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The kidney and the regulation of the internal environment

17.1 Introduction

Human beings, like all animals, feed on other organisms both to provide material for tissue growth and maintenance and to provide themselves with the resources for other activities such as reproduction. This life style inevitably leads to the intake of variable quantities of essential body constituents such as sodium, potassium, and water, and to the production of metabolic waste products. Nevertheless, the body needs to maintain a close control over the composition of the body fluids and this is the principal role of the kidneys. They achieve this by regulating the composition of the blood and thereby the composition of the extracellular fluid. The production of urine of variable com­position is, therefore, a necessary part of the homeostatic role of the kidney. About 1—1.5 liters of urine are normally produced each day, containing about 50—70 g of solids, chiefly urea and sodium chloride. Urine volume and osmolality vary both with fluid intake and with fluid loss through sweating and in the feces.

The chemical composition of the urine is very variable (Table 17.1) and changes with the diet. Although the urine contains traces of most of the plasma constituents, some substances, such as protein, glucose, and amino acids, are not normally detected. Other substances are much more concentrated in the urine than they are in plasma (e.g. creatinine, phosphate, and urea). The urine is normally somewhat acid compared to the plasma or extracellular fluid (its pH usually lies between 5 and 6 compared to 7.4 for plasma).

Normal, fresh urine has a slight aromatic odor which can readily be masked by odors from certain foodstuffs (e.g. coffee or garlic) but decomposition of urine by bacterial action generates an unpleasant fetid odor due to the production of ammonia. The characteristic color is principally due to the presence of pigments known as urochromes. In disease the color of the urine can vary and so give important diagnostic clues.

In addition to their primary regulatory and excretory roles, the kidneys also produce the hormone erythropoietin, which regu­lates the production of red cells (Chapter 13) and an enzyme, renin, which is important in the regulation of sodium balance via aldosterone secretion (Chapter 28). They also form 1,25-dibydroxycholecalciferol (also called calcitriol) from vitamin D which plays an important role in calcium balance (Chapter 12).

Table 17.1 Comparison between the composition of the plasma and that of urine







mmoles I"1




mmoles I*1




mmoles Г"1




mmoles I"1




mmoles I"1




mmoles I"1




mmoles I"1




mmoles I*1




mmoles I"1





Uric acid



mmoles I"1




mmoles I"'1








mOsm kg"1

The data given in the table are the values that would encompass 95 per cent of a population of normal healthy adults. Note that while the concentration of the principal constituents of the plasma is maintained relatively constant, the composition of the urine is subject to considerable variation. Moreover, some important constituents of plasma such as protein, glucose, and bicarbonate are absent from normal urine. Others such as creatinine, NH.j, phosphate, and urea are present in far higher concentrations in the urine.

17.2 The anatomic organization of the kidney and urinary tract

The kidneys lie high in the abdomen on its posterior wall on either side of the vertebral column (Til—L3). In adults, each kidney is about 11 cm long and 6 cm wide and weighs about 140 g. A simple diagram of the gross structure of the kidney is shown in Fig. 17.1. On the medial aspect there is an indentation called the Ы/us through which the renal artery enters and the renal vein and ureter leave. Each kidney is covered by a tough, fibrous, inelastic capsule which serves to restrict changes in volume in response to any increase in blood pressure.

If a kidney is cut open, two regions are easily recognized—a dark brown cortex and a pale inner region which is divided into


17 The kidney and the regulation of the internal environment

Fig. 17.1 Diagrammatic representation of a cross-sectional view of the left kidney to show the principal anatomic features.

the medulla and the renal pelvis. The renal pelvis contains the major renal blood vessels and is the region where the ureter ori­ginates. The medulla of each human kidney is divided into a series of large conical masses known as the renal pyramids which have their origin at the border between the cortex and the medulla. The apex or papilla of each pyramid lies in the central space of the renal pelvis which collects the urine prior to its passage to the bladder. The central space can be divided into two or three large areas, known as the major calyces, which divide in turn into the minor calyces that collect the urine from the renal papillae.

As befits their role as regulators of the internal environment, the kidneys receive a copious blood supply from the abdominal aorta via the renal arteries. Venous drainage is via the renal veins into the inferior vena cava. The renal circulation is regulated by nerves from both the parasympathetic and sympathetic divisions of the autonomic nervous system (see below). The kidneys form the upper part of the urinary tract and the urine they produce is delivered to the bladder by a pair of ureters. The bladder con­tinuously accumulates urine and it periodically empties its contents via the urethra under the control of an external sphinc­ter—a process known as micturition. Like the kidneys, the lower urinary tract receives innervation from both divisions of the autonomic nervous system.

