rene e ipertensione roberto pontremoli università degli studi di genova dipartimento di medicina...

Rene e IpertensioneRene e Ipertensione

Roberto PontremolRoberto Pontremolii

Università degli Studi di Genova Università degli Studi di Genova Dipartimento di Medicina Interna e SpecialitàDipartimento di Medicina Interna e Specialità MedicheMediche

• Il rene è un sensore di rischio CV nell’IE (1976-2004)

Rene e ipertensione

• Il rene “colpevole” di ipertensione (1827-2004) - secondaria - essenziale

• Il rene “vittima” dell’ipertensione. La terapia antipertensiva è il mezzo renoprotettivo più efficace (1919-2004)


Il rene “colpevole” di ipertensione secondaria

Associazione tra malattie renali e ipertensione (1827-31)

R Bright1789-1859


Evidenza di sostanze pressorie nel tessuto e/o nella vena renale (1898-1940)

RENINA (1898) IPERTENSINA (1939) / ANGIOTENSINA

(1940)

R.A.A.Tigerstedt E. Braun Menendez I.H.Page 1853-1923 1903-1959 1901-1991


Esperimenti sulla capacità renale di generare ipertensione STENOSI ARTERIA RENALE (1932-41)

PA ARP Vol. Plasmatico

normale

normale

normale

OSTRUZIONE URETERALE UNILATERALE (1936-37)

H.Goldblatt, 1891-1977

Il rene “colpevole” di ipertensione essenziale

A.Guyton G.Bianchi J. Laragh B. Brenner

The dominant role of the kidney in long term BP regulationThe dominant role of the kidney in long term BP regulation

The Renal Function Curve:The Renal Function Curve: BP is controlled so that Fluid OutputFluid Output equilibrates with Fluid IntakeFluid Intake

Sod

ium

inta

ke

or O

utp

ut

(x n

orm

al)

Arterial Pressure, mmHg50 100 150 200 250

10

8

6

4

2

1

0

normal

elevated pressure

Modified from Guyton AC et al. Am J Med 1972

(A) (C)

(B)



Clinical Science and Molecular Medicine (1974) 47, 435-448

Long term blood pressure Long term blood pressure regulation is set by the kidney in ratsregulation is set by the kidney in rats

Data are mean SE

Grisk O et al., J Hypertens 2002

0

20

40

60

80

100

120

140

160

180

MA

P ,m

mH

g

SHRSham operated

P <0.0001

SHR + BB.1K BB.1KSham operated

n= 10 n= 8 n= 8

P <0.0001

Hypertension may be transplanted with Hypertension may be transplanted with the kidney in humansthe kidney in humans

Data are mean SE Guidi E. et al., JASN 1996

0

0,5

1

1,5

2

2,5

L

og A

HT

Un

its

All R

P= 0.71

P = 0.003

R - R +

P = 0.015

D -D +

Milan Kidney Transplantation Program 1969-83, 67 D and 85 R, mean Fo-up 8 yrs (1-20)



Laragh JH et al. Am J Med 52: 633-652, 1972

The vasoconstriction-volume spectrum in normotension and in the pathogenesis of hypertension

Laragh JH. Fed Proc 41; 2415-2423, 1982

Atrial natriuretic hormone, the renin-aldosterone axis, and blood pressure-electrolyte homeostasis

Laragh JH. N Engl J Med 313: 1330-40, 1985

Intrauterine growth retardation

Reduction in filtration surface

area

Acquired glomerular

sclerosis

Systemic/glomerular hypertension

Impaired renal development

Brenner B, Am J Kidney Dis 1994

Reduction in Reduction in filtration surface filtration surface

areaarea

0

25

50

75

100

125

150

175

200

225

N°

of g

lom

eru

li (*

104 )

HT Controls

Nephron number in patients with primary hypertensionNephron number in patients with primary hypertension

Modified from Keller G. et al. N Eng J Med 2003

0

1

2

3

4

5

6

7

8

9

Vol

um

e of

glo

mer

uli

(x 1

0- 4 m

m3 )

Data are median (25th-75th percentile); Ht (n=10) and C (n=10) were matched for age, height and body weight

Mean number of intact glomeruliMean number of intact glomeruli- 46.6 %- 46.6 %

Mean glomerular volumeMean glomerular volume+ 133 %+ 133 %


Rene e ipertensione




4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.00 2 4 6 8 10 12 14 16 18

Optimal (<120/80)“normal”high normalstage 1 HTstage 2 HTstage 3 HTstage 4 HT (> 210/120)

years since screening

En

d-s

tag

e r

en

al d

isease

du

e t

o a

ny c

au

se (

%)

From Klag et al., 1996

Incidence of ESRD according to BP

Alb

um

inu

ria

(ug /

min

)G

FR

(ml/m

in/1

.73m

2 )

From Parving H-H, Am J Kidney Dis 1993

-2 -1 0 1 2 3 4 5 6 7years

1250

750

250

GFR: -11.3

105

95

85

75

65

55

45

125

115

105

95

MA

BP

(m

mH

g)

