritis(MPGN), in which 70% to 80% of patients are affected. Minimalchange nephropathy (MCN) is a notable exception. Tubulointerstitialdisorders such as analgesic nephropathy, medullary cystic diseases,and chronic reflux nephropathies are less commonly affected.APKD—adult-onset polycystic kidney disease; CIN—chronic intersti-tial nephritis; FSGN—focal segmental glomerulonephritis; MGN—membranous glomerulonephritis. (Data from Smith and Dunn [1].)

2.3Renal Parenchymal Disease and Hypertension

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MDRD: Study A

Mea

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US Population

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Acute IN

EarlyLate

FIGURE 2-4

Prevalence of hypertension requiring therapy as a function of the degree of chronic renalfailure in the Modification of Diet in Renal Disease (MDRD) trial on progressive renalfailure. The mean age of these patients was 52 years, with glomerular disease (25%) andpolycystic disease (24%) being the most common renal diagnoses in this trial. In Study B,more than 90% of patients were treated with antihypertensive agents, including diuretics,to achieve an overall average blood pressure of 133/81 mm Hg. In general, the moresevere the level of renal dysfunction, the more antihypertensive therapy is required toachieve acceptable blood pressures. Patients with glomerular filtration rates (GRFs) below10 mL/min were hypertensive in 95% of cases. NHANES—National Health and NutritionExamination Survey. (Data from Klahr and coworkers [2].)

FIGURE 2-5

Hypertension in acute renal disease. Acute renal failure is defined as transient increases inserum creatinine above 5.0 mg/dL. During the course of acute renal failure, worsening ofpreexisting levels or newly detected hypertension (>140/90 mm Hg) is common and almostuniversally observed in patients with acute glomerulonephritis (GN). Many of thesepatients have lower pressures as the course of acute renal injury subsides, although resid-ual abnormalities in renal function and sediment may remain. Blood pressure returns tonormal in some but not all of these patients. Overall, 39% of patients with acute renalfailure develop new hypertension. IN—interstitial nephritis. (Adapted from Rodriguez-Iturbe and coworkers [3]; with permission.)

FIGURE 2-6 (see Color Plate)

Micrograph of an onion skin lesion from a patient with malignanthypertension.


Pathophysiology of Hypertension in Renal Disease

Increased extracellular fluid volumeDecreased glomerular filtration rateImpaired sodium excretionIncreased renal nerve activityIneffective natriuresis, eg, atrial natriuretic peptide resistance

Increased contractionIncreased adrenergic activation

Increased vasoconstrictionIncreased adrenergic stimuliInappropriate renin-endothelin releaseIncreased endothelin-derived contracting factorIncreased thromboxane

Decreased vasodilationDecreased prostacyclinDecreased nitric oxide

Blood pressure = xCardiac output Systemic vascular resistance

FIGURE 2-7

Pathophysiologic mechanisms related tohypertension in parenchymal renal disease:schematic view of candidate mechanisms. Thebalance between cardiac output and systemicvascular resistance determines blood pressure.Numerous studies suggest that cardiac outputis normal or elevated, whereas overall extra-cellular fluid volume is expanded in mostpatients with chronic renal failure. Systemicvascular resistance is inappropriately elevatedrelative to cardiac output, reflecting a net shiftin vascular control toward vasoconstrictingmechanisms. Several mechanisms affectingvascular tone are disturbed in patients withchronic renal failure, including increasedadrenergic tone and activation of the renin-angiotensin system, endothelin, and vasoac-tive prostaglandins. An additional feature insome disorders appears to depend on reducedvasodilation, such as in impaired productionof nitric oxide.

2

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Normal intake

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FIGURE 2-8

A, The relationship between renal artery perfusion pressure andsodium excretion (which defines “pressure natriuresis”) has beenthe subject of extensive research. Essential hypertension is charac-terized by higher renal perfusion pressures required to achievedaily sodium balance. B, Distortion of this relationship routinelyoccurs in patients with parenchymal renal disease, illustrated here

as “loss of renal mass.” Similar effects are observed in conditionswith disturbed hormonal effects on sodium excretion (aldos-terone-stimulated kidneys) or reduced renal blood flow as a result of an arterial stenosis (“Goldblatt” kidneys). In all of theseinstances, higher arterial pressures are required to maintain sodium balance.


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Total net loss ofsodium=1741 mEq

Sodium losses duringhemodialysis or ultrafiltration

Cumulative urinary sodium loss

Cumulative dailysodium intake

S M T W TH F S S M TB Days

–1200

–400

FIGURE 2-9

Sodium expansion in chronic renal failure. The degree of sodiumexpansion in patients with chronic renal failure can be difficult toascertain. A, Shown are data regarding body weight, plasma renin

activity, and blood pressure (before and after administration of anACE inhibitor) over 11 days of vigorous fluid ultrafiltration.Sequential steps were undertaken to achieve net negative sodiumand volume losses by means of restricting sodium intake (10 mEq/d)and initiating ultrafiltration to achieve several liters of negativebalance with each treatment. A negative balance of nearly 1700 mEqwas required before evidence of achieving dry weight was observed,specifically a reduction of blood pressure. Measured levels of plasmarenin activity gradually increased during sodium removal, and bloodpressure became dependent on the renin-angiotensin system, asdefined by a reduction in blood pressure after administration of theangiotensin-converting enzyme inhibitor captopril. Achieving adequatereduction of both extracellular fluid volume and sodium is essentialto satisfactory control of blood pressure in patients with renal failure.B, Daily and cumulative sodium balance.

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Angiotensin II inhibitor, µg/kg/min5 10 50 100 10 10

FIGURE 2-10

Interaction between sodium balance and angiotensin-dependence in malignant hypertension.Studies in a patient with renal dysfunction and accelerated hypertension during blockadeof the renin-angiotensin system using Sar-1-ala-8-angiotensin II demonstrate the interactionbetween angiotensin and sodium. Reduction of blood pressure induced by the angiotensinII antagonist was reversed during saline infusion with a positive sodium balance and reductionin circulating plasma renin activity. Administration of a loop diuretic (L40 [furosemide],40 mg intravenously) induced net sodium losses, restimulated plasma renin activity, andrestored sensitivity to the angiotensin II antagonist. Such observations further establish thereciprocal relationship between the sodium status and activation of the renin-angiotensinsystem [5]. (From Brunner and coworkers [5]; with permission.)


A

Normalperson

Hemodialysis,bilateral

nephrectomy

Hemodialysis, nonephrectomy

Neurogram

Electrocardiogram

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Deoxycorticosterone acetate–salt administration, d

ShamRenal denervated

120

140

FIGURE 2-11

A, Sympathetic neural activation in chronicrenal disease. Adrenergic activity is dis-turbed in chronic renal failure and may par-ticipate in the development of hypertension.Microneurographic studies in patientsundergoing hemodialysis demonstrateenhanced neural traffic (panel A) thatrelates closely to peripheral vascular tone [6].Studies in patients in whom native kidneysare removed by nephrectomy demonstratenormal levels of neural traffic, suggesting thatafferent stimuli from the kidney modulatecentral adrenergic outflow. B, Delayed onsethypertension in denervated rats. Panel Bshows evidence from experimental studies indenervated animals subjected to deoxycortico-sterone–salt hypertension. The role of therenal nerves in modifying the developmentof hypertension is supported by studies ofrenal denervation that show a delayed onsetof hypertension, although no alteration inthe final level of blood pressure was achieved.NS—not significant. (Panel A fromConverse and coworkers [6]; with permis-sion. Panel B from Katholi and coworkers[7]; with permission.)


FIGURE 2-12

Major candidate mechanisms that may elevate peripheral vascularresistance in renal parenchymal disease. Some data support each ofthese pathways, although rarely does one mechanism predominate.Experimental studies suggest that endothelin-1 may magnify interstitialfibrosis and contribute to hypertension in some models; however,rarely is the effect major [8,9]. Most levels of vasodilators, includingnitric oxide, prostacyclin, and atrial natriuretic peptide, are normalor elevated in patients with renal disease. The vasodilators appearto buffer the vasoconstrictive actions of angiotensin II, which maybe increased abruptly if the vasodilator is removed, as occurs withinhibition of cyclo-oxygenase with the use of nonsteroidal anti-inflammatory drugs.

MAJOR CANDIDATE MECHANISMS THAT MAY ELEVATE PERIPHERAL VASCULAR RESISTANCE IN RENAL PARENCHYMAL DISEASE

Increased vasoconstrictors

Renin-angiotensin system

Endothelin

Prostanoids: thromboxane

Arginine vasopressin

Endogenous digitalis-like substance: ouabain (?)

Impaired or relatively inadequate vasodilators

Nitric oxide: inadequate compensation

Vasodilator prostaglandins: prostacyclin 2

Natriuretic peptides: atrial natriuretic peptide

Kallikrein-kinin system

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Horizontal bars=mean valuesP<0.01 vs basal

Sham-operated rats Rats with renal mass reduction

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FIGURE 2-13

Urinary endothelin in renal disease. A, Urinary endothelin levels inpatients with cyclosporine-induced renal dysfunction and hypertensionbefore and after liver transplantation. These patients had near-normalkidney function before liver transplantation, after which their glomeru-lar filtration rates decreased from 85 to 55 mL/min, on average. Thesedata underscore the observation that the kidney itself is a rich sourceof vasoactive materials and that renal excretion of substances such asendothelin is independent of circulating blood levels [10]. Endothelin hasproperties that both facilitate vasoconstriction and enhance mitogenicand fibrogenic responses, perhaps accelerating interstitial fibrosis inthe kidney. Early withdrawal of cyclosporine leads to reversal of a

diminished glomerular filtration rate. With time, however, thesechanges lose the feature of reversibility [11]. B, Renal ablation.Urinary endothelin levels in rats exposed to reduced renal massachieved by 5/6 nephrectomy. As in humans, plasma levels ofendothelin were dissociated from urinary levels, and injectedendothelin was not excreted. These results suggest that urinary levelswere of renal origin. These studies further support the concept that thediminished nephron number elicits production of potent vasoactiveand inflammatory materials that may accelerate irreversible parenchy-mal injury. (Panel A from Textor and coworkers [10]; with permis-sion. Data in panel B from Benigni and coworkers [12].)


Systemic hypertension

Increased glomerular pressure

Increased glomerular pressure

Increased glomerular volume

Impaired autoregulation

Cellular proliferation

Renal parenchymal disease

Increased angiotensinIncreased norepinephrineIncreased endothelin

Increased cytokineIncreased growth factors

Decreased afferent resistanceDecreased efferent resistance

FIGURE 2-14

Mechanisms of glomerular injury in hypertension and progressiverenal failure. This schematic diagram summarizes the general mech-anisms by which disturbances linked to elevated arterial pressure inpatients with parenchymal renal disease may lead to further tissueinjury. Hemodynamic changes lead to increased glomerular perfusionpressures, whereas local activation of growth factors, angiotensin,and probably several other factors both worsen peripheral resistanceand increase tissue fibrotic mechanisms. (From Smith and Dunn [1].)

PHARMACOLOGIC AGENTS THAT COMMONLYAGGRAVATE OR INDUCE HYPERTENSION INPARENCHYMAL RENAL DISEASE

Other agents

Over-the-counter sympathomimeticagents, eg, phenylpropanolamine

Supplements containing ephedrine

Oral contraceptives (less common with low-dose forms)

Amphetamines and stimulants, eg, methylphenidate hydrochloride and cocaine

Corticosteroids

Cyclosporine

Erythropoietin

Nonsteroidal anti-inflammatory drugs

FIGURE 2-15

Many pharmacologic agents affect blood pressure levels or theeffectiveness of antihypertensive therapy. Shown here are severalagents that commonly lead to worsening hypertension and are like-ly to be administered to patients with renal disease.

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*

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*

*

*

**

Results=means±standard error*P<0.05 compared with controls

FIGURE 2-16

Increase in arterial pressure induced by inhibition of nitric oxide.A, Intra-arterial pressure in rabbits during N-nitro-L-argininemethyl ester (L-NAME) infusion. B, Decrease in renal plasma flowand glomerular filtration rate in the blood pressures of rats duringnitric oxide inhibition.



60

80

100

120

140

9

13

15

17

19

21

11

C

Uri

nar

y fl

ow

rate

, mL/

min

Uri

nar

y so

diu

m

excr

etio

n, µ

Eq/m

in

Control

Control10 µg/kg/min L–NAME50 µg/kg/min L–NAME

Results=means±standard error*P<0.05 compared with controls

60' 120' 180'

*

*

*

*

*


C, Urine flow rate and urinary sodium excretion over time. Inhibitionof nitric oxide synthesis from L-arginine by a competitive substratesuch as L-NAME produces dose-dependent and widespread vaso-constriction, leading to an increase in blood pressure [13]. Withinspecific regional beds such as the kidney, inhibition of nitric oxideproduces a decrease in renal plasma flow, diminished glomerularfiltration, and sodium retention [14]. The magnitude of these changesin normal animals and humans suggests that tonic nitric oxide produc-tion is a major endothelial buffering mechanism preserving vasculartone. The degree to which renal parenchymal disease alters the pro-duction of nitric oxide is not known precisely. In some situations,such as nephrotoxicity associated with cyclosporine administration,endothelial production of nitric oxide appears to be substantiallyimpaired [15]. (Panel A from Rees and coworkers [13]; with per-mission. Panel B from Lahera and coworkers [14]; with permission.)

Clinical Features of Hypertension in Renal Disease

A. HYPERTENSION IN PARENCHYMAL RENAL DISEASE: CLINICAL MANIFESTATIONS OF HYPERTENSIVE DISEASE

Central nervous system

Stroke

Intracerebral hemorrhage

Cardiovascular disease

Myocardial infarction

Congestive heart failure

Atherosclerotic vascular disease

Claudication and limb ischemia

Aneurysm

Progressive renal injury

End-stage renal disease

Increased proteinuria

FIGURE 2-17

A and B, Major target organ manifestations of hypertension producing cardiovascularmorbidity and mortality in patients with renal disease. More than half of deaths are relatedto cardiovascular disease in both patients on dialysis and transplantation recipients. Theseobservations underscore the major risk for cardiovascular morbidity and mortality associatedwith hypertension in the population with chronic renal failure. (From Whitworth [16];with permission.)

20

50

60

70

80

90

100

40

0

B

Perc

enta

ge o

f to

tal

Dialysis

CardiacVascularInfectionOther

10

30

Transplantation


FIGURE 2-18

Based on average blood pressure values, a strong direct relationshipwas found between arterial pressure and left ventricular hypertrophy,left ventricular chamber dilation (by echocardiography), and systolicdysfunction in patients undergoing dialysis for end-stage renal disease.After prolonged follow-up, blood pressures fell with the onset ofcongestive heart failure and manifest coronary artery disease. Withthe onset of cardiac failure, there appeared to be an inverse rela-tionship between arterial pressure and mortality. From the outset,the strongest predictor of congestive heart failure was elevatedblood pressure. (Adapted from Foley and coworkers [17].)

10

25

30

35

40

20

0

B

Perc

enta

ge o

f to

tal

Left ventricularhypertrophy

5

15

Systolicdysfunction

Left ventricularchamber dilation

0.0 10a 12n 2p 4p 6p 8p

Awake: 156/101 mm Hg

Blood pressure valuesHeart rate

Nocturnal: 167/100 mm Hg

10p 12m 2a 4a 6a 8a

Real time data

Blo

od

pre

ssu

re, m

m H

g

50

0

90100

150140

200

250

MMMMMMMM

MMMMRxFd Fd ZZZZZ ZZZZZZZZZZZZZZZZZZ ZZZRx Rx

FIGURE 2-19

Around-the-clock ambulatory blood pressuremonitoring in a patient with renal disease.Loss of diurnal blood pressure patternshave been implicated in increased rates oftarget organ injury in patients with hyper-tension. In normal persons with essentialhypertension, nocturnal pressures decreasedby at least 10% and were associated with adecrease in heart rate. Several conditions havebeen associated with a loss of the nocturnaldecrease in pressure, particularly chronicsteroid administration and chronic renalfailure. Such a loss in normal circadianrhythm, in particular loss of the nocturnaldecrease in blood pressure is more commonlyassociated with left ventricular hypertrophyand lacunar strokes (manifested as enhancedT-2 signals in magnetic resonance images)and increased rates of microalbuminuria.Data from a single subject with end-stagerenal disease studied with are depicted here.

A

Blood pressureLeft ventricular

hypertrophy

Blood pressureDeath: Congestive heart failure

Overall mortality

Congestiveheart failure



Hypertension accelerates the rate of progressive renal failure inpatients with parenchymal renal disease. A, Photomicrograph ofmalignant phase hypertension. Regardless of the cause of renal disease,untreated hypertension leads to more rapid loss of remaining nephronsand decline in glomerular filtration rates. A striking example ofpressure-related injury may be observed in patients with malignantphase hypertension. This image is an open biopsy specimen obtainedfrom a patient with papilledema, an expanding aortic aneurysm, and

A

blood pressure level at approximately 240/130 mm Hg. The biopsyspecimen shows the following features of malignant nephrosclerosis:these patients develop vascular and glomerular injury, which canprogress to irreversible renal failure. Before the introduction of antihy-pertensive drug therapy, patients with malignant phase hypertensionroutinely proceeded to uremia. Effective antihypertensive therapy canslow or reverse this trend in some but not all patients. B, Progressiverenal failure in malignant hypertension over 8 years.

0.04

0.10

0.12

0.08

0.00

Pro

po

rtio

n w

ith

ESR

D

10 32 54 76 98 1110 1312 1514 1716

A Years from beginning therapy to ESRD

SBP>180n=11,912 menP<0.001

165<SBP≤180

SBP≤1650.02

0.06

40

100

80

0

Inci

den

ce p

er 1

00,0

00 p

erso

n-y

ears

, %

<117 117–123 124–130 131–140 >140B Systolic blood pressure, mm Hg

5.43

15.83

5.41

27.34

9.1

26.18

14.22

37.2132.37

83.1

White=300,645Black=20,222

N=332,544 men

20

60

FIGURE 2-21

Blood pressure levels and rates of end-stage renal disease (ESRD). A,Line graph showing Kaplan-Meier estimates of ESRD rates; 15-yearfollow-up. B, Age-adjusted 16-year incidence of all-cause ESRD inmen in the Multiple Risk Factor Intervention Trial (MRFIT). Large-scale epidemiologic studies indicate a progressive increase in the riskfor developing ESRD as a function of systolic blood pressure levels.Follow-up of nearly 12,000 male veterans in the United Statesestablished that systolic blood pressure above 165 mm Hg at the initialvisit was predictive of progressively higher risk of ESRD over a 15-year

follow-up period [18]. Similarly, follow-up studies after 16 years ofmore than 300,000 men in MRFIT demonstrated a progressive increasein the risk for ESRD, most pronounced in blacks [19]. These datasuggest that blood pressure levels predict future renal disease. However,it remains uncertain whether benign essential hypertension itselfinduces a primary renal lesion (hypertensive renal disease nephroscle-rosis) or acts as a catalyst in patients with other primary renal disease,otherwise not detected at initial screening. SBP—systolic bloodpressure. (Panel A from Perry and coworkers [18]; with permission.)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1/C

reat

inin

e

May1979

Feb1982

Nov1984

Aug1987

May1990

Jan1993

Oct1995

Jul1998

B Date


3

20

30

40

50

1

Cr-

1/s, m

L/m

mol

-1C

cr, m

L/m

in

–400 –200 0 +200 +400

Chronic glomerulonephritis:

Rates of progression over time decreaseafter reduction of BP from 149/102 mm Hgto treated level, 136/90 mm Hg.

Days

2

4 –12

–6

–18

Dec

reas

e in

glo

mer

ula

r fi

ltra

tio

n r

ate,

mL/

min

/y

86 92

Study A: mean GFR: 39 mL/min/1.73 m2

N=585: range: 25–55 mL/min

Protein excretion, g/d0–0.250.25–1

1.0–3.0≥3.0

98 107Mean follow-up MAP, mm Hg

–15

–9

0

–3

–12

–6

–18

–15

–9

0

–3

FIGURE 2-22

Rates of progression in glomeruloneophritis. The decrease in glomeru-lar filtration rate is illustrated. The rates of decline decreased con-siderably with administration of antihypertensive drug therapy.Among other mechanisms, the decrease in arterial pressure lowerstranscapillary filtration pressures at the level of the glomerulus [20].This effect is correlated with a reduction in proteinuria and slowerdevelopment of both glomerulosclerosis and interstitial fibrosis. Adistinctive feature of many glomerular diseases is the massive pro-teinuria and nephron loss associated with high single-nephronglomerular filtration, partially attributable to afferent arteriolarvasodilation. The appearance of worsening proteinuria (>3 g/d) isrelated to progressive renal injury and development of renal failure.Reduction of arterial pressure can decrease urinary protein excre-tion and slow the progression of renal injury. Ccr—creatinine clear-ance rate; Cr

-1/s—reciprocal creatinine, expressed as 1/creatinine.(From Bergstrom and coworkers [20]; with permission.)

FIGURE 2-23

Blood pressure, proteinuria, and the rate of renal disease progression:results from the Modification of Diet in Renal Disease (MDRD)trial. Shown are rates of decrease of glomerular filtration rate(GFR) for patients enrolled in the MDRD trial, depending on levelof achieved treated blood pressure during the trial [21]. A componentof this trial included strict versus conventional blood pressure control.The term strict was defined as target mean arterial pressure (MAP)of under 92 mm Hg. The term conventional was defined as MAPof under 107 mm Hg. The rate of decline in GFR increased at higherlevels of achieved MAP in patients with significant proteinuria(>3.0 g/d). No such relationship was evident over the duration ofthis trial (mean, 2.2 years) for patients with less severe proteinuria.These data emphasize the importance of blood pressure in deter-mining disease progression in patients with proteinuric nondiabeticrenal disease. No distinction was made in this study regarding therelative benefits of specific antihypertensive agents. (From Petersonand coworkers [21]; with permission.)

FIGURE 2-24

Blood pressure and rate of progressive renal failure. Rates of diseaseprogression (defined as the slope of 1/creatinine) were determined in86 patients who reached end-stage renal disease and dialytic therapy.The rates of progression were defined between mean creatinine levelsof 3.8 mg/dL (start) and 11.4 mg/dL (end) over a mean duration of33 months [22]. Brazy and coworkers [22] demonstrated that theslope of disease progression appeared to be related to the range ofachieved diastolic blood pressure during this interval. Hence, theseauthors argue that more intensive antihypertensive therapy maydelay the need for replacement therapy in patients with end-stagerenal disease. As noted in the Modification of Diet in Renal Diseasetrial, such benefits are most apparent in patients with proteinuriaover a shorter follow-up period. (From Brazy and coworkers [22];with permission.)

Effects of Antihypertensive Therapy on Renal Disease Progression

–0.010

–0.006

0Slo

pe

of 1

/cre

atin

ine

vs t

ime,

dL/

mg

mo

Range of diastolic blood pressure (mm Hg) foreach quartile of the population

85–9070–85 90–96

–0.012

–0.008

96–113


CLASSES OF ANTIHYPERTENSIVE AGENTS USED IN TREATMENT OF CHRONIC RENAL DISEASE

Diuretics:

Thiazide class

Loop diuretics

Potassium-sparing agents

Adrenergic inhibitors

Peripheral agents, eg, guanethidine

Central �-agonists, eg, clonidine, methyldopa, and guanfacine

�-Blocking agents, eg, doxazosin

�-Blocking agents

Combined �-� blocking agents, eg, labetalol

Vasodilators

Hydralazine

Minoxidil

Classes of calcium-channel blocking agents

Verapamil

Diltiazem

Dihydropyridine

Angiotensin-converting enzyme inhibitors

Angiotensin receptor blockers

FIGURE 2-25

The current classification of agents applied for chronic treatmentof hypertension as summarized in the report by the Joint NationalCommittee on Prevention, Detection, Evaluation and Treatment ofHigh Blood Pressure [23]. Attention must be given to drug accu-mulation and limitations of individual drug efficacy as glomerularfiltration rates decrease in chronic renal disease. Potassium levelsmay increase during administration of potassium-sparing agentsand medications that inhibit the renin-angiotensin system, especial-ly in patients with impaired renal function [24].

35

60

45

50

55

25

GFR

, mL/

min

/1.7

3 m

2 /y

–6 0 6 12 18 24 30 36 42 48A Time, mo

Conventional Strictn=87 patientsBars=95% confidence intervals for GFR estimates

30

40

–1

4

1

2

3

–3

Rat

e o

f ch

ange

in G

FR, m

L/m

in/1

.73

m2 /y

Strict ConventionalB Blood pressure control group

Mean ±SEM

–2

0

FIGURE 2-26

Strict blood pressure control and progression of hypertensivenephrosclerosis. Whether vigorous blood pressure reduction reducesprogression of early parenchymal renal disease in blacks withnephrosclerosis is not yet certain. A and B, A randomized prospectivetrial comparing strict (panel A) blood pressure control (defined asdiastolic blood pressure [DBP] <80 mm Hg) with conventional (panelB) levels of diastolic control between 85 and 95 mm Hg for morethan 3 years could not identify a reduction in rates of disease progres-sion [25]. Of patients, 68 of 87 were black. Rates of progression in

these patients were low. It should be emphasized that entry criteriaexcluded patients with diabetes and massive proteinuria. Initialstudies from the African American Study of Kidney Disease trial confirm that biopsy findings in most patients with clinical features ofhypertension were considered consistent with primary hypertensivedisease [26]. Whether lower than normal levels of blood pressure inthese patients will prevent progression to end-stage renal disease overlonger time periods remains to be determined. GFR—glomerular filtration rate. (From Toto and coworkers [25]; with permission.)


100

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

49

Creatinine ≥1.5 mg/dL Placebo Captopril

48 44 40 33 23 16 7 153 53 52 51 48 36 25 17 8

Years of follow-up

Pati

ents

wh

o d

ied

or

nee

ded

d

ialy

sis

or

tran

spla

nta

tio

n, %

P=0.002

P=0.14

10

0

20

30

50

40

60

70

80

90

153

Creatinine <1.5 mg/dL Placebo Captopril

150 148 146 138 98 84 52 25154 154 152 150 147 104 78 47 29

FIGURE 2-27

Angiotensin-converting enzyme (ACE)inhibitors and chronic renal disease.Progression of type I diabetic nephropathy to renal failure was reduced in the ACEinhibitor arm of a trial comparing conven-tional antihypertensive therapy with a regimen containing the ACE inhibitor captopril. All patients in this trial had significant proteinuria (>500 mg/d). Themost striking effect of the ACE inhibitorregimen was seen in patients with higherserum creatinine levels (>1.5 mg/dL) asshown in the top two lines. It should benoted that calcium channel blocking drugswere excluded from this trial and the ACEinhibitor arm had somewhat lower arterialpressures during treatment. These data offersupport to the concept that ACE inhibitionlowers intraglomerular pressures, reducesproteinuria, and delays the progression ofdiabetic nephropathy by more mechanismsthan can be explained by pressure reductionalone. (Data from Lewis and coworkers [27].)

2.6

2.4

0 1 2 3A Years

Benazepril: n=583 patients; creatinine=1.5–4.0Placebo

239

262

2.0

2.2

2.6

2.4

0 1 2 3B Years

Benazepril: n=583 patients; creatinine=1.5–4.0Placebo

117

137

2.0

2.2

FIGURE 2-28

Angiotensin-converting enzyme (ACE) inhibition in nondiabetic renaldisease. A and B, Shown here are serum creatinine levels from the12-month (panel A) and 36-month (panel B) cohorts followed in thebenazepril trial. In this trial, 583 patients were randomized to therapywith or without benazepril [28]. Slight reductions in the rates ofincrease in creatinine and of stop points in the ACE inhibitor groupoccurred; however, these reductions were modest. Whereas these

data support a role for ACE inhibition, the results are considerablyless convincing than are those for diabetic nephropathy. These resultsargue that some groups may not experience major benefit from ACEinhibition over the short term. Preliminary reports from recent studieslimited to patients with proteinuria suggest that rates of progressionwere substantially reduced by treatment with ramipril [29]. (FromMaschio and coworkers [28]; with permission.)


CONCLUSIONS AND RECOMMENDATIONS OF THE SIXTH REPORT OF THE JOINT NATIONAL COMMITTEE ON PREVENTION, DETECTION,EVALUATION AND TREATMENT OF HIGH BLOOD PRESSURE, 1997

1. Hypertension may result from renal disease that reduces functioning nephrons.

2. Evidence shows a clear relationship between high blood pressure and end-stage renal disease.

3. Blood pressure should be controlled to ≤130/85 mm Hg (<125/75 mm Hg) in patients with proteinuria in excess of 1 g/24 h.

4. Angiotensin-converting enzyme inhibitors work well to lower blood pressure and slow progression of renal failure.

FIGURE 2-29

Conclusions and Recommendations of theSixth Report of the Joint NationalCommittee (JNC) on Prevention, Detection,Evaluation and Treatment of High Blood,1997 [23]. The JNC Committee has empha-sized the importance of vigorous bloodpressure control with any agents needed,rather than specific classes of medication.Angiotensin-converting enzyme inhibitors in proteinuric disease are the exception.

References

1. Smith MC, Dunn MJ: Hypertension in renal parenchymal disease. InHypertension: Pathophysiology, Diagnosis and Management. Edited byLaragh JH, Brenner BM. New York: Raven Press; 1995:2081–2102.

2. Klahr S, Levey AS, Beck GJ, et al.: The effects of dietary proteinrestriction and blood-pressure control on the progression of chronicrenal disease. N Engl J Med 1994, 330:877–884.

3 Rodriguez-Iturbe B, Baggio B, Colina-Chouriao J, et al.: Studies on therenin-aldosterone system in the acute nephritic syndrome. Kidnet Int1981, 445–453

4. Curtiss JJ, Luke RG, Dustan HP, et al.: Remission of essential hyperten-sion after renal transplantation. N Engl J Med 1983, 309:1009–1015.

5. Brunner HR, Gavras H, Laragh JH: Specific inhibition of the renin-angiotensin system: a key to understanding blood pressure regulation.Prog Cardiovasc Dis 1974; 17:87–98.

6. Converse RL, Jacobsen TN, Toto RD, et al.: Sympathetic overactivity inpatients with chronic renal failure. N Engl J Med1992, 327:1912–1918.

7. Katholi RE, Nafilan AJ, Oparil S: Importance of renal sympathetictone in the development of DOCA-salt hypertension in the rat.Hypertension 1980, 2:266–273.

8. Benigni A, Zoja C, Cornay D, et al.: A specific endothelin subtype Areceptor antagonist protects against injury in renal disease progression.Kidney Int 1993, 44:440–444.

9. Levin ER: Mechanisms of disease: endothelins. N Engl J Med 1995,333:356–363.

10. Textor SC, Burnett JC, Romero JC, et al.: Urinary endothelin and renalvasoconstriction with cyclosporine or FK506 after liver transplantation.Kidney Int 1995, 47:1426–1433.

11. Sandborn WJ, Hay JE, Porayko MK, et al.: Cyclosporine withdrawal fornephrotoxicity in liver transplant recipients does not result in sustainedimprovement in kidney function and causes cellular and ductopenicrejection. Hepatology 1994, 19:925–932.

12. Benigni A, Perico N, Gaspari F, et al.: Increased renal endothelin pro-duction in rats with renal mass reduction. Am J Physiol 1991,260:F331–F339.

13. Rees DD, Palmer RMJ, Moncada S: Role of endothelium-derived nitricoxide in the regulation of blood pressure. Proc Natl Acad Sci U S A1989, 86:3375–3378.

14. Lahera V, Salom MG, Miranda-Guardiola F, et al.: Effects of N-nitro-L-arginine methyl ester on renal function and blood pressure. Am JPhysiol 1991, 261:F1033–F1037.

15. Gaston RS, Schlessinger SD, Sanders PW, et al.: Cyclosporine inhibitsthe renal response to L-arginine in human kidney transplant recipients.J Am Soc Nephrol 1995, 5:1426–1433.

16. Whitworth JA: Renal parenchymal disease and hypertension. InClinical Hypertension. Edited by Robertson JIS. Amsterdam: Elsevier,1992:326–350.

17. Foley RN, Parfrey PS, Harnett JD, et al.: Impact of hypertension oncardiomyopathy, morbidity and mortality in end-stage renal disease.Kidney Int 1996, 49:1379–1385.

18. Perry HM, Miller JP, Fornoff JR, et al.: Early predictors of 15-yearend-stage renal disease in hypertensive patients. Hypertension 1995,25(part 1):587–594.

19. Klag MJ, Whelton PK, Randall BL, et al.: End-stage renal disease inAfrican-American and White men. JAMA 1997, 277:1293–1298.

20. Bergstrom J, Alvestrand A, Bucht H, Guttierrez A: Progression of chronicrenal failure in man is retarded with more frequent clinical follow-upsand better blood pressure control. Clin Nephrol 1986, 25:1–6.

21. Peterson JC, Adler S, Burkart JM, et al.: Blood pressure control, pro-teinuria and the progression of renal disease. Ann Intern Med 1995;123:754–762.

22. Brazy PC, Stead WW, Fitzwilliam JF: Progression of renal insufficiency:role of blood pressure. Kidney Int 1989, 35:670–674.

23. JNC Committee: Sixth Report of the Joint National Committee onPrevention, Detection, Evaluation and Treatment of High Blood Pressure.Bethesda, MD: National Institutes of Health Publication; 1997.

24. Textor SC: Renal failure related to ACE inhibitors. Semin Nephrol1997, 17:67–76.

25. Toto RD, Mitchell HC, Smith RD, et al.: “Strict” blood pressure controland progression of renal disease in hypertensive nephrosclerosis.Kidney Int 1995, 48:851–859.

26. Fogo A, Breyer JA, Smith MC, et al.: Accuracy of the diagnosis ofhypertensive nephrosclerosis in African-Americans: a report from theAfrican American Study of Kidney Disease (ASSK) trial. Kidney Int1997; 51:244–252.

27. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med1993, 329:1456–1462.

28. Maschio G, Alberti D, Janin G, et al.: Effect of the angiotensin-convertingenzyme inhibitor benazepril on the progression of chronic renal insuf-ficiency. N Engl J Med 1996, 334:939–945.

29. Ruggenenti P, Perna A, Mosconi M, et al.: The angiotensin convertingenzyme inhibitor ramipril slows the rate of GFR decline and the pro-gression to end-stage renal failure in proteinuric, non-diabetic chronicrenal diseases [abstract]. J Am Soc Nephrol 1997, 8:147A.

30. Giatras I, Lau J, Levey AS: Effect of angiotensin-converting enzymeinhibitors on the progression of non-diabetic renal disease: a meta-analysis of randomized trials. Ann Intern Med 1997, 127:345.

3

Renovascular Hypertensionand Ischemic Nephropathy

The major issues in approaching patients with renal artery steno-sis relate to the role of renal artery stenosis in the managementof hypertension, ie, “renovascular hypertension,” and to the

potential for vascular compromise of renal function, ie, “ischemicnephropathy.” Ever since the original Goldblatt experiment in 1934,wherein experimental hypertension was produced by renal arteryclamping, countless investigators and clinicians have been intrigued bythe relationship between renal artery stenosis and hypertension. Muchdiscussion has focused on the pathophysiology of renovascular hyper-tension, the renin angiotensin system, diagnostic tests to detect pre-sumed renovascular hypertension, and the relative merits of surgicalrenal revascularization (SR), percutaneous transluminal renal angio-plasty (PTRA), and drug therapy in managing patients with renalartery stenosis and hypertension. Hemodynamically significant renalartery stenosis, when bilateral or affecting the artery to a solitary func-tioning kidney, can also lead to a reduction in kidney function(ischemic nephropathy). This untoward observation may be reversedby interventive maneuvers, eg, surgical renal revascularization, PTRA,or renal artery stenting. The syndrome of “ischemic renal disease” or“ischemic nephropathy” now looms as an important clinical condi-tion and has attracted the fascination of nephrologists, vascular sur-geons, and interventional cardiologists and radiologists.

The detection of renal artery stenosis in a patient with hyperten-sion usually evokes the assumption that the hypertension is due to therenal artery stenosis. However, renal artery stenosis is not synony-mous with “renovascular hypertension.” On the basis of autopsystudies and clinical angiographic correlations, high-grade atheroscle-rotic renal artery stenosis (ASO-RAS) in patients with mild bloodpressure elevation or in patients with normal arterial pressure is wellrecognized. The vast majority of patients with ASO-RAS who havehypertension have essential hypertension, not renovascular hyperten-sion. These hypertensive patients with ASO-RAS are rarely cured oftheir hypertension by interventive procedures that either bypass or

Marc A. Pohl

C H A P T E R


CLASSIFICATION OF RENALARTERY DISEASE

Disease

Atherosclerosis

Fibrous dysplasia

Medial (30%)

Perimedial (5%)

Intimal (5%)

Incidence, %*

60–80

20–40

dilate the stenotic lesion. Thus, it is critical to distinguishbetween the anatomic presence of renal artery stenosis, inwhich a stenotic lesion is present but not necessarily causinghypertension, and the syndrome of renovascular hypertensionin which significant arterial stenosis is present and sufficient toproduce renal tissue ischemia and initiate a pathophysiologicsequence of events leading to elevated arterial pressure. In thefinal analysis, proof that a patient has the entity of “renovas-cular hypertension” rests with the demonstration that thehypertension, presumed to be “renovascular,” can be eliminat-ed or substantially ameliorated following removal of the steno-sis by surgical or endovascular intervention, or by removingthe kidney distal to the stenosis.

Although the great majority of patients diagnosed as havingrenovascular hypertension have this syndrome because of main renalartery stenosis, hypertension following unilateral renal trauma,

chronic subcapsular hematoma, and unilateral ureteral obstructionmay also be associated with hypertension that is relieved when the affected kidney is removed. These clinical analogues of theexperimental Page kidney reflect the syndrome of renovascularhypertension (RVHT), but without main renal artery stenosis.Takayasu’s arteritis and atheroembolic renal disease are additionalexamples of RVHT without main renal artery stenosis.Accordingly, the anatomic presence of renal artery stenosisshould not be equated with renovascular hypertension and thesyndrome of RVHT need not reflect renal artery stenosis.

This chapter reviews the types of renal arterial disease asso-ciated with RVHT, the pathophysiology of RVHT, clinical features and diagnostic approaches to renal artery stenosis andRVHT, evolving concepts regarding ischemic nephropathy, andmanagement considerations in patients with renal artery stenosis,presumed RVHT, and ischemic renal disease.

FIGURE 3-1

Classification of renal artery disease. Two main types of renal arterial lesions form theanatomic basis for renal artery stenosis. Atherosclerotic renal artery disease (ASO-RAD) is the most common cause of renal artery disease, accounting for 60% to 80% of all renalartery lesions. The fibrous dysplasias are the other major category of renal artery disease,and as a group account for 20% to 40% of renal artery lesions. Arterial aneurysm andarteriovenous malformation are rarer types of renal artery disease.

A B

FIGURE 3-2

Angiographic examples of atherosclerotic renal artery disease (ASO-RAD). A, Aortogramdemonstrating severe nonostial atherosclerotic renal artery disease of the left main renal artery.B, Intra-arterial digital subtraction aortogram showing severe proximal right renal artery stenosis(ostial lesion) and moderately severe narrowing of the left renal artery due to atherosclerosis.

*Percent of renal artery lesions.

Atherosclerotic renal artery disease is typi-cally associated with atherosclerotic changesof the abdominal aorta (see panel B). ASO-RAD predominantly affects men and womenin the fifth to seventh decades of life but isuncommon in women under the age of 50.Anatomically, the majority of these patientsdemonstrate atherosclerotic plaques locatedin the proximal third of the main renal artery.In the majority of cases (70% to 80%), theobstructing lesion is an aortic plaque invad-ing the renal artery ostium (ostial lesion).Twenty to 30 percent of patients with ASO-RAD demonstrate atherosclerotic narrowing1 to 3 cm beyond the takeoff of the renalartery (nonostial lesion). Nonostial lesionsare technically more amenable to percuta-neous transluminal renal angioplasty (PTRA)than ostial ASO-RAD lesions, which aretechnically difficult to dilate and have a highrestenosis rate after PTRA. Renal arterystenting has gained wide acceptance for ostiallesions. Endovascular intervention for nonos-tial lesions includes both PTRA and stents.Surgical renal revascularization is used forboth ostial and nonostial ASO-RAD lesions.(From Pohl [1]; with permission.)

3.3Renovascular Hypertension and Ischemic Nephropathy

NATURAL HISTORY OF ATHEROSCLEROTIC RENOVASCULAR DISEASE: REPORTS OF SERIAL ANGIOGRAMS

First author

Wollenweber

Meaney

Dean

Schreiber

Tollefson

Total

Year

1968

1968

1981

1984

1991

Months of follow-up, n/n

12/88

6/120

6/102

12/60

15/180

Patients, n

30

39

35

85

48

237

Progression, n (%)

21 (70)

14 (36)

10 (29)

37 (44)

34 (71)

116 (49)

Total occlusion

NA

3 (8)

4 (11)

14 (I6)

7 (15)

28 (14)

FIGURE 3-3

Natural history of atherosclerotic renovascular disease.Retrospective studies, based on serial renal angiograms, suggestthat atherosclerotic renal artery disease (ASO-RAD) is a progres-sive disorder. This figure summarizes retrospective series on thenatural history of ASO-RAD. A large series from the ClevelandClinic in nonoperated patients indicated progression of renal arteryobstruction in 44%; progression to total occlusion occurred in16% of these patients. Reduction in ipsilateral renal size is associ-ated with angiographic evidence of progression in contrast topatients with nonprogressive (angiographically) ASO-RAD.

Zierler and coworkers have prospectively studied the progres-sion of ASO-RAD by sequential duplex ultrasonography. The

cumulative incidence of progession of lesions with less than 60% reduction in lumen diameter progressing to more than 60%reduction in lumen diameter was 30% at 1 year, 44% at 2 years,and 48% at 3 years. Progression to total occlusion occurred onlyin arteries with a baseline reduction in lumen diameter of morethan 60%. The cumulative incidence of progression to totalocclusion in patients with baseline stenosis of 60% or greaterwas 4% at 1 year, 4% at 2 years, and 7% at 3 years. Blood pressure control and serum creatinine were not predictors ofprogression. The risk of renal parenchymal atrophy over time inkidneys with ASO-RAD has also been described. (Table adaptedfrom Rimmer and Gennari [2]; with permission.)

FREQUENCY AND NATURAL HISTORY OF FIBROUS RENAL ARTERY DISEASES

Lesion

Intimal fibroplasia andmedial hyperplasia

Perimedial fibroplasia

Medial fibroplasia

Frequency, %*

10

10–25

70–85

Threat to renal function

++++

++++

—

Risk of progression

++++

++++

++

FIGURE 3-4

Frequency and natural history of fibrous renal artery diseases. There are four types of fibrousrenal artery disease (fibrous dysplasias): medial fibroplasia, perimedial fibroplasia, intimalfibroplasia, and medial hyperplasia. Although the true incidence of these specific types offibrous renal artery disease is not clearly defined, medial fibroplasia is the most common, estimated to account for 70% to 85% of fibrous renal artery disease. The majority of patientswith medial fibroplasia are almost exclusively women who are diagnosed between the ages of25 to 50 years. Although medial fibroplasia progresses to higher degrees of stenosis in aboutone third of cases, complete arterial occlusion or ischemic atrophy of the involved kidney israre. Intervention on this type of fibrosis dysplasia is for relief of hypertension because thethreat of progressive medial fibroplasia to renal function is negligible. Perimedial fibroplasia is

the second most common type of fibrousdysplasia, accounting for 10% to 25% offibrous renal artery lesions. This lesion alsooccurs predominantly in women, is diagnosedbetween the ages of 15 and 30, is frequentlybilateral and highly stenotic, and may progressto total arterial occlusion. These patientsshould undergo surgical renal revascularizationto relieve hypertension and to avoid loss ofrenal function. Intimal fibroplasia and medialhyperplasia (usually indistinguishable angio-graphically) are not common, accounting foronly 5% to 10% of fibrous renal arterylesions. Intimal fibroplasia occurs primarily inchildren and adolescents. Medial hyperplasia is found predominantly in adolescents; angio-graphically it appears as a smooth linearstenosis that may extend into the primaryrenal artery branches. Medial hyperplasia, likeintimal fibroplasia, is a progressive lesion andis associated with ipsilateral renal atrophy.Surgical renal revascularization is recommendedfor patients with either intimal fibroplasia ormedial hyperplasia to avoid lifelong antihyper-tensive therapy and to avert renal atrophy.

*Frequency relates to frequency of only the fibrous renal artery diseases.


A

B

FIGURE 3-5

Arteriogram and schematic diagrams ofmedial fibroplasia. A, Right renal arteri-ogram demonstrating weblike stenosis with interposed segments of dilatation(large beads) typical of medial fibroplasia(“string of beads” lesion). B, Schematic diagram of medial fibroplasia.

The lesion of medial fibroplasia characteris-tically affects the distal half of the main renalartery, frequently extending into the branches,is often bilateral, and angiographically givesthe appearance of multiple aneurysms (“stringof beads”). Histologically, this beaded lesion is characterized by areas of proliferation offibroblasts of the media surrounded byfibrous connective tissue (stenosis) alternatingwith areas of medial thinning (aneurysms).Inspection of the renal angiogram in panel Aindicates that the width of areas of aneurys-mal dilatation is wider than the nonaffectedproximal renal artery, an angiographic clue to medial fibroplasia. (Panel A from Pohl [1];with permission.)

AB

FIGURE 3-6

Arteriogram and schematic diagram of peri-medial fibroplasia. A, Selective right renalarteriogram shows a tight stenosis in themid portion of the renal artery with a smallstring of beads appearance, typical of peri-medial fibroplasia. B, Schematic diagram ofperimedial fibroplasia.

Perimedial fibroplasia, accounting for10% to 25% of the fibrous renal artery dis-eases, is also observed almost exclusively inwomen. The stenotic lesion occurs in themid and distal main renal artery or branchesand may be bilateral. Angiographically, serialstenoses are observed with small beads, whichare smaller in diameter than the unaffectedportion of the renal artery. This highlystenotic lesion may progress to total occlu-sion; collateral blood vessels and renal atro-phy on the involved side are frequentlyobserved. Pathologically, the outer layer ofthe media varies in thickness and is denselyfibrotic, producing a severe reduction inlumen diameter (panel B). Renal artery dis-section and/or thrombosis are common.(Panel A from Pohl [1]; with permission.)


AB

FIGURE 3-7

Arteriogram and schematic diagram of intimal fibroplasia. A, Selective right renalarteriogram demonstrating a localized,highly stenotic, smooth lesion involving thedistal renal artery, from intimal fibroplasia.B, Schematic diagram of intimal fibroplasia.

Intimal fibroplasia occurs primarily inchildren and adolescents and angiographi-cally gives the appearance of a localized,highly stenotic, smooth lesion, with post-stenotic dilatation. It may occur in the prox-imal portion of the renal artery as well as in the mid and distal portions of the renalartery, is progressive, and is occasionallyassociated with dissection or renal infarc-tion. Pathologically, idiopathic intimal fibro-plasia is due to a proliferation of the intimallining of the arterial wall. Intimal fibroplasiaof the renal artery may also occur as anevent secondary to atherosclerosis or as areactive intimal fibroplasia consequent to aninciting event such as prior endarterectomyor balloon angioplasty. (Panel A from Pohl[1]; with permission.)

ATHEROSCLEROTIC RENAL ARTERY DISEASE VERSUS MEDIAL FIBROPLASIA

Atherosclerotic

Men and women

Age >50–55 y

Total occlusion common

Ischemic atrophy common

Surgical intervention or angioplasty:

Mediocre cure rates of the hypertension

Less amenable to PTRA

Medial fibroplasia

Women

Age 20–40 y

Total occlusion rare

Ischemic atrophy rare

Surgical intervention or angioplasty:

Good cure rates of the hypertension

More amenable to PTRA

FIGURE 3-8

A comparison of atherosclerotic renal artery disease and medial fibroplasia. The mostcommon types of renal artery disease (atherosclerotic renal artery disease [ASO-RAD] andmedial fibroplasia) are compared here. In general, ASO-RAD is observed in men andwomen older than 50 to 55 years of age, whereas medial fibroplasia is observed primarilyin younger white women. Total occlusion of the renal artery and, hence, atrophy of the

kidney beyond the stenosis are relativelycommon with ASO-RAD, but ischemicatrophy of the kidney ipsilateral to the medialfibroplasia lesion is rare. Surgical interventionor pecutaneous transluminal renal angioplasty(PTRA) typically produce good cure rates forthe hypertension in medial fibroplasia andthese lesions are technically quite amenable toPTRA. In contrast, ASO-RAD is, technically,much less amenable to PTRA (particularlyostial lesions), and surgical intervention orPTRA produce mediocre-to-poor cure ratesof the hypertension. ASO-RAD and medialfibroplasia may cause hypertension and when the hypertension is cured or markedlyimproved following intervention, the patientmay be viewed as having “renovascularhypertension.” This sequence of events is far more likely to occur in patients withmedial fibroplasia than in patients with ASO-RAD. ASO-RAD and medial fibroplasiainvolve both main renal arteries in approxi-mately 30% to 40% of patients.


