Medical Physiology, 3rd Edition

Functional Anatomy of the Kidney

We begin this discussion with a macroscopic view and progress to the microscopic level as we describe the nephron, the functional unit of the kidney that is repeated approximately 1 million times within each kidney.

The kidneys are paired, retroperitoneal organs with vascular and epithelial elements

The human kidneys are paired, bean-shaped structures that lie behind the peritoneum on each side of the vertebral column (Fig. 33-1A). They extend from the twelfth thoracic vertebra to the third lumbar vertebra. The two kidneys together comprise somewhat less than 0.5% of the total body weight; in men, each kidney weighs 125 to 170 g, whereas in women, each kidney weighs 115 to 155 g.

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FIGURE 33-1 Structure of the urinary system. B, Posterior view of the right kidney.

A fibrous, almost nondistensible capsule covers each kidney (see Fig. 33-1B). In the middle of the concave surface, a slit in the capsule—the hilus—serves as the port of entry for the renal artery and nerves and as the site of exit for the renal vein, the lymphatics, and the ureter. The hilus opens into a shallow space called the renal sinus, which is completely surrounded by renal parenchyma except where it connects with the upper end of the ureter. The renal sinus includes the urine-filled spaces: the renal pelvis proper and its extensions, the major and the minor calyces. Blood vessels and nerves also pass through the sinus. The renal capsule reflects into the sinus at the hilus so that its inner layers line the sinus, and the outer layers anchor to the blood vessels and renal pelvis.

A section of the kidney (see Fig. 33-1B) reveals two basic layers, the cortex (granular outer region) and the medulla (darker inner region). The granularity of the cortex results from the presence of glomeruli, microscopic tufts of capillaries, and a large number of highly convoluted epithelial structures in the form of tubules. The medulla lacks glomeruli and consists of a parallel arrangement of tubules and small blood vessels.

The medulla is subdivided into 8 to 18 conical renal pyramids, whose bases face the cortical-medullary border; the tip of each pyramid terminates in the renal pelvis. At the tip of each pyramid are perforations, almost invisible to the naked eye, through which urine flows into the minor calyces of the renal sinus.

The kidneys have a very high blood flow and glomerular capillaries flanked by afferent and efferent arterioles

Although the kidneys comprise <0.5% of total body weight, they receive ~20% of the cardiac output. This high blood flow provides the blood plasma necessary for forming an ultrafiltrate in the glomeruli. The renal circulation has a unique sequence of vascular elements: a high-resistance arteriole (the efferent arteriole), followed by a high-pressure glomerular capillary network for filtration, followed by a second high-resistance arteriole (the afferent arteriole), followed by a low-pressure capillary network that surrounds the renal tubules (peritubular capillaries) and takes up the fluid absorbed by these tubules.

The main features of the renal vascular system are illustrated in Figure 33-1B and C. A single renal artery enters the hilus and divides into anterior and posterior branches, which give rise to interlobar and then arcuate arteries. The latter arteries skirt the corticomedullary junction, where they branch into ascending interlobular arteries that enter the cortex and give rise to numerous afferent arterioles. These give rise to glomerular capillaries that rejoin to form efferent arterioles. For nephrons in the superficial portion of the cortex, the efferent arterioles are the origin of a dense peritubular capillary network that supplies oxygen and nutrients to the tubules in the cortex. The afferent and efferent arterioles determine the hydrostatic pressure in the interposed glomerular capillaries. The tone of both arterioles is under the control of a rich sympathetic innervation, as well as a wide variety of chemical mediators.

Very small branches of the arcuate artery, or the proximal portion of the interlobular artery, supply a subpopulation of “juxtamedullary” glomeruli that are located at or near the junction of cortex and medulla. The efferent arterioles of these nephrons descend into the renal papillae to form hairpin-shaped vessels called the vasa recta, which provide capillary networks for tubules in the medulla. Some 90% of the blood entering the kidney perfuses superficial glomeruli and cortex; only ~10% perfuses juxtamedullary glomeruli and medulla.

