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Structure and function of the kidney 

Structure and function of the kidney
Chapter:
Structure and function of the kidney
Author(s):

A.O. Phillips

and Steve Riley

DOI:
10.1093/med/9780199204854.003.2101_update_001

Update:

Kidney and mineral bone disease—additional information on the role of the kidney in the homeostatic process of calcium metabolism and the recognition of FGF-23 as a contributor to this feedback mechanism.

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Essentials

The kidney is responsible for control of water, electrolyte (particularly sodium and potassium), and acid–base balance and for excretion of metabolic wastes, and it has important functions as an endocrine organ, including key roles in renin, vitamin D, and erythropoietin production or metabolism.

The nephron—beginning at the glomerulus, the functional unit of the kidney is the nephron, through which glomerular filtrate passes to be finally excreted as urine. The nephron is divided into anatomically and functionally distinct sections that work together to maintain homeostasis.

Renal function—in simple terms, in an adult human under no particular physiological or pathophysiological stress, about 100 ml of glomerular filtrate is generated from plasma each minute, 99 ml of which is reabsorbed, leaving a urinary volume of 1 ml/min. Metabolic wastes within the plasma (e.g. urea and creatinine) are not reabsorbed (or only some fraction of them), hence they are concentrated in the urine, and some wastes are also secreted into the urine by the renal tubules. The bulk of sodium and water is reabsorbed in the proximal tubules, as are other small molecules that the body retains (e.g. glucose and amino acids), with fine-tuning of sodium and water excretion effected in the distal part of the nephron under the influences of aldosterone and ADH, respectively.

Introduction

The kidney is engaged in many tasks, including control of water, electrolyte (particularly sodium and potassium), and acid–base balance and excretion of metabolic wastes, and it has important functions as an endocrine organ, including key roles in renin, vitamin D, and erythropoietin production or metabolism. Most recently its role in the production of key growth factors during development has been highlighted.

The kidney is formed by the fusion of a number of lobes. In coronal section, the outer rim of the kidney (cortex) containing all the glomeruli and convoluted tubules can easily be distinguished from the pyramidal shaped medulla containing the loops of Henle and the collecting ducts that project into the renal pelvis as the papillae.

The nephron

The functional unit of the kidney is the nephron, which begins at the glomerulus (Fig. 21.1.1). The urinary space (the cavity between the glomerulus and its surrounding Bowman’s capsule) leads into the proximal tubule, which itself can be subdivided into a convoluted segment and a straight segment. The straight segment of the proximal tubule descends into the medulla and changes abruptly into the descending limb of loop of Henle. This loop penetrates for varying distances into the medulla before returning to the cortex. The longer loops pass all the way into the inner medulla, while the short loops only reach the outer medulla. Generally speaking, long loops belong to nephrons of glomeruli lying adjacent to the medullary region, while the shorter loops belong to the more superficial glomeruli. The descending limb of loop of Henle bends sharply back at its lowest point to form the ascending limb, which at another abrupt transition forms the medullary part of the thick ascending limb. This leads up into the cortex where it becomes convoluted and comes into close contact with the vascular pole of its own glomerulus, forming the juxtaglomerular apparatus. Further along the nephron, the thick ascending limb becomes the distal convoluted tubule and then the connecting tubule, which joins the cortical collecting duct. Each collecting duct receives connecting tubules from about a dozen nephrons and then opens onto the surface of a papilla.

Fig. 21.1.1 The nephron and its blood supply.

Fig. 21.1.1
The nephron and its blood supply.

Williams JD, et al. Clinical atlas of the kidney. Gower Publishing, London.