Contralateralkidney

Stenotickidney

Ischemia

Renin

Angiotensin II

AldosteroneVasoconstriction

• Intrarenal hemodynamics• Sodium retention

• Supressed renin• Pressure natriuresis

FIGURE 3-9

Schematic representation of renovascular hypertension. Renovascularhypertension may be defined as the secondary elevation of bloodpressure produced by any of a variety of conditions that interferewith the arterial circulation to kidney tissue and cause renal ischemia.Almost always, renovascular hypertension is caused by obstructionof the renal artery or its branches, and demonstration of causalitybetween the renal artery lesion and the hypertension is essential to this definition.

Pathophysiology of Renovascular Hypertension

This diagram shows the classic model of two-kidney, one clip (2K,1C) Goldblatt hypertension, wherein one renal artery is constricted and the contralateral kidney is left intact. In thepresence of hemodynamically sufficient unilateral renal arterystenosis, the kidney distal to the stenosis is rendered ischemic,activating the renin angiotensin system, and producing high levels of angiotensin II, causing a “vasoconstrictor” type ofhypertension. Numerous studies have established the causal relationship between angiotensin II–mediated vasoconstrictionand hypertension in the early phase of this experimental model.In addition, the high levels of angiotensin II stimulate the adren-al cortex to elaborate larger amounts of aldosterone such thatthe “stenotic kidney” demonstrates sodium retention. This sec-ondary aldosteronism also produces hypokalemia. The degree of renal artery stenosis necessary to produce hemodynamicallysignificant reductions in perfusion, triggering renal ischemia and activation of the renin angiotensin system, generally doesnot occur until a reduction of 80% or more in both lumen diameterand cross-sectional area of the renal artery takes place. Lesserdegrees of renal artery constriction do not initiate this sequenceof events.

This model of 2K,1C Goldblatt hypertension implies that the contralateral (nonaffected) kidney is present, and that itsrenal artery is not hemodynamically significantly narrowed. As illustrated, the “contralateral kidney” demonstrates sup-pressed renin production and undergoes a pressure natriuresis,presumably because of angiotensin II–initiated vasoconstrictionand sodium retention, leading to systemic elevation of bloodpressure that then results in suppression of renin release andenhanced excretion of sodium (pressure natriuresis) by the “contralateral kidney.”


Clip I II III

Blood pressure

Renin

Change in blood pressure on removing clip

Phase

FIGURE 3-10

Sequential phases in two-kidney, one-clip (2K,1C) experimental reno-vascular hypertension. The schematic representation of renovascularhypertension depicted in Figure 3-9 is an oversimplification. Infact, the course of experimental 2K,1C hypertension may be dividedinto three sequential phases. In phase I, renal ischemia and activationof the renin angiotensin system are of fundamental importance,and in this early phase of experimental hypertension, the bloodpressure elevation is renin- or angiotensin II–dependent. Acuteadministration of angiotensin II antagonists, administration ofangiotensin-converting enzyme (ACE) inhibitors, removal of therenal artery stenosis (ie, removal of the clip in the experimentalanimal or removal of the “stenotic kidney”) promptly normalizesblood pressure. Several days after renal artery clamping, renin levelsfall, but blood pressure remains elevated. This second phase ofexperimental 2K,1C hypertension may be viewed as a pathophysio-logic transition phase that, depending on the experimental modeland species, may last from a few days to several weeks. During thistransition phase (phase II), salt and water retention are observed asa consequence of the effect of hypoperfusion of the stenotic kidney;

augmented proximal tubular reabsorption of sodium and waterand angiotensin II–induced stimulation of aldosterone secretioncontribute to this sodium and water retention. In addition, the highlevels of angiotensin II stimulate thirst, which further augmentsexpansion of the extracellular fluid volume. The expanded extra-cellular fluid volume results in a progressive suppression of peripheralrenin activity. During this transition phase, the hypertension is stillresponsive to removal of the unilateral renal artery stenosis, toangiotensin II blockade, or unilateral nephrectomy, although thesemaneuvers do not normalize the blood pressure as promptly andconsistently as in the acute phase.

After several weeks, a chronic phase (phase III) ensues whereinunclipping the renal artery of the experimental animal does not lowerthe blood pressure. This failure of “unclipping” to lower the bloodpressure in this chronic phase (III) of 2K,1C hypertension is due towidespread arteriolar damage to the “contralateral kidney,” conse-quent to prolonged exposure to high blood pressure and high levelsof angiotensin II. In this chronic phase of 2K,1C renovascular hyper-tension, extracellular fluid volume expansion and systemic vasocon-striction are the main pathophysiologic abnormalities. The pressurenatriuresis of the “contralateral kidney” blunts the extracellularfluid volume expansion caused by the “stenotic kidney;” but as thecontralateral kidney suffers vascular damage from extended exposureto elevated arterial pressure, its excretory function diminishes andextracellular fluid volume expansion persists. In this third phase ofexperimental 2K,1C hypertension, acute blockade of the reninangiotensin system fails to lower blood pressure. Sodium depletionmay ameliorate the hypertension but does not normalize it. Theclinical surrogate of phase III experimental 2K,1C hypertension isduration of hypertension. Widespread clinical experience indicatesthat major improvements in blood pressure control or cure of thehypertension following renal revascularization or even removal of the kidney ipsilateral to the renal artery stenosis are rarely observed in patients with a long duration (ie, >5 years) of hypertension.(Adapted from Brown and coworkers [3]; with permission.)

Two-kidney hypertension One-kidney hypertension

Bloodpressure

Renin Volume

High Normal

Bloodpressure

Renin Volume

Normal High

FIGURE 3-11

Schematic representation of two types of experimental hypertension.The discussion so far of the pathophysiology of renovascularhypertension has focused on the two-kidney, one-clip model of renovascular hypertension (“two-kidney hypertension”), wherein theartery to the “contralateral kidney” is patent and the “contralateral”nonaffected kidney is present. Elevated peripheral renin activity,normal plasma volume, and hypokalemia are typically associatedwith the elevated arterial pressure. There is another type of “reno-vascular hypertension” known as “one-kidney” hypertension,wherein in the experimental model, one renal artery is constrictedand the contralateral kidney is removed. Although there is an initialincrease in renin release responsible for the early rise in blood pressurein “one-kidney” hypertension as in “two-kidney” hypertension, theabsence of an unclipped contralateral kidney allows for sodiumretention early in the course of this one-kidney, one-clip (1K,1C)model. Renin levels are suppressed to normal levels in conjunctionwith high blood pressure which is maintained by salt and waterretention. Thus, extracellular fluid volume expansion is a primefeature of “one-kidney” hypertension.


A. LESIONS PRODUCING THE SYNDROME OF RENOVASCULARHYPERTENSION (“TWO-KIDNEY HYPERTENSION”)*

Unilateral atherosclerotic renal arterial disease

Unilateral fibrous renal artery disease

Renal artery aneurysm

Arterial embolus

Arteriovenous fistula (congenital and traumatic)

Segmental arterial occlusion (traumatic)

Pheochromocytoma compressing renal artery

Unilateral perirenal hematoma or subcapsular hematoma (compressing renal parenchyma)

*Implies contralateral (nonaffected) kidney present.

B. LESIONS PRODUCING THE SYNDROME OF RENOVASCULARHYPERTENSION (“ONE-KIDNEY HYPERTENSION”)*

Stenosis to a solitary functioning kidney

Bilateral renal arterial stenosis

Aortic coarctation

Vasculitis (polyarteritis nodosa and Takayasu’s arteritis)

Atheroembolic disease

*Implies total renal mass ischemic.

FIGURE 3-12

Lesions producing the syndrome of reno-vascular hypertension. A, Two-kidneyhypertension. The most common clinicalcounterpart to “two-kidney” hypertensionis unilateral renal artery stenosis due to eitheratherosclerotic or fibrous renal artery disease.Unilateral renal trauma, with developmentof a calcified fibrous capsule surroundingthe injured kidney causing compression ofthe renal parenchyma, may produce reno-vascular hypertension; this clinical situation isanalogous to the experimental Page kidney,wherein cellophane wrapping of one of twokidneys causes hypertension, which isrelieved by removal of the wrapped kidney.

B, One-kidney hypertension. Clinicalcounterparts of experimental one-kidney,one-clip (“one kidney”) hypertensioninclude renal artery stenosis to a solitaryfunctioning kidney, bilateral renal arterialstenosis, aortic coarctation, Takayasu’sarteritis, fulminant polyarteritis nodosa,atheroembolic renal disease, and renalartery stenosis in a transplanted kidney. In some parts of the world, eg, China andIndia, Takayasu’s arteritis is a frequentcause of renovascular hypertension.

STEPS IN MAKING THE DIAGNOSIS OF RENOVASCULAR HYPERTENSION

1. Demonstration of renal arterial stenosis by angiography

2. Determination of pathophysiologic significance of the stenotic lesion

3. Cure of the hypertension by intervention, ie, revascularization, percutaneous trans-luminal angioplasty, nephrectomy

FIGURE 3-13

Steps in making the diagnosis of renovascular hypertension (RVHT).With the exception of oral contraceptive use and alcohol ingestion,RVHT is the most common cause of potentially remediable secondaryhypertension. RVHT is estimated to occur with a prevalence of 1%to 15%. Some hypertension referral clinics have estimated a preva-lence of RVHT as high as 15%, whereas other prevalence data suggestthat less than 1% to 2% of the hypertensive population has RVHT.

Although elderly atherosclerotic hypertensive individuals often haveatherosclerotic renal artery disease, their hypertension is usuallyessential hypertension, not RVHT. On balance, the prevalence ofRVHT in the general hypertensive population is probably no morethan 2% to 3%. The particular appeal of diagnosing RVHT centersaround its potential curability by an interventive maneuver such assurgical revascularization, percutaneous transluminal renal angio-plasty (PTRA), or renal artery stenting. Whether or not to use theseinterventions for the goal of improving blood pressure depends onthe likelihood such intervention will improve the blood pressure.

The overwhelming majority of patients with RVHT will have thissyndrome because of main renal artery stenosis. Therefore, the firststep in making the diagnosis of RVHT is to demonstrate renal arterystenosis by one of several imaging procedures and, eventually, byangiography. The second step in establishing the probability thatthe renal artery stenosis is instrumental in promoting hypertensionis to determine the pathophysiologic significance of the stenoticlesion. Finally, the hypertension, presumed to be renovascular inorigin, is proven to be RVHT when the elevated blood pressure iscured or markedly ameliorated by an interventive maneuver such assurgical revascularization, PTRA, renal artery stent, or nephrectomy.


DIAGNOSIS OF RENAL ARTERIAL STENOSIS

Clinical clues

Age of onset of hypertension <30 y or >55 y

Abrupt onset of hypertension

Acceleration of previously well-controlled hypertension

Hypertension refractory to an appropriate three-drug regimen

Accelerated retinopathy

Systolic-diastolic abdominal bruit

Evidence of generalized atherosclerosis obliterans

Malignant hypertension

Flash pulmonary edema

Acute renal failure with use of angiotensin-convertingenzyme inhibitors or angiotensin II receptor-blockers

Diagnostic tests

Duplex ultrasonography

Radionuclide renography

Captopril renography

Captopril provocation test

Intravenous digital subtraction angiography

Rapid sequence IVP

Magnetic resonance angiography

Spiral CT angiography

CO2 angiography

Conventional (contrast) angiography

FIGURE 3-14

Diagnosis of renal artery stenosis. Clinical clues suggesting renal artery stenosis, some ofwhich suggest that the stenosis is the cause of the hypertension, are listed on the left. Thewell-documented age of onset of hypertension in an individual under the age of 30 or overage 55 years, particularly if the hypertension is severe and requiring three antihypertensivedrugs, is a strong clinical clue to renal artery stenosis and predicts that the stenosis is causingthe hypertension. The patient with a long history of mild hypertension, easily controlled withone or two drugs, who, particularly in older age, develops severe and refractory hypertension,is likely to have developed atherosclerotic renal artery stenosis as a contributor to underlying

longstanding essential hypertension. Grade IIIhypertensive retinopathy, malignant hyper-tension, and flash pulmonary edema all suggest renal artery stenosis with or withoutrenovascular hypertension. The observationof a diastolic bruit in the abdomen of a youngwhite women suggests fibrous renal arterydisease and, further, is a reliable clinical cluethat the hypertension will be helped substan-tially by surgical renal revascularization orpercutaneous transluminal renal angioplasty.

The diagnostic tests listed along the rightside are used mainly to detect renal arterystenosis (ie, the anatomic presence of dis-ease). Captopril renography is also used to predict physiologic significance of thestenotic lesion. The popularity of thesediagnostic tests in detecting renal arterystenosis varies from institution to institu-tion; correlations with percent stenosis bycomparative angiography are widely vari-able. A substantial fall in blood pressurefollowing initiation of an angiotensin-con-verting enzyme inhibitor or angiotensin IIreceptor blocker suggests RVHT. With theexception of a diastolic abdominal bruitand accelerated retinopathy, no clear-cutphysical findings definitely discriminatepatients with RVHT from the larger pool of patients with essential hypertension.

FIGURE 3-15

Renal duplex ultrasound for diagnosis of renal artery stenosis. Duplex ultrasound scanningof the renal arteries is a noninvasive screening test for the detection of renal artery stenosis.It combines direct visualization of the renal arteries (B-mode imaging) with measurement of various hemodynamic factors in the main renal arteries and within the kidney (Doppler),thus providing both an anatomic and functional assessment. Unlike other noninvasive screeningtests (eg, captopril renography), duplex ultrasonography does not require patients to dis-continue any antihypertensive medications before the test. The study should be performedwhile the patient is fasting. The white arrow indicates the aorta and the black arrow the leftrenal artery, which is stenotic. Doppler scans (bottom) measure the corresponding peak systolicvelocities in the aorta and in the renal artery. The peak systolic velocity in the left renal arterywas 400 cm/s, and the peak systolic velocity in the aorta was 75 cm/s. Therefore, the renal-aortic ratio was 5.3, consistent with a 60% to 99% left renal artery stenosis. (From Hoffmanand coworkers [4]; with permission.)


COMPARISON OF DUPLEX ULTRASOUND WITH ARTERIOGRAPHY

0–59

60–99

100

Total

0–59

62

1

0

63

Percent stenosis by arteriogram

60–79

0

31

1

32

80–99

1

67

1

69

100

1

0

22

23

Total

64

99

24

187

Sensitivity, 0.98.

Specificity, 0.98.

Positive predictive value, 0.99.

Negative predictive value, 0.97.

DETERMINATION OF PATHOPHYSIOLOGICSIGNIFICANCE OF THE STENOTIC LESION

Duration of hypertension <3–5 y

Appearance of lesion on angiogram (>75% stenosis)

Systolic-diastolic bruit in abdomen

Renal vein renin ratio >1.5

Positive captopril provocation test or captopril renogram

Abnormal rapid sequence IVP

Hypokalemia

FIGURE 3-16

Comparison of duplex ultrasound with arteriography. A total of102 consecutive patients with both duplex ultrasound scanning ofthe renal arteries and renal arteriography were prospectively studied.All patients in this study had difficult-to-control hypertension,unexplained azotemia, or associated peripheral vascular disease,giving them a high pretest likelihood of renovascular hypertension.Sixty-two of 63 arteries that showed less than 60% stenosis by formalarteriography, were identified by duplex ultrasound scanning.

Twenty-two of 23 arteries with total occlusion on arteriographywere correctly identified by duplex ultrasound. Thirty-one of 32arteries with 60% to 79% stenosis using arteriography were identifiedas having 60% to 99% stenosis on duplex ultrasound and 67 of 69arteries with 80% to 99% stenosis on arteriography were detectedto have 60% to 99% stenosis on ultrasound. A current limitationof duplex ultrasound is the inability to consistently distinguishbetween more than and less than 80% stenosis (considered to bethe magnitude of stenosis required for hemodynamic significance of the lesion). Nevertheless, duplex ultrasound is currently highlysensitive and specific in patients with a high likelihood of renovasculardisease in detecting patients with more or less than 60% renal arterystenosis. Accessory renal arteries are difficult to identify by ultra-sound and remain a limitation of this test. (Adapted from Olin and coworkers [5]; with permission.)

FIGURE 3-17

Determination of pathophysiologic significance of the stenoticlesion. The second step in making the diagnosis of renovascularhypertension (RVHT) is to determine the pathophysiologic signif-icance of the stenotic lesion demonstrated by angiography. Thelikelihood of cure of the hypertension by an interventive maneu-ver is greatly enhanced when one or more of the items listed hereare present. A positive captopril provocation test, abnormal rapidsequence intravenous pyelogram (IVP), or positive captopril

renogram not only suggest the anatomic presence of renal arterystenosis but also imply that the stenosis is instrumental in pro-ducing the hypertension. Reductions of lumen diameter of lessthan 70% to 80% generally do not initiate renal ischemia or acti-vation of the renin angiotensin system; thus, before recommend-ing a renal revascularization procedure, severe renal artery steno-sis (>75% reduction in lumen diameter) should be observed onthe renal angiogram. A lateralizing renal vein renin ratio (a com-parison of renin harvested from the renal vein ipsilateral to therenal artery stenosis with the renin level from renal vein of thecontralateral kidney), particularly when renin production fromthe contralateral kidney is suppressed, suggests that an interven-tion on the renal artery stenosis will cure or markedly amelioratethe hypertension in about 90% of cases. Conversely, cure ormarked improvement in blood pressure following renal revascu-larization has been reported in nearly 50% of cases in theabsence of lateralizing renal vein renins. Hypokalemia, in theabsence of diuretic therapy, strongly suggests that the hyperten-sion is renovascular in origin, consequent to secondary aldostero-nism. The sensitivity of an IVP in detecting unilateral RVHT isrelatively poor (about 75%) and the overall sensitivity in detect-ing patients with bilateral renal artery disease is only about 60%.Because RVHT has a low prevalence in the general population, anegative IVP provides strong evidence (98% to 99% certainty)against RVHT.

Percent stenosisby ultrasound


RENIN CRITERIA FOR CAPTOPRIL TEST THATDISTINGUISH PATIENTS WITH RVHT FROM THOSE WITH ESSENTIAL HYPERTENSION

Stimulated PRA of 12 ng/mL/h or more

Absolute increase in PRA of 10 ng/mL/h or more

Percent increase in PRA

Increase in PRA of 150% if baseline PRA >3 ng/mL/h

Increase in PRA of 400% if baseline PRA <3 ng/mL/h

FIGURE 3-18

The captopril test: renin criteria that distinguish patients withrenovascular hypertension from those with essential hypertension.The captopril provocation test evolved because the casual measure-ment of peripheral plasma renin activity (PRA) has been of little

value as a diagnostic screening test for renovascular hypertension(RVHT). The notion that patients with high PRA, even in theface of high urinary sodium excretion, might turn out to haveRVHT has not been supported by numerous clinical observations.However, the short-term (60- to 90-minute) response of bloodpressure and PRA to an oral dose (25 to 50 mg) of captopril hasgained recent popularity as a screening test for presumed RVHT.Preparation of patients for this test is vital; ideally patientsshould discontinue their antihypertensive medications, maintain a diet adequate in salt, and have good renal function. A baselineblood pressure and PRA are obtained after which captopril isadministered; 60 minutes after captopril administration, a “post-captopril” PRA is obtained along with repeat measurements ofblood pressure. Early reports with this test indicated a high sensi-tivity and specificity (95% to 100%) in identifying RVHT if allthree of the renin criteria listed here were met. Subsequentreports have not been as encouraging such that the overall sensi-tivity of this captopril test is only about 70%, with a specificityof approximately 85%. (Adapted from Muller and coworkers [6];with permission.)

1.0

0.8

0.6

0.4

0.2

0

0 8 16 24 32 40 48

Rel

ativ

e ac

idit

y

Time, min

BladderRight kidneyLeft kidney

A

FIGURE 3-19

Captopril renography. A, TcDPTA time-activity curves duringbaseline. B, TcDPTA time-activity curves after captopril adminis-tration. These curves represent a captopril renogram in a patientwith unilateral left renal artery stenosis. This diagnostic test has beenused to screen for renal artery stenosis and to predict renovascularhypertension. Captopril renography appears to be highly sensitiveand specific for detecting physiologically significant renal arterystenosis. Scintigrams and time-activity curves should both be analyzedto assess renal perfusion, function, and size. If the renogram followingcaptopril administration is abnormal (panel B, demonstrating delayedtime to maximal activity and retention of the radionuclide in the rightkidney), another renogram may be obtained without captopril forcomparison. The diagnosis of renal artery stenosis is based on

1.0

0.8

0.6

0.4

0.2

0

Rel

ativ

e ac

idit

y

0 8 16 24 32 40 48Time, min

BladderRight kidneyLeft kidney

B

asymmetry of renal size and function and on specific, captopril-induced changes in the renogram, including delayed time to maximalactivity (≥11 minutes), significant asymmetry of the peak of eachkidney, marked cortical retention of the radionuclide, and markedreduction in the calculated glomerular filtration rate of the kidneyipsilateral to the stenosis. One must interpret the clinical and reno-graphic data with caution, as protocols are complex and diagnosticcriteria are not well standardized. Nevertheless, captopril renogra-phy appears to be an improvement over the captopril provocationtest, with many reports indicating sensitivity and specificity from80% to 95% in predicting an improvement in blood pressure following intervention. (Adapted from Nally and coworkers [7]; with permission.)


Suggested work-up for renovascular hypertension

Index of clinical suspicion

Moderate (≈5%–15%)

Normalor high

Low

No further work-up

Captopril test, or captopril renogram, or stimulated renal vein renins,

or (?) duplex ultrasound

Arteriogram + renalvein renins

Low (<1%) High (>25%)PRA

Negative Positive

?

FIGURE 3-20

Suggested work-up for renovascular hypertension. Because the prevalence of renovascular hyper-tension (RVHT) among hypertensive persons in general is approximately 2% or less, widespreadscreening for renovascular disease is not justified. Despite the proliferation of diagnostic tests

now available to detect renal artery stenosisand several tests designed to predict the physiologic significance of the stenotic lesion,the index of clinical suspicion for RVHTremains the focal point of the work-up forRVHT. A brief duration of moderately severehypertension is the most important cluedirecting subsequent work-up for RVHT. If the index of clinical suspicion (see Fig. 3-14) is high, it is reasonable to proceed directly toformal renal arteriography with renal vein renin determination. Alternatively, in patientshighly suspected to have RVHT, a captoprilrenogram followed by a renal arteriogram may be recommended. Strong argumentsagainst RVHT include 1) long duration (morethan 5 years) of hypertension, 2) old age, 3) generalized atherosclerosis, 4) increasedserum creatinine, and 5) a normal serum potassium concentration. For these patients,particularly if the blood pressure is only mini-mally elevated or easily controlled with one ortwo antihypertensive medications, furtherwork-up for RVHT is not indicated. (Adaptedfrom Mann and Pickering [8]; with permission.)

Ischemic Nephropathy

FIGURE 3-21

Aortogram in a 62-year-old white woman demonstrating subtotal occlusion of the leftmain renal artery supplying an atrophic left kidney and high-grade ostial stenosis of theproximal right renal artery from atherosclerosis. This patient presented in 1977 with arecent appearance of hypertension and a blood pressure of 170/115 mm Hg. Three yearspreviously, when diagnosed with polycythemia vera, an IVP was normal. She was fol-lowed closely between 1974 and 1977 by her physician and was always normotensiveuntil the hypertension suddenly appeared. A repeat rapid sequence IVP demonstrated areduction in the size of the left kidney from 14 cm in height (1974) to 11.5 cm in height(1977). The serum creatinine was 2.6 mg/dL. The renal arteriogram shown here indi-cates high-grade bilateral renal artery stenosis with the left kidney measuring 11.5 cm in height, and the right kidney measuring 14.5 cm in height. Renal vein renins wereobtained and lateralized strongly to the smaller left kidney. The blood pressure was well controlled with inderal and chlorthalidone. Right aortorenal reimplantation wasundertaken solely to preserve renal function. Postoperatively the serum creatinine fell to1.5 mg/dL and remained at this level for the next 13 years. Blood pressure continued torequire antihypertensive medication, but was controlled to normal levels with inderaland chlorthalidone.


12.0

11.0

10.0

9.0

8.0

7.0

6.0

5.0

4.0

3.0

2.0

1.0

0

Admission Medicaltherapy

Surgery orangioplasty

Seru

m c

reat

inin

e, m

g/dL Pt. 7

Pt. 3

Pt. 6

Pt. 8

Pt. 2Pt. 1

Pt. 4

Pt. 3

FIGURE 3-22

Effects of medical therapy and surgery or angioplasty on serumcreatinine levels. This figure describes eight patients hospitalizedbecause of severe hypertension and renal insufficiency. With med-ical management of the hypertension (antihypertensive drug thera-py), four of the eight patients developed substantial worsening oftheir renal function as measured by serum creatinine; three of thesefour patients demonstrated improvement following surgery orangioplasty. The other four patients (patients one to four) did notdemonstrate a worsening serum creatinine level with medical thera-py; but three of these four patients showed improved renal func-tion following surgery or angioplasty. (Adapted from Ying andcoworkers [9]; with permission.)

A

B

FIGURE 3-23

Improved renal function demonstrated by intravenous pyelographyfollowing left renal revascularization. A, preoperative IVP (5-minutefilm) in a 65-year-old white man with a 15-year history of hyperten-sion; serum creatinine 2.6 mg/dL. Note poorly functioning left kidney,which measured 11.5 cm in height. B, post operative IVP (5-minutefilm) obtained following left aortorenal saphenous vein bypass graftingto the left kidney. Note the prompt function and increased height(14.0 cm) of the revascularized left kidney versus the preoperativeIVP. (From Novick and Pohl [10]; with permission.)

The clinical story of the patient in Figure 3-21, the benefits ofsurgical renal revascularization or pecutaneous transluminal renalangioplasty (Fig. 3-22), and the radiographic evidence of improvedrenal function after renal revascularization (Fig. 3-23) are examplesof ischemic nephropathy. Two definitions of ischemic nephropathyare suggested herein: 1) clinically significant reduction in renalfunction due to compromise of the renal circulation; and 2) clinicallysignificant reduction in glomerular filtration rate due to hemody-namically significant obstruction to renal blood flow, or renal failuredue to renal artery occlusive disease.


ATHEROSCLEROTIC RENAL ARTERY STENOSIS IN 395 PATIENTS WITH GENERALIZED ATHEROSCLEROSIS OBLITERANS AND IN PATIENTS WITH CORONARY ARTERY DISEASE

Abdominal aortic aneurysm

Aorto-occlusive disease

Lower extremity disease

Suspected renal artery stenosis

Coronary artery disease

Patients, n

109

21

189

76

76

817

Percent of patients with >50% stenosis

38

33

39*

70†

29†

20‡

*50% in diabetic patients.†Data from Vetrovec and coworkers [12].‡Data from Harding [13].

CLINICAL PRESENTATIONS OF ISCHEMIC RENAL DISEASE

Acute renal failure, frequently precipitated by a reduction in blood pressure (ie, angiotensin-converting enzyme inhibitors plus diuretics)

Progressive azotemia in a hypertensive patient with known renal artery stenosis treated medically

Progressive azotemia in a patient (usually elderly) with refractory hypertension

Unexplained progressive azotemia in an elderly patient

Hypertension and azotemia in a renal transplant patient

FIGURE 3-24

Atherosclerotic renal artery stenosis inpatients with generalized atherosclerosisobliterans and in patients with coronaryartery disease (CAD). Atherosclerotic renalartery stenosis is common in older patientswith and without hypertension simply as aconsequence of generalized atherosclerosisobliterans. Approximately 40% of consecu-tively studied patients undergoing arteriographyfor routine evaluation of abdominal aorticaneurysm, aorto-occlusive disease, or lowerextremity occlusive disease have associatedrenal artery stenosis (more than 50% unilateralrenal artery stenosis) and nearly 30% ofpatients undergoing coronary angiographymay have incidentally detected unilateralrenal artery stenosis. Approximately 4% to 13% of patients with CAD or peripheralvascular disease have more than 75% bilateralrenal artery stenosis. Correlations of hyper-cholesterolemia and cigarette smoking withrenal artery atherosclerosis are not unequiv-ocally clear, but they probably representrisk factors for renal artery atherosclerosisjust as they represent risk factors foratherosclerosis in other vascular beds.(Adapted from Olin and coworkers [11];with permission.)

FIGURE 3-25

Clinical presentations of ischemic renal disease. The clinical presen-tation of a patient likely to develop renal failure from atheroscle-rotic ischemic renal disease is that of an older (more than 50 years)individual demonstrating progressive azotemia in conjunction withantihypertensive drug therapy, risk factors for generalized athero-sclerosis obliterans, known renal artery disease, refractory hyper-tension, and generalized atherosclerosis. Acute renal failure precipi-tated by a reduction in blood pressure below a “critical perfusionpressure,” and particularly with the use of angiotensin converting-enzyme inhibitors (ACEI) or angiotensin II receptor blockers plusdiuretics, strongly suggests severe intrarenal ischemia from arterio-lar nephrosclerosis and/or severe main renal artery stenosis.

Unexplained progressive azotemia in an elderly patient with clinicalsigns of vascular disease with minimal proteinuria and a bland urinarysediment also suggest ischemic nephropathy. (Adapted fromJacobson [14]; with permission.)


A B

FIGURE 3-26

Mild stenosis (less than 50%) due to athero-sclerotic disease of the left main renal artery(panel A) that has progressed to high-grade(75% to 99%) stenosis on a later arteri-ogram (panel B). Underlying the concept of renal revascularization for preservation of renal function is the notion that athero-sclerotic renal artery disease (ASO-RAD) is a progressive disorder. The sequentialangiograms in Figures 3-26 and 3-27 showangiographic progression of ASO-RAD overtime. In patients demonstrating progressiverenal artery stenosis by serial angiography, adecrease in kidney function as measured byserum creatinine and a decrease in ipsilateralkidney size correlate significantly with pro-gressive occlusive disease. Patients demon-strating more than 75% stenosis of a renalartery are at highest risk for progression tocomplete occlusion. (From Novick [15];with permission.)

FIGURE 3-27

A, Normal right main renal artery and minimal atheroscleroticirregularity of left main renal artery on initial (1974) aortogram.B, Repeat aortography (1978) showed progression to moderate

A B

stenosis of the right main renal artery (arrow) and total occlusionof left main renal artery (arrow). (From Schreiber and coworkers[16]; with permission.)


PREDICTORS OF KIDNEY SALVAGEABILITY

Kidney size >9 cm (laminography)

Function on either urogram or renal flow scan

Filling of distal renal arteries (by collaterals) angiographically, with total proximal occlusion

Glomerular histology on renal biopsy

FIGURE 3-29

Predictors of kidney salvageability. In evaluating patients as candidates for renal revascularization to preserve or improverenal function, some determination should be made of the

A B

FIGURE 3-30

This abdominal aortogram reveals com-plete occlusion of the left main renal artery(panel A) with filling of the distal renalartery branches from collateral supply ondelayed films (panel B). The observationof collateral circulation when the mainrenal artery is totally occluded proximallysuggests viable renal parenchyma. (FromNovick and Pohl [10]; with permission.)

potential for salvable renal function. Clinical clues suggestingrenal viability include 1) kidney size greater than 9 cm (pole-to-pole length) by laminography (tomography); 2) some function of the kidney on either urogram or renal flow scan; 3) filling ofdistal renal arteries (by collaterals) angiographically, when themain renal artery is totally occluded proximally (see Fig. 3-30);and 4) well-preserved glomeruli with minimal interstitial scarring(see Fig. 3-31) on renal biopsy. Patients with moderately severeazotemia, eg, serum creatinine more than 3-4 mg/dL, are likelyto have severe renal parenchymal scarring (see Fig. 3-32), whichrenders improvement in renal function following renal revascu-larization unlikely. Exceptions to this observation are cases oftotal main renal artery occlusion wherein kidney viability ismaintained via collateral circulation (see Figure 3-30). A kidneybiopsy may guide subsequent decision making regarding renalrevascularization for the goal of improving kidney function.

CLINICAL CLUES TO BILATERAL ATHEROSCLEROTICRENOVASCULAR DISEASE

Generalized atherosclerosis obliterans

Presumed renovascular hypertension

Unilateral small kidney

Unexplained azotemia

Deterioration in renal function with BP reduction and/or ACE inhibitor therapy

Flash pulmonary edema

FIGURE 3-28

Clinical clues to bilateral atherosclerotic renovascular disease. The patient at highest risk for developing renal insufficiency fromrenal artery stenosis (ischemic nephropathy) has sufficient arterialstenosis to threaten the entire renal functioning mass. These high-risk patients have high-grade (more than 75%) arterial stenosis to a solitary functioning kidney or high-grade (more than 75%)bilateral renal artery stenosis. Patients with two functioning kidneys with only unilateral renal artery stenosis are not at significant risk for developing renal insufficiency because the

entire renal functioning mass is not threatened by large vesselocclusive disease.

Clinical clues to the high-risk patient are similar to the clinicalpresentations of ischemic renal disease shown in Figure 3-25. Nearly75% of adults with a unilateral small kidney have sustained thisrenal atrophy due to large vessel occlusive disease from atherosclerosis.One third of these patients with a unilateral small kidney havehigh-grade stenosis of the artery involving the contralateral normal-sized kidney. Flash pulmonary edema is another clue to bilateralrenovascular disease or high-grade stenosis involving a solitaryfunctioning kidney. These patients, usually hypertensive and withdocumented coronary artery disease and underlying hypertensiveheart disease, present with the abrupt onset of pulmonary edema.Left ventricular ejection fractions in these patients are not seriouslyimpaired. Flash pulmonary edema is associated with atheroscleroticrenal artery disease and may occur with or without severe hypertension.

Renal revascularization to preserve kidney function or to preventlife-threatening flash pulmonary edema may be considered in patientswith high-grade arterial stenosis to a solitary kidney or high-gradebilateral renal artery stenosis. Pecutaneous transluminal renalangioplasty (PTRA), renal artery stenting, or surgical renal revascu-larization may be employed. Patients with chronic total renal arteryocclusion bilaterally or in a solitary functioning kidney are candidatesfor surgical renal revascularization, but are not candidates (from atechnical standpoint) for PTRA or renal artery stents.


FIGURE 3-31

Renal biopsy of a solitary left kidney in a 67-year-old woman whohad been anuric and on chronic dialysis for 9 months. The biopsyshows hypoperfused retracted glomeruli consistent with ischemia.There is no evidence of active glomerular proliferation or glomerularsclerosis. Note intact tubular basement membranes and negligibleinterstitial scarring. Left renal revascularization resulted in recoveryof renal function and discontinuance of dialysis with improvement inserum creatinine to 2.0 mg/dL. (From Novick [15]; with permission.)

FIGURE 3-32

Pathologic specimen of kidney beyond a main renal artery occlusionin a patient with severe bilateral renal artery stenosis and a serumcreatinine of 4.5 mg/dL. The biopsy demonstrates glomerular scle-rosis, tubular atrophy, and interstitial fibrosis. The magnitude ofglomerular and interstitial scarring predict irreversible loss of kidneyviability. (From Pohl [1]; with permission.)

FIGURE 3-33

Severe atherosclerosis involving the abdominal aorta, renal, and iliac arteries. This abdominalaortogram demonstrates a ragged aorta, total occlusion of the right main renal artery, andsubtotal occlusion of the proximal left main renal artery. Such patients are at high-risk foratheroembolic renal disease following aortography, selective renal arteriography, pecutaneoustransluminal renal angioplasty, renal artery stenting, or surgical renal revascularization.


“Purple toe” syndrome reflecting peripheral atheroembolic disease in the patient in Figure 3-33 (ragged aorta), following an abdominal aortogram.


FIGURE 3-35

Pathologic specimen of kidney demonstrating atheroembolic renaldisease (AERD). Microemboli of atheromatous material are readilyidentified by the characteristic appearance of cholesterol crystalinclusions that appear in a biconvex needle-shaped form. In routineparaffin-embedded histologic sections, the cholesterol is not seenbecause the methods used in preparing sections dissolve the crystals;the characteristic biconvex clefts in the glomeruli (or blood vessels)persist, allowing easy identification. Several patterns of renal failurein patients with AERD are recognized: 1) insult (eg, abdominalaortogram) leads to end-stage renal disease (ESRD) over weeks to months; 2) insult leads to chronic stable renal insufficiency; 3) multiple insults (repeated angiographic procedures) lead to astep-wise rise in serum creatinine eventuating in end-stage renalfailure; and 4) insult leading to ESRD over several weeks tomonths with recovery of some renal function allowing for discontinuance of dialysis.

FIGURE 3-36

Renal biopsy demonstrating severe arteriolar nephrosclerosis.Arteriolar nephrosclerosis is intimately associated with hypertension.The histology of the kidney in arteriolar nephrosclerosis shows considerable variation in intensity and extent of the arteriolarlesions. Thickening of the vessel wall, edema of the smooth musclecells, hypertrophy of the smooth muscle cells, and hyaline degenera-tion of the vessel wall may be apparent depending on the severity ofthe nephrosclerosis. In addition to the vascular lesions of arteriolarnephrosclerosis there are abnormalities of glomeruli, tubules, andinterstitial areas that are believed to be secondary to the ischemiathat results from arteriolar insufficiency. Arteriolar nephrosclerosisis observed in patients with longstanding hypertension; the moresevere the hypertension, the more severe the arteriolar nephrosclerosis.Arteriolar nephrosclerosis may also be seen in elderly normotensiveindividuals and is frequently observed in elderly patients with gener-alized atherosclerosis or essential hypertension.

Nephrosclerosis

Atheroembolism

Atherosclerosis

FIGURE 3-37

Schematic representation of ischemic nephropathy. Patients with atherosclerotic renal artery disease (ASO-RAD) often have coexisting renal parenchymal disease with varying degrees ofnephrosclerosis (small vessel disease) or atheroembolic renal disease. Whether or not the renalinsufficiency is solely attributable to renal artery stenosis, nephrosclerosis, or atheroembolic renaldisease is difficult to determine. The term “ischemic nephropathy” is more complex than beingsimply due to atherosclerotic renal artery stenosis. In addition, in the azotemic patient with ASO-RAD, one should exclude other potential or contributing causes of renal insufficiency such asobstructive uropathy, primary glomerular disease (suggested by heavy proteinuria), drug-relatedrenal insufficiency (eg, nonsteroidal anti-inflammatory drugs), and uncontrolled blood pressure.


36%DM

29%High blood

pressure3%Cyst

5%Urology

12%CGN

4%Miscellaneous

11%Other

FIGURE 3-38

Distribution of endstage renal disease diagnoses. Atherosclerotic renal artery disease (ASO-RAD) has been claimed to contribute to the ESRD population. This diagram from the USRenal Data System Coordinating Center 1994 report indicates that 29% of calendar year1991 incident patients entered ESRD programs because of “hypertension (HBP).” No reno-vascular disease diagnosis is listed. Crude estimates of the percentage of patients enteringESRD programs because of ASO-RAD range from 1.7% to 15%. Precise bases for makingthese estimates are both unclear and confounded by the high likelihood of coexisting arterio-lar nephrosclerosis, type II diabetic nephropathy, and atheroembolic renal disease. ASO-RADas a major contributor to the ESRD population is probably small on a percentage basis, occu-pying some portion of the ESRD diagnosis “hypertension (HBP).” For dialysis-dependentpatients with ASO-RAD, predictors of recovery of renal function following renal revascular-ization and allowing for discontinuance of dialysis (temporary or permanent) include 1) bilat-eral (vs unilateral) renal artery stenosis, 2) a relatively fast rate of decline of estimatedglomerular filtration rate (less than 6 months) prior to initiation of dialysis; and 3) mild-to-moderate arteriolar nephrosclerosis angiographically.

TREATMENT OPTIONS FOR RENOVASCULARHYPERTENSION AND ISCHEMIC NEPHROPATHY

Pharmacologic antihypertensive therapy

PTRA

Renal artery stents

Surgical renal revascularization

FIGURE 3-39

Treatment options for renovascular hypertension and ischemicnephropathy. The main goals in the treatment of renovascular hyper-tension or ischemic nephropathy are to control the blood pressure,to prevent target organ complications, and to avoid the loss of renalfunction. Although the issue of renal function may be viewed asmutually exclusive from the issue of blood pressure control, uncon-trolled hypertension may hasten a decline in renal function, andrenal insufficiency may produce worsening hypertension. Even in thepresence of excellent blood pressure control, progressive arterialstenosis might worsen renal ischemia and promote renal atrophy andfibrosis. Therapeutic options include pharmacologic antihypertensivetherapy, percutaneous transluminal renal angioplasty (PTRA), renalartery stents, and surgical renal revascularization. Pharmacologic anti-hypertensive therapy is covered in more detail separately in this Atlas.

Treatment of Renovascular Hypertension and Ischemic Nephropathy

INCREASING COMORBIDITY IN PATIENTSUNDERGOING RENOVASCULAR SURGERY

Condition

Angina

Prior MI

CHF

Cerebrovascular disease

Diabetes

Claudication

1970–1980

21.4

16.3

12.2

11.2

7.1

35.7

1980–1993

29.9

27.0

23.7*

24.8*

18.1*

56.4*

*P <0.001.

FIGURE 3-40

Comorbidity in patients undergoing renovascular surgery. Patientspresenting for renovascular surgery or endovascular renal revascu-larization are at high-risk for complications during interventionbecause of age, and frequently associated coronary, cerebrovascular,or peripheral vascular disease. As the population ages, the percentageof patients being considered for interventive maneuvers on therenal artery has increased significantly. Approximately 30% ofpatients currently undergoing interventive approaches to renalartery disease have angina, or have had a previous myocardialinfarction. Congestive heart failure, cerebrovascular disease (eg, carotidartery stenosis), diabetes mellitus, and claudication are frequentcomorbid conditions in these patients. Their aortas are often ladenwith extensive atherosclerotic plaque (Fig. 3-33), making angiographicinvestigation or endovascular renal revascularization hazardous.(Adapted from Hallet and coworkers [17]; with permission.)

Comorbidity, %


DIMINISHED OPERATIVE MORBIDITY AND MORTALITY FOLLOWING SURGICALREVASCULARIZATION FOR ATHEROSCLEROTIC RENOVASCULAR DISEASE

Preoperative screening and correction of coronary and carotid artery disease

Avoidance of operation on severely diseased aorta

Unilateral revascularization in patients with bilateral renovascular disease

FIGURE 3-41

Diminished operative morbidity and mortality following surgical revascularization foratherosclerotic renovascular disease. Operative morbidity and mortality in patients under-going surgical revascularization have been minimized by selective screening and/or correc-tion of significant coexisting coronary and/or carotid artery disease before undertakingelective surgical renal revascularization for atherosclerotic renal artery disease. Screeningtests for carotid artery disease include carotid ultrasound and carotid arteriography.Screening tests for coronary artery disease include thallium stress testing, dipyridamolestress testing, dobutamine echocardiography, and coronary arteriography. Aortorenal

bypass with saphenous vein grafting is a frequently used surgical approach inpatients with nondiseased abdominal aortas.Severe atherosclerosis of the abdominalaorta may render an aortorenal bypass orrenal endarterectomy technically difficultand potentially hazardous to perform.Effective alternate bypass techniques includesplenorenal bypass for left renal revascular-ization, hepatorenal bypass for right renalrevascularization, ileorenal bypass, benchsurgery with autotransplantation, and useof the supraceliac or lower thoracic aorta(usually less ravaged by atherosclerosis).Simultaneous aortic replacement and renalrevascularization are associated with anincreased risk of operative mortality incomparison to renal revascularization alone.Some surgeons advocate unilateral renalrevascularization in patients with bilateralrenovascular disease.

DC

BA

FIGURE 3-42

Schematic diagram of alternate bypassprocedures. A, Hepatorenal bypass toright kidney. B, Splenorenal bypass to leftkidney. C, Ileorenal bypass to left kidney.D, Autotransplantation.


A B

FIGURE 3-43

Percutaneous transluminal renal angioplasty (PTRA) of the renal artery.A, High-grade (more than 75%) nonostial atherosclerotic stenosis of theleft main renal artery in a patient with a solitary functioning kidney (rightrenal artery totally occluded). Note gradient of 170 mm Hg across thestenotic lesion. B, Balloon angioplasty of the left main renal artery wassuccessfully performed with reduction in the gradient across the stenoticlesion from 170 mm Hg pre-PTRA to 15 mm Hg post-PTRA. Repeataortogram 3 years later demonstrated patency of the left renal artery.

PTRA of the renal artery has emerged as an important inter-ventional modality in the management of patients with renalartery stenosis. PTRA is most successful and should be the initialinterventive therapeutic maneuver for patients with the medialfibroplasia type of fibrous renal artery disease (eg, Fig.3-5A).Excellent technical success rates have also been attained fornonostial atherosclerotic lesions of the main renal artery, asshown here.

FIGURE 3-44

High-grade athero-sclerotic renal arterystenosis at theostium of the rightmain renal artery ina 68-year-old manwith a totallyoccluded left mainrenal artery. Severalattempts at balloondilatation wereunsuccessful. Overthe subsequent 10days, severe renalinsufficiency devel-oped (serum creati-nine increasing from2.0 to 12.0 mg/dL)requiring dialysis.Renal function neverimproved and thepatient remained on dialysis.

FIGURE 3-45

Palmaz stent, expanded. Because percutaneous transluminal renalangioplasty (PTRA) has suboptimal long-term benefits for athero-sclerotic ostial renal artery stenosis, endovascular stenting has gainedwide acceptance. Renal artery stenting may be performed at the timeof the diagnostic angiogram, or at some time thereafter, dependingon the physician’s preference and the risk to the patient of repeatedangiographic procedures. From a technical standpoint, indicationsfor renal artery stenting include 1) as a primary procedure for ostialatherosclerotic renal artery disease (ASO-RAD), 2) technical difficul-ties in conjunction with attempted PTRA, 3) post-PTRA dissection,4) post-PTRA abrupt occlusion, and 5) restenosis following PTRA. It is unclear what the long-term patency and restenosis rates will befor renal artery stenting for ostial disease. Preliminary observationssuggest that the 1-year patency rate for stents is approximately twicethat for PTRA.


A. SURGICAL REVASCULARIZATION VERSUS PTRAFOR ATHEROSCLEROTIC RENAL ARTERY DISEASE

Lesion

Nonostial

(20%)

Ostial

(80%)

Successful PTRA, %

80–90

25–30

Successful surgical revascularization, %

90

90

FIGURE 3-46

Abdominal aortogram in a 63-year-old male, 6 months following placement of a Palmazstent. Note wide patency of the left main renal artery.

B. SURGICAL REVASCULARIZATION VERSUS PTRA FOR FIBROUS RENAL ARTERY DISEASE

Lesion

Main

(50%)

Branch

(50%)

Successful PTRA, %

80–90

NA

Successful surgicalrevascularization, %

90

90

FIGURE 3-47

Surgical revascularization vs percutaneous transluminal renalangioplasty (PTRA) for renal artery disease. A, Success rates foratherosclerotic renal artery disease (ASO-RAD). B, Success ratesfor fibrous renal artery disease. Success of either PTRA or surgi-cal renal revascularization is viewed in terms of “technical” suc-cess and “clinical” success. For PTRA, technical success reflectsa lumen patency with less than 50% residual stenosis (ie, suc-cessful establishment of a patent lumen). For surgical revascular-ization, technical success is the demonstration of good bloodflow to the revascularized kidney determined during surgery, orpostoperatively by DPTA renal scan or other immediate postop-erative imaging procedures. Technical success with either PTRAor surgical revascularization is rarely defined by postoperativeangiography. “Clinical” success may be defined as improvedblood pressure or improvement in kidney function, and/or reso-lution of flash pulmonary edema. Technical and clinical success-es do not necessarily occur together because technical successmay be apparent, but without improvement in blood pressure or renal function.

The “percent success” for PTRA and surgical revascularizationdepicted above are estimates, and reflect primarily “technical” successfor both nonostial and ostial lesions in ASO-RAD. Technical successrates for surgical revascularization are high, approximating 90%,with little difference in the technical success rates between ostialand nonostial lesions. For PTRA, technical success rates are muchhigher for nonostial lesions. There is a high rate of restenosis at 1year (≈50% to 70%) for ostial ASO-RAD, which has promoted theuse of renal artery stents for these lesions.

The success rates of surgical renal revascularization and PTRAfor stenosis of the main renal artery in fibrous renal artery diseaseare comparable, approximately 90%. Hypertension is more pre-dictably improved with surgical revascularization and PTRA infibrous renal artery disease in comparison with ASO-RAD. Technicalsuccess rates with surgical renal revascularization are high forbranch fibrous renal artery disease, but long-term technical andclinical success rates are not available for PTRA of branch lesionsdue to fibrous dysplasia. NA—not available. (Adapted from Pohl[18]; with permission.)


COMPLICATIONS OF TRANSLUMINAL ANGIOPLASTY OF THE RENAL ARTERIES

Contrast-induced ARF (mild or severe)

Atheroembolic renal failure

Rupture of the renal artery

Dissection of the renal artery

Thrombotic occlusion of the renal artery

Occlusion of a branch renal artery

Balloon malfunction (may lead to inability to remove balloon)

Balloon rupture

Puncture site hematoma, hemorrhage, or vessel tear

Median nerve compression (axillary approach)

Renal artery spasm

Mortality (≤1%)

FIGURE 3-48

Complications of transluminal angioplasty of the renal arteries.The more common complications of PTRA are contrast-inducedacute renal failure (ARF) and atheroembolic renal failure.Dissection of the renal artery, occlusion of a branch renal artery,and occasionally thrombotic occlusion of the main renal arterymay occur. In experienced hands, rupture of the renal artery israre. Minor complications relate primarily to the puncture site.When the axillary approach is used (because of severe iliac andlower abdominal aortic atherosclerosis), median nerve compressionmay transpire. Some of these complications of percutaneous trans-luminal renal angioplasty, particularly atheroembolic renal failureand/or contrast-induced acute renal failure (ARF) may also beobserved with renal artery stent procedures.