Lymph vessels, which drain the interstitial fluid of the cortex and may contain high concentrations of renal hormones such as erythropoietin, leave the kidney by following arteries toward the hilus. Lymphatics are absent from the renal medulla, where they would otherwise tend to drain the high-osmolality interstitial fluid, which is necessary for producing a concentrated urine (see pp. 809–817).

The functional unit of the kidney is the nephron

Each kidney consists of 800,000 to 1,200,000 nephrons. Each nephron is an independent entity until the point at which its initial collecting tubule merges with another tubule (Fig. 33-2).

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FIGURE 33-2 Structure of the nephron.

A nephron consists of a glomerulus and a tubule. The glomerulus is a cluster of blood vessels from which the plasma filtrate originates. The tubule is an epithelial structure consisting of many subdivisions, designed to convert the filtrate into urine. These two entities—vascular and epithelial—meet at the blind end of the tubule epithelium, which is called Bowman's capsule or the glomerular capsule. This capsule surrounds the glomerulus and contains Bowman's space, which is contiguous with the lumen of the tubule. It is here that filtrate passes from the vascular system into the tubule system.

The remainder of the nephron consists of subdivisions of the tubule (see Fig. 33-2). The epithelial elements of the nephron include Bowman's capsule, the proximal tubule, thin descending and thin ascending limbs of the loop of Henle, thick ascending limb of the loop of Henle, distal convoluted tubule, and connecting tubule. The connecting tubule imageN33-1 leads further into the initial collecting tubule, the cortical collecting tubule, and medullary collecting ducts.

N33-1

Definition of a Nephron

Contributed by Erich Windhager, Gerhard Giebisch

The connecting tubule, initial collecting tubule, cortical collecting tubule, and medullary collecting duct all derive embryologically from the ureteric bud. Because the more proximal elements all derive embryologically from the metanephric blastema, the segments from the connecting tubule through the medullary collecting duct were treated in the past as an entity separate from the other components of the nephron. Today, the term nephron usually includes both the proximal segments and the collecting-duct system.

Within the renal cortex, as noted above, one can distinguish two populations of nephrons (see Fig. 33-2). Superficial nephrons have short loops extending to the boundary between outer and inner medulla. Juxtamedullary nephrons, which play a special role in the production of a concentrated urine, have long loops that extend as far as the tip of the medulla.

The renal corpuscle has three components: vascular elements, the mesangium, and Bowman's capsule and space

The renal corpuscle, the site of formation of the glomerular filtrate, comprises a glomerulus, Bowman's space, and Bowman's capsule.

During the development of the kidney, the interaction between the ureteric bud—which gives rise to the urinary system from the collecting duct to the ureters—and the surrounding loose mesenchyme (Fig. 33-3A) leads to the branching of the ureteric bud and condensation of the mesenchyme (see Fig. 33-3B). These condensed cells differentiate into an epithelium that forms a hollow, S-shaped tubular structure (see Fig. 33-3C) that gives rise to the nephron's tubular elements between Bowman's capsule and the connecting segment. The distal portion of the S-shaped tubular structure elongates and connects with branches of the developing ureteric bud (see Fig. 33-3D). At the same time, the blind proximal end of this S-shaped tubule closely attaches to the arterial vascular bundle that develops into the glomerular capillary tuft. Thinning of the epithelium on one circumference of the blind end of the S-shaped tubule leads to the emergence of the future parietal layer of Bowman's capsule. In contrast, the opposite visceral layer thickens and attaches to the glomerular capillaries (see Fig. 33-3D). These visceral epithelial cells later fold and develop into podocytes (see Fig. 33-3E).