Start of antihypertensive treatment

GFR: -3.5

GFR: -1.2

GFR: -1.3

Blood Pressure reduction conveys renal protectionBlood Pressure reduction conveys renal protection

0

1

2

3

4

5

6

7

ACE-I

NON ACE-I

x2 S

cre

at/

100 p

ts/

year

Renal Protection: the importance of RAAS Blockade

6.7 %4.3 %

Jafar TH et al., Ann Intern Med 2002

Non diabetic renal disease patients: meta-analysis

RRR 36 %, NNT 42N= 1850 patients, 11 studies mean follow-up 2. 2 yrsMAP 103 vs 106

ACE-I

NON ACE-I

0

1

2

3

4

5

6

7

8

ARB

NON ARB

Renal Protection: the importance of RAAS Blockade

7.9%

6.5 %

Based on Renaal and IDNT database

Type 2 diabetic renal disease patients: meta-analysis

ARB

NON ARB

x2 S

cre

at/

100 p

ts/

year

RRR 28%, NNT 40N= 3228 patients, 2 studies mean follow-up 2.9 yrsMAP 97 vs 99


Rene e ipertensione




The kidney as a sensor of CV riskThe kidney as a sensor of CV risk

Cardiovascular risk

3-5 xCRF

RRT

Tx

graft failure

Phases of progressive renal

disease

20 -200 x

5x

20 -200 x

Mild renal dysfunctionMild renal dysfunction

• serum creatinine >1.4 mg/dl (women) or > 1.5 mg/dl (men)

• creatinine clearance 60-70 ml/min

and/or• microalbuminuria (30-300 mg/die)

• proteinuria

Formula di Cockroft-Gault per il calcolo della clearance della creatinina

(140-età) x peso corporeo

(creatininemia x 72) *

* x 0.85 se donna

Microalbuminuria:Microalbuminuria: tecniche di raccolta tecniche di raccolta

AERAER (Albumin excretion rate)(Albumin excretion rate) overnight o 24 oreovernight o 24 ore

20-200 ug/min20-200 ug/mincioècioè

30-300 mg/24 ore30-300 mg/24 ore

ACRACR (Albumin/creatinine ratio)(Albumin/creatinine ratio)

2.5-25 mg/mmol2.5-25 mg/mmol

Albuminuria spotAlbuminuria spot 20-150 mg/L20-150 mg/L

N

Serum Creatinine

(> 1.5, m; > 1.4 f)

%

Creat. Clear.

(< 60-70 ml/min)

%

HOTHOT 18 790 2.5 12.3

INSIGHTINSIGHT 6 321 3.1 29.1

HOPEHOPE 9 173 10.5 36.4

Prevalence of Mild Renal Dysfunction in Hypertensive PatientsPrevalence of Mild Renal Dysfunction in Hypertensive Patients

High-normal serum creatinine is a predictor of CV risk in EH: the PIUMA study

Follow-up, yrs

Schillaci G. et al., Arch Intern Med 2001

Q1 Screat ( 0.94 m; 0.79 f) Q2 Screat (0.95-1.04 m; 1.05-1.17 f) Q3 Screat (1.05-1.17 m; 0.87-0.95 f) Q4 Screat ( 1.18 m; 0.96 f)

0.9

0.8

0.6

0.5 (%)

CV

eve

nts

per

pat

ien

t-yr

Cv

even

t-fr

ee s

urv

ival

1

0.7

00 2 4 6 8

Q1

Q2

Q3

N= 1829, p < 0.003 by log-rank test

Quartiles of Serum creatinine

p < 0.05 Q1vs Q4

0

1

2

3

4

10

Q4

1 2 3 4

RR 1.30 (C.I. 1.07-1.59), p 0.01 for each 0.23 mg/dL S creat.

Adjusted for age, sex, smoking, cholesterol, LVH, protU, BP, Tx

Microalbuminuria: an Microalbuminuria: an independentindependent predictor of ischemic predictor of ischemic heart disease in hypertensive patientsheart disease in hypertensive patients

70

82 104 6 yrs0

P < 0.003

From Jensen et al., Hypertension, 2000

Microalbuminuria, n= 20

Normoalbuminuria, n= 184 100

Pop

ula

tion

wit

hou

t IH

D, %

85

LV

MI ,

g/m

2.7

0,6

0,65

0,7

0,75

0,8

IMT

, mm

P<0.0001

45

50

55

60

P<0.0001

LVH 57%

Normal renal

function

Mild renal dysfunction

Mild renal dysfunction and hypertensive TOD

n= 358, HT duration 36 mos (median), BP 158/101 mmHg G. Leoncini et al., JASN 2004

LVH 76% Carotid

Plaque 20%

Carotid Plaque

27%

Carotid Plaque

27%

O.R. 2.75 (C.I. 1.33-5.67), p

< 0.01 of

having either LVH and/or carotid ATS

rene e ipertensione roberto pontremoli università degli studi di genova dipartimento di medicina...

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