The renal blood supply

Structure

The renal artery divides into the interlobar arteries and enters the renal substance at the columns of Bertin (the area between adjacent lobes). At the junction of the cortex and medulla, the arteries divide again and form the arcuate arteries (Fig. 21.1.1). Each arcuate artery gives rise to cortical radial arteries that ascend through the cortex: there is no direct arterial supply to the medulla. The afferent glomerular arteries arise from the cortical radial arteries and directly supply the glomeruli. Efferent glomerular arteries drain the glomeruli and then supply the peritubular capillaries of the cortex and medulla, a unique arrangement meaning that the peritubular capillary supply is exclusively postglomerular. Efferent glomerular arteries can be divided into two types: those from the superficial and midcortical glomeruli supply the capillary plexus of the cortex and those from juxtamedullary glomeruli form the blood supply to the renal medulla. Within the outer stripe, they divide into the descending vasa recta, which penetrate the inner stripe in vascular bundles. The renal medulla is drained by the ascending vasa recta, which traverse the inner stripe within the vascular bundle and then join the cortical radial veins. The vascular bundles of the medulla represent the vascular component of the countercurrent exchange mechanism between the blood entering and leaving the medulla. Interestingly, the vascular bundles are organized such that the perfusion of the inner medulla is kept totally separate from the perfusion of the outer medulla. The cortical radial veins join the arcuate veins to eventually form the interlobular veins, which run alongside corresponding arteries.

Function

Renal blood flow is influenced by intrarenal and extrarenal factors. Autoregulation within the kidney maintains a relatively stable blood flow to the glomerulus over a range of arterial pressure. This phenomenon seems to be mediated by events intrinsic to the kidney since it has been demonstrated in both denervated and isolated kidney preparations.

The glomerulus

Structure

On entering the glomerulus (Fig. 21.1.2a), the afferent arteriole divides into primary capillary branches, each of which gives rise to an anastomosing capillary network that forms a glomerular lobule. These capillaries then coalesce into the efferent arteriole within the tuft. The structural organization of the capillaries is unlike that found in any other part of the body, with the capillary basement membrane (glomerular basement membrane) forming the barrier across which filtrate is generated. Embryologically, the glomerulus is the interface between the ureteric bud (or hollow nephrogenic vesicle) and the metanephrogenic cap, which develops into the capillary plexus. The result of this is a basement membrane formed by the fusion of the basement membrane of the capillaries and the basement membrane of the nephrogenic vesicle. This glomerular basement membrane forms the skeletal framework of the glomerular tuft.

Fig. 21.1.2 The glomerulus: (a) structure; and (b) regulation of glomerular blood flow by vasoactive agents.

Fig. 21.1.2
The glomerulus: (a) structure; and (b) regulation of glomerular blood flow by vasoactive agents.

Although on electron microscopy the glomerular basement membrane appears as a three-layer structure with a central lamina densa and outer lamina rara interna and externa, this is probably an artefact. Freeze–fracture studies have suggested uniformity in the basement membrane from its outer to inner aspects. The major components of the membrane include a framework of type IV collagen linked by heparan sulphate proteoglycans and laminin, the basement membrane charge being provided by the heparan sulphate component (subtypes of which include perlican and agrican). Type IV collagen consists of a triple helix of fibres with a large noncollagenous globular domain at the C-terminal end (called NC1). This NC1 domain of the collagen molecule is the target for Goodpasture’s disease, and mutations of the collagen chains are responsible for Alport’s syndrome.

The endothelial cells, the basement membrane, and the podocytes form the filtration barrier. The endothelial cells are fenestrated (60 and 100 nm in diameter) and the lack of a diaphragm across the fenestrations exposes the basement membrane directly to the glomerular capillary contents. The luminal surface of the endothelial cells is negatively charged by polyanionic glycoproteins, but these are not present on the fenestrae. The capillary loops are incomplete (a tube of fenestrated endothelial cells surrounded only on its epithelial aspect by a basement membrane) and are held together on their inner aspect by the mesangial cells. Thus the basement membrane has an opening on its mesangial aspect so that the endothelial cells are in direct contact with the mesangium. At the vascular pole of the glomerulus the capillary basement membrane is reflected to form the parietal epithelium of Bowman’s capsule.

