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Water deficit,salt excess

Hypertonic environment

= solute particles

Cell shrinks Cell swells

Water excess,salt deficit

Hypotonic environment

H2O

H2O

1 2

Renal Physiology

Unit TOC to come

FPO


Renal Physiology I Features and FunctionsA-2 Features and Functions I Renal Physiology

A. Features and Functions

A.1 Fluid CompartmentsThe role of the kidneys is to maintain a balance between water content and concentration of solutes in the body through urine production. The water content and specific solutes are divided into intra- and extracellular fluids.

Types of Body Fluid

Water is the major component of body fluid compartments. It accounts for about 60% of body weight and is referred to as total body water (TBW). The percentage of body weight made up of TBW varies with gender and age (Fig A.1). Women tend to have a lower percentage of TBW. This percentage declines with increased age and increased amounts of body fat.

Intracellular fluid (ICF) is ~40% of body weight. It is the fluid within the body’s cells (cytoplasm) (Fig A.2).

0.75

0.64

0.530.46

Young Old

WomenMen

Infant

WomenMen

0.53

1.00

Frac

tion

of T

BW to

bod

y w

eigh

t

Fig A.1 ▶ Total body water (TBW) content.

Tota

l bod

yH

2O =

0.6

ECF

ICF

0.015

0.045

~0.19

~0.35

Transcellular H2OPlasma H2O

Interstitial H2O

Cellular H2O(ICF)

Evan

s bl

ue Inul

in

Antip

yrin

e

Indicator

Fraction ofbody weight

Fig A.2 ▶ Fluid compartments of the body. ECF, extracellular fluid; ICF, intracellu-lar fluid.


Renal Physiology I Features and Functions Features and Functions I Renal Physiology A-3

Extracellular fluid (ECF) is ~20% of body weight. It is made up of the following components:

1. Plasma volume (~4%)2. Interstitial fluid volume (~15%) – Includes lymph3. Transcellular fluid volume (~1–3%) – Includes cerebrospinal fluid, peritoneal fluid, synovial fluids, and secretions

The kidneys directly regulate the concentration of water and solutes in the ECF, keeping the overall concentrations throughout the body at a healthy level. This is called the range of normal value for any substance.

Measuring the Sizes of Body Fluid CompartmentsThe volumes of fluid compartments can be measured indirectly by indicator dilution methods.

General equation The volume of a compartment is found by determining the final concentration of a known quantity of a marker substance that has been added to the compartment using the equation

V = Q/C, where

– V is the volume at which the substance X is uniformly distributed– C is the measured final concentration of X.– Q is the quantity of X added to the compartment, minus the amount lost from the compartment by

excretion or metabolism during the measurement.

Estimation ProceduresThe volume of different components of body water cannot be measured directly, so substances are added to specific components, and their dilution provides an estimate of the volume.

Total body water can be measured using

1. Antipyrine2. Tritiated water (THO)3. Deuterium oxide (D2O)

Extracellular fluid volume is measured using substances that will not enter cells:

1. Saccharides (e.g., inulin, sucrose, or mannitol)2. Ions (e.g., thiosulfate, thiocyanate, or radioactive chloride)

Interstitial fluid volume is not measured directly but is calculated as the difference between ECF and plasma volume.

Plasma volume is determined using substances that neither leave the vasculature nor enter red blood cells.

1. Evans blue dye2. Radioactive serum albumin

Another method is to label red blood cells with 32P or 51Cr and reinject them into the circulation. The dilution of tagged red blood cells and the hematocrit are used to determine red blood cell volume and plasma volume.

Intracellular fluid volume is calculated as the difference between TBW and ECF volume.



Solutes in Body FluidsNormally functioning kidneys regulate the concentrations of solutes to keep them at a healthy level despite fluctuations in intake and metabolism.

Electrolytes account for up to 95% of the total solutes. They are the most abundant constituents of body fluids next to water. Organic solutes (glucose, amino acids, urea, etc.) constitute only a small por-tion of total solutes. Electrolytes

1. Contribute to osmotic pressure2. Function as substrates for membrane transport3. Determine membrane potential and pH of body fluids

Intracellular solutes

1. K+ and Mg2+ are the major cations2. Proteins and phosphates are the major anions

Extracellular solutes

1. Na+, Cl–, and HCO3– are the major ions2. Proteins – Interstitial fluid is relatively free of proteins. – Plasma has important proteins.

A.2. Functions of the KidneysThe role of the kidneys is to maintain the volume and composition of the extracellular fluid (ECF). They do this by regulating urine content through filtration, reabsorption, and secretion. Urine is more or less concentrated and has more or less total volume depending on the need to rid the body of water, ions, or both. The concentrations of the following four factors are regulated through the kidneys’ production of urine.

1. Water2. Electrolytes, such as Na+, K+, PO4

2–, and Cl–

3. Acid or base (pH) content (H+)4. Nitrogenous by-products (from metabolism of proteins, mainly urea)

In addition to these functions, the kidneys release hormones such as renin and erythropoietin.

Water balance. The water intake (liquids consumed and metabolically produced) normally equals water output (evaporation from the skin and lungs plus losses via urine, sweat, and feces) (Fig A.3).

Volume of water intake is

– Influenced by sociological and habitual factors– Controlled primarily by thirst mechanisms in the hypothalamus

Final control of body water is precisely regulated by water loss in the kidneys.

Osmolality

Osmolality is the concentra-tion of osmotically active sol-ute particles in any compart-ment. The osmolality of the ICF and ECF compartments are normally the same. Aver-age value for osmolality = 290 mOsm/kg of body water (range 275–304 mOsm/kg). The common rounded value is 300 mOsm/kg. Osmolality is regulated in any one person within a few mOsm/kg. In ICF, K+, charged proteins, and as-sociated ions contribute to os-molality, whereas in ECF, NaCl content is key.

Conservation of Volume

The total amount of substances taken in and produced by the body equals the total amount consumed and excreted. All substances in the body fluids come from either intake or metabolism. All substances are eliminated by either excretion or metabolic consumption.

Renal Shutdown

Acute renal failure produces coma and death in a few days, due to acidosis, hyperkalemia (high plasma potassium), and hyponatremia (low plasma sodium). Urea and creatinine levels are also elevated.



Electrolytes are affected only by ingestion and excretion. Sodium and potassium are the most im-portant electrolytes for osmotic balance in the body. Electrolyte output is tightly regulated via urinary excretion.

pH regulation The kidneys regulate acid–base balance by reabsorbing or producing bicarbonate and by excreting excess acid (H+).

Elimination of by-products The kidneys also rid the body of many waste substances and foreign chemicals, such as drugs and pesticides.

Hormones Produced by the KidneysRenin helps to regulate total body Na+, ECF volume, and blood pressure.

Vasoactive substances (prostaglandins and kinins) are autocoids, which act on

– Renal hemodynamics– Na+ and water excretion– Renin release

Hormones regulating vitamin D3 stimulate calcium absorption from gut, bone, and renal tubular fluid. The liver converts vitamin D3 to the 25-hydroxy form, which the kidneys convert to the most ac-tive vitamin D form, cholecalciferol.

Erythropoietin stimulates red blood cell formation.

Elimination of Substances

Besides the kidneys, the liver breaks down drugs and other substances, but ultimately those simpler compounds are excreted by the kidneys (or in the feces).

Erythropoietin

Patients on renal dialysis often require injections of erythro-poietin. It helps to stimulate their production of red blood cells and avoid anemia. Their kidneys are not functioning, so they do not produce eryth-ropoietin.

Deficit

Excess

Increasedthirst

Increasedurine output

0.3 L

0.9 L

1.3 L

Intake:~2.5 L/day

Supplied by:

water of oxidation

food

beverages

Output:~2.5 L/day

Excreted:in feces

by respirationand perspiration

as urine 0.9 L

1.5 L

0.1 L

Water balance

Fig A.3 ▶ Water balance.



A.3 Renal Anatomy and ProcessesThe kidney has an outermost cortical layer and a central medullary layer (Fig A.4). The functional unit of the kidney is the nephron. Each nephron is a tube that starts and ends in the cortex and has a short or long loop into the medulla (Fig. A.5).

PapillaKidney

Renal vein

Ureter

Renal artery

Cortex

Outer medulla

Inner medulla

Afferent arteriole

Peritubular capillarynetwork

Interlobular artery

Arcuate artery

Glomerulus

Vasa rectaLoop of Henle

Corticalnephron

Juxtamedullarynephron

Distaltubule

Proximaltubule

Collecting duct

Inner stripe

Outer stripe

1

23

4

4

5

6

1

7

8

9

Fig A.4 ▶ Anatomy of the kidney.

1-arcuate arteries2-interlobular arteries3- proximal convoluted

tubule4-proximal straight tubule5-thin descending limb6-thick ascending limb7-distal convoluted tubule8-connecting tubule9-collecting duct

Afferent arteriole

Glomerularcapillaries

Capsularspace

Origin ofproximal tubule

Bowmancapsule

PodocytePedicel Endothelium

Basement membrane

Urine side

Blood side

Slit membrane

Fenestrae50 –100 nm

Pores 5 nm

Glomerulus

Efferent arteriole

Fig A.5 ▶ Glomerulus and Bowman capsule. Capillaries in the vascular glomeru-lus have intimate contact with the membranes of Bowman capsule, the begin-ning of the nephron. Each nephron has two arterioles and two sets of capillar-ies associated with it.



Sequence of blood flow through the kidneys

1. Arterial blood is delivered to glomerular capillaries via afferent arterioles.2. Plasma passes through glomerular membrane pores.3. Plasma filtrate passes into the Bowman capsule.4. Blood that is not filtered leaves the glomerulus via efferent arterioles.5. Blood flows into peritubular capillaries surrounding the nephrons.

Processes taking place in the nephron

1. Ultrafiltration: as blood passes through the kidneys, substances are removed. [XREF]2. Tubular reabsorption: substances that the body needs are returned to the blood. [XREF]3. Tubular secretion: substances are added to the filtrate and excreted. [XREF]

Renal energy sources. Different parts of the kidney have different energy sources. The renal cortex makes use of aerobic oxidative metabolism (mostly of fatty acids). Renal medullary structures metabo-lize glucose anaerobically.

Glomerular Filtration

Glomerular filtration is indis-criminate, as everything in plasma is filtered except large proteins. Glomerular capillaries and basement membranes are freely permeable only to small solutes. Glomerular filtrate contains the same concentra-tions of small molecules as the plasma. Normally, the filtrate will be almost free of larger molecules, namely proteins.