FACTORS TO CONSIDER IN SELECTION OF TREATMENTFOR PATIENTS WITH RENAL ARTERY DISEASE

Is renal artery disease causing hypertension?

Severity of hypertension

Specific type of renal artery disease and threat to renal function

General medical condition of patient

Relative efficacy and risk of medical antihypertensive therapy, PTRA, renal artery stenting, surgical revascularization

FIGURE 3-49

Selection of treatment for patients with renal artery disease. Inselecting treatment options for patients with renal artery disease,there are several factors to consider: what is the likelihood thatthe renal artery disease is causing the hypertension? For patientswith fibrous renal artery disease the likelihood is high; for patientswith atherosclerotic renal artery disease (ASO-RAD), the likeli-hood for a cure of hypertension is small. The more severe thehypertension, the greater the inclination to intervene with eithersurgery or balloon angioplasty. For children, adolescents, andyounger adults, most of whom will have fibrous renal artery dis-ease, intervention is usually recommended to avoid lifelong anti-hypertensive therapy. Cardiovascular comorbidity is high forpatients with ASO-RAD and appropriate caution in approachingthese patients is warranted, weighing the relative efficacy and riskof medical antihypertensive therapy, percutaneous transluminalrenal angioplasty (PTRA), renal artery stenting, and surgicalrevascularization. Local experience and expertise of the treatingphysicians must be considered as well in selection of treatmentoptions for these patients.

References

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3. Brown JJ, Davies DL, Morton JJ, et al.: Mechanism of renal hyper-tension. Lancet 1976, 1:1219–1221.

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5. Olin JW, Piedmonte MR, Young JR, et al.: The utility of duplexultrasound scanning of the renal arteries for diagnosing significantrenal artery stenosis. Ann Intern Med 1995, 122:833–838.

6. Muller FB, Sealey JE, Case DB, et al.: The captopril test for identifying ren-ovascular disease in hypertensive patients. Am J Med 1986, 80:633–644.

7. Nally JV, Olin JW , Lammert MD: Advances in noninvasive screening forrenovascular hypertension disease. Cleve Clin J Med 1994, 61:328–336.

8. Mann SJ, Pickering TG: Detection of renovascular hypertension: stateof the art: 1992. Ann Intern Med 1992, 117:845–853.

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Textor SC: Renovascular hypertension. Curr Opin Nephrol Hyperten1993, 2:775–783.

Working Group on Renovascular Hypertension: Detection, evaluation, andtreatment of renovascular hypertension. Final report. Arch Intern Med1987, 147:820–829.

Hughes JS, Dove HG, Gifford RW Jr, Feinstein AR: Duration of bloodpressure elevation in accurately predicting surgical cure of renovascularhypertension. Am Heart J 1981, 101:408–413.

Svetkey LP, Himmelstein SI, Dunnick NR, et al.: Prospective analysis ofstrategies for diagnosing renovascular hypertension. Hypertension1989, 14:247–257.

Setaro JF, Saddler MC, Chen CC, et al.: Simplified captopril renographyin diagnosis and treatment of renal artery stenosis. Hypertension1991, 18:289–298.

Novick AC, Pohl MA, Schreiber M, et al.: Revascularization for preservationof renal function in patients with atherosclerotic renovascular disease.J Urol 1983, 129:907–912.

Gifford RW Jr, McCormack LJ, Poutasse EF: The atrophic kidney: its rolein hypertension. Mayo Clin Proc 1965, 40:834–852.

Pickering TG, Herman L, Devereux RB, et al.: Recurrent pulmonary oedemain hypertension due to bilateral renal artery stenosis: treatment byangioplasty or surgical revascularisation. Lancet 1988, 2:551–552.

United States Renal Data System Coordinating Center: Incidence and causesof treated ESRD. In The USRDS 1994 Annual Data Report. Editedby Agodoa LYC, Held PJ, Port FK. Bethesda: USRDS CoordinatingCenter; 1994:43–54.

Mailloux LU, Napolitano B, Bellucci AG, et al.: Renal vascular diseasecausing end-stage renal disease, incidence, clinical correlates, and outcomes: a 20-year clinical experience. Am J Kidney Dis 1994,24:622–639.

Appel RG, Bleyer AJ, Reavis S, Hansen KJ: Renovascular disease in olderpatients beginning renal replacement therapy. Kidney Int 1995,48:171–176.

Hansen KJ, Thomason RB, Craven TE, et al.: Surgical management of dialysis-dependent ischemic nephropathy. J Vasc Surg 1995, 21:197–209.

Hallett JW Jr, Fowl R, O’Brien PC, et al.: Renovascular operations inpatients with chronic renal insufficiency: do the benefits justify therisks? J Vasc Surg 1987, 5:622–627.

Conlon PJ, Athirakul K, Kovalik E, et al.: Survival in renal vascular disease.J Am Soc Nephrol 1998, 9:252–256.

Textor SC, McKusick MA, Schirger AA, et al.: Atherosclerotic renovasculardisease in patients with renal failure. Adv Nephrol Necker Hosp1997, 27:281–295.

Novick AC, Straffon RA, Stewart BH, et al.: Diminished operative morbidityand mortality in renal revascularization. JAMA 1981, 246:749–753.

Khauli RB, Novick AC, Ziegelbaum M: Splenorenal bypass in the treatmentof renal artery stenosis: experience with sixty-nine cases. J Vasc Surg1985, 2:547–551.

Chibaro EA, Libertino JA, Novick AC: Use of the hepatic circulation forrenal revascularization. Ann Surg 1984, 199:406–411.

Novick AC, Stewart R: Use of the thoracic aorta for renal revascularization.J Urol 1990, 143:77–79.

Tarazi RY, Hertzer NR, Beven EG, et al.: Simultaneous aortic reconstructionand renal revascularization: risk factors and late results in eighty-ninepatients. J Vasc Surg 1987, 5:707–714.

Hollenberg NK: Medical therapy of renovascular hypertension: efficacy andsafety of captopril in 269 patients. Cardiovasc Rev Rpts 1983, 4:852–879.

Pohl MA: Medical management of renovascular hypertension. In RenalVascular Disease. Edited by Novick AC, Scoble J, Hamilton G.London: WB Saunders; 1996, 339–349.

Palmaz JC, Kopp DT, Hayashi H, et al.: Normal and stenotic renal arteries:Experimental balloon-expandable intraluminal stenting. Radiology1987, 164:705–708.

Blum U, Krumme B, Flugel P, et al.: Treatment of ostial renal-arterystenoses with vascular endoprostheses after unsuccessful balloonangioplasty. N Engl J Med 1997, 336:459–465.

Harden PN, MacLeod MJ, Rodger RSC, et al.: Effect of renal-arterystenting on progression of renovascular renal failure. Lancet 1997,349:1133–1136.

Fiala LA, Jackson MR, Gillespie DL, et al.: Primary stenting of atheroscleroticrenal artery ostial stenosis. Ann Vasc Surg 1998, 12:128–133.

Canzanello VJ, Millan VG, Spiegel JE, et al.: Percutaneous transluminalrenal angioplasty in management of atherosclerotic renovascularhypertension: results in 100 patients. Hypertension 1989,13:163–172.

Plouin PF, Chatellier G, Darne B, Raynaud A, for the Essai MulticentriqueMedicaments vs. Angioplastie (EMMA) Study Group: Blood pressureoutcome of angioplasty in atherosclerotic renal artery stenosis: a randomized trial. Hypertension 1998, 31:823–829.

Textor SC: Revascularization in atherosclerotic renal artery disease [clinical conference]. Kidney Int 1998, 53:799–811.

4

Adrenal Causes ofHypertension

The adrenal gland is involved in the production of a variety ofsteroid hormones and catecholamines that influence bloodpressure. Thus, it is not surprising that several adrenal disorders

may result in hypertension. Many of these disorders are potentiallycurable or responsive to specific therapies. Therefore, identifyingadrenal disorders is an important consideration when elevated bloodpressure occurs suddenly or in a young person, is severe or difficult totreat, or is associated with manifestations suggestive of a secondaryform of hypertension. Because these occurrences are relatively rare, itis necessary to have a high index of suspicion and understand thepathophysiology on which the diagnosis and treatment of these problemsis based.

Three general forms of hypertension that result from excessive produc-tion of mineralocorticoids, glucocorticoids, or catecholamines are reviewedin the context of their normal production, metabolism, and feedbacksystems. The organization of this chapter provides the background forunderstanding the normal physiology and pathophysiologic changeson which effective screening and diagnosis of adrenal abnormalities arebased. Therapeutic options also are briefly considered. Primary aldos-teronism, Cushing’s syndrome, and pheochromocytoma are discussed.

Myron H. Weinberger

C H A P T E R


Adrenal Hypertension

PHYSIOLOGIC MECHANISMS IN ADRENAL HYPERTENSION

Disorder

Primary aldosteronism

Cushing’s syndrome

Pheochromocytoma

Cause

Autonomous hypersecretionof aldosterone (hyperminer-alocorticoidism)

Hypersecretion of cortisol(hyperglucocorticoidism)

Hypersecretion of catecholamines

Pathophysiology

Increased renal sodium andwater reabsorption,increased urinary excretion of potassiumand hydrogen ions

Increased activation of mineralocorticoid receptor (?), increasedangiotensinogen (reninsubstrate) concentration

Vasoconstriction, increasedheart rate

Pressure mechanism

Extracellular fluid volumeexpansion, hypokalemia(?), alkalosis

Extracellular fluid volumeexpansion (?), increasedangiotensin II (vasocon-striction and increasedperipheral resistance)

Increased peripheral resistance, increased cardiac output

FIGURE 4-1

The causes and pathophysiologies of thethree major forms of adrenal hypertensionand the proposed mechanisms by whichblood pressure elevation results.

Histology of the Adrenal

Capsule

Zona

glomerulosa

Zona

fasciculata

Zona

reticularis

Medulla

Normal human

suprarenal gland

Human suprarenal

gland after

administration

of crude ACTH

FIGURE 4-2

Histology of the adrenal. A cross section of the normal adrenalbefore (left) and after (right) stimulation with adrenocorticotropichormone (ACTH) [1]. The adrenal is organized into the outeradrenal cortex and the inner adrenal medulla. The outer adrenalcortex is composed of the zona glomerulosa, zona fasciculata, andzona reticularis. The zona glomerulosa is responsible for produc-tion of aldosterone and other mineralocorticoids and is chieflyunder the control of angiotensin II (see Figs. 4-3 and 4-5). Thezona fasciculata and zona reticularis are influenced primarily byACTH and produce glucocorticoids and some androgens (see Figs.4-3 and 4-19). The adrenal medulla produces catecholamines andis the major source of epinephrine (in addition to the organ ofZuckerkandl located at the aortic bifurcation) (see Fig. 4-25.)

4.3Adrenal Causes of Hypertension

Adrenal Steroid Biosynthesis

17-HydroxypregnenolonePregnenolone Dehydroepiandrosterone

CH3

CH3

C=OC=OOH

OHOH

17-Hydroxypregnenolone

CH3

C=O–OH

OO

OH

OHOH

Pregnenolone

CH3

C=O

O

11-Deoxycortisol

CH2OH

C=OOH

O11-Deoxycorticosterone

OH2OH

C=O

O

Cortisol

CH2OH

C=OOH

OCorticosterone

18-Hydroxylase18-OH-Dehrydrogenase

CH2OH

C=O

O

OH

Aldosterone

CH2OH

C=O

O

O

∆4 Androstene 3,17-dione

O

OHC

21-Hydroxylase

11β-Hydroxylase

3 β-OH-Dehydrogenase: ∆5 ∆4 Isomerase

17α−H

ydro

xylase

Zonaglomerulosa

only}

FIGURE 4-3

Adrenal steroid biosynthesis. The sequence ofadrenal steroid biosynthesis beginning withcholesterol is shown as are the enzymesresponsible for production of specific steroids[2]. Note that aldosterone production nor-mally occurs only in the zona glomerulosa(see Fig. 4-2). (From DeGroot and coworkers[2]; with permission.)


Morning 6 AM Noon 6 PM Morning

Aldosterone

Cortisol

PRA

ACTH

FIGURE 4-4

Circadian rhythmicity of steroid production and major stimulatoryfactors. Aldosterone and cortisol and their respective major stimulatoryfactors, plasma renin activity (PRA) and adrenocorticotropic hormone(ACTH), demonstrate circadian rhythms. The lowest values for all ofthese components are normally seen during the sleep period when theneed for active steroid production is minimal. ACTH levels increaseearly before awakening, stimulating cortisol production in prepara-tion for the physiologic changes associated with arousal. PRA increas-es abruptly with the assumption of the upright posture, followed byan increase in aldosterone production and release. Both steroidsdemonstrate their highest values through the morning and early after-noon. Cortisol levels parallel those of ACTH, with a marked declinein the afternoon and evening hours. Aldosterone demonstrates abroader peak, reflecting the postural stimulus of PRA.

↓Perfusion pressure

↓Sodium content

↑Extracellular fluid volume

↑Sodium reabsorption

Aldosterone

Juxtaglomerularapparatus

Renin

Angiotensin II

Adrenal complex

Zona glomerulosa

K+ ACTH

↑Perfusion pressure

↑Sodium content

↑Extracellular fluid volume

↑Sodium reabsorption

Aldosterone

Juxtaglomerularapparatus

Renin

Angiotensin II

Adrenal complex

Zona glomerulosa

K+ ACTH

Kidney Kidney

1 9

6 12

2 10

11

14 13

5 8

4 7

A BNormal Primary aldosteronism

FIGURE 4-5

Control of mineralocorticoid production. A, Control of aldosterone production under normal circumstances.A decrease in renal perfusion pressure or tubular sodium content (1) at the level of the juxtaglomerular apparatusand macula densa of the kidney triggers renin release (2). Renin acts on its substrate angiotensinogen to generateangiotensin I, which is converted rapidly by angiotensin-converting enzyme to angiotensin II. Angiotensin IIthen induces peripheral vasoconstriction to increase perfusion pressure (6) and acts on the zona glomerulosaof the adrenal cortex (3) (see Fig. 4-2) to stimulate production and release of aldosterone (4). Potassium andadrenocorticotropic hormone (ACTH) also play a minor role in aldosterone production in some circumstances.Aldosterone then acts on the cells of the collecting duct of the kidney to promote reabsorption of sodium (andpassively, water) in exchange for potassium and hydrogen ions excreted in the urine. This increased secretionpromotes expansion of extracellular fluid volume and an increase in renal tubular sodium content (5) that furthersuppresses renin release, thus closing the feedback loop (servomechanism). B, Abnormalities present in primaryaldosteronism. Autonomous hypersecretion of aldosterone (7) leads to increased extracellular fluid volumeexpansion and increased renal tubular sodium content. These elevated levels are a result of increased renal

sodium and water reabsorption (8) at theexpense of increasedpotassium and hydrogenion excretion in theurine. The increase insodium and volume thenincrease systemic bloodpressure and renal perfusion pressure andsodium content (9),thereby suppressing further renin release(10) and angiotensin IIproduction (11). Thus,in contrast to the nor-mal situation depicted in panel A, the levels ofangiotensin II are highlysuppressed and thereforedo not contribute to anincrease in systemicblood pressure (12). Inprimary aldosteronism,ACTH (13) has a domi-nant modulatory role ininfluencing aldosteroneproduction and hypo-kalemia, resulting fromincreased urinary potas-sium exchange for sodium, which has anegative effect on aldos-terone production (14).


FIGURE 4-6

Types of primary aldosteronism. (Data from Weinberger andcoworkers [3].)

Aldosteronism

TYPES OF PRIMARY ALDOSTERONISM

Relative frequency, %

65

30

2

<1

<1

<1

Types

Solitary adrenal adenoma

Bilateral adrenal hyperplasia

Unilateral adrenal hyperplasia

Glucocorticoid-remediable aldosteronism

Bilateral solitary adrenal adenomas

Adrenal carcinoma

SCREENING TESTS FOR PRIMARY ALDOSTERONISM

Specificity, %

≈20

40–60

60

60

98

100

Sensitivity, %

75

>99

70

90

99.8

96

Test

Serum potassium ≤3.5 mEq/L

Plasma renin activity ≤4 ng/mL/90 min

Urinary aldosterone ≥20 µg/d

Plasma aldosterone ≥15 ng/dL

Plasma aldosterone–plasma renin activity ratio ≥15

Plasma aldosterone–plasma renin activity ratio ≥30

FIGURE 4-7

Screening tests for primary aldosteronism. Serum potassium levelsrange from 3.5 to normal levels of patients with primary aldostero-nism. Most hypertensive patients with hypokalemia have secondaryrather than primary aldosteronism. The plasma aldosterone-to-plas-ma renin activity (PRA) ratio (disregarding units of measure) is themost sensitive and specific single screening test for primary aldos-teronism. However, because of laboratory variability, normal rangesmust be developed for individual laboratory values. A randomperipheral blood sample can be used to obtain this ratio even whilethe patient is receiving antihypertensive medications, when theeffects of the medications on PRA and aldosterone are considered.(Data from Weinberger and coworkers [3,4].)

LOCALIZING TESTS FOR PRIMARY ALDOSTERONISM

Specificity, %

≈60

≈65

≈80

?

>95

Sensitivity, %

≈50

≈50

≈70

?

>92

Test

Adrenal computed tomographic scan

Adrenal isotopic scan

Adrenal venography

Adrenal magnetic resonance imaging

Adrenal venous blood sampling withadrenocorticotropic hormone infusion

FIGURE 4-8

Localizing tests for primary aldosteronism. Adrenal venous bloodsampling with determination of both aldosterone and cortisol concentrations during adrenocorticotropic hormone stimulationprovides the most accurate way to identify unilateral hyperaldos-teronism. This approach minimizes artefact owing to episodicsteroid secretion and to permit correction for dilution of adrenalvenous blood with comparison of values to those in the inferiorvena cava. (see Fig. 4-12). (Data from Weinberger and coworkers [3].)

A

FIGURE 4-9

Normal and abnormal adrenal isotopic scans. A, Normal scan.Increased bilateral uptake of I131-labeled iodo-cholesterol of nor-mal adrenal tissue is shown above the indicated renal outlines.



B


B, Intense increase in isotopic uptake by the left adrenal (as viewedfrom the posterior aspect) containing an adenoma.

A B

FIGURE 4-10

Adrenal venography in primary aldostero-nism. A, Typical leaflike pattern of the nor-mal right adrenal venous drainage. B, Incontrast, marked distortion of the normalvenous anatomy by a relatively large (3-cm-diameter) adenoma of the left adrenal.Most solitary adenomas responsible for pri-mary aldosteronism are smaller than 1 cmin diameter and thus usually cannot be seenusing anatomic visualizing techniques.

0

10

20

30

40

50

60

8 AM

SupineNoon

Upright8 AM

SupineNoon

Upright8 AM

SupineNoon

Upright

Normal Adenoma Hyperplasia

Pla

sma

ald

ost

ero

ne,

ng/

dL

A B C

In normal persons the increase in plasmarenin activity associated with upright postureresults in a marked increase in plasma aldos-terone at noon compared with that at 8 AM

(see Fig. 4-4). In adenomatous primaryaldosteronism, the plasma renin activity ismarkedly suppressed and does not increaseappreciably with upright posture. Moreover,aldosterone production is modulated byadrenocorticotropic hormone (which decreasesfrom high levels at 8 AM to lower values atnoon (see Fig. 4-4). Thus, these patientstypically demonstrate lower levels of aldos-terone at noon than they do at 8 AM. Inpatients with bilateral adrenal hyperplasia,the plasma renin activity tends to be moreresponsive to upright posture and aldos-terone production also is more responsiveto the renin-angiotensin system. Thus, pos-tural increases in aldosterone usually areseen. Exceptions to these changes occur inboth forms of primary aldosteronism, how-ever, making the postural test less sensitiveand specific [3].

FIGURE 4-11

Changes in plasma aldosterone with upright posture. A–C, Depicted are individual datafor persons showing temporal and postural changes in plasma aldosterone concentrationin normal persons (panel A), and in patients with primary aldosteronism owing to a solitaryadrenal adenoma (panel B) or to bilateral adrenal hyperplasia (panel C). Blood is sampledat 8 AM, while the patient is recumbent, and again at noon after 4 hours of ambulation.


ACTH ACTH

AC

AC

AC

A Bilateral aldosteronism

ACTH ACTH

AC

AC

AC

B Unilateral aldosteronism

FIGURE 4-12

Adrenal venous blood sampling during infusion of adrenocortico-tropic hormone (ACTH) [3]. A, Bilateral aldosteronism. A schematicrepresentation of the findings in primary aldosteronism owing tobilateral adrenal hyperplasia is shown on the left. When blood issampled from both adrenal veins and the inferior vena cava duringACTH infusion, the aldosterone-to-cortisol ratio is similar in bothadrenal effluents and higher than that in the inferior vena cava. Insuch cases, medical therapy (potassium-sparing diuretic combinationssuch as hydrochlorothiazide plus triamterene, amiloride, or spiro-lactone and calcium channel entry blockers) usually is effective. B,Unilateral aldosteronism. On the right is depicted the findings in apatient with a unilateral right adrenal lesion. This lesion can bediagnosed by an elevated aldosterone-to-cortisol ratio in right adrenal

venous blood compared with that of the left adrenal and the inferiorvena cava. Even if the venous effluent cannot be accurately sampledfrom one side (as judged by the levels of cortisol during ACTHinfusion), when the contralateral adrenal venous effluent has analdosterone-to-cortisol ratio lower than that in the inferior venacava, it can be inferred that the unsampled side is the source ofexcessive aldosterone production (unless there is an ectopic source).In such cases, surgical removal of the solitary adrenal lesion usuallyresults in normalization of blood pressure and the attendant metabolicabnormalities. Medical therapy also is effective but often requireshigh doses of Aldactone® (GD Searle & Co., Chicago) (200 to 800mg/d), which may be intolerable for some patients because of sideeffects. A—aldosterone; C—cortisol.


0 1 2 3 4 5 6 0 2 4 640

60

80

100

120

140

160

8

40

60

80

100

120

140

160

60

80

100

120

140

160

180

200100

200100

200100

SpironolactoneDexamethasone

mg

Father

Son 1

Son 2

Blo

od

pre

ssu

re

A

B

CWeeks Months

FIGURE 4-14

Glucocorticoid-remediable aldosteronism. A–C, Seen are the effectsof dexamethasone and spironolactone on blood pressure in a father(panel A) and two sons, one aged 6 years (panel B) and the otheraged 8 years (panel C). Blood pressure levels are shown before andafter treatment with dexamethasone (left) or spironolactone (right) [5].Note that the maximum blood pressure reduction with dexamethasonerequired more than 2 weeks of treatment. Similarly, the maximumresponse to spironolactone was both time- and dose-dependent.


A section of a typical adrenal adenoma in primary aldosteronismpathology. A relatively large (2-cm-diameter) adrenal adenomawith its lipid-rich (bright yellow) content is shown.


0 1 2 3 4

0

1.0

0.8

0.6

0.4

0.2

5

0 1 2 3 4

5

10

15

20

25

5 0 1 2 3 4

5

10

15

20

25

5

0 1 2 3 4

10

20

30

40

50

5 0 1 2 3 4

3

4

5

6

7

Changes with dexamethasone

Dexamethasone

Plas

ma

ald

ost

ero

ne,

ng

/100

mL

Seru

m p

ota

ssiu

m, m

Eq/L

Plas

ma

ren

in a

ctiv

ity,

ng

AI/

mL-

3hr

Plas

ma

cort

iso

l,µg

/ 10

0 m

L

Uri

nar

y al

do

ster

on

e,µg

/ 24

h

Weeks

C D

A B

E

FIGURE 4-15

Humoral changes in glucocorticoid-remediable aldosteronism with dexamethasone. A–E, Depicted are the changesin plasma cortisol (panel A), urinary aldosterone (panel B), plasma renin activity (PRA) (panel C), plasma aldos-terone (panel D), and serum potassium (panel E) before and after dexamethasone administration in the patients in Figure 4-14. Note that before dexamethasone administration, serum cortisol was in the normal range and wasmarkedly suppressed after treatment. Urinary aldosterone was completely normal and plasma aldosterone was

elevated in only onepatient before dexametha-sone administration. Thediagnosis was made bydemonstrating that the plasma aldosteroneconcentration failed tosuppress normally afterintravenous saline infu-sion (2 L/4 h) [6]. Afterdexamethasone adminis-tration, both plasma andurinary aldosterone levelsdecreased markedly(except for one occasionwhen it is suspected thatthe patient did not com-ply with dexamethasonetherapy). PRA, which wasmarkedly suppressedbefore treatment,increased with dexa-methasone. Note also that serum potassium levels were normal in two of the three patientsbefore treatment withdexamethasone butincreased with therapy in all three [5]. All ofthese changes reverted tocontrol baseline valueswhen dexamethasonetherapy was discontinued.

Aldosterone Aldosterone

Aldosterone+

18–OH cortisol+

18–OXO cortisol

Cortisol

ACTH

AII

ACTH

AII

Cortisol+

Fasciculata Fasciculata

Glomerulosa Glomerulosa

Aldosterone Aldosterone

ChimericAldos

A B

FIGURE 4-16

Normal and chimeric aldosterone synthasein glucocorticoid-remedial aldosteronism(GRA). A, Normal relationship between thestimuli and site of adrenal cortical steroidproduction. Aldosterone synthase normallyresponds to angiotensin II (AII) in the zonaglomerulosa, resulting in aldosterone synthe-sis and release (see Figs. 4-2 and 4-3). B, InGRA, a chimeric aldosterone synthase generesults from a mutation, which stimulatesproduction of aldosterone and other steroidsfrom the zona glomerulosa under the controlof adrenocorticotropic hormone (ACTH)(Fig. 4-17). Thus, when ACTH production issuppressed by steroid administration, aldos-terone production is reduced.


3'5'3'5'3'5'

3'5' 3'5'

3'5'3'5'

11–OHase

Aldosterone synthase Chimeric gene 11–OHase

Unequal crossing over

FIGURE 4-17

Mutation of the (11-OHase) chimeric aldosterone synthase gene[8]. The unequal crossing over between aldosterone synthase and11-hydroxylase genes resulting in the mutated gene responsible forglucocorticoid-remedial aldosteronism is described.

Cushing’s Syndrome

A

B


Physical characteristics of Cushing’s syndrome. A, Side profile of a patient with Cushing’ssyndrome demonstrating an increased cervical fat pad (so-called buffalo hump), abdominalobesity, and thin extremities and petechiae (on the wrist). The round (so-called moon)facial appearance, plethora, and acne cannot be seen readily here. B, Violescent abdominalstriae in a patient with Cushing’s syndrome. Such striae also can be observed on the innerparts of the legs in some patients.


Pituitary

ACTH Cortisol

CRF

(–) (–)

Adrenal cortex(zona fasciculatazona reticularis)

Pituitary

ACTH ↑ Cortisol


Pituitary

↑ ACTH ↑ Cortisol


(–)

FIGURE 4-19

Normal pituitary-adrenal axis. Corticotropin-releasing factor (CRF) acts to stimulate therelease of adrenocorticotropic hormone(ACTH) from the anterior pituitary. ACTHthen stimulates the adrenal zona fasciculataand zona reticularis to synthesize and releasecortisol (see Figs. 4-2 and 4-3). The increasedlevels of cortisol feed back to suppress addi-tional release of ACTH. As shown in Figure4-4, ACTH and cortisol have circadian patterns.

FIGURE 4-20

Pituitary Cushing’s disease. Pituitary Cushing’sdisease results from excessive production ofadrenocorticotropic hormone (ACTH), typ-ically owing to a benign adenoma. ExcessACTH stimulates both adrenals to produceexcessive amounts of cortisol and results inbilateral adrenal hyperplasia. The increasedcortisol production does not suppress ACTHrelease, however, because the pituitary tumoris unresponsive to the normal feedback sup-pression of increased cortisol levels. Thediagnosis usually is made by demonstrationof elevated levels of ACTH in the face ofelevated cortisol levels, particularly in theafternoon or evening, representing loss ofthe normal circadian rhythm (see Fig. 4-4).Radiographic studies of the pituitary (com-puted tomographic scan and magnetic reso-nance imaging) will likely demonstrate thesource of increased ACTH production. Whenthe pituitary is the source, surgery and irra-diation are therapeutic options.

FIGURE 4-21

Adrenal Cushing’s syndrome. AdrenalCushing’s syndrome typically is caused by a solitary adrenal adenoma (rarely by carci-noma) producing excessive amounts of cortisol autonomously. The increased levelsof cortisol feed back to suppress release ofadrenocorticotropic hormone (ACTH) andcorticotropin-releasing factor. The findingof very low ACTH levels in the face of elevated cortisol values and a loss of thecircadian pattern of cortisol confirm thediagnosis (see Fig. 4-4). Additional anatomicstudies of the adrenal (computed tomographicscan and magnetic resonance imaging) usuallydisclose the source of excessive cortisol pro-duction. Surgical removal usually is effective.


Pituitary

ACTH

ACTH

Cortisol


EctopicTumor

Cushing's syndrome: ectopic etiology

(–)

SCREENING TESTS FOR CUSHING’S SYNDROME

Sensitivity, %

≈75

>90

>95

Specificity, %

≈60

≈60

>95

Test

Elevated PM serum cortisol

Elevated urinary 17-hydroxy corticosteroids

Elevated urinary free cortisol

FIGURE 4-22

Ectopic etiology of Cushing’s syndrome. Rarely, Cushing’s syn-drome may be due to ectopic production of adrenocorticotropichormone (ACTH) from a malignant tumor, often in the lung. Insuch cases, hypercortisolism is associated with increased levels ofACTH-like peptide; however, no pituitary lesions are found.Patients with ectopic Cushing’s syndrome often are wasted andhave other manifestations of malignancy.

FIGURE 4-23

Screening tests for Cushing’s syndrome. Whereas elevated eveningplasma cortisol levels typically indicate abnormal circadian rhythm,other factors such as stress also can cause increased levels late inthe day. Urinary levels of 17-hydroxy corticosteroids may beincreased in association with obesity. In such cases, repeat measure-ment after a period of dexamethasone suppression may be requiredto distinguish this form of increased glucocorticoid excretion fromCushing’s syndrome. The measurement of urinary-free cortisol isthe most sensitive and specific screening test.

the morning hours (see Fig. 4-4). In pitu-itary Cushing’s disease and ectopic forms of Cushing’s syndrome, elevated values areobserved, especially in the afternoon andevening. The next step in differentiation isan anatomic evaluation of the pituitary.When no abnormality is found, the nextstep is a search for a malignancy, typicallyin the lung. The finding of low ACTH lev-els points to the adrenal as the source ofexcessive cortisol production, and anatomicstudies of the adrenal are indicated. CT—computed tomography; MRI—magneticresonance imaging.

FIGURE 4-24

Algorithm for differentiation of Cushing’s syndrome. The first step in the differentiation of Cushing’s syndrome after diagnosing hypercortisolism is measurement of plasmaadrenocorticotropic hormone (ACTH) levels. Typically, these should be reduced after


FIGURE 4-25

Synthesis, actions, and metabolism of catecholamines. Depicted is the synthesis of catecholamines in the adrenal medulla [9].Epinephrine is only produced in the adrenal and the organ ofZuckerkandl at the aortic bifurcation. Norepinephrine and dopaminecan be produced and released at all other parts of the sympatheticnervous system. The kidney is the primary site of excretion of

catecholamines and their metabolites, as noted here. The kidney also can contribute catecholamines to the urine. The relative contributions of norepinephrine and epinephrine to biologic events is noted by the plus signs. BMR—basal metabolic rate; CNS—central nervous system; NEFA—nonesterified fatty acids;VMA—vanillylmandelic acid.

Catecholamines


Pheochromocytoma

8:30

PM

10

PM

2

AM

5:00

AM

7:45

AM

9

AM

10

AM

11

AM

12

Noon

1

PM

10

20

6070

8090

110120

130140

160170

180190

210220

230240

304050

100

150

200

250

0

Calibrate2-min intervals 5-min intervals

Blood pressure taken at

Blo

od

pre

ssu

re, m

m H

g

During the attack:Blood pressure, 192/100 mm HgPulse 108Respirations, 24

FIGURE 4-26

Paroxysmal blood pressure pattern in pheochromocytoma. Note the extreme variability of blood pressure in this patientwith pheochromocytoma during ambulatory blood pressuremonitoring [9]. Whereas most levels were within the normal

range, episodic increases to levels of 200/140 mm Hg wereobserved. Such paroxysms can be spontaneous or associatedwith activity of many sorts. (Adapted from Manger and Gifford[9]; with permission.)


Neurofibroma associated with pheochromocytoma. Neurofibromasare sometimes found in patients with pheochromocytoma. Theselesions are soft, fluctuant, and nontender and can appear anywhereon the surface of the skin. These lesions can be seen in profile inFigure 4-28.

FIGURE 4-28

Café au lait lesionsin a patient withpheochromocytoma.These light-brown-colored (coffee-with-cream-colored)lesions, sometimesseen in patients withpheochromocytoma,usually are largerthan 3 cm in thelargest dimension.In this particularpatient, neurofibro-mas also are presentand can be seen inprofile.


DISORDERS ASSOCIATED WITHPHEOCHROMOCYTOMA

Cholelithiasis

Renal artery stenosis

Neurofibromas

Café au lait lesions

Multiple endocrine neoplasia, types II and III

Von Hippel-Lindau syndrome (hemangioblastoma and angioma)

Mucosal neuromas

Medullary thyroid carcinoma

FIGURE 4-29

Disorders associated with pheochromocytoma. In addition to the neurofibromas andcafé au lait lesions depicted in Figures 4-27 and 4-28, several other associated abnormal-ities have been reported in patients with pheochromocytoma. (From Ganguly et al. [9];with permission.)

COMMON SYMPTOMS AND FINDINGS IN PHEOCHROMOCYTOMA

Symptoms

Severe headache

Perspiration

Palpitations, tachycardia

Anxiety

Tremulousness

Chest, abdominal pain

Nausea, vomiting

Weakness, fatigue

Weight loss

Dyspnea

Warmth, heat intolerance

Visual disturbances

Dizziness, faintness

Constipation

Finding

Hypertension:

Sustained

Paroxysmal

Pallor

Retinopathy:

Grades I and II

Grades III and IV

Abdominal mass

Associated multiple endocrineadenomatosis

Patients, %

82

67

60

45

38

38

35

26

15

15

15

12

7

7

61

24

44

40

53

9

6

FIGURE 4-30

Common symptomsand findings in pheo-chromocytoma. Notethat severe hyperten-sive retinopathy,indicative of intensevasoconstriction, frequently isobserved. (Adaptedfrom Ganguly et al. [10].)

SCREENING AND DIAGNOSTIC TESTS IN PHEOCHROMOCYTOMA

Specificity, %

≈80

≈85

>99

Sensitivity, %

≈85

≈75

>99

Test

Elevated 24-h urinary catecholamines,vanillylmandelic acid, homovanillicacid, metanephrines

Abnormal clonidine suppression test

Elevated urinary “sleep” norepinephrine

FIGURE 4-31

Screening and diagnostic tests in pheochromocytoma. Drugs, incom-plete urine collection, and episodic secretion of catecholamines caninfluence the tests based on 24-hour urine collections in a patientwith a pheochromocytoma. The clonidine suppression test is fraughtwith false-negative and false-positive results that are unacceptablyhigh for the exclusion of this potentially fatal tumor. The “sleep”norepinephrine test eliminates the problems of incomplete 24-hoururine collection because the patient discards all urine before retiring;saves all urine voided through the sleep period, including the firstspecimen on arising; and notes the elapsed (sleep) time [10]. The sleepperiod is typically a time of basal activity of the sympathetic nervoussystem, except in patients with pheochromocytoma (see Fig. 4-32).


100

1000

0

10

Patient I

Patient II

Patient III

Patient IV

Patient V

Patient VI

Maximum for normal

Maximum for hypertensive

Slee

p u

rin

ary

no

rep

inep

hri

ne

excr

etio

n,

µg

Normalmean + SD

Hypertensivemean + SD

FIGURE 4-32

Nocturnal (sleep) urinary norepinephrine. The values for urinaryexcretion of norepinephrine are shown for normal persons andpatients with essential hypertension as mean plus or minus SD[10]. Values for patients with pheochromocytoma are indicated bysymbols. Note that the scale is logarithmic and the highest valuefor patients with normal or essential hypertension was less than 30µg, whereas the lowest value for a patient with pheochromocytomawas about 75 µg. Most patients with pheochromocytomas had val-ues an order of magnitude higher than the highest value forpatients with essential hypertension.

LOCALIZATION OF PHEOCHROMOCYTOMA

Sensitivity, %

≈40

≈60

≈85

>95

Specificity, %

≈50

≈75

≈85

>95

Test

Abdominal plain radiograph

Intravenous pyelogram

Adrenal isotopic scan (meta-iodobenzoylguanidine)

Adrenal computed tomographic scan

FIGURE 4-33

Localization of pheochromocytoma. Once the diagnosis ofpheochromocytoma has been made it is very important to localizethe tumor preoperatively so that the surgeon may remove it with aminimum of physical manipulation. Computed tomographic scanor MRI appears to be the most effective and safest techniques forthis purpose [10]. The patient should be treated with �-adrenergicblocking agents for 7 to 10 days before surgery so that the contractedextracellular fluid volume can be expanded by vasodilation.

FIGURE 4-34

Intravenous pyelo-gram in pheochro-mocytoma. Note thedisplacement of theleft kidney (right) bya suprarenal mass.


A B

C D

FIGURE 4-35

A–D, Computed tomographic scans in four patients with pheochro-mocytoma [10]. The black arrows identify the adrenal tumor in

A B

FIGURE 4-36 (see Color Plates)

A and B, Pathologic appearance of pheochromocytoma before(panel A) and after (panel B) sectioning. This 3.5-cm-diameter

these four patients. Three patients have left adrenal tumors, and inone patient (panel B) the tumor is on the right adrenal.

tumor had gross areas of hemorrhage noted by the dark areas visible in the photographs.


References

1. Netter FH: Endocrine system and selected metabolic diseases. In CibaCollection of Medical Illustrations, vol. 4; 1981:Section III, Plates 5, 26.

2. DeGroot LJ, et al.: Endocrinology, edn 2. Philadelphia: WB Saunders;1989:1544.

3. Weinberger MH, Grim CE, Hollifield JW, et al.: Primary aldostero-nism: diagnosis, localization and treatment. Ann Intern Med 1979,90:386–395.

4. Weinberger MH, Fineberg NS: The diagnosis of primary aldosteronismand separation of subtypes. Arch Intern Med 1993, 153:2125–2129.

5. Grim CE, Weinberger MH: Familial, dexamethasone-suppressiblenormokalemic hyperaldosteronism. Pediatrics 1980, 65:597–604.

6. Kem DC, Weinberger MH, Mayes D, Nugent CA: Saline suppressionof plasma aldosterone and plasma renin activity in hypertension. ArchIntern Med 1971, 128:380–386.

7: Lifton RP, Dluhy RG, Powers M: Hereditary hypertension caused bychimeric gene duplications and ectopic expression of aldosterone syn-thase. Nat Genet 1992, 2:66–74.

8. Lifton RP, Dluhy RG, Powers M: A glucocorticoid-remediable aldos-terone synthase gene causes glucocorticoid-remediable aldosteronismand human hypertension. Nature 1992, 355:262–265.

9. Manger WM, Gifford RW Jr: Pheochromocytoma. New York:Springer-Verlag; 1977:97.

10. Ganguly A, Henry DP, Yune HY, et al.: Diagnosis and localization ofpheochromocytoma: detection by measurement of urinary norepineph-rine during sleep, plasma norepinephrine concentration and computedaxial tomography (CT scan). Am J Med 1979, 67:21–26.

5

Insulin Resistance and Hypertension

Resistance to insulin-stimulated glucose uptake is associated withincreased risk for cardiovascular disease [1]. Risk factors forcardiovascular disease tend to cluster within individuals, and

insulin resistance may be the link between hypertension and dyslipidemia.Depending on the populations studied and methodologies used fordefining insulin resistance, approximately 25% to 40% of nonobesenondiabetic patients with hypertension are insulin-resistant [2]. Insulinresistance also has been observed in genetic and acquired animal modelsof hypertension. A constellation of insulin resistance, reactive hyperin-sulinemia, increased triglycerides, decreased high-density lipoproteincholesterol, and hypertension was designated as syndrome X byReaven in 1988 [3].

Although a number of putative mechanisms have been proposed, itis unclear whether insulin resistance or reactive hyperinsulinemia, orboth, actually cause hypertension. The recent observations that insulin-sensitizing agents attenuate the development of hypertension lend credence to this hypothesis [4]. As discussed subsequently, however,these agents may lower blood pressure by different mechanisms.Whatever mechanism may be involved, the observation that a singleagent may have the capacity to both increase insulin sensitivity andlower blood pressure is potentially of considerable clinical significance.

Non–insulin-dependent diabetes mellitus represents an extreme ofinsulin resistance. Among diabetics, a two- to threefold increasedprevalence of hypertension exists. Hypertension is associated with afourfold increase in mortality among patients with non–insulin-depen-dent diabetes, and antihypertensive drug therapy has a beneficialimpact on both macrovascular and microvascular disease [5]. Despitethe potential concern that diuretics may augment insulin resistance,diabetic patients benefit from antihypertensive therapy with diuretics.The renal protective effect of antihypertensive drugs varies among different classes of agents. Angiotensin-converting enzyme inhibitorsdecrease proteinuria and retard the progression of renal insufficiencyin diabetic patients with normal blood pressure and hypertension.

Theodore A. Kotchen

C H A P T E R


This benefit is independent of an effect on blood pressure and may be related specifically to the capacity of these agentsto dilate the efferent renal arteriole. Results of studies evalu-ating the effects of calcium antagonists on the progression ofdiabetic nephropathy are varied. Some studies suggest that

dihydropyridine calcium antagonists accelerate the progres-sion of diabetic nephropathy, particularly in the short term.Additional studies are required to evaluate the antihyperten-sive potential of insulin-sensitizing agents in patients withnon–insulin-dependent diabetes.

Tota

l cho

lest

erol

, mm

ol/L

70 80

Diastolic blood pressure, mm HgA90 100 70 80 90 100

5.0

6.0

5.5

20–29 y 20–29 y

30–39 y

40–49 y

30–39 y

50–54 y

6.5

7.0Men Women

40–49 y

B. NATIONAL HEALTH AND NUTRITIONEXAMINATION SURVEY II

1. Persons with blood pressure >140/90 mm Hg or taking medication for hypertension:

40% have cholesterol >240 mg/dL

2. Persons with blood cholesterol >240 mg/dL:

46% have blood pressure >140/90 mm Hg

FIGURE 5-1

Hyperlipidemia and hypertension. A, Epidemiologic studies docu-ment an association between serum cholesterol and blood pressurein men and women. B, Based on data from the National Health

and Nutrition Examination Survey II, persons with hypertensionhave a high prevalence of hyperlipidemia and vice versa [6]. (Panel A from Bonna and Thelle [7]; with permission.)

Dyslipidemia, hypertension

ObesityGlucose tolerance ↓ Diabetes type II

Epidemiologic + clinical associationHereditary + acquired mechanisms

Insulin-resistanceHyperinsulinemia

B. HYPERTENSION ANDINSULIN RESISTANCE

Type II diabetes mellitus

Obesity

Essential hypertension

Salt sensitive (?)

Experimental hypertension

Dahl-salt-sensitive rats

Spontaneously hypertensive rats

FIGURE 5-2

Insulin resistance and hypertension. A, Genetic and nutritional factors con-tribute to insulin resistance and resultanthyperinsulinemia. In addition to obesityand type II diabetes, hyperlipidemia andhypertension also may be associated withinsulin resistance. Insulin resistance mayaccount for the association of hyperlipi-demia with hypertension. B, Insulin resis-tance is associated with hypertension in anumber of clinical and experimental set-tings. (Panel A from Ferrari andWeidmann [8]; with permission.)

5.3Insulin Resistance and Hypertension

00

40

20

60

Plas

ma

insu

lin, µ

U/m

L

30 60 90 120Time, min

0

80

40

120

140Hypertensive patients

Control group

Plas

ma

gluc

ose,

mg/

100

mL

*

*

*

00

400

600

200

800

Insu

lin, p

mol

/L

30 60 90 120 150

Time, min

**

04

8

6

10

Glu

cose

, mm

ol/L

30 60 90 120 150

1 mmol/l = 0.0555 mg/dL

1 pmol/L = 7.175 µU/mL

Salt-sensitiveSalt-resistant

FIGURE 5-3

Insulin resistancebased on glucoseand insulin responsesto glucose load. Inresponse to an oralglucose load of 75 g,compared with per-sons with normalblood pressure,patients with hyper-tension tend to havehigher plasma glucoseand insulin levels.These data suggestthat patients withhypertension areinsulin resistant.(From Ferranniniand coworkers [9];with permission.)

FIGURE 5-4

Salt sensitivity.Persons who havesalt-sensitive hyper-tension tend to be more insulin-resistant than arethose who are salt-resistant. That is,patients who are salt-sensitive have higherplasma glucose andinsulin responses toa glucose load thando those who aresalt-resistant. (From Bigazzi andcoworkers [10];with permission.)

Cou

nt

0 2

M value at clamp, mg/kg/min

4 6 8 10 12 14

0

4

2

6

16

14

12

10

8

Hypertensive subjects

Control subjects

FIGURE 5-5

Insulin sensitivity. Insulin sensitivity alsomay be assessed using the euglycemic insulinclamp technique. The frequency distributionfor insulin-mediated glucose disposal duringeuglycemic insulin clamping (M value) differsin persons with normal blood pressure andthose with hypertension. The percentage ofpersons with hypertension consideredinsulin-resistant depends on the definitionof insulin resistance. In this study, 27% ofpatients with hypertension were classifiedas being insulin-resistant based on an M valueover two SDs above the mean for personswith normal blood pressure. (From Lindand coworkers [2]; with permission.)

SYNDROME X AND ASSOCIATED CONDITIONS

Hypertension

Hyperinsulinemia

Increased triglycerides

Decreased high-density lipoprotein cholesterol

Increased low-density lipoprotein cholesterol

Decreased plasminogen activator

Increased plasminogen activator inhibitor

Increased blood viscosity

Increased uric acid

Increased fibrinogen (?)

FIGURE 5-6

As originally defined, syndrome X includes hypertension, hyperinsulinemia, increased plasma triglycerides, and decreased HDL cholesterol. The syndrome also may be associated with clustering of additional cardiovascular disease risk factors.


Obesity Nutrition Genetic predisposition

Compensatoryhyperinsulinemia

HyperglycemiaHyperlipidemia

Increased sympathetic nervous

system activity

Vasculargrowth

Increased α1–

adrenegic receptors

AntinatriuresisImpaired endothelium-dependent vasodilation

Resistance toinsulin-stimulated

glucose uptake

FIGURE 5-7

Hypertension associated with insulin resis-tance. It is unclear whether hyperinsuline-mia associated with insulin resistance caus-es hypertension, although a number ofpotential mechanisms have been proposed.

Hypercholesterolemia (low-density lipoprotein, lipoprotein (a))

Increased endothelial superoxideanion production

Endothelial injury

Increased degradation of nitric oxide

Impaired endothelium-dependent vasodilation

FIGURE 5-8

Metabolic conse-quences of insulinresistance. Theseconsequences alsomay affect peripher-al vascular resistance.Hypercholesterolemiamay result in vascularendothelial injuryand, hence, impairedvasodilation.

High glucose

Decreased nitricoxide production

Protein kinase Cactivation

Increased sodium-hydrogenantiport activity

FIGURE 5-9

Results of high glu-cose concentrations.High glucose con-centrations mayinhibit nitric oxideproduction and alterion transport in vas-cular smooth musclecells, favoring vaso-constriction.

SO2

NH NHCR1 R2

C NH CH2

NH NHCCH2

SO2

C1

CH2 O

O

R1 ON NH

NH

O

NH

O

NH2

CR1

R2C

N NH

NH NH

NH2

OCH

3C

H3C

C

S

NH

CH2

CH2

CH2

CH2

CH3 O

O

S

NH

N

Sulfonylureas

Glyburide

Biguanides

Metformin

Thiazolidinediones

Pioglitazone

FIGURE 5-10

Effects of chemically distinct oral hypo-glycemic agents onblood pressure.Sulfonylureas stimulateendogenous insulinsecretion and do notlower blood pressure. In contrast, biguanidesand thiazolidinedionesincrease insulin sensitivitywithout stimulatingendogenous insulinsecretion, and drugs inthese classes lowerblood pressure.

Syst

olic

blo

od p

ress

ure,

mm

Hg

0 2

DayA

4 6 8 10 12 14 16 18 20 22

80

120

100

140

160ControlPioglitazone

FIGURE 5-11

Pioglitazone in the treatment of hypertension in rats. A, Systolicblood pressures in Dahl-salt-sensitive rats treated with either vehicle orpioglitazone (a thiazolidinedione) for 3 weeks. Pioglitazone attenuateddevelopment of hypertension in this animal model. Weight gain didnot differ in the two groups.