The nephron is the functional unit of the kidney

Each human kidney contains about 1.25 million nephrons, which are the functional units of the kidney. Each nephron consists of a renal or malpighian corpuscle attached to a long, thin, convoluted

tube and its associated blood supply. The renal corpuscle is about 200/xm in diameter while the tubules are about 55 /xm in diameter and 50—65 mm in length. This arrangement provides a very large ratio of surface area to volume and is well adapted for the exchange of solutes between the tubular fluid and the cells of the tubular epithelium (Fig. 17.2). The renal corpuscle consists of an invaginated sphere (Bowman's capsule) that envelops a tuft of capillaries known as a glomerulus. The glomerular capillaries ori­ginate from an afferent arteriole and recombine to form an efferent arteriole (Fig. 17.3).

The proximal tubule arises directly from Bowman's capsule. It is about 30-60/xm in diameter and 15 mm in length. The epithelial cells of the proximal tubule are cuboidal in appearance and rich in mitochondria. They are closely fused with one another via tight junctions at the apical end and the luminal surface is densely covered by microvilli giving rise to a promi­nent brush border. The lateral surfaces of the basolateral mem­branes have an extensive series of interdigitating processes that greatly increase their surface area. The space between the baso­lateral regions of the cells is called the lateral intercellular space.

The proximal tubule connects with the intermediate tubule also known as the descending limb of the loop of Henle. Here the epithelial cells are thin and flattened (the wall thickness is only 1-2 /xm). Compared to the cells of the proximal tubule, these cells have few mitochondria. The thin descending limb turns and ascends towards the cortex finally merging with the thick segment which is about 12 mm in length. The cells of the thick segment are cuboidal with extensive invaginations of the baso­lateral membrane. Like the cells of the proximal tubule, they are rich in mitochondria, suggestive of a major role in active transport.

^ 17.2 The anatomic organization of the kidney and urinary tract


Fig. 17.2 A diagram of a short-looped (cortical) and long-looped (juxtamedullary) nephron to show their basic organization. Note that the early distal tubule of each type of nephron is in contact with its own glomerulus.

The nephrons of the outer renal cortex (the cortical or superficial nepbrons) have short loops of Henle (the thin segment is as little as 2 mm in length) some of which lie entirely within the cortex. In contrast, the nephrons nearest the medulla (the juxtamedullary nephrons) have long loops which penetrate deep into the medulla. About 15 per cent of the nephrons in humans have long loops and in these nephrons the thin segments (which may be as much as 14 mm in length) pass deep into the renal papillae.

The thick ascending limb of the loop of Henle and the initial segment of the distal tubule contact the afferent arteriole close to the glomerulus from which the tubule originated. The tubular epithelium is modified to form the macula densa and the wall of the afferent arteriole is thicker due to the presence of juxta­glomerular cells. The juxtaglomerular cells, macula densa, and associated mesangeal cells form the juxtaglomerular apparatus (Fig. 17.3)- The juxtaglomerular cells of the arteriole secrete an enzyme called renin that has an important role in the regulation of aldosterone secretion from the adrenal cortex. In this way the juxtaglomerular apparatus plays an important role in the regula­tion of sodium balance (see Section 17.7 and Chapters 12 and 28). The distal tubule arises from the ascending limb of the loop of Henle and is about 5 mm in length. Here the tubular wall is composed of cuboidal cells similar in appearance to those of the ascending thick limb. The distal tubules of a number of nephrons merge via connecting tubules to form collecting ducts, which are up to 20 mm in length and which pass through the cortex and medulla to the renal pelvis. The epithelium of the collecting ducts consists of two cell types, principal cells (or

Fig. 17.3 The principal features of a renal glomerulus and the juxtaglomerular apparatus. The wall of the afferent arteriole is thickened close to the point of contact with the distal tubule where the juxtaglomerular cells are located. These cells secrete the enzyme renin in response to low sodium in the distal tubule.


17 The kidney and the regulation of the internal environment

Fig. 17.4 Ultrastructure of the cells that constitute the nephron.

P-cells), which play an important role in the regulation of sodium balance, and intercalated cells (or I-cells), which are important in regulating acid-base balance. A diagrammatic representation of the cellular ultrastructure of the nephron is shown in Fig. 17.4.

The renal circulation is arranged in a highly ordered manner

The renal artery enters the hilus and branches to form the inter-lobular arteries which subsequently give rise to the arcuate arteries which course around the outer medulla. The arcuate arteries lead to cortical radial arteries (sometimes called the interlobular arteries) that ascend towards the renal capsule branching en route to form the afferent arterioles of the Bowman's capsule (Fig. 17.5). The afferent arterioles give rise glomerular capillaries within the Bowman's capsule which then recombine to leave via efferent arterioles.

The efferent arterioles of the outer cortex give rise to a rich supply of capillaries that invest the renal tubules (the peritubular capillaries). Blood from the peritubulat capillaries first drains into stellate veins and thence into the cortical radial veins and arcuate veins. In contrast, the efferent arterioles close to the medulla (a juxtamedullary efferent arteriole) give rise to a seties of straight vessels known as the descending vasa recta (from the Latin for straight vessel) which provide the blood supply of the outer and inner medullary regions. Blood from the ascending vasa recta drains into the arcuate veins.