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FIGURE 33-3 Development of the glomerulus and Bowman's capsule. G and H, The four major layers of the glomerular filtration barrier. I, Model of podocyte foot processes and slit membrane. The diagram shows nephrin and other proteins of the slit diaphragm. Akt, protein kinase B; CD2AP, CD2-associated protein; DAG, diacylglycerol; Fyn, a Src kinase; IP3, inositol 1,4,5-trisphosphate; IQGAP, IQ motif containing GTPase activating protein; PI3K, phosphatidylinositol 3-kinase; PLC, phospholipase C; Rac, a GTPase; SYNJ, synaptojanin; TRPC6, transient receptor potential cation channel, subfamily C, member 6. (A–E, Modified from Ekblom P: In Seldin DW, Giebisch G: The Kidney, 2nd ed. New York, Raven Press, 1992, pp 475–501; H and I, modified from Zenker M, Machuca E, Antignac C: Genetics of nephrotic syndrome: New insights into molecules acting at the glomerular filtration barrier. J Mol Med 87:849–857, 2009.)

In the mature kidney (see Fig. 33-3F), foot processes of the podocytes cover the glomerular capillaries. These podocytes, modified epithelial cells, thus represent the visceral layer of Bowman's capsule. Beginning at the vascular pole, the podocytes are continuous with the parietal layer of Bowman's capsule. Glomerular filtrate drains into the space between these two layers (Bowman's space) and flows into the proximal tubule at the urinary pole of the renal corpuscle.

The glomerular filtration barrier between the glomerular capillary lumen and Bowman's space comprises four elements with different functional properties (see Fig. 33-3G): (1) a glycocalyx covering the luminal surface of endothelial cells, (2) the endothelial cells, (3) the glomerular basement membrane, and (4) epithelial podocytes.

The glycocalyx consists of negatively charged glycosaminoglycans (GAGs; see p. 39) that may play a role in preventing leakage of large negatively charged macromolecules.

Endothelial cells of the glomerular capillaries are almost completely surrounded by the glomerular basement membrane and a layer of podocyte foot processes (Fig. 33-4). The exception is a small region toward the center of the glomerulus, where the endothelial cells have neither basement membrane nor podocytes and come into direct contact with mesangial cells, which resemble smooth muscle. Filtration occurs away from the mesangial cells, at the peripheral portion of the capillary wall, which is covered with basement membrane and podocytes. The endothelial cells contain large fenestrations, 70-nm holes that provide no restriction to the movement of water and small solutes—including proteins or other large molecules—out of the lumen of the capillary (Fig. 33-5). Thus, the endothelial cells probably serve only to limit the filtration of cellular elements (e.g., erythrocytes).

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FIGURE 33-4 Glomerular capillary covered by the foot processes of podocytes. This scanning electron micrograph shows a view of glomerular capillary from the vantage point of Bowman's space. The outer surfaces of the capillary endothelial cells are covered by a layer of interdigitating foot processes of the podocytes. The podocyte cell body links to the foot processes by leg-like primary and secondary processes.

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FIGURE 33-5 Inner aspect of glomerular capillary, showing fenestrations of endothelial cells. This scanning electron micrograph shows a view of the glomerular capillary wall from the vantage point of the capillary lumen. Multiple fenestrations, each ~70 nm in diameter, perforate the endothelial cells.

The basement membrane, located between endothelial cells and podocyte foot processes (see Fig. 33-3G), separates the endothelial layer from the epithelial layer in all parts of the glomerular tuft. The basement membrane itself has three layers (see Fig. 33-3H): (1) an inner thin layer (lamina rara interna); (2) a thick layer (lamina densa), and (3) an outer thin layer (lamina rara externa). The basement membrane makes an important contribution to the permeability characteristics of the filtration barrier by restricting intermediate-sized to large solutes (molecular weight > 1 kDa). Because the basement membrane contains heparan sulfate proteoglycans (HSPGs), it especially restricts large, negatively charged solutes (see Fig. 34-4A).