The outer aspect of the filtration barrier is provided by the epithelial cells (podocytes), which interdigitate on the surface of the glomerular lobules. The foot processes of adjacent podocytes are separated by the filtration slits, which are bridged by the slit diaphragms and are the sites through which the glomerular filtrate passes. The pores have a central proteinaceous core with side arms linking to each adjacent cell, forming a structure with a zipper-like appearance and a width of about 40 nm. The luminal surface of the podocyte and the slit diaphragm are rich in negative charge, being covered in glycoproteins. The podocyte surface adjacent to the basement membrane expresses a number of adhesion proteins that ensure firm anchorage to the membrane.

The mesangium forms the pillar to which the glomerular basement membrane scaffold is attached. The interaction between the mesangial cells and the basement membrane provides the mechanism for the contractility of the glomerular tuft, and the means whereby the surface area of the tuft can be varied. The spaces between the mesangial cells are filled by the mesangial matrix that consists of a number of different collagens, as well as glycoproteins, fibronectin, and proteoglycans. This mesangial matrix provides a channel for the migration of a variety of molecules from the glomerular capillaries, with trafficking centrally towards the vascular pole of the glomerulus.

Function

The glomerular filtration barrier, consisting of the endothelial pores, the glomerular basement membrane, and slit diaphragms, will exclude molecules on the basis of size, shape, and charge. Size selectivity is imparted by the matrix of the glomerular basement membrane itself, as well as by the integrity of the podocytes. The matrix, formed by the type IV collagen molecules, consists of a series of interlinking pores, the narrowest of which determines the size of molecules that can pass through. Thus any pathological change to the structure of the matrix is likely to result in a greater permeability of the glomerular basement membrane. The resistance to the movement of water and small molecules is provided by the endothelial pores, the basement membrane, and the available surface area of the slit diaphragms, with the last of these probably being the effective barrier. The charge barrier, whose efficiency is disputed, is provided by the negative charge of the basement membrane and to a lesser extent by the surface of the endothelial and epithelial cells.

The effectiveness of the filtration barrier is dependent not only on the integrity of the basement membrane but also on the function of the epithelial cells. Most studies have demonstrated that changes in barrier function are closely correlated with significant alteration to the podocytes. These include changes in the surface area of the slit diaphragm (slit diaphragm frequency) as well as detachment of podocytes from the basement membrane. There is now a large body of evidence to suggest that heparan sulphate proteoglycans are involved in both the charge- and size-selective properties of the glomerular basement membrane and, furthermore, that alterations in glomerular basement membrane heparan sulphate proteoglycans may be important in the development of proteinuria.

Production of glomerular filtrate

The number of functioning glomeruli and the filtration rate at each single glomerulus determine the glomerular filtration rate (GFR). There are approximately a million glomeruli per human kidney, of which 90% are in the outer two-thirds of the cortex and fairly homogeneous in terms of structure and function. The remaining 10%, which are located in the juxtamedullary region, are larger, with a higher single-nephron GFR (SNGFR) compared with cortical glomeruli.

SNGFR is determined by a number of factors. First, the pressure of blood in the glomerular capillary and the hydrostatic pressure of the fluid in Bowman’s space determine the pressure difference that drives the movement of fluid across the glomerular capillary wall, the transglomerular hydrostatic pressure difference or Δ‎P. Second, the gradient in colloid osmotic pressure, also known as the oncotic pressure (Δπ‎), across the filtration barrier: this is equal to the colloid osmotic pressure within the glomerular capillary less the colloid osmotic pressure in Bowman’s space (which, in effect, is zero). The difference between Δ‎P and Δπ‎ is the net ultrafiltration pressure. Other determining factors are water permeability (K) and f (the area available for filtration, namely the surface area of the slit pores between podocytes), these two being combined as the glomerular filtration coefficient or ultrafiltration coefficient (Kf ). Hence:

SNGFR=(ΔPΔπ)×Kf

SNGFR can be regulated by alterations in the ultrafiltration coefficient Kf, the net ultrafiltration pressure, or both. A change in the net ultrafiltration pressure may arise owing to a change in the hydraulic pressure Δ‎P, the capillary plasma oncotic pressure Δπ‎, and/or the initial glomerular capillary plasma flow rate (which dictates changes in protein concentration with distance along a capillary network and hence affects colloid osmotic pressure).