Renal Physiology I Glomerular FiltrationB-8 Glomerular Filtration I Renal Physiology

B. Glomerular Filtration

B.1 Key Renal RatesThe following renal rates characterize glomerular filtration.

Glomerular filtration rate (GFR) is the volume of plasma filtered per minute by all glomeruli in the kidneys. The magnitude of the GFR is an index of kidney function.

– The average GFR for a healthy 70 kg (154 lb) man is 125 mL/min.– GFR is lower in children and women and higher in larger people.

Renal plasma flow (RPF) is the volume of plasma entering the kidneys per minute.

– Average RPF is ~600 mL/min.– About 20% of this RPF is filtered at the glomerulus, so the GFR is about 120 mL/min.

Filtration fraction is the fraction (one fifth) of total plasma volume that is filtered. If filtration frac-tion increases, then GFR increases. The filtration fraction increases when the resistance to blood flow in efferent arterioles increases.

Renal blood flow (RBF) is the amount of blood supplied to the kidneys.

– This constitutes ~1 L/min, or 20% of cardiac output.

RBF is a little less than double the RPF, as plasma represents about 55 to 60% of whole blood. Changes in renal blood flow affect total body blood pressure. Blood pressure increases when RBF decreases.

B.2 Factors Affecting Glomerular FiltrationThree factors determine the glomerular filtration rate (GFR).

1. Filtration forces2. Permselectivity of glomerular membranes3. Rate of renal plasma flow (RPF)

Filtration ForcesUltrafiltration of plasma occurs as plasma moves from glomerular capillaries into the Bowman capsule under the influence of net filtration pressures (Fig B.1). Glomerular filtration is the same mechanism as systemic capillary filtration. The balance between hydrostatic and oncotic forces across the glomerular membrane determines the direction of fluid movement (just like for systemic capillaries).


Renal Physiology I Glomerular Filtration Glomerular Filtration I Renal Physiology B-9

Net filtration pressure driving water and solutes across the glomerular membrane is affected by three pressures.

1. Glomerular capillary hydrostatic pressure – (Pc, 45 mm Hg) in an outward direction2. Hydrostatic pressure in the Bowman capsule – (Pt, 10 mm Hg) inward3. Colloid osmotic pressure of plasma in glomerular capillaries – (πp, 28 mm Hg) inward

The equation is

net glomerular filtration pressure = Pc – Pt – πp

Net glomerular filtration pressure is normally about 7 mm Hg.

Glomerular versus systemic capillaries. The glomerular capillaries are much more permeable than average systemic capillaries. Approximately 180 L/day of fluid are filtered across glomerular capillaries, whereas only 4 L/day of fluid would have been filtered if these were systemic capillaries with their forces and properties. The ultrafiltration coefficient (Kf: membrane permeability × surface area) for glomerular capillaries is about 40 to 50 times greater than for systemic capillaries.

Permselectivity of Glomerular MembranesThe permeability of glomerular membranes to solutes is dictated by the permselectivity of the glom-erular filtration barrier.

Barrier layers 1. Capillary endothelial cells2. Endothelial basement membrane3. Epithelial cells of the Bowman capsule

xa b

Pa PbDP

Water flux JV = Kf · (DP – Dpx)

Dpx

Pa > Pb

andDP > Dpx

Water filtrationfrom a to b

ExampleGlomerularcapillary

Blood

Dp(= oncotic pressureof plasma proteins)

DPFiltratePrimary

urine

Fig B.1 ▶ Filtration.

Stones

Any obstruction in the renal pelvis and ureters will in-crease hydrostatic pressure in the Bowman capsule. Kidney stones are one such obstruc-tion and greatly reduce the GFR. Uric acid kidney stones may sometimes be dissolved by alkalinizing the urine with intake of potassium citrate. Kidney stones that are < 0.5 in. (1.27 cm) in diameter can be fragmented by applying focused ultrasound waves (lithotripsy).


Renal Physiology I Glomerular FiltrationB-10 Glomerular Filtration I Renal Physiology

Factors affecting permeability 1. Electrical charge2. Weight and size of particles that pass the barrier – Less than 10,000 molecular weight passes through the filtration barrier. – Particles that are 7.5 to 10 nm in diameter and are surrounded by positive charges pass through

the “pores” or “channels.”

The barrier is most permeable to small neutral or positively charged molecules and relatively imperme-able to large negatively charged molecules, such as proteins.

Rate of Renal Plasma FlowThe rate of RPF depends on the function of the heart and the cardiovascular system. If cardiac function is impaired, renal function will also be impaired. RPF is discussed in [XREF].

B.3 Hemodynamics of Glomerular Filtration Renal Oxygen ConsumptionThe kidneys are perfused by more blood per unit of tissue weight than any major organ except the heart. They also consume more oxygen than any organ except the heart. High renal oxygen consumption reflects the amount of energy required for reabsorption of the filtered Na+. Renal arteriovenous (AV) oxy-gen content difference is lower than that of other organs. Renal venous blood is redder than that leaving other organs. Renal blood flow is far in excess of its basal oxygen requirements. Unlike other organs, most of the blood flow is not for intracellular metabolic needs, but for membrane transport processes.

Blood flow to the glomerulus is finely controlled by many factors that act on arterioles that are both afferent and efferent to the glomerulus. Regulation of glomerular filtration rate (GFR) is linked to regulation of renal plasma flow (RPF), because the flow of plasma to the kidneys determines the rate of filtration. The overall magnitudes of RPF and GFR are influenced by the following three factors:

1. Renal autoregulation2. Autonomic innervation3. Vascular resistance

Renal AutoregulationRPF and GFR remain almost constant over a wide range of mean arterial blood pressures (80–180 mm Hg) (Fig B.2). As blood pressure increases over this range, resistance in afferent arterioles increases pro-portionately to minimize large increases in RPF and GFR (Fig B.3). Autoregulation is an intrinsic property of the kidney, independent of neural influences and extrarenal humoral stimulation. Autoregulation helps to decouple the renal regulation of salt and water excretion from fluctuations in arterial blood pressure. There are two intrarenal mechanisms responsible for renal autoregulation:

1. Myogenic mechanism – Intrinsic property of the afferent arteriolar smooth muscle2. Tubuloglomerular feedback mechanism – Feedback loop between the macula densa of the distal tubule and the afferent arteriole of the

same nephron

Barrier Damage Effects

A damaged glomerular filtra-tion barrier may allow more proteins to be filtered. Small molecules are less affected by a damaged barrier, as they are already highly permeable. Nephrotic syndrome (non-specific kidney damage) can be caused by many diseases, drugs, or allergies. Nephrotic syndrome results in severe loss of proteins into the urine and hypoproteinemia (decreased blood levels of protein, espe-cially albumin).


Renal Physiology I Glomerular Filtration Glomerular Filtration I Renal Physiology B-11

Autonomic InnervationWhen sympathetic tone is increased, GFR tends to decrease less than RPF because both afferent and efferent arterioles are constricted. Pathologic conditions, drugs, and hormones may also reduce GFR by reducing filtration surface area and Kf (filtration coefficient).

Renal response to autonomic nervous system activation. 1. Both afferent and efferent arterioles are innervated by sympathetic vasoconstrictor nerves.2. Arterioles will constrict in response to sympathetic activation, such as a loud sound. – Reduced renal blood flow, glomerular filtration, and urine flow – Increased filtration fraction3. There is no sympathetic activity in a denervated kidney. – Na+ reabsorption decreases. – Urine flow increases. – Afferents from renal baroreceptors travel with sympathetic nerves to the central nervous sys-

tem.

Vascular ResistanceEven in the face of autoregulation of the kidneys as a whole, changes in RPF and GFR can occur through local changes in vascular resistance of afferent and efferent arterioles (Fig B.3). Resistance changes can be caused by actions of the autonomic nervous system and various vasoactive humoral agents.

1. Increase in sympathetic activity to the kidney – Afferent and efferent arteriolar vasoconstriction – Increased renal vascular resistance – Decreased GFR2. Decrease in sympathetic tone – Decreased renal vascular resistance – Increased GFR

00 40 80 120 160 200 240

4

3

2

1

0

Mean pressure in renal artery (mmHg)

Rena

l blo

od fl

ow (m

L/m

in p

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Glo

mer

ular

filtr

atio

n ra

te (m

L/m

in p

er g

tiss

ue)

GFR

RBF

Range ofautoregulation

0.6

0.4

0.2

Fig B.2 ▶ Autoregulation of renal blood flow (RBF) and glomerular fil-tration rate (GFR).

010

20

3040

50

60

70

80

90

100

(mmHg)

Inte

rlob.

arte

ry, a

ff. ar

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Rena

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mer

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Fig B.3 ▶ Renal blood pressure.


Renal Physiology I Glomerular FiltrationB-12

Table B.1 ▶ Changes to Resistance in Renal Arterioles

Change in resistance Afferent arterioles Efferent arterioles

Increase Both RPF and GFR ↑ RPF ↓ GFR ↑

Decrease Both RPF and GFR ↓ RPF ↑ GFR ↓

Vasoactive substances cause resistance changes in the arterioles.1. Vasoconstrictors: catecholamines, angiotensin II, vasopressin, prostaglandins, and endothelin2. Vasodilators: atrial natriuretic peptide (ANP), acetylcholine (ACh), adenosine, kinins, and nitric oxide

(NO)

Effects of changes in resistance. Depending on which arterioles are affected, RPF and GFR change in different ways (Table B.1).

Effects of altered resistance in efferent arterioles 1. Increased resistance: – Peritubular capillary blood flow increases. – Reabsorption from the proximal and distal tubules increases (especially Na+).2. Decreased resistance: – Filtration fraction decreases. – Hydrostatic pressure increases. – Plasma colloid osmotic pressure decreases in the peritubular capillaries.

Resistance in Arterioles

Because the afferent and effer-ent arterioles are in series, the total resistance to blood flow in the kidneys is the sum of their resistances.


Renal Tubular Transport I Renal Physiology C-13

C. Renal Tubular Transport

C.1 Active Tubular TransportThe glomerular capillaries filter ~180 L of fluid a day into the nephrons, yet only ~1.5 L of urine a day are excreted. Thus, > 99% of what is filtered is reabsorbed from the renal tubules.