Podocytes have foot interdigitating processes that cover the basement membrane (see Fig. 33-4). Between these interdigitations (the nose-like structures in Fig. 33-3H) are filtration slits (see Fig. 33-3H); the interdigitations are connected by thin diaphragmatic structures—the slit diaphragms—with pores ranging in size from 4 to 14 nm. Glycoproteins with negative charges cover the podocyte bodies, the interdigitations, and the slit diaphragms. These negative charges contribute to the restriction of filtration of large anions (Fig. 34-4A). The extracellular domains of the integral membrane proteins nephrin and NEPH1 from adjacent podocytes appear to zip together to help form the slit diaphragm. Podocin and other proteins also contribute to the slit diaphragm (see Fig. 33-3I). Phosphotyrosine motifs on the intracellular domains of some of these proteins may recruit other molecules involved in signaling events that control slit permeability. Genetic defects in any of several of these protein can make the filtration barrier leaky, leading to the appearance of large proteins (e.g., albumin) in the urine—nephrotic syndrome. For example, the genetic absence of nephrin leads to congenital nephrotic syndrome of the Finnish type, characterized by severe proteinuria. imageN33-2

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Finnish-Type Nephrosis

Contributed by Gerhard Giebisch, Erich Windhager

A critical protein in slit diaphragm is nephrin, a protein specifically located at the slit diaphragm of glomerular podocytes. Nephrin plays an essential role in the maintenance of normal glomerular permeability because its absence leads to severe proteinuria. Thus, a rare human autosomal disease characterized by absence of nephrin (Finnish-type nephrosis with massive albuminuria) further supports the critical role of slit-diaphragm proteins in defining glomerular permeability to macromolecules. Figure 33-3 provides a view of glomerular filtration slits and includes slit-diaphragm proteins of functional importance. It is likely that changes in phosphorylation of podocyte proteins modulate the permeability properties of the slit membrane to proteins.

References

Benzing T. Signaling at the slit diaphragm. J Am Soc Nephrol. 2004;15:1382–1391.

Tryggvason K. Unraveling the mechanisms of glomerular ultrafiltration: Nephrin, a key component of the slit diaphragm. J Am Soc Nephrol. 1999;10:2440–2445.

Supporting the glomerular capillary loops is a network of contractile mesangial cells, which secrete the extracellular matrix. This network is continuous with the smooth-muscle cells of the afferent and efferent arterioles. The matrix extends to the “extraglomerular” mesangial cells (see Fig. 33-3F). The juxtaglomerular apparatus (JGA) includes the extraglomerular mesangial cells, the macula densa, and the granular cells. The macula densa (from the Latin macula [spot] + densa [dense]) is a patch of specialized tubule epithelial cells—at the transition between the TAL and the distal tubule—that contacts its own glomerulus (see Fig. 33-3F). These cells have strikingly large nuclei and are closely packed, and thus they have a plaque-like appearance. The granular cells in the wall of afferent arterioles, also called juxtaglomerular or epithelioid cells, are specialized smooth-muscle cells that produce, store, and release the enzyme renin (see p. 841). The JGA is part of a complex feedback mechanism that regulates renal blood flow and filtration rate (see pp. 750–751), and it also indirectly modulates Na+ balance (see pp. 841–842) and systemic blood pressure (see pp. 554–555).

The tubule components of the nephron include the proximal tubule, loop of Henle, distal tubule, and collecting duct

Figure 33-6 illustrates the ultrastructure of the cells of the different tubule segments. Table 33-1 lists these segments and their abbreviations. imageN33-3 Based on its appearance at low magnification, the proximal tubule can be divided into the proximal convoluted tubule (PCT; Fig. 33-6A), and the proximal straight tubule (PST; see Fig. 33-6B). However, based on ultrastructure, the proximal tubule can alternatively be subdivided into three segments: S1, S2, and S3. The S1 segment starts at the glomerulus and includes the first portion of the PCT. The S2 segment starts in the second half of the PCT and continues into the first half of the PST. Finally, the S3 segment includes the distal half of the PST that extends into the medulla.

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FIGURE 33-6 Structure of tubule cells along the nephron. Because of the wide range of tubule diameters along the nephron, the scaling factors for tubule cross sections differ for panels A to K. However, the individual cells next to the tubule cross sections are drawn to the same scale.