The kidneys are innervated by

sympathetic and parasympathetic nerve


The kidneys have a rich nerve supply and are innervated both by sympathetic postganglionic fibers from the sympathetic para-vertebral chain (T12—L2) and by efferent fibers from the vagus nerve. The postganglionic sympathetic nerve fibers travel along the major arteries supplying the renal cortex as far as afferent arterioles. The vagal parasympathetic fibers synapse in a gan­glion in the hilus and appear to innervate the efferent arterioles. The sympathetic supply is adrenergic while the parasympathetic fibers are cholinergic. This innervation provides extrinsic control for the renal circulation which can override the intrinsic auto-regulation which is discussed in the next section.

^ 17.3 Renal blood flow is maintained by autoregulation

In normal adults the total renal blood flow (i.e. the blood flow for both kidneys) has been measured by a number of methods and is about 1.25 1 min"1 or about 25 per cent of the resting cardiac output. The renal cortex has the highest blood flow— about five times that of the outer medulla and 20 times that of the inner medulla. If arterial pressure is altered over the range 10-26 kPa (80-200 mmHg), the renal blood flow remains remarkably constant (Fig. 17.6). The stability of renal blood flow

17.3 Renal blood flow is maintained by autoregulation


Fig. 17.5 A diagrammatic representation of the principal features of the renal circulation. The diagram shows the circulation after the renal artery has branched to form the interlobular artery. Arterial blood shown in red, venous blood in blue. Note that the efferent arterioles of the superficial nephrons give rise to the peritubular capillaries, while those of the juxtaglomerular nephrons give rise to straight vessels that pass deep into the renal medulla (the vasa recta).

persists after denervation and can be observed in isolated per­fused kidneys. It is therefore due to mechanisms intrinsic to the kidneys and is called autoregulation.

What are the mechanisms that underlie autoregulation? Two hypotheses have been advanced, the myogenic hypothesis and the metabolic hypothesis.

The myogenic hypothesis proposes that autoregulation is due to the response of the renal arterioles to stretch. An increase in pressure will distend the arteriolar wall, stretch the smooth muscle fibers, and elicit a contractile response. This will increase vascular resistance and decrease blood flow (see also Section 15.9). The metabolic hypothesis proposes that metabolites from

the renal tissue maintain a degree of vasodilatation. An increase in perfusion pressure will lead to an increased blood flow, which in turn will leach out more metabolites and so decrease the vasodilatation. Other humoral factors such as prostaglandins and nitric oxide may also act as vasodilators. Additionally, the macula densa of the juxtaglomerular apparatus has been postu­lated to play a role in maintaining the vasomotor tone of the afferent and efferent arterioles of the glomerulus (see Section 17.7). In summary, it is probable that both myogenic and meta­bolic factors are responsible for the maintenance of blood flow in the kidney. Despite powerful autoregulation, renal blood flow is subject to modulation; for example, it falls during exercise and

Fig. 17.6 The autoregulation of renal blood flow. The renal blood flow for an isolated dog kidney was first allowed to stabilize at a perfusion pressure of 133 kPa (100 mmHg). The perfusion pressure was then abruptly altered to a new value and the blood flow measured immediately after the change in pressure (white circles). After a short period the blood flow stabilized at a new level (shown by the red circles). The data show that the steady-state renal blood flow remains essentially constant once the arterial pressure rises above about 10 kPa (80 mmHg).


17 The kidney and the regulation of the internal environment

Fig. 17.7 The fall in mean blood pressure across the renal circulation. Note the relatively high pressure in the glomerular capillaries and that the pressure in the peritubular capillaries (2 kPa or 15 mmHg) is lower than the plasma oncotic pressure (here about 4.7 kPa or 35 mmHg). Consequently, fluid reabsorption occurs along their length, unlike the capillaries of other vascular beds. Note that when the afferent arterioles constrict, the pressure in the glomerular capillaries falls and when the efferent arterioles constrict, the pressure in the glomerular capillaries rises.

following severe hemorrhage. This additional regulation is achieved both by the activity in the renal nerves and by humoral factors circulating in the blood. As we have already seen, the kidney receives a substantial innervation from both the sym­pathetic and parasympathetic divisions of the autonomic nervous system. Sympathetic stimulation causes vasoconstriction of the afferent arterioles and thus reduces renal blood flow. The role of the cholinergic fibers is less clear but they may act as vaso­dilators. Both epinephrine and norepinephrine cause vaso­constriction in the renal circulation but norepinephrine acts mainly on the renal cortex. Angiotensin II and antidiuretic hormone (vasopressin) are other powerful vasoconstrictors which play a significant role in regulating blood flow through the kidneys.

The mean pressures at key points in the renal circulation are illustrated in Fig. 17.7. Note that vasoconstriction in the afferent arterioles reduces pressure in the glomerular capillaries and that vasoconstriction in the efferent arterioles will increase it.