B. HEMODYNAMIC MEASUREMENTS IN DAHL-SALT-SENSITIVE RATS

Control group

Group treated with pioglitazone

Mean intra-arterialpressure, mm Hg

129 ±1

121 ±3*

Cardiac index,mL/min/100 g

51.4 ±1.6

59.1±1.7*

Total peripheral resistance,mm Hg/mL/min/100 g

2.50 ±0.07

2.07 ±0.07*


B, Direct intra-arterial pressure and cardiac index (thermodilution) in these same chronicallyinstrumented, conscious pioglitazone-treated and control rats. Compared with control ani-mals, rats treated with pioglitazone had lower mean arterial pressure, higher cardiac index,and lower total peripheral resistance. Thus, attenuation of hypertension by pioglitazone is dueto a reduction of peripheral resistance. (From Dubey and coworkers [11]; with permission.)

AGENTS THAT INCREASE INSULIN SENSITIVITY, DECREASE PLASMA LIPIDCONCENTRATIONS, AND LOWER BLOOD PRESSURE IN ANIMAL MODELSAND PRELIMINARY STUDIES IN HUMANS

Thiazolidinediones

Metformin


Humans (?)

Vanadyl sulfate


Fructose-fed rats

Etomoxir


Clofibrate


Fenfluramine derivatives

Fructose-fed rats

Humans

Lovastatin/pravastatin



Human (?)

FIGURE 5-13

Agents that increase insulin sensitivity,decrease plasma lipid concentrations, andlower blood pressure in animal models andpreliminary studies in humans.

80

160

180

120

100

140

200

Mea

n ar

teria

l pre

ssur

e, m

m H

g

Clofibrate Vehicle

Dahl-S

Clofibrate Vehicle

Dahl-R

FIGURE 5-14

Clofibrate in prevention of hypertension inrats. Clofibrate prevents the development ofhypertension in Dahl salt-sensitive rats.This agent does not affect blood pressure inDahl salt-resistant rats. (From Roman andcoworkers [12]; with permission.)

EFFECT OF CHOLESTEROL REDUCTION ON BLOOD PRESSURE RESPONSETO MENTAL STRESS IN PATIENTS WITH NORMAL BLOOD PRESSURE ANDHIGH CHOLESTEROL

Placebo group

Group treated with lovastatin

Systolic blood pressure

Baseline

141

133*

Stress

122

119

StressBaseline

78

75

69

67

Diastolic blood pressure

FIGURE 5-15

In humans with normal blood pressure who have high serum cholesterol concentrations,treatment with lovastatin lowers serum cholesterol and attenuates the systolic blood pressure response to mathematics-induced stress. (From Sung and coworkers [13]; with permission.)

MODELS IN WHICHTHIAZOLIDINEDIONES LOWERBLOOD PRESSURE

Dahl-S rat

1-Kidney, 1-clip rat

Obese Zucker rat

Fructose-fed rat

L-NNA–treated rat

SHR

Obese rhesus monkey

Watanabe hyperlipidemic rabbit

Obese human

FIGURE 5-12

Thiazolidinediones lower blood pressure inseveral models of experimental hyperten-sion and in obese humans.

*P<0.05


ANTIHYPERTENSIVE MECHANISMS OF INSULIN-SENSITIZING AGENTS

Block agonist-induced calcium ion entry into vascular smooth muscle cells

Inhibit agonist-mediated vasoconstriction

Inhibit growth of vascular smooth muscle cells

Augment endothelium-dependent vasodilation

Direct effect

Metabolic effect

Natriuresis

Increase 20-hydroxy-eicosatetraenoic acid production

Increase renal medullary blood flow

FIGURE 5-16

Insulin-sensitizing and lipid-lowering agents may lower blood pressure by a number of different mechanisms. Different agentsmay act through different mechanisms.

0.65

0.85

0.90

0.95

1.00

0.75

0.70

0.80

1.05

Intr

acel

lula

r [C

a2+] i

0 100 200

R172 #1–8 + 20 ng/mL PDGF

300 400 500 600 700 800

Time, sA

0.60

0.80

0.85

0.90

0.70

0.65

0.75

0.95

Intr

acel

lula

r [C

a2+] i

0 100 200

R172 #31–41 + 2 ug/mL ciglitazone + 20 ng/mL PDGF

300 400 500 600 700 800

Time, sB

0

200

250

300

150

100

50

350

[Ca2+

] i(nM

)Basal

(286)

Arginine vasopressin

(290)

*

*

DeltaPeak

(73)

(59)

Control

Metformin

50

0

250

300

350

200

150

100

400

450[C

a2+] i(n

M)

Basal

(286)

Thrombin

(290)

*

*

DeltaPeak

(213)

(231)

* P<0.05

* P<0.05

FIGURE 5-17

Use of ciglitazone to abolish calcium concentration elevation. Ciglitazone, a thiazolidinedione,abolishes agonist-stimulated sustained elevations of intracellular calcium concentrations.Shown are time-dependent plots of changes in intracellular calcium (in arbitrary units;[Ca2+]i) induced by platelet-derived growth factor (PDGF) in human gliobastoma cellswith and without preincubation with ciglitazone. A, Addition of PDGF to control cells isindicated by the vertical line. B, An identical experiment conducted on cells pretreated withciglitazone. The capacity of this agent to shorten the duration of agonist-stimulatedincreases in intracellular calcium may result in attenuation of both growth of vascularsmooth muscle cells and vasoconstriction. (From Pershadsingh and coworkers [14]; with permission.)

FIGURE 5-18

Use of metformin to attenuate intracellularcalcium concentration elevation. Metforminis a biguanide that attenuates agonist-stimu-lated increases of intracellular calcium con-centrations in vascular smooth muscle. (FromBhalla and coworkers [15]; with permission.)

5.7Insulin Resistance and HypertensionC

ell n

umbe

r (x

104 )

0 2

Days in culture

4 6 8 10 12 14

Insulin

Insulin + pioglitazone(days 0–6)

Insulin + pioglitazone

0.4% FCS

0

12

8

4

16

20

24

28FIGURE 5-19

Effect of pioglitazone on insulin-induced proliferation of arterialsmooth muscle cells. Inhibition of insulin-stimulated vascularhyperplasia and hypertrophy is one potential mechanism by whichinsulin-sensitizing and lipid-lowering agents may decrease peripheralresistance. Two kinds of evidence suggest that thiazolidinedionesinhibit the growth of vascular smooth muscle cells in vitro. Shownhere, pioglitazone inhibits insulin-stimulated proliferation of vascularsmooth muscle cells. Pioglitazone also inhibits 3H-thymidine incor-poration in vascular smooth muscle cells (Fig. 5-19). FCS—fetalcalf serum. (From Dubey and coworkers [11]; with permission.)

FIGURE 5-20

Effect of pioglitazone on 3H-thymidine incorporation in vascular smooth muscle cells. 3H-thymidine incorporation is stimulated by insulin, fetal calf serum (FCS), and epidermalgrowth factor (EGF). Pioglitazone inhibits 3H-thymidine incorporation stimulated by eachof these mitogens. Similar observations have been made with pravastatin and lovastatin.(From Dubey and coworkers [11]; with permission.)

0.0010

80

100

40

20

60

120

3 H-T

hym

idin

e in

corp

orat

ion,

% o

f con

trol

0.01 0.1 10 1001

Pioglitazone concentration, uM

Insulin = 1 mU/mL

5% FCS

EGF = 100 mg/mL

Control0

1

2

3

Nor

epin

ephr

ine

x 10

–8 (l

og M

)

Insulin+

pioglitazone

*

Insulin Pioglitazone

Perc

ent

of c

hang

e

0 100 200

Norepinephrine,ng/kg/min

300 400 500

0

10

20

30

40

50

Perc

ent

of c

hang

e

0 100 200

Angiotensin II,ng/kg/min

300 400 500

0

10

20

30

40

50Control

Pioglitazone

Control

Pioglitazone

FIGURE 5-21

Decreases in mean arterial pressure in rats treated with pioglita-zone and control Dahl-salt-sensitive rats in response to gradedinfusions of norepinephrine and angiotensin II. In vivo, pressorresponses to norepinephrine and angiotensin are II attenuated inDahl-salt-sensitive rats treated with pioglitazone [16]. (FromKotchen and coworkers [16]; with permission.)

FIGURE 5-22

Half-maximal values for norepinephrine-induced contraction in aortic strips preincubatedwith insulin, pioglitazone, or both. In vitro, pressor responsiveness of aortic strips to norep-inephrine-induced contraction is inhibited by preincubation with insulin plus pioglitazone[16]. The half-maximal value is increased for strips incubated with insulin plus pioglitazone(ie, higher concentrations of norepinephrine are required to achieve half-maximal contraction)but not in strips incubated with insulin alone or pioglitazone alone.


MP B

AcetylcholineSodium

nitroprusside

Nitric oxidesynthase

Bradykinin

Endothelium

Smooth muscle

EDRF-nitric oxide

Gq protein

Nitric oxideL-arginine

Gi protein

Substance PFIGURE 5-23

Impaired endothelium-dependent vascularrelaxation and insulin resistance. Insulinresistance is associated with impairedendothelium-dependent vascular relaxation,which is a defect that may be corrected byinsulin-sensitizing agents. One approach toevaluating vascular endothelial function isto measure vascular relaxation in responseto acetylcholine. EDRF—endotheliumderived relaxing factor.

Control0

1

2

3

4

5

Ace

tylc

holin

e x

10–

7 (log

M)

Insulin+

pioglitazone

*

Insulin Pioglitazone

Prot

ein,

pm

ol/m

in/m

g

Liver

*

Cortex

20-Hydroxy-eicosotetraenoic acid

0

10

20

30

40

50

60

*

Outer medulla

*

Control, n = 9

Clofibrate, n = 12

* P<0.05

Na+

3 Na+

20-HETE

AA

Na+

Ca2+ Mg2+

AllbradykininvasopressinCa2+

K+

K+

PLA

PLC

2 K+

K+

K+

(+)

2 Cl–

Cl–

R

FIGURE 5-24

Half-maximal values for acetylcholine-induced vasodilation in aortic strips prein-cubated with insulin, pioglitazone, or both. Inthe presence of insulin, pioglitazone augmentsendothelium-dependent vasodilation. In vitro,the half-maximal values for acetylcholine-induced vasodilation is less in aortic stripsincubated with insulin plus pioglitazone (ie,the strips are more responsive to acetylcholine)than in control strips or strips incubatedwith insulin alone or pioglitazone alone [16].

FIGURE 5-25

Effect of clofibrate on 20-hydroxy-eicosate-traenoic (20-HETE) production in Dahl-salt-sensitive rats. Insulin stimulates sodiumreabsorption in the proximal tubule.Consequently, lowering plasma insulin con-centrations by increasing insulin sensitivitywould potentially result in less sodiumretention. In addition, clofibrate inducesrenal P-450 fatty acid w-hydroxylase activityand, hence, increases metabolism of arachi-donic acid to 20-HETE. (From Roman andcoworkers [12]; with permission.)

FIGURE 5-26

20-Hydroxy-eicosotetraenoic acid inhibitschloride transport in the thick ascendinglimb of the loop of Henle. This inhibitionresults in a natriuretic effect in the Dahl-salt-sensitive rat. This may be themechanism by which clofibrate preventshypertension in this animal model.

BENEFITS OF CONTROL OFHYPERTENSION AND DIABETES

Hypertension

Decreased nephropathy

Decreased retinopathy

Decreased stroke, myocardial infarction

Drug specific (?)

Diabetes (type I)

Decreased nephropathy

Decreased retinopathy

Decreased neuropathy

FIGURE 5-27

Benefits of hypertension control and blood glucose controls are well established in diabeticpatients. Noninsulin-dependent diabetes mellitus represents an extreme of insulin resistance, and hypertension is a major contributor to the cardiovascular complications of diabetes. Despite the potential concern that diuretics increase insulin resistance, overall cardiovascular disease morbidity and mortality are reduced in diabetic patients with hypertension by antihypertensive therapy with regimens that include diuretics.


–2

750

250

1250

Alb

umin

uria

,µg

/min

–1 0 2 31 5 64

Time, y

105

Start of antihypertensive treatment

GFR: 0.94(mL/min/mo)



95

115

125

Mea

n ar

teria

l blo

odpr

essu

re, m

m H

g

65

55

85

75

105

95

Glo

mer

ular

filt

rati

on ra

te,

mL/

min

/1-7

3 m

2

FIGURE 5-28

Course of diabeticnephropathy duringeffective antihyper-tensive treatment inpatients with overtdiabetic nephropa-thy. Effective antihy-pertensive therapywith regimens thatinclude diureticsalso decreases therate of progressionof renal failure(both the glomerularfiltration rate andalbumin excretion)in patients with dia-betic nephropathy.(From Parving andcoworkers [17];with permission.)

EFFECT OF ANTIHYPERTENSIVE AGENTS ON INSULIN SENSITIVITY AND RENAL FUNCTION IN DIABETIC PATIENTS

Insulin sensitivity

Increase

Decrease

Decrease

Increase

0

Increase

Agent


Diuretics

�-Blockers

�1-Blockers

Calcium ion antagonists

Dihydropyridines

Others

Renal protection

+

?

0

0

-?+?

FIGURE 5-29

Different antihypertensive agents have different effects on insulinsensitivity, and in diabetic patients, on renal function. Questionmark indicates inconsistent study results; plus sign indicates a protective effect; minus sign indicates no protection.

Perc

ent d

oubl

ing

of b

asel

ine

crea

tinin

e

0.0 0.5

Years of follow-up

1.0 1.5 2.0 2.5 3.0 3.5 4.0

0

15

10

5

20

30

25

3540

45

50Placebo

Captopril

Percent risk reduction = 48.5% (16–69)P = 0.007

A

Prop

ortio

n w

ith e

vent

0 1

Years from randomization

2 3 4 4.5

0.0

0.1

0.2

0.3

0.4

0.5Risk reduction = 50.5%P = 0.006

Placebo

Captopril

B

FIGURE 5-30

Cumulative incidence of events in patients with diabetic nephropathyin captopril and placebo groups. A, Time to doubling of serum cre-atinine. B, Time to end-stage renal disease or death. In type I diabeticpatients with nephropathy and either normal blood pressure or hyper-tension, treatment with angiotensin-converting enzyme inhibitors

decreases proteinuria and retards the rate of progression of renalinsufficiency. The cumulative incidence of doubling of serum creati-nine concentrations over time and development of end-stage renaldisease are less in patients treated with captopril than in those treat-ed with placebo. (From Lewis and coworkers [18]; with permission.)


CHANGES OF MEAN BLOOD PRESSURE, PROTEINURIA, AND GLOMERULAR FILTRATION RATE IN TREATMENT WITHDIFFERENT ANTIHYPERTENSIVE AGENTS IN PATIENTS WITH INSULIN-DEPENDENT DIABETES MELLITUS ANDNON–INSULIN-DEPENDENT DIABETES MELLITUS WHO HAVE MICROALBUMINURIA OR MACROALBUMINURIA

Treatment type

Placebo

Conventional (diuretics and �-blockers)


Calcium antagonists:

All except nifedipine and nitrendipine

Nifedipine

Nitrendipine

Patients, n

244

213

489

63

63

39

�MBP, %

-2-10

-16

-16

-12

-17

�UProt, %

+39

-20

-52

-42

+2

-48

�GFR, %

-8-9-1

+2

-48

+30

FIGURE 5-31

Despite similar control of hypertension, different classes of antihyper-tensive agents have different effects on renal function in patients with

1. Kotchen TA, Kotchen JM, O’Shaughnessy IM: Insulin and hyperten-sive cardiovascular disease. Curr Opin Cardiol 1996, 11:483–489.

2. Lind L, Berne C, Lithell H: Prevalence of insulin resistance in essentialhypertension. J Hypertens 1995, 17:1457–1462.

3. Reaven GM: Role of insulin resistance in human disease. Diabetes1988, 37:1595–1607.

4. Kotchen TA: Attenuation of hypertension by insulin-sensitizingagents. Hypertension 1996, 28:219–223.

5. Nadig V, Kotchen TA: Insulin sensitivity, blood pressure and cardio-vascular disease. Cardiol Rev 1997, 5:213–219.

6. National High Blood Pressure Education Program and NationalCholesterol Education Program: Working Group Report onManagement of Patients with Hypertension and High BloodCholesterol. National Institutes of Health Publication No. 90-2361.National Institutes of Health, 1990.

7. Bonna KH, Thelle DJ: Association between blood pressure and serumlipids in a population: the Tromso study. Circulation 1991,83:1305–1324.

8. Ferrari P, Weidmann P: Insulin, insulin sensitivity and hypertension. J Hypertens 1990, 8:491–500.

9. Ferrannini E, Buzzigoli E, Bonadonna R, et al.: Insulin resistance inessential hypertension. N Engl J Med 1987, 317:350–357.

10. Bigazzi R, Bianchi S, Baldari G, et al.: Clustering of cardiovascularrisk factors in salt-sensitive patients with essential hypertension: roleof insulin. Am J Hypertens 1996, 9:24–32.

11. Dubey RK, Zhang HY, Reddy SR, et al.: Pioglitazone attenuateshypertension and inhibits growth in renal arteriolar smooth muscle inrats. Am J Physiol 1993, 265:R726–R732.

12. Roman RJ, Ma Y-H, Frohlich B, et al.: Clofibrate prevents the devel-opment of hypertension in Dahl salt-sensitive rats. Hypertension1993, 21:985–988.

13. Sung BH, Izzo JL, Wilson MF: Effects of cholesterol reduction on BPresponse to mental stress in patients with high cholesterol. Am JHypertens 1997, 10:592–599.

14. Pershadsingh H, Szollosi J, Benson S, et al.: Effects of ciglitazone onblood pressure and intracellular calcium metabolism. Hypertension1993, 21:1020–1023.

15. Bhalla RC, Toth KF, Tan EQ, et al.: Vascular effects of metformin:possible mechanisms for its antihypertensive action in the sponta-neously hypertensive rat. Am J Hypertens 1996, 9:570–576.

16. Kotchen TA, Zhang HY, Reddy S, et al.: Effect of pioglitazone on vascular reactivity in vivo and in vitro. Am J Physiol 1996,260:R660–R666.

17. Parving H-H, Andersen AR, Smidt UM, et al.: Effect of antihypertensivetreatment on kidney function in diabetic nephropathy. Br Med J 1987,294:1443–1447.

18. Lewis EJ, Hunsicker LG, Bain RP, et al.: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med1993, 329:1456–1462.

19. Bretzel RG: Effects of antihypertensive drugs on renal function in patientswith diabetic nephropathy. Am J Hypertens 1997, 10:208S–217S.

References

diabetic nephropathy. GFR—glomerular filtration rate; MBP—mean blood pressure; Uprot—urine protein. (From Bretzel [19]; with permission.)

6

The Role of Hypertension in Progression of Chronic Renal Disease

Hypertension is a cause and consequence of chronic renal dis-ease. Data from the United States Renal Data System(USRDS) identifies systemic hypertension as the second most

common cause of end-stage renal disease, with diabetes mellitus beingthe first. Renal failure in patients with hypertension has many causes,including functional impairment secondary to vascular disease andhypertensive nephrosclerosis. Even in those in whom hypertension isnot the primary process damaging the kidney, elevations in systemicblood pressure may accelerate the rate at which kidney function islost. This accelerated loss of kidney function occurs particularly inpatients with glomerular diseases and clinically evident proteinuria.

Hypertension may damage the kidney by several mechanisms. Becauseautoregulation of glomerular pressure is impaired in chronic renal dis-ease, elevations in systemic blood pressure also are associated withincreased glomerular capillary pressure. Glomerular hypertension resultsin increased protein filtration and endothelial damage, causing increasedrelease of cytokines and other soluble mediators that promote replace-ment of normal kidney tissue by fibrosis. An important factor contribut-ing to progressive renal disease is activation of the renin-angiotensin sys-tem, which not only tends to increase blood pressure but also promotescell proliferation, inflammation, and matrix accumulation.

Numerous studies in experimental animals suggest that antihyper-tensive drugs can slow the progression of chronic renal disease. Drugsthat inhibit the renin-angiotensin system may be more effective thanare other agents in retarding renal disease progression.

For many reasons, the effects of angiotensin II receptor antago-nists and angiotensin-converting enzyme (ACE) inhibitors may not

Lance D. DworkinDouglas G. Shemin

C H A P T E R


be identical. Calcium channel blockers also are beneficial insome settings; however, this effect is critically dependent onthe degree of blood pressure reduction.

The relationship between hypertension and progression ofchronic renal disease has been examined in a number of clinicaltrials. Individuals with systemic hypertension are at increasedrisk for developing end-stage renal disease. The rate at whichkidney function is lost increases in patients with poorly con-trolled systemic hypertension. Antihypertensive therapy canslow the rate of loss of kidney function in patients with diabet-ic and nondiabetic renal disease. Studies suggest that ACEinhibitors are particularly useful in patients with hypertensionand proteinuria of over 1g/24 h. Calcium channel blockers alsomay slow the progression of renal disease; however, whether all

classes of calcium channel blockers have equivalent renal pro-tective effects is uncertain.

Patients with hypertension and chronic renal disease shouldbe treated aggressively. A 24-hour urine collection determinesthe extent of proteinuria. The patient who excretes more than1 g/24 h of protein or who has diabetes mellitus should receivean ACE inhibitor. The target in this group of patients is toreduce the blood pressure to lower than 120/80 mm Hg. Mostoften, reaching this goal requires the use of combinations ofantihypertensive agents, diuretics, or calcium channel blockers.Patients who excrete less than 1 g/24 h of protein may be treatedaccording to standard recommendations with diuretics, betablockers, ACE inhibitors, or other agents. The target bloodpressure for this group of patients is lower than 130/85 mm Hg.

Hypertension and Kidney Damage

Proteinuria

Partial lossof function

Fibrosisapoptosis

Compensatorygrowth

Afferentvasodilation

Renin AIIactivation

Systemichypertension

Release ofcytokines andgrowth factors

Increasedwall tension

Glomerularhypertension

Capillaryinjury

FIGURE 6-1

Hypothesis identifying systemic hypertension as a central factor contributing to the progres-sion of chronic renal disease. After partial loss of kidney function resulting from an unde-fined primary renal disease, a number of secondary processes develop that promote progres-sive kidney failure. Activation of the renin-angiotensin system is a common event in patientswith chronic renal disease. In these patients, renin levels are either elevated or at least not

appropriately suppressed for the degree ofvolume expansion, elevation in blood pres-sure, or both. Activation of the renin-angiotensin system and the relative salt andwater excess contribute to the developmentof systemic hypertension in most patientswith chronic renal disease. Systemic hyper-tension and a decrease in preglomerular vas-cular resistance lead to an increase inhydraulic pressure within the glomerularcapillaries. Glomerular hypertension has anumber of adverse effects, includingincreased protein filtration, which promotesrelease of cytokines and growth factors bymesangial cells and downstream tubularepithelial cells. A partial loss of kidney func-tion also is a potent stimulus for compen-satory renal growth. Glomerular hypertro-phy and hypertension combine to increasecapillary wall tension, promoting endothe-lial cell activation and injury, again causingrelease of cytokines and growth factors andrecruitment of inflammatory cells. Thesemediators stimulate processes such as apop-tosis, causing loss of normal kidney cellsand increased matrix production, whichleads to glomerular and interstitial fibrosisand scarring. As additional nephrons aredamaged secondarily the cycle is repeatedand amplified, causing progression to end-stage renal failure. AII—antiotensin II.

6.3The Role of Hypertension in Progression of Chronic Renal Disease

40 80 100 120 140 16060 180

Typical autoregulatory response innormal kidneysRPF, GRF, and P

GC vary with

perfusion pressure in chronicrenal failure

PG

C, R

PF,

or

GFR

Renal perfusion pressure, mm Hg

FIGURE 6-2

Imaginary autoregulation curves in normal and diseased kidneys.Plotted on the y-axis are renal plasma flow (RPF), glomerular filtration rate (GFR), and glomerular capillary hydraulic pressure(PGC) with undefined units. Ordinarily, RPF, GFR, and PGC remainrelatively constant over a wide range of perfusion pressures withinthe physiologic range, from approximately 80 to 140 mm Hg.Because autoregulatory ability is impaired in the kidneys of personswith chronic renal disease, these patients who develop systemichypertension also are likely to have glomerular hypertension.

PGC

PGC=

MAP ↑MAPRA ↑R

A

RE ↓RE

Baseline Increased perfusion pressureA B

FIGURE 6-3

Mechanism of autoregulation of glomerular capillary pressure in asingle glomerulus from a normal kidney. A, Baseline. B, Increasedperfusion pressure. Glomerular pressure is determined by three fac-tors: mean arterial pressure (MAP) or perfusion pressure, and therelative resistance of both the afferent and efferent arterioles. Theinitial response to an increase in MAP is an increase in afferent arteriolar resistance (RA), preventing transmission of the elevatedsystemic pressure to the glomerular capillaries. Efferent arteriolarresistance (RE) also may decline. This decrease decompresses theglomerulus, helping to limit the increase in glomerular capillaryhydraulic pressure (PGC), and maintains constant renal plasma flow.

PGC

PGC<

MAP ↑MAP↓R

A↓RA

↓RE

→RE

Baseline Increased perfusion pressureA B

FIGURE 6-4

Mechanism of failure of autoregulation in a glomerulus from adamaged kidney. A, Baseline. B, Increased perfusion pressure. To compensate for a partial loss of function, surviving glomeruliundergo adaptive changes to increase the filtration rate. Theseinclude a reduction in afferent (RA) and efferent (RE) arteriolarresistances, tending to increase renal plasma flow and the glomeru-lar filtration rate. In this setting, an increase in mean arterial pres-sure (MAP) is transmitted directly to the glomerular capillaries,resulting in glomerular capillary hypertension, increased protein filtration, and hemodynamically mediated capillary injury. PGC—glomerular capillary hydraulic pressure.


Effects of Antihypertensive Agents on Experimental Kidney Injury

-1 -2 -3 -4 -5 -6 -7 -8 -9-100

60

40

20

0

-20

-40

-60

-80

-10

Ch

ange

in s

cler

osi

s, %

Change in PGC

, mm Hg

Unx–SHR

Remnant–HD

Remnant–LD

Doc–salt

NSN

Results of the linear regression analysis

Effects of going from low to high dose of

triple therapy

FIGURE 6-5

Effects of triple therapy on glomerular pressure and injury.Relationship between the change in glomerular capillary hydraulicpressure (PGC) and the extent of glomerular injury (sclerosis) in

five separate studies. In these studies, rats with experimental renaldisease were given similar antihypertensive agents. Studies wereconducted in several different animal models of hypertension andrenal disease, including the following: uninephrectomized sponta-neously hypertensive rats (Unx SHR); rats with a remnant kidneygiven either relatively high-dose (remnant-HD) or low-dose (rem-nant-LD) drug therapy; rats with desoxycorticosterone-salt–induced hypertension (Doc-salt); and rats with nephrotoxicserum nephritis (NSN), an immune-mediated form of glomerulardisease (NSN) [1–5]. In all these studies, untreated rats were com-pared with those receiving a combination of three antihypertensiveagents (triple therapy), including hydralazine, reserpine, and a thi-azide diuretic. In rats with remnant kidneys, separate studiesexamined the effects of low or high doses of these agents. A closecorrelation was revealed between the degree of reduction inglomerular capillary pressure produced by triple therapy and sub-sequent development of glomerular sclerosis. The data are consis-tent with the hypothesis that antihypertensive agents lessenglomerular injury by reducing glomerular capillary pressure. In thestudies in rats with remnant kidneys, only a relatively high dose ofthe drugs was effective in reducing pressure and injury, suggestingthat aggressive antihypertensive therapy is more likely to slowprogression of renal disease. This finding is particularly true forantihypertensive combinations that include direct vasodilators,such as the triple-therapy regimen. By dilating the afferent arteri-ole, regimens such as these tend to further impair autoregulationof glomerular pressure in the setting of chronic renal disease.(From Weir and Dworkin [6]; with permission.)

80 100 120 140 160 180

0

400

350

300

250

200

150

100

50

200

Glo

mer

ula

r in

jury

sco

re

Overall averaged systolic blood pressure at final 8 week, mm Hg

No treatmentEnalaprilLow dose triple therapyHigh dose triple therapy

FIGURE 6-6

Correlation between systolic blood pressure and glomerular injury in rats with remnant kidneys. In these rats, blood pressure was con-tinuously monitored by implanting a blood pressure sensor in theabdominal aorta connected telemetrically to a receiver. The time-averaged blood pressure in rats with remnant kidneys that wereuntreated or given the angiotensin-converting enzyme inhibitorenalapril or triple therapy (combination of hydralazine, reserpine,and a thiazide diuretic) was correlated with morphologic evidence ofglomerular injury. A close correlation was found between the aver-age blood pressure and extent of glomerular injury that developed inthese rats. It is proposed that, because of impaired autoregulation inchronic renal disease, elevations in systemic blood pressure are asso-ciated with glomerular hypertension in these rats. The higher the sys-temic pressure, the higher the glomerular pressure is predicted to beand the more glomerular injury is observed. These data provideadditional evidence that systemic hypertension produces glomerularinjury by causing elevation in glomerular pressure, and that antihy-pertensive therapy reduces injury by reducing glomerular capillarypressure. (From Griffen and coworkers [7]; with permission.)


T

T

PGC PGCRGC

RGC

BA

Tension=pressure x radiusFIGURE 6-7

The wall tension hypothesis. A, Normal. B, Chronic renal failure.After a partial loss of kidney function, compensatory adaptationswithin surviving nephrons include renal vasodilation. Vasodilationleads to an increase in glomerular capillary pressure and compen-satory renal growth associated with an increase in the radius of theglomerular capillaries. According to the LaPlace equation, wall ten-sion in a blood vessel is equal to the product of the transmural pres-sure and the radius of the vessel. In a surviving glomerular capillaryof a damaged kidney, therefore, wall tension increases not onlybecause of the increase in glomerular pressure but also because ofan increase in capillary radius. Elevations in wall tension contributeto progressive renal disease by damaging the endothelial and epithe-lial cells lining the glomerular capillaries. By reducing wall tension,maneuvers that decrease either glomerular pressure or glomerularcapillary radius are predicted to be beneficial. PGC—glomerular capillary hydraulic pressure; RGC—glomerular capillary radius; T—tension. (From Dworkin and Benstein [8]; with permission.)

A B

C D

FIGURE 6-8

Scanning electron micrographs of vascularcasts of glomeruli from normal or uni-nephrectomized rats. A, A glomerulus froma rat having had a sham operation, showinga uniform capillary pattern. (Panels B–Ddisplay casts from uninephrectomized rats.)B, A uniform pattern with most capillariesbeing approximately the same size. C andD, Nonuniform patterns in which individualcapillary loops (indicated by asterisks) aremarkedly dilated. In dilated capillary loops,wall tension is elevated and capillary walldamage is most likely to occur. The segmen-tal nature of the capillary dilation mayexplain why glomerular sclerosis that even-tually develops in remnant kidneys is alsofocal in early stages of the disease process.(Panels A–D �≈320.) (From Nagata andcoworkers [9]; with permission.)


Release of cytokinesand growth factors

Increased proteinfiltration

A IIHyperplasia and

hypertrophy

Systemic and glomerularhypertension

FIGURE 6-9

The central role of angiotensin II(AII) in promoting progressive kid-ney failure. Based on studies in which the renin-angiotensin systemhas been blocked and renal injury ameliorated, it has been suggest-ed that activation of this system is a crucial factor promoting pro-gressive kidney failure. Increased activity of the renin-angiotensinsystem also may help explain the association between hypertension

Role of the Renin Angiotensin System

and progression of renal disease. AII may promote renal injury byseveral mechanisms. Activation of the renin-angiotensin system isone mechanism leading to an increase in systemic blood pressure,the result of peripheral vasoconstriction. Glomerular hypertensionresults not only from the increase in systemic blood pressure butalso because of the ability of AII to constrict efferent arterioles, con-tributing to an increase in glomerular pressure. Glomerular hyper-tension damages the glomerular capillary wall and promotes injuryby multiple mechanisms (see Fig. 6-1). An increase in glomerularpressure tends to increase protein filtration directly. In addition, evidence suggests that AII alters the permeability of the glomerularcapillary wall to macromolecules, directly increasing protein filtra-tion. By activating mesangial and epithelial cells, proteinuria itself is a factor promoting progressive kidney failure. Evidence also existsthat AII directly stimulates production of various growth factorsand cytokines by kidney cells, including fibrogenic cytokines such astransforming growth factor-beta and platelet-derived growth factor.Release of these factors has been linked to the development ofglomerular sclerosis and interstitial fibrosis. AII also stimulates pro-liferation and growth of kidney cells that contribute to progressionof renal disease.

0

20

60

40

80

100

120

Remnant ACE I Triple

0

20

60

40

80

100

120


Pro

tein

uri

a, g/

24

h

0

10

20

30


0

20

40

60

80


Mea

n a

rter

ial p

ress

ure

, mm

Hg

Glo

mer

ula

r p

ress

ure

, mm

Hg

Glo

mer

ula

r in

jury

, %

* **

**

FIGURE 6-10

Angiotensin-converting enzyme (ACE)inhibitors and low-dose triple therapy. Theeffects of ACE inhibitors are compared withthose of low-dose triple therapy on systemicand glomerular pressure, proteinuria, andmorphologic evidence of glomerular injury in rats with remnant kidneys. Both ACEinhibitors and triple therapy caused similarreductions in mean arterial pressure in ratswith remnant kidneys; however, glomerularpressure declined only in the group treatedwith ACE inhibitors, by approximately 10 mm Hg. ACE inhibitor—induced reduc-tions in systemic and glomerular pressurewere associated with a reduction in protein-uria and morphologic evidence of glomerularinjury. The data suggest that ACE inhibitorsare superior to low-dose triple therapy in pre-venting glomerular injury in chronic renaldisease. The data support the importance ofincreased glomerular pressure as a determi-nant of glomerular injury. ACE inhibitorsmay be more effective than are other agents,specifically because of their ability to reduceglomerular pressure. It should be noted, how-ever, that significant reductions in glomerularpressure and injury may be achieved evenwith the triple-therapy regimen when signifi-cantly higher doses than those used in thecurrent study are administered (see Figs. 6-5and 6-6). Asterisk indicates P < 0.05 versusremnant. (Data from Anderson andcoworkers [10].)


30

0.00050.0001

0.001

0.01

0.1

1

6040 50

Effective pore radius, AA

Small selective

pores

Large nonselective

pores

Frac

tio

nal

vo

lum

e flu

x at

CA

=0

30

0.00050.0001

0.001

0.01

0.1

1

6040 50

Effective pore radius, AB

Frac

tio

nal

vo

lum

e flu

x at

CA

=0

Small selective

pores

Large nonselective

pores

FIGURE 6-11

Effect of renal vein constriction on glomerular protein filtration. Therole of angiotensin II (AII) in modulating macromolecular clearanceacross the glomerular capillary wall has been examined by Yoshiokaand coworkers [11]. These authors used a model of renal vein constriction to increase glomerular pressure and markedly increaseprotein filtration. They calculated the volume flux through the smallselective pores (effective pore radius, 40–50 Å) within the glomerularcapillary wall and through the large nonselective pores. A, Volumefluxes under control conditions (hatched bars) and during renal vein

constriction (open bars). Renal vein constriction causes an increase in filtration through large nonselective pores, which accounts forincreased protein filtration. B, Effects of renal vein constriction were again examined, alone (open bars) and during administration of the AII receptor antagonist saralasin (hatched bars). Saralasinreduced volume flux through the large pores, indicating that increased endogenous AII action was largely responsible for proteinuria during renal vein constriction. (From Yoshioka andcoworkers [11]; with permission.)

A

D

B

C


Local activation of the renin-angiotensin sys-tem and production of fibrogenic cytokines inexperimental chronic renal disease. In situreverse transcriptase was performed in ratswith remnant kidneys to examine the level ofgene expression for angiotensinogen and trans-forming growth factor-beta (TGF-beta). Ratsstill had not developed widespread morpholog-ic evidence of glomerular injury 24 days aftersubtotal nephrectomy. A, At this point in time(arrows), staining for angiotensinogen messen-ger RNA (mRNA) was observed along thewall of a dilated capillary loop (CL) and in anadjacent cluster of mesangial cells. B, TGF-beta mRNA was present in an identical patternin a contiguous section (arrows). C and D,Staining for angiotensinogen (panel C) andTGF-beta (panel D) is examined in kidneysfrom rats treated with the angiotensin receptorantagonist losartan from the time of nephrec-tomy. Administration of losartan markedlyreduced expression of both factors in remnantkidneys. The findings are consistent with thehypothesis that endothelial injury is associatedwith increased angiotensinogen productionand local activation of the renin-angiotensinsystem, leading to increased expression of TGF-beta and progressive glomerular fibrosis. (FromLee and coworkers [12]; with permission.)


0

100

90

80

70

60

50

40

30

20

10

**

**

**

Control A II CGP CGP+A II

PD PD +A II

los los +A II

fg R

AN

TES

/ 10

4 cel

ls

* P< 0.05 vs cells treatedwith A II alone

** P< 0.01 vs unstimulatedcontrols

A

0

15

10

5

Control m

edium

A II medium

Control m

edium + anti-RANTES Ab

A II medium + anti-R

ANTES Ab

A II medium +m normal goat Ig

G

DMEM + 10-6 M A II

Mig

rate

d m

on

ocy

tes

* P<0.05 vs control medium** P<0.05 vs A II medium without

antibody

**

*

*

B

FIGURE 6-13

Angiotensin II (AII) may be a proinflammatory molecule. The effectof AII on production of the chemokine RANTES was examined incultured glomerular endothelial cells. A, Effects of AII on secretionof RANTES by cultured glomerular endothelial cells. AII markedlystimulated RANTES secretion. Of note is that AII-induced RANTESsecretion was prevented by incubation with the AT2 receptor antag-onists SCP-42112A (CGP) or PD 1231777 (PD) but not by the AT1receptor antagonist losartan (los). These finding suggest AT2 recep-tors mediate the increase in secretion of RANTES. B, Results of achemotactic assay for human monocytes. Migration of monocytes

was assessed using a modified Boyden chamber. Migration of monocyteswas stimulated by conditioned medium from glomerular endothelial cellsthat were exposed to AII. This effect was blocked by incubation of themedium with an anti-RANTES antibody but not by control serum.The anti-RANTES antibody alone was also without effect, as was AIIin the absence of conditioned media. The findings are consistent withthe hypothesis that AII promotes glomerular inflammation by bindingto AT2 receptors, promoting RANTES secretion and infiltration ofinflammatory monocytes and macrophages. fg—femtograms. (FromWolf and coworkers [13]; with permission.)

BradykininSubstance PEnkephalin

Inactivefragments

Renin

ACE

Otherproteases

Angiotensinogen

Angiotensin I

Angiotensin II

Angiotensin III and IV

CAGECathepsin G

Tonin

tPACathepsin G

Tonin

Renin-angiotensin systemsFIGURE 6-14

Renin-angiotensin systems. For many reasons the effects ofangiotensin-converting enzyme (ACE) inhibitors and angiotensinII (AII) type 1 AT1 receptor antagonists on the progression ofchronic renal disease may not be identical. In the classic path-way, renin cleaves angiotensinogen to form AI, which is furthercleaved by ACE to form biologically active AII. ACE inhibitorsinhibit the renin-angiotensin system by reducing the activity ofACE and decreasing AII formation. ACE also catalyzes otherimportant pathways, however, including the breakdown ofvasodilator substances such as bradykinin, substance P, andenkephalin. Increased levels of these substances might accountfor some of the biologic effects of ACE inhibition. Levels ofthese substances would not increase after administration of anAT1 receptor antagonist. In contrast, inhibition of the renin-angiotensin system by ACE inhibitors may be incompletebecause other proteases may catalyze to conversion of angio-tensinogen to AII (on the right). CAGE— chymostatin-sensitiveangiotensin II–generating enzyme; t-PA—tissue plasminogen activator. (Adapted from Dzau and coworkers [14].)


Angiotensin II

Angiotensin III and IV

Proteases

VasoconstrictionAldosterone

Growth

ClearanceApoptosis

Vasodilation

AT 1

AT 2

AT 4

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS VERSUS ANGIOTENSIN II ANTAGONISTS IN EXPERIMENTAL RENAL DISEASE

Angiotensin II antagonists equivalent toangiotensin-converting enzyme inhibitors

Remnant kidney

Passive Heymann nephritis

Chronic rejection

Two-kidney, one-clip hypertension

Streptozocin-induced diabetes

Puromycin aminonucleoside

Obstructive uropathy

Munich-Wistar Furth/Ztm rat

Angiotensin II antagonists inferior toangiotensin-converting enzyme inhibitors

Uninephrectomized spontaneously hypertensive rats

Obese Zucker rats

Passive Heymann nephritis

-80

0

-20

-40

-60

MAP PGC

PROT SCLER

Red

uct

ion

, %

NifedipineFelodipineAmlodipine

FIGURE 6-16

Shown are results of studies comparing theeffects of angiotensin II (AII) receptor antago-nists and angiotensin-converting enzyme(ACE) inhibitors on experimental renal injury.AII receptor antagonists were as effective aswere ACE inhibitors in the remnant kidneymodel; streptozotocin-induced diabetic rats;the puromycin aminonucleoside model ofprogressive glomerular sclerosis, preventinginterstitial fibrosis associated with obstructiveuropathy; and an inherited model of glomeru-lar sclerosis, the Munich-Wistar Furth/Ztmrat [17–21]. In contrast, AII receptor antago-nists were somewhat less effective than wereACE inhibitors in several other animal mod-els of chronic renal disease, includinguninephrectomized spontaneously hyperten-sive rats, obese Zucker rats, and the passiveHeymann nephritis model of membranousglomerulonephritis [22–24]. Clinical trials arenecessary to determine whether these classesof drugs will be equally effective in preventingprogressive renal disease in humans.

FIGURE 6-15

Subclasses of angiotensin receptors. Another theoretic reason theactions of angiotensin-converting enzyme (ACE) inhibitors andangiotensin II (AII) receptor antagonists may differ. All of the AIIreceptor antagonists currently available for clinical use selectively blockthe AT1 receptor. This receptor appears to transduce most of the well-known effects of AII, including vasoconstriction, stimulation of cellgrowth, and secretion of aldosterone. Increasingly, however, potentiallyimportant actions of other angiotensin receptors are being discovered.For example, AT2 receptors may be involved in regulation of apoptosisand modulation of inflammation by way of secretion of RANTES (seeFig. 6-13) [13,15]. AT4 receptors bind other angiotensins preferentiallyand may promote endothelially mediated vasodilatation [16]. Activityof all pathways is reduced after administration of ACE inhibitors,whereas only AT1 receptor–mediated events are blocked by drugs cur-rently available. Whether these differences will have important conse-quences for progression of renal disease is currently unknown.

FIGURE 6-17

Three calcium channel blockers and their effects in experimental ani-mals. The results of several studies examining the effects of three dif-ferent dihydropyridine calcium channel blockers on hemodynamicsand injury in the uninephrectomized spontaneously hypertensive ratmodel of progressive glomerular sclerosis are summarized. The threedrugs produced graded declines in mean arterial pressure (MAP),with nifedipine causing the greatest and amlodipine the least reduc-tion in systemic pressure. Micropuncture determinations of glomeru-lar capillary hydraulic pressure (PGC) revealed that only nifedipineand felodipine caused glomerular pressure to decline significantly.These drugs reduced both the protein excretion rate (PROT) andmorphologic evidence of glomerular injury (SCLER). The data areconsistent with the hypothesis that antihypertensive agents amelioraterenal damage by reducing glomerular pressure and that, for calciumchannel blockers, significant reductions in PGC occur only when drugadministration causes a marked decline in systemic pressure. (FromDworkin [25,26]; with permission.)


ROLE OF HYPERTENSION IN CHRONIC RENAL DISEASE

Cause

Renal artery stenosis or occlusion

Atheroembolic disease

Hypertensive nephrosclerosis

Contributors to disease progression

Diabetes mellitus

Glomerulonephritis

Tubulointerstitial disease (?)

Adult-onset polycystic kidney disease (?)

The Effect of Hypertension on Renal Disease

FIGURE 6-18

The impact of hypertension on the incidence of end-stage renaldisease (ESRD) is vastly underestimated if one considers onlythose patients in whom systemic hypertension is the primaryprocess resulting in loss of kidney function. The group ofpatients in whom ESRD is attributed to hypertension undoubt-edly includes persons with renal disease of several causes. Someof these causes are occlusive disease of the main renal arteries asa result of atherosclerotic disease, atheroembolic disease of thekidneys, and hypertensive nephrosclerosis. The exact incidenceof these processes within the hypertensive population withchronic renal disease is unknown. Even more commonly, poorlycontrolled systemic hypertension accelerates the rate of loss ofkidney function in many patients in whom the primary cause ofrenal injury is another process altogether. This fact is particular-ly true in patients with glomerular diseases such as diabeticnephropathy and chronic glomerulonephritis [27,28]. Whethersystemic hypertension also contributes to loss of kidney functionin patients with tubulointerstitial or cystic disease of the kidneyis less certain [29].

0 10 20 30 40 50 60 70 800

100

90

80

70

60

50

40

30

20

10

90

Mean GFR, mL/min/1.73m2

Hyp

erte

nsi

ve p

erso

ns,

%

FIGURE 6-19

Hypertension prevalence corresponds with decreased glomerularfiltration rate (GFR). Hypertension is common in glomerular,tubular, vascular, and interstitial renal disease and becomesincreasingly prevalent as renal function declines. In almost 200patients screened for the Modification of Diet in Renal Diseasestudy, the prevalence of hypertension increased as the GFRdecreased and hypertension was almost universal as the GFRapproached 10 mL/min [29].

Volume/ total body sodiumexcess

Stimulation ofrenin-angiotensin

system

Augmentedsympathetic

tone

FIGURE 6-20

Multifactorial mechanisms for hypertension in clinical renal disease. An increasedintravascular volume, owing to decreased renal excretion of sodium and water as theglomerular filtration rate declines, is probably the primary cause. Activation of sympa-thetic tone and involvement of the renin-angiotensin system, which is inappropriatelystimulated in the setting of volume expansion, have been demonstrated in renal failure.Decreased activity of nitric oxide and other vasorelaxants and increased activity ofendothelin and other endogenous vasoconstrictors also are probably contributory.


0 5 100

100

80

60

40

20

15

Time since biopsy, y

Free

of r

enal

failu

re, %

Normotensive (n=79)

Hypertensive (n=69)

(53)

(30)

(18)

(2)

(7)

(17)

FIGURE 6-21

Consistent relationship between hypertension and progressiverenal disease. Analysis of the Modification of Diet in RenalDisease study, which involved patients with a heterogeneous mis-cellany of renal diagnoses, showed that the degree of elevationof the mean arterial blood pressure correlated with the decline inthe glomerular filtration rate [30]. This finding has been con-firmed in cohorts of patients with the same renal disease. Inimmunoglobulin A (IgA) nephropathy, eg, the presence of highblood pressure at diagnosis is a strong predictor for developmentof end-stage renal disease. In this study by Radford and cowork-ers [31] of 148 patients with IgA nephropathy, 69 patients withhypertension had a much higher risk of proceeding to renal fail-ure than did the 79 patients who were normotensive.

0 10 20 30 40 50 60 70 800

1.0

0.8

0.6

0.4

0.2

90

Pro

bab

ility

of s

urv

ival

HBP before age 35 NBP after age 35

Age, y

FIGURE 6-22

Relationship between hypertension and renal failure. Johnson andGabow [32] studied over one thousand patients with autosomal domi-nant polycystic kidney disease. These authors demonstrated that the timeof renal survival was much shorter for patients with hypertension com-pared with patients whose blood pressure was normal (see Fig. 6-21).Renal survival was defined as the time period before the need for dialy-sis. HBP–high blood pressure; NBP–normal blood pressure.

0 10

100

80

60

40

2

Free

of r

enal

en

dp

oin

ts, %

Time, y

<120 mm Hg>120 mm Hg

Systolic blood pressure

P<0.001

FIGURE 6-23

Hypertension accelerates progression of renal failure in children and adults. For 2 years,Wingen and coworkers [33] followed almost 200 children and adolescents with renal dis-ease, aged 2 to 18 years. Here, renal survival is defined as stability of the creatinine clear-ance rate. Compared with patients with systolic blood pressures lower than 120 mm Hg,those with systolic blood pressures higher than 120 mm Hg had more rapid developmentof renal death. Renal death was defined as a decrease in the creatinine clearance rate by10 mL/min/1.73 m2.


0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

0

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

18

Years since screening

ESR

D d

ue

to a

ny

cau

se, %

OptimalNormal but not optimalHigh normalStage 1 hypertensionStage 2 hypertensionStage 3 hypertensionStege 4 hypertension

Deterioratingrenal

function

Deterioratingrenal

function

Controlleddiastolic blood pressure

<90 min Hg

Uncontrolleddiastolic blood pressure

<90 min Hg

Stablerenal

function

Stablerenal

function

16% 12%

FIGURE 6-24

There long has been controversy over whether hypertensionalone, without renal disease, can cause renal failure, especially inwhites. Recent convincing epidemiologic evidence, however, links

FIGURE 6-25

Hypertension and impact on progression of renal disease caused byhypertension. In a study of 94 patients with essential hypertensionand an initially normal serum creatinine concentration, Rostandand coworkers [35] showed that hypertension control apparentlyhad little impact on progression of renal disease. When patientswere divided into those with diastolic blood pressures higher andlower than 90 mm Hg, the percentage whose renal function deteri-orated was equivalent in both groups. Blacks were at especiallyhigh risk; 23% of black patients with diastolic blood pressuresbelow 90 mm Hg had worsened renal function over time, com-pared with 11% of white patients with diastolic blood pressureslower than 90 mm Hg.