TABLE 33-1

Tubule Segments of the Nephron

TUBULE SEGMENT

ABBREVIATION

Proximal convoluted tubule

PCT

Proximal straight tubule

PST

Thin descending limb of loop of Henle

tDLH

Thin ascending limb of loop of Henle

tALH

Thick ascending limb of loop of Henle

TAL

Distal convoluted tubule

DCT

Connecting tubule

CNT

Initial collecting tubule

ICT

Cortical collecting tubule

CCT

Outer medullary collecting duct

OMCD

Inner medullary collecting duct

IMCD

N33-3

Tubule Segments of the Nephron

Contributed by Erich Windhager, Gerhard Giebisch

In Figure 33-6, we identified 11 distinct segments (lettered A through K) in the nephron. The following is a description of the cells that make up each of these segments.

A. Proximal convoluted tubule (PCT). The first portion of the PCT consists of S1 cells, and the latter portion of S2 cells. Both cells have abundant apical microvilli and a deeply infolded basolateral membrane. They also have a rich supply of mitochondria, which lie between the infoldings. These complexities diminish from the S1 to the S2 segments.

B. Proximal straight tubule (PST). The first portion of the PST consists of S2 cells, and the latter portion of S3 cells. The ultrastructural complexity diminishes from the S2 to the S3 segments.

C. Thin descending limb (tDLH). The cells are less complex and flatter than those of the S3 segment of the proximal tubule.

D. Thin ascending limb (tALH). Away from the nucleus, the cells are even thinner than those of the descending limb.

E. Thick ascending limb (TAL). The cells, which lack microvilli, are substantially taller and more complex than those of the thin limbs.

F. Distal convoluted tubule (DCT). The cells are very similar to those of the TAL.

G. Connecting tubule (CNT). This segment consists of both connecting-tubule cells, which secrete kallikrein, and intercalated cells, which are rich in mitochondria.

H. Initial collecting tubule (ICT). The ICT is defined as the segment just before the first confluence of tubules. About one third of the cells in this segment are intercalated cells, and the rest are principal cells.

I. Cortical collecting tubule (CCT). The CCT is defined as the segment after the first confluence of tubules. The cells in this segment are very similar to those in the ICT.

J. Outer medullary collecting duct (OMCD). The principal cells in this nephron segment have a modest cell height. The number of intercalated cells progressively decreases along the length of this segment.

K. Inner medullary collecting duct (IMCD). This segment consists only of principal cells. Even at the beginning of the IMCD, the principal cells are taller than in the OMCD. At the end of the IMCD, the “papillary” collecting-duct cells are extremely tall.

Both the apical (luminal) and basolateral (peritubular) membranes of proximal-tubule cells are extensively amplified (see Fig. 33-6A, B). The apical membrane has infoldings in the form of a well-developed brush border. This enlargement of the apical surface area correlates with the main function of this nephron segment; namely, to reabsorb the bulk of the filtered fluid back into the circulation. A central cilium, which may play a role in sensing fluid flow, protrudes from the apical pole of proximal-tubule cells and nearly all the other types of tubule cells.

The basolateral membranes of adjacent proximal-tubule cells form numerous interdigitations, bringing abundant mitochondria in close contact with the plasma membrane. The interdigitations of the lateral membranes also form an extensive extracellular compartment bounded by the tight junctions at one end and by the basement membrane of the epithelium at the other end. Proximal-tubule cells contain lysosomes, endocytic vacuoles, and a well-developed endoplasmic reticulum. Proximal-tubule cells also have a prominent Golgi apparatus (see p. 21), which is important for synthesizing many membrane components, sorting them, and targeting them to specific surface sites. From the S1 to the S3 segments, cell complexity progressively declines, correlating with a gradual decrease of reabsorptive rates along the tubule. Thus, the cells exhibit a progressively less developed brush border, diminished complexity of lateral cell interdigitations, a lower basolateral cell membrane area, and a decrease in the number of mitochondria.