^ 17.4 The nephron regulates the internal

environment by ultrafiltration followed by

selective modification of the filtrate

Regulation of the plasma composition occurs via three key processes:

  1. filtration;

  2. reabsorption;

  3. secretion.

First, some of the plasma flowing through the glomerular capillaries is filtered and passes into Bowman's space and then

the tubular fluid is modified as it passes along the renal tubules by the passage of some substances from the tubular fluid to the blood (reabsorption) and by the secretion of other substances from the blood into the filtrate. Proof that the nephron works in this way was originally obtained by sampling the fluid in Bowman's capsule by micropuncture (Box 17.1). Analysis of this fluid shows that it has the same composition as that of plasma except that there is very little protein. The simplest explanation of this key observation is that the capsular fluid is formed by filtering out large molecules such as proteins and allowing the free passage of small molecules such as glucose. This process is known as ultrafiltration and the fluid formed in this way is called the glomerular filtrate.

The barrier that restricts the passage of fluid from the capillary into Bowman's capsule consists of three components (Fig. 17.8). First, there is the capillary wall itself, which con­sists of endothelial cells interspersed with many fine pores or fenestrae. Secondly, the endothelial cells abut a basement mem­brane which consists of fibrils of negatively charged glyco-proteins. Finally, the epithelial cells or podocytes of the capsular membrane do not form a continuous layer but extend thin processes known as pedicels over the basement membrane, leaving gaps that provide filtration slits. The resulting combination pro­vides a filter that allows the free passage of molecules with a radius of less than about 1.8 nm. This arrangement makes the glomerular capillaries very much more permeable to water and to solutes than capillaries in other vascular beds.

From the data shown in Table 17.2 it is clear that substances with a low molecular weight pass through the membrane freely but that there is an effective barrier to all but the smallest of proteins. Myoglobin passes through the filter relatively easily, hemoglobin passes only with difficulty, and albumin, the small-

17.4 The nephron: ultrafiltration and modification of the filtrate 367

Box 17.1 Direct measurements of the composition of tubular fluid can be achieved by micropuncture methods

Important insights into the function of the renal tubules can be gained by knowing the composition of the tubular fluid at dif­ferent parts of the nephron. This can be achieved by penetrating the tubule wall with a very small rnicropipette and sucking up a sample of the fluid for chemical analysis. This is known as micropuncture. If the micropipettes contain pressure transducers, it is possible to measure the pressures in the afferent and efferent arterioles as well as that in Bowman's space. These micropuncture methods have been used extensively to study tubular function in situ in anesthetized animals.

Table 17.2 The relationship between molecular radius and glomerular permeability

Substance Molecular Effective Filtrate/ mass radius plasma (Da) (nm)

Water 18 0.1 1.0 Urea 60 0.16 1.0 Glucose 180 0.36 1.0 Sucrose 342 0.44 1.0 Inulin 5 200 1.48 0.98 Myoglobin 17 000 1.95 0.75 Hemoglobin 68 000 3.25 0.03 Serum albumin 69 000 3.55 -0.005

Figure 1. A simple schematic diagram to illustrate the principle of micropuncture

In the first application of this method a droplet of oil was injected at the top of the proximal tubule and a micropipette inserted into Bowman's capsule (see above). The fluid in Bowman's space was aspirated and analyzed for protein and elec­trolytes. Later variants of the technique have employed oil droplets to isolate sections of tubule, a fluid of known com­position is then injected into the isolated segment and aspirated after a set period of time. Finally, this fluid is analyzed for changes in its composition.

The methods outlined above have provided a great deal of information regarding the function of superficial nephrons but, by their nature, they cannot provide information about the deeper segments of the nephron or about the juxtamedullary nephrons. To overcome this difficulty, methods have been devel­oped that permit the isolation of particular segments of individ­ual nephrons. The transport processes occurring in these isolated segments can then be studied by microperfusion techniques

est of the plasma proteins, has about a fifth of the permeability of hemoglobin and about one-hundredth of the permeability of small molecules like glucose.

Even the largest of the plasma proteins are much smaller than the filtration slits that can be seen with the aid of the electron

The ratio of the concentration of a substance in the filtrate to that found in the plasma is a direct measure of the ease with which it passes through the glomerular filter. A ratio of 1 indicates free passage and a ratio of 0 would indicate complete inability to pass the filter.

microscope. The barrier to the passage of proteins appears to be due to the meshwork of protein fibrils that form the basement membrane. Experiments with charged and neutral dextrans (high molecular weight carbohydrates) show that the barrier depends both on the size of a molecule and on its charge. The barrier is more permeable to neutral or positively charged mole­cules than it is to negatively charged ones. Thus albumin (mole­cular mass 69 kDa), which has a strong negative charge at physiological pH, is retained in the plasma by mutual repulsion between its negative charge and that of the glycoproteins of the basement membrane. In contrast, hemoglobin (68 kDa), which is not strongly charged at physiological pH, passes through the glomerular filter five to six times more easily than albumin. Fortunately, unlike albumin, hemoglobin is contained within the red cells and is not normally present in the plasma.