The renal transport for substances that are actively transported can be characterized by the capacity of the renal tubules to transport the substances at any one time. There is an upper limit for the rate of transport either in the reabsorptive or secretory direction.

Maximum Tubular Transport CapacityThe maximum tubular transport capacity (Tm) is the highest attainable rate of tubular transport of any given solute. Transport systems exhibiting tubular transport maxima are known as Tm-limited trans-port processes. The existence of the Tm phenomenon can be explained in terms of saturation of the transport carriers and/or transport sites for a particular substance along the renal tubules. Substances with a reabsorptive Tm include phosphate and sulfate ions, glucose and other monosaccharides, many amino acids, and Krebs cycle intermediates.

Threshold concentration: reabsorption. The plasma concentration at which a reabsorbed solute reaches its Tm and begins to appear in urine is its threshold concentration and is characteristic for that substance. Glucose is not normally excreted, because all filtered glucose is reabsorbed. It will be excreted when it is at high plasma concentrations (> 300 mg/100 mL). This is indicative of diabetes mellitus (liter-ally large volume of sweet urine). If the glomerular filtration rate (GFR) remains constant, the filtered glucose will be proportional to the plasma glucose concentration. As plasma glucose and consequently the filtered load increase,

1. Renal glucose transport sites become saturated.2. Maximum transport rate of glucose is reached.

The amount of glucose not being reabsorbed will start spilling into the urine. Further increases in plasma glucose concentration will be followed by increases in the amount of glucose excreted. The maximum reabsorptive rate (Tm) for glucose is ~400 mg/min.

Threshold concentration: secretion. Some substances can also be secreted by Tm mechanisms: organic acids (e.g., uric acid and p-aminohippuric acid [PAH]), organic bases (e.g., creatinine and his-tamine), and other compounds not normally found in the body (e.g., penicillin and morphine). These secretory transport systems are important for the elimination of drugs and other foreign chemicals from the body. Secretory rates of these substances will increase as their arterial concentrations increase until their secretory Tms are reached. At concentrations above threshold,

1. Secretory rates reach a plateau.2. Contribution of the secretion process to total urinary excretion decreases.3. Amount excreted continues to increase slowly as the concentration in the glomerular filtrate in-

creases.

Gradient-limited transport processes. For some solutes, there is no definite upper limit for the rate of renal tubular transport (no Tm). Rates of transport are limited by the solute concentration gradient differences between the filtrate and the peritubular blood. Sodium reabsorption along the nephron is an example of a gradient-limited transport process.

-

Peritubular Capillary Pressure

Pressures in peritubular capil-laries are comparable to capil-laries in other organs. Capillary osmotic pressure is greater than interstitial os motic pres-sure. This is due to the pres-ence of plasma proteins. Capillary osmotic pressure is greater than capillary hydro-static pressure. This facilitates reabsorption of water from the renal tubule.


Renal Physiology I Renal Tubular TransportC-14 Renal Tubular Transport I Renal Physiology

C.2 Renal ClearanceRenal clearance measures the efficiency of kidneys in removing a substance from plasma. It can be used to quantitatively measure the intensity of several renal functions, that is, filtration, reabsorption, and secretion. Renal clearance is defined as the theoretical volume of plasma from which a given substance is completely cleared by the kidneys per unit time. Each substance has a specific renal clearance value. In general, for a given substance X, renal clearance of X is the ratio of its excretion rate to its concentra-tion in plasma.

Calculation of Renal Clearance (a Modification of the Fick Equation)The equation for clearance of X is as follows:

Cx = (Ux × V)/Px,

where Cx is the renal clearance of the substance in mL/min; Ux and Px are the concentrations of sub-stance X (mg/mL) in urine and plasma, respectively; and V is urine output or flow rate (mL/min).

Measurement of the factors for renal clearance

– V is obtained by measuring the volume of urine produced per unit time.– Concentrations of substance X are measured in the urine sample (Ux) and in the plasma (Px).

Meaning of Renal Clearance MeasurementsFiltration, reabsorption, and secretion mechanisms all contribute to urinary excretion (or plasma clear-ance). The value for renal clearance of a substance gives information about how that substance is han-dled by the kidneys (Fig C.1). The direction and the rate of net renal tubular transport of a substance can be quantitatively determined using its renal clearance measurement.

Conservation of volume. At any one time, the total renal excretion of a substance must equal the algebraic sum of the three processes given in Table C.1.

Filtration

Reabsorption

Lowexcretion rate

Filtration

Secretion

Highexcretion rate

+ +

GlucoseAmino acidsNa+, Cl–, etc.

Organic anions orcations (e.g., PAH and atropine, resp.)

1 2

Fig C.1 ▶ Clearance levels. PAH, p-aminohippuric acid.


Renal Physiology I Renal Tubular Transport Renal Tubular Transport I Renal Physiology C-15

Table C.1 ▶ Conservation of Volume Equations

Total amount excreted = Amount filtered + Amount secreted – Amount reabsorbed

Total amount excreted (Excretion rate, mg/min) = Ux ×.V̇

Ux = concentration of substance X in urine (mg/mL)

Amount filtered (Filtered load, mg/min) = Px ×.GFR V̇ = urine flow rate (mL/min)

Net amount secreted (mg/min) = Amount excreted – Amount filtered

Px = concentration of substance X in plasma (mg/mL)

Net amount reabsorbed (mg/min) = Amount filtered – Amount excreted

GFR = glomerular filtration rate (mL/min)

Tm limitation. The renal clearance method can be used to determine whether or not renal transport of a substance is a Tm-limited transport process. This is done by constructing a renal titration curve, a combined plot of the filtered load, the urinary excretion rate, and the transport rate of substance X against the increasing plasma concentrations of X. The transport rate becomes constant at high plasma concentrations of X for a Tm-limited transport process.

Renal Clearance of Various SolutesInulin is a nontoxic polysaccharide that is not bound to plasma proteins. Inulin is freely filtered at the glomerulus. It is neither reabsorbed nor secreted by renal tubules. The amount of inulin excreted in the urine is only the amount that is filtered at the glomerulus. The volume of plasma cleared of inulin per minute is equal to the volume of plasma filtered per minute, that is, glomerular filtration rate (GFR) (Fig C.2). Measurement of GFR, using the renal clearance of a substance such as inulin, is useful in evaluating renal disease.

==

Inulin

Amount excreted/time=

Urinary inulin concentration . (urine volume/time)

GFR » ~120 mL/min per 1.73 m2 body surface

(mL/min)

Urinary inulinconcentrationrises due to H2Oreabsorption

No

secr

etio

nN

o re

abso

rptio

n

GFR = .VU

Uln

Pln.

Amount filtered/time=

Plasma inulin concentration . (filtered volume/time)

U ln (g/L) . ·VU (mL/min) = P ln (g/L) . GFR (mL/min)

H2O

Fig C.2 ▶ Inulin clearance = glomerular filtration rate (GFR).



Creatinine is an end product of skeletal muscle creatine metabolism. Creatinine has a fairly constant concentration in plasma under normal conditions. The 24-hour creatinine clearance is used clinically to estimate GFR. Renal clearance of creatinine gives a slightly greater estimate of GFR than inulin, because it is secreted in small amounts in addition to being filtered and not reabsorbed. Creatinine is used rather than inulin, even though inulin is more accurate, because creatinine does not need to be administered as it is endogenously produced. Because plasma creatinine levels are stable, endogenous creatinine pro-duction normally equals creatinine clearance by the kidney.

Creatinine level versus glomerular filtration rate. There is an inverse relationship between plasma creatinine level and the magnitude of GFR. If GFR decreases to half of normal, creatinine pro-duction will exceed renal clearance, and serum creatinine will double. If GFR decreases to one fourth of normal, serum creatinine will increase 4 times. An increase in plasma creatinine concentration is an indicator of a decrease in GFR of similar proportion.

Urea is filtered, and some is passively reabsorbed (Fig C.3). Urea clearance is a poor estimate of GFR. It only works when urea reabsorption is a constant fraction of its filtered load. Plasma level of urea is used to estimate renal function by the same inverse relationship as serum creatinine. Serum urea level is expressed as blood urea nitrogen (BUN) concentration. When GFR falls, BUN concentration usually rises in parallel to serum creatinine. Urea clearance or BUN concentration is not a reliable indicator of the magnitude of GFR, because plasma urea concentration varies widely, depending on

1. Protein intake2. Protein catabolism3. Variable renal reabsorption of urea under different states of hydration affected by antidiuretic hor-

mone (ADH)

Decline in GFR

The most clinically significant deficit in renal function with aging is the decline in GFR. This decline is due to the declines in renal plasma flow, cardiac output, and renal tissue mass. Creatinine clearance, the index of GFR, also decreases with age. Plasma creatinine con-centration remains constant with age. Decreased creatinine production from a reduction in muscle mass occurring with age is matched by decreased renal creatinine excretion. Plasma creatinine concentra-tion is not reliable as an esti-mate of renal function in el-derly individuals.

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ein

vas

a re

cta

Ureaconcentration

(mmol/L)

Passivereabsorption

Urea

Impermeable to ureaU

rea

perm

eabi

lity

subj

ect t

o AD

H c

ontr

ol

FEurea

Recirculation of urea

Rest:

100 %100 %

50 %

40 %

5

500

Fig C.3 ▶ Urea in the kidney.



Glucose. The renal clearance of glucose is zero at normal plasma glucose concentration (80 mg/100 mL). Clearance is zero at up to 300 mg/100 mL, not because it is not filtered, but because all filtered glu-cose is reabsorbed in proximal tubules. If plasma glucose levels increase 4 times the normal,

1. Renal reabsorptive rate of glucose will reach its Tm (transport maximum).2. Glucose excretion will increase until its clearance approaches GFR.

At high plasma glucose concentrations, the majority of excreted glucose comes from its unreabsorbed filtered load.

P-aminohippuric acid. The renal clearance of p-aminohippuric acid (PAH) is greater than GFR, be-cause it is filtered and also secreted into renal tubules (Fig C.4). More PAH is excreted than the amount originally filtered.

Renal clearance of PAH can be used to estimate the magnitude of renal plasma flow. All plasma-supply-ing nephrons can be cleared of PAH when PAH is below its secretory Tm. PAH will be completely cleared from the plasma by renal excretion during a single circuit of plasma flow through the kidney.