B3 F4 F12 F20 F2815

0

3

6

9

12

F36

Time, mo

Dec

line

in G

FR m

L/m

in

Blood pressure

Low BP group

Usual BP group

FIGURE 6-26

Lower-than-usual blood pressure (BP) target. The Modification ofDiet in Renal Disease study [36] also prospectively examined theeffect of a lower-than-usual BP target in a larger cohort of patientswith renal insufficiency. Patients were randomized to two targetBPs: a usual mean arterial pressure (MAP) target of 107 mm Hg,corresponding to a BP of 140/90 mm Hg; or a low MAP target of92 mm Hg, corresponding to a BP of 125/75 mm Hg. The changesin the glomerular filtration rate (GFR) in the two groups over a 3-year follow-up period are depicted. (The y-axis depicts the changesin GFR, and the x-axis represents months. For example, F36 means36 months after initiation of the study.) Patients in the two groupshad statistically equivalent declines in GFR. Over the last 6 monthsof the study, however, a trend toward greater stabilization in renalfunction occurred in the group randomized to the lower target.

hypertension to later development of renal failure. In over300,000 men screened for the Multiple Risk Factor InterventionTrial, Klag and coworkers [34] showed that a single blood pres-sure measurement was strongly correlated with the risk of end-stage renal disease (ESRD) later in life. Even men with high-nor-mal blood pressures (defined as a systolic pressure of 130 to 139mm Hg or a diastolic blood pressure of 85 to 89 mm Hg) were ata statistically significant greater risk for ESRD than were menwith blood pressures under 120/80 mm Hg. This risk increasessequentially with the higher stage of hypertension. This studyused definitions of hypertension discussed in the Fifth Report ofthe Joint National Committee on Detection, Evaluation andTreatment of High Blood Pressure (JNC-5). Stage I hypertensionis defined as a systolic pressure of 140 to 159 mm Hg and a dias-tolic pressure of 90 to 99 mm Hg. Stage II hypertension isdefined as a systolic pressure of 160 to 179 mm Hg and a dias-tolic pressure of 100 to 109 mm Hg. Stage III hypertension is asystolic pressure of 180 to 209 mm Hg and a diastolic pressure of110 to 119 mm Hg. Stage IV hypertension is a systolic pressureof 210 mm Hg or higher and a diastolic blood pressure of 120mm Hg or greater. The highest relative risk for renal failure wasamong persons with stage III or IV hypertension.


12

0

4

8

12

0

4

8

Mea

n r

ate

of G

FR d

eclin

e, m

L/m

in/y

n=420 n=101 n=54 n=136 n=63 n=32

31–<3 31–<3<1 <1

Baseline urinary protein, g/d

Study 1 Study 2

Patients randomized to low BP targetPatients randomized to the usual BP target

FIGURE 6-27

Two patient groups in the study of diet inrenal disease. The Modification of Diet inRenal Disease (MDRD) study involved twopatient groups. The group in which patientshad moderate renal dysfunction (glomerularfiltration rate [GFR] between 25 and 55mL/min) was called Study 1. The other group,which included patients who had more severerenal dysfunction (with a GFR between 13and 24 mL/min) was called Study 2. Theeffects of the lower blood pressure (BP) targeton patients with proteinuria in Studies 1 and2 are shown. The y-axis divides patients inStudies 1 and 2 into three groups, dependingon urinary protein excretion. The x-axis rep-resents the rate of GFR decline. In the subsetof patients in the MDRD trial in both Studies1 and 2 who had massive proteinuria (proteinover 3 g/24 h), the lower blood pressure hadan especially salutary effect: the decline inGFR was much slower [37].

0 6 12 18 24 300.60

1.00

0.95

0.90

0.85

0.80

0.75

0.70

0.65

Renal survival

Proteinuria: <1g/24h

mean BP: <107 mm Hg

Proteinuria: <1g/24h

mean BP: >107 mm Hg

Proteinuria: <1–3g/24h

mean BP: <107 mm Hg

Proteinuria: <1–3g/24h

mean BP: >107 mm Hg

Time, mo

FIGURE 6-28

Proteinuria as a marker for progressive renal disease. Nephroticproteinuria may be a more important and independent marker forprogression of renal disease than is hypertension. That is, patientsin whom massive proteinuria and hypertension coexist have theworst renal prognosis. In a study of over 400 patients with renalinsufficiency followed over 2 years, Locatelli and coworkers [38]found that patients who had both a mean blood pressure (BP)higher than 107 mm Hg and protein excretion of 1 to 3 g/24 h hadthe lowest rates of renal survival.

-12 -6 0 6 12 18 24 3010

100

90

80

70

60

50

40

30

20

36

Evolution of creatinine clearance

Cre

atin

ine

clea

ran

ce, m

L/m

in

Group A Group B

FIGURE 6-29

The effect of reduction of proteinuria on the stabilization of renalfunction. The observations that the potentially correctable factors ofhypertension and proteinuria predict the decline of renal function leadto the hypothesis that antihypertensive agents in the angiotensin-con-verting enzyme (ACE) inhibitor class may be especially important intreatment of hypertension in renal disease. Praga and coworkers [39]investigated 46 patients with nondiabetic renal disease and massiveproteinuria treated with the ACE inhibitor captopril. These authorsfound that proteinuria was decreased by about half. In patients withthe greatest reduction in proteinuria (group A), a greater stabilizationof renal function occurred over time when compared with those(group B) whose reduction in proteinuria was less.


0 0.5 1.0 1.5 2.0 2.5 3.0 3.50

50

45

40

35

30

25

20

15

10

5

4.0

P=0.007

Placebo

Captopril

Perc

enta

ge w

ith

do

ub

ling

of b

asel

ine

crea

tin

ine

Years of follow-up

FIGURE 6-30

Large study of patients with diabetes mellitus and renal diseaserandomly assigned to captopril or placebo. Lewis and coworkers[40] have studied the use of the angiotensin-converting enzymeinhibitor captopril in patients with type I diabetes mellitus whohave diabetic nephropathy and proteinuria. Captopril providesstrong protection against progression of renal disease. Thosepatients treated with captopril had a significant decrease in pro-teinuria and a slower rate of disease progression, as defined bythe time to doubling of the serum creatinine, as compared withpatients randomized to placebo.

0

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

Ramipril

Placebo

n=20n=36n=61M

ean

rat

e o

f GFR

, mL/

min

/mo

Baseline urinary protein excretion, 1g/24h

FIGURE 6-31

Study of patients with renal disease not associated with diabetesrandomly assigned to ramipril or placebo. A study structured simi-larly to that in Figure 6-30 examined the use of the angiotensin-converting enzyme inhibitor ramipril in over 150 patients withnondiabetic renal disease [41]. The primary conclusion of the studyis summarized. Blood pressure and proteinuria decreased more sig-nificantly in the patients treated with ramipril. This group had sig-nificantly lower rates of decline in glomerular filtration rate (GFR)over time. This effect was increasingly striking as the baseline levelof proteinuria increased and was most pronounced in patients witha urinary protein excretion of over 7 g per 24 hours.

Reference

Zucchelli et al. [43]Kamper et al. [44]Brenner (Unpublished data)

Toto (Unpublished data)

van Essen et al. [45]Hannedouche et al. [46]Bannister et al. [47]Himmelmann et al. [48]Becker et al. and Ihle et al. [49,50]Maschio et al. [51]

Overall

Country

ITDENUSAUSAHOLFRAUSSWAUS

EUR

Year

199219921993199319941994199419951996

1996

Patients, n

121701121241031005126070

583

Favors ACE inhibitors Favors other drugs

0.01 0.02 0.05 0.1 0.2 0.5 1 2 5 10 20 50 100

Relative risk for ESRD

FIGURE 6-32

Meta-analysis of over 1500 patients withrenal insufficiency. A recent meta-analysisexamined randomized studies comparing an angiotensin-converting enzyme inhibitor(ACE) to other antihypertensive agents[42]. None of the individual studiesshowed that the relative risk for develop-ment of end-stage renal disease (ESRD)was statistically lower in patients treatedwith ACE inhibitors. The pooled relativerisk, incorporating data from all the stud-ies, however, was lower in the cohortgroups treated with ACE inhibitors.


Glomerularbasement

membrane

Podocytes

No change inproteinuria

Decreasedproteinuria

Dihydropyridinecalcium channel blockers

Non-dihydropyridinecalcium channel blockers

NifedipineAmlodipineFelodipineIsradipine

Nisolodipine

DiltiazemVerapamil

FIGURE 6-33

Calcium channel blockers. Calcium channel blockers are prescribedwidely to patients with normal renal function and affect renal pro-tein excretion variably. The general consensus is that the nondihy-dropyridine calcium channel blockers diltiazem and verapamildecrease proteinuria, whereas the dihydropyridine agents have min-imal or minor effects on proteinuria.

FIGURE 6-34

The effect of calcium channel blockers on preservation of renal func-tion. Most studies of angiotensin-converting enzyme (ACE) inhibitorsversus other agents did not examine calcium channel blockers. In apaper by Zucchelli and coworkers [43], patients with nondiabeticrenal diseases and hypertension initially were treated with adrenergicantagonists, diuretics, and vasodilators. These patients were then ran-domized to treatment with the dihydropyridine calcium entry antago-nist nifedipine or to the ACE inhibitor enalapril. The rate of declinein renal function was most rapid in the pre-randomization phase inpatients treated with conventional antihypertensive agents, mostlyadrenergic antagonists. The rate of decline then slowed after random-ization. No significant difference in rates of decline was seen inpatients treated with nifedipine compared with those treated withcaptopril. (From Zucchelli and coworkers [43]; with permission.)

0 6 12 18 24 30 360

100

80

60

40

20

42

Time, mo

Ren

al s

urv

ival

, %

CaptoprilNifedipine

1998181816

1989181816

1990181816

1991181715

1992161613

1993161511

1994151511

20

40

60

LisinoprilNDCCBsAtenolol

Cre

atin

ine

clea

ran

ce, m

L/m

in/1

.73

m2

Atenolol

NDCCBs

Lisinopril

FIGURE 6-35

The effect of angiotensin-converting enzyme inhibitors and other antihyperten-sive agents on stabilization of renal func-tion in non–insulin-dependent diabetes.Bakris and coworkers [52] studied patientswith non–insulin-dependent diabetes melli-tus, hypertension, proteinuria, and pre-sumed diabetic nephropathy. These patientswere randomized to treatment with theangiotensin-converting enzyme inhibitorlisinopril; the beta-blocker atenolol; or anondihydropyridine calcium channel block-er (NDCCB), either verapamil or diltiazem.The primary conclusion of the study is sum-marized. The change in glomerular filtra-tion rate as a function of time is depicted ingroups of patients receiving lisinopril, calci-um channel blockers, or atenolol. The crea-tinine clearance rate declined in all threegroups. However, the slope of the declinewas significantly greater in the group treat-ed with atenolol and not significantly dif-ferent between the groups treated withlisinopril and the calcium entry antagonist.


090

120

115

110

105

100

95

FV6FV3RVGFR2GFR1Baseline

Mea

n B

P, m

m H

g

AtenololAmiodipineEnalapril

Time, mo

FIGURE 6-36

Race and ethnicity in choice of antihypertensive agents. Racial andethnic differences also may be important in determining the choiceof antihypertensive agent to delay progression of chronic renal dis-ease. Blacks are at much higher risk than are whites for progres-sion of renal disease. In addition, a more aggressive antihyperten-sive program may be beneficial to blacks. In the Modification ofDiet in Renal Disease study, a trend toward a more gradual declinein renal function in blacks randomized to the low mean bloodpressure target was seen [36]. Blacks tend to have a better bloodpressure response to administration of diuretics than do whites. Ina large study of patients with normal renal function, blacks alsoresponded well to calcium channel blockers [53]. The African-American Study of Kidney Disease and Hypertension (AASK), cur-rently in progress, is examining the hypothesis that a lower-than-usual blood pressure goal will have a renal protective effect inrenal disease with hypertension. A preliminary finding from thestudy is depicted. The study randomized blacks with hypertensionto the beta-blocker atenolol, the dihydropyridine calcium channelblocker amlodipine, or the angiotensin-converting enzymeenalapril. In the initial 6 months of the study, the mean arterialblood pressure decreased most significantly in the short term withamlodipine [54]. GFR–glomerular filtration rate.

Blood pressure: 130/85 mm Hg or higher with renal disease

Proteinuria: 1G/24h or more

Begin ACE inhibitorTarget blood pressure: 125/75 mm Hg or lower

If hyperkalemia or acute renal failure develops, evaluate possible causes

If no other precipitant, decrease ACE inhibitor doseAdd diuretic, calcium channel blocker

A

Blood pressure:> 130/185 mm HG or higher with renal disease

Proteinuria: 1g/24h or less

Diabetic or primary glomerular disease

Yes No

Treatment with ACE inhibitorTarget blood pressure:

125/75 mm Hg or lower

Treatment with diuretic,ACE inhibitor, orcalcium channel

blocker

B

FIGURE 6-37

Treatment of patients with renal disease and high-normal or elevatedblood pressure (BP). A, All patients should have a measurement of 24-hour protein excretion. If the protein excretion is over 1 g/24 h, anangiotensin-converting enzyme (ACE) inhibitor should be started. Thegoal of hypertension control in patients with azotemia who have mas-sive proteinuria should be a blood pressure of 125/75 mm Hg or lower.It is unlikely that an ACE inhibitor alone will be able to decrease theblood pressure to this level before hyperkalemia or hemodynamicallymediated acute renal failure intervenes. A diuretic and medications fromother classes, such as a calcium channel blocker, should then be added.

Management of Hypertension in Clinical Renal Disease

B, When protein excretion is less than 1 g/24 h, the blood pres-sure should be lowered to at least 130/85 mm Hg. No conclusiveevidence exists to support the use of one antihypertensive agentor class of agents over another. However, in patients at risk forprogressive proteinuria (eg, diabetic patients with microalbumin-uria), ACE inhibitors should be used. Given the importance ofsodium retention in the hypertension in renal disease, a loop or thiazide diuretic is a reasonable initial treatment. An ACEinhibitor or calcium channel blocker should be added as a second-line agent.


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34. Klag MJ, Whelton PK, Randall BL, et al.: Blood pressure and end-stage renal disease in men. N Engl J Med 1996, 334:13–18.

35. Rostand SG, Brown G, Kirk KA, et al.: Renal insufficiency in treatedessential hypertension. N Engl J Med 1989, 320:684–688.

36. Klahr S, Levey A, Beck GJ, et al. for the Modification of Diet in RenalDisease Study Group. N Engl J Med 1994, 330:877–884.

37. Peterson JC, Adler S, Burkart JM, et al. for the Modification of Dietin Renal Disease Study Group. Ann Intern Med 1995, 123:754–762.

38. Locatelli F, Marcelli D, Comelli M, et al. for the Northern ItalianCooperative Study Group: proteinuria and blood pressure as causalcomponents of progression to end-stage renal failure. Nephrol DialTransplant 1996, 11:461–467.

39. Praga M, Hernandez E, Montoyo C, et al.: Long-term beneficialeffects of angiotensin-converting enzyme inhibition in patients withnephrotic proteinuria. Am J Kidney Dis 1992, 20:240–248.

40. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD for the CollaborativeStudy Group: The effect of angiotensin-converting enzyme inhibitionon diabetic nephropathy. N Engl J Med 1993, 329:1456–1462.


41. Gruppo Italiano di Studi Epidemiologici in Nefrologia: Randomisedplacebo-controlled trial of effect of ramipril on decline in glomerularfiltration rate and risk of renal failure in proteinuric, non-diabeticnephropathy. Lancet 1997, 349:1857–1863.

42. Giatras I, Lau J, Levey AS for the Angiotensin-Converting EnzymeInhibition and Progressive Renal Disease Study Group: Effect ofangiotensin-converting enzyme inhibitors on the progression of nondi-abetic renal disease: a meta-analysis of randomized trials. Ann InternMed 1997, 127:337–345.

43. Zucchelli P, Zuccala A, Borghi M, et al.: Long-term comparisonbetween captopril and nifedipine in the progression of renal insuffi-ciency. Kidney Int 1992, 42:452–458.

44. Kamper AI, Strandgaard S, Leyssac PP: Effect of enalapril on the progression of chronic renal failure: a randomized controlled trial.Am J Hypertens 1992, 5:423–430.

45. van Essen GG, Apperloo AJ, Sluiter WJ, et al.: Is ACE inhibition superior to conventional antihypertensive therapy in retarding progres-sion in non-diabetic renal disease? J Am Soc Nephrol 1996, 7:1400.

46. Hannedouche T, Landais P, Goldfarb B, et al.: Randomized controlledtrial of enalapril and beta-blockers in non-diabetic chronic renal failure. BMJ 1994, 309:833–837.

47. Bannister KM, Weaver A, Clarkson AR, Woodroffe AJ: Effect ofangiotensin-converting enzyme and calcium channel inhibition on progression of IgA nephropathy. Contrib Nephrol 1995, 111:184–193.

48. Himmelmann A, Hansson L, Hannson BG, et al.: ACE inhibition preserves renal function better than beta-blockers in the treatment of essential hypertension. Blood Pressure 1995, 4:85–90.

49. Becker GJ, Whitworth JA, Ihle BU, et al.: Prevention of progression in non-diabetic chronic renal failure. Kidney Int Suppl 1994,45:S167–S170.

50. Ihle BU, Whitworth JA, Shahinfar S, et al.: Angiotensin-convertingenzyme inhibition in nondiabetic progressive renal insufficiency: acontrolled double-blind trial. Am J Kidney Dis 1996, 27:489–495.

51. Maschio G, Aliberti D, Janin G, et al.: Effect of the angiotensin-converting enzyme inhibitor benazepril on the progression of renalinsufficiency. N Engl J Med 1996, 334:939–945.

52. Bakris GL, Copley JB, Vicknair N, et al.: Calcium channel blockersversus other antihypertensive therapies on progression of NIDDMassociated nephropathy. Kidney Int 1996, 50:1641–1650.

53. Materson BJ, Reda DJ, Cushman WC, et al.: Single-drug therapy forhypertensive men: a comparison of six antihypertensive agents withplacebo. N Engl J Med 1993, 328:914–921.

54. Hall WD, Kusek JW, Kirk KA, et al. for the African-American Studyof Kidney Disease and Hypertension Pilot Study Investigators. Am JKidney Dis 1997, 29:720–728.

7

Pharmacologic Treatmentof Hypertension

This chapter reviews the currently available classes of drugs usedin the treatment of hypertension. To best appreciate the com-plexity of selecting an antihypertensive agent, an understanding

of the pathophysiology of hypertension and the pharmacology of thevarious drug classes used to treat it is required. A thorough under-standing of these mechanisms is necessary to appreciate more fully theworkings of specific antihypertensive agents. Among the factors thatmodulate high blood pressure, there is considerable overlap. The drugtreatment of hypertension takes advantage of these integrated mecha-nisms to alter favorably the hemodynamic pattern associated withhigh blood pressure.

Garry P. ReamsJohn H. Bauer

C H A P T E R


↑ Preload

BLO OD PRE SSURE = C ARDIAC OUTPUT × PER IPHER AL VA SCUL AR RE SISTANCEHyp er tens ion = Increa sed CO and/or Increa sed PVR

Stress Obesity

↑ Fluid volume Volumeredistribution

Functionalconstriction

Structuralhypertrophy

Hyper-insulinemia

Geneticalteration

Geneticalteration

Renalsodium

retention

Excesssodiumintake

Endothelium-derivedfactors

Decreasedfiltrationsurface

Sympatheticnervous over-

activity

Renin-angiotensin

excess

Cellmembranealteration

↑ Contractility

Autoregulation

Pathogenesis of hypertension

FIGURE 7-1

Pathogenesis of hypertension. Mean arterial pressure (MAP) is theproduct of cardiac output (CO) and peripheral vascular resistance

Pathogenesis of Hypertension

Incr

ease

, %

SS

Mean arterial pressure

0

10

20

NSS

FIGURE 7-2

Blood pressure changes and diet. Many hypertensive patients appear to be sodium sensitive,as first suggested by studies in 19 hypertensive subjects who were observed after “normal”(109 mmol/d), “low” (9 mmol/d), and “high” (249 mmol/d) sodium intake [2]. This figureshows the percent increase in mean blood pressure in salt-sensitive (SS) and non–salt-sensi-tive (NSS) patients with hypertension when their diet was changed from low sodium tohigh sodium. Vertical lines indicate mean ± standard deviation. (From Kawasaki et al. [2];with permission.)

(PVR). There are a large number of control mechanisms involvedin every type of hypertension. (From Kaplan [1]; with permission.)

7.3Pharmacologic Treatment of Hypertension

Extr

acel

lula

r flu

idvo

lum

e, L

0 4 8 12 16Days

151617181920 33 %

Bloo

d vo

lum

e,L

5.0

5.5

6.020 %

5 %

Mea

n ci

rcul

ator

yfil

ling

pres

sure

,m

m H

g

10121416 60 %

20 %

Pres

sure

gra

dien

tfo

r ven

ous

retu

rn, m

m H

g

10

50

111213

40 %

35 %

44 %

Card

iac

outp

ut,

L/m

in

55606570

5 %

38 %

45 %

4 %

Tota

l per

iphe

ral

resi

stan

ce,

mm

Hg/

L/m

in

152025303540

–11 %

Arte

rial p

ress

ure,

mm

Hg

100110120130140150

22.5 %

Set-point elevated

FIGURE 7-3

Cardiac output. An increase in cardiac output has been suggestedas a mechanism for hypertension, particularly in its early border-line phase [3,4]. Sodium and water retention have been theorizedto be the initiating events. Sequential changes following salt load-ing are depicted [3]. The resultant high cardiac output perfuses theperipheral tissues in excess of their metabolic requirements, result-ing in a normal autoregulatory (vasoconstrictor) pressure. Theearly phase of high cardiac output and normal peripheral vascularresistance gradually changes to the characteristic feature of thesustained hypertensive state: normal cardiac output and highperipheral vascular resistance. Shown here are segmental changesin the important cardiovascular hemodynamic variables in the firstfew weeks following the onset of short-term salt-loading hyperten-sion. Note especially that the arterial pressure increases ahead ofthe increase in total peripheral resistance. (From Guyton andcoworkers [3]; with permission.)


500 1000

VO2 mL min–1 m–2 VO2 mL min–1 m–2 VO2 mL min–1 m–2

DAP

MAP

SAP

BP,

mm

Hg

HR

bea

ts m

in–

1SI

mL

stro

ke–

1 m

–2

CI L

min

–1 m

–2

TPR

I dyn

s c

m–

5 m

–2

100

120

140

160

180

200

500 1000

30

50

70

60

100

150

500 1000

5

10

1000

2000

3000

4000

FIGURE 7-4

Peripheral vascular resistance. Most established cases of hypertensionare associated with an increase in peripheral vascular resistance [5].These alterations may be related to a functional constriction, thetype observed under the influence of circulating or tissue-generatedvasoconstrictors, or may be a result of structural alterations in theblood vessel. Solid line indicates values at start of the study [9];

dashed line indicates results after 10 years; dotted line indicates resultsafter 20 years. BP—blood pressure; CI—cardiac index; DAP—diastolicarterial blood pressure; HR—heart rate; MAP—mean arterial pressure;SAP—systolic arterial blood pressure; SI—stroke index; TPRI—totalperipheral resistance index; VO2—oxygen consumption. (From Lund-Johansen [5]; with permission.)


CLASSES OF ANTIHYPERTENSIVE DRUGS

Diuretics: benzothiadiazides, loop, and potassium-sparing

�-adrenergic and �1/�-adrenergic antagonists

Central �2-adrenergic agonists

Central/peripheral adrenergic neuronal-blocking agent

Peripheral �1-adrenergic antagonists

Moderately selective peripheral �1-adrenergic antagonist

Peripheral adrenergic neuronal blocking agents

Direct-acting vasodilators

Calcium antagonists


Tyrosine hydroxylase inhibitor

Angiotensin II receptor antagonists

Classes of Antihypertensive Drugs and Their Side Effects

FIGURE 7-5

Classes of antihypertensive drugs. There are 12 currently availableclasses of antihypertensive agents.

Time

Rx No Rx

PRA

TPRCO

TPR

CO

ISF

PV

BP

FIGURE 7-6

Hemodynamic response to diuretics. Diuretics reduce mean arterialpressure by their initial natriuretic effect [6]. Acutely, this is achievedby a reduction in cardiac output mediated by a reduction in plasmaand extracellular fluid volumes [7]. Initially, peripheral vascularresistance is increased, mediated in part by stimulation of the renin-angiotensin system. During sustained diuretic therapy, cardiac outputreturns to pretreatment levels, probably reflecting restoration ofplasma volume. Chronic blood pressure control now correlates witha reduction in peripheral vascular resistance. BP—blood pressure;CO—cardiac output; ISF—interstitial fluid; PRA—plasma reninactivity; PV—plasma volume; Rx—treatment; TPR—total peripheralresistance. (Adapted from Tarazi [7].)


A. DIURETICS: BENZOTHIADIAZIDES (PARTIAL LIST) AND RELATED DIURETICS

Generic (trade) name

Hydrochlorothiazide (G)

(Hydrodiuril, Microzide)

Chlorthalidone (G)

(Hygroton)

Indapamide

(Lozol)

Metolazone

(Mykrox)*;

(Zaroxolyn)

First dose, mg

12.5

12.5

1.25

0.5

2.5

Usual dose

12.5–50 mg QD

12.5–50 mg QD

2.5–5.0 mg

0.5–1.0

2.5–10 mg QD

Maximum dose

100

100

5

1

20

Duration of action, h

6–12

48–72

15–18

12–24

12–24

*Marketed only for treatment of hypertension.

(G)—generic available.

B. DIURETICS: LOOP


Bumetanide (G)

(Bumex)

Ethacrynic Acid

(Edecrin)

Furosemide (G)

(Lasix)

Torsemide

(Demadex)

First dose, mg

0.5

25

20

5

Usual dose

0.5–2 mg bid

25–50 mg bid

20–120 mg bid

5–50 mg bid

Maximum dose

10

200

600

100


4–6

6–8

6–8

6–8


C. DIURETICS: POTASSIUM-SPARING DIURETICS


Spironolactone (G)

(Aldactone)

Amiloride (G)

(Midamor)

Triamterene (G)

(Dyrenium)

First dose, mg

25

5

50

Usual dose

50–1 00 mg QD

5–10 mg QD

50-100 mg bid

Maximum dose

400

20

300


48–72

24

7–9


FIGURE 7-7

A–C. Diuretics: benzothiadiazides and related agents, loop diuretics,and potassium-sparing agents. A partial list of benzothiadiazidesand their related agents is given [6]. With the exception of inda-pamide and metolazone, their dose-response curves are shallow;they should not be used when the glomerular filtration rate isless than 30 mL/min/1.73 m2. The second group listed is loop

diuretics. Because of their steep dose-response curves and natri-uretic potency, they are especially useful when the glomerular filtration rate is less than 30 mL/min/1.73 m2. The third group is the potassium-sparing diuretics. The major therapeutic use ofthese drugs is to attenuate the loss of potassium induced by theother diuretics.


Loopdiuretics

Lumen

HCO3

HCO3H2CO3

H2O + CO2H2O + CO2

H2CO3

Na

CAI CACAI

PT

CA

H

3Na

2K

Blood

Lumen Blood

Lumen Blood

NaK

2Cl

TAL

3Na

2K~

DCT

diuretics

Na

Cl

3Na

2K~

~

Lumen

PCDCT

DT

PT

LH

CD

Blood

Na channel

blockers

Na

K

3Na

2K~

FIGURE 7-8

Mechanisms of action of diuretics. This figure depicts the major sites and mechanisms of action of diuretic drugs [8]. The diuretic/natriuretic action of benzothiadiazide-type diuretics is predicated on their gaining access to the luminal side of the distal convoluted tubule and inhibiting Na+ - Cl- cotransport by competing for the chloride site.

The diuretic/natriuretic action of loop diuretics is predicated on their gaining access to the luminal side of the thick ascending limb of the loop of Henle and inhibitingNa+ - K+ -2Cl- electroneutral cotransport by competing for the chloride site.

The diuretic/natriuretic action of potassium-sparing diuretics ispredicated on their gaining access to the luminal side of the principalcells located in the late distal tubule and cortical collecting duct andblocking luminal sodium channels. Because Na+ uptake is blocked,the lumen negative voltage is reduced, inhibiting K+ secretion. Thepotassium-sparing diuretic spironolactone does this indirectly by competing with aldosterone for its cytosolic receptor. CA—carbonicanhydrase; CAI—carbonic anhydrase inhibitor; CD—collecting duct;DCT—distal convoluted tubule; DT—distal tubule; LH—loop ofHenle; PC—principal cell; PT—proximal tubule; TAL—thick ascend-ing limb. (From Ellison [8]; with permission.)


THE SIDE EFFECT PROFILE OF DIURETIC THERAPY

Side effects

Thiazide-type diuretic

Azotemia

Hypochloremia, hypokalemia, metabolic alkalosis

Hypomagnesemia

Hyponatremia

Hypercalcemia

Hyperuricemia

Carbohydrate intolerance

Hyperlipidemia

Increased total triglyceride

Increased total cholesterol

Loop-type diuretics

Ototoxicity

Hypocalcemia

Potassium-sparing diuretics

Hyperkalemia

Decreased sexual function, gynecomastia, menstrualirregularity, hirsutism

Renal stone

Mechanisms

Enhanced proximal fluid and urea reabsorption secondaryto volume depletion

Increased delivery of sodium to distal tubule facilitating Na+-K+ and Na+-H+ exchange; increased net acid excretion;increased urinary flow rate; secondary aldosteronism

Increase fractional Mg2+ excretion by inhibiting reabsorp-tion in ascending limb of loop of Henle

Impaired free water clearance (distal cortical diluting segment)

May reflect an increased protein-bound fraction secondaryto volume depletion

Impair enhanced proximal fluid and urate reabsorptionsecondary to volume depletion

Hypokalemia impairing insulin secretion; decreased insulin sensitivity

May be due to extracellular fluid depletion

High plasma concentration of furosemide or ethacrynic acid

Increase fractional excretion of calcium by interfering withreabsorption in loop of Henle

Blocks potassium excretion

Spironolactone only; lower circulatory testosterone levelsby increasing metabolic clearance and/or preventingcompensatory rise in testicular androgen production

Triamterene only

FIGURE 7-9

The side effect profile of diuretic therapy.The complications of diuretic therapy aretypically related to dose and duration oftherapy, and they decrease with lowerdosages. This table lists the most commonside effects of diuretics and their proposedmechanism of action [6].


Adrenal gland

KidneyE

β-b

lock

ers

Effe

cto

r ce

ll

β1

β2

Heart ↓ CO

BP

↑ TPR

NE

NE

Sympatheticneuron

+

Bloodvessels

FIGURE 7-10

�-adrenergic antagonists. �-adrenergic antagonists attenuate sym-pathetic activity through competitive antagonism of catecholaminesat both �1- and �2-adrenergic receptors [6,9]. In the absence ofpartial agonist activity (PAA), the acute systemic hemodynamiceffects are a decrease in heart rate and cardiac output and an increasein peripheral vascular resistance proportional to the degree of cardio-depression; blood pressure is unchanged. Chronically, there is a gradualdecrease in blood pressure proportional to the fall in peripheralvascular resistance, which is dependent on the degree of cardiacsympathetic drive. �-adrenergic antagonists with sufficient partialagonist activity to maintain heart rate and cardiac output may notevoke acute reflex vasoconstriction: Blood pressure falls propor-tional to the decrease in peripheral resistance (see Fig. 7-11) [10].BP—blood pressure; CO—cardiac output; E—epinephrine; NE—norepinephrine; TPR—total peripheral resistance.

80

Time (hours to days)

90

100

110

120

Vas

cula

r re

sist

ance

, %

Car

dia

c o

utp

ut,

%M

AP,

%

130

80

100

90

80

100

90

FIGURE 7-11

Hemodynamic changes associated with �-adrenergic blockade. Time course of hemody-namic changes after treatment with a �-adrenergic blocker devoid of partial agonist activ-ity (PAA) (solid line) as compared with hemodynamic changes after administration of a�-adrenergic blocker with sufficient PAA to replace basal sympathetic tone (eg, pindolol)(broken line). MAP—mean arterial pressure. (From Man in’t Veld and Schalekamp [10];with permission.)


A. DOSING SCHEDULES FOR �-ADRENERGIC ANTAGONISTS: NON-SELECTIVE (�1 AND �2) ADRENERGIC ANTAGONISTS THAT LACK PARTIAL AGONIST ACTIVITY


Nadolol (G)

(Corgard)

Propranolol (G)

(Inderal)

(Inderal LA)

Timolol (G)

(Blockadren)

First dose, mg

40

40

80

10

Usual daily dose, mg

40–240 QD

40–120 bid

80–240 QD

10–30 bid

Maximum daily dose, mg

320

480

480

60


>24

>12

>12

>12

G—generic available.

B. DOSING SCHEDULES FOR �-ADRENERGIC ANTAGONISTS: NON-SELECTIVE (�1 AND �2) ADRENERGIC ANTAGONISTS WITH PARTIAL AGONIST ACTIVITY


Pindolol (G)

(Visken)

Carteolol

(Cartrol)

Penbutolol

(Levatol)

First dose, mg

5

2.5

10


10–30 bid

2.5–10 QD

10–20 QD


60

10

40


12

24

24


C: DOSING SCHEDULES FOR �-ADRENERGIC ANTAGONISTS: �1-SELECTIVE ADRENERGIC ANTAGONISTS THAT LACK PARTIAL AGONIST ACTIVITY


Atenolol (G)

(Tenormin)

Metoprolol Tartrate (G)

(Lopressor)

Metoprolol Succinate

(Toprol-XL)

Betaxolol

(Kerlone)

Bisoprolol

(Zebeta)

First dose, mg

50

50

50

5

5


50–100 QD

50–150 bid

100–300 QD

10–20 QD

5–20 QD


200

400

400

40

40


24

12

12

>24

12


FIGURE 7-12

Dosing schedules for �-adrenergic antagonists. A, Nonselective �-adrenergic antagonists that lack partial agonist activity. B, Nonselective

�-adrenergic antagonists with partial agonist activity. C, �1-selectiveadrenergic antagonists that lack partial agonist activity.



D. DOSING SCHEDULES FOR �-ADRENERGIC ANTAGONISTS: �1-SELECTIVE ADRENERGIC ANTAGONISTS WITH WEAK PARTIAL AGONIST ACTIVITY


Acebutolol

(Sectrol)

First dose, mg

200


400–800 QD


1200


24

E. DOSING SCHEDULES FOR �-ADRENERGIC ANTAGONISTS: �1-NONSELECTIVE �-ADRENERGIC ANTAGONISTS LABETALOL (G)


Labetalol (G)

(Normodyne)

(Trandate)

Carvedilol

(Coreg)

First dose, mg

100

6.25


100-600 bid

6.25-25 bid


2400

50


12

6



D, �1-selective adrenergic antagonists with weak partial agonistactivity. E, �1-nonselective �-adrenergic antagonists.


PHARMACOKINETICS OF �-ADRENERGIC ANTAGONISTS

Nadolol

Propranolol

Propranolol LA

Timolol

Pindolol

Carteolol

Penbutolol

Atenolol

Metoprolol tartrate

Metoprolol succinate

Betaxolol

Bisoprolol

Acebutolol

Labetalol

Carvedilol

Absorption

30%–40%

>90%

>90%

>90%

>90%

>90%

>90%

50–60%

>90%

>90%

>90%

>90%

70%

>90%

>90

Solubility

Hydrophilic

Lipophilic

Lipophilic

Lipophilic

Lipophilic

Hydrophilic

Lipophilic

Hydrophilic

Lipophilic

Lipophilic

Lipophilic

Equal

Lipophilic

Lipophilic

Lipophilic

Peak concentration, h

2–4

1–3

6

1–2

1–2

1–3

2–3

2–4

1–2

7

1.5–6

2–4

2–4

1–2

1–2

First-pass hepaticmetabolism

<10%

60%

80%

50%

<10%

<10%

<10%

<10%

50%

50%

<10%

20%

30%

60%

70–80%

Active metabolite

None

Yes

Yes

None

None

Yes

Yes

None

None

None

None

None

Yes

None

Yes

Plasma half-life, h

20–24

3–4

10

3–4

3–4

5–6

5

6–7

3–7

3–7

14–22

9–12

3–4

3–4

7–10

Dose reduction in renal failure

Yes

No

No

No

Yes

Yes

Yes

Yes

No

No

Yes

Yes

Yes

No

No

FIGURE 7-13

Pharmacokinetics of �-adrenergic antagonists.

THE SIDE EFFECT PROFILE OF �-ADRENERGIC ANTAGONISTS

Side effects

Bronchospasm

Bradycardia

Congestive heart failure; decrease inexercise tolerance

Claudication

Constipation, dyspepsia

Central nervous system manifestations(sleep disturbances, depression)

Sexual dysfunction (impotence,decrease libido)

Impaired glucose tolerance

Prolonged insulin-induced hypoglycemia

Hepatocellular necrosis

Withdrawal syndromeUnstable anginaMyocardial infarction

DyslipidemiaIncreased total triglyceridesDecreased high-density lipoproteins

cholesterol

Mechanisms

Blockade of �2-adrenergic receptors; increased airway resistance

Blockade of atrial �1/�2-adrenergic receptors; decrease in heart rate

Blockade of ventricular �1-adrenergic receptors

Blockade of peripheral vascular �2-adrenergic receptors

Blockade of gastrointestinal �1/�2-adrenergic receptors; decreased motili-ty and relaxation of sphincter tone

Blockade of CNS �1/�2-adrenergic receptors

Unknown

Impaired �2-adrenergic–mediated islet cell insulin secretion; increasehepatic glucose, and/or decrease insulin-stimulated glucose disposal

Block epinephrine-mediated counterregulatory mechanisms

Labetalol only, idiosyncratic reaction

Acute overshoot in heart rate with increased myocardial oxygen demanddue to increase in number and/or sensitivity of �-adrenergic receptorsduring chronic blockade

Increased �-adrenergic tone; reduced lipoprotein lipase activity

FIGURE 7-14

The side effect profile of �-adrenergicantagonists. The side effect profile of beta-blockers is related to the specific blockadeof �1 or �2 receptors. This table lists themore common side effects and their pro-posed mechanism(s) of action [6,9].


Inhibition of centralsympathetic activity

Blood pressurereduction

Nucleustractussolitarii

Rostralventrolateral

medulla

I1-Imidazolinereceptor

NTS RVLM

α-Methyldopaguanfacineguanabenz

Stimulates Stimulates

Clonidine

Phsysiologic effect of central α2-adrenergic agonists

Central α2adrenoceptor

FIGURE 7-15

Central �2-adrenergic agonists. Central �2-adrenergic agonists cross the blood-brain barrierand stimulate �2-adrenergic receptors in the vasomotor center of the brain stem [6,9].Stimulation of these receptors decreases sympathetic tone, brain turnover of norepinephrine,and central sympathetic outflow and activity of the preganglionic sympathetic nerves. Thenet effect is a reduction in norepinephrine release. The central �2-adrenergic agonist clonidinealso binds to imidazole receptors in the brain; activation of these receptors inhibits centralsympathetic outflow. Central �2-adrenergic agonists may also stimulate the peripheral �2-adrenergic receptors that mediate vasoconstriction; this effect predominates at high plasmadrug concentrations and may precipitate an increase in blood pressure. The usual physiologiceffect is a decrease in peripheral resistance and slowing of the heart rate; however, outputis either unchanged or mildly decreased. Preservation of cardiovascular reflexes preventspostural hypotension.

CENTRAL �2-ADRENERGIC ANTAGONISTS


�-Methyldopa (G) (Aldomet)

Clonidine (G) (Catapres)

Clonidine TTS (Catapres-TTS)

Guanabenz (Wytensin)

Guanfacine (Tenex)

First dose, mg

250

0.1

2.5 mg (TTS-1)

4

1

Usual daily dose

250–1000 mg bid

0.1–0.6 mg bid/tid

2.5–7.5 mg (TTS–1 to TTS–3) qwk

4–16 mg bid

1–3 mg QD

Maximum daily dose

3000

2.4

15 mg (TTS-3x2) 9 wk

64

3

Duration of action

24–48 h

6–8 h

7 d

12 h

36 h

G—generic available; TTS—transdermal patch.

FIGURE 7-16

Central �2-adrenergic agonists. �-Methyldopa is a methyl-substitutedamino acid that is active only after decarboxylation and conversionto �-methyl-norepinephrine. The antihypertensive effect results fromaccumulation of �2-adrenergic receptors, displacing and competing withendogenous catecholamines. Methyldopa is absorbed poorly(<50%); peak plasma concentrations occur in 2 to 4 hours. It ismetabolized in the liver and excreted in the urine mainly as the inactiveO-sulfate conjugate. The plasma half-life of methyldopa (1 to 2 hours)and its metabolites is prolonged in patients with renal insufficiency;dose reduction is required.

Clonidine, an imidazoline derivative, acts by stimulating eithercentral �2-adrenergic receptors or imidazole receptors. Clonidine maybe administered orally or by a transdermal delivery system (TTS).When given orally, it is absorbed well (>75%); peak plasma con-centrations occur in 3 to 5 hours. Clonidine is metabolized mainlyin the liver; fecal excretion ranges from 15% to 30%, and 40% to60% is excreted unchanged in the urine. In patients with renal

insufficiency, the plasma half-life (12 to 16 hours) may be extendedto more than 40 hours; dose reduction is required. When clonidineis administered transdermally, therapeutic plasma levels are achievedwithin 2 to 3 days.

Guanabenz, a guanidine derivative, is highly selective for central�2-adrenergic receptors. It is absorbed well (>75%); peak plasmalevels are reached in 2 to 5 hours. Guanabenz undergoes extensivehepatic metabolism; less than 2% is excreted unchanged in the urine.The plasma half-life (approximately 6 hours) is not prolonged inpatients with renal insufficiency.

Guanfacine is a phenylacetyl-guanidine derivative with a longerplasma half-life than guanabenz. It is absorbed well (>90%); peakplasma concentrations are reached in 1 to 4 hours. The drug isprimarily metabolized in the liver. Guanfacine and its metabolitesare excreted primarily by the kidneys; 24% to 37% is excreted asunchanged drug in the urine. The plasma half-life (15 to 17 hours)is not prolonged in patients with renal insufficiency [6,9].


THE SIDE EFFECT PROFILE OF CENTRAL �2-ADRENERGIC AGONISTS

Side effects

Sedation/drowsiness

Xerostoniia (dry mouth)

Gynecomastia in men, galactorrhea in women

Drug fever, hepatotoxicity, positiveCoombs test with or without hemolytic anemia

Sexual dysfunction, depression,decreased mental acuity

“Overshoot hypertension”RestlessnessInsomniaHeadacheTremorAnxietyNausea and vomitingA feeling of impending doom

Mechanisms

Stimulation of �2-adrenergic receptors inthe brain

Centrally mediated inhibition of cholinergic transmission

Reduced central dopaminergic inhibitionof prolactin release (methyldopa only)

Long-term tissue toxicity (methyldopa only)

Stimulation of �2-adrenergic receptor in the brain

Acute excessive sympathetic discharge in the face of chronic downregulationof central �2-adrenergic receptors inan inhibitory circuit during chronictreatment when treatment is stopped

FIGURE 7-17

The side effect profile of central �2-adrenergic agonists. The sideeffect profile of these agents is diverse [6,9].

Postganglionicadrenergicnerve ending

Preganglionicneuron

Indicates blockade

Brain stem

Ganglion

Vascular smooth muscle cells

NE

NE

NE

NE

α2

β1α1

FIGURE 7-18

Central and peripheral adrenergic neuronal blocking agents.Rauwolfia alkaloids act both within the central nervous system andin the peripheral sympathetic nervous system [6,9]. They effectivelydeplete stores of norepinephrine (NE) by competitively inhibitingthe uptake of dopamine by storage granules and by preventing theincorporation of norepinephrine into the protective chromaffingranules; the free catecholamines are destroyed by monoamine oxidase. The predominant pharmacologic effect is a markeddecrease in peripheral resistance; heart rate and cardiac output are either unchanged or mildly decreased.


CENTRAL PERIPHERAL ADRENERGIC-NEURONAL BLOCKING AGENT


Reserpine (G) (Serpasil)


0.1–.25 QD

First dose, mg

0.1


0.5

Duration of action

2–3 wk

FIGURE 7-19

Central and peripheral adrenergic neuronal blocking agents. Reserpineis the most popular rauwolfia product used. It is absorbed poorly(approximately 30%); peak plasma concentrations occur in 1 to 2hours. Catecholamine depletion begins within 1 hour of drugadministration and is maximal in 24 hours. Catecholamines arerestored slowly. Chronic doses of reserpine are cumulative. Blood

pressure is maximally lowered 2 to 3 weeks after beginning therapy.Reserpine is metabolized by the liver; 60% of an oral dose is recoveredin the feces. Less than 1% is excreted in the urine as unchanged drug.The plasma half-life (12 to 16 days) is not prolonged in patientswith renal insufficiency.

THE SIDE EFFECT PROFILE OF RESERPINE

Side effects

Altered CNS functionInability to concentrateDecrease mental acuitySedationSleep disturbanceDepression

Nasal congestion/rhinitis

Increased GI motility,increased gastric acid secretion

Increased appetite/weight gain

Sexual dysfunctionImpotenceDecreased libido

Mechanisms

Depletion of serotonin and/or catecholamine

Cholinergic effects

Cholinergic effects

Unknown

Unknown

FIGURE 7-20

The side effect profile of the central and peripheral adrenergic neuronalblocking agents [10,13]. Reserpine is contraindicated in patients with ahistory of depression or peptic ulcer disease. CNS—central nervous system; GI—gastrointestinal.

Peripheraladrenergicnerve ending


NE

NE

NE

NE

NE

NE

NE

α1

β1α2

Indicates blockade

FIGURE 7-21

Peripheral �1-adrenergic antagonists. �1-Adrenergic antagonistsinduce dilation of both resistance (arterial) and capacitance (venous)vessels by selectively inhibiting postjunctional �1-adrenergic receptors[6,9]. The net physiologic effect is a decrease in peripheral resistance;reflex tachycardia and the attendant increase in cardiac output donot predictably occur. This is due to their low affinity for prejunctional�2-adrenergic receptors, which modulate the local control of nor-epinephrine release from sympathetic nerve terminals by a negativefeedback mechanism (see Fig. 7-22) [11]. NE—norepinephrine.


Postganglionicsympathetic neuron

Postsynapticα- receptors

Synapticcleft

Targetorgan

Response

Effectorcell

NA

Synapticcleft

Nerve impulseinducesexocytotic NA release +

NA

–

αPresynapticβ-receptor

Presynapticα-receptor

Postsynapticα-receptor

α

β

Vesiclecontaining NA

Varicosity

Varicosities

SympatheticC-fiber

FIGURE 7-22

Adrenergic synapse. Nerve activity releasesthe endogenous neurotransmitter noradren-aline (NA) and also adrenaline from thevaricosities. Noradrenaline and adrenalinereach the postsynaptic �-adrenoceptors (or�-adrenoceptors) on the cell membrane ofthe target organ by diffusion. On receptorstimulation, a physiologic or pharmacologiceffect is initiated. Presynaptic �2-adrenocep-tors on the membrane (enlarged area), whenactivated by endogenous noradrenaline aswell as by exogenous agonists, inhibit theamount of transmitter noradrenaline releasedper nerve impulse. Conversely, the stimulationof presynaptic �2-receptors enhances nora-drenaline release from the varicosities. Oncenoradrenaline has been released, it travelsthrough the synaptic cleft and reaches both�- and �-adrenoceptors at postsynapticsites, causing physiologic effects such asvasoconstriction or tachycardia. (Adaptedfrom Van Zwieten [11].)

PERIPHERAL �1-ADRENERGIC ANTAGONISTS


Prazosin (G) (Minipress)

Terazosin (Hytrin)

Doxazosin (Cardura)

First dose, mg

1

1

1


2-6 bid/tid

2-5 QD/bid

2-4 QD


20

20

16

Duration of action

6-12 w

12-24 h

24 h


FIGURE 7-23

Peripheral �1-adrenergic antagonists. Prazosin is a lipophilichighly selective �1-adrenergic antagonist. It is absorbed well(approximately 90%) but undergoes variable first-pass hepaticmetabolism. Peak plasma concentrations occur in 2 to 3 hours. It is extensively metabolized by the liver and predominantlyexcreted in the feces. The plasma half-life of prazosin (2 to 4 hours) is not prolonged in patients with renal insufficiency.

Terazosin is a water-soluble quinazoline analogue of prazosinwith about one third of its potency. It is completely absorbed and undergoes minimal first-pass hepatic metabolism. Peak plasma concentrations occur in 1 to 2 hours. It is extensively

metabolized by the liver and predominantly excreted in the feces. The plasma half-life of terazosin (approximately 12 hours)is not prolonged in patients with renal insufficiency.

Doxazosin is also a water-soluble quinazoline analogue of prazosin, with about half its potency. It is absorbed well butundergoes significant first-pass hepatic metabolism; bioavail-ability is approximately 65%. Peak concentrations occur in 2 to 3 hours. It is extensively metabolized by the liver and primarily eliminated in the feces. The plasma half-life of doxa-zosin (approximately 22 hours) is not prolonged in patients with renal insufficiency [6,9].