The amount of fluid passing through into Bowman's capsule is governed by the balance of hydrodynamic forces (Fig. 17.8 and Box 17.2). Hydrostatic pressure in the capillaries acts to force the plasma out of the capillaries but the plasma proteins cannot pass into the glomerulus and are retained within the blood. The osmotic pressure they exert (oncotic pressure) opposes the hydro­static force due to capillary pressure. In addition, there is a small pressure within the capsule itself which also opposes the hydro­static pressure with the capillaries. The sum of the opposing pressures is called the net filtration pressure. The rate at which the kidneys form the ultrafiltrate is known as the glomerular filtration rate or GFR and has units of milliliters per minute.

The pressure within Bowman's capsule {the capsularpressure) is about 1.3 kPa (10 mmHg) and it arises because the movement of fluid from the capillaries of the glomerulus is restricted by the diameter of the tubular lumen. The capsular pressure is derived from the pressure in the afferent arterioles and provides the force required to propel the filtrate through the nephron.


17 The kidney and the regulation of the internal environment

Fig. 17.8 A diagrammatic representation of the filtration barrier in the glomerulus and the hydrodynamic forces that determine the rate of ultrafiltration. (For calculation of the Starling forces see Box 17.2). Fluid from the plasma is forced out by the pressure in the giomerular capillaries but this is opposed by the pressure in the Bowman's capsule and by the osmotic pressure exerted by the plasma proteins (the oncotic pressure).

Box 17.2 Calculation of the Starling forces governing the formation of the giomerular filtrate

The relationship between the glomerular filtration rate (GFR) and the hydrodynamic forces responsible for the formation of the filtrate is

given by the relationship:

where Kf is the filtration coefficient and represents the amount of fluid filtered for each unit of pressure in a minute. P is the hydrostatic pres­sure in the capillaries, Пвс the osmotic pressure exerted by the protein in the capsular fluid. PBC is the pressure within the Bowman's capsule and Попс the oncotic pressure of the plasma. The net filtration pressure (Pf) is the result of the forces tending to force fluid from the glomeru­lus minus those opposing filtration:

so that

Measurements made in a strain of rats that have very superficial glomeruli show that the capillary pressure is about 6 kPa (about 45 mmHg)—somewhat higher than that of the capillaries of other internal organs where average capillary pressures range from 1.3 to 4 kPa. The pressure within Bowman's capsule has been measured at 1.3 kPa (about 10 mmHg ) and the oncotic pressure in normal plasma is about

  1. kPa (25 mmHg) as the blood enters the afferent arteriole and about 4.7 kPa (35 mm Hg) as it leaves the glomerulus via the efferent
    arteriole. The osmotic pressure attributable to the proteins in Bowman's capsule is negligible in normal subjects. Thus the net filtration pres­
    sure at the afferent end of the glomerular capillaries (i.e. the pressure forcing fluid from the giomerular capillaries) is (6 + 0) — (3.3 + 1.3) =

  1. kPa (c. 10 mmHg ). As the blood traverses the glomerular capillaries the net filtration pressure declines as the oncotic pressure rises. By
    the time the blood leaves the glomerulus the net filtration pressure is much less as the forces tending to drive fluid from the blood into the
    capsular space are opposed by the rise in oncotic pressure. If the oncotic pressure rises to 4.7 kPa, the forces tending to force fluid from the
    capillaries will be balanced by those opposing filtration ((6 + 0) - (4.7 + 1.3) = 0 kPa).

As the GFR in humans is about 125 ml min"1 (see p. 369), K{has a value of about 100 ml min~' kPa~' (or 12.5 ml min~' mmHg"1). This is nearly a thousand times greater than the permeability of those vascular beds that do not have fenestrated capillaries.

^ 17.5 Tubular absorption and secretion 369

The concept of clearance helps to clarify

how the kidney handles different


Measurement of the GFR is important to an understanding of renal physiology but it cannot be measured directly. It can, however, be estimated by measuring the rate of excretion of sub­stances that are freely filtered but are then neither absorbed nor secreted by the renal tubules.

The rate at which a substance is excreted is simply its con­centration in the urine (Uc) multiplied by the amount of urine produced per minute (V) so:

rate of excretion = Uc X Vmg min"1

The rate of excretion of a substance must also depend upon its concentration in the plasma (Pc) and the ratio of the rate of excretion to the plasma concentration represents the minimum volume of plasma from which the kidneys could have obtained the excreted amount. This volume is called the clearance {C) and is expressed in milliliters per minute. Thus:

r C =

ml mm

  1. The nephron regulates the internal environment by first filtering the
    plasma and then reabsorbing substances from, or secreting substances
    into, the tubular fluid.