– Eighty-five to 90% of the total plasma flowing through the kidney is cleared of PAH.– Ten to 15% of the renal plasma flow is not filtered and bypasses renal tubules.

PAH clearance only approximates renal plasma flow. It is a measure of effective renal plasma flow (ERPF).

Effective renal blood flow (ERBF) is calculated from the effective renal plasma flow (ERPF) and hematocrit (Hct).

– Plasma is only about 55 to 60% of the blood.– ERBF = ERPF/(1 – Hct).

At higher plasma PAH concentrations, renal secretory transport of PAH reaches its Tm. Then the contri-bution of secretion to renal clearance of PAH decreases. As plasma PAH levels increase, renal clearance of PAH decreases toward the value of GFR.

C.3 Mechanisms of Renal Tubular TransportThe Na+–K+ adenosinetriphosphatase (ATPase) pump uses energy to establish a gradient for transport. Other specific membrane symporters and carriers facilitate transport of various substances. Renal tu-bular transport of solutes requires transepithelial movement of solutes at both the luminal and baso-lateral membranes. Renal tubular transport requires the transport systems at both membranes to work together in series.

Diabetes

The high plasma glucose levels in diabetes exceed its Tm, so glucose in the collecting ducts causes an osmotic diuresis.

PAH concentration in plasma (free PAH) (mmol/L)

PAH

am

ount

/tim

e (m

mol

/min

)

Excreted PAH

Secreted PAH

Filtered PAH

Saturation

1 2 3 4 5

0.25

0.50

0.75

1.00

0

Fig. C.4 ▶ Secretion and excretion of p-aminohippuric acid (PAH).



Sodium-Dependent Secondary Active TransportOrganic substances including glucose are reabsorbed in proximal tubules by Na+-dependent secondary active transport. Na+–K+ ATPase in the basolateral membranes of renal tubule cells establishes an elec-trochemical gradient for Na+,

– Extruding Na+ from cells– Pumping K+ across the basolateral membrane

Glucose. The electrochemical gradient for Na+ provides the energy for the uphill glucose transport into cells across the luminal brush border membrane. Glucose accumulates within the cells. Glucose leaves cells across the basolateral membrane by facilitated diffusion. The transport systems for glucose on both membranes are specific for the D-forms of sugars. They are inhibited by D-sugar analogues and specific inhibitors.

Other organic solutes (phosphate, amino acids, Krebs cycle intermediates, and metabolic intermedi-ates) are reabsorbed from proximal tubules by cotransport with Na+ across the luminal membrane (Fig C.5). They are transported by facilitated diffusion across the basolateral membrane.

P-aminohippuric acid is taken up into the proximal tubule cells from peritubular capillary blood across the basolateral membrane. It moves against its electrochemical gradient by an active transport mechanism specific for organic anions. This is called the PAH di- and tricarboxylate transport mecha-nism, through which PAH

1. Accumulates within proximal tubule cells.2. Is secreted into luminal fluid by facilitated diffusion.

Transport of Ions and WaterSodium ions are actively reabsorbed along the whole length of the renal tubule (Fig C.6). Na+ moves from the tubular lumen into cells down its electrochemical gradient by several mechanisms.

1. Cotransport with other solutes (e.g., glucose and Cl–)2. Countertransport (exchange) with H+

3. Simple diffusion via Na+ channels

-

Lumen Cell Blood

Brush bordermembrane

Basolateralmembrane

Glucose,amino acids(several systems),phosphate,lactate,sulfate,dicarboxylates

LuminalNa+ symport

Passivecarrier transport

xb

a

ATP

b

a

Na+

x

x

x

Na+

Na+

Fig. C.5 ▶ Reabsorption of organic sub-stances. ATP, adenosine triphosphate.

Urea

Urea

Glucose,aminoacids,phosphate,lactate,sulfate

Secondaryactive

Na+: Primary activeCl– : Secondary active

Primary activeand passive

Secondaryactive

Metabolites,drugs,

PAH

Na+: Primary activeCl– : Secondary active

Na+

Cl–

H2O

K+

K+

H+

Na+

Cl–

Ca2+

Mg+Cl–H2O

Na+

Ca2+

K+NH3 H+

Ca2+

NaCl

NaCl

Fig C.6 ▶ Overview of important transport processes along the nephron.

Pink – Active reabsorptionYellow – Passive reabsorptionBlue – Active transport secretionGreen – Passive cellular secretionPurple – Active cellular secretion



After Na+ enters cells, it is actively transported across the basolateral membrane by the Na+–K+ ATPase system.

Chloride ions are mostly passively reabsorbed. The concentration gradient favors the movement of Cl– from lumen to peritubular blood. This gradient is established by NaHCO3 and water.

Potassium ions are reabsorbed in the proximal tubule and early distal tubule by

1. Active transport at luminal membranes (H+–K+ ATPase)2. Passive outflux at peritubular membranes3. Paracellular (between cells) pathway

Water is passively reabsorbed by osmosis in response to solute osmotic gradients (Fig C.7). Antidi-uretic hormone (ADH) affects permeability of the collecting duct.

Hydrogen ions are generated from carbonic acid within renal cells. Carbonic acid is formed by hydra-tion of CO2 within renal cells in a reaction catalyzed by carbonic anhydrase. H+ is secreted across the luminal membrane by

1. Secondary active transport coupled to Na+ entry (Na+–H+ exchange)2. Primary active transport (H+ ATPase)

In the distal tubule, secreted H+ (via H+ ATPase) combines with other urinary buffers (HPO42– and NH3).

The products are then excreted in the urine.

Secreted H+ also reacts with filtered HCO3– in the proximal tubular lumen to form carbonic acid with the

aid of carbonic anhydrase present on the external luminal membranes of proximal tubule cells.

1. Carbonic acid in proximal tubule fluid dissociates into CO2 and H2O.2. CO2 diffuses back into proximal tubule cells and is rehydrated in the cells to carbonic acid.3. Carbonic acid dissociates to HCO3

– and H+.4. HCO3

– crosses basolateral membranes into peritubular blood.5. H+ is resecreted into the tubular lumen.6. Secreted H+ is converted into H2O in cells of the proximal tubule, and filtered HCO3

– from proximal tubule fluid is transferred to peritubular blood.

H2O followsNaCl, etc.

290

mO

sm/k

g H

2O60

0Co

rtex

Out

er m

edul

laIn

ner m

edul

la

High osmolalityof interstitium:

H2O outflow

NaCl

H2O

per

mea

bilit

ysu

bjec

t to

ADH

con

trol

Plasmawater Water follows NaCl

Maximumantidiuresis

Maximumwater diuresis

FEH2O

5 % andmore

Rest:

1200

Rest:

High H2Opermeabilityin antidiuresis

ADH

Wat

ertig

ht

GFR=

100%

0.5 %

25%

35%

10%

220

65%

Fig C.7 ▶ Water reabsorption and excretion. ADH, antidiuretic hormone; GFR, glomerular filtration rate.



C.4 Transport Processes along the NephronSegments of the nephron are characterized by distinct combinations of permeabilities and electric and osmotic potentials. As a result, substances are secreted or resorbed in specific segments of the nephron. The key segments are the proximal tubule, the thick ascending limb of the loop of Henle, and the late distal tubule and collecting duct.

Proximal TubuleGlomerular filtrate. Sixty-five to 90% of the glomerular filtrate is normally reabsorbed in the proxi-mal tubule. The reabsorption is isosmotic. Reabsorption of Na+ and other solutes tends to decrease osmolality of tubular fluid and raise osmolality of surrounding interstitial fluid transiently.

Water is reabsorbed in response to the osmotic gradient in the same proportion as solutes. The proxi-mal tubule has relatively high permeability to water, resulting in the reabsorbed fluid moving from in-terstitial space into peritubular capillaries by bulk flow. This is caused by the net balance of hydrostatic and oncotic pressures acting across the capillary walls.

Potential difference. There are small transepithelial potential differences across the tubule. In the early part of the proximal tubular lumen, the potential difference is slightly negative (–4 mV). In the late part of the proximal tubule, the potential difference becomes slightly positive (+3 mV).

Reabsorbed substances. Na+, K+, Ca2+, Cl–, HCO3–, phosphate, sulphate, and water are reabsorbed. Na+–K+ ATPase in the peritubular membrane transports Na+.

– Na+ travels across the luminal membrane by passive transport.– K+ is reabsorbed passively by its concentration gradient from tubule to capillary.

If this ATPase is inhibited, less Na+ transport will cause decreased secondary transport of

– Glucose, amino acids, and lactate– Ions like K+, Cl–, and Ca2+

– HCO3– reabsorption by an H+–Na+ antiporter

– Urea and Cl– are reabsorbed by passive diffusion due to concentration differences.

Secreted substances – Organic acids and NH3

– Hydrogen ions are actively secreted against a concentration gradient of 25:1.

Glomerulotubular balance. Under steady-state conditions, a relatively constant fraction of the fil-tered Na+ is reabsorbed in the proximal tubule despite variations in glomerular flow rate (GFR). The absolute rate of Na+ reabsorption in the proximal tubule will increase proportionately with the increase in GFR or Na+ filtered load. This helps to minimize changes in Na+ excretion that follow changes in GFR.

Loop of HenleThe two parts of the loop of Henle have different characteristics.

1. Descending limb – Relatively permeable to water – Poorly permeable to solutes like Na+, Cl–, and urea – Less relevant to transport in the nephron



2. Thick ascending limb – Impermeable to water – Ions and salts are reabsorbed without water – Primary site for dilution of urine – Transepithelial potential difference is 10 mV lumen positive

Reabsorbed substances. There is net transepithelial reabsorption of Na+, Cl–, and K+. Na+, K+, and Cl– enter cells together by a secondary active transport process (cotransport of K+ and Cl– with Na+). Na+ is transported out of cells at the peritubular side by an Na+–K+ ATPase. Cl– leaves cells on the peritubular side by a passive mechanism. Net K+ reabsorption in this segment is very small compared with net re-absorption of Na+ and Cl–. The thick ascending loop of Henle is also the major site for Mg2+ reabsorption. This occurs paracellularly (between cells) through tight junctions. Reabsorption of ions and water in this segment produces high ion and osmolar concentration gradients between the lumen of the ascending limb of the loop of Henle and the peritubular fluid (medullary interstitium).

Late Distal Tubule and Collecting DuctWater reabsorption is dissociated from salt reabsorption in these segments. The permeability to water of the distal nephron is under the control of antidiuretic hormone (ADH).