Time, h

Mea

n B

P, m

m H

gM

ean

BP,

mm

Hg

Mea

n B

P, m

m H

g

0700 0900 1100 1300 1500 1700

80

90

100

110

120

Prazosin, 2 mg

Day 4

Prazosin, 2 mg

Day 1

Placebo

Day 0

LyingStanding

130

140

100

110

120

130

140

150

50

60

70

80

90

100

110

120

130

140

FIGURE 7-24

The side effect profile of the peripheral �1-adrenergic antagonists.�1-Adrenergic antagonists are associated with relatively few sideeffects [6,9]; the most striking is the “first-dose effect” [12]. Itoccurs 30 to 90 minutes after the first dose and is dose dependent.It is minimized by initiating therapy in the evening and by carefuldose titration. The “first-dose effect” is exaggerated by fasting,upright posture, volume contraction, concurrent �-adrenergicantagonism, or excessive catecholamine activity (eg, pheochromo-cytoma). (From Graham and coworkers [12]; with permission.)




NE

NE

NE

NE

NE

NE

NE

α1

β1α2

α2

Indicates blockade FIGURE 7-25

Moderately selective peripheral �1-adrenergic antagonists.Phenoxybenzamine is a moderately selective peripheral �1-adrenergicantagonist [6,9]. It is 100 times more potent at �1-adrenergicreceptors than at �2-adrenergic receptors. Phenoxybenzamine bindscovalently to �-adrenergic receptors, interfering with the capacityof sympathomimetic amines to initiate action at these sites.Phenoxybenzamine also increases the rate of turnover of norepi-nephrine (NE) owing to increased tyrosine hydroxylase activity,and it increases the amount of norepinephrine released by eachnerve impulse owing to blockade of presynaptic �2-adrenergicreceptors [11]. The net physiologic effect is a decrease in peripheralresistance and increases in heart rate and cardiac output. Posturalhypotension may be prominent, related to blockade of compensatoryresponses to upright posture and hypovolemia. The degree ofvasodilation is dependent on the degree of adrenergic vascular tone.

MODERATELY SELECTIVE PERIPHERAL �1-ADRENERGIC ANTAGONIST


Phenoxybenzamine (Dibenzyline)


20-40 bid

First dose, mg

10

Maximum of action, mg

120

Duration of action

3–4 d

FIGURE 7-26

Moderately selective peripheral �1-adrenergic antagonists.Phenoxybenzamine is the only drug in its class. Absorption is variableand incomplete (20% to 30%). Peak blockade occurs in 3 to 4hours. Its plasma half-life is 24 hours. The duration of action is

approximately 3 to 4 days. Phenoxybenzamine is primarily used inthe management of preoperative or inoperative pheochromocytoma.Efficacy is dependent on the degree of underlying excessive �-adrenergicvascular tone [6,9].


THE SIDE EFFECT PROFILE OF PHENOXYBENZAMINE

Side effects

Nasal congestion

Miosis

Sedation

Weakness, lassitude

Sexual dysfunctionInhibition of ejaculation

Tachycardia

Mechanisms

�-adrenergic receptor blockade


Unknown

Impairment of compensatory vasoconstriction producingorthostatic hypotension


Uninhibited effects of epinephrine, norepinephrine anddirect or reflex sympathetic nerve stimulation on the heart

FIGURE 7-27

The side effect profile of phenoxybenzamine. The common sideeffects are listed [6,9].



NE

NE

NE

NE

α2

β1α1

Indicates blockade FIGURE 7-28

Peripheral adrenergic neuronal blocking agents. Peripheral adrenergicneuronal blocking agents are selectively concentrated in the adren-ergic nerve terminal by an active transport mechanism, or “norepi-nephrine pump” [6,9]. They act by interfering with the release ofnorepinephrine (NE) from neuronal storage sites in response to nervestimulation and by depleting norepinephrine from nerve endings.Acutely, cardiac output is reduced, caused by diminished venousreturn and by blockade of sympathetic �-adrenergic effects on theheart; peripheral resistance is unchanged. Following chronic therapy,peripheral resistance is decreased, along with modest decreases inheart rate and cardiac output.


PERIPHERAL ADRENERGIC-NEURONAL BLOCKING AGENTS


Guanethidine (Ismelin)

Guanadrel (Hylorel)

First dose, mg

10

5


25–75 QD

10–50 bid


150

150

Duration of action

7–21 d

4–14 h

FIGURE 7-29

Peripheral adrenergic neuronal blocking agents. Guanethidine isthe prototype peripheral adrenergic neuronal blocking agent.Absorption is incomplete and variable; only 3% to 30% is absorbedover 12 hours. Peak plasma levels are reached in 6 hours. The drugrapidly leaves the plasma for extravascular storage sites, includingsympathetic neurons. Guanethidine is eliminated with a plasmahalf-life of 4 to 8 days, a time course that corresponds with its anti-hypertensive effect. Approximately 24% of the drug is excretedunchanged in the urine; the remainder is metabolized by the liverinto more polar, less active, metabolites that are excreted in theurine and feces. When therapy is initiated or the dosage is changed,three half-lives (approximately 15 days) are required to accumulate

THE SIDE EFFECT PROFILE OF PERIPHERAL ADRENERGIC-NEURONAL BLOCKING AGENTS

Side effects

Decrease renal function (GFR)

Fluid retention/weight gain

Dizziness/weaknessSyncope

Intestinal cramping/diarrhea

Sexual dysfunctionRetrograde ejaculationImpotenceDecreased libido

Sinus bradycardiaAtrioventricular block

Bronchospasm

Congestive heart failure

Mechanisms

Decreased renal perfusion; effect is magnified in the upright position

Decreased filtered load and fractional excretion of sodium; diuretic should beused in combination

Postural hypotension accentuated by hot weather, alcohol ingestion, and/or physical exercise

Unopposed parasympathetic activity, increasing gastrointestinal motility

Inhibition of bladder neck closure, unknown

Interferes with cardiac sympathetic compensating reflexes

Catecholamine depletion aggravates airway resistance

Decreased cardiac output

FIGURE 7-30

The side effect profile of peripheral adren-ergic neuronal blocking agents. The specificside effects of this class are related to eitherexcessive sympathetic blockade or a relativeincrease in parasympathetic activity. GFR—glomerular filtration rate.

87.5% of a steady-state level. By administering loading doses ofguanethidine at 6-hour intervals (the nearly maximal effect from asingle oral dose), blood pressure can be lowered in 1 to 3 days. Inpatients with severe renal insufficiency, drug excretion is decreased;dose reduction is required.

Guanadrel is a guanethidine derivative with a short therapeutichalf-life. Absorption is greater than 85%; peak plasma concentra-tions are reached in 1 to 2 hours. Guanadrel is metabolized by theliver. Elimination occurs through the kidney; approximately 40%of the drug is excreted unchanged in the urine. In patients withrenal insufficiency, the plasma half-life (10 to 12 hours) is pro-longed; dose reduction is required [6,9].


VGC VGCROCLeakPlasma

membrane

Ca2+

Ca2+

Ca2+Ca2+

Ca2+

SR SR

Myofilaments

Contraction of vascularsmooth muscle

Hypertension

Activation of

Alt

ered

cal

ciu

mm

etab

olis

m (

?)

FIGURE 7-31

Direct-acting vasodilators. Direct-acting vasodilators may have aneffect on both arterial resistance and venous capacitance vessels;however, the currently available oral drugs are highly selective forresistance vessels [6,9]. Their specific mechanism of vascular relax-ation and reason for selectivity are unknown. By altering cellular calci-um metabolism, they interfere with the calcium movements respon-sible for initiating or maintaining a contractile state. The net physi-ologic effect is a decrease in peripheral vascular resistanceassociated with increases in heart rate and cardiac output. Theseincreases in heart rate and cardiac output are related directly tosympathetic stimulation and indirectly to the baroreceptor reflexresponse. ROC—receptor-operated channel; SR—sarcoplasmicreticulum; VGC—voltage-gaited channels.

DIRECT-ACTING VASODILATORS


Hydralazine (G) (Apresoline)

Minoxidil (G) (Loniten)

First dose, mg

10

5


50–100 bid/tid

10–20 QD/bid


300

80


10–12

75


FIGURE 7-32

Direct-acting vasodilators. Hydralazine is the prototype of direct-acting vasodilators. Absorption is more than 90%. Peak plasmalevels occur within 1 hour but may vary widely among individuals.This is because hydralazine is subject to polymorphic acetylation;slow acetylators have higher plasma levels and require lower drugdoses to maintain blood pressure control compared with rapidacetylators. Bioavailability for slow acetylators ranges from 30%to 35%; bioavailability for rapid acetylators ranges from 10% to16%. Hydralazine undergoes extensive hepatic metabolism; it ismainly excreted in the urine in the form of metabolites or asunchanged drug. The plasma half-life is 3 to 7 hours. Dose reductionmay be required in the slow acetylator with renal insufficiency.

Minoxidil is a substantially more potent direct-acting vasodilatorthan hydralazine. Absorption is greater than 95%. Peak plasma levelsoccur within 1 hour. Following a single oral dose, blood pressuredeclines within 15 minutes, reaches a nadir between 2 and 4 hours,and recovers at an arithmetically linear rate of 30% per day.Approximately 90% is metabolized by conjugation with glucuronicacid and by conversion to more polar products. Known metabolites,which are less pharmacologically active than minoxidil, are excreted in the urine. The plasma half-life of minoxidil is approximately 4hours; dose adjustments are unnecessary in patients with renal insuf-ficiency. Minoxidil and its metabolites are removed by hemodialysisand peritoneal dialysis; replacement therapy is required [6,9].


↑ Myocardialcontractility

↓ Venouscapacitance

↑ Peripheralvascular

resistance

↓ Peripheralvascular

resistance

↑ Plasma andextracellularfluid volume

↓ Arterialpressure

↑ Circulatingangiotensin

↑ Aldosteronesecretion

VASODILATORS

Side effects of direct-acting vasodilators

PROPRANOLOL

DIURETICS

↑ Heart rate

↑ Sympatheticfunction

↑ Cardiacoutput

↓ Sodiumexcretion

↑ Plasmarenin

activity

FIGURE 7-33

The side effect profile of direct-actingvasodilators. The most common and mostserious effects of hydralazine and minoxidilare related to their direct or reflex-mediatedhemodynamic actions, including flushing,headache, palpitations, anginal attacks, andelectrocardiographic changes of myocardialischemia [6,9]. These effects may be pre-vented by concurrent administration of a �-adrenergic antagonist. Sodium retentionwith expansion of extracellular fluid volumeis a significant problem. Large doses ofpotent diuretics may be required to preventfluid retention and the development ofpseudotolerance [13]. (From Koch-Weser[13]; with permission.)

Repeated administration of hydralazinecan lead to a reversible syndrome thatresembles disseminated lupus erythematosus.The incidence is dose dependent; it rarelyoccurs in patients receiving less than 200mg/day. Hypertrichosis is a common trouble-some but reversible side effect of minoxidil;it develops during the first 3 to 6 weeks oftherapy in approximately 80% of patients.

VGC VGCROCPlasma

membrane

Ca2+

Ca2+

Ca2+Ca2+

Ca2+

SR SR

Myofilaments

FIGURE 7-34

Calcium antagonists. The calcium antagonists share a commonantihypertensive mechanism of action: inhibition of calcium ionmovement into smooth muscle cells of resistance arterioles throughL-type (long-lasting) voltage-operated channels [6,9]. The ability ofthese drugs to bind to voltage-operated channels, causing closure ofthe gate and subsequent inhibition of calcium flux from the extra-cellular to the intracellular space, inhibits the essential role of calci-um as an intracellular messenger, uncoupling excitation to contrac-tion. Calcium ions may also enter cells through receptor-operatedchannels. The opening of these channels is induced by binding neu-rohumoral mediators to specific receptors on the cell membrane.Calcium antagonists inhibit the calcium influx triggered by thestimulation of either �-adrenergic or angiotensin II receptors in adose-dependent manner, inhibiting the influence of �-adrenergic ago-nist and angiotensin II on vascular smooth muscle tone. The netphysiologic effect is a decrease in vascular resistance.

Although all the calcium antagonists share a basic mechanism ofaction, they are a highly heterogeneous group of compounds thatdiffer markedly in their chemical structure, pharmacologic effectson tissue specificity, pharmacologic behavior side-effect profile, andclinical indications [6,9,14]. Because of this, calcium antagonistshave been subdivided into several distinct classes: phenylalkamines,dihydropyridines, and benzothiazepines. ROC—receptor-operatedchannel; SR—sarcoplasmic reticulum; VGC—voltage-gaited channels.

B. DOSING SCHEDULES FOR CALCIUM ANTAGONISTS: DIHYDROPYRIDINE DERIVATIVES



A. DOSING SCHEDULES FOR CALCIUM ANTAGONISTS: PHENYLALKAMINE DERIVATIVE

First dose, mg

80

90

120

180


Verapamil (G) (Isoptin, Calan)

Verapamil SR (Isoptin SR, Calan SR)

Verapamil SR—pellet (Veralan)

Verapamil COER-24 (Covera HS)

Usual dose, mg

80–120 tid

90–240 bid

240–480 QD

180–480 qhs


480

480

480

480


8

12–24

24

24



Amlodipine (Norvasc)

Felodipine (Plendil)

Isradipine (DynaCirc)

Isradipine CR (DynaCirc CR)

Nicardipine SR (Cardine SR)

Nifedipine Caps (G) (Procardia)

Nifedipine ER (Adalat CC)

Nifedipine GITS (Procardia XL)

Nisoldipine (Sular)

First dose, mg

5

5

2.5

5

30

10

30

30

20

Usual dose, mg

5–10 QD

5–1 0 QD

2.5-5 bid

5–20 QD

30–60 bid

10–30 tid/qid

30–90 QD

30–90 QD

20–40 QD


10

20

20

20

120

120

120

120

60


24

24

12

24

12

4–6

24

24

24

C. DOSING SCHEDULES FOR CALCIUM ANTAGONISTS: BENZODIAZEPINE DERIVATIVE


Diltiazem (G) (Cardizem)

Diltiazem SR (Cardizem SR)

Diltiazem CD (Cardizem CD)

Diltiazem XR (Dilacor XR)

Diltiazem ER (Tiazac)

First dose, mg

60

180

180

180

180

Usual dose, mg

60–120 tid/qid

120–240 bid

240–480 QD

180–480 QD

180–480 QD


480

480

480

480

480


8

12

24

24

24


FIGURE 7-35

A–C. Dosing schedules for calcium antagonists: phenylalkamine derivatives, dihydropyridine derivatives, and benzothiazepine derivatives.


PHARMACOKINETICS OF CALCIUM ANTAGONISTS

Verapamil

Amlodipine

Felodipine

Isradipine

Nicardipine

Nifedipine

Nisoldipine

Diltiazem

Absorption, %

>90

>90

>90

>90

>90

>90

>85

>80

First-pass hepatic

70%–80%

Minimal

Extensive

Extensive

Extensive

20%–30%

Extensive

50%

Peak concentration

1–2 h (tablet)5 h (SR caplet)7–9 h (SR pellet)

11 h (COER)

6–12 h

2.5–5 h

1–2 h (tablet)7–18 h (CR)

1–4 h (SR)

<30 min (cap)2.5–5 h (ER)6 h GITS)

6–12 h

2–3 h (tablet)6–11 h (SR)

10–14 h (CD)4–6 h (XR)7 h (ER)

Route of elimination

Liver

Liver

Liver

Liver

Liver

Liver

Liver

Liver

Active metabolite

Yes

No

No

No

No

No

Yes

Yes

Plasma half-life, h

4–12 (tablet)12 (SR pellet)

30–50

11–16

8

8–9

22424

7–12

4–65–75–85–104–10

Dose reduction

No

No

No

No

No

No

No

Yes

FIGURE 7-36

Pharmacokinetics of the calcium antagonists: phenylalkamine derivatives,dihydropyridine derivatives, and benzothiazepine derivatives.

THE SIDE EFFECTS PROFILE OF CALCIUM ANTAGONISTS

Side effects

DihydropyridineHeadache, flushing, palpitation, edema

PhenylalkylamineConstipationBradycardia, AV block congestive heart failure

BenzodiazepineBradyarrhythmia, AV block congestive heart failure

Mechanism

Potent peripheral vasodilator

Negative inotropic, dromotropic, chronotropic effects

Negative inotropic, dromotropic, chronotropic effects

FIGURE 7-37

The side effect profile of calcium antagonists[10,13,18]. AV—atrioventricular.


Bradykinin

Inactivefragments

Renal tubularsodium reabsorption

Functions::

ACE inhibition and angiotensin II type I receptor antagonists: mechanisms for decrease in peripheral vascular resistance

Aldosteronerelease

Sympathetic activity(central and peripheral)

Baroreceptorsensitivity

Vasoconstriction,vascular smooth

muscle

Remodeling,vascular smooth

muscle

Nitric oxide

Prostaglandin E2

Prostaglandin I2

AT2 receptor

AT1receptor

? Function

Non-ACE enzymes

ACE

1

2

3

4

–

–

–

–

+

+

+ +

+

+

–

+

Renin

Bloodpressure

Non-renin enzymesAngiotensinogen(renin substrate)

Angiotensin I(decapeptide)

Angiotensin II(octapeptide)

FIGURE 7-38

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin IItype I receptor antagonists. Angiotensin-converting enzymeinhibitors and angiotensin II type I receptor antagonists lowerblood pressure by decreasing peripheral vascular resistance; thereis usually little change in heart rate or cardiac output [6,9,15].

Mechanisms proposed for the observed decrease in peripheralresistance are shown [15]. Sites of pharmacologic blockade in therenin angiotensin system: 1) renin inhibitors, 2) ACE inhibitors, 3) angiotensin II type I receptor antagonists, 4) angiotensin II type II receptor antagonists.


A. DOSING SCHEDULES FOR SULFHYDRYL-CONTAINING ACE INHIBITOR


Captopril (G) (Capoten)

First dose, mg

12.5

Usual dose, mg

12.5–50 bid/tid

Maximum dose, mg

150

FIGURE 7-39

A–C. Classification of and dosing schedule for angiotensin-convertingenzyme (ACE) inhibitors. Angiotensin-converting enzyme inhibitorsdiffer in prodrug status, ACE affinity, potency, molecular weight and


6–12

B. DOSING SCHEDULES FOR CARBOXYL-CONTAINING ACE INHIBITORS


Benazepril (Lotensin)

Enalapril (Vasotec)

Lisinopril (Prinivil,Zestril)

Moexipril (Univasc)

Quinapril (Accupril)

Ramipril (Altace)

Trandolapril (Mavik)

First dose, mg

10

5

10

7.5

5–10

2.5

1

Usual dose, mg

10–20 QD

5–10 QD/bid

20–40 QD

7.5–15 QD/bid

20–40 QD

2.5–20 QD/bid

2–4 QD

Maximum dose, mg

40

40

40

30

40

40

8


24

12–24

24

24

24

24

24

C. DOSING SCHEDULES FOR PHOSPHINIC ACID–CONTAINING ACE INHIBITOR


Fosinopril (Monopril)

First dose, mg

10

Usual dose, mg

20–40 QD/bid

Maximum dose, mg

40


24


conformation, and lipophilicity [6,9]. They are generally classifiedinto one of three main chemical classes according to the ligand ofthe zinc ion of ACE: sulfhydryl, carboxyl, or phosphinic acid.


PHARMACOKINETICS OF ACE INHIBITORS

Captopril

Benazepril

Enalapril

Lisinopril

Moexipril

Quinapril

Ramipril

Trandolapril

Fosinopril

Absorption, %

60–75

37

55–75

25

> 20

60

50–60

70

36

Prodrug

No

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Peak concentration (active component), h

1

1–2

3–4

6–8

1–2

2

2–4

4–10

3

Route of elimination

Kidney

Kidney/liver

Kidney

Kidney

Kidney

Kidney

Kidney/liver

Kidney/liver

Kidney/liver

Plasma half-life, h

2

10–11

11

12

2–9

25

13–17

16–24

12

Dose reduction(renal disease)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

FIGURE 7-40

Pharmacokinetics of angiotensin-converting enzyme (ACE) inhibitors: sulfhydryl-containing, carboxyl-containing, and phosphinic acid–containing.

THE SIDE EFFECTS PROFILE OF ACE INHIBITORS

Side effects

Cough, angioedema Laryngeal edema

Lightheadedness, syncope

Hyperkalemia

Acute renal failure

Mechanisms

Potentiation of tissue kinins

Excessive hypotension in patients with high basal peripheral vascular resistance—high renin states, like volume contraction, impaired cardiac output

Decreased aldosterone; potassium-containing salt substitutes and supplements should be avoided

Extreme hypotension with impaired efferent arteriolar autoregulation

FIGURE 7-41

The side effect profile of angiotensin-con-verting enzyme (ACE) inhibitors. ACEinhibitors are well tolerated; there are fewside effects [6,9].


Time, min

–15 0

Captopril 50 mg

Renal arterystenosis

Essentialhypertension

Captopril 50 mg

30 60 –15 0 30 60

10

100

Plas

ma

ren

in, m

U/L

Tota

l glo

mer

ula

rfi

ltra

tio

n r

ate,

mL/

min

Tota

l eff

ecti

vere

nal

pla

sma

flo

w,

mL/

min

Art

eria

lp

ress

ure

, mm

Hg

1000

80

100

90

280

440

360

110

110

190

230

150

70

FIGURE 7-42

Angiotensin-converting enzyme (ACE) inhibition in acute renal failure.ACE inhibitors may produce functional renal insufficiency in patientswith essential hypertension and hypertensive nephrosclerosis, inpatients with severe bilateral renal artery stenosis, or in patientswith stenosis of the renal artery of a solitary kidney. The postulatedmechanism for this effect is diminished renal blood flow (decreasein systemic pressure, compromising flow through a fixed stenosis)in combination with diminished postglomerular capillary resistance(ie, decrease in angiotensin II–mediated efferent arteriolar tone). Inunilateral renal artery stenosis, a drop in the critical perfusion andfiltration pressures may result in a marked drop in single-kidneyglomerular filtration rate (GFR); however, the contralateral kidneymay show an increase in both effective renal plasma flow (ERPF)and GFR due to attenuation of the intrarenal effects of angiotensinII on vascular resistance and mesangial tone. Thus, total “net”GFR may be normal, giving the false appearance of stability [16].Although ACE inhibition may invariably decrease the GFR of thestenotic kidney, it is unlikely to cause renal ischemia owing topreservation of ERPF; GFR usually returns to pretreatment valuesfollowing cessation of therapy.

Shown is the effect of captopril (50 mg) on total clearances of131I-sodium iodohippurate (ERPF) and 126I-thalamate (GFR) in 14patients with unilateral renal artery stenosis and in 17 patients withessential hypertension. The effects after 60 minutes of captopril onsystolic and diastolic intra-arterial pressure (P < 0.001) and of reninwere significant. (From Wenting and coworkers [16]; with permission.)

FIGURE 7-43

Tyrosine hydroxylase inhibitor. Metyrosine (�-methyl-para-tyrosine)is an inhibitor of tyrosine hydroxylase, the enzyme that catalyzesthe conversion of tyrosine to dihydroxyphenylalanine [6,9]. Becausethis first step is rate limiting, blockade of tyrosine hydroxylaseactivity results in decreased endogenous levels of circulating cate-cholamines. In patients with excessive production of catecholamines,metyrosine reduces biosynthesis 36% to 79%; the net physiologiceffect is a decrease in peripheral vascular resistance and increases inheart rate and cardiac output resulting from the vasodilation. Thedegree of vasodilation is dependent on the degree of blockade ofadrenergic vascular tone. NE—norepinephrine.

Tyrosine


Tyrosine hydroxylase


Dihydroxyphenylalanine

NE

α2

β1α1

Indicates blockade


TYROSINE HYDROXYLASE INHIBITOR


Metyrosine (Demser)

First dose, mg

250


25 qid

Maximum dose, mg

1000 qid


3–4

FIGURE 7-44

Tyrosine hydroxylase inhibitor. Metyrosine is the only drug in itsclass. The initial recommended dose is 1 g/d, given in divided doses.This may be increased by 250 to 500 mg daily to a maximum of 4 g/d. The usual effective dosage is 2 to 3 g/d. The maximum bio-chemical effect occurs within 2 to 3 days. In hypertensive patients inwhom there is a response, blood pressure decreases progressivelyduring the first days of therapy. In patients who are usually nor-motensive, the dose should be titrated to the amount that willreduce circulating or urinary catecholamines by 50% or more.

Following discontinuation of therapy, the clinical and biochemicaleffects may persist 2 to 4 days. Metyrosine is variably absorbedfrom the gastrointestinal tract; bioavailability ranges from 45% to 90%. Peak plasma concentrations are reached in 1 to 3 hours.The plasma half-life is 3 to 4 hours. Metyrosine is not metabolized;the unchanged drug is recovered in the urine. Drug dosage shouldbe reduced in patients with renal insufficiency. Metyrosine is exclu-sively used in the management of preoperative or inoperativepheochromocytoma [6,9].

THE SIDE EFFECTS PROFILE OF METYROSINE

Mechanisms

Depletion of CNS dopamine

Poor urine solubility

Direct irritant to bowel mucosa

Following drug withdrawal

Side effects

CNS symptomsSedationExtrapyramidal signs

DroolingSpeech difficultyTremorTrismusParkinsonian syndrome

Psychic dysfunctionAnxietyDepressionDisorientationConfusion

Crystalluria, uroliathiasis

Diarrhea

Insomnia (temporary)

FIGURE 7-45

The side effect profile of metyrosine. The adverse reactions observedwith metyrosine are primarily related to the central nervous systemand are typically dose dependent [6,9]. Metyrosine crystalluria(needles or rods), which is due to the poor solubility of the drug inthe urine, has been observed in patients receiving doses greaterthan 4 g/d. To minimize this risk, patients should be well hydrated.CNS—central nervous system.


ANGIOTENSIN II RECEPTOR ANTAGONISTS


Losartan (Cozaar)

Valsartan (Diovan)

Irbesaftan (Avapro)

First dose, mg

50

80

150

Usual dose, mg

50–100 QD/bid

80–160 QD

150–300 QD

Maximum dose, mg

100

320

300


12–24

24

24

FIGURE 7-46

Angiotensin II receptor antagonists. These drugs antagonizeangiotensin II–induced biologic actions, including proximal sodiumreabsorption, aldosterone release, smooth muscle vasoconstriction,vascular remodeling, and baroreceptor sensitivity. Antihypertensiveefficacy appears dependent on an activated renin-angiotensin system;bilateral nephrectomy and volume expansion abolish their activity.Losartan is a nonpeptide, specific angiotensin II receptor antagonistacting on the antagonist AT1 subtype receptor. Peak response occurswithin 6 hours of dosing. It is readily absorbed; peak plasma concen-trations are achieved within 1 hour. It has a relatively short terminalhalf-life of 1.5 to 2.5 hours. Oral bioavailability is approximately33%. Losartan undergoes extensive first-pass hepatic metabolismto the predominant circulatory form of the drug Exp-3174. Thismetabolite is 15 to 30 times more potent than losartan with a

longer half-life (between 4 and 9 hours). The metabolite is clearedequally by the liver and the kidney; there may be enhanced hepaticclearance in renal insufficiency [15]. Dose reduction is not requiredin patients with renal insufficiency.

Valsartan is a nonpeptide, specific angiotensin II antagonist actingon the AT1 subtype receptor. Peak response occurs within 6 hoursof dosing. Peak plasma concentrations are reached 2 to 4 hoursafter dosing. The average elimination half-life is about 6 hours.Oral bioavailability is approximately 25%. Dose reduction is notrequired in patients with renal insufficiency [15].

Irebsartan is a nonpeptide, specific angiotensin II antagonist actingon the AT1 subtype receptor. Peak response occurs in 4 to 8 hours.There is no active metabolite. Dose reduction is not required inpatients with renal insufficiency [15].

THE SIDE EFFECTS PROFILE OF ANGIOTENSIN IIRECEPTOR ANTAGONISTS

Side effects

Hyperkalemia

Acute renal dysfunction

Mechanisms

Blockade of angiotensin IIReduced aldosterone secretion

Hypotension with impaired efferent anteriolarautoregulation

FIGURE 7-47

The side effect profile of angiotensin II receptor antagonists.Angiotensin II receptor antagonists are well tolerated. In contrastto the angiotensin-converting enzyme (ACE) inhibitors, cough andangioedema are rarely (if at all) associated with this class of antihy-pertensive drug. Similar to ACE inhibitors, however, hyperkalemiaand acute renal failure may occur in patients at risk [15].


Prevention and Treatment of High Blood Pressure

FIGURE 7-48

Prevention and treatment of high blood pressure. The aim of anti-hypertensive therapy is risk reduction. Since the relationshipbetween blood pressure and cardiovascular risk is continuous, thegoal of treatment might be the maximum tolerated reduction inblood pressure. There is controversy concerning what constituteshypertension and how far systolic or diastolic blood pressureshould be lowered, however. The Sixth Report of the JointNational Committee on Detection, Evaluation, and Treatment ofHigh Blood Pressure (JNC VI) [17] provides a new classification ofhypertension and recommends that risk stratification be used todetermine if lifestyle modification or drug therapy with adjunctivelifestyle modification be initiated according to the patient’s bloodpressure classification (see Fig. 7-50). Major risk factors includesmoking, dyslipidemia, diabetes mellitus, an age of 60 or older,male sex or postmenopausal state for women, and a family historyof cardiovascular disease in women younger than 65 and in menyounger than 55. Target organ damage includes heart disease (leftventricular hypertrophy, angina pectoris, prior myocardial infarction,heart failure), stroke or transient ischemic attack, and nephropathy.Prevention and management of hypertension-related morbidity andmortality may best be accomplished by achieving a systolic bloodpressure below 140 mm Hg and a diastolic blood pressure below90 mm Hg; lower if tolerable. Recently, more aggressive bloodpressure control has been advocated in patients with renal diseaseand hypertension, particularly in those patients with a urinary proteinexcretion of greater than 1 g/d. Blood pressure control in the rangeof 125/80 mm Hg (mean arterial pressure of 108 mm Hg) has beenshown to slow the progression of renal disease [18,19]. This targetedblood pressure control may therefore be advisable in the majorityof patients with hypertension. Regardless, each patient should betreated according to their cerebrovascular, cardiovascular, or renalrisks; their specific pathophysiology or target organ damage; andtheir concurrent disease states. A uniform blood pressure goal (target)probably does not exist for all hypertensive patients, and lowermay not always be better.

JNC VI CLASSIFICATION OF HYPERTENSION

Category*

Optimal†

Normal

High normal

Hypertension‡

Stage 1Stage 2Stage 3

Systolic (mm Hg)

<120

<130

130–139

140/159160/179

≥-180

*Not taking anithypertensive drugs and not acutely ill. When systolic and diastolicblood pressures fall into different categories, the higher category should be selected toclassify the individual’s blood pressure status. For example, 160/92 mm Hg should beclassified as stage 2 hypertension, and 174/120 mm Hg should be classified as stage 3hypertension. Isolated systolic hypertension is defined as systolic blood pressure of 140mm Hg or greater and diastolic blood pressure of less than below 90 mm Hg andstaged appropriately (eg, 170/82 mm Hg is defined as stage 2 isolated hypertension). In addition to classifying stages of hypertension on the basis of average blood pressurelevels, clinicians should specify presence of target organ disease and additional risk factors. This specifically is important for risk classification.†Optimal blood pressure with respect to cardiovascular risk is below 120/80 mm Hg.Unusually low readings should be evaluated for clinical significance.‡Based on the average of two or more readings taken at each of two or more visitsafter an initial screening. JNC—Joint National Committee.

Diastolic (mm Hg)

<80

<85

85–89

90/99100/109

≥110

and

and

or

ororor


JNC VI DECISION ANALYSIS FOR TREATMENT

Blood pressure stages(mm Hg)

High normal(130–139/85–89)

Stage 1(140–159/90–99)

Stages 2 and 3(>160/≥100)

Risk group A (no risk factors, noTOD/CCD)*

Lifestyle modification

Lifestyle modification (up to 12 months)

Drug therapy

Risk group B (at least 1 risk factor,not including diabetes;no TOD/ CCD)

Lifestyle modification

Lifestyle modification (up to 6 months)

Drug therapy

Risk Group C(TOD/CCD and/or diabetes, with or with-out other risk factors)†

Drug therapy‡

Drug therapy

Drug therapy

Lifestyle modification should be adjunctive therapy for all patients recommended for pharmacologic therapy.

*TOD/CCD indicates target organ disease/clinical cardiovascular disease.†For patients with multiple risk factors, clinicians should consider drugs as initial therapy plus lifestyle modifications.‡For those with heart failure, renal insufficiency, or diabetes.

FIGURE 7-49

Decision analysis for treatment based on theSixth Report of the Joint National Committeeon Detection, Evaluation, and Treatment ofHigh Blood Pressure (JNC VI) [17].

CRITERIA FOR INITIAL DRUG THERAPY

Reduce peripheral vascular resistance

No sodium retention

No compromise in regional blood flow

No stimulation of the renin-angiotensin-aldosterone system

Favorable profile with concomitant diseases

Once a day dosing

Favorable adverse effect profile

Cost effective (low direct and indirect cost)

FIGURE 7-50

Selection of initial drug therapy. The Sixth Report of the JointNational Committee on Prevention, Detection, Evaluation, andTreatment of High Blood Pressure (JNC VI) recommends thateither a diuretic or a �-blocker be chosen as initial drug therapy,based on numerous randomized controlled trials that show reductionin morbidity and mortality with these agents [17]. Not all authoritiesagree with this recommendation.

In selecting an initial drug therapy to treat a hypertensive patient,several criteria should be met [6,9]. The drug should decreaseperipheral resistance, the pathophysiologic hallmark of all hypertensivediseases. It should not produce sodium retention with attendantpseudotolerance. The drug should neither stimulate nor suppressthe heart, nor should it compromise regional blood flow to targetorgans such as the heart, brain, or the kidney. It should not stimulatethe renin-angiotensin-aldosterone axis. Drug selection should considerconcomitant diseases such as arteriosclerotic cardiovascular andperipheral vascular disease, chronic obstructive pulmonary disease,diabetes mellitus, hypertensive cardiovascular disease, congestiveheart failure, and hyperlipidemia. Drug dosing should be infrequent.The drug’s side effect profile, including its effect on physical state,emotional well-being, sexual and social function, and cognitiveactivity, should be favorable. Drug costs, both direct and indirect,should be reasonable. It is readily apparent that no current class ofantihypertensive drug fulfills all these criteria.


CANDIDATES FOR INITIAL DRUG THERAPY OF MILD TO MODERATE HYPERTENSIVE DISEASE

Peripheral vascular resistance

Sodium homeostasisUrinary sodium excretionExtracellular fluid volumePseudotolerance

Target organ functionHeart rate, cardiac outputCerebral functionRenal function (GFR)

Renin-angiotensin-aldosteronePlasma renin activityPlasma angiotensin IIPlasma aldosterone

Concurrent disease efficacyCoronary diseasePeripheral vascular diseaseObstructive airway diseaseDiabetes mellitusDyslipidemiaSystolic dysfunction

ACE inhibitors

Decrease

Increase/no changeNo changeNo

No changePreserveNo change/increase

IncreaseDecreaseDecrease/no change

No effectNo effectNo effectMay benefitNo effectBenefit

Angiotensin II type Ireceptor antagonists

Decrease


No changePreserveNo change

IncreaseIncreaseDecrease/no change

No effectNo effectNo effectMay benefitNo effectBenefit

�1-adrenergic antagonists

Decrease

May decreaseMay increaseNo

May increasePreserveNo change

No changeNo changeNo change

No effectNo effectNo effectNo effectBenefitNo effect

�1-adrenergicantagonists

Decrease

No changeNo changeNo

DecreasePreserveNo change/decrease

DecreaseDecreaseDecrease/no change

BenefitMay aggravateMay aggravateMay aggravateMay aggravateMay aggravate

Calcium antagonists

Decrease


Class specificPreserveNo change/increase

No changeNo changeNo change

BenefitMay benefitNo effectNo effectNo effectNo effect

Thiazide-typediuretics

Decrease

IncreaseDecreaseNo

No changePreserveNo change

IncreaseIncreaseIncrease

No effectNo effectNo effectMay aggravateAggravateBenefit

FIGURE 7-51

Options for monotherapy. Given the drugs that we have and theirpharmacologic profiles, what are the best classes for initial drug therapy?Alphabetically, they include 1) angiotensin-converting enzyme (ACE)inhibitors, 2) �1-adrenergic antagonists, 3) angiotensin II type I receptorantagonists, 4) �1-adrenergic antagonists, 5) calcium antagonists, and

6) thiazide-type diuretics [6,9,15]. All these drugs, given as monotherapy,are effective in lowering blood pressure in 50% to 60% of patientswith mild to moderate hypertension. �1-adrenergic antagonists, ACEinhibitors, and angiotensin II receptor antagonists are less efficaciousin blacks than in whites.


Options for subsequent antihypertensive therapy

Not at goal blood pressure (<140/<90 mm Hg);lower goal in patients with diabetes mellitus or renal disease

No response or troublesome side effects Inadequate response but well tolerated

Sustitute another drug from a different classAdd a second agent from a different class

(diuretic if not already used)

Not a goal blood pressure

Continue adding agents from other classesConsider referral to a hypertension specialist

FIGURE 7-52

Options for subsequent antihypertensivetherapy. The majority of patients with mildto moderate hypertension can be controlledwith one drug. If, after a 1- to 3-monthinterval, the response to the initial choice oftherapy is inadequate, however, threeoptions for subsequent antihypertensivedrug therapy may be considered: 1) increasethe dose of the initial drug, 2) discontinuethe initial drug and substitute a drug fromanother class, or 3) add a drug from anotherclass (combination therapy). Recommendationsfrom the Sixth Report of the Joint NationalCommittee on Detection, Evaluation, andTreatment of High Blood Pressure (JNC VI)are provided [17].

COMBINATION THERAPIES

Mild to moderate (stage 1 or 2) hypertension

Addition of low-dose thiazide-type diuretic to:

ACE inhibitor

�1-adrenergic antagonist


Angiotensin III receptor antagonist

Severe (Stage 3) hypertension

Classic triple drug therapy

Diuretic


Direct-acting vasodilator

ACE inhibitor plus calcium antagonist

�1-adrenergic antagonist plus �1-adrenergic antagonist

�1-adrenergic antagonist plus dihydropyridine calcium antagonist

FIGURE 7-53

Combination therapies. If a second drug is required, the addition of a low-dose thiazide-type diuretic to a nondiuretic drug will usually enhance the effectiveness of the first drug[6,9,17]. Newly developed formulations, using combinations of low doses of two agentsfrom different classes, are available and effective and may minimize the likelihood of adose-dependent adverse effect. The fixed doses used in these formulations were chosen tocontrol mild to moderate (JNC VI stage 1 or 2) hypertension. More severe (JNC VI stage 3)cases of hypertension that are unresponsive to this therapeutic strategy may respond eitherto a variety of combination therapies given together as separate formulations or to classictriple-drug therapy (ie, diuretic, �-adrenergic antagonist, and direct-acting vasodilator) [6,9].ACE—angiotensin-converting enzyme; JNC—Joint National Committee.


JNC VI LIFE STYLE MODIFICATIONS

Lose weight if overweight

Limit alcohol intake to no more than 1 oz (30 mL) ethanol (eg, 24 oz [720 mL] beer, 10 oz [300 mL] wine, or 2 oz [60 mL] 100-proof whiskey) per day or 0.5 oz (15 mL)ethanol per day for women and lighter weight people

Increase aerobic physical activity (30 to 45 minutes most days of the week)

Reduce sodium intake to no more than 100 mmol/d(2.4 g sodium or 6 g sodium chloride)

Maintain adequate intake of dietary potassium (approximately 90 mmol/d)

Maintain adequate intake of dietary calcium and magnesium for general health

Stop smoking and reduce intake of dietary saturated fat and cholesterol for overall cardiovascular health

FIGURE 7-54

Follow-up in antihypertensive therapy. During follow-up visits,pharmacologic therapy should be reconfirmed or readjusted. As arule, antihypertensive therapy should be maintained indefinitely.Cessation of therapy in patients who were correctly diagnosed ashypertensive is usually (but not always) followed by a return ofblood pressure to pretreatment levels. After blood pressure hasbeen controlled for 1 year and at least four visits, however, attemptsshould be made to reduce antihypertensive drug therapy “in adeliberate, slow, and progressive manner;” such “step-down therapy”may be successful in patients following lifestyle modification [17].Patients for whom drug therapy has been reduced or discontinuedshould have regular follow-up, since blood pressure may increaseagain to hypertensive levels. JNC—Joint National Committee.

CAUSES OF RESISTANT HYPERTENSION

Patient’s failure to adhere to drug therapy

Physician’s failure to diagnose a secondary cause of hypertensionRenal parenchymal hypertensionRenovascular hypertensionMineralocorticoid excess state (eg, primary aldosteronism)PheochromocytomaDrug-induced hypertension (eg, sympathomimetic, cyclosporine)Illicit substances (eg, cocaine, anabolic steroids)Glucocortoid excess state (eg, Cushing’s syndrome)Coarctation of the aortaHormonal disturbances (eg, thyroid, parathyroid, growth hormone, serotonin)Neurologic syndromes (eg, Guillain-Barré syndrome, porphyria, sleep apnea)

Physician’s failure to recognize an adverse drug–drug interactionSee Physician’s Desk Reference

Physician’s failure to recognize the development of secondary drug resistanceSodium retention with pseudotolerance, secondary to diuretic resistance or excess

sodium intakeIncreased heart rate, cardiac output secondary to drug-induced reflex tachycardia Increased peripheral vascular resistance secondary to drug-induced stimulation of

the renin-angiotensin system

FIGURE 7-55

Resistant hypertension. Causes of failure to achieve or sustain controlof blood pressure with drug therapy are listed [6,9].


FIGURE 7-56

Diuretic resistance. Diuretic resistance mayresult from patient noncompliance, impairedbioavailability in an edematous syndrome,impaired diuretic secretion by the proximaltubule, protein binding in the tubule lumen(eg, nephrotic syndrome), reduced glomerularfiltration rate, or enhanced sodium chloridereabsorption [7,8]. Resultant fluid retentionwill attenuate the effectiveness of most anti-hypertensive drugs. Renal mechanisms,problems, and solutions are provided in thistable [6,8,9].

DIURETIC RESISTANCE

Problem

Limits active transport of diureticsinto proximal tubular fluid, reducinginhibitory effect at a more distalintraluminal membrane site

Limits absolute amount of sodium filtered

Sodium recaptured at late distaltubule and collecting duct

Mechanism

Reduced renal blood flow

Reduced glomerular filtration rate

Secondary hyperaldosteronism

Solution

Use of large doses of a diuretic andappropriate dosing interval to achieve a therapeutic tubular drug concentration

Use loop diuretics with steep doseresponse curve and/or block multiplesites of sodium reabsorption: loopdiuretic with thiazide-like diuretic

Addition of a potassium-sparing diureticto above, to maintain urinesodium/potassium ratio > 1

References

1. Kaplan NM: Clinical Hypertension, edn 6. Baltimore: Williams &Wilkins; 1994:50.

2. Kawasaki T, Delea CS, Bartter FC, Smith H: The effect of high-sodiumand low-sodium intakes on blood pressure and other related variablesin human subjects with idiopathic hypertension. Am J Med 1978,64:193–198.

3. Guyton AC, Coleman TG, Yang DB, et al.: Salt balance and long-termblood pressure control. Annu Rev Med 1980, 31:15–27.

4. Julius S, Krause L, Schork NJ: Hyperkinetic borderline hypertensionin Tecumseh, Michigan. J Hypertens 1991, 9:77–84.

5. Lund-Johansen P: Cetra haemodynamics in essential hypertension atrest and during exercise: a 20-year follow-up study. J Hypertens 1989,7(suppl 6): 552–555.

6. Bauer JH, Reams GP: Mechanisms of action, pharmacology, and useof antihypertensive drugs. In The Principles and Practice of Nephrology.Edited by Jacobson HR, Striker GE, Klahr S. St. Louis: Mosby;1995:399–415.

7. Tarazi RC: Diuretic drugs: mechanisms of antihypertensive action. InHypertension: Mechanisms and Management. The 26th HahnemannSymposium. Edited by Oneti G, Kim KE, Moer JH. New York: Gruneand Stratton; 1973:255.

8. Ellison DH: The physiologic basis of diuretic synergism: its role intreating diuretic resistance. Ann Intern Med 1991, 114:886–894.

9. Bauer JH, Reams GP: Antihypertensive drugs. In The Kidney, edn 5.Edited by Brenner BM. Philadelphia: W.B. Saunders Co.; 1995:2331–2381.

10. Man in’t Veld AJ, Schalekamp MADH: How intrinsic sympathomimeticactivity modulates the haemodynamic responses to �-adrenoceptorantagonists: a clue to the nature of their antihypertensive mechanism.Br J Clin Pharmac 1982, 13:2455–2575.

11. Van Zwieten PA: Antihypertensive drug interacting with �-and �-adreno-ceptors: a review of basic pharmacology. Drugs 1988, 35(suppl 6):6–19.

12. Graham RM, Thornell IR, Gain JM, et al.: Prazosin: the first dosephenomenon. Br Med J 1976, 2:1293–1294.

13. Koch-Weser J: Vasodilation drugs in the treatment of hypertension.Arch Intern Med 1974, 133:1017–1025.

14. Entel SI, Entel EA, Clozel J-P: T-type Ca2+ channels and pharmacologicalblockade: potential pathophysiological relevance. Cardiovasc DrugsTher 1997, 11:723—739.

15. Bauer JH, Ream GP: The angiotensin II type 1 receptor antagonists.Arch Intern Med 1995, 155:1361–1368.

16. Wenting GJ, Tan-Tjiong HL, Derkx FMH, et al.: Split renal functionafter captopril in unilateral renal artery stenosis. Br Med J 1974,288:886–890.

17. JNC VI: The Sixth Report of the Joint National Committee onDetection, Evaluation, and Treatment of High Blood Pressure. ArchIntern Med 1993, 153:154–183.

18. Peterson JC, Adler S, Burkart JM, et al.: Blood pressure control, proteinuria, and the progression of renal disease. Ann Intern Med1995, 123:754–762.

19. Hebert LA, Kusek JW, Greene T, et al.: Effects of blood pressure con-trol on progressive renal disease in blacks and whites. Hypertension1997, 30 (part 1):428–435.

8

Hypertensive Crises

Most patients with hypertension remain asymptomatic for manyyears, until complications from atherosclerosis, cerebrovasculardisease, or congestive heart failure supervene. In some patients,

this so-called benign course is punctuated by a hypertensive crisis.Hypertensive crisis is defined as the turning point in the course of anillness at which acute management of the elevated blood pressureplays a decisive role in the eventual outcome [1]. The haste with whichblood pressure must be controlled varies with the type of hypertensivecrisis. If the patient’s outcome is to be optimal, however, the crucialrole of hypertension in the disease process must be identified and aplan for management of the blood pressure successfully implemented.The absolute level of the blood pressure clearly is not the most importantfactor in determining the existence of a hypertensive crisis. For example,in children, pregnant women, and other previously normotensive personsin whom mild to moderate hypertension develops suddenly, a hyper-tensive crisis can occur at a level of blood pressure that normally iswell-tolerated by adults with chronic hypertension. Furthermore, acrisis can occur in adults with mild to moderate hypertension with theonset of acute end-organ dysfunction involving the heart or brain.

Charles R. Nolan

C H A P T E R


HYPERTENSIVE CRISES


(Hypertensive neuroretinopathy present)

Benign (nonmalignant) hypertension with acute complications

(Acute organ system dysfunction without hypertensive neuroretinopathy)

Hypertensive encephalopathy (also common in malignant hypertension)

Acute hypertensive heart failure (also common in malignant hypertension)

Acute aortic dissection

Central nervous system catastrophe


Subarachnoid hemorrhage

Severe head trauma

Acute myocardial infarction or unstable angina

Active bleeding, including postoperative bleeding

Uncontrolled hypertension in patients requiring surgery

Severe postoperative hypertension

Post–coronary artery bypass hypertension

Post–carotid endarterectomy hypertension

Catecholamine excess states

Pheochromocytoma

Monoamine oxidase inhibitor–tyramine interactions

Miscellaneous hypertensive crises

Preeclampsia and eclampsia

Scleroderma renal crisis

Autonomic hyperreflexia in quadriplegic patients

FIGURE 8-1

Malignant hypertension is a clinical syndrome characterized bymarked elevation of blood pressure, with widespread acute arterio-lar injury (hypertensive vasculopathy). Funduscopy reveals hyper-tensive neuroretinopathy with flame-shaped hemorrhages, cotton-wool spots (soft exudates), and sometimes papilledema. Regardlessof the severity of blood pressure elevation, malignant hypertensioncannot be diagnosed in the absence of hypertensive neuroretinopa-thy. Thus, hypertensive neuroretinopathy is an extremely importantclinical finding, indicating the presence of a hypertension-inducedarteriolitis that may involve the kidneys, heart, and central nervoussystem. In malignant hypertension, rapid and relentless progressionto end-stage renal disease occurs if effective blood pressure controlis not implemented. Mortality can result from acute hypertensiveheart failure, intracerebral hemorrhage, hypertensive encephalopa-thy, or complications of uremia. Malignant hypertension representsa hypertensive crisis given that adequate control of blood pressureclearly prevents these morbid complications. Even in patients withso-called benign (nonmalignant) hypertension, in which hyperten-sive neuroretinopathy is absent, a hypertensive crisis may occur basedon the development of concomitant acute end-organ dysfunction.Hypertensive crises caused by benign hypertension with acute complications include hypertension in the setting of hypertensiveencephalopathy, acute hypertensive heart failure, acute aortic dissection, intracerebral hemorrhage, subarachnoid hemorrhage,severe head trauma, acute myocardial infarction or unstable angina,and active bleeding. Poorly controlled hypertension in patientsrequiring surgery increases the risk of intraoperative cerebral ormyocardial ischemia and postoperative acute renal failure. Severepostoperative hypertension, including post–coronary artery bypasshypertension and post–carotid endarterectomy hypertension, increasesthe risk of postoperative bleeding, hypertensive encephalopathy,pulmonary edema, and myocardial ischemia. The various catecholamine excess states can cause a hypertensive crisis withhypertensive encephalopathy or acute hypertensive heart failure.Preeclampsia and eclampsia represent hypertensive crises unique topregnancy. Scleroderma renal crisis is a hypertensive crisis becausefailure to adequately control blood pressure with a regimen thatincludes a converting enzyme inhibitor results in rapid irreversibleloss of renal function. Hypertensive crises as a result of autonomichyperreflexia induced by bowel or bladder distention also can occurin patients with quadriplegia. The sudden onset of hypertension inthis setting can lead to hypertensive encephalopathy or acute pulmonary edema. Each hypertensive crisis is discussed in moredetail in the figures that follow.