  2. The barrier that restricts the passage of fluid from the giomerular
    capillaries into Bowman's capsule consists of the capillary endothehal
    cells; a basement membrane, which consists of negatively charged
    glycoproteins; and the podocytes of the epithelial cells of the capsular
    membrane. These components prevent the passage of large molecular
    weight substances while allowing the free filtration of substances
    with a low molecular weight.

  3. The amount of fluid passing into Bowman's capsule is governed by
    the net filtration pressure which is determined by the balance of
    hydrodynamic forces acting on the glomerular capillaries. The sum of
    the opposing pressures is called the net filtration pressure. The rate at
    which the kidneys form the ultrafiltrate is known as the glomerular
    filtration rate or GFR and has units of milliliters per minute.

  4. Renal clearance is defined as the volume of plasma completely cleared
    of a given substance in one minute. The clearance of a substance that
    is freely filtered but is neither secreted nor reabsorbed by the tubular
    cells gives a measure of the glomerular filtration rate or GFR. Inulin
    or creatinine are commonly used to estimate the GFR.

  5. It a substance has a clearance smaller than the GFR, either the
    kidneys must reabsorb it (e.g. glucose) or it is not freely filtered (e.g.
    proteins). If a substance has a clearance larger than the GFR, it must
    be secreted by the kidneys.

Renal clearance can therefore be defined as the volume of plasma completely cleared of a given substance in 1 minute. It is a theoretical concept and represents the ideal situation; for most substances, due to the limitations of the tubular transport processes, a larger volume of plasma is incompletely cleared.

Inulin clearance can be used to measure the glomerular filtration rate

To estimate the GFR it is necessary to measure the clearance of a substance that is freely filtered but is neither secreted nor reabsorbed by the tubular cells. In addition, such a substance should have no influence on any physiological function that may alter renal function, such as blood pressure or blood flow. These criteria are met by the plant polysaccharide inulin (molecular mass 5200 Da) which is excreted by the kidneys in direct pro­portion to its plasma concentration over a very wide range (see Fig. 17.10a). The GFR measured by the inulin clearance is about 120-130 ml min^1 for adult men and about 10 per cent less than this for women of similar size.

Despite its advantages, the use of inulin is not very conve­nient for clinical purposes as a steady infusion needs to be main­tained for accurate measurement. For this reason it is desirable to use a naturally occurring substance. Creatinine, a metabolite of creatine, is eliminated chiefly by filtration, with a small com­ponent (about 10 per cent) due to tubular secretion. Creatinine clearance is therefore often used to measure GFR in clinical practice.

^ 17.5 Tubular absorption and secretion

As explained earlier, urine production by the kidney occurs via three processes (Fig. 17.9). The plasma is first filtered and then substances are either removed from the filtrate by reabsorption or added to it by secretion. Reabsorption is defined as movement of a substance from the tubular fluid to the blood and this process occurs either via the tubular cells—the transcellular route—or between rhe cells—the paracellular route.

Tubular secretion is defined as movement of a substance from the blood into the tubular fluid. It may occur as a result of primary or secondary active transport of solutes by the tubular cells (trans-cellular movement) or it may occur via the paracellular route as a result of concentration or electrical gradients that favor movement into the tubular fluid.

How is it possible to tell whether a substance is secreted or reabsorbed by the renal tubules? When a substance is simply filtered and excreted unchanged, the amount excreted is directly pro­portional to the plasma concentration (see Fig. 17.10a). The amount excreted represents the filtered load. If it is reabsorbed, the amount excrered will be less than the filtered load (see Fig. 17.10b) and if filtration is followed by tubular secretion the amount appearing in the urine will be greater than the filtered load (see Fig. 17.10c). The detailed cellular mechanisms by which substances are absorbed or secreted will be discussed later.

As discussed in Box 17.3, the difference between the filtered load and the amount excreted by the kidney is the amount that


17 The kidney and the regulation of the internal environment

Fig. 17.9 The main processes that lead to the formation of urine by the nephron. Fluid is forced out from the plasma by pressure and passes along the nephron where it is reabsorbed either through the cells that line the nephron (the transcellular pathway) or via the tight junctions (the paracellular pathway). Some substances are secreted into the lumen by the cells that line the tubules while other substances pass into the tubules via the tight junctions. Both secretion and reabsorption may occur by either passive or active transport.

has either been reabsorbed or secreted. Thus, if a substance has a clearance less than that of inulin, the tubular cells must have a mechanism for reabsorbing it. For example, glucose and ammo acids are freely filtered but healthy people have virtually no glucose or free amino acids in their urine so there must be tubular mechanisms for the reabsorption of these substances. Conversely, if a substance has a clearance greater than that of inulin, the tubules must have a capacity for secreting that sub­stance from the blood into the tubular fluid. For example, as much as 70 per cent of the dye phenol red is removed from the blood in a single pass through the kidneys. Since 75 per cent is bound to plasma proteins only 5 per cent of the dye could have appeared in the urine as a result of filtration. The remainder must have been secreted into the tubule.