Sodium reabsorption. The peritubular membrane has an Na+–K+ ATPase. Na+ moves passively through the luminal membrane. Na+ concentration in the tubular fluid can be reduced to zero. Aldosterone stim-ulates Na+ reabsorption.

Cl– reabsorption is mostly passive through the paracellular pathway.

Potassium secretion. K+ is secreted in distal tubules and cortical collecting ducts by passive entry of K+ from cells into the lumen.

The luminal membrane is more permeable than the peritubular membrane. Because most filtered K+ is reabsorbed in the proximal tubule, the rate of K+ excretion is proportional to its secretory rate in the distal nephron.

The rate of K+ secretion is controlled by the following factors:

1. Cell K+ content (depending on K+ intake and acid–base balance)2. Tubular fluid flow rate (depending on Na+ excretion rate)3. Transepithelial potential difference (influenced by K+ intake and Na+ excretion rate)4. Aldosterone, which stimulates K+ secretion in the cortical collecting duct

If dietary K+ is elevated for a few days, the area of basolateral membrane of cortical collecting ducts will increase. This facilitates secretion of K+ into the ducts. If plasma K+ (hyperkalemia) were to stay elevated, nerves and muscles would be more excitable.

Ca2+ reabsorption is facilitated by parathyroid hormone (PTH) and the activated form of vitamin D in the distal tubule. PTH inhibits phosphate reabsorption in the proximal tubule.

Hydrogen ions are actively secreted against a concentration gradient of 1000:1 via an H+–ATPase system.

– Tubular fluid can be significantly acidified in the distal nephron– Aldosterone stimulates H+ secretion.

Diuretics

Loop diuretics inhibit Na+ and Cl– reabsorption in the thick ascending limb, which causes increased urine flow and de-creased osmolality in the medullary interstitium. An ex-ample is furosemide, which is potent because it acts where one fourth of filtered Na+ is re-absorbed.


Renal Physiology I Water/Solute RegulationD-22 Water/Solute Regulation I Renal Physiology

D. Water/Solute Regulation

D.1 Concentration and Dilution of UrineThe kidneys are able to produce urine that is either more concentrated or more diluted than plasma. The range of urine concentrations is from 50 to 1200, or slightly more mOsm/kg H2O. The ability of the kidneys to concentrate urine makes it possible for a person to survive with minimal or excessive water intake. Antidiuretic hormone (ADH) regulates the water content in the urine through its effects on the permeability of the distal tubule and collecting duct.

Countercurrent SystemThe countercurrent multiplication system in the loop of Henle conserves water. The hairpin turn and close apposition of descending and ascending limbs of the loop of Henle in the medulla of the kidney provide the proper structure (counterflow) for the operation of a countercurrent multiplier (Fig D.1).

Countercurrent exchange (water) in loop (e.g., vasa recta)

Countercurrent multiplier (Henle loop) Countercurrent systems in renal medulla

Collecting duct

Vasarecta

Henle loop

Watertight

Cortex

Medulla

600 600 600600

600 800

800800 800

10001000 1000800 1000

12001000

1200mOsm/kg H2O

H2O

600 600 600

800800 800

10001000 1000

600

400400 400 400

1200

800

1000

600

400

800

200

H2O

NaCl

NaCl

NaCl

NaCl

NaCl

NaCl

1200

Fig D.1 ▶ Countercurrent systems.


Renal Physiology I Water/Solute Regulation Water/Solute Regulation I Renal Physiology D-23

Epithelial permeability characteristics. The epithelia of the loop of Henle have special perme-ability characteristics.

1. Descending limb of the loop of Henle is – Highly permeable to water – Poorly permeable to solutes2. Ascending limb is – Relatively impermeable to water – Permeable to Na+ and Cl–

3. Thick ascending limb – Na+ and Cl– are actively reabsorbed in the thick ascending limb of the loop of Henle. These per-

meability and transport characteristics allow the ascending limb to separate its solute transport from water transport.

Horizontal osmotic gradient. The separation of solute and water transport creates a horizontal os-motic gradient between tubular fluid in the ascending limb and that in the descending limb. This hori-zontal osmotic gradient is then multiplied vertically along the length of the descending loop of Henle. This system generates an osmotic gradient within the tubular fluid of the descending limb from ~300 mOsm/kg H2O at its start to 1200 mOsm/kg H2O at the bend of the loop.

Medullary interstitium. A concentration gradient is established within the medullary interstitium (extracellular fluid) from the renal cortex to the inner renal medulla.

1. Nephron segment is highly permeable to water.2. Medullary interstitium is equilibrated with the fluid in the descending limbs.3. Highest concentration is at the tip of the papilla.

Sequence of events as fluid flows through the loop of Henle:

1. Isosmotic tubular fluid from the proximal tubule enters the descending limb of the loop of Henle.2. Fluid becomes more concentrated as it moves toward the bend of the loop. – Fluid in the descending limb equilibrates osmotically with fluid within the medullary intersti-

tium. – Extracellular fluid is more concentrated toward the bend of the loop.3. Concentrated fluid at the bend of the loop then becomes progressively more diluted as it flows

through the ascending loop of Henle. – Na+ and Cl– can be reabsorbed without water following. – Tubular fluid is hyposmotic (100 mOsm/kg H2O) at the end of the loop. – Hyposmotic in antidiuresis when urine flow is slow

Role of the Vasa RectaThe vasa recta are hairpin capillary beds that are located beside the loops of Henle and collecting ducts. They are

– Formed from efferent arterioles of juxtamedullary glomeruli.– Permeable to solutes– Permeable to water similar to other systemic capillaries

The vasa recta act as a passive countercurrent exchanger system.

1. Solutes are transported out of the ascending loop of Henle.2. Solutes diffuse down their concentration gradients into the descending vasa recta.3. Blood in the descending vasa recta becomes progressively more concentrated as it equilibrates with

the corticomedullary osmotic gradient.



Ascending vasa recta. In the ascending vasa recta, solutes diffuse back into the medullary intersti-tium, eventually entering the descending vasa recta. Blood leaving the renal medulla becomes progres-sively less concentrated as solutes return to the inner medulla. Solutes recirculate within the renal medulla, keeping the solute concentration high within the medullary interstitium.

Passive equilibration. The blood within each limb of the vasa recta is passively equilibrated with the preexisting medullary osmotic gradient at each horizontal level. This helps maintain the medullary osmotic gradient necessary for the production of hyperosmotic urine. If blood flow is too rapid in the vasa recta, the osmotic gradient will decrease.

Role of UreaUrea and NaCl are the two major solutes within the medullary interstitium. Filtered urea undergoes net reabsorption passively in the proximal tubule.

Concentration. Urea concentration at the end of the proximal tubule is approximately twice that of plasma because of water reabsorption. The concentration in the tubular fluid is further increased in the thin loop of Henle. More urea is secreted into the tubular fluid from the medullary interstitium. Urea concentration in the tubule fluid remains high until the fluid flows through collecting ducts.

Medullary recycling of urea. The thick ascending loop of Henle and distal tubule have low perme-ability to urea, whereas collecting ducts are more permeable to urea. Urea therefore diffuses out of the medullary collecting ducts. It enters the interstitium and vasa recta, as well as reentering the descend-ing loop of Henle.

Urea constitutes ~40% of papillary osmolality in the presence of ADH (antidiuresis).

1. ADH increases the permeability of medullary collecting ducts to urea as well as to water.2. Less than 10% of medullary interstitial osmolality is due to urea in the absence of ADH (water diure-

sis).

The medullary recycling of urea helps establish the osmotic gradient within the medulla.

1. There is less energy expenditure (urea transport is passive).2. Water is conserved.

Measurement of Concentrating and Diluting AbilityQuantitative assessment. The simplest method is to measure maximum and minimum urine osmo-lality. The more practical, common method is to quantify water excretion. This quantification is based on the concept that urine flow can be divided into two components.

1. Urine volume needed to excrete solutes at the same concentration as that in plasma (volume of isosmotic urine = osmolal clearance [Cosm])

2. Volume of water that is free of solutes (free water)

Solute-free water. The kidney generates solute-free water in the ascending limb of the loop of Henle by reabsorption of Na+ and Cl– without water. Solute-free water can be either removed or added back to plasma by excreting dilute or concentrated urine.

Free water clearance. (CH2O) is defined as the amount of distilled water that must be subtracted from or added to the urine (per unit time) to make that urine isosmotic with plasma.

CH2O = urine flow rate – osmolal clearance

Osmolal clearance = urine flow rate 3 urine osmolality/plasma osmolality



Table D.1 outlines urine concentration effects for the three types of urine.

Table D.1 ▶ Urine Concentration

Urine type CH2O Results

Hyposmotic Positive Free water is removed from body

Hyperosmotic Negative Solutes are removed without water, or free water is added to body

Isosmotic Zero None

D.2 Regulation of Water and SaltThe kidneys regulate extracellular fluid volume and osmolarity by altering

– Amount of water excreted– Amount of sodium excreted

The kidneys work with the cardiovascular and endocrine systems to ensure that the cells of the body are bathed in salty fluid of relatively constant composition (Fig D.2).

Water BalanceMechanisms. The regulation of body water depends on the balance between the rates of water move-ment into and out of the body. Two major and one minor mechanism are responsible for water bal-ance.

1. Thirst – Controls water intake2. ADH – Regulates urinary water excretion3. Perspiration – Adds to water (and salt) excretion

Water deficit,salt excess

Hypertonic environment

= solute particles

Cell shrinks Cell swells

Water excess,salt deficit

Hypotonic environment

H2O

H2O

1 2

Fig D.2 ▶ Hypertonic and hypotonic cell environments.