Glomeruli contain receptors for a number of hormones that are capable of modifying the GFR (see Fig. 21.1.2b). These include vasoconstrictors such as adenosine, angiotensin II, and endothelin, as well as vasodilators such as dopamine, bradykinin, prostacyclin, and nitric oxide. Some of these vasoactive molecules are produced within the kidney, whereas others are delivered by the systemic circulation, and many studies have examined the effects of hormones on glomerular ultrafiltration. It is clear from the preceding discussion that, in addition to Δ‎P (i.e. change in hydraulic pressure), the GFR is dependent on the capillary plasma flow rate and the ultrafiltration coefficient (Kf ), all of which may be altered by hormones. Vasoconstrictor substances such as angiotensin II and noradrenaline are capable of producing substantial reductions in renal plasma flow, generally with little change in GFR. Angiotensin II, for example, causes constriction of both afferent and efferent arterioles, with a resultant decrease in capillary plasma flow and a reduction in Kf, but little change in the SNGFR due to an increase in Δ‎P. Increased afferent arterial tone caused by endothelin or adenosine will decrease renal blood flow, decrease Δ‎P, and therefore decrease GFR. By contrast, dilatation of the afferent arteriole by nitric oxide or prostaglandins will also cause an increase in Δ‎P, but with an increase in renal blood flow and hence an increase in GFR.

In the normal adult human, water is filtered by the glomerulus at a rate of 80 to 200 ml/min. The GFR is critically related to all functions of the kidney and is closely regulated by mechanisms that maintain a constant high value for GFR. In practical clinical terms, the estimation of GFR is achieved by measuring the serum creatinine and employing an algorithm that allows for the age and sex of the patient (eGFR), or by estimating the renal clearance of a substance that is freely filtered at the glomerulus and not absorbed or secreted by the renal tubules. For a discussion of the methods of measuring GFR in clinical practice, see Chapter 21.4.

The proximal convoluted tubule

Structure

The main function of the proximal tubule is to reabsorb the bulk of filtered water and solutes, and its structure shows numerous adaptations for this purpose. Proximal tubular epithelial cells are tall and columnar with a well-developed brush border, resulting in a 40-fold increase in the apical surface area of the cells (Fig. 21.1.3). In addition, they possess extensive basolateral interdigitation, increasing the basolateral cell surface area. The apices of the cells are held together by junctional complexes: these are called ‘tight junctions’ (zona occludens), of the leaky variety, with a low electrical resistance that allows some transepithelial transport. The bases of the cells rest on the tubular basement membrane, which separates them from the peritubular capillaries. Another characteristic feature is the presence of large numbers of mitochondria, intimately associated with the basolateral cell membranes where the Na+,K+-ATPase is located, and whose function is to provide the energy source for fluid and electrolyte reabsorption.

Fig. 21.1.3 Proximal tubular cell function. Principal transport processes of the proximal tubular cell.

Fig. 21.1.3
Proximal tubular cell function. Principal transport processes of the proximal tubular cell.

Function

Sodium and water reabsorption

About seven-eighths of the volume of the glomerular filtrate is reabsorbed in the proximal tubule. Sodium enters the proximal tubular cells passively from the tubular fluid down an electrochemical gradient that is the driving force for fluid and electrolyte reabsorption. This gradient is produced by the action of the Na+,K+-ATPase on the basal surface, which transports sodium out of the cell in excess of the potassium transported into the cell, thereby generating a transmembrane potential of −70 mV. Chloride ions follow the same route by cotransport with Na+, and the resulting increase in osmolality in the intercellular spaces results in the absorption of water by osmosis, such that the volume of the filtrate in the renal tubule is substantially reduced by the time it reaches the beginning of the loop of Henle, although its net osmolality does not change. In addition to this transcellular route for the transport of salt and water, there is also a paracellular route through the ‘leaky’ tight junctions.