8.3Hypertensive Crises

HYPERTENSIVE SYNDROMES SOMETIMES MISDIAGNOSED AS HYPERTENSIVE CRISES

Severe uncomplicated hypertension

(Severe hypertension without hypertensive neuroretinopathy or acute end-organ dysfunction, formerly known as urgent hypertension)

Benign hypertension with chronic end-organ complications

Chronic renal insufficiency from primary renal parenchymal disease

Chronic congestive heart failure from systolic or diastolic dysfunction

Atherosclerotic coronary vascular disease (previous myocardial infarction, stable angina)

Cerebrovascular disease (history of transient ischemic attack or cerebrovascular accident)

FIGURE 8-2

Hypertensive syndromes sometimes misdiagnosed as hypertensivecrises. It should be noted that the finding of severe hypertensiondoes not always imply the presence of a hypertensive crisis. Inpatients with severe uncomplicated hypertension (formally knownas urgent hypertension) in which severe hypertension is not accom-panied by evidence of malignant hypertension or acute end-organdysfunction, eventual complications due to stroke, myocardialinfarction, or congestive heart failure tend to occur over months toyears, rather than hours to days. Long-term control of blood pressurecan prevent these eventual complications. However, a hypertensivecrisis cannot be diagnosed because no evidence exists that acutereduction of blood pressure results in improvement in short- orlong-term prognosis. Moreover, the presence of chronic hypertensiveend-organ complications in a patient with nonmalignant hypertensiondoes not imply the existence of a hypertensive crisis requiring rapidcontrol of blood pressure. The category of benign hypertensionwith chronic complications includes hypertensive patients withchronic renal insufficiency due to underlying primary renalparenchymal disease, chronic congestive heart failure as a result of either systolic or diastolic dysfunction, atherosclerotic coronaryvascular disease (stable angina or previous myocardial infarction),or chronic cerebrovascular disease (previous transient ischemicattacks or cerebrovascular accident). Long-term inadequate bloodpressure control increases the risk of further deterioration of end-organ function in each of these conditions. However, no evidenceexists that rapid control of blood pressure is necessary to prevent fur-ther complications. Therefore, a true hypertensive crisis does not exist.


Vascular damage

Volumedepletion

Spontaneousnatriuresis

Essentialhypertension

Forced vasodilation(sausage-string)

Critical level orRate of increase

Severe hypertension

Chronic renal failure

Renalischemia

↑ Catecholamines↑ Vasopressin↑ Renin/Angiotensin II

Pathophysiology of malignant hypertension

Denudation of epithelium ↑ Endothelial permeability

Platelet adherencePDGF release

Smooth muscle proliferation

Low potassiumdiet

Deposition of mucopolysaccharide

ExtravasationFibrinogen

Fibrin deposition Arteriolar wall

Necrosis of smooth muscle

Narrowing of vascular lumen

Renal ischemia

Musculomucoid intimal hyperplasia

Fibrinoidnecrosis

Accelerated glomerular obsolescence

Tubular atrophy

Interstitial fibrosis

Lumen

Localizedintravascularcoagulation

Decreased prostacyclin Oral contraceptives Cigarette smoking

Renal parenchymal diseaseRenal artery stenosisEndocrine hypertension

in thickening and remodeling of arteriolarwalls that may be an adaptive mechanismto prevent vascular damage from themechanical stress of hypertension. However,when the blood pressure increases suddenlyor increases to a critical level, these adaptivemechanisms may be overwhelmed, resultingin vascular damage. As a result of themechanical stress of increased transmuralpressure, focal segments of the arteriolarvasculature become dilated, producing asausage-string pattern. Endothelial perme-ability increases in the dilated segments,leading to extravasation of fibrinogen, fibrindeposition in the media, and necrosis ofsmooth muscle cells (fibrinoid necrosis).Platelet adherence to damaged endotheliumwith release of platelet-derived growth factorinduces migration of smooth muscle cells tothe intima where they proliferate (neointimalproliferation) and produce mucopolysac-charide. These cells also produce collagen,resulting in proliferative endarteritis, musculomucoid hyperplasia, and eventually,fibrotic obliteration of the vessel lumen.Occlusion of arterioles leads to acceleratedglomerular obsolescence and end-stagerenal disease. Other factors may synergizewith hypertension to damage the arterialvasculature. Renal ischemia leads to activa-tion of the renin-angiotensin system that cancause further elevation of blood pressure andprogressive vascular damage. Spontaneousnatriuresis early in the course of malignanthypertension leads to volume depletion withactivation of the renin-angiotensin system orcatecholamines that further elevates bloodpressure. It also is possible that angiotensinII may be directly vasculotoxic. Activationof the clotting cascade within the lumen ofdamaged vessels may lead to fibrin depositionwith localized intravascular coagulation.Thus, microangiopathic hemolytic anemia isa common finding in malignant hypertension.Cigarette smoking and oral contraceptiveuse may contribute to development ofmalignant hypertension by decreasingprostacyclin production in the vessel walland thereby inhibiting repair of hypertension-induced vascular injury. Low dietary intakeof potassium may help promote vascularsmooth muscle proliferation and thereforepredisposes to the development of malig-nant hypertension in Blacks with severeessential hypertension. PDGF—platelet-derived growth factor.

FIGURE 8-3

Pathophysiology of malignant hypertension. The vicious cycle of malignant hypertension is best demonstrated in the kidneys. This cycle also applies equally well to the vascularbeds of the retina, pancreas, gastrointestinal tract, and brain [1]. In this scheme, severehypertension is central. Hypertension may be either essential or secondary to any one of avariety of causes. Because not all patients develop malignant hypertension despite equallysevere hypertension, the interaction between the level of blood pressure and the adaptivecapacity of the vasculature may be important. In this regard, chronic hypertension results


Occlusion of vessels

Vascular lesions in malignant hypertension


Fibrinoid necrosis Proliferative endarteritis

Ischemia

Pancreatic Necrosis Hemorrhage

GI Hemorrhage Bowel necrosis

Renal Glomerulosclerosis Tubular atrophy Interstitial fibrosis

Cardiac Left ventricular dysfunction

CNS Intracerebral hemorrhage Hypertensive encephalopathy

Retinal Hemorrhages Cotton-wool spots Papilledema

FIGURE 8-4

Distribution of vascular lesions in malignanthypertension. Malignant hypertension isessentially a systemic vasculopathy inducedby severe hypertension. Fibrinoid necrosis andproliferative endarteritis occur throughout thebody in numerous vascular beds, leading toischemic changes. In the retina, striate hem-orrhages and cotton-wool spots develop.The finding of hypertensive neuroretinopathyis the clinical sine qua non of malignanthypertension. Vascular lesions in the gastro-intestinal tract (GI) can lead to hemorrhageor bowel necrosis. Hemorrhagic pancreatitisalso can occur. Cerebrovascular lesions canlead to cerebral infarction or intracerebralhemorrhage. Hypertensive encephalopathyalso can develop as a result of failure ofautoregulation with cerebral overperfusionand edema (Fig. 8-22). Vascular lesions alsocan develop in the myocardium; however,acute hypertensive heart failure is largely theresult of acute diastolic dysfunction inducedby the marked increase in afterload thataccompanies malignant hypertension (Figs. 8-24 and 8-25). CNS—central nervous system.

COMMON CAUSES OF MALIGNANT HYPERTENSION

Primary (essential) malignant hypertension*Secondary malignant hypertension

Primary renal diseaseChronic glomerulonephritis*Chronic pyelonephritis*Analgesic nephropathy*Immunoglobulin A nephropathy*Acute glomerulonephritisRadiation nephritis

Renovascular hypertension*Oral contraceptivesAtheroembolic renal disease (cholesterol embolism)Scleroderma renal crisisAntiphospholipid antibody syndromesChronic lead poisoningEndocrine hypertension

Aldosterone-producing adenoma (Conn’s syndrome)Cushing’s syndromeCongenital adrenal hyperplasiaPheochromocytoma

*Most common causes of malignant hypertension.

become apparent when a renal biopsy is performed. Recently,immunoglobulin A (IgA) nephropathy has been reported as anincreasingly frequent cause of malignant hypertension. In one series of 66 patients with IgA nephropathy, 10% developed malignanthypertension [3]. Chronic atrophic pyelonephritis in children, oftena result of underlying vesicoureteral reflux, is the most common causeof malignant hypertension [4]. In Australia, malignant hypertensioncomplicates up to 7% of cases of analgesic nephropathy [5].Transient malignant hypertension responsive to volume expansionhas been reported in analgesic nephropathy. It has been suggestedthat interstitial disease with salt-wasting is important in the patho-genesis by causing profound volume depletion with activation ofthe renin-angiotensin axis. Malignant hypertension is both an earlyand late complication of radiation nephritis that can occur up to11 years after radiotherapy. Renovascular hypertension from eitherfibromuscular dysplasia or atherosclerosis is a well-recognizedcause of malignant hypertension. In a series of 123 patients withmalignant hypertension, renovascular hypertension was found in43% of Whites and 7% of Blacks [6]. Among women of childbearingage, oral contraceptives can cause malignant hypertension [7]. Inthe absence of underlying renal disease, with discontinuation of thedrug, long-term prognosis is excellent. Severe hypertension thatmay become malignant is a common complication of atheroembolicrenal disease. In patients presenting with malignant hypertension inthe weeks to months after an arteriographic procedure, a carefulhistory and physical should be performed to look for evidence ofatheroembolism. Scleroderma renal crisis is the most life-threateningcomplication of progressive systemic sclerosis. Scleroderma renalcrisis is characterized by hypertension that may enter the malignantphase. Even in the absence of hypertensive neuroretinopathy sug-gesting malignant hypertension, the renal lesion in sclerodermarenal crisis is virtually indistinguishable from primary malignantnephrosclerosis [8]. Patients with antiphospholipid antibody syn-drome, either primary or secondary to systemic lupus erythematosus,can develop malignant hypertension with renal insufficiency as a result of thrombotic microangiopathy [9]. The endocrine causes of hypertension only rarely lead to malignant hypertension.Pheochromocytoma can cause hypertensive crises owing to hyper-tensive encephalopathy or acute hypertensive heart failure in theabsence of hypertensive neuroretinopathy (malignant hypertension).

FIGURE 8-5

Malignant hypertension is not a single disease entity but, rather, asyndrome in which the hypertension can be either primary (essential)or secondary to any one of a number of different causes [2]. AmongBlack patients the underlying cause is almost always essential hyper-tension that has entered a malignant phase. The most common secondary causes of malignant hypertension are primary renalparenchymal disorders. Chronic glomerulonephritis is thought tobe the cause of malignant hypertension in up to 20% of cases. Unlessa history of an acute nephritic episode or long-standing hematuria orproteinuria is available, the underlying glomerulonephritis may only

RENAL CHANGES IN HYPERTENSION

Retinal arteriosclerosis and arteriosclerotic retinopathy (benign hypertension)

Focal or diffuse arteriolar narrowing

Arteriovenous crossing changes

Broadening of the light reflex

Copper or silver wiring

Perivasculitis (parallel white lines around the arteries)

Solitary round hemorrhages

Hard exudates

Central or branch venous occlusion

Hypertensive neuroretinopathy (malignant hypertension)

Generalized arteriolar narrowing

Striate (flame-shaped) hemorrhage*

Cotton-wool spots*

Papilledema*

Star figure at the macula

*Features that distinguish hypertensive neuroretinopathy from retinal arteriosclerosis.

hypertension (diagnostic of malignant hypertension) is quite differ-ent from the clinical significance of a hard exudate in the fundus ofa 60-year-old man with moderate hypertension. The prognosticand therapeutic implications of these two types of exudates clearlyare different, although both would be classified as grade III. Forthis reason, the Keith and Wagener classification has been sup-planted by the more clinically useful classification of hypertensiveretinopathy shown here. This classification system draws a distinc-tion between retinal arteriosclerosis with arteriosclerotic retinopa-thy, which is characteristic of benign hypertension, and hyperten-sive neuroretinopathy, which defines the existence of malignanthypertension [12,13]. Retinal arteriosclerosis, which is character-ized histologically by the accumulation of hyaline material in arte-rioles, occurs in elderly normotensive persons or in the setting oflong-standing benign hypertension. Funduscopic findings reflectingretinal arteriosclerosis include arteriolar narrowing, arteriovenouscrossing changes, perivasculitis, and changes in the light reflex withcopper or silver wiring. Arteriosclerotic retinopathy manifests assolitary round hemorrhages in the periphery of the fundus andhard exudates. The finding of retinal arteriosclerosis is of no prog-nostic significance with regard to the risk of coronary atherosclero-sis or cerebrovascular disease. The arteries visualized with the oph-thalmoscope are technically arterioles with a diameter of 0.1 mm.Hyaline arteriolosclerosis of the retinal vessels is a process entirelydistinct from the atherosclerotic process that affects larger muscu-lar arteries. Thus, the finding of retinal arteriosclerosis cannot pre-dict the presence of atherosclerosis of the coronary or cerebral ves-sels. This lack of clinical significance of retinal arteriosclerosis inhypertensive patients contrasts dramatically with the importanceand prognostic significance of the finding of hypertensive neu-roretinopathy. This finding is the clinical sine qua non of malignanthypertension. The appearance of striate hemorrhages or cotton-wool spots with or without papilledema closely parallels the devel-opment of fibrinoid necrosis and proliferative endarteritis in thekidney and other organs. Thus, the presence of hypertensive neu-roretinopathy predicts the development of end-stage renal disease,or other life-threatening hypertensive complications, within a yearif adequate control of the blood pressure is not achieved.


Nonsuppressible aldosteronism

Renal potassium-wastingwith hypokalemia

Metabolic alkalosis

Resolves slowly over 1 year after control of blood pressure

Antihypertensivetreatment with

resolution of malignanthypertension

Activation of renin-angiotensinaxis

Vascular lesions heal

Renin levelsdecrease rapidly

Renal ischemia

Tertiary hyperaldosteronism after treatment of malignant hypertension

Bilateral adrenal hyperplasia


FIGURE 8-6

Tertiary hyperaldosteronism after treatment of malignant hyperten-sion. The diagnosis of primary hyperaldosteronism must be madewith caution in patients with a history of malignant hypertension.After successful treatment of malignant hypertension, plasma reninactivity rapidly normalizes, whereas aldosterone secretion mayremain elevated for up to a year. This phenomenon has been attrib-uted to persistent adrenal hyperplasia induced by long-standinghyperreninemia during the malignant phase [10]. During this phaseof tertiary hyperaldosteronism, despite suppressed renin activity,hypokalemia, metabolic alkalosis, and aldosterone levels that arenot suppressible, mimic primary hyperaldosteronism. Adrenalimaging studies reveal bilateral nodular adrenal hyperplasia. Withcontinued long-term control of blood pressure this hyperaldostero-nism remits spontaneously.

FIGURE 8-7

Funduscopic findings are pivotal in the diagnosis of malignanthypertension. Keith and Wagener [11] graded retinal findings inhypertensive patients as follows: grade I, arteriolar narrowing;grade II, arteriovenous crossing changes; grade III, hemorrhagesand exudates; grade IV, the changes in grade III plus papilledema.Although this classification of hypertensive retinopathy is of greathistorical importance, its clinical utility has several limitations, eg,it is extremely difficult to quantify arteriolar narrowing. In thisregard, a tendency exists for significant observer bias such thatpatients with mild hypertension and questionable narrowing areinvariably assigned to grade I. More importantly, this classificationdoes not distinguish the retinal changes of benign and malignanthypertension. For example, the clinical significance of a cotton-wool spot appearing in the fundus of a young man with severe



Fundus photography of retinal arteriosclerosis in benign hypertension. Funduscopy in a60-year-old man reveals the characteristic changes of retinal arteriosclerosis, includingarteriolar narrowing, mild arteriovenous crossing changes, copper wiring, and perivasculitis(parallel white lines around blood columns). The striate hemorrhages, cotton-wool spots,and papilledema characteristic of malignant hypertension are absent.


Fundus photography of arteriosclerotic retinopathy in benign hypertension. Funduscopy ina 52-year-old woman with benign hypertension demonstrates a solitary round hemorrhagecharacteristic of arteriosclerotic retinopathy.


Fundus photography of striate hemorrhages in hypertensive neuroretinopathy. Funduscopicfindings in a 53-year-old woman with secondary malignant hypertension as a result ofunderlying immunoglobulin A nephropathy, demonstrating striate or flame-shaped hemorrhages (arrows). The appearance of small striate hemorrhages often is the first sign that malignant hypertension has developed. These hemorrhages are most commonlyobserved in a radial arrangement around the optic disc. The retinal circulation is underautoregulatory control such that under normal circumstances as blood pressure increases,arterioles constrict to maintain constant retinal blood flow. The appearance of striate hemorrhages implies that autoregulation has failed. Striate hemorrhages are a result ofbleeding from superficial capillaries in the nerve fiber bundles near the optic disc. Thesecapillaries originate directly from arterioles so that when autoregulation fails, the high systemic pressure is transmitted directly to the capillaries. This process leads to breaks inthe continuity of the capillary endothelium. The resultant hemorrhages extend along nervefiber bundles parallel to the retinal surface. The hemorrhages often have a frayed distalborder owing to extravasation of blood between nerve fiber bundles.



Fundus photography of cotton-wool spots in hypertensive neuroretinopathy. Cotton-woolspots (arrows) are the most characteristic feature of malignant hypertension. They usuallysurround the optic disc and most commonly occur within three disc-diameters of the opticdisc. Cotton-wool spots result from ischemic infarction of retinal nerve fiber bundles owingto arteriolar occlusion caused by proliferative arteriopathy in retinal vessels. Fluoresceinangiography demonstrates that cotton-wool spots are areas of retinal nonperfusion.Embolization of pig retina with glass beads produces immediate neuronal cell edema followedby accumulation of mitochondria and other subcellular organelles in ischemic nerve fibers. It has been postulated that the normal axoplasmic flow of subcellular organelles is disruptedby retinal ischemia such that accumulation of organelles in ischemic nerve fiber bundlesresults in a visible white patch. Cotton-wool spots tend to distribute around the optic discbecause nerve fiber bundles are most dense in this region. The detection of cotton-wool spotsis a crucial clinical finding because they are the retinal manifestation of the malignant hyper-tension-induced systemic vasculopathy that also causes proliferative endarteritis and ischemiain the kidney and other organs. (This is the same patient as in Fig. 8-10.)


Fundus photography of papilledema in hypertensive neuroretinopathy. Funduscopic find-ings in a 23-year-old Black man noted incidentally to be severely hypertensive during aroutine dental clinic visit. Papilledema of the optic disc is apparent, with surrounding cot-ton-wool spots and striated hemorrhages. The pathogenesis of papilledema in hypertensiveneuroretinopathy is unclear. Intracranial pressure is not always increased in patients withmalignant hypertension and papilledema. Papilledema has been produced experimentallyin Rhesus monkeys by occlusion of the long posterior ciliary artery that supplies the opticnerve. As in cotton-wool spots, indeed papilledema may result from hypertensive vascu-lopathy–induced ischemia of nerve fiber bundles in the optic disc. Thus, in hypertensiveneuroretinopathy, papilledema essentially may represent a giant cotton-wool spot resultingfrom ischemia of the optic nerve. When papilledema occurs in malignant hypertension, italmost always is accompanied by striated hemorrhages and cotton-wool spots. Whenpapilledema occurs alone, the possibility of a primary intracranial process such as tumoror cerebrovascular accident should be considered.


Fundus photography of far-advanced hypertensive neuroretinopathy. Funduscopy in this30-year-old man with malignant hypertension demonstrates all the characteristic featuresof hypertensive neuroretinopathy. These features include striate hemorrhages, cotton-woolspots, papilledema, and a star figure at the macula.


0–8

1–0

0–6

0

Esti

mat

ed s

urv

ival

20 6Years

4 108

2843 1016 No. without papilledema6

7496 2645 No. with papilledema

No papilledemaPapilledema

14

0–4

FIGURE 8-14

Prognosis in accelerated hypertension versus malignant hypertension.In the original Keith and Wagener [11] classification of hypertensiveretinopathy, malignant hypertension (grade IV) was defined by thepresence of papilledema, whereas the term accelerated hypertension(grade III) was used when hemorrhages and exudates occurred inthe absence of papilledema. However, more recent studies indicatethat the prognosis is the same in hypertensive patients with striatehemorrhages and cotton-wool spots whether or not papilledema ispresent. In this regard, the World Health Organization has recom-mended that accelerated hypertension and malignant hypertension beregarded as synonymous terms for the same disease. Demonstratedare the effects of the presence or absence of papilledema on survivalamong 139 hypertensive patients with hypertensive neuroretinopathy(striated hemorrhages and cotton-wool spots) [14]. By multivariateanalysis, after controlling for age, gender, smoking habit, initialserum creatinine concentration, and initial and achieved bloodpressure, the presence of papilledema did not influence prognosis.(From McGregor [14] et al.; with permission.)


Micrograph of fibrinoid necrosis in malignant hypertension.Fibrinoid necrosis of the afferent arterioles and interlobular arterieshas traditionally been regarded as the hallmark of malignanthypertension. The characteristic finding is the deposition in thearteriolar wall of a granular material that is a bright-pink color onhematoxylin and eosin staining. On Masson trichrome staining, asillustrated, the granular fibrinoid material is bright red (arrow).The fibrinoid material usually is found in the media of the vessel;however, deposition in the intima also may occur. Whole or frag-mented erythrocytes may be extravasated into the arteriolar wall.These hemorrhages account for the petechial hemorrhages that giverise to the peculiar flea-bitten appearance of the capsular surface ofthe kidney in malignant hypertension. Fibrinoid necrosis is thoughtto result from the mechanical stress placed on the vessel wall bysevere hypertension. Forced vasodilation occurs when there is failureof autoregulation of renal blood flow, which leads to endothelialinjury with seepage of plasma proteins into the vessel wall. Contactof plasma constituents with smooth muscle cells activates the coag-ulation cascade, and fibrin is deposited in the wall. Fibrin depositsthen cause necrosis of smooth muscle cells (fibrinoid necrosis).(Masson trichrome stain, original magnification � 100.)



Micrograph of proliferative endarteritis in malignant hypertension(musculomucoid intimal hyperplasia). In malignant nephrosclerosis,the interlobular (cortical radial) arteries reveal characteristic lesions.These lesions are variously referred to as proliferative endarteritis,endarteritis fibrosa, musculomucoid intimal hyperplasia, or theonionskin lesion. The typical finding is marked thickening of theintima that obstructs the vessel lumen. In severely affected vesselsthe luminal diameter may be reduced to the caliber of a single ery-throcyte. Occasionally, complete obliteration of the lumen by asuperimposed fibrin thrombus occurs.

Traditionally, three patterns of intimal thickening have beendescribed [15]. (1) The onionskin pattern consists of pale layers ofelongated concentrically arranged myointimal cells along with deli-cate connective tissue fibrils that give rise to a lamellar appearance.The media often appears as an attenuated layer stretched aroundthe expanded intima. (2) In the mucinous pattern, intimal cells aresparse. Seen is an abundance of lucent, faintly basophilic-stainingamorphous material. (3) In fibrous intimal thickening, seen are fewcells with an abundance of hyaline deposits, reduplicated bands ofelastica, and coarse layers of collagen. The renal histology in Blackswith malignant hypertension demonstrates a characteristic findingin the larger arterioles and interlobular arteries known as musculo-mucoid intimal hyperplasia, with an abundance of cells and a smallamount of myxoid material (that is light blue in color on hema-toxylin and eosin staining) between the cells [16, 17]. These variousintimal findings may represent progression over time from an ini-tially cellular lesion to fibrosis of the intima. Electron microscopydemonstrates that in each type of intimal thickening the most abun-dant cellular element is a modified smooth muscle cell. This cell iscalled a myointimal cell. Proliferative endarteritis is thought tooccur as a result of phenotypic modulation of medial smooth mus-cle cells that dedifferentiate from the normal contractile phenotypeto acquire a more embryologic proliferative-secretory phenotype. Ithas been proposed that the endothelial injury in malignant hyper-tension results in attachment of platelets with release of platelet-derived growth factor (PDGF) that may induce the phenotypicchange in smooth muscle cells. PDGF stimulates chemotaxis ofmedial smooth muscles to the intima, where they proliferate andsecrete mucopolysaccharide and later collagen and other extracellu-lar matrix proteins, resulting in proliferative endarteritis, musculo-mucoid hyperplasia, and ultimately fibrous intimal thickening.(Hematoxylin and eosin stain, original magnification � 100.)

SPECTRUM OF CLINICAL RENAL INVOLVEMENT IN MALIGNANT HYPERTENSION

Progressive subacute deterioration of renal function to end-stage renal disease

Transient deterioration of renal function with initial blood pressure control

Oliguric acute renal failure

Established renal failure

FIGURE 8-17

Malignant hypertension is a progressive systemic vasculopathy inwhich renal involvement is a relatively late finding. In this regard,patients with malignant hypertension can present with a spectrumof renal involvement ranging from normal renal function with minimalalbuminuria to end-stage renal disease (ESRD) indistinguishablefrom that seen in primary renal parenchymal disease. In patientsinitially exhibiting preserved renal function, in the absence of adequateblood pressure control, it is common to observe subacute deterio-ration of renal function to ESRD over a period of weeks to months.Transient deterioration of renal function with initial control ofblood pressure is a well-documented entity in patients initiallyexhibiting mild to moderate renal impairment. Occasionally,patients with malignant hypertension initially exhibit oliguric acuterenal failure, necessitating initiation of dialysis within a few days ofhospitalization. Because erythrocyte casts sometimes appear in theurine sediment, malignant nephrosclerosis initially may be misdiag-nosed as a rapidly progressive glomerulonephritis or systemic vasculitis[18]. Careful examination of the fundus for evidence of hypertensiveneuroretinopathy confirms the diagnosis of malignant hypertension.

Patients with malignant hypertension can also present with estab-lished renal failure. Often, it is impossible to determine clinicallywhether a patient initially exhibiting hypertensive neuroretinopathyand renal failure has primary malignant hypertension or secondarymalignant hypertension with underlying primary renal parenchymaldisease. The presence of normal-sized kidneys on ultrasonographysupports a diagnosis of primary malignant nephrosclerosis thatpotentially is reversible with long-term blood pressure control.However, a renal biopsy may be required for definitive diagnosis.All patients with malignant hypertension should receive aggressiveantihypertensive therapy to prevent further renal damage, regardlessof the degree of renal impairment. Control of blood pressure inpatients with malignant hypertension and renal insufficiency oftencauses further deterioration of renal function, especially when theinitial glomerular filtration rate (GFR) is less than 20 mL/min.However, a fall in GFR is not a contraindication to intensive bloodpressure control aimed at normalization of blood pressure. Controlof hypertension protects other vital organs, such as the heart andbrain, whose function cannot be replaced. Moreover, with rigidblood pressure control, renal function may eventually recover overthe ensuing months, even in patients with apparent ESRD owing toprimary malignant nephrosclerosis [19,20].



Micrograph of hyaline arteriolar nephrosclerosis in benign hyper-tension. It is important to draw a clear distinction between malig-nant hypertension and benign hypertension with regard to renalhistology and clinical renal involvement. In benign arteriolarnephrosclerosis caused by benign hypertension, the characteristichistologic lesion is hyaline arteriosclerosis. In hyaline arteriosclero-sis there is expansion of the intima of afferent arterioles with hya-line material that stains a pale-pink color on periodic acid–Schiffstaining (large arrow). Patchy (focal) ischemic atrophy of theglomeruli usually is seen. Many glomeruli appear normal, whereassome are completely hyalinized. Atrophic tubules (small arrows),sometimes filled with amorphous material, may be seen in thevicinity of ischemic glomeruli. The severity of the glomerular andtubular changes generally reflect the extent of vascular involvementwith hyaline arteriosclerosis. On gross examination, the kidneysare small with a granular-appearing capsular surface (contractedgranular kidney). The loss of renal mass primarily is due to a thin-ning of the cortex. In untreated malignant hypertension, relentlessprogression to end-stage renal disease (ESRD) occurs within a year.In contrast, in benign hypertension, without underlying renal dis-ease or superimposed malignant hypertension, despite well-estab-lished folklore to the contrary, ESRD seldom develops [21,22]. Inbenign hypertension, there is a usually a long asymptomatic phase,with eventual complications resulting from cerebrovascular disease,atherosclerotic disease, or congestive heart failure, in the absenceof significant renal impairment despite histologic evidence ofbenign nephrosclerosis. In this regard, patients classified as havingESRD owing to “hypertensive nephrosclerosis” typically exhibitadvanced disease initially, making the original process that initiatedthe renal disease difficult to detect. Moreover, significant racial biasmay occur in the clinical diagnosis of the cause of ESRD [23].Nephrologists presented with identical case histories of hypotheti-cal patients with ESRD and hypertension in which the race is arbi-trarily stated to be Black or White, tend to diagnose hypertensivenephrosclerosis in Blacks and chronic glomerulonephritis inWhites. It has been proposed that many of the patients presumedclinically to have ESRD owing to benign hypertension, actuallyhave occult intrinsic renal disease with chronic glomerulonephritis,unrecognized bilateral atherosclerotic renal artery stenosis withischemic nephropathy, atheroembolic renal disease, or episodes ofmalignant hypertension that had gone undetected [21,22]. (Periodicacid–Schiff stain, original magnification � 100.)


FIGURE 8-19

Malignant hypertension must be treated expeditiously to preventcomplications such as hypertensive encephalopathy, acute hypertensiveheart failure, and renal failure. The traditional approach to patientswith malignant hypertension has been the initiation of potent par-enteral agents. Listed are the settings in which parenteral antihy-pertensive therapy is mandatory in the initial management ofmalignant hypertension. Parenteral therapy generally should beused in patients with evidence of acute end-organ dysfunction orthose unable to tolerate oral medications. Nitroprusside is thetreatment of choice for patients requiring parenteral therapy.Diazoxide, employed in minibolus fashion to avoid sustained over-shoot hypotension, may be advantageous in patients for whommonitoring in an intensive care unit is not feasible. It generally issafe to reduce the mean arterial pressure by 20% or to a level of160 to 170 mm Hg systolic over 100 to 110 mm Hg diastolic. Theuse of a short-acting agent such as nitroprusside has obviousadvantages because blood pressure can be stabilized quickly at ahigher level if complications develop during rapid blood pressurereduction. When no evidence of vital organ hypoperfusion is seenduring this initial reduction, the diastolic blood pressure can belowered gradually to 90 mm Hg over a period of 12 to 36 hours.Oral antihypertensive agents should be initiated as soon as possible tominimize the duration of parenteral therapy. The nitroprussideinfusion can be weaned as the oral agents become effective. Thecornerstone of initial oral therapy should be arteriolar vasodilatorssuch as calcium channel blockers, hydralazine, or minoxidil. Usually,�-blockers are required to control reflex tachycardia, and a diureticmust be initiated within a few days to prevent salt and water retention,in response to vasodilator therapy, when the patient’s dietary saltintake increases. Diuretics may not be necessary as a part of initialparenteral therapy because patients with malignant hypertensionoften present with volume depletion (Fig. 8-20).

Many patients with malignant hypertension definitely require initialparenteral therapy. However, some patients may not yet have evidenceof cerebral or cardiac dysfunction or rapidly deteriorating renalfunction and therefore do not require instantaneous control of bloodpressure. These patients often can be managed with an intensive oralregimen, often with a �-blocker and minoxidil, designed to bringthe blood pressure under control within 12 to 24 hours. After theimmediate crisis has resolved and the patient’s blood pressure hasbeen controlled with initial parenteral therapy, oral therapy, orboth, lifelong surveillance of blood pressure is mandatory. If bloodpressure control lapses, malignant hypertension can recur evenafter years of successful antihypertensive therapy. Triple therapywith a diuretic, �-blocker, and a vasodilator often is required tomaintain satisfactory long-term blood pressure control.

INDICATIONS FOR PARENTERAL THERAPY IN MALIGNANT HYPERTENSION

Hypertensive encephalopathy

Rapidly failing vision

Pulmonary edema


Rapid deterioration of renal function

Acute pancreatitis

Gastrointestinal hemorrhage or acute abdomen from mesenteric vasculitis

Patients unable to tolerate oral therapy because of intractable vomiting


Intravascular volume depletion

Activation of the renin-angiotensin axis

Angiotensin II–mediated vasoconstriction

Pressure-induced natriuresis and diuresis

Viciouscircle

Abrupt increase in blood pressure


Role of diuretics to treat malignant hypertension

FIGURE 8-20

Role of diuretics in the treatment of malignant hypertension.Traditionally, it had been taught that patients with malignanthypertension require potent parenteral diuretics in conjunctionwith potent vasodilator therapy during the initial phase of manage-ment of malignant hypertension. However, evidence now exists tosuggest that parenteral diuretic therapy during the acute managementphase actually may be deleterious. In experimental animals, sponta-neous natriuresis appears to be the initiating event in the transitionfrom benign to malignant hypertension, and treatment with volumeexpansion leads to resolution of the malignant phase [24]. Rapidweight loss often occurs in patients with malignant hypertension,which is consistent with a pressure-induced natriuresis. In analgesicnephropathy, profound volume depletion often accompanies malignanthypertension, perhaps owing to tubular dysfunction with salt-wasting[5]. In this setting, restoration of normal volume status actuallylowers blood pressure and leads to resolution of the malignantphase. Thus, some patients with malignant hypertension may benefitfrom a cautious trial of volume expansion. Volume depletion shouldbe suspected when there is exquisite sensitivity to vasodilator therapywith a precipitous decrease in blood pressure at relatively low infusionrates. Even patients with malignant hypertension complicated bypulmonary edema may not be total-body salt and water overloaded.Pulmonary congestion in this setting may result from acute hyper-tensive heart failure caused by an acute decrease in left ventricular(LV) compliance precipitated by severe hypertension. In this setting,pulmonary edema occurs owing to a high LV end-diastolic pressurewith normal LV end-diastolic volume (Fig. 8-24). Thus, the needfor diuretic therapy during the initial phases of management ofmalignant hypertension depends on a careful assessment of volumestatus. Unless obvious fluid overload is present, diuretics shouldnot be given initially. Overdiuresis may result in deterioration ofrenal function owing to superimposed volume depletion. Moreover,volume depletion may further activate the renin-angiotensin systemand other pressor hormone systems. Although vasodilator therapywill eventually result in salt and water retention by the kidneys, anincrease in total body sodium content cannot occur unless thepatient is given sodium. Eventually, during long-term treatmentwith oral vasodilators, the use of diuretics becomes imperative toprevent fluid retention and adequately control blood pressure.


Prompt blood pressure reduction with nitroprusside

New or progressive focal findings(suspect primary central nervous

system process)

Dramatic clincal improvement(diagnostic of hypertensive

encephalopathy)

Pathogenesis and treatment of hypertensive encephalopathy

Hypertensive encephalopathy(headache, vomiting, altered mental status, seizures)

Cerebral edema

Failure of autoregulation of cerebral blood flow(breakthrough of autoregulation)

Sudden onset or severe hypertension

Forced vasodilation of cerebral arterioles

Endothelial damage(increased permeability to

plasma proteins)

Cerebral hyperperfusion(increased capillary

hydrostatic pressure)

Malignant hypertension(hypertensive neuroretinopathy

present)

Sudden or severe nonmalignant hypertension

(hypertensive neuroretinopathy absent)

FIGURE 8-21

Pathogenesis and treatment of hypertensive encephalopathy.Hypertensive encephalopathy is a hypertensive crisis in which acutecerebral dysfunction is attributed to sudden or severe elevation ofblood pressure [25–27]. Hypertensive encephalopathy is one of themost serious complications of malignant hypertension. However,malignant hypertension (hypertensive neuroretinopathy) need notbe present for hypertensive encephalopathy to develop. Hypertensiveencephalopathy also can occur in the setting of severe or suddenhypertension of any cause, especially if an acute elevation of bloodpressure occurs in a previously normotensive person, eg, frompostinfectious glomerulonephritis, catecholamine excess states, oreclampsia. Under normal circumstances, autoregulation of the cerebralmicrocirculation occurs, and therefore, cerebral blood flow remainsconstant over a wide range of perfusion pressures. However, in thesetting of sudden severe hypertension, autoregulatory vasoconstric-tion fails and there is forced vasodilation of cerebral arterioles withendothelial damage, extravasation of plasma proteins, and cerebralhyperperfusion with the development of cerebral edema. Thisbreakthrough of cerebral autoregulation underlies the developmentof hypertensive encephalopathy. In patients with chronic hypertension,structural changes occur in the cerebral arterioles that lead to a shiftin the autoregulation curve such that much higher blood pressurescan be tolerated without breakthrough. This phenomenon mayexplain the clinical observation that hypertensive encephalopathyoccurs at much lower blood pressure in previously normotensivepersons than it does in those with chronic hypertension. Clinicalfeatures of hypertensive encephalopathy include severe headache,blurred vision or occipital blindness, nausea, vomiting, and alteredmental status. Focal neurologic findings can sometimes occur. Ifaggressive blood pressure reduction is not initiated, stupor, convul-sions, and death can occur within hours. The sine qua non ofhypertensive encephalopathy is the prompt and dramatic clinicalimprovement in response to antihypertensive drug therapy. When adiagnosis of hypertensive encephalopathy seems likely, antihyper-tensive therapy should be initiated promptly without waiting forthe results of time-consuming radiographic examinations. The goalof therapy, especially in previously normotensive patients, shouldbe reduction of blood pressure to normal or near-normal levels asquickly as possible. Theoretically, cerebral blood flow could bejeopardized by rapid reduction of blood pressure in patients withchronic hypertension in whom the lower limit of cerebral bloodflow autoregulation is shifted to a higher blood pressure. However, clinical experience has shown that prompt blood pressure reductionwith the avoidance of frank hypotension is beneficial in patientswith hypertensive encephalopathy [25]. Of the conditions in thedifferential diagnosis of hypertension with acute cerebral dysfunc-tion, only cerebral infarction might be adversely affected by theabrupt reduction of blood pressure. Pharmacologic agents thathave rapid onset and short duration of action such as sodiumnitroprusside should be used so that the blood pressure can betitrated carefully, with close monitoring of the patient’s neurologicstatus. A prompt improvement in mental status with blood pressurereduction confirms the diagnosis of hypertensive encephalopathy.Conversely, when blood pressure reduction is associated with newor progressive focal neurologic deficits, the presence of a primarycentral nervous system event, such as cerebral infarction, should beconsidered.


FIGURE 8-22

Hypertensive encephalopathy can complicate malignant hyperten-sion of any cause. However, not all patients with hypertensiveencephalopathy have hypertensive neuroretinopathy, indicating thepresence of malignant hypertension. In fact, hypertensiveencephalopathy most commonly occurs in previously normotensivepersons who experience a sudden onset or worsening of hyperten-sion. In acute postinfectious glomerulonephritis, the abrupt onsetof even moderate hypertension may cause breakthrough ofautoregulation of cerebral blood flow, resulting in hypertensiveencephalopathy. Eclampsia can be viewed as a variant of hyperten-sive encephalopathy that complicates preeclampsia. Moreover,hypertensive encephalopathy is a common complication of cate-cholamine-induced hypertensive crises such as pheochromocytoma,monoamine oxidase inhibitor–tyramine interactions, clonidinewithdrawal, phencyclidine (PCP) poisoning, and phenyl-propanolamine overdose. Cocaine use also can induce a suddenincrease in blood pressure accompanied by hypertensiveencephalopathy. In children, acute lead poisoning, high-dosecyclosporine for bone marrow transplantation, femoral lengtheningprocedures, and scorpion envenomation may be accompanied bythe sudden onset of hypertension with hypertensive encephalopa-thy. Acute renal artery occlusion resulting from thrombosis or renalembolism can induce hypertensive encephalopathy. Likewise,atheroembolic renal disease (cholesterol embolization) can cause asudden increase in blood pressure complicated by encephalopathy.Recombinant erythropoietin therapy occasionally results inencephalopathy and seizures. This complication is unrelated to theextent or rate of increase in hematocrit; however, it is associatedwith a rapid increase in blood pressure, especially if the patientwas normotensive previously. Transplantation renal artery stenosisor acute renal allograft rejection may cause sudden severe hyper-tension with encephalopathy. Hypertensive encephalopathy maycomplicate acute or chronic spinal cord injury. Sudden elevation ofblood pressure occurs owing to autonomic stimulation by bowel orbladder distention or noxious stimulation in a dermatome belowthe level of the injury. Hypertensive encephalopathy also may com-plicate the rebound hypertension that follows coronary arterybypass procedures or carotid endarterectomy.

CAUSES OF HYPERTENSIVE ENCEPHALOPATHY

Malignant hypertension of any cause

Acute glomerulonephritis, especially postinfectious

Eclampsia

Catecholamine-induced hypertensive crises

Pheochromocytoma

Monoamine oxidase inhibitor–tyramine interactions

Abrupt withdrawal of centrally acting �2-agonists

Phenylpropanolamine overdose

Cocaine-hydrochloride or alkaloid (crack cocaine) intoxication

Phencyclidine (PCP) poisoning

Acute lead poisoning in children

High-dose cyclosporine for bone marrow transplantation in children

Femoral lengthening procedures

Scorpion envenomation in children

Acute renal artery occlusion from thrombosis or embolism

Atheroembolic renal disease (cholesterol embolization)

Recombinant erythropoietin therapy

Transplantation renal artery stenosis

Acute renal allograft rejection

Paroxysmal hypertension in acute or chronic spinal cord injuries

Post–coronary artery bypass or post–carotid endarterectomy hypertension


5.0

0

2.5

120

0

60

90

30

200

0

100

200

0

NS

NSNSNS

AHHF NF

100

60

0

P<0.005

30

45

15

150

Stroke work index, g m/m2 LVEDP, mm Hg LVEDV, mL/m2

MAP, mm Hg Heart rate, beats/min Cardiac index, L/min/m2

0

ANS

Baseline hemodynamics in acute hypertensive heart failure (AHHF) vs no failure (NF)

75

20

50

60

40

0

C

LVFP

, mm

Hg

8040 160

LVEDV, mL/m2

Left ventricular compliance at baseline and with nitroprusside

120 240200

10

30

AHHF: baselineAHHF: with nitroprussideNo failure: baselineNo failure: with nitroprusside

6

9

0

B

Car

dia

c o

utp

ut,

L/m

in

Mea

n a

rter

ial

pre

ssu

re, m

m H

g

LVED

P, m

m H

g

P<0.005

Hemodynamic parameters at baseline (B) and during nitroprusside (NP) infusion

NS

3

100

150

200

0

P<0.005 P<0.005

50

20

30

40

0

P<0.005 P<0.025

10

AHHFNF

B B

B

B B

B

NPNP

NP

NPNP

NP

in both groups had electrocardiographic evidence of LV hypertrophycaused by long-standing hypertension.

A, Baseline hemodynamic measurements before treatmentrevealed that the following measurements were the same in bothgroups: mean arterial pressure (MAP), heart rate, cardiac index,systemic vascular resistance, and stroke work index. Likewise, theLV end-diastolic volume (LVEDV) was similar in both groups. Infact, the only hemodynamic difference between the groups was asignificant elevation of LV filling pressure (LVFP) (pulmonary capil-lary wedge pressure) in the group with pulmonary edema. In acutehypertensive heart failure the finding of elevated LV end-diastolicpressures (LVEDPs), despite normal ejection fraction and cardiacindex, implies the presence of isolated diastolic dysfunction. Theincreased LV end-diastolic pressure (LVEDP), despite similarLVEDV, can only be explained by a decrease in LV compliance inpatients with acute hypertensive heart failure. B, The importanceof an acute decrease in LV compliance in the pathogenesis of acutehypertensive heart failure (AHHF) was confirmed in these patientsby the hemodynamic response to vasodilator therapy. Sodiumnitroprusside infusion resulted in prompt resolution of pulmonaryedema in the group having AHHF, with the LVEDP decreasingfrom a mean of 43 to 18 mm Hg. C, The decrease in filling pres-sure during nitroprusside therapy in patients with AHHF was notcaused by venodilation with decreased venous return because theLVEDV actually increased during nitroprusside infusion. Thus, theresponse to sodium nitroprusside therapy was mediated through adecrease in systemic vascular resistance that led to an immediateimprovement in LV compliance and reduction in wedge pressuredespite an increase in LVEDV. These findings suggest that the prox-imate cause of AHHF is an elevation of the systemic vascular resis-tance that precipitates acute diastolic dysfunction (decreased LVcompliance) with elevated pulmonary capillary wedge pressure,resulting in pulmonary edema. NS— not significant. (Adapted fromCohn and coworkers [28]; with permission.)

FIGURE 8-23

Pathogenesis of acute hypertensive heart failure. Both malignanthypertension and severe benign hypertension can be complicated byacute pulmonary edema caused by isolated diastolic dysfunction. Inacute hypertensive heart failure the compromise of left ventricular (LV)diastolic function occurs as a result of a decrease in LV compliancecaused by an increased workload imposed on the heart by the markedelevation in systemic vascular resistance. Illustrated are the hemody-namic derangements in acute hypertensive heart failure in a study thatcompared five patients with severe essential hypertension complicatedby acute pulmonary edema with a control group of five patients withequally severe hypertension but no pulmonary edema [28]. Patients


20

50

60

40

0

Left

ven

tric

ula

r en

d-d

iast

olic

pre

ssu

re, m

m H

g

8040 160

Nitroprusside

AHH

F

Normal

120

Left ventricular end-diastolic volume, mL/m2

240200

10

30

FIGURE 8-24

Treatment of acute hypertensive heart failure. The left ventricular(LV) end-diastolic pressure-volume relationships (compliancecurves) in acute hypertensive heart failure (AHHF) before and aftertreatment with sodium nitroprusside are represented schematically.In AHHF, the pressure-volume curve is shifted up and to the left,reflecting an acute decrease in LV compliance caused by severe systemic hypertension. In this setting, a higher than normal LVend-diastolic pressure (LVEDP) is required to achieve any givenlevel of LV end-diastolic volume (LVEDV). Normal LV systolicfunction (ejection fraction and cardiac output) is maintained but at the expense of a very high wedge pressure that results in acutepulmonary edema. Treatment with sodium nitroprusside causes a reduction in the elevated systemic vascular resistance, with a concomitant decrease in impedance to LV ejection. As a result, LVcompliance improves. Pulmonary edema resolves owing to a reduc-tion in LVEDP, despite the fact that LVEDV actually increases dur-ing treatment. Sodium nitroprusside is the preferred drug for treat-ment of AHHF. There is no absolute blood pressure goal. The infu-sion should be titrated until signs and symptoms of pulmonaryedema resolve or the blood pressure decreases to hypotensive lev-els. Rarely is it necessary to lower the blood pressure to this extent,however, because reduction to levels still within the hypertensiverange is usually associated with dramatic clinical improvement.Although hemodynamic monitoring is not always required, it isessential in patients in whom concomitant myocardial ischemia orcompromised cardiac output is suspected. After the hypertensivecrisis has been controlled and pulmonary edema has resolved, oralantihypertensive therapy can be substituted as the patient isweaned from the nitroprusside infusion. As in the treatment ofhypertensive patients with chronic congestive heart failure symp-toms owing to isolated diastolic dysfunction, agents such as �-blockers, angiotension-converting enzyme inhibitors, or calciumchannel blockers may represent logical first-line therapy. Theseagents directly improve diastolic function in addition to reducingsystemic blood pressure. In patients with malignant hypertensionor resistant hypertension, however, adequate control of blood pres-sure may require therapy with more than one drug. Potent direct-acting vasodilators such as hydralazine or minoxidil may be usedin conjunction with a �-blocker to control reflex tachycardia and a diuretic to prevent reflex salt and water retention.