Table D.2 ▶ Hyposmotic and Hyperosmotic Urine

Type Hyposmotic Hyperosmotic

Conditions Hydration Dehydration

Concentration Low High

Permeability of distal tubule and collecting duct

Low High

Water resorbed Low High

Salts resorbed Normal Low

Comparison to distal tubular fluid Remains hyposmotic Isosmotic

Typical urine concentration 100 mOsm/kg H2O 1200 mOsm/kg H2O

Factors Affecting Water BalanceAntidiuretic hormone (vasopressin) is a peptide hormone synthesized in hypothalamic neurons of the supraoptic nucleus. It is

1. Transported in axons to the posterior pituitary2. Stored in nerve terminals until released by conducted action potentials3. Released into the pituitary circulation and travels in the blood

Plasma osmolality is the most important regulator of ADH release. Total solute concentration within body fluids is significantly affected by water gain or deficit (Fig D.3). The circulating level of ADH regu-lates the amount of water reabsorption from distal tubules and collecting ducts by the following sequen-tial negative-feedback control system:

1. Increase in plasma osmolality2. Increase in ADH3. Stimulation of hypothalamic osmoreceptor neurons4. Further increase in ADH5. Increase in H2O reabsorption6. Dilution of plasma

Blood volume. A decrease in blood volume stimulates ADH release. Atrial baroreceptors normally inhibit ADH release. A decrease in atrial pressure counteracts this inhibitory effect (disinhibition).Mechanism of action of ADH:

1. Binds to specific receptors on basolateral membranes of epithelial cells of the distal nephron2. Acts on distal tubules, especially collecting ducts3. Activates an adenylate cyclase second messenger system to insert water pores into membranes4. Increases the permeability of luminal membranes to water5. Increases plasma volume

Water IntakeWater intake is regulated through a thirst center located in the hypothalamus. Thirst is stimulated by both an increase in plasma osmolality and a reduced extracellular fluid volume. These are the same stimuli that affect ADH secretion. The hormone angiotensin II is also an important stimulus for thirst.

Water LossDehydration is the loss of water, with concentration of salt in the remaining body fluids (Fig D.4).

Diabetes Mellitus

Osmotic diuresis is the loss of water in the urine due to the presence of unreabsorbed sol-utes. Patients with diabetes mellitus have sugar in their urine that “carries” water with it. Net reabsorption of Na+ is reduced, because there is a larger gradient for passive Na+ diffusion from the intersti-tium to the proximal tubular lumen.

Diabetes Insipidus

Diabetes insipidus occurs if ADH is not synthesized or re-leased or if its receptors are not functioning. Water is not reabsorbed from the distal tubules and collecting ducts. ADH may not be available if the posterior pituitary is damaged. In the absence of ADH to pro-mote water reabsorption from the collecting duct, the patient produces a water diuresis with hypotonic urine.

Water Intoxication

Excessive voluntary drinking of water can decrease plasma osmolality to dangerous levels. For example, a person “purg-ing” their gut by drinking 4 L of plain water will experience hyponatremia, low plasma [Na+]. The kidneys excrete very dilute urine, but some electro-lytes are lost as well.



Water deficit Water excess

H2O reab-sorption

H2O reab-sorption

Osmolality Atrial pressure

Thirst

ADH

decreases increasesWater excretion:

Osmolality

Posterior lobeof pituitary

AT II

1 2

Fig. D.3 ▶ Regulation of water balance. ADH, antidiuretic hormone; AT II, angiontensin II.

.

NormalIsos-

moticvolumedeficit

Waterdeficit

Saltdeficit

Salt

ICR

ECR

Vom

iting

, dia

rrhe

a,di

uret

ics,

blo

od lo

ss,

burn

s

Pers

pira

tion,

hyp

er-

vent

ilatio

n, o

smot

ic d

iure

sis,

ADH

def

icit

(dia

bete

s in

sipi

dus)

Vom

iting

, dia

rrhe

a,pe

rspi

ratio

n,al

dost

eron

e de

ficit

Hea

rt fa

ilure

,ki

dney

dis

ease

Exce

ssiv

e flu

id in

take

or

ADH

sec

retio

n,ga

stric

lava

ge,

infu

sion

of g

luco

se s

olut

ion

Inta

ke o

f sea

wat

er, s

tero

idho

rmon

es, i

ncre

ased

aldo

ster

one,

infu

sion

of h

yper

toni

c sa

line

solu

tion

Isos-motic

volumeexcess

Waterexcess

Saltexcess

H2O H2O

H2OH2O

1 2 3 4 5 6

Fig D.4 ▶ Disturbances of salt and water homeostasis. ADH, antidiuretic hor-mone; ECR, extracellular; ICR, intracellular.



Sweating can increase from 0.1 to 5 L/hour in a bout of heavy exercise. Sweat is hyposmotic, so body fluids become more hyperosmotic.

Diarrhea causes isosmotic loss of both water and solutes. Kidneys produce a small volume of very concentrated urine to conserve water.

Hemorrhage or excessive blood loss is isosmotic. Compensations include increased heart rate and a shift of fluid from interstitial to plasma. There is increased secretion of renin and ADH and production of angio-tensin II. Best replacements are also isosmotic, such as blood, plasma, and normal saline (0.9% NaCl).

Loss of water without ions. Giving distilled water intravenously lyses red blood cells due to osmotic forces.

1. Loss is prevented by giving a 5% glucose solution with normal osmolality2. Body metabolizes the glucose quickly, leaving an increase in water without ions.

Sodium BalanceSodium is the most abundant solute in extracellular fluid (ECF). The status of Na+ balance is an important factor, as it determines

1. Volume of the ECF compartment2. Long-term regulation of blood pressure

Sodium concentration is regulated through

1. Water balance (indirectly)2. Glomerular filtration3. Change in volume of ECF4. Tubular reabsorption5. Renin–angiotensin–aldosterone system

Regulation of sodium through water balance. Sodium and water balance are linked because whenever water is added, sodium concentration decreases, and vice versa. Plasma [Na+] is first regulated by conservation or excretion of water. Na+ is the primary osmotic component of ECF. Osmoreceptors and ADH regulate plasma [Na+] indirectly.

Renal regulation: glomerular filtration and tubular reabsorption. The kidneys regulate sodium concentration balance and thereby ECF volume. The amount of Na+ excretion is regulated according to Na+ intake. Excretion is the result of glomerular filtration and tubular reabsorption.

Glomerular filtration occurs when the plasma concentration of sodium is too high. A slight increase in plasma osmolarity (usually Na+ and Cl–) will cause a 100-fold increase in the concentration of ions in the urine. Approximately 180 L/day of glomerular filtrate are concentrated into 1.5 L/day of urine.

Autoregulation of the glomerular filtration rate (GFR) automatically prevents excessive changes in the rate of Na+ excretion in response to spontaneous changes in blood pressure. If the kidneys did not autoregulate, then increased blood pressure would increase renal blood flow and GFR. This would filter more Na+ and give less time for Na+ reabsorption in the renal tubule, increasing Na+ excretion.

Tubuloglomerular feedback adjusts sodium reabsorption to match the GFR and compensates for changes in the filtered load of Na+ due to acute changes in GFR when Na+ and volume are normal. Macu-lar densa cells in the distal tubule signal the adjacent afferent arteriole to constrict after GFR increases, thereby decreasing GFR. If glomerulotubular balance were abolished,

1. Na+ excretion would vary more directly with GFR. – Increased GFR increases Na+ excretion, so Na+ intake would need to increase.2. Na+ balance and ECF volume would be restored.

[XREF: see Fig 171A2]



Tubular reabsorption of Na+. The kidneys conserve Na+ by normally reabsorbing 99.4% of filtered Na+. Aldosterone stimulates Na+ reabsorption in the collecting ducts by

1. Increasing the permeability of the luminal membrane2. Increasing permeability to K+

Aldosterone secretion is increased in response to

1. Decreased ECF volume2. Increased plasma K+ concentration by a direct action in the adrenal cortex3. Increased plasma angiotensin II concentration

Renin–Angiotensin–Aldosterone SystemThis messenger system is the most important regulator of Na+ balance.

Location. Chemicals in the renin–angiotensin cascade are synthesized in specific locations.

1. Renin is synthesized in the juxtaglomerular cells of the renal afferent arterioles.2. Angiotensinogen is an inactive plasma protein synthesized in the liver.

Action 1. Renin acts on angiotensinogen to form angiotensin I in the bloodstream (Fig D.5).2. Angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE). – ACE is located primarily in pulmonary capillary endothelium. – ACE activity is also present in capillary endothelial cells.3. Angiotensin II stimulates the release of aldosterone, which is synthesized in the zona glomerulosa of

the adrenal cortex.

Normalization ofplasma volume andblood pressure

Acute drop in: Plasma volumeand blood pressure

Convertingenzyme

Angiotensinogen

Renin

Renin secretion

Craving for salt

Thirst

GFR and RBF Aldosterone

Reduced salt and water excretion

Increased fluid and salt intake

Generalvasoconstriction

Adrenal cortex

Angiotensin II

Angiotensin I

1 2 3 4 5 6 7 8 9 10 11 12 1314

1Asp

2Arg

3Val

4Tyr

5Ile

6His

7Pro

8Phe

1Asp

2Arg

3Val

4Tyr

5Ile

6His

7Pro

8Phe

9His

10Leu

Fig D.5 ▶ Renin–angiotensin system. GFR, glomerular filtration rate; RBF, renal blood flow.


Renal Physiology I Water/Solute RegulationD-30

Renin release factors ultimately influence renal excretion of Na+. Renin release is

1. Increased by low blood pressure2. Decreased by increased stretch of right atrial mechanoreceptors

The most important stimulus for renin release is depletion of the ECF compartment volume. This re-sponse is detected by baroreceptors in the renal afferent arterioles. Increased renal sympathetic nerve activity and angiotensin II levels directly increase Na+ reabsorption to increase ECF volume.

Natriuretic hormones, a humoral Na+-losing system, act to increase renal excretion of Na+. One such hormone is atrial natriuretic peptide (ANP). ANP is released from the atria in response to stretch of the atria. This stretch is due to an expansion of the ECF compartment. ANP increases Na+ excretion by

1. Raising GFR2. Reducing tubular reabsorption of Na+ in collecting ducts

ANP also inhibits renin and aldosterone secretion.

Other influences on Na+ reabsorption. Renal interstitial hydraulic pressure can also influence Na+ reabsorption. Higher pressure decreases Na+ reabsorption. Renal tubular Na+ reabsorption increases in disease states when there is a decrease in the renal effective ECF volume.

Fight or Flight

The sympathetic nervous system is activated by stress, producing the “fight or flight” response. Renal blood flow is maintained during such re-sponses by autoregulation. Cardiac output and blood pressure increase to supply increased blood flow to active skeletal muscles. Renal func-tion still must be maintained, especially to deal with me-tabolites and H+ from muscle activity.