Reabsorption of other substances

The proximal tubule is also responsible for the reabsorption of other substances such as glucose, phosphate, amino acids, and organic anions, including citrate and lactate. These enter the proximal tubular cells across the apical membrane by a series of cotransport systems, each of which binds one or more sodium ions and its specific substrate, and carries them across the cell membrane (Fig. 21.1.3). Thus, the rate of sodium entry into the cell is linked by cotransport systems to the reabsorption of these substances.

The energy for secondary active transport or cotransport of substances (glucose, phosphate, etc.) against their concentration gradient is therefore provided indirectly by Na+,K+-ATPase, which is responsible for the concentration gradient for sodium across the cell membrane. This is illustrated by the reabsorption of glucose, which involves brush-border, Na+-coupled glucose transporters, termed SGLT, and basolateral facilitated glucose transporters (GLUT). In the human, the main site for glucose reabsorption is the early S1 segment of the proximal tubule, where 90% of the filtered glucose is reabsorbed, such that only a small fraction of the filtered load reaches the S2 and S3 segments. Glucose reabsorption in the S1 proximal tubular segment is mediated by a low-affinity, high-capacity, Na+/glucose cotransporter, SLGT2, and reabsorption in the later segments is mediated by a high-affinity, low-capacity SGLT1. Similarly, the high rate of glucose efflux characteristic of the early proximal tubular segment is mediated by the low-affinity, facultative glucose transporter GLUT2 and high-affinity GLUT1, whereas only GLUT1 is produced in the late proximal tubule where a minor portion of the filtered glucose load is reabsorbed.

The kidneys are also involved in maintenance of the acid–base balance of the body by regulating the serum bicarbonate concentration to approximately 24 mmol/litre. The proximal tubule reabsorbs between 80 and 90% of the filtered bicarbonate, largely by the following mechanism. H+ is secreted by the Na+/H+-exchanger on the luminal membrane. It then reacts with the filtered HCO3 to form H2CO3, which is converted to CO2 and H2O catalysed by carbonic anhydrase present on the luminal brush-border membrane. H2O diffuses passively into the cell where it is split to yield the H+ that is secreted and OH, and the hydroxyl ion then reacts with CO2 (catalysed by carbonic anhydrase) to yield HCO3, which exits the cell via a Na/HCO3 synporter, thus restoring filtered HCO3 to the plasma.

Structure and function of the kidneyThe kidney has a key role in the homeostatic mechanisms that maintain calcium and phosphate balance in health. Inactive vitamin D (25-hydroxyvitamin D2) that has been produced in the skin and hydroxylated in the liver is filtered at the glomerulus attached to vitamin D binding protein. This vitamin–protein complex is reabsorbed via receptor-mediated endocytosis by the proximal tubular cell (and probably cells further down the nephron) where the enzyme 1-α‎-hydroxylase completes the activation of the molecule. The feedback mechanisms that regulate 1-α‎-hydroxylase are complex. Fibroblast growth factor 23 (FGF23), a hormone produced in bone, inhibits the production of activated vitamin D and also acts as phosphaturic agent. This may have a direct bearing on the increased cardiovascular risk associated with declining kidney function

Handling of protein

In addition to its role in fluid and electrolyte balance, almost all the protein that is filtered at the glomerulus is reabsorbed by the proximal tubule via a process of endocytosis. To date, four major routes of tubular handling of peptides have been identified: (1) reabsorption of filtered protein/peptides by endocytosis and intracellular lysosomal degradation, (2) luminal hydrolysis and reabsorption of free amino acids, (3) carrier-mediated reabsorption of small intact peptides, and (4) peritubular uptake of peptides. The most important of these is probably the endocytotic route.