Where polar substances are reabsorbed or secreted via the transcellular route (e.g. glucose) a carrier molecule is required to permit their movement across the plasma membrane. Since there are a limited number of carriers on the luminal membrane, the clearance of a substance that is transported by the tubule depends upon the total amount presented to the tubule in a given period of time. The amount of solute delivered to the tubule per minute that just saturates its transport process is called the transfer or transport maximum (Tm).

The concentration dependence of glucose clearance provides a clear example of the Tm concept as applied to tubular transport. If glucose is infused into the blood, the plasma concentration rises above its normal level of about 4.5 mM but no glucose appears in the urine until the plasma concentration exceeds 10—12 mM. This value is known as the renal threshold. Above the renal threshold the amount of glucose appearing in the urine increases slowly at first, then, as the transport process responsible for glucose reabsorption becomes fully saturated (above about

Box 17.3 Calculating the amount of a substance transported by the renal tubules

The difference between the filtered load and the amount excreted by the kidneys is the amount of a substance that has been reabsorbed or secreted by the tubules and it may be simply calculated using the following relationship:

Ts = US.V - GFR X Ps (mg mm-1)

where Ts is the amount of substance (e.g. glucose) transported, GFR is the glomerular filtration rate, Ps and Us are the plasma and urine concentrations (mg ml"1), and V the urine flow rate. When Ts is negative, the substance has been reabsorbed; when Ts is positive, the substance has been secreted into the tubular fluid. Consider the data relating to the excretion of phosphate and PAH summarized in the following table:

Phosphate PAH Units

Plasma concentration (P) 0.9 0.05 mg mh1 Urine concentration ДО) 30 25 mg ml"1 Urine flow rate (V) 1.0 1.0 ml mkr1 Inulin clearance (GFR) 100 100 ml min'-1

The amount of phosphate transported is: (30 x 1) — {0.9 x 100) = —60 mg min1. So the amount of phosphate excreted is 60 mg min"1 less than the filtered load. This difference represents the phosphate that has been reabsorbed by the tubules. For PAH, the amount transported is: (25 X 1) - (0.05 X 100) = 20 mg min"1.

In this case 20 mg min"1 more PAH appears in the urine than can be accounted for by simple filtration. Thus it must have been secreted by the tubules.

17.5 Tubular absorption end secretion


17 mM), the increase in urinary glucose is proportional to the increase in the plasma concentration.

Assuming that the GFR has remained constant at 120 ml min"1, an increase in plasma glucose above 17 mM exceeds the capacity of the tubules to reabsorb glucose. In this situation, the amount of glucose being delivered to the tubule would be:

17 X 1CH X 120 = 2.04 mmole min"1 or 367 mg of glucose a minute.

This represents the transport maximum for glucose (Tmg). The Tm varies with body size and tends to be lower in women than in men of the same size. Plasma glucose levels significantly greater than the renal threshold often occur in patients with inadequately controlled diabetes mellitus (see Section 27.6) and the appearance of glucose in the urine is known as glycosuria. Glycosuria is accompanied by an increase in urine production known as an osmotic diuresis.

The difference between the filtered load of glucose and the amount excreted by the kidneys is the amount of glucose that has been reabsorbed (Box 17.3). The line relating the amount of glucose absorption to the plasma concentration is curved at its upper end (Fig. 17.10b). This curvature is known as splay. Differences in the transport capacity of different nephrons may

Fig. 17.10 The relationship between the plasma concentration and the amount excreted in the urine: (a) for substances that are subject only to filtration; (b) filtration followed by reabsorption; and (c) filtration plus secretion, (a) The amount of inulin excreted plotted as a function of the plasma inulin concentration. The amount excreted is the urine concentration times the urine flow rate (U X V) and the slope of the line is the clearance (C) which is 120 ml min"1 in this case. Note that the amount of inulin excreted is directly proportional to the plasma concentration, (b) The quantities of glucose reabsorbed and excreted plotted as a function of the plasma concentration. The blue line shows that glucose appears in the urine when the plasma concentration exceeds about 12 mmoles I"1. This is known as the renal threshold for glucose. Above about 18 mmoles I"1 the extra amount of glucose excreted is directly proportional to the plasma concentration. The red line shows the filtered load in mmoles per minute and this is calculated from the GFR (here taken as 120 ml min"1) and the plasma concentration. The green line indicates the amount of glucose reabsorbed by the tubules, which is the difference between the filtered load and the amount excreted. Reabsorption reaches a maximum when the glucose load exceeds 2 mmoles (360 mg) a minute. This is the transport maximum for glucose, or Tmg. (c) The amount of PAH excreted plotted as a function of the plasma concentration. The blue line indicates the amount excreted (in mg min"1) while the filtered load is indicated by the green line. The amount secreted by the tubules (indicated by the red line) is given by the difference between the filtered load and the amount excreted. Tubular secretion of PAH reaches a maximum when the plasma concentration is about 18 mg dl"1 and the TmPAH is about 80 mg min"1.

account partly for the splay but it is also a feature of carrier-mediated transport.