In comparison with the S3 segment of the proximal tubule, the cells lining the thin descending limb (tDLH) and thin ascending limb (tALH) of the loop of Henle are far less complex (see Fig. 33-6C, D), with few mitochondria and little cell membrane amplification. In superficial nephrons, the thin ascending limbs are extremely abbreviated (see Fig. 33-2). However, they form a major part of the long loops of the juxtamedullary nephrons.

Epithelial cells lining the thick ascending limb of the loop of Henle (TAL), which terminates at the macula densa, are characterized by tall interdigitations and numerous mitochondria within extensively invaginated basolateral membranes (see Fig. 33-6E). This complex cell machinery correlates with the key role these cells play in making the medullary interstitium hyperosmotic.

Until the latter part of the 20th century, morphologists defined the classic distal tubule—on the basis of light microscopic studies—as the nephron segment stretching from the macula densa to the first confluence of two nephrons in the collecting-duct system. Today, we subdivide the classic distal tubule into three segments, based on ultrastructural studies: the distal convoluted tubule (starting at the macula densa), the connecting tubule, and the initial collecting tubule. What was classically termed the early distal tubule is mainly the distal convoluted tubule, whereas the classically termed late distal tubule is mainly the initial collecting tubule.

The distal convoluted tubule (DCT) begins at the macula densa and ends at the transition to the connecting tubule (see Fig. 33-6F). The cells of the DCT are similar in structure to those of the thick ascending limb. However, significant cell heterogeneity characterizes the tubule segments that follow.

The connecting tubule (CNT), which ends at the transition to the initial collecting tubule, consists of two cell types: CNT cells and intercalated cells. CNT cells (see Fig. 33-6G) are unique in that they produce and release renal kallikrein, a serine protease—attached to the apical membrane—that modulates apical membrane channels and transporters. We discuss intercalated cells below.

The two segments following the CNT, the initial collecting tubule (ICT, up to the first confluence) and the cortical collecting tubule (CCT, after the confluence), are identical. They are composed of intercalated and principal cells, which exhibit striking morphological and functional differences. Intercalated cells, similar in structure to the intercalated cells of the CNT, make up about one third of the lining of these collecting-tubule segments (see Fig. 33-6H, I). They are unusual among tubule cells in that they lack a central cilium. One subpopulation of these cells (A- or α-intercalated cells) secretes H+ and reabsorbs K+, whereas another (B- or β-intercalated cells) secretes imagePrincipal cells make up about two thirds of the cells of the ICT and CCT (see Fig. 33-6H, I). Compared with intercalated cells, principal cells have fewer mitochondria, only modestly developed invaginations of the basolateral membrane, and a central cilium on the apical membrane. Principal cells reabsorb Na+ and Cl and secrete K+.

The medullary collecting duct is lined mostly by one cell type that increases in cell height toward the papilla (see Fig. 33-6J, K). The number of intercalated cells diminishes beginning at the outer medullary collecting duct. Cells in this segment continue the transport of electrolytes and participate in the hormonally regulated transport of water and of urea. At the extreme end of the medullary collecting duct (i.e., the “papillary” collecting duct or duct of Bellini), the cells are extremely tall.

The tightness of tubule epithelia increases from the proximal to the medullary collecting tubule

Epithelia may be either “tight” or “leaky,” depending on the permeability of their tight junctions (see pp. 136–137). In general, the tightness of the tubule epithelium increases from the proximal tubule to the collecting duct. In the leaky proximal tubule, junctional complexes are shallow and, in freeze-fracture studies, show only a few strands of membrane proteins (see pp. 43–44). In contrast, in the relatively tight collecting tubule, tight junctions extend deep into the intercellular space and consist of multiple strands of membrane proteins. Tubule segments with tight junctions consisting of only one strand have low electrical resistance and high solute permeability, whereas tubules with several strands tend to have high electrical resistance and low permeability.

Gap junctions (see pp. 158–161) provide low-resistance pathways between some, but not all, neighboring tubule cells. These gap junctions are located at various sites along the lateral cell membranes. Electrical coupling exists among proximal-tubule cells, but not among heterogenous cell types, such as those found in the connecting and collecting tubules.