In recent years, there has been considerable interest in the role of proteinuria in the progression of renal disease. Among the hypotheses currently under investigation are those that focus on the effect of excess protein trafficking on the generation of profibrotic factors by proximal tubular cells and the subsequent initiation of interstitial fibrosis. These theories suggest that cells of the proximal tubule play a role in maintaining the normal architecture of the renal interstitium. In support are numerous studies demonstrating that tubular cells are a rich source of many components of the extracellular matrix, which may modify matrix turnover by alterations in the synthesis of both matrix-degrading enzymes and their inhibitors, as well as through the production of cytokines. More recent studies have suggested that cells of the proximal tubule may migrate into the interstitium and transdifferentiate into the cortical fibroblasts during conditions of inflammation.

Interplay between the regulation of GFR and proximal tubular function

One aspect of the control of renal function is the correlation between the volume of filtrate produced by the glomerulus and the reabsorptive capacity of the renal tubule. The movement of sodium and water from the proximal tubular lumen into the capillarynetwork depends on the hydrostatic pressure of the blood in the peritubular capillary complex, as well as the osmotic pressure of the blood within those capillaries. An increased hydrostatic pressure will reduce reabsorption, but an increased oncotic pressure will enhance reabsorption. Thus, increased systemic blood pressure will increase the pressure within the interstitium and result in the movement of sodium from the interstitial fluid into the lumen (pressure natriuresis).

The loop of Henle

The loop of Henle begins where the straight (S3) part of the proximal tubule changes abruptly in diameter to become the descending thin limb. Long loops pass into the inner medulla, before performing a hairpin bend and returning as the thin ascending limb, when an abrupt transition at the inner stripe of the outer medulla marks the beginning of the thick ascending limb, which is structurally distinct from its thin counterpart. In the case of the short loops, the transition to ascending thick limb takes place before the bend, so that the thick part of the tubule forms the loop.

Although there are only minor structural differences between the thin segments of descending and ascending limbs, there are major differences in their permeability properties. The thin descending limb, like the proximal tubule, is highly permeable to water as a result of the presence of aquaporin 1, whereas the thin ascending limb is impermeable to water. By contrast, the descending limb is impermeable to sodium, whereas significant sodium and urea reabsorption occurs in the thin ascending limb. This allows an osmotic gradient to be established in the medulla, which is the basis of the countercurrent multiplier mechanism (Fig. 21.1.4).

Fig. 21.1.4 Diagram to illustrate the mechanism of concentration of the urine. The darkened part of the nephron is impermeable to water. 1, Active transport of Na+ and Cl− into the insterstitium; 2, reabsorption of Na+ and Cl−; passive absorption of water under ADH control; 3, increased concentration of urea in tubule following reabsorption of water; 4, urea passes into the interstitium, thereby increasing osmolality; 5, the increased interstitial osmolality results in more water being extracted; 6, this leads to an increased salt concentration in the loop of Henle; 7, in the ascending limb, salt diffuses into the interstitium, further increasing its osmolality; 8, in the presence of ADH, the permeability of the distal nephron and collecting ducts is increased and water is reabsorbed; 9, water is removed from the interstitium by vasa recta.

Fig. 21.1.4
Diagram to illustrate the mechanism of concentration of the urine. The darkened part of the nephron is impermeable to water. 1, Active transport of Na+ and Cl into the insterstitium; 2, reabsorption of Na+ and Cl; passive absorption of water under ADH control; 3, increased concentration of urea in tubule following reabsorption of water; 4, urea passes into the interstitium, thereby increasing osmolality; 5, the increased interstitial osmolality results in more water being extracted; 6, this leads to an increased salt concentration in the loop of Henle; 7, in the ascending limb, salt diffuses into the interstitium, further increasing its osmolality; 8, in the presence of ADH, the permeability of the distal nephron and collecting ducts is increased and water is reabsorbed; 9, water is removed from the interstitium by vasa recta.

Williams JD, et al. Clinical atlas of the kidney. Gower Publishing, London.

The juxtaglomerular apparatus

The juxtaglomerular apparatus comprises the macula densa, the extraglomerular mesangium, the terminal portion of the afferent arteriole with its renin-producing granular cells, and the early portions of the efferent arteriole.