As discussed earlier, tubular secretion (movement of a sub­stance from the blood to the tubulat lumen) may be either active


17 The kidney and the regulation of the internal environment

or passive. Active tubular secretion occurs by carrier-mediated processes analogous to those discussed above for glucose reabsorption but operating in the opposite direction. It is known that many organic substances are secreted by the tubules, includ­ing para-aminohippurate (PAH), penicillin, and other organic anions and cations. The relationships between nitration, secretion, and excretion of PAH are illustrated in Fig. 17.10c.

To summarize, if a substance has a clearance less than inuiin, the tubular cells must reabsorb it or there must be a barrier to its filtration (or both). As discussed above, the cut-off for free filtration depends both on the charge of the molecule and its molecular weight. Conversely, if a substance has a clearance greater than that of inuiin, the tubular cells must secrete it.

The clearance of PAH can be used to estimate renal plasma flow

Analysis of arterial blood and of blood taken from the renal vein shows that some substances, such as PAH, are almost totally removed from the plasma in a single passage through the kidney by filtration and secretion. This property is exploited to estimate the renal plasma flow (RPF) in a noninvasive way using the Fick principle (Chapter 15).

Amount appearing in urine per minute . _,

Arteriovenous difference for PAH

Since we can readily measure urine flow rate and urinary con­centration, the amount of PAH excreted per unit time can be calculated. The PAH content in a sample of venous blood taken from a peripheral vein can be measured and will be the same as that of arterial plasma. If we neglect the small amount of PAH in the venous blood leaving the kidney, the clearance of PAH can be calculated and provides a good estimate of total RPF (i.e. the total for both kidneys). It should be noted, however, that this way of estimating renal plasma flow is reliable only while the tubular transport mechanism is not saturated—a situation that generally applies only when the plasma concentration is low (the Tm for PAH is about 80 mg min4; see Box 17.4).

From estimates of GFR and renal plasma flow we can deter­mine the proportion of plasma filtered. This is called the filtra­tion fraction. If the GFR is 125 ml min4 and renal plasma flow is 625 ml min4 the filtration fraction is 125/625 or 20 per cent.

The GFR is regulated by

glomerulo-tubular feedback; this

regulation may be overridden by

sympathetic nerve activity

For efficient operation of the kidney the GFR must be well matched to the transport capacity of the tubules. Too small a GFR and the kidneys may be unable to regulate the internal environment, too large a GFR and the transport capacity for ammo acids, glucose, and ions will be exceeded. Changes in the

^ 17,4 The use of inuiin and PAH clearance to estimate GFR and renal plasma flow

Two experiments were performed on the same subject to determine GFR and renal plasma flow. Experiment 1:



Plasma (mg ml"1) Urine (mg ml"1) Urine flow rate (ml

mm l)

0.25 12.5 2.5

0.08 20.0 2.5

Experiment 2:



Plasma (mg nil4) Urine (mg ml"1) Urine flow rate (mi


0.24 6 5.0


25.0 5.0

Calculating the clearances for inuiin and PAH:

Experiment 1:

Inuiin clearance = (12.5 X 2.5)/0.25 = 125 ml min4

PAH clearance = (20.0 X 2.5)/0.08 = 625 ml min4

Experiment 2:

Inuiin clearance = (6.0 x 5.0)/0.24 = 125 ml miff-1

PAH clearance = (25.0 X 5.0)/0.36 = 347 ml min4

In experiment 1 normal values are obtained for GFR (inuiin clearance) and renal plasma flow (PAH clearance, see text) but in experiment 2 the GFR is normal but apparent renal plasma flow is 60 per cent of normal. Obviously the assumption that PAH clearance is a measure of renal plasma flow must be questioned. Inspection of the data shows plasma PAH to be nearly five times higher in experiment 2 than in experiment 1. Here is the clue to the problem.

The amount of PAH delivered to the kidneys is 50 mg min4 in experiment 1 and 225 mg min4 in experiment 2. In experiment 1 all of this is excreted but in experiment 2 only 125 mg min4 is excreted. Of this 45 mg min4 are filtered. The difference is a measure of the total transport capacity—in this case 80 mg min4. The amount of solute delivered to the tubule that just saturates the transport process is called the transport maximum orTm.

GFR will markedly alter the filtered load of sodium in par­ticular. Under normal conditions the filtered load of sodium is about 25 200 mmoles day"1 (daily 180 lirers of plasma are filtered and plasma sodium is approximately 140 mmoles I"1). Less than 1 per cent of this is normally excreted and sodium

^ 17.5 Tubular absorption and secretion
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