Proximal(Type A)

Aortic dissection

Distal(Type B)

Ascending aorta

Transverseaortic arch Descending

aorta

FIGURE 8-25

Aortic dissection. Classification of aortic dissection is based on thepresence or absence of involvement of the ascending aorta [29].The dissection is defined as proximal if there is involvement of theascending aorta. The primary intimal tear in proximal dissectionmay arise in the ascending aorta, transverse aortic arch, or descendingaorta. In distal dissections, the process is confined to the descendingaorta without involvement of the ascending aorta, and the primaryintimal tear occurs most commonly just distal to the origin of theleft subclavian artery. Proximal dissections account for approximately57% and distal dissections 43% of all acute aortic dissections.Acute aortic dissection is a hypertensive crisis requiring immediateantihypertensive treatment aimed at halting the progression of thedissecting hematoma. The three most frequent complications ofaortic dissection are acute aortic insufficiency, occlusion of majorarterial branches, and rupture of the aorta with fatal hemorrhage(location of rupture-hemorrhage: ascending aorta–hemopericardiumwith tamponade, aortic arch–mediastinum, descending thoracicaorta–left pleural space, abdominal aorta– retroperitoneum).Patients with acute dissection should be stabilized with intensiveantihypertensive therapy to prevent life-threatening complicationsbefore diagnostic evaluation with angiography. The initial therapeuticgoal is the elimination of pain that correlates with halting of thedissection, and reduction of the systolic pressure to the 100 to 120mm Hg range or to the lowest level of blood pressure compatiblewith the maintenance of adequate renal, cardiac, and cerebral perfusion [30]. Even in the absence of systemic hypertension theblood pressure should be reduced. Antihypertensive therapy shouldbe designed not only to lower the blood pressure but also to decreasethe steepness of the pulse wave. The most commonly used treatmentregimens consist of initial treatment with intravenous �-blockerssuch as propranolol, metoprolol, or esmolol followed by treatmentwith sodium nitroprusside. After control of the blood pressure,angiography or transesophageal echocardiography, or both, shouldbe performed. The need for surgical intervention is determined basedon involvement of the ascending aorta. In proximal dissections, sur-gical therapy is clearly superior to medical therapy alone (70% vs26% survival, respectively). In contrast, in patients with distal dissection, intensive drug therapy alone leads to an 80% survivalrate compared with only 50% in patients treated surgically. Theexplanation for the advantage of surgical therapy in proximal dissection is probably that the risks of complications such as cerebralischemia, acute aortic insufficiency, and cardiac tamponade arehigher and managed more effectively with surgery. Because thesecomplications do not occur in distal dissection, in the absence ofocclusion of a major arterial branch or development of a saccularaneurysm during long-term follow-up, medical therapy is preferred.Patients with distal dissection tend to be elderly with more advancedaortic atherosclerosis and therefore are at higher risk of complicationsfrom operative intervention. (Adapted from Wheat [29]; with permission.)


Manage postoperative hypertension with nitroprusside in patients with complications

or labetalol in patientswithout complications

Carefully institute oral antihypertensives at low-dose

and titrate based on orthostaticblood pressure measurements

Manage intraoperative hypertension with

sodium nitroprusside

Administer blood pressure andantianginal medications the

morning of surgery

Postpone elective surgery untilblood pressure adequatelycontrolled for 2–3 weeks

Increased risks of Cerebral ischemia Myocardial ischemia Acute renal failure

Increased perioperative morbidityand mortality

Hypotension(45% Decrease in mean

arterial pressure)

Decreased cardiac output (30%)Decreased systemic vascular

resistance (27%)

General anesthesia

Inadequate preoperative blood pressure control

(diastolic blood pressure >110 mm Hgor mild to moderate hypertension

in patients with history of cerebrovascular accident, myocardial ischemia, heart

failure, or renal insufficiency

Poorly controlled hypertension in surgical patients

is imperative [32]. Even though the blood pressure in patients withsevere or complicated hypertension usually can be controlled withinhours using aggressive parenteral therapy, such precipitous controlof blood pressure carries the risk of significant complications suchas hypovolemia, electrolyte abnormalities, and marked intraoperativeblood pressure lability. General anesthesia is accompanied by a 30%decrease in cardiac output. In normotensive persons and patientswith adequately treated hypertension, anesthesia is not associatedwith a decrease in systemic vascular resistance. Therefore, thedecrease in mean arterial pressure (MAP) is modest (25–30%).However, in patients with inadequate preoperative blood pressurecontrol, anesthesia is associated with a concomitant decrease insystemic vascular resistance (SVR) of approximately 27%. Thecombined decrease in cardiac output and SVR leads to a profounddecrease in MAP (45%) during anesthesia [33]. This intraoperativehypotension predisposes to myocardial ischemia, cerebrovascularaccidents, and acute renal failure. Therefore, in patients with diastolicblood pressure over 110 mm Hg or these other high-risk groups,elective surgery should be postponed and blood pressure broughtunder control for a few weeks before surgery, if possible. Ideally,sustained adequate preoperative blood pressure control should bethe goal in all hypertensive patients [34]. In patients with adequatelytreated hypertension, oral antihypertensive, and antianginal med-ications should be continued up to and including the morning ofsurgery, administered with small sips of water. Because hypovolemiaincreases the risk of intraoperative hypotension and postoperativeacute renal failure, diuretics should be withheld for 1 to 2 dayspreoperatively except in patients with overt heart failure or fluidoverload. Adequate potassium repletion should be given to correcthypokalemia well in advance of surgery. Continuation of �-blockersto within a few hours of surgery does not impair cardiac functionand has been shown to decrease the risks of dysrhythmia andmyocardial ischemia during surgery. In patients with complicationsand a history of cardiovascular disease or heart failure, or aftercoronary artery bypass surgery, postoperative hypertension shouldbe managed with short-acting agents such as nitroglycerin ornitroprusside. In patients without complications, intermittentintravenous infusions of labetalol may be useful for managementof mild to moderate postoperative hypertension until the preoperativeoral antihypertensive agents can be resumed. Many patients withlong-standing hypertension, even if severe, require much smallerdoses of antihypertensive medications in the early postoperativecourse. Thus, the preoperative regimen should not be restartedautomatically. Measurement of orthostatic blood pressures shouldbe used as a guide to dosage adjustment during the postoperativerecovery period. In most instances, the need for antihypertensivemedications will gradually increase over a few days to weeks toeventually equal the preoperative requirement.

FIGURE 8-26

Poorly controlled hypertension in the patient requiring surgery.Hypertension in the preoperative patient is a common problem.Poor control of preoperative hypertension, with a diastolic bloodpressure higher than 110 mm Hg, is a relative contraindication toelective surgery. In such patients, perioperative morbidity and mor-tality are increased because of a higher incidence of intraoperativehypotension accompanied by myocardial ischemia and a heightenedrisk of acute renal failure [31]. Malignant hypertension clearly represents an excessive surgical risk and all but lifesaving emergencysurgery should be deferred until the blood pressure can be controlledand organ function stabilized. Mild to moderate uncomplicatedhypertension with diastolic blood pressure less than 110 mm Hgdoes not appear to increase the risk of surgery significantly andtherefore is not an absolute indication to postpone elective surgery.However, patients with mild to moderate hypertension and preexist-ing complications such as ischemic heart disease, cerebrovasculardisease, congestive heart failure, or chronic renal insufficiency, represent a subgroup with significantly increased perioperative risk.In these patients, adequate preoperative control of blood pressure


Systemic hypertension

Increased left ventricular end-diastolic pressure

Hypertensive encephalopathy(Fig. 8-21)

Increased risk of postoperative mediastinal bleeding

Impaired subendocardial perfusioncausing myocardial ischemia

Acute hypertensive heart failurewith pulmonary edema

(Figs. 8-23 and 8-24)

Treat with nitroprussideor intravenous nitroglycerin

Increased systemic vascular resistance

Increased sympathetic tone owing to activation or pressor reflexes from heart, coronary arteries, or great vessels

Paradoxical hypertensive responseto intravascular volume depletion

Coronary artery bypassgraft surgery

Hypertensive crises after bypass surgery

Increased impedance toleft ventricular ejection

Acute diastolic dysfunction(decreased left ventricular compliance)

FIGURE 8-27

Hypertensive crisis after coronary artery bypass surgery. Paroxysmal hypertension in theimmediate postoperative period is a frequent and serious complication of cardiac surgery[35,36]. Paroxysmal hypertension is the most frequent complication of coronary arterybypass surgery, occurring in 30% to 50% of patients. It occurs just as often in normotensivepatients as it does in those with a history of chronic hypertension. The increase in bloodpressure usually occurs during the first 4 hours after surgery. The hypertension resultsfrom a dramatic increase in systemic vascular resistance (SVR) without a change in thecardiac output and is most commonly mediated by an increase in sympathetic tone owingto activation of pressor reflexes from the heart, great vessels, or coronary arteries. Hyper-volemia, although often cited as a potential mechanism of postoperative hypertension, is arare cause of postbypass hypertension except in patients with renal failure. In fact, increasedSVR owing to marked sympathetic overreaction to volume depletion is a common, oftenunrecognized, cause of severe postoperative hypertension [37]. Patients with this paradoxicalhypertensive response to hypovolemia are exquisitely sensitive to vasodilator therapy and

may develop precipitous hypotension witheven low-dose infusions of nitroglycerin ornitroprusside. Hypertension in this settingshould be treated using careful volumeexpansion with crystalloid solutions orblood if required. Post–coronary arterybypass hypertension represents a hypertensivecrisis because the heightened SVR increasesthe impedance to left ventricular (LV) ejection(afterload) that can result in an acute decreasein ventricular compliance with elevation ofLV end-diastolic pressure (LVEDP) and acutehypertensive heart failure with pulmonaryedema (Figs. 8-23 and 8-24). The increasein LVEDP also impairs subendocardial perfusion and can cause myocardialischemia. Moreover, the elevated bloodpressure increases the risk of mediastinalbleeding in these recently heparinized patients.The initial management of postbypass hyper-tension should focus on attempts to amelio-rate reversible causes of sympathetic activa-tion, including patient agitation on emergencefrom anesthesia, tracheal or nasopharyngealirritation from the endotracheal tube, pain,hypothermia with shivering, ventilator asyn-chrony, hypoxia, hypercarbia, and volumedepletion. If these general measures fail tocontrol the blood pressure, further therapyshould be guided by measurement of systemichemodynamics. Intravenous nitroglycerin ornitroprusside is the drug of choice to providea controlled decrease in SVR and bloodpressure. Nitroglycerin may be the preferreddrug because it dilates intracoronary collateralarteries [35,36]. Therapy with �-blockers isnot indicated in this setting and may bedetrimental because these drugs impair cardiacoutput and cause a further increase in SVR.Labetalol also has been shown to cause asignificant reduction in cardiac output inpostbypass hypertension. Postbypass hyper-tension is usually transient and resolves by6 to 12 hours postoperatively, so that thevasodilatory therapy can be weaned. Thehypertension usually does not recur afterthe initial episode in the immediate postop-erative period.


Sudden increase in perfusion pressurein arteriocapillary bed that was

previously protected from hypertension

Failure of autoregulation of cerebral blood flow(breakthrough of autoregulation)

Overperfusion of cerebral circulation

Vessel rupture(hemorrhage and infarction)

Hypertensive crises after carotid endarterectomy

Carotid endarterectomy

Postoperative hypertension(mechanism unknown)

Repair of high-gradestenosis

FIGURE 8-28

Hypertensive crisis after carotid endarterectomy. Hypertension inthe immediate postoperative period occurs in up to 60% of patientsafter carotid endarterectomy [38]. A history of chronic hypertension,especially if the blood pressure is poorly controlled preoperatively,dramatically increases the risk of postoperative hypertension. Themechanism of post-endarterectomy hypertension is unknown. Theincidence of hypertension is the same whether or not the carotidsinus nerve is preserved. Hypertension after endarterectomy is ahypertensive crisis because it is associated with increased risk ofintracerebral hemorrhage and increases the postoperative mortalityrate [39]. A mechanism for the development of post–carotidendarterectomy cerebral hemorrhage owing to postoperative hyper-tension has been proposed. In patients with high-grade carotidartery stenosis, the distal cerebral circulation has been relativelyprotected from systemic hypertension. In this regard, the autoregu-latory curve may be shifted to a lower threshold to compensate forreduced perfusion pressure. After repair of the obstructing lesion, arelative increase in perfusion pressure occurs in the cerebral arterio-capillary bed. In the setting of systemic hypertension the increasedblood flow and perfusion pressure may overwhelm the autoregula-tory mechanisms. Overperfusion and rupture may then occur,resulting in hemorrhagic infarction. Because poor preoperative bloodpressure control increases the risk of postoperative hypertension,strict blood pressure control is essential before elective carotidendarterectomy. Furthermore, intra-arterial pressure should bemonitored in the operating room and in the immediate postoperativeperiod. Ideally, the patient should be awake and extubated beforereaching the recovery room so that serial neurologic examinationscan be performed to assess for the development of focal deficits.When the systolic blood pressure exceeds 200 mm Hg, an intravenousinfusion of sodium nitroprusside should be initiated to maintainthe systolic blood pressure between 160 and 200 mm Hg. The useof a short-acting parenteral agent is imperative to avoid overshoothypotension and cerebral hypoperfusion.


Even with cautious bloodpressure reduction using

parenteral agents

Altered blood flow autoregulation in the ischemic penumbra

surrounding the infarct

Failure of autoregulationwith worsening ischemia

Extension of infarct

Risks of antihypertensive therapy in acute cerebral infarction

Exaggerated response tooral antihypertensives

Spontaneous resolutionwithin first week

Reflex increase insystemic blood pressure

Acute cerebral infarction

FIGURE 8-29

Risks of antihypertensive therapy in acute cerebral infarction. Cerebralinfarction results from partial or complete occlusion of an arteryby an atherosclerotic plaque or embolization of atherothromboticdebris from a more proximal plaque. These atherothromboticinfarcts typically involve the cerebral cortex, cerebellar cortex, orpons; these infarcts are to be contrasted with hypertension-inducedlipohyalinosis of the small penetrating cerebral end-arteries that isthe principal cause of the small lacunar infarcts occurring in thebasal ganglia, pons, thalamus, cerebellum, and deep hemisphericwhite matter. Hypertension occurs in up to 85% of patients withacute cerebral infarction, even in previously normotensive persons[40]. This early elevation of blood pressure probably represents aphysiologic response to brain ischemia. Because of the known benefitsof antihypertensive therapy with regard to stroke prevention, itpreviously had been assumed that acute reduction of blood pressurewould also be of benefit in acute cerebral infarction. However, noevidence exists to suggest that acute reduction of blood pressure isbeneficial in this setting. In fact, reports exist of worsening neurologicstatus, apparently precipitated by emergency treatment of hypertensionin patients with cerebral infarction [41]. In the setting of acute cerebral

infarction, hypertension tends to be very labile and exquisitely sensitiveto hypotensive therapy. Thus, even modest doses of oral antihyper-tensive agents can lead to profound and devastating overshoothypotension with extension of the infarct [42]. An additional rationalefor not treating hypertension in the acute setting is based on evidencethat local autoregulation of cerebral blood flow is impaired in theso-called ischemic penumbra, which surrounds the area of acuteinfarction [43]. Without intact autoregulation, the regional bloodflow in this marginal zone of ischemia becomes critically dependenton the perfusion pressure. Thus, the presence of mild to moderatesystemic hypertension may actually be protective, and acute reductionof blood pressure may cause a regional reduction in blood flowwith extension of the infarct. Thus, in most cases of cerebral infarctionit is prudent to allow the blood pressure to seek its own level duringthe first few days to weeks after the event. In most cases the hyper-tension tends to resolve spontaneously, without any specific therapy,over the first week as brain function recovers. When hypertensionpersists for more than 3 weeks after a completed infarction, reductionof the blood pressure into the normal range with oral antihyperten-sives is appropriate. Although benign neglect of mild to moderatehypertension is prudent in acute cerebral infarction, there may becertain indications for active treatment of blood pressure. Whenthe diastolic blood pressure is sustained at over 130 mm Hg, cautiousreduction of blood pressure into the ranges of 160 to 170 mm Hgsystolic and 100 to 110 mm Hg diastolic may be appropriate. Instroke patients requiring anticoagulation therapy, moderate controlof severe hypertension also should be considered. Cautious bloodpressure reduction is indicated when stroke is accompanied by otherhypertensive crises such as acute myocardial ischemia or acutehypertensive heart failure. Stroke caused by carotid occlusion by aproximal aortic dissection mandates aggressive blood pressurereduction into the normal range to halt the dissection process. Inthe setting of sudden severe hypertension, it may be difficult to distinguish hypertensive encephalopathy with focal neurologic findingsfrom cerebral infarction. Because rapid reduction of blood pressureis lifesaving in patients with hypertensive encephalopathy, a cautiousdiagnostic trial of blood pressure reduction may be warranted (Fig. 8-21). If blood pressure reduction is deemed necessary in patients withacute cerebral infarction, treatment should be initiated using smalldoses of a short-acting parenteral agent such as sodium nitroprusside.Use of oral or sublingual nifedipine is associated with excessive risk ofprolonged overshoot hypotension. Oral clonidine loading also is con-traindicated because of the risk of hypotension and because sedativeside effects interfere with the assessment of mental status.


Reflex increase in blood pressure(Cushing's reflex)

Increased risk of rebleeeding(expansion of hematoma)

Impairment of autoregulation ofblood flow in ischemic area

surrounding hematoma(shift of lower limit of

autoregulation)

Cerebral hyperperfusionwith cerebral edema

Sodium nitroprusside

Hypertension may help maintain blood flow inischemic areas

Cautious blood pressure reduction by no more than 20%

of presenting mean arterial pressure (intra-arterial and

intracranial pressure monitoringto ensure adequate cerebral

perfusion pressure)


Hypertensive crises from intracerebral hemorrhage

FIGURE 8-30

Hypertensive crises due to intracerebral hemorrhage. Chronic hypertension is the majorrisk factor for intracerebral hemorrhage. The most common sites of hemorrhage are thesmall-diameter penetrating cerebral end-arteries in the basal ganglia, pons, thalamus, cere-bellum, and deep hemispheric white matter. Lacunar infarcts arise from the same vesselsand are similarly distributed. Intracerebral hemorrhage characteristically begins abruptlywith headache and vomiting followed by steadily increasing focal neurologic deficits andalteration of consciousness [44]. More than 90% of hemorrhages rupture through brainparenchyma into the ventricles, producing bloody cerebrospinal fluid. Patients presentingwith intracerebral hemorrhage are invariably hypertensive. In contrast to cerebral infarction,the hypertension does not tend to decrease spontaneously during the first week. The patient’scondition worsens steadily over a period of minutes to days until either the neurologic deficitstabilizes or the patient dies. When death occurs, most often it is due to herniation causedby the expanding hematoma and surrounding edema. Treatment of hypertension in the settingof intracerebral hemorrhage is controversial. An increase in intracranial pressure accompaniedby a reflex increase in systemic blood pressure almost always occurs. Because cerebral perfusionpressure is a function of the difference between arterial pressure and intracranial pressure,reduction of blood pressure could compromise cerebral perfusion. Moreover, as in cerebralinfarction, autoregulation is impaired in the area of marginal ischemia surrounding thehemorrhage. In contrast, cerebral vasogenic edema may be exacerbated by hypertension.Moreover, hypertension may increase the risk of rebleeding with expansion of the hematoma.Thus, in deciding to treat hypertension in the setting of intracerebral hemorrhage, a pre-carious balance must be struck between beneficial reduction in cerebral edema on the onehand, and deleterious reduction of cerebral blood flow on the other. Studies have shownthat the lower limit of autoregulation after intracerebral hemorrhage is approximately80% of the initial blood pressure; therefore, a 20% decrease in mean arterial pressureshould be considered the maximal goal of blood pressure reduction during the acute stage[45]. Antihypertensive therapy should be undertaken only in conjunction with intracranialand intra-arterial pressure monitoring to allow for assessment of cerebral perfusion pressure.The short duration of action of nitroprusside makes its use preferable over other agentswith a longer duration of action and the risk of sustained overshoot hypotension, despitethe theoretic concern that nitroprusside treatment could lead to an increase in intracranialpressure by way of dilation of cerebral veins and arteries.


Hypertensive crisis with pheochromocytoma

Intravascular volumedepletion

Increased risk of intraoperativeand postoperative hypotension

Pheochromocytoma

Episodic release ofcatecholamines

Paroxysmal hypertension

Acute treatment withnitroprusside or phentolamine

followed by β-blockers

Pressure-inducednatriuresis and diuresis

Intracerebralhemorrhage

Acute hypertensive heart failure with pulmonary edema

(Figs. 8-23 and 8-24)

Hypertensive encephalopathy(Fig. 8-21)

FIGURE 8-31

Hypertensive crisis with pheochromocytoma. In most patients, pheochromocytoma causessustained hypertension that sometimes becomes malignant as evidenced by the presence ofhypertensive neuroretinopathy. Paroxysmal hypertension is present in approximately 30%of patients. Spontaneous paroxysms consist of severe hypertension, headache, profusediaphoresis, pallor, coldness of hands and feet, palpitations, and abdominal discomfort.Paroxysmal hypertension in pheochromocytoma represents a hypertensive crisis because itcan lead to intracerebral hemorrhage, hypertensive encephalopathy, or acute hypertensiveheart failure with pulmonary edema. Prompt control of the blood pressure is mandatory toprevent these life-threatening complications. Although the nonselective �-blocker phentolamineoften is cited as the treatment of choice for pheochromocytoma-related hypertensive crises,sodium nitroprusside is equally effective and easier to administer [46]. Only after bloodpressure has been controlled with nitroprusside or phentolamine can intravenous �-blockers,such as esmolol, labetalol, or propranolol, be used to control tachycardia or arrhythmias.After resolution of the hypertensive crisis, oral antihypertensive agents should be institutedas the parenteral agents are weaned. The nonselective �-blocker phentolamine usually isadministered orally for 1 to 2 weeks before elective surgery. After adequate �-blockade isachieved, based on the presence of moderate orthostatic hypotension, oral �-blocker therapycan be initiated as needed to control tachycardia. Oral or intravenous �-blockers shouldnever be administered before adequate �-blockade. Doing so can precipitate a hypertensivecrisis as the result of intense �-adrenergic vasoconstriction that is no longer opposed by �-adrenergic vasodilatory stimuli. Careful attention to volume status also is mandatory inthe preoperative period. Catecholamine-induced hypertension induces a pressure natriure-sis with volume depletion. Moreover, alleviation of the chronic state of vasoconstriction by�-blockade results in increases in both arterial and venous capacitances. Preoperative volumeexpansion, guided by measurement of central venous pressure or wedge pressure often isadvocated to reduce the risk of intraoperative hypotension [47]. During surgery, rapid andwide fluctuations in blood pressure should be anticipated. Careful intraoperative monitoringof intra-arterial pressure, cardiac output, wedge pressure, and systemic vascular resistanceis mandatory to manage the rapid swings in blood pressure. Despite adequate preoperative�-blockade with phenoxybenzamine, severe hypertension can occur during intubation orintraoperatively as a result of catecholamine release during tumor manipulation. Sodiumnitroprusside is the treatment of choice for controlling acute hypertension owing topheochromocytoma during surgery. At the opposite end of the spectrum, profound intra-operative hypotension can occur. Hypotension or even frank shock can supervene afterisolation of tumor venous drainage from the circulation, with resultant abrupt decrease incirculating catecholamine levels. Volume expansion is the treatment of choice for intraop-erative and postoperative hypotension [46]. Pressors only should be employed whenhypotension is unresponsive to volume repletion.


Severe paroxysm of hypertension

Intracerebral hemorrhageHypertensive encephalopathy(Fig. 8-21)

Acute hypertensive heart failurewith pulmonary edema

(Figs. 8-24 and 8-25)

Vasoconstriction(increased systemic vascular resistance)

Massive release of catecholamines Tachyarrhythmias

Increased circulatingtyramine level

Ingestion of tyramine-containing food

Accumulation of catecholamines innerve terminal storage granules

Impaired degradation of intracellular amines(epinephrine, norepinephrine, dopamine)

Monoamine oxidase inhibitor therapy

Hypertension crises secondary to monoamine oxidase inhibitor–tyramine interactions

Hepatic monamine

oxidase inhibition

with decreased

oxidative metabolism

of tyramine

FIGURE 8-32

Hypertensive crises secondary to monoamine oxidase inhibitor–tyramine interactions.Severe paroxysmal hypertension complicated by intracerebral or subarachnoid hemorrhage,hypertensive encephalopathy, or acute hypertensive heart failure can occur in patients treatedwith monoamine oxidase (MOA) inhibitors after ingestion of certain drugs or tyramine-containing foods [48,49]. Because MAO is required for degradation of intracellular amines,including epinephrine, norepinephrine, and dopamine, MAO inhibitors lead to accumulationof catecholamines within storage granules in nerve terminals. The amino acid tyramine is apotent inducer of neurotransmitter release from nerve terminals. As a result of inhibitionof hepatic MAO, ingested tyramine escapes oxidative degradation in the liver. In addition,the high circulating levels of tyramine provoke massive catecholamine release from nerveterminals, resulting in vasoconstriction and a paroxysm of severe hypertension. A hyper-adrenergic syndrome resembling pheochromocytoma then ensues. Symptoms include severepounding headache, flushing or pallor, profuse diaphoresis, nausea, vomiting, and extremeprostration. The mean increase in blood pressure is 55 mm Hg systolic and 30 mm Hgdiastolic [49]. The duration of the attacks varies from 10 minutes to 6 hours. Attacks canbe provoked by the ingestion of foods known to be rich in tyramine: natural or agedcheeses, Chianti wines, certain imported beers, pickled herring, chicken liver, yeast, soysauce, fermented sausage, coffee, avocado, banana, chocolate, and canned figs.Sympathomimetic amines in nonprescription cold remedies also can provoke neurotransmitterrelease in patients treated with an MAO inhibitor. Either sodium nitroprusside or phentolaminecan be used to manage this type of hypertensive crisis. Because most patients are normotensivebefore onset of the crisis the goal of blood pressure treatment should be normalization ofthe blood pressure. After blood pressure control, intravenous �-blockers may also berequired to control heart rate and tachyarrhythmias. Because the MAO inhibitor–tyraminehypertensive crisis is self-limited, parenteral antihypertensive agents can be weaned withoutinstitution of oral antihypertensive agents.


Dilation of arteriolar resistance vessels(decreased systemic vascular resistance)

Venodilation(increased venous capacitance)

Decreased blood pressure Afterload reduction

Metabolized bycGMP-specific

phosphodiesterases

Mechanism of action and metabolism of nitroprusside

Activation of guanylate cyclase

Nitrosocysteine

Combination of nitrosogroup with cysteine

Nitroprusside

CN-

+NO

CN- CN-

Fe++t

1/2=3–4 min

t1/2

=1 wk

t1/2

=2–3min

Metabolized by direct combination

with -SH groups in erythrocytes

and tissues

CN- CN-

Free cyanide (CN-)

Thiocyanate

Renal excretion

cGMP accumulation in vascular smooth muscle

FIGURE 8-33

Mechanism of action and metabolism of nitroprusside. Sodiumnitroprusside is the drug of choice for management of virtually allhypertensive crises, including malignant hypertension, hypertensiveencephalopathy, acute hypertensive heart failure, intracerebralhemorrhage, perioperative hypertension, catecholamine-relatedhypertensive crises, and acute aortic dissection (in combinationwith a �-blocker) [1,50]. Sodium nitroprusside is a potent intravenoushypotensive agent with immediate onset and brief duration of action.The site of action is the vascular smooth muscle. Nitroprusside hasno direct action on the myocardium, although it may affect cardiacperformance indirectly through alterations in systemic hemodynamics.Nitroprusside is an iron (Fe) coordination complex with five cyanidemoieties and a nitroso (NO) group. The nitroso group combines withcysteine to form nitrosocysteine and other short-acting S-nitrosothiols.Nitrosocysteine is a potent activator of guanylate cyclase, therebycausing cyclic guanosine monophosphate (cGMP) accumulationand relaxation of vascular smooth muscle [51,52]. Nitroprussidecauses vasodilation of both arteriolar resistance vessels and venouscapacitance vessels. Its hypotensive action is a result of a decreasein systemic vascular resistance. The combined decrease in preloadand afterload reduces myocardial wall tension and myocardial oxygendemand. The net effect of nitroprusside on cardiac output andheart rate depends on the intrinsic state of the myocardium. Inpatients with left ventricular (LV) systolic dysfunction and elevatedLV end-diastolic pressure, nitroprusside causes an increase in strokevolume and cardiac output as a result of afterload reduction andheart rate may actually decrease in response to improved cardiacperformance. In contrast, in the absence of LV dysfunction, venodi-lation and preload reduction can result in a reflex increase in sym-pathetic tone and heart rate. For this reason, nitroprusside must beused in conjunction with a �-blocker in acute aortic dissection. Thehypotensive action of nitroprusside appears within seconds and isimmediately reversible when the infusion is stopped. The cGMP invascular smooth muscle is rapidly degraded by cGMP-specific phos-phodiesterases. Nitroprusside is rapidly metabolized with a half-life(t1/2) of 3 to 4 minutes. Cyanide is formed as a short-lived intermediateproduct by direct combination with sulfhydryl (SH) groups in ery-throcytes and tissues. The cyanide groups are rapidly converted tothiocyanate by the liver in a reaction in which thiosulfate acts as asulfur donor. Thiocyanate is excreted by the kidneys, with a half-lifeof 1 week in patients with normal renal function. Thiocyanateaccumulation and toxicity can occur when a high-dose or prolongedinfusion is required, especially in patients with renal insufficiency.When these risk factors are present, thiocyanate levels should bemonitored and the infusion stopped if the level is over 10 mg/dL.Thiocyanate toxicity is rare in patients with normal renal functionrequiring less than 3 µg/kg/min for less than 72 hours [50]. Cyanidepoisoning is a very rare complication, unless hepatic clearance ofcyanide is impaired by severe liver disease or massive doses ofnitroprusside (over 10 µg/kg/min) are used to induce deliberatehypotension during surgery [50].

8.27Hypertensive CrisesV

AR

IOU

S A

NT

IHY

PER

TEN

SIV

E D

RU

GS

FOR

PA

REN

TER

AL

USE

IN T

HE

MA

NA

GEM

ENT

OF

MA

LIG

NA

NT

HY

PER

TEN

SIO

N A

ND

OT

HER

HY

PER

TEN

SIV

E C

RIS

ES

Mec

han

ism

of

acti

on

Dire

ct a

rter

iola

r va

sodi

lati

on a

nd

veno

dila

tion

Dire

ct a

rter

iola

r va

sodi

lati

on

Gan

glio

nic

bloc

kage

w

ith

veno

dila

tion

and

arte

riola

r va

sodi

lati

on

Dire

ct v

enod

ilati

on a

tlo

w d

oses

; com

bine

dve

nodi

lati

on a

nd

arte

riola

r di

lati

on a

thi

gher

dos

esSe

lect

ive

�1-

and

no

ncar

dios

elec

tive

�

-blo

cker

; art

erio

lar

and

veno

us d

ilati

on

Non

sele

ctiv

e �

-blo

cker

Dire

ct a

rter

iola

r va

sodi

lati

on

Dec

reas

e sy

mpa

thet

icne

rvou

s sy

stem

act

ivi-

ty v

ia C

NS

�2

stim

ula-

tion,

dec

reas

e sy

stem

icva

scul

ar re

sist

ance

Sym

path

etic

dys

func

-ti

on o

win

g to

cen

tral

and

perip

hera

l cat

e-ch

olam

ine

dysf

unc-

tion

; dec

reas

ed S

VR

,de

crea

sed

CO

Dru

g

Sodi

um

nitr

opru

ssid

e

Dia

zoxi

de

Trim

etha

phan

ca

msy

late

Nit

rogl

ycer

in

Labe

talo

l

Phen

tola

min

e

Hyd

rala

zine

Met

hyld

opa

Rese

rpin

e

On

set

of a

ctio

n

Inst

anta

neou

s

1–2

min

Min

utes

Min

utes

Min

utes

2–3

min

10–

30 m

in

2–4

h

2–4

h

Peak

eff

ect

Imm

edia

te

10–

15 m

in

Min

utes

Min

utes

5–50

min

5 m

in

30–

60 m

in

4–6

h

2–4

h

Dur

atio

n o

f act

ion

2–3

min

aft

er in

fusi

onst

oppe

d

4–24

h

5–10

min

aft

er in

fu-

sion

sto

pped

1–5

min

aft

er in

fusi

onst

oppe

d

16–

18 h

15–

30 m

in

3–9

h

4–6

h

2–8

h

Met

hod

of

adm

inis

trat

ion

Con

tinu

ous

infu

sion

:In

itia

l, 0.

5 µg

/kg/

min

Ave

rage

, 3 µ

g/kg

/min

Max

imum

, 10

µg/k

g/m

in

IV m

inib

olus

: 50–

100

mg

IV g

iven

rap

idly

ove

r5–

10 m

in. T

otal

dos

e,15

0–60

0 m

g

Con

tinu

ous

infu

sion

:In

itia

l, 0.

5 m

g/m

inM

axim

um, 5

.0 m

g/m

in

Con

tinu

ous

infu

sion

:In

itia

lly, 5

µg/

min

Incr

ease

by

5 µg

/min

over

3–

5 m

in

IV m

inib

olus

: Ini

tial

, 20

mg

over

2 m

in T

hen

40–

80 m

g ov

er 1

0 m

in.

Max

imum

, 300

mg

IV b

olus

: 1–

5 m

g ov

er 5

min

IV b

olus

: 5–

10 m

g ov

er20

–30

min

orc

onti

nu-

ous

infu

sion

400

µg/

mL

solu

tion

Loa

ding

dos

e:20

0–30

0 µg

/min

for

30–6

0 m

in M

aint

enan

cein

fusio

n: 5

0–15

0 µg

/min

IV o

f 250

–50

0 m

g ov

er 6

–8

h

Intr

amus

cula

r:In

itia

l, 0.

5–1.

0 m

g2–

4 m

g ov

er 3

h

2–4

mg

over

3–

12 h

Adv

anta

ges

Prec

ise

titr

atio

n of

BP. C

onsi

sten

tly

effe

ctiv

e w

hen

othe

r dr

ugs

fail.

Pare

nter

al a

gent

of

cho

ice

for

hype

rten

sive

cris

esLo

ng d

urat

ion

ofac

tion

. Con

stan

tm

onito

ring

not

requ

ired

afte

r in

i-ti

al t

itra

tion

Bloc

ks b

aror

ecep

-to

r-m

edia

ted

sym

path

etic

ca

rdia

c st

imul

atio

n

Theo

reti

c ad

van-

tage

s ov

er n

itro

-pr

ussi

de in

set

ting

of m

yoca

rdia

lis

chem

iaC

onti

nuou

s m

onito

ring

not

requ

ired

Use

ful i

n ca

tech

olam

ine-

rela

ted

cris

es

Prov

en e

ffic

acy

and

safe

ty in

hy

pert

ensiv

e cr

ises

of p

regn

ancy

Non

e—no

t re

com

men

ded

for

use

in h

yper

ten-

sive

cris

es

Non

e—no

t re

com

men

ded

for

use

in h

yper

ten-

sive

cris

es

Dis

adva

nta

ges

Mon

itorin

g in

ICU

requ

ired

Sust

aine

d hy

pote

nsio

n w

ithC

NS

and

myo

car-

dial

isch

emic

can

occu

r. Re

flex

sym

-pa

thet

ic c

ardi

acst

imul

atio

nPa

rasy

mpa

thet

icbl

ocka

de

Fails

to

cont

rol B

Pin

som

e pa

tien

ts

�-b

lock

age

can

wor

sen

cong

esti

vehe

art

failu

re,

bron

chos

pasm

,he

art

bloc

k

Shor

t du

rati

on o

fac

tion

Del

ayed

ons

et

of a

ctio

n,

unpr

edic

tabl

ehy

pote

nsiv

e ef

fect

Del

ayed

ons

et

of a

ctio

n,

unpr

edic

tabl

ehy

pote

nsiv

e ef

fect

Del

ayed

ons

et

of a

ctio

n,

unpr

edic

tabl

ehy

pote

nsiv

e ef

fect

Sid

e ef

fect

s

Nau

sea,

vom

iting

,ap

preh

ensio

n.Th

iocy

anat

e to

xic-

ity w

ith p

rolo

nged

infu

sion,

rena

lin

suffi

cien

cy

Nau

sea,

vom

itin

g,hy

perg

lyce

mia

,m

yoca

rdia

lis

chem

ia, u

terin

eat

ony

Dry

mou

th, b

lurr

edvi

sion

, urin

ary

rete

ntio

n, p

aral

yt-

ic il

eus,

resp

irato

-ry

arr

est

Hea

dach

e, n

ause

a,vo

mit

ing,

pa

lpit

atio

ns,

abdo

min

al p

ain

Nau

sea,

vom

itin

g,pa

rest

hesi

as,

head

ache

, br

adyc

ardi

a

Tach

ycar

dia,

ar

rhyt

hmia

s,

naus

ea, v

omit

ing,

diar

rhea

, exa

cer-

bati

on o

f pep

tic

ulce

r di

seas

eH

eada

che,

ang

ina

Seda

tion

Nas

al c

onge

stio

n,C

NS

seda

tion

,br

adyc

ardi

a,

exac

erba

tes

pep-

tic

ulce

r di

seas

e,de

pres

sion

Com

men

ts

Dis

c ont

inue

if

thio

cyan

ate

leve

l >

10 m

g/dL

Con

trai

ndic

ated

in

aort

ic d

isse

ctio

n,ce

rebr

ovas

cula

r di

seas

e, m

yoca

rdia

lis

chem

ia

Tilt-

bed

enha

nces

effe

ct; t

achy

phyl

axis

afte

r 24

–48

h;

cont

rain

dica

ted

in re

spira

tory

in

suff

icie

ncy

and

glau

com

a;

pote

ntia

tes

succ

inyl

chol

ine

Dila

tes

intr

acor

onar

yco

llate

rals

Con

trai

ndic

ated

inph

eoch

rom

ocyt

oma,

hear

t fai

lure

, ast

hma,

hear

t bl

ock

>1

degr

ee, a

fter

cor

o-na

ry a

rter

y by

pass

graf

t su

rger

yN

itro

prus

side

equ

ally

effic

acio

us in

ca

tech

olam

ine-

rela

ted

cris

es

Con

trai

ndic

ated

in

aort

ic d

isse

ctio

n,

athe

rosc

lero

tic

coro

nary

vas

cula

r di

seas

e

Con

trai

ndic

ated

inhy

pert

ensi

veen

ceph

alop

athy

,C

NS

cata

stro

phe

Con

trai

ndic

ated

inhy

pert

ensi

veen

ceph

alop

athy

,C

NS

cata

stro

phe,

cum

ulat

ive

hypo

ten-

sive

resp

onse

BP—

bloo

d pr

essu

re; C

NS—

cent

ral n

ervo

us s

yste

m; C

O—

card

iac

outp

ut; I

CU

—in

tens

ive

care

uni

t; IV

—in

trav

enou

s; SV

R—sy

stem

ic v

ascu

lar

resi

stan

ce.

FIGURE 8-34

Sodium nitroprusside remains the treatment of choice in virtuallyall hypertensive crises requiring rapid blood pressure control with

parenteral therapy. However, other parenteral antihypertensiveagents may be useful in certain circumstances.


50

150

200

100

0

Mea

n a

rter

ial p

ress

ure

, mm

Hg

Baseline mean arterial pressure

Lower limit ofautoregulation

Lowest tolerated meanarterial pressure

Uncontrolled hypertensives (n=13)

Controlled hypertensives (n=9)

Normotensives (n=10)

79±

10%

72±

29%

74±

12%

45±

6%46±

16%

45±

12%

blood pressure required to reach the autoregulatory limit. Thus, areduction in MAP of approximately 20% to 25% was required ineach group to reach the threshold. This result indicates that a considerable safety margin exists for blood pressure reductionbefore cerebral autoregulation of blood flow fails, even in patientswith severe untreated hypertension. Moreover, symptoms of cerebralischemia did not develop until the blood pressure was reduced substantially below the autoregulatory threshold because even inthe face of reduced blood flow, cerebral metabolism can be main-tained and ischemia prevented by an increase in oxygen extractionby the tissues. The lowest tolerated MAP, defined as the level atwhich mild symptoms of brain hypoperfusion developed (ie, yawning,nausea, and hyperventilation), was 65 ±10 mm Hg in patients withuncontrolled hypertension, 53 ±18 mm Hg in persons with treatedhypertension, and 43 ±8 mm Hg in normotensive persons. Thenumbers on the bars illustrate that these MAP values were approx-imately 45% of the baseline blood pressure level in each group.Thus, symptoms of cerebral hypoperfusion did not occur until theMAP was reduced by an average of 55% from the presenting level.In the reported cases of neurologic sequelae sustained during rapidreduction of blood pressure in patients with hypertensive crises, theMAP was reduced by more than 55% of the presenting blood pres-sure. This frank hypotension was sustained for a period of hours todays, mostly as a result of treatment with bolus diazoxide, whichhas long duration of action [54]. The general guideline for acuteblood pressure reduction in the treatment of hypertensive crises isreduction of systolic blood pressure to 160 to 170 mm Hg anddiastolic pressure to 100 to 110 mm Hg, which equates to MAPsof 120 to 130 mm Hg. Alternatively, the initial goal of antihyper-tensive therapy can be a 20% reduction of the MAP from thepatient’s initial level at presentation. This level should be above thepredicted autoregulatory threshold. Once this goal is obtained thepatient should be evaluated carefully for evidence of cerebralhypoperfusion. Further reduction of blood pressure can then beundertaken in a controlled fashion based on the overall clinical status of the patient. Of course, in previously normotensive persons in whom hypertensive crises develop, such as patients with acuteglomerulonephritis complicated by hypertensive encephalopathy,the autoregulatory curve should not yet be shifted. Therefore, theinitial goal of therapy should be normalization of blood pressure.In terms of avoiding sustained overshoot hypotension in the treat-ment of hypertensive crises, the use of potent parenteral agentswith short duration of action, such as sodium nitroprusside orintravenous nitroglycerin, has obvious advantages. If neurologicsequelae develop during blood pressure reduction with these agents,these sequelae can be reversed quickly by tapering the infusion andallowing the blood pressure to stabilize at a higher level. Agentswith a long duration of action have an inherent disadvantage inthat excessive reduction of blood pressure cannot be reversed easily. Thus, bolus diazoxide, labetalol, minoxidil, hydralazine,converting enzyme inhibitors, calcium channel blockers, and central �2-agonists should be used with extreme caution in patientsrequiring rapid but controlled blood pressure reduction in the setting of hypertensive crises. (Adapted from Strandgaard [53];with permission.)

FIGURE 8-35

Risks of rapid blood pressure reduction in hypertensive crises. Ithas been argued over the years that rapid reduction of blood pressurein the setting of hypertensive crises may have a detrimental effecton cerebral perfusion because the autoregulatory curve of cerebralblood flow is shifted upward in patients with chronic hypertension.Conversely, this upward shift protects the brain from hypertensiveencephalopathy in the face of severe hypertension. However, thisautoregulatory shift could be deleterious when the blood pressureis reduced acutely because the lower limit of autoregulation is shiftedto a higher level of blood pressure. Theoretically, aggressive reductionof the blood pressure in chronically hypertensive patients couldinduce cerebral ischemia. Nonetheless, in clinical practice, moderatelycontrolled reduction of blood pressure in patients with hypertensivecrises rarely causes cerebral ischemia. This clinical observation maybe explained by the fact that even though the cerebral autoregulatorycurve is shifted in patients with chronic hypertension, a considerabledifference still exists between the initial blood pressure at presentationand the lower limit of autoregulation. Illustrated are the differencesin the lower autoregulatory threshold during blood pressure reductionwith trimethaphan in patients with uncontrolled hypertension andtreated hypertension, and those in the control group [53]. At leasteight of the 13 patients with uncontrolled hypertension had hyper-tensive neuroretinopathy consistent with malignant hypertension.The control groups included nine patients with a history of severehypertension in the past whose blood pressure was effectively controlled at the time of study and a group of 10 normotensivepersons. Baseline mean arterial pressures (MAPs) in the threegroups were 145 ±17 mm Hg, 116 ±18 mm Hg, and 96 ±17 mmHg, respectively. The lower limit of blood pressure at which autoreg-ulation failed was 113 ±17 mm Hg in persons with uncontrolledhypertension, 96 ±17mm Hg in persons with treated hypertension,and 73 ±9 mm Hg in normotensive persons. Although the absolutelevel at which autoregulation failed was substantially higher inpatients with uncontrolled hypertension, the percentage reductionin blood pressure from the baseline level required to reach theautoregulatory threshold was similar in each group. The numberson the bars indicate the percentage reduction from the baseline



Step 1 Step 2 Step 3

Noncompliant Compliant with current blood pressure regimen

Evaluate reason for inadequateblood pressure control andadjust maintenance antihypertensive drug regimen

Severe hypertension(diastolic blood pressure > 115 mm Hg)

Hypertensive neuroretinopathy absent

Arrange outpatient follow-up todocument adequate blood pressure control over the ensuing days to weeks and change drug treatment regimen as required

Patient education regarding the chronic nature of hypertensionand importance of long-termcompliance and blood pressurecontrol to prevent complications

"Ran out" ofmedications

Drugside effects

Cannot afforddrugs

Switch to genericthiazide diuretic

Add low-dose thiazide diuretic to existing

monotherapy with CCB, CEI, β-blocker, α

2-agonist

Switch to drugof another class

Restart


Hypertensive neuroretinopathy present(striate hemorrhages, cotton-wool spots

with or without papilledema)

Treat malignant hypertension(Fig. 8-20)

Acute end-organdysfunction

No acute end-organdysfunction

Treat as hypertensive crisis(see preceding figures)

FIGURE 8-36

Severe uncomplicated hypertension. The benefits of acute reduction in blood pressure in the setting of true hypertensive crises are obvious. Fortunately, true hypertensive crises are relativelyrare events that almost never affect hypertensive patients. Another type of presentation that ismuch more common than are true hypertensive crises is that of the patient who initiallyexhibits severe hypertension (diastolic blood pressure >115 mm Hg) in the absence of hyperten-sive neuroretinopathy or acute end-organ damage that would signify a true crisis. This entity,known as severe uncomplicated hypertension, is very commonly seen in the emergency depart-ment or other acute-care settings. Of patients with severe uncomplicated hypertension, 60% areentirely asymptomatic and present for prescription refills or routine blood pressure checks, orare found to have elevated pressure during routine physical examinations. The other 40% ofpatients initially exhibit nonspecific findings such as headache, dizziness, or weakness in theabsence of evidence of acute end-organ dysfunction. In the past, this entity was referred to asurgent hypertension, reflecting the erroneous notion that acute reduction of blood pressure,over a few hours before discharge from the acute-care facility, was essential to minimize the risk of short-term complications from severe hypertension. Commonly employed treatment regimens included oral clonidine loading or sublingual nifedipine. However, in recent years thepractice of acute blood pressure reduction in severe uncomplicated hypertension has been ques-tioned [55,56]. In the Veterans Administration Cooperative Study of patients with severe hyper-tension, there were 70 placebo-treated patients who had an average diastolic blood pressure of 121 mm Hg at entry. Among these untreated patients, 27 experienced morbid events at amean of 11 ± 8 months of follow-up. However, the earliest morbid event occurred only after 2 months [57]. These data suggest that in patients with severe uncomplicated hypertension inwhich severe hypertension is not accompanied by evidence of malignant hypertension or acuteend-organ dysfunction, eventual complications from stroke, myocardial infarction, or congestive

heart failure tend to occur over months toyears, rather than hours to days. Althoughlong-term control of blood pressure clearly canprevent these eventual complications, a hyper-tensive crisis cannot be diagnosed because noevidence exists that acute reduction of bloodpressure results in an improvement in short- orlong-term prognosis. Acute reduction of bloodpressure in patients with severe uncomplicatedhypertension with sublingual nifedipine or oralclonidine loading was once the de facto stan-dard of care. This practice, however, often wasan emotional response on the part of the treat-ing physician to the dramatic elevation ofblood pressure or motivated by the fear ofmedico-legal repercussions in the unlikelyevent of a hypertensive complication occurringwithin hours to days [55]. Although observingand documenting the dramatic decrease inblood pressure is a satisfying therapeuticmaneuver, there is no scientific basis for thisapproach. At present, no literature exists tosupport the notion that some goal level ofblood pressure reduction must be achievedbefore the patient with severe uncomplicatedhypertension leaves the acute-care setting [58].In fact, acute reduction of blood pressure oftenis counterproductive because it can produceuntoward side effects that render the patientless likely to comply with long-term drug therapy. Instead, the therapeutic interventionshould focus on tailoring an effective well-tolerated maintenance antihypertensive regi-men with patient education regarding thechronic nature of the disease process and theimportance of long-term compliance and med-ical follow-up. If the patient has simply runout of medicines, reinstitution of the previous-ly effective drug regimen should suffice. If thepatient is thought to be compliant with anexisting drug regimen, a sensible change in theregimen is appropriate, such as an increase ina suboptimal dosage of an existing drug or the addition of a drug of another class. In this regard, addition of a low dose of a thi-azide diuretic as a second-step agent to exist-ing monotherapy with converting enzymeinhibitor (CEI), angiotensin II receptor blocker,calcium channel blocker (CCB), �-blocker, orcentral �2-agonist often is remarkably effec-tive. Another essential goal of the acute inter-vention should be to arrange suitable outpa-tient follow-up within a few days. Gradualreduction of blood pressure to normotensivelevels over the next few days to a week shouldbe accomplished in conjunction with frequentoutpatient visits to modify the drug regimenand reinforce the importance of lifelong com-pliance with therapy. Although less dramaticthan acute reduction of blood pressure in theacute-care setting, this type of approach to thetreatment of chronic hypertension is more like-ly to prevent long-term hypertensive complica-tions and recurrent episodes of severe uncom-plicated hypertension.


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References

(2) robert w. schrier - atlas of diseases of the kidney volume 03 (pdf)

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