The thick ascending limb of the loop of Henle returns to its own glomerulus, where the cells that lie nearest to the glomerulus become taller to form the macula densa, the most obvious structural feature being that these cells are tightly packed and have large nuclei. The basal aspect of the macula densa is firmly attached to the extraglomerular mesangium.

The granular cells (also termed the juxtaglomerular cells) are assembled in clusters within the terminal portion of the afferent arteriole. These are modified smooth muscle cells containing cytoplasmic granules in which renin is stored. This enzyme is responsible for controlling the synthesis of angiotensin II by converting angiotensinogen to angiotensin I, which is in turn converted to angiotensin II by the action of the angiotensin-converting enzyme.

Granular cells appose the extraglomerular mesangial cells, adjacent smooth muscle cells, and endothelial cells, and are densely innervated by sympathetic nerve terminals. The secretion of renin by the granular cells is controlled by signals generated intrarenally (such as perfusion pressure and tubular fluid composition) and extrarenally, owing to changes in sympathetic output and by stimuli that decrease the extracellular fluid volume and blood pressure. Many factors may therefore be involved in the control of renin release, a particularly important one of these being an intrarenal baroreceptor mechanism that causes renin secretion to increase when the intrarenal arteriolar pressure at the granular cells is decreased. A major level of control also lies in the macula densa, where renin secretion is inversely proportional to the concentration of Cl or Na+ in the tubular fluid. Decreased delivery of Na+ and Cl to the macula densa is associated with increased renin secretion. Angiotensin II, by contrast, inhibits renin secretion by its direct action on the granular cells; it is also a major stimulant of aldosterone secretion, thereby stimulating sodium retention (see below), which closes the renin–angiotensin–aldosterone negative-feedback loop. In addition to these factors, increased activity of the sympathetic nervous system increases renin secretion, both by increased circulating catecholamines and by way of the renal sympathetic nerves.

It has been postulated that the intrarenal renin–angiotensin mechanism is the prime hormonal mediator of the tubuloglomerular feedback system, whereby a stimulus perceived at the macula densa, presumably related to luminal flow or ion concentration, influences filtration rate (Fig. 21.1.5). Evidence for this is inconclusive and it is almost certainly not the sole mediator of this feedback mechanism.

Fig. 21.1.5 Tubuloglomerular feedback: (a) anatomical basis; and (b) putative mechanism.

Fig. 21.1.5
Tubuloglomerular feedback: (a) anatomical basis; and (b) putative mechanism.

The distal tubule and collecting duct

The bulk of sodium and water reabsorption occurs in the proximal tubule, but fine regulation is necessary to maintain precise sodium and water balance. The distal tubule and the collecting duct are responsible for the necessary final adjustments that ultimately determine the rate of urinary water and sodium excretion, a mechanism substantially influenced by ADH (also known as vasopressin) and aldosterone, respectively.

Structure

The distal convoluted tubule begins just beyond the macula densa and ends at the cortical collecting duct. Its structure is similar to that of the main part of the thick ascending limb of the loop of Henle. The collecting duct system includes the connecting tubule and the cortical and medullary collecting ducts. The connecting tubule and the collecting ducts, unlike the distal tubule, are lined by two cell types: principal cells, with small basal infoldings, some mitochondria, and small microvilli; and intercalated cells with darkly staining cytoplasm that contains mitochondria, smooth endoplasmic reticulum, and prominent Golgi apparatus. There are at least two types of intercalated cells, distinguished on the basis of immunocytochemical and functional characteristics: type A cells express H+-ATPase at their luminal membrane and secrete H+ ions, whereas type B cells express H+-ATPase at their basolateral membrane and secrete HCO3 ions.

Function

Cells of both the connecting tubule and the collecting duct are sensitive to ADH, but only those of the collecting duct are sensitive to mineralocorticoids. The renal concentrating and diluting processes are ultimately dependent on the ability of ADH to modulate the water permeability of collecting ducts. Regulation of ADH is dependent on osmoreceptors in the hypothalamus, which recognize changes in extracellular fluid osmolality, but release of ADH can be stimulated in the absence of changes in plasma osmolality, e.g. by intravascular volume depletion, pain, and nausea. Once released from the posterior pituitary, ADH exerts its biological action on water excretion by binding to receptors in the basolateral membrane of the collecting duct (Fig. 21.1.6), resulting in increased adenylate cyclase activity, increased cAMP formation, and ultimately insertion of aquaporin 2 channels into the apical (luminal) cell membrane that make it more permeable to water.