Response to a large Na+ load

In response to ingesting a large amount of sodium (6000 mg [103 mEq]), the kidneys will quickly conserve water to maintain osmolality, although the osmolarity of both the ECF and the ICF will increase. [XREF Fig. 175 E6] Excretion of the excess Na+ is much slower than conserving water, but the kid-neys do both. Eventually, the Na+ load will be excreted as more hypertonic urine.

Hypertension

Hypertension can result if the kidneys lose their sensitivity to increased blood pressure. The “pressure diuresis” hypothesis suggests that high blood pres-sure causes less excretion of Na+ than normal. One treat-ment for hypertension is to re-duce the plasma [angiotensin II]. This is done by giving drugs that inhibit the action of ACE.

Sodium Retention

Diseases such as cirrhosis of the liver and heart failure cause Na+ retention. This in turn causes generalized edema. Diuretics are given to increase excretion of both Na+ and excess fluid.


Acid–Base Balance I Renal Physiology E-31

E. Acid–Base Balance

E.1 Nonrenal MechanismsAcid–base balance, or the concentration of H+ in the extracellular fluid (ECF), is tightly regulated.

– Mean pH of arterial blood is 7.40 or [H+] ~40 nmoles/L– pH is controlled within a small range, 7.37 to 7.42 (+ or – 5% from the mean value)

This delicate balance is threatened continuously by additions of extra acids or bases to body fluids from metabolic processes (Fig E.1). Table E.1 outlines the mechanisms of acid–base balance.

pH

Dietary intakeand metabolism

Hemoglobin,plasma

proteins,phosphates,

etc.

Liver

Kidney

Respiration

or

Nonbicarbonatebuffers

Henderson-Hasselbalch equation

as H2PO4 –

2 HCO3– + 2 NH4

+ Urea, etc.

HCO3–

H2O

H+ CO2 OH– CO2

HCO3–

CO2

HCO3–

H+

CO2

– log [H+] = = pKa + log[HCO3

–]______[CO2]

NH4 +

Fig E.1 ▶ Factors affecting blood pH.

Respiration

Cellular respiration produces some 20,000 mmoles of CO2 (or H2CO3, volatile acid) daily. This is a tremendous acid load, but it is continuously elimi-nated by the lungs, so pH is not changed under normal conditions. The lungs are 200 times as effective in excreting acid (as CO2) as the kidneys. The kidneys excrete about 60 mmoles of H+ per day.

Acids and Bases

Nonvolatile acids or fixed acids come from protein diets (e.g., H2SO4 and H3PO4). Acids mea-sure about 50 to 100 mEq of H+ added per day. Bases come from vegetarian diets (e.g., lactate and citrate). Fixed acid concentrations may also rise during exercise or many patho-logical conditions.


Renal Physiology I Acid–Base BalanceE-32 Acid–Base Balance I Renal Physiology

Buffering SystemsChanges in pH are buffered by systems within the body. The most important buffers in the body are phosphate, protein, and bicarbonate buffers.

Phosphate buffer. (HPO42–/H2PO4

–) has a pK of 6.8.

– pK is close to 7.4– Concentration is low– Contributes little to the buffering capacity of the ECF– Important chemical buffer within intracellular fluid

Protein buffers include various intracellular proteins and proteins in blood. Plasma proteins and he-moglobin are strong buffers.

– Abundant in blood– Broad-ranged pK values

Hemoglobin helps buffer H+ generated from CO2 during CO2 transport in blood from tissues to the lungs. The buffering capacity of hemoglobin is further enhanced during the process of deoxygenation. Deoxy-genated hemoglobin is less acidic than oxygenated hemoglobin. It can act as a base and accept extra H+ formed from CO2 within red cells during the passage of CO2 from tissues to the lungs. The enhanced buffering capacity of deoxygenated hemoglobin prevents significant pH changes between arterial and venous blood during CO2 transport.

Bicarbonate buffer. (HCO3–/H2CO3 or HCO3

–/pCO2) is the most important physiological buffer of ECF

(Fig E.2) even though its pK of 6.1 is far from 7.4 due to its high concentration in plasma (24 mM).

The buffer pair can be tightly regulated, CO2 by the lungs and HCO3– by the kidneys. All buffer pairs in

plasma are in equilibrium with the same concentration of H+. A change in the buffering capacity of the entire blood buffer system will be reflected by a change in the buffering capacity of only one buffer pair (isohydric principle). The acid–base status or pH of ECF can be evaluated by examining only the bicar-bonate buffer system (Fig. E.2).

Utilization of Various BuffersAddition of buffer to extracellular fluid. When the acid–base disturbance is derived from the addi-tion of the bicarbonate buffer pair to ECF, > 95% of the buffering will be done by proteins and phosphates within cells, because the HCO3

– buffer system cannot buffer itself.

Addition of acids or bases to extracellular fluid. When the acid–base disturbance is derived from the addition of fixed acids or bases, extracellular buffering by HCO3 will account for nearly half of the total chemical buffering occurring in the body fluids, leaving about half for proteins and phosphates within cells.

Table E.1 ▶ Mechanisms of Acid–Base Balance

Type Action Response time Effectiveness

Chemical buffering Maintains pH Seconds Both acid and base

Respiratory Excretes acid Minutes Acid only

Renal Excretes acid and base Days Base more than acid

Buffers

Buffers are chemicals that prevent wide swings in pH by combining or releasing H+. Thus, the pH change will be moderated in response to the addition of H+ or base to the body.

pK

pK is calculated from the disso-ciation constant of an acid or a base. It is the pH at which a buffer pair is most effective.

Buffer Pair

A buffer pair is an acid or base and its salt. The ratio of the two concentrations and their pK determine the pH of the buffer.


Renal Physiology I Acid–Base Balance Acid–Base Balance I Renal Physiology E-33

Respiratory RegulationChanges in ventilation can cause or correct disturbances in the acid–base balance. Changes of CO2 excre-tion rapidly affect plasma pH.

Compensation for changes in pH

1. Acidic or alkaline arterial pH is detected.2. Signals from respiratory chemoreceptors change the rate of alveolar ventilation.3. Resulting hyper- or hypoventilation changes arterial pCO2

to return arterial pH to normal.

E.2 Renal Regulation of Acid–Base BalanceThe respiratory system cannot by itself restore pH to normal. The body supply of HCO3

– needs to be re-stored after chemical buffering, and the buffered acids or bases in the body fluids need to be eliminated. The renal system performs these two tasks to finally restore acid–base balance. The kidneys regulate acid–base balance in three ways.

1. Conservation of filtered HCO3–

– More than 99.9% of filtered HCO3– is reabsorbed by renal tubules

– Prevents the development of acidosis due to loss of HCO3–

2. Replenishment of depleted HCO3– (formation of new HCO3

–)3. Excretion of excess H+

Alveolar contact time

Normal

Constant

Alveolar contact time

Constant

Increased elimination Decreased eliminationpCO2

Tissue

constant

falls

pCO2

constantpCO2

rises

Normal

H+ elevated OH– elevated

OH–

CO2 CO2

CO2

H++ H

CO3 –

CO2

OH

–+ CO2

HCO

3 –

pCO2pCO2

+ H+

H+

CO2

1 2

+ OH–

pCO2

Fig E.2 ▶ Bicarbonate buffers.



Conservation of BicarbonateNormal urine is almost totally free of HCO3

–. Bicarbonate is reabsorbed in three locations in the nephron:

1. Proximal tubules – Eighty to 90% of the filtered load is reabsorbed2. Loops of Henle – Another 2% of the filtered load is reabsorbed3. Distal tubules and collecting ducts – Eight percent is reabsorbed

Reabsorption in the proximal tubule. Secreted H+ is combined with filtered HCO3– in tubular fluid.

This is catalysed by luminal carbonic anhydrase. The secreted H+ is consumed by reactions with HCO3–,

keeping H+ concentration in the tubular fluid low. The slightly higher pH favors more H+ secretion as well as preventing H+ reabsorption.

Reabsorption in the distal nephron. Some secreted H+ combines with HCO3– without the action of

luminal carbonic anhydrase. Further HCO3– reabsorption occurs.

Factors Influencing ReabsorptionFiltered load of HCO3

– can vary widely. The rate of HCO3– reabsorption increases proportional to the

load. Increased concentration of HCO3– in the filtrate causes

1. Increased tubular fluid pH2. Increased H+ secretion3. Increased HCO3

– reabsorption

Extracellular fluid volume. An expansion of extracellular fluid (ECF) volume results in decreased Na+ reabsorption. This decreases Na+-coupled H+ secretion and so decreases HCO3

– reabsorption.

Carbon dioxide concentration. High arterial pCO2 will increase the rate of HCO3

– reabsorption. This may be through the effects of pCO2

on HCO3– formation in blood. It also may act on the cellular produc-

tion and secretion of H+. The dependence of HCO3– reabsorption on pCO2

allows the kidneys to respond to acid–base disturbances originating from respiratory causes.

Ion concentrations. High concentrations of other extracellular ions reduce the rate of HCO3– reab-

sorption.

1. High plasma [Cl–] decreases HCO3– reabsorp-

tion.2. High plasma [K+] decreases H+ secretion and

HCO3– reabsorption.

Hormones. HCO3– reabsorption is affected by cer-

tain hormones:

1. Corticosteroids, aldosterone, and angiotensin II enhance HCO3

– reabsorption.2. Parathyroid hormone decreases HCO3

– reab-sorption.

Table E.2 outlines the factors influencing the reab-sorption of bicarbonate (HCO3

–).

Table E.2 ▶ Factors Influencing Reabsorption of Bicarbonate

Factor Effect of increased concentration

HCO3–load

Increased reabsorptionCorticosteroids/ aldosterone/ angiotensin II

Volume of ECF

Decreased reabsorption

Concentration of CO2

Concentration of Cl–

Concentration of K+

Parathyroid



Replenishment of BicarbonateHydrogen ions are produced within renal cells from carbonic acid with carbonic anhydrase and secreted into tubular fluid. H+ remains in tubular fluid as part of the buffer pairs and later is excreted. HCO3

– is formed within renal cells at the same time. HCO3

– is transported across the basolateral membrane by a Cl––HCO3

– exchanger. One new moiety of HCO3– is formed within renal cells for every H+ that is secreted

and excreted with non-HCO3– buffers. This “new” HCO3

– is added to body fluids.

Titratable acid is urinary phosphate buffer that combines with secreted H+ (i.e., H2PO4–). It can be

measured as the amount of strong base required to titrate 1 mL of urine back to the pH of the glomerular filtrate or plasma. The amount of titratable acid formed is limited by the supply of urinary phosphate buffer.

– Seventy-five percent of filtered phosphate (HPO42–) is reabsorbed

– Twenty-five percent of a low plasma phosphate is left to buffer

Ammonia Buffer SystemThe NH3/NH4

+ buffer system has a pK of 9.2. It is a relatively poor buffer in the pH range found in tubular fluid (pK is far from 7.4), but there is a plentiful supply of NH3 from renal cells.

NH3 is produced within proximal tubule cells by transamination reactions of glutamine. Medullary NH3 is uncharged and lipid soluble. It freely diffuses across cell membranes down its concentration gra-dient. In the lumen of the collecting duct, NH3 combines with secreted H+ to form NH4

+.

Ammonium ion (NH4+) is charged and relatively impermeable. NH4 is “trapped” in the tubular fluid

and excreted in urine in the form of neutral salts (NH4)2SO4 or NH4Cl. This transport process is called diffusion trapping or nonionic diffusion.

Effectiveness. The effectiveness of the NH3 buffer system is enhanced during an acid load. The rate of synthesis of NH3 is regulated according to the acid–base status of the person. More NH3 is synthesized during acidosis, permitting more excretion of excess acid. Under normal conditions all filtered HCO3

– is reabsorbed, and an additional 40 to 60 mmoles of acid is secreted. This contributes 40 to 60 mmoles of new HCO3

– to blood and replenishes the HCO3– used to buffer the acid produced from metabolism. The

secreted acid is excreted with HPO42– (25%) or NH3 (75%).

E.3 Acid–Base DisturbancesNormal ValuesTable E.3 lists the normal values of factors that describe the acid–base status of extracellular fluid (ECF).

Abnormal values. When acid–base balance is dis-turbed, pH changes, and other normal values change also.

– Acidosis is the state in which arterial pH is < 7.36 (> 10% < 7.40).

– Alkalosis is the state in which arterial pH is > 7.44 (> 10% > 7.40).

Table E.3 ▶ Normal Values of Variables that Describe the Acid–Base Status of Extracellular Fluid

Factor Normal value

Arterial pH 7.4

Concentration of HCO3– 24 mM

pCO240 mm Hg

[HCO3–]/ pCO2

ratio 20:1

Efficiency of Ammonia and Phosphate

Ammonia is more effective than phosphate at buffer-ing the secreted H+. A large amount of H+ can be excreted without urine pH dropping to a very low level.

Acid Secretion at Low pH

H+ secretion is a gradient- limited transport process. The distal nephron cannot trans-port H+ against a concentration gradient exceeding 1000:1. This occurs when urine pH equals 4.4. The body cannot excrete any more excess H+ if the urine pH drops below 4.4.



DisturbancesRespiratory disturbance changes H+ concentration by a primary change in pCO2

because pCO2 is regulated

by the rate of alveolar ventilation. Metabolic disturbance changes primarily the concentration of HCO3–

due to the addition or loss of fixed acids or bases derived from metabolic processes.There are four primary acid–base disturbances:

1. Respiratory acidosis2. Respiratory alkalosis3. Metabolic acidosis4. Metabolic alkalosis

Response to acidosis. During acidosis the kidneys compensate by excreting more acidic urine. They

1. Continue to completely reabsorb HCO3–

2. Increase excretion of titratable acid and NH4+

Response to alkalosis. During alkalosis cell pH rises, causing

1. Decreased driving force for H+ secretion2. Decreased HCO3

– reabsorption3. Alkalinized urine4. Decreased NH3 retention5. Decreased acid excretion6. Increased HCO3

– elimination

Quantitation of renal tubular acid secretion and excretion.

Total rate of H+ secretion = Rate of HCO3– reabsorption + rate of titratable acid excretion +

rate of NH4+ excretion

Total rate of H+ excretion = Rate of titratable acid excretion + rate of NH4+ excretion = Total rate of

new HCO3- being added to the blood

In most cases a primary disturbance of one origin is accompanied by a secondary or compensatory re-sponse of the opposite origin. The compensatory response shifts pH toward its normal value by allowing HCO3

– to increase or decrease from its normal value.

Compensatory response. The efficiency of compensatory responses is indicated by how close arte-rial pH is brought back to 7.4.

– Metabolic disturbances are almost instantaneous– Primary respiratory disturbances require several days

Respiratory Acidosis and AlkalosisRespiratory acidosis (RAc) results from high pCO2. It is due to failure of the lungs to excrete CO2 ad-equately (Fig E.3). This can happen with pulmonary disease or decreased alveolar ventilation secondary to drugs, such as morphine. It is characterized by

1. Increased carbonic acid2. Increased HCO3

– concentration3. Change in [HCO3

–]/ pCO2 ratio to < 20:1 (change in pCO2 is greater)

4. Fall in plasma pH

Hyperkalemia

Hyperkalemia (elevated po-tassium levels) occurs during acidosis. K+ is taken up by tu-bular cells in exchange for H+ secretion via the H+–K+ adeno-sinetriphosphatase (ATPase) antiporter.



Renal compensation for the increased pCO2 involves

1. Increased H+ production and secretion from renal tubular cells2. Increased HCO3

– reabsorption3. Increased H+ excretion4. Production of “new” HCO3

–

These compensations return the [HCO3–]/ pCO2

ratio closer to 20:1.

Ion concentration changes

1. Plasma [Cl–] decreases2. Plasma [K+] increases – Kidney secretes more H+ as compensation – Kidney reabsorbs more K+ with operation of the H+–K+ ATPase antiport protein

But: [HCO3–]act and pCO2 are increased

NBB is regenerated

HCO3–

CO2

Bicarbonate buffer Nonbicarbonate buffer (NBB)

normal: pH 7.4

pH

Decreased pulmonaryelimination of CO2

Respiratory acidosis:

HCO3–

CO2

Buffering by NBB– only

2Renal compensationLiver

Renal compensation of acidosisis achieved: pH

Kidney

1Buffering

Increased pulmonary elimination of CO2

Increasedproduction (kidney)and sparing (liver)

2HCO3– + 2NH4

+ Urea

Increasedexcretion

HCO3–

NBB-HNBB–

NBB– + H+ NBB-H

HCO3– + H+ CO2 + H2O

HCO3– + H+ ® CO2 + H2O

8.07.57.0

H+

CO2

8.07.57.0

H+

NH4+

H2O

HCO3–

H+ + OH–

CO2

Fig E.3 ▶ Respiratory acidosis.



Compensated respiratory acidosis (cRAc) is indicated by

1. Near normal pH2. Still some elevation in pCO2

3. Increased plasma HCO3–

Respiratory alkalosis (RAk) results from low pCO2 due to excessive loss of CO2 (e.g., hyperventila-tion). RAk

1. Decreases HCO3– concentration

2. Raises the [HCO3–]/ pCO2 ratio to > 20:1

3. Raises the pH

Renal compensation involves

1. Decreased CO2 within renal cells2. Decreased reabsorption of HCO3

–

3. Decreased H+ secretion into the tubules4. Increased excretion of HCO3

–

5. Further decreased plasma [HCO3–]

Compensations return the [HCO3–]/ pCO2

ratio nearer to 20:1.

Compensated respiratory alkalosis (cRAk) is indicated by

1. Near normal pH2. Still-depleted HCO3

– store

Metabolic Acidosis and AlkalosisMetabolic acidosis (MAc) results from abnormal retention of fixed metabolic acids (e.g., diabetes) (Fig E.4). It is characterized by

1. Decreased HCO3– concentration

2. Decreased [HCO3–]/ pCO2

ratio to < 20:13. Decreased pH

Respiratory compensation causes

1. Stimulation of the respiratory center to eliminate more CO2

2. Reduction in H2CO3– concentration

Renal compensation also occurs unless acidosis is due to renal failure. It results in

1. Virtually complete reabsorption of HCO3–

2. Increase in plasma [Cl–], because more Na+ is absorbed with Cl– than with HCO3–

3. Increased excretion of titratable acid and NH4+

An acute episode can be partly compensated by increased HCO3– production.

Compensated metabolic acidosis (cMAc) is indicated by

1. pH closer to 7.4 but not quite normal2. [HCO3

–]/ pCO2 ratio returns to 20:1

3. Further decrease in HCO3–



Metabolic alkalosis (MAk) results from

1. Excessive loss of H+ (e.g., loss of HCl from vomiting)2. Excessive intake or retention of bases (e.g., NaHCO3, lactate)

It is characterized by an

1. Increase in – HCO3

– concentration – [HCO3

–]/ pCO2 ratio > 20:1

– pH – Intracellular [K+]2. Decrease in – Plasma [Cl–] – Plasma [K+] due to the H+–K+ ATPase transporter

Bicarbonate buffer Nonbicarbonate buffer (NBB)

Normal: pH 7.4

Non-respiratory (metabolic) acidosis: pH

Stimulation of chemosensors

Total ventilation increasesIncreased pulmonary

elimination of CO2

pH rises

AdditionalHCO3

– consumptionNBB– is regenerated

Buffering by NBB–Buffering by HCO3–

Respiratory compensation

Increased renal excretion of H+ and NH4+

Addition of H+

2 Respiratory compensation

HCO3– replenished

But: [HCO3–]act and pCO2 are decreased

pH

1 Buffering

8.0

7.07.4 7.4

of acidosis is achieved:

HCO3– + H+ ® CO2 + H2O

HCO3– + H+ ® CO2 + H2O

NBB– + H+ ® NBB–H

NBB-HNBB–HCO3–

CO2

CO2

CO2

CO2

H+

H+H+

a

b

c

Fig E.4 ▶ Metabolic acidosis.


Renal Physiology I Acid–Base BalanceE-40

Respiratory compensation causes

1. Retention of CO2

2. Increased H2CO3 concentration

Renal compensation involves increased renal excretion of HCO3–. Paradoxical aciduria may occur; when

all filtered HCO3– is reabsorbed, any further H+ secretion lowers pH. The effectiveness of respiratory com-

pensation is limited. Retention of CO2 will tend to increase H+ secretion and HCO3– reabsorption. These

are the reverse effects of renal compensation.

Compensated metabolic alkalosis (cMAk) is indicated by

1. pH closer to 7.4 but not quite normal2. [HCO3

–]/ pCO2 ratio returns to 20:1

3. Further increase in plasma HCO3–


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