The principal cells of the collecting duct are responsible for the modulation of sodium reabsorption. Entry of sodium into these cells occurs down a concentration gradient through specific sodium ion channels in the luminal membrane. This creates a negative potential difference in the lumen, which promotes either the secretion of potassium or the reabsorption of chloride via the paracellular route. These processes, which are the final regulators of sodium balance, are under the control of aldosterone, which increases the number of open sodium ion channels in the luminal membrane (Fig. 21.1.7). As previously discussed, angiotensin II is a major stimulant of aldosterone secretion. Hence activation of the renin–angiotensin system during periods of volume depletion leads to increased aldosterone production and sodium retention, whereas, when volume-replete, the system is suppressed and renin release and aldosterone secretion are reduced, resulting in natriuresis. Although the acute production of aldosterone is linked to the renin–angiotensin system, other mechanisms (including some relating to sodium or potassium balance) can also affect the ability of the adrenal glands to produce aldosterone.

Fig. 21.1.7 The action of aldosterone on the collecting duct. Aldosterone stimulates an increase in the numbers and activity of apical ENaC and ROMK, and of basolateral Na+,K+-ATPase by direct and indirect effects.

Fig. 21.1.7
The action of aldosterone on the collecting duct. Aldosterone stimulates an increase in the numbers and activity of apical ENaC and ROMK, and of basolateral Na+,K+-ATPase by direct and indirect effects.

The intercalated cells of the collecting duct are involved in maintenance of the acid–base balance. The method by which they excrete acid by generating ammonium ions is discussed in Chapter 12.11.

The interstitium

The renal interstitium is the space that is not occupied by the glomeruli and nephrons, and the vasculature of the kidney can be thought of as lying within it. The interstitium amounts to some 5 to 7% of the volume of the cortex, 3 to 4% of the outer stripe, 10% of the inner stripe, and up to 30% of the inner medulla. It is involved in virtually all functions of the healthy kidney, as well as in many pathological events. The transit of molecules from the tubules to the blood necessitates a crossing of the interstitial space, and vice versa, hence changes to the interstitium have a profound effect on the function of the tubules and indeed of the nephron itself.

The cells of the interstitium are not homogeneous but comprise different cell types that vary anatomically within the kidney and between health and disease. The main cellular component is the fibroblast, but there is evidence to suggest that there is a significant difference between the phenotype of the cortical fibroblast and that of the inner medullary fibroblast. Fibroblasts are important for the integrity of the interstitial matrix and are considered to be the source of matrix component production, as well as being responsible for their turnover. The renal fibroblasts also have endocrine functions: those of the cortex are the source of erythropoietin; the inner medullary fibroblasts produce significant amounts of prostaglandins, primarily prostaglandin E2, and have a function in modifying electrolyte transport. Renal fibroblasts may have a pivotal role in renal interstitial fibrosis; it is now well established that the progression of renal disease is intimately linked to the degree of renal interstitial fibrosis, and it is likely that the key cell involved in this is the cortical fibroblast.

Dendritic cells are present in small numbers throughout the interstitium and expressmajor histocompatibility complex (MHC) class II receptors. In addition, there are a few macrophages as well as some large lymphocytes. Dendritic cells, macrophages, and lymphocyte-like cells mostly have immunological and defence-like functions.

Further reading

Alpern RJ, Herbert SC (eds) (2007). Seldin and Giebischs the kidney: physiology and pathophysiology, 4th edition. Academic Press, London.Find this resource:

    Brenner B (ed) (2007). Brenner and Rectors the kidney, 8th edition. Saunders, Philadelphia.Find this resource: