Histology: Urinary

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The urinary system

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consists of the paired kidneys; paired ureters, which lead from the kidneys to the urinary bladder; and the urethra,which leads from the bladder to the exterior of the body.

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The kidneys

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conserve body fluid and electrolytes and remove metabolic waste. Like the lungs and liver, the kidneys retrieve essential materials and dispose of wastes. They conserve water, essential electrolytes, and metabolites, and they remove certain waste products of metabolism from the body. The kidneys play an important role in regulating and maintaining the composition and volume of extracellular fluid. They also are essential in maintaining acid–base balance by excreting hydrogen ions when bodily fluids become too acidic or excreting bicarbonates when bodily fluids become too basic. The kidneys are highly vascular organs; they receive a pproximately 25% of the cardiac output. The kidneys produce urine, initially a glomerular ultrafiltrate of the blood or primary urine, which is then modified by selective resorption and specific secretion by the cells of the kidney. The final urine is conveyed by the ureters to the urinary bladder, where it is stored until discharged via the urethra. The final urine contains water and electrolytes as well as waste products, such as urea, uric acid, and creatinine, and breakdown products of various substances.

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Vitamin D: inactive precursor: undergoes a series of transformations to become the fully active hormone that regulates: plasma calcium levels.

Derived: • Skin, in which vitamin D3 (cholecalciferol) is rapidly produced by the action of ultraviolet light on the precursor 7-dehydrocholesterol. The skin is the major source of vitamin D3, especially in regions where food is not supplemented with vitamin D. Typically, 30 minutes to 2 hours of sunlight exposure per day can provide enough vitamin D to fulfill daily body requirements for this vitamin. • Diet, from which vitamin D3 is absorbed by the small intestine in association with chylomicrons. In the blood vitamin D3 is bound to vitamin D–binding protein and transported to the liver. The first transformation occurs in the liver and involves hydroxylation of vitamin D3 to form 25-OH vitamin D3. This compound is released into the bloodstream and undergoes a second hydroxylation in the proximal tubules of the kidney to produce the highly active 1,25-(OH)2 vitamin D3(calcitriol). The process is regulated indirectly by an increase in plasma Ca2concentration, which triggers secretion of PTH, or directly by a decrease in circulating phosphates, which in turn stimulates activity of 1 -hydroxylase responsible for conversion of 25-OH vitamin D3 into active 1,25-(OH)2 vitamin D3. Active 1,25-(OH)2 vitamin D3 stimulates intestinal absorption of Ca2 and phosphate and mobilization of Ca2 from bones. It is therefore necessary for normal development and growth of bones and teeth. The related compound vitamin D2 (ergocalciferol) undergoes the same conversion steps as vitamin D3 and produces the same biologic effects. Patients with end-stage chronic kidney diseases have inadequate conversion of vitamin D into active metabolites resulting in vitamin D3 deficiency. In adults, v itamin D3 deficiency is manifested by impaired bone mineralization and reduced bone density. Therefore, patients with chronic kidney diseases, especially those on prolonged renal hemodialysis are often supplemented with vitamin D3 and calcium to avoid severe disturbance of calcium homeostasis because of secondary hyperparathyroidism, a condition prevalent in these patients.

Vitamin D3 deficiency = rickets = abnormal bone ossification.

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The kidney: Fx: endocrine organ.

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Endocrine activities of the kidneys include

• Synthesis and secretion of the glycoprotein hormone erythropoietin (EPO), which acts on the bone marrow and regulates red blood cell formation in response to decreased blood oxygen concentration. EPO is synthesized by endothelial cells of the peritubular capillaries in the renal cortex and acts on specific receptors expressed on the surface of erythrocyte progenitor (Er-P) cells in the bone marrow. The recombinant form of erythropoietin (RhEPO) is used for the treatment of anemia in patients with end-stage renal disease. It is also used to treat anemia resulting from bone marrow suppression that develops in AIDS patients undergoing treatment with antiretroviral drugs, such as azidothymidine (AZT). • Synthesis and secretion of the acid protease renin, an e nzyme involved in control of blood pressure and blood volume. Renin is produced by juxtaglomerular cells and cleaves circulating angiotensinogen to release angiotensin I (see page 713). • Hydroxylation of 25-OH vitamin D3, a steroid precursor produced in the liver, to hormonally active 1,25-(OH)2 vitamin D3. This step is regulated primarily by parathyroid hormone (PTH), which stimulates activity of the enzyme1-hydroxylase and increases the production of the active hormone (see Folder 20.1).

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GENERAL STRUCTURE OFTHEKIDNEY

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The kidneys are large, reddish, bean-shaped organs located on either side of the spinal column in the retroperitoneal space of the posterior abdominal cavity. They extend from the 12th thoracic to the 3rd lumbar vertebrae, with the right kidney positioned slightly lower. Each kidney measures approximately 10 cm long 6.5 cm wide (from concave to convex border) 3 cm thick. On the upper pole of each kidney, embedded within the renal fascia and a thick protective layer of perirenal adipose tissue, lies an adrenal gland. The medial border of the kidney is concave and contains a deep vertical fissure, called the hilum, through which the renal vessels and nerves pass and the expanded, funnel-shaped origin of the ureter, called the renal pelvis, exits. A section through the kidney shows the relationship of these structures as they lie just within the hilum of the kidney in a space called the renal sinus (Fig. 20.1). Although not shown in the illustration, the space between and around these structures is filled largely with loose connective tissue and adipose tissue. Capsule The kidney surface is covered by a connective tissue capsule. The capsule consists of two distinct layers: an outer layer of fibroblasts and collagen fibers, and an inner layer with a cellular component of myofibroblasts (Fig. 20.2). The contractility of the myofibroblasts may aid in resisting volume and pressure variations that can accompany variations in kidney function. Its specific role, however, is unknown. The capsule passes inward at the hilum, where it forms the connective tissue covering of the sinus and becomes continuous with the connective tissue forming the walls of the calyces and renal pelvis (see Fig. 20.1).

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Cortex and Medulla

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Examination with the naked eye of the cut face of a fresh, hemisected kidney reveals that its substance can be divided into two distinct regions:

• Cortex, the outer reddish brown part

• Medulla, the much lighter-colored inner part The color seen in the cut surface of the unfixed kidney reflects the distribution of blood in the organ. Approximately 90% to 95% of the blood passing through the kidney is in the cortex; 5% to 10% is in the medulla.The cortex is characterized by renal corpuscles and their associated tubules. The cortex consists of renal corpuscles along with the convoluted tubules and straight tubules of the nephron, the collecting tubules, collecting ducts,and an extensive vascular supply. The nephron is the basic functional unit of the kidney and is described in a following section. The renal corpuscles are spherical structures, barely visible with the naked eye. They constitute the beginning segment of the nephron and contain a unique capillary network called a glomerulus. Examination of a section cut through the cortex at an angle perpendicular to the surface of the kidney reveals a s eries ofvertical striations that appear to emanate from the medulla (see Fig 20.1). These striations are the medullary rays (of Ferrein). Their name reflects their appearance, as the striations seem to radiate from the medulla. Approximately 400 to 500 medullary rays project into the cortex from the medulla.Each medullary ray is an aggregation of straight tubules and collecting ducts. Each medullary ray contains straight tubulesof the nephrons and collecting ducts. The regions between medullary rays contain the renal corpuscles, the convoluted tubules of the nephrons, and the collecting tubules. These areas are referred to as cortical labyrinths. Each nephron and its collecting tubule (which connects to a collecting duct in the medullary ray) form the uriniferous tubule.The medulla is characterized by straight tubules, collecting ducts, and a special capillary network, the vasa recta. The straight tubules of the nephrons and the collecting ducts continue from the cortex into the medulla. They are accompanied by a capillary network, the vasa recta, that runs in parallel with the various tubules. These vessels represent the vascular part of the countercurrent exchange system that regulates the concentration of the urine. The tubules in the medulla, because of their arrangement and differences in length, collectively form a number of conical structures called pyramids. Usually 8 to 12 but as many as 18 pyramids may be present in the human kidney. The bases of the pyramids face the cortex, and the apices face the renal sinus. Each pyramid is divided into an outer medulla (adjacent to the cortex) and an inner medulla. The outer medulla is further subdivided into an inner stripe and an outer stripe. The zonation and stripes are readily recognized in a sagittal section through the pyramid of a fresh specimen. They reflect the location of distinct parts of the nephron at specific levels within the pyramid (Fig. 20.3).The renal columns represent cortical tissue contained within the medulla. The caps of cortical tissue that lie over the pyramids are sufficiently extensive that they extend peripherally around the lateral portion of the pyramid, forming the renal columns (of Bertin). Although renal columns contain the same components as the rest of the cortical tissue, they are regarded as part of the medulla. In effect, the amount of cortical tissue is so extensive that it “spills” over the side of the pyramid much as a large scoop of ice cream extends beyond and overlaps the sides of an ice cream cone. The apical portion of each pyramid, which is known as the papilla, projects into a minor calyx,a cup-shaped structure that represents an extension of the renal pelvis. The tip of the papilla, also known as the area cribrosa, is perforated by the openings of the collecting ducts (Fig. 20.4). The minor calyces are branches of the two or three major calyces that in turn are major divisions of the renal pelvis (see Fig. 20.1).

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This photomicrograph of a Mallory-Azan–stained section shows the capsule (cap) and part of the underlying cortex. The outer layer of the capsule (OLC) is composed of dense connective tissue. The fibroblasts in this part of the capsule are relatively few in number; their nuclei appear as narrow, elongate, red-staining profiles against a blue background representing the stained collagen fibers. The inner layer of the capsule (ILC) consists of large numbers of myofibroblasts whose nuclei appear as round or elongate, redstaining profiles, depending on their orientation within the section. Note that the collagen fibers in this layer are relatively sparse and that the myofibroblast nuclei are more abundant than those of the fibroblasts in the outer layer of the capsule. x180 magnification.

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Kidney Lobes and Lobules

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The number of lobes in a kidney equals the number of medullary pyramids. Each medullary pyramid and the associated cortical tissue at its base and sides (one half of each adjacent renal column) constitutes a lobeof the kidney. The lobar organization of the kidney is conspicuous in the developing fetal kidney (Fig. 20.5). Each lobe is reflected as a convexity on the outer surface of the organ, but they usually disappear after birth. The surface convexities typical of the fetal kidney may persist, however, until the teenage years and, in some cases, into adulthood. Each human kidney contains 8 to 18 lobes. Kidneys of some animals possess only one pyramid; these kidneys are classified as unilobar, in contrast to the multilobar kidney of the human. A lobule consists of a collecting duct and all the nephrons that it drains. The lobes of the kidneyare further subdivided into lobules consisting of a central medullary ray and surrounding cortical material (Fig. 20.6 and Plate 75, page 730). Although the center or axis of a lobule is readily identifiable, theboundaries between adjacent lobules are not obviously demarcated from one another by connective tissue septa. The concept of the lobule has an important physiologic basis; the medullary ray containing the collecting duct for a group of nephrons that drain into that duct constitutes the renal secretory unit. It is the equivalent of a glandular secretory unit or lobule.

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The Nephron

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The nephron is the structural and functional unit of the kidney. The nephron is the fundamental structural and functional unit of the kidney (see Fig. 20.3). Each human kidney c ontains a pproximately 2 million nephrons. Nephrons are r esponsible for the production of urine and correspond to the secretory part of other glands. The collecting ducts are responsible for the final concentration of the urine and are analogous to the ducts of exocrine glands that modify the concentration of the secretory product. Unlike the typical e xocrine gland in which the secretory and duct portions arise from a single epithelial outgrowth, nephrons and their collecting tubules arise from separate primordia and only later become connected.

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Diagram of two types of nephrons in the kidney and their associated collecting duct systems. A longlooped nephron is shown on the left, and a short-looped nephron is shown on the right. The relative position of the cortex, medulla, papilla, and capsule are indicated. The inverted cone-shaped area in the cortex represents a medullary ray. The parts of the nephron are indicated by number: 1, renal corpuscle including the glomerulus and Bowman’s capsule; 2, proximal convoluted tubule; 3, proximal straight tubule; 4, descending thin limb; 5, ascending thin limb; 6, thick ascending limb (distal straight tubule); 7, macula densa located in the final portion of the thick ascending limb; 8, distal convoluted tubule; 9, connecting tubule; 9*, collecting tubule that forms an arch (arched collecting tubule); 10,cortical collecting duct; 11,outer medullary collecting duct;and 12,inner medullary collecting duct. (Modified from Kriz W, Bankir L. A standard nomenclature for structures of the kidney. The Renal Commission of the International Union of Physiological Sciences (IUPS). Kidney Int 1988;33:1–7.)

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General Organization of the Nephron

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The nephron consists of the renal corpuscle and a tubule system. As stated previously, the renal corpuscle represents the beginning of the nephron. It consists of the glomerulus, a tuft of capillaries composed of 10 to 20 capillary loops, surrounded by a double-layered epithelial cup, the renal or Bowman’s capsule. Bowman’s capsule is the initial portion of the nephron, where blood flowing through the glomerular capillaries undergoes filtration to produce the glomerular ultrafiltrate. The glomerular capillaries are supplied by an afferent arterioleand are drained by an efferent arteriole that then branches, forming a new capillary network to supply the kidney tubules. The site where the afferent and efferent arterioles penetrate and exit from the parietal layer of Bowman’s capsule is called the vascular pole. Opposite this site is the urinary pole of the renal corpuscle, where the proximal convoluted tubule begins (see Fig. 20.7). Continuing from Bowman’s capsule, the remaining parts of the nephron (the tubular parts) are as follows: • Proximal thick segment, consisting of the proximal convoluted tubule (pars convoluta) and the proximal straight tubule (pars recta) • Thin segment, which constitutes the thin part of the loop of Henle • Distal thick segment, consisting of the distal straight tubule (pars recta) and the distal convoluted tubule (pars convoluta) The distal convoluted tubule connects to the collecting tubule, often through a connecting tubule, thus forming the uriniferous tubule (i.e., the nephron plus collecting tubule; see Fig. 20.3).

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Tubes of the Nephron

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The tubular segments of the nephron are named according to the course that they take (convoluted or straight), location (proximal or distal), and wall thickness (thick or thin). Beginning from Bowman’s capsule, the sequential parts of the nephron consist of the following tubules: • Proximal convoluted tubule originates from the urinary pole of Bowman’s capsule. It follows a very tortuous or convoluted course and then enters the medullary ray to continue as the proximal straight tubule. • Proximal straight tubule, commonly referred to as thethick descending limb of the loop of Henle, descends into the medulla. • Thin descending limb is the continuation of the proximal straight tubule within the medulla. It makes a hairpin turn and returns toward the cortex. • Thin ascending limb is the continuation of the thin descending limb after its hairpin turn. • Distal straight tubule, which is also referred to as the thick ascending limb of the loop of Henle, is the continuation of the thin ascending limb. The distal straight tubule ascends through the medulla and enters the cortex in the medullary ray to reach the vicinity of its renal corpuscle of origin. Thedistal straight tubule then leaves the medullary ray and makes contact with the vascular pole of its parent renal corpuscle. At this point, the epithelial cells of the tubule adjacent to the afferent arteriole of the glomerulus are modified to form the macula densa. The distal tubule then leaves the region of the corpuscle and becomes the distal convoluted tubule. • Distal convoluted tubule is less tortuous than the proximal convoluted tubule; thus, in a section showing the cortical labyrinth, there are fewer distal tubule profiles than proximal tubule profiles. At its termination, the distal convoluted tubule empties into a collecting duct that lies in the medullary ray via either an arched collecting tubule or a shorter tubule simply called the connecting tubule.The loop of Henle forms the entire U-shaped portion of a nephron. The proximal straight tubule, the thin descending limb with its hairpin turn, the thin ascending limb, and the distal straight tubule are collectively called the loop of Henle. In some nephrons, the thin descending and ascending segments are extremely short; therefore, the hairpin turn may be made by the distal straight tubule.

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Types of Nephrons

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Several types of nephrons are identified, based on the location of their renal corpuscles in the cortex (see Fig. 20.3):

• Subcapsular nephronsor cortical nephronshave their renal corpuscles located in the outer part of the cortex. They have short loops of Henle, extending only into the outer medulla. They are typical of the nephrons described previously, wherein the hairpin turn occurs in the distal straight tubule. • Juxtamedullary nephrons make up about one eighth of the total nephron count. Their renal corpuscles occur in proximity to the base of a medullary pyramid. They have long loops of Henle and long ascending thin segments that extend well into the inner region of the pyramid. These structural features are essential to the urine-concentrating mechanism, which is described in a further section.

• Intermediate nephrons or midcortical nephrons have their renal corpuscles in the midregion of the cortex. Their loops of Henle are of intermediate length.

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Collecting Tubules and Ducts

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The collecting tubules begin in the cortical labyrinth, as either connecting tubules or arched collecting tubules, and proceed to the medullary ray, where they join the collecting ducts. The collecting ducts within the cortex are referred to as cortical collecting ducts. When cortical collecting ducts reach the medulla, they are referred to as medullary collecting ducts. These ducts travel to the apex of the p yramid, where they merge into larger collecting ducts (up to 200 m), the papillary ducts (ducts of Bellini) that open into the minor calyx (see Fig. 20.4). The area on the papilla that contains the openings of these collecting ducts is called the area cribrosa.

In summary, the gross appearance of the kidney parenchyma reflects the structure of the nephron. The renal corpuscle and the proximal and the distal convoluted tubules are all located in and make up the substance of the cortical labyrinths. The portions of the straight proximal and straight distal tubules and the descending thin and ascending thin limbs of the loop of Henlein the cortex are located in and make up the major portion of the medullary rays. The thin descending and thin ascending limbs of the loop of Henle are always located in the medulla. Thus, the arrangement of the nephrons (and the collecting tubules and ducts) accounts for the characteristic appearance of the cut surface of the kidney, as can be seen in Figure 20.6.

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Filtration Apparatus of the Kidney

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The renal corpuscle contains the filtration apparatus of the kidney, which consists of the glomerular endothelium, underlying glomerular basement membrane, and the visceral layer of Bowman’s capsule. The renal corpuscleis spherical and has an average diameter of 200 m. It consists of the glomerular capillary tuft and the surrounding visceral and parietal epithelial layers of B owman’s capsule (Fig. 20.8). The filtration apparatus, also called glomerular ltration barrier, enclosed by the parietal layer of Bowman’s capsule, consists of three different components: • Endothelium of the glomerular capillaries, which possesses numerous fenestrations (Fig. 20.9). These fenestrations are larger (70 to 90 nm in diameter), more n umerous, and more irregular in outline than fenestrations in other capillaries. Moreover, the diaphragm that spans the fenestrations in other capillaries is absent in the glomerular capillaries. E ndothelial cells of glomerular capillaries possess a largenumber of aquaporin-1 (AQP-1) water channels that allow the fast movement of water through the epithelium. Secretory products of endothelial cells, such as nitric oxide (NO) or prostaglandins (PGE2), play an important role in the pathogenesis of several thrombotic glomerular diseases. • Glomerular basement membrane (GBM), a thick (300 to 370 nm) basal lamina that is the joint product of the e ndothelium and the podocytes, the cells of the visceral layer of Bowman’s capsule. Because of its thickness, it is prominent in histologic sections stained with the periodic acid–Schiff (PAS) procedure (see Fig. 1.2, page 6). The GMB is composed of a network consisting of type IV collagen (mainly 3, 4, and 5 chains), laminin, nidogen, entactin, t ogether with proteoglycans such as agrin and perlecan, as well as multiadhvesive glycoproteins (see page 138). GBM can also be visualized employing immunofluorescence techniques using antibodies directed to a specific chain of type IV collagen (Fig20.10). Mutation in the gene encoding for the 5 chain of type IV collagen gives rise to the Alport’s syndrome

(hereditary glomerulonephritis), manifesting by hematuria (presence of the red blood cells in the urine); proteinuria (presence of signicant amount of protein in the urine); and progressive renal failure. In Alport’s syndrome, the GBM becomes irregularly thickened with laminated lamina densa and fails to serve as an effective ltration barrier.

• Visceral layer of Bowman’s capsule, which contains specialized cells called podocytes or visceral epithelial cells. These cells extend processes around the glomerular capillaries (Fig. 20.11 and Plate 76, page 732). The podocytes arise during embryonic development from one of the blind ends of the developing nephron through invagination of the end of the tubule to form a double-layered epithelial cup. The inner cell layer (i.e., the visceral cell layer) lies in a pposition to a capillary network, the glomerulus, which forms at this site. The outer layer of these cells, the parietal layer, forms the squamous cells of Bowman’s capsule. The cup eventually closes to form the spherical structure containing the glomerulus. As they differentiate, the podocytes extend processes around the capillaries and develop numerous s econdary processes called pedicels or foot processes. The foot processes interdigitate with foot processes of neighboring podocytes, a feature that can be clearly seen with the scanning electron microscope (SEM; Fig. 20.12). The elongated spaces between the interdigitating foot p rocesses, called ltration slits, are about 40 nm wide and covered by an u ltrathin ltration slit diaphragm that spans the filtration slit slightly above the GBM (Fig. 20.13, inset).Nephrin is an important structural protein of the filtration slit diaphragm. Recent studies of the ltration slit diaphragm revealed its complex protein structure as a zipper-like sheet configuration with a central density. A transmembrane protein, nephrin is706 a key structural and functional component of the slit diaphragm. Nephrin molecules emerging from opposite foot processes interact in the center of the slit (homophilic interactions), forming a central density with pores on both sides (Fig. 20.14). This intercellular protein sheet also contains other adhesion molecules, such as Neph-1, Neph-2, P-cadherin, FAT1, and FAT 2. The filtration slit diaphragm is firmly anchored to numerous actin filaments within the foot processes of podocytes. Regulation and maintenance of the actin cytoskeleton of podocytes has emerged as a critical process for regulating size, patency, and selectivity of the filtration slits. Mutations in the nephrin gene (NPHS1) are associated with congenital nephrotic syndrome, a disease characterized by massive proteinuria and edema. Endothelial surface layer of glomerular capillaries and subpodocyte space also make an important contribution to overall glomerular function. The filtration apparatus is a very complex semipermeable barrier, with properties that allow for high filtration rate of water, nonrestricted passage of small and middle-sized molecules, and almost total exclusion of serum albumins and other larger proteins. The filtration apparatus may thus be described as a barrier having two discontinuous cellular layers, the endothelium of glomerular capillaries and visceral layer of Bowman’s capsule applied to either side of a continuous extracellular layer of the glomerular basement membrane. These three layers have traditionally been considered as the glomerular filtration barrier. However, recently two additional physiologically important layers, the endothelial surface layer ofglomerular capillaries and subpodocyte space are included as part of the filtration apparatus. • Endothelial surface layer of the glomerular capillaries consists of a thick carbohydrate–rich meshwork (200–400 nm) attached to the luminal surface of glomerular endothelial cells. It contains glycocalyx, which refers to plasma membrane-bound negatively charged proteoglycans (such as perlecan, syndecan, and versican) associated with glycosaminoglycan side-chains (such as heparan sulphate and chondroitin sulphate) and peripheral membrane proteins. Plasma proteins (e.g., albumins) adsorbed from the blood coat the luminal surface of glycocalyx. • Subpodocyte space represents a narrow space between the foot processes with their filtration slit diaphragms on one side and a cell body of the podocyte on the other side (see Fig. 20.13). Recent three-dimensional reconstruction of these spaces revealed their interconnected but structurally restrictive character. They cover approximately 60% of the entire surface area of the glomerular filtration barrier and may function in regulating glomerular fluid flux across the filtration apparatus. The glomerular basement membrane (GBM) acts as a physical barrier and an ion-selective filter. As discussed earlier, the GBM contains type IV and XVIII collagens, sialoglycoproteins, and other noncollagenous glycoproteins (e.g., laminin, fibronectin, entactin), as well as proteoglycans (e.g., perlecan, agrin) and glycosaminoglycans, particularly heparan sulfate (Fig. 20.15). These components are localized in particular portions of the GBM: • The lamina rara externa, adjacent to the podocyte processes. It is particularly rich in polyanions, such as heparan sulfate, that specifically impede the passage of negatively charged molecules. • The lamina rara interna, adjacent to the capillary e ndothelium. Its molecular features are similar to those of the lamina rara externa. • The lamina densa, the overlapping portion of the two basal laminae, sandwiched between the laminae rarae. It contains type IV collagen, which is organized into a network that acts as a physical filter. Type XVIII collagen, perlecan, and agrin are responsible for the bulk of anionic charges found in glomerular basement membrane. The laminin and other proteins present in the laminae rara i nterna and externa are involved in the attachment of the endothelial cells and podocytes to the GBM. The GBM restricts the movement of particles, usually proteins, larger than approximately 70,000 daltons or 3.6 nm r adius (e.g., albumin or hemoglobin). Although albumin is not a usual constituent, it may sometimes be found in urine, indicating that the size of albumin is close to the effective pore size of the filtration barrier. The polyanionic glycosaminoglycans of the laminae rarae have strong negative charges and restrict the movement of anionic particles and molecules across the GBM, even those smaller than 70,000 daltons. Despite the ability of the filtration barrier to restrict protein, several grams of protein do pass through the barrier each day. Thisprotein is reabsorbed by endocytosis in the proximal convoluted tubule. Albuminuria (presence of signicant amounts of albumin in the urine) or hematuria (presence of signicant amounts of red blood cells in the urine) indicate physical or functional damage to the GBM. In such cases (e.g., diabetic nephropathy), the number of anionic sites, especially in the lamina rara externa, is signicantly reduced. The filtration slit diaphragm acts as a size-selective filter. The narrow slit pores formed by the foot processes of podocytes and the filtration slit diaphragms act as physical barriers to restrict the movement of solutes and solventsacross the filtration barrier. The discovery of specific proteins that form the slit diaphragmhas led to new insights into the function of the filtration apparatus in the kidney. Most of the proteins found in the diaphragm are crucial for normal development and function of the kidney. The slit diaphragm architecture accounts for a true size-selective filter properties, which determine the molecular sieving characteristics of the glomerulus. Several mechanisms prevent clogging of the filtration slit diaphragms. These include, the negative charges of glycosaminoglycans in the GBM, negative charges of the podocyte cell membrane, and the phagocytic function of mesangial cells in the renal corpuscle.Changes in different components of the filtration apparatus influence the functions of one another. The molecular structure and composition of each component of the glomerular filtration barrier has important consequences for adjacent components of the barrier. For instance, molecular changes in the GBM not only modify the contribution of this layer but also modify the rate at which solutes and solvents pass through the endothelium of glomerular capillaries on one side and the visceral layer of the Bowman’s capsule on the other. In addition, it is important to understand that glomerular filtration barrier is not a passive but an active structure that can remodel itself and modify its own permeability. Simple squamous epithelium constitutes the parietal layer of Bowman’s capsule. The parietal layer of Bowman’s capsule contains parietal epithelial cells and forms a simple squamous epithelium. At the urinary pole of the renal corpuscle, the parietal layer is continuous with the cuboidal epithelium of the proximal convoluted tubule (see Figs. 20.7 and 20.11). Proliferation of parietal epithelial cells is a typical diagnostic feature in certain types of glomerulonephritis (inammation of the glomerulus). For an example of such a disease, see Folder 20.2. The space between the visceral and parietal layers of Bowman’s c apsule is called the urinary space or Bowman’s space (see Fig. 20.11). It is the receptacle for the glomerular ultrafiltrate (primary urine) produced by thefiltration apparatus of the renal corpuscle. At the urinary pole of the renal corpuscle, the urinary space is continuous with the lumen of the proximal convoluted tubule.

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Embryonic Image

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Glomer

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Mesangium

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The renal corpuscle contains an additional group of cells called mesangial cells. These cells and their extracellular matrix constitute the mesangium. It is most obvious at the vascular stalk of the glomerulus and at the interstices of adjoining glomerular capillaries. Mesangial cells are positioned much the same as pericytes, in that they are enclosed by the GBM (Fig. 20.16). The mesangial cells are not confined entirely to the renal corpuscle; some are located outside the corpuscle along the vascular pole, where they are also designated as lacis cellsand form part of what is called the juxtaglomerular apparatus (see Fig. 20.7). Important functions of the mesangial cells follow: • Phagocytosis and endocytosis. Mesangial cells remove trapped residues and aggregated proteins from the GBM and filtration slit diaphragm, thus keeping the glomerular filter free of debris. They also endocytose and process a v ariety of plasma proteins including immune complexes. Maintaining the structure and function of glomerular barrier is the primary function of the mesangial cells. • Structural support. Mesangial cells produce components of mesengial matrix, which provide support for the 710 podocytes in the areas where the epithelial basement membrane is absent or incomplete (see Fig 20.16). • Secretion. Mesangial cells synthesize and secrete a variety of molecules such as interleukin 1 (IL-1), PGE2, and platelet-derived growth factor (PDGF), which play a central role in response to glomerular injury. • Modulation of glomerular distension. Mesangial cells have contractile properties. In the past, it was suggested that contraction of mesangial cells could increase the intraglomerular blood volume and filtration pressure. Recent studies revealed that mesangial contribution to glomerular filtration rate is minimal, and the mesangial cells may function in regulating glomerular distension in response to increased blood pressure. • Clinically, it has been observed that mesangial cells proliferate in certain kidney diseases, in which abnormal amounts of protein and protein complexes are trapped in the GBM. Proliferation of mesangial cells is a prominent feature in the immunoglobulin A (IgA) nephropathy (Berger disease), membranoproliferative glomerulonephritis, lupus nephritis, and diabetic nephropathy.Embryologically, mesangial, and juxtaglomerular cells (discussed in a following paragraph) are derived from smooth muscle cell precursors. Although mesangial cells are clearly phagocytotic, they are unusual in the sense that they are not derived from the usual precursor cells of the mononuclear phagocytotic system, the blood-borne monocytes

Hint 15

As discussed earlier in the section on the basal lamina assembly (see Chapter 5, page 139), the major building block of any basement membrane, including glomerular basement membrane (GBM), is the type IV collagen molecule. Its core structure is composed of three -chain monomers, each representing one or more of six types of -chains known for type IV collagen (see Table 6.2; page 165). Each molecule has three domains: an aminoterminus 7S domain, a middle collagenous helical domain, and a carboxy-terminus noncallagenous NC1 domain. Molecular architecture of type IV collagen is a key to understanding pathophysiology of glomerular kidney diseases. For instance, an autoimmune response to the noncollagenous NC1 domain of the 3-chain of type IV collagen [3(IV)] in the GBM is responsible for the development of anti-GBM antibody-induced glomerulonephritis. This condition is characterized by a linear deposition of immunoglobulin G (IgG) antibodies in the GBM. In some individuals, anti-GBM antibodies may cross-react with alveolar basement membrane in the lungs, producing Goodpasture syndrome. The clinical feature of Goodpasture syndrome is rap idly progressive glomerulonephritis (inflammation in the glomeruli) and pulmonary hemorrhage due to disruption of the air–blood barrier. In response to deposition of IgG in the glomerulus, the complement system is activated andcirculating leukocytes elaborate a variety of proteases, leading to disruption of the GBM and deposition of fibrin. Fibrin, in turn, stimulates the proliferation of parietal cells lining Bowman’s capsule and cause influx of monocytes from the circulation. The product of these reactions is often seen within the glomerulus as a crescent, a characteristic microscopic feature of glomerulonephritis (Fig. F20.2.1). Most patients affected by Goodpasture syndrome have a severe crescentic glomerulonephritis with transiently elevated levels of circulating anti-GBM antibodies. Formation of anti-GBM antibodies is most likely triggered by viruses, cancers, pharmacologic agents, and chemical compounds found in a variety of paints, solvents, and dyes. Individuals with Goodpasture syndrome present with both respiratory and urinary symptoms. These include shortness of breath, cough, and bloody sputum, as well as hematuria (blood in urine), proteinuria (proteins in the urine), and other symptoms of progressing kidney failure. The main therapeutic goal in treating Goodpasture syndrome is to remove the circulating pathogenic antibodies from the blood. This is achieved by plasmapheresis, in which blood plasma is removed from the circulation and replaced by fluid, protein, or donated plasma. In addition, treatment with immunosuppressive drugs and corticosteroids is beneficial to keep the immune system from producing pathogenic autoantibodies.

Front 16

Juxtaglomerular Apparatus

Back 16

The juxtaglomerular apparatus includes the macula densa, the juxtaglomerular cells, and the extraglomerular mesangial cells. Lying directly adjacent to the afferent and efferent arterioles and adjacent to some extraglomerular mesangial cells at thvascular pole of the renal corpuscle is the terminal portion of the distal straight tubule of the nephron. At this site, the wall of the tubule contains cells that are referred to collectively as the macula densa. When viewed in the light microscope, the cells of the macula densa are distinctive, in that they are narrower and usually taller than other distal tubule cells (see Fig. 20.7). The nuclei of these cells appear crowded, even to the extent that they appear partially superimposed over one another, thus the name “macula densa.” In this same region, the smooth muscle cells of the adjacent afferent arteriole (and, sometimes, the efferent arteriole) are modified. They contain secretory granules, and their nuclei are spherical, as opposed to the typical elongate smooth muscle cell nucleus. These juxtaglomerular cells(see Fig. 20.7) require spe cialstains to reveal the secretory vesicles in the light microscope. The juxtaglomerular apparatus regulates blood pressure by activating the renin–angiotensin–aldosterone system. In certain physiologic (low sodium intake) or pathologic conditions (decrease in volume of circulating blood because of hemorrhage or reduction in renal perfusion owing to compression of the renal arteries), juxtaglomerular cells are responsible for activating the renin–angiotensin–aldosterone system (RAAS). This system plays an important role in maintaining sodium homeostasis and renal hemodynamics. The granules of the juxtaglomerular cells contain an aspartyl protease, called renin,which is synthesized, stored, and released into the bloodstream from the modified smooth muscle cells. In the blood, renin catalyzes the hydrolysis of a circulating 2-globulin, angiotensinogen,to produce the d ecapeptide angiotensin I. Then, • Angiotensin I is converted to the active octapeptide angiotensin II by angiotensin-converting enzyme (ACE) present on the endothelial cells of lung capillaries. • Angiotensin II stimulates the synthesis and release of the hormone aldosterone from the zona glomerulosa of the adrenal gland (see page 766). • Aldosterone, in turn, acts on collecting ducts to increase reabsorption of sodium and concomitant reabsorption of water, thereby raising blood volume and pressure. • Angiotensin II is also a potent vasoconstrictor that has a regulatory role in the control of renal and systemic vascular resistance. The juxtaglomerular apparatus functions not only as an endocrine organ that secretes renin but also as a sensor of blood volume and tubular fluid composition. The cells of the macula densa monitor the Na concentration in the tubular fluid and regulate both the glomerular filtration rate and the release of renin from the juxtaglomerular cells. The decreased Naconcentration in the distal convoluted tubule is believed to be a stimulus for unique ion-transporting molecules expressed on the apical membrane of macula densa cells. These molecules include Na/2Cl/K cotransporters, Na/H exchangers, and pH- and calcium-regulated K channels. Activation of membrane transport pathways changes the intracellular ion concentration within the macula densa cells and initiates signaling mechanisms by releasing various mediators such as ATP, adenosine, nitric oxide (NO), and prostaglandins (PGE2). These molecules act in a paracrine manner and signal both the underlying juxtaglomerular cells of the afferent arteriole to secrete renin and the vascular smooth muscle cells to contract. Ani ncrease in blood volume sufficient to cause stretching of the juxtaglomerular cells in the afferent arteriole may be the stimulus that closes the feedback loop and stops secretion of renin.

Hint 16

For years, cardiologists and nephrologists believed that chronic essential hypertension, the most common form of hypertension, was somehow related to an abnormality in the RAAS. However, 24-hour urine renin levels in such patients were usually normal. Not until a factor in the venom of a South American snake was shown to be a potent inhibitor of angiotensin-converting enzyme (ACE) in the lung did investigators have both a clue to the cause of chronic essential hypertension and a new series of drugs with which to treat this common disease.The “lesion” in chronic essential hypertension is now believed to be excessive production of angiotensin II in the lung. Development of the so-called ACE inhibitors—captopril, enalapril, and related derivatives of the original snake venom factor—has revolutionized the treatment of chronic essential hypertension. These antihypertensive drugs do not cause the often-dangerous side effects of the diuretics and -blockers that were previously the most commonly used drugs for control of this condition.

Front 17

Kidney Tubules Fx:

Back 17

As the glomerular ultraltratepasses through the uriniferous and collecting tubules of the kidney, it undergoes changes that involve both active and passive absorption, as well as secretion. • Certain substances within the ultrafiltrate are reabsorbed, some partially (e.g., water, sodium, and bicarbonate) and some completely (e.g., glucose). • Other substances (e.g., creatinine and organic acids and bases) are added to the ultrafiltrate (i.e., the primary urine) by secretory activity of the tubule cells. Thus, the volume of the ultrafiltrate is reduced substantially, and the urine is made hyperosmotic. The long loop of Henle and the collecting tubules that pass parallel to similarly arranged blood vessels, the vasa recta, serve as the basis for the countercurrent multiplier mechanism that is instrumental in concentrating the urine, thereby making it hyperosmotic.

Hint 17

Urinalysisis an important part of the examination of patients with suspected renal disease. It typically includes several measurement of physical, biochemical, and microscopic urine characteristics such as pH, specific gravity (indirect measurement of ion concentration), bilirubin, concentration of intermediate compounds derived from the fatty acid metabolism known as ketone bodies, hemoglobin, and concentration of the proteins. Important part of this analysis includes the determination of the amount of protein excreted in the urine. The excretion of excessive amounts of protein (i.e., proteinuria [albuminuria]) is an important diagnostic sign of renal disease. Normally, less than 150 mg of protein is excreted in the urine each day. Although excessive excretion of protein almost always indicates renal disease, extreme exercise, such as jogging, or severe dehydration may produce increased proteinuria in individuals without renal disease. Microscopic examination of the urine may reveal presence of red and white blood cells, mineral crystals, and pathogenic agents such as bacteria or fungi. Often these elements areenclosed within the cylindrical structures called urinary casts. The matrix of urinary cast is formed by an 85- kilodalton protein, uromodulin (Tamm-Horsfall protein) that precipitate in the lumen of distal convoluted tubes and collecting ducts during a disease process.

Front 18

Proximal Convoluted Tubule

Back 18

The proximal convoluted tubule is the initial and major site of reabsorption. The proximal convoluted tubule receives the ultrafiltrate from the urinary space of Bowman’s capsule. The cuboidal cells of the proximal convoluted tubule have the elaborate surface specializations associated with cells engaged in absorption and fluid transport. They exhibit the following features: • A brush border, composed of relatively long, closely packed, and straight microvilli (Fig. 20.17) • A junctional complex, consisting of a narrow, tight junction that seals off the intercellular space from the lumen of the tubule and a zonula adherens that maintains the adhesion between neighboring cells • Plicae or folds located on the lateral surfaces of the cells, which are large flattened processes, alternating with similar processes of adjacent cells (see Fig. 20.16) • Extensive interdigitation of basal processes of adjacent cells (Figs. 20.18 and 20.19) • Basal striations, consisting of elongate mitochondria concentrated in the basal processes and oriented vertically to the basal surface (see Fig. 20.18) In well-fixed histologic preparations, the basal striations and the apical brush border help to distinguish the cells of the proximal convoluted tubule from those of the other tubules. At the very base of the proximal convoluted tubule cell, in the interdigitating processes, bundles of 6-nm microfilaments are present (see arrows, Figs. 20.18 and 20.19). These actin filaments may play a role in regulating the movement of fluid from the basolateral extracellular space across the tubule basal lamina toward the adjacent peritubular capillary. Of the 180 L/day of ultrafiltrate entering the nephrons, approximately 120 L/day, or 65% of the ultrafiltrate, is reabsorbed by the proximal convoluted tubule. Two major proteins are responsible for fluid reabsorption in the proximal convoluted tubules:

• Na/K-ATPase pumps, transmembrane proteins that are localized in the lateral folds of the plasma membrane. They are responsible for the reabsorption of Na, which is the major driving force for reabsorption of water in the proximal convoluted tubule. As in the intestinal and gallbladder epithelia, this process is driven by active transport of Na into the lateral intercellular space. Active transport ofNa is followed by passive diffusion of Clto maintain electrochemical neutrality. The accumulation of NaCl in the lateral intercellular spaces creates an osmotic gradient that draws water from the lumen into the intercellular compartment. This compartment distends as the amount of fluid in it increases; the lateral folds separate to allow this distension. • AQP-1, a small (30 kilodaltons) transmembrane protein that functions as a molecular water channel in the cell membrane of proximal convoluted tubules. Movement of water through these membrane channels does not require the high energy of Na/K-ATPase pumps. Immunocytochemical methods can be used to demonstrate the presence of these proteins. • The hydrostatic pressure that builds up in the distended intercellular compartment, presumably aided by contractile activity of the actin filaments in the base of the tubule cells, drives an essentially isosmotic fluid across the tubule basement membrane into the renal connective tissue. Here, the fluid is reabsorbed into the vessels of the peritubular capillary network. The proximal convoluted tubule also reabsorbs amino acids, sugars, and polypeptides. As in the intestine, the microvilli of proximal convoluted tubule cells are covered with a well-developed glycocalyx that contains several ATPases, peptidases, and high concentrations of disaccharidases. In addition to amino acids and monosaccharides, the ultrafiltrate also contains small peptides and disaccharides. The latter adsorb on the glycocalyx for further digestion before internalization of the resulting amino acids and monosaccharides (including glucose). Also, as in the gut, amino acid and glucose resorption in the proximal convoluted tubule depends on active Na transport. Proteins and large peptides are endocytosed in the proximal convoluted tubule. Deep tubular invaginations are present between the microvilli of the proximal convoluted tubule cells. Proteins in the ultrafiltrate, on reaching the tubule lumen, bind to the glycocalyx that covers the plasma membrane of the invaginations. Then endocytotic vesicles containing the bound protein bud from the invaginations and fuse in the apical cytoplasm to form large protein-containing early endosomes (see Fig. 20.18). These early endosomes are destined to become lysosomes, and the endocytosed proteins are degraded by acid hydrolases. The amino acids produced in the lysosomal degradation are recycled into the circulation via the intercellular compartment and the interstitial connective tissue. Also, the pH of the ultrafiltrate is modified in the proximal convoluted tubule by the reabsorption of bicarbonate and by the specific secretion into the lumen of exogenous organic acids and organic bases derived from the peritubular capillary circulation.

Hint 18

Aquaporins (AQPs) are a recently recognized family of small, hydrophobic, transmembrane proteins that mediate water transport in the kidney and other organs (i.e., liver, gallbladder). To date, 13 proteins have been characterized and cloned. The molecular size of AQPs ranges from 26 to 34 kilodaltons. Each protein consists of six transmembrane domains arranged to form a distinct pore. The sites where AQPs are expressed implicate their role in water transport, such as renal tubules (water reabsorption), brain and spinal cord (cerebrospinal fluid reabsorption), pancreatic acinar cells (secretion of pancreatic fluids), lacrimal apparatus (secretion and resorption of tears), and eye (aqueous humor secretion and reabsorption). Most AQPs are selective for the passage of water (AQP-1, AQP-2, AQP-4, AQP-5, AQP-6, and AQP-8), whereas others, such as AQP-3, AQP-7, and AQP-9, called aquaglyceroporins, also transport glycerol and other larger molecules in addition to water. Prominent members of the AQP family include • AQP-1, expressed in kidney (proximal convoluted tubules) and other cell types such as hepatocytes and red blood cells. AQP-1 is also expressed in the lymphnodes, endothelial cells lining lymphatic sinuses, and on the vascular endothelium of high endothelial venules as well as in the endothelial cells of intestinal lacteals. • AQP-2, present in the terminal portion of the distal convoluted tubules and in the epithelium of collecting tubules and ducts. AQP-2 is under the regulation of antidiuretic hormone (ADH) and is thus known as an ADHregulated water channel. Mutation of the AQP-2 gene has been linked to congenital nephrogenic diabetes insipidus. • AQP-3 and AQP-4 have also been detected in the basolateral cell surface of the light cells of kidney collecting ducts as well in the gastrointestinal epithelium (AQP-3), pancreatic acinar cells (AQP-12), and the brain and spinal cord (AQP-4). Current research into the function and structure of the AQP proteins may lead to the development of water channel blockers that could be used to treat hypertension, congestive heart failure, and brain swelling and to regulate intracranial or intraocular pressure

Front 19

Proximal Straight Tubule

Back 19

The cells of the proximal straight tubule (i.e., the thick descending limb of the loop of Henle) are not as specialized for absorption.

They are shorter, with a less well-developed brush border and with fewer and less complex lateral and basolateral processes. The mitochondria are smaller than those of the cells of the convoluted segment and are randomly distributed in the cytoplasm. There are fewer apical invaginations and endocytotic vesicles, as well as fewer lysosomes.

Front 20

Thin Segment of Loop of Henle

Back 20

As noted above, the length of the thin segmentvaries with the location of the nephron in the cortex. Juxtamedullary nephrons have the longest limbs; cortical nephrons have the shortest. Furthermore, various cell types are present in the thin segment. In the light microscope, it is possible to detect at least two kinds of thin segment tubules, one with a more squamous epithelium than the other. Electron microscopic examination of the thin segments of various nephrons reveals further differences, namely, the existence of four types of epithelial cells (Fig. 20.20): • Type I epithelium is found in the thin descending and ascending limbs of the loop of Henle of short-looped nephrons. It consists of a thin, simple epithelium. The cells have almost no interdigitations with neighboring cells and few organelles. • Type II epithelium, found in the thin descending limb of long-looped nephrons in the cortical labyrinth, consists of taller epithelium. These cells possess abundant organelles and have many small, blunt microvilli. The extent of lateral interdigitation with neighboring cells varies by species. • Type IIIepithelium, found in the thin descending limb in the inner medulla, consists of a thinner epithelium. The cells have a simpler structure and fewer microvilli than type II epithelial cells. Lateral interdigitations are absent.• Type IV epithelium, found at the bend of long-looped nephrons and through the entire thin ascending limb, consists of a low, flattened epithelium without microvilli. The cells possess few organelles. The specific functional roles of the four cell types in the thin segment are not yet clear, although this segment is part of the countercurrent exchange system that functions in concentrating urine. Morphologic differences, such as microvilli, mitochondria, and degree of cellular interdigitation, probably reflect specific active or passive roles in this process. The thin descending and ascending limbs of the loop of Henle differ in structural and functional properties. Studies of ultrafiltrate that enters the thin descending limb and leaves the thin ascending limb of the loop of Henle reveal dramatic changes in ultrafiltrate osmolality. The ultrafiltrate that enters the thin descending limb is isosmotic, whereas the ultrafiltrate leaving the thin ascending limb is hyposmotic to plasma. This change is achieved by reabsorbing more salts than water. The two limbs of the loop of Henle have different permeabilities and thus different functions: • The thin descending limbof the loop of Henle is highly permeableto water and much less permeable to solutes like NaCl and urea. Because the interstitial fluid in the medulla is hyperosmotic, water diffuses out of this nephron segment. In addition, a small amount of NaCl and urea enters the nephron at this site. The cells of this limb do not actively transport ions; thus the increased tubular fluid osmolality that occurs in this nephron segment is caused in large part by the passive movement of water into the p eritubular connective tissue Further, the thin ascending limb is largely impermeable to water, so that at this site, as the salt concentration increases in the interstitium, the interstitium becomes hyperosmotic and the fluid in the lumen of the nephron becomes hyposmotic. In addition, epithelial cells lining the thick ascending limb produce an 85-kilodalton protein called uromodulin (Tamm-Horsfall protein) that influences NaCl reabsorption and urinary concentration ability. Uromodulin also modulates cell adhesion and signal transduction by interacting with various cytokines, as well as it inhibits the aggregation of calcium oxalate crystals (preventing kidney stones formation) and provides a defense against urinary tract infection. In individuals with inflammatory kidney diseases, a precipitated uromodulin is detected in urine in the form of urinary casts (see Folder 20.3).

Front 21

Distal Straight Tubule

Back 21

The distal straight tubule is a part of the ascending limb of the loop of Henle. The distal straight tubule(thick ascending limb), as previously noted, is a part of the ascending limb of the loop of Henleand includes both medullary and cortical portions, with the latter located in the medullary rays. The distal straight tubule, like the ascending thin limb, transports ions from the tubular lumen to the interstitium. The apical cell membrane in this segment has electroneutral transporters (synporters) that allow Cl, Na, and K to enter the cell from the lumen. Na is actively transported across the extensive basolateral plications by the Na/K-ATPase pumps; Cl and K diffuse out from the intracellular space by the Cl and K channels. Some K ions leak back into the tubular fluid through K channels, causing the tubular lumen to be positively charged with respect to the interstitium. This positive gradient provides the driving force for the reabsorption of many other ions such as Ca2 and Mg2. Note that this significant movement of ions occurs without the movement of water through the wall of the distal straight tubule, resulting in separation of water from its solutes. In routine histologic preparations, the large cuboidal cells of the distal straight tubule stain lightly with eosin, and the lateral margins of the cells are indistinct (Plate 77, page 734). The nucleus is located in the apical portion of the cell and sometimes, especially in the straight segment, causes the cell to bulge into the lumen. As noted above, these cells have extensive basolateral plications, and there are numerous mitochondria associated with these basal folds (Fig. 20.21). They also have considerably fewer and less well-developed microvilli than proximal straight tubule cells (compare Figs. 20.18 and 20.19).

Front 22

Distal Convoluted Tubule

Back 22

The distal convoluted tubule exchanges Na for K under aldosterone regulation. The distal convoluted tubule, located in the cortical labyrinth, is only about one third as long (5 mm) as the proximal convoluted tubule. This short tubule is responsible for • reabsorption of Naand secretion of K into the ultrafiltrate to conserve Na. • reabsorption of bicarbonate ions, with concomitant secretion of hydrogen ions, leading to further acidification of the urine. • secretion of ammoniumin response to the kidneys’ need to excrete acid and generate bicarbonate. Aldosterone, secreted by the adrenal gland and released under stimulation by angiotensin II, increases the reabsorption of Na and secretion of K. These effects increase blood volume and blood pressure in response to increased blood Na concentration.

Front 23

Collecting Tubules and Collecting Ducts

Back 23

The collecting tubules as well as the cortical collecting ducts and medullary collecting ducts are composed of simple epithelium. The collecting tubules and cortical collecting ducts have flattened cells, somewhat squamous to cuboidal in shape. The medullary collecting ducts have cuboidal cells, with a transition to columnar cells as the ducts increase in size. The collecting tubules and ducts are readily distinguished from proximal and distal tubules by virtue of the cell boundaries that can be seen in the light microscope (Plate 77, page 734). Two distinct types of cells are present in the collecting tubules and collecting ducts: • Light cells, also called collecting duct cells orCD cells, are the principal cells of the system. They are pale-staining cells with true basal infoldings rather than processes that interdigitate with those of adjacent cells. They possess a single primary cilium and relatively few short microvilli (Fig. 20.22). They contain small, spherical mitochondria. These cells possess an abundance of antidiuretic hormone (ADH)–regulated water channels, aquaporin-2 (AQP-2), which are responsible for water permeability of the collecting ducts. In addition, aquaporins AQP-3 and AQP-4 are present within the basolateral membrane of these cells. • Dark cells, also called intercalated (IC) cells, occur in considerably smaller numbers. They have many mitochondria, and their cytoplasm appears denser. Microplicae, cytoplasmic folds, are present on their apical surface, as well as microvilli. The microplicae are readily observed with the SEM but may be mistaken for microvilli with the TEM (see Fig. 20.22). They do not show basal infoldings but have basally located interdigitations with neighboring cells. Numerous vesicles are present in the apical cytoplasm. The intercalated cells are involved in the secretion of H (-intercalated cells) or bicarbonate (-intercalated cells), depending on the whether the kidneys need to e xcrete acid or alkali. The -intercalated cell actively secretes H into the collecting duct lumen via ATP-dependent pumps and r eleases HCO3 via Cl/HCO3 exchangers located in their basolateral cell membrane. The -intercalated cells have opposite polarity and secrete bicarbonate ions into the lumen of the collecting duct. B ecause of the nature of the diet and thus the need to e xcrete acid, the epithelium of collecting ducts contains more - than -intercalated cells. The cells of the collecting ducts gradually become taller as the ducts pass from the outer to the inner medulla and become columnar in the region of the renal papilla. The number of dark cells gradually decreases until there are none in the ducts as they approach the papilla.

Front 24

INTERSTITIAL CELLS

Back 24

The connective tissue of the kidney parenchyma, called interstitial tissue, surrounds the nephrons, ducts, and blood and lymphatic vessels. This tissue increases considerably in amount from the cortex (where it constitutes approximately 7% of the volume) to the inner region of the medulla and papilla (where it may constitute more than 20% of the volume). In the cortex, two types of interstitial cells are recognized: cells that resemble fibroblasts, found between the basement membrane of the tubules and the adjacent peritubular capillaries, and occasional macrophages. In their intimate relationship with the base of the tubular epithelial cells, the fibroblasts resemble the subepithelial fibroblasts of the intestine. These cells synthesize and secrete the collagen and glycosaminoglycans of the extracellular matrix of the interstitium. In the medulla, the principal interstitial cells resemble myofibroblasts. They are oriented to the long axes of the tubular structures and may have a role in compressing these structures. The cells contain prominent bundles of actin filaments, abundant rough endoplasmic reticulum (rER), a welldeveloped Golgi complex, and lysosomes. Prominent lipid droplets in the cytoplasm appear to increase and decrease in relation to the diuretic state.

//Most fibroblasts originate within the interstitial tissue through a mechanism called epithelial–mesenchymal transition. The conversion of tubular epithelial cells into a mesenchymal phenotype is initiated by an alteration in the balance of local cytokine concentrations. During persistent injury and chronic inflammation of the kidney parenchyma, fibroblasts increase their numbers and, by secreting excess extracellular matrix, destroy normal interstitial architecture of the kidney. Research studies suggest that in renal fibrosis, more than one third of all disease-related fibroblasts originate from tubular epithelial cells at the site of injury. Proliferation of fibroblasts in response to local mitogens usually leads to irreversible renal failure characterized by tubulointerstitial nephritis. Recent therapeutic interventions in renal fibrosis are directed toward inhibiting fibroblast formation by shifting local cytokine balance in favor of reversal mesenchymal– epithelial transition.

Front 25

Histophysiology

Back 25

The countercurrent multiplier system creates hyperosmotic urine. The term countercurrent indicates a flow of fluid in adjacent structures in opposite directions. The ability to excrete hyperosmotic urine depends on the countercurrent multiplier system that involves three structures: • Loop of Henle, which acts as a countercurrent multiplier. The ultrafiltrate moves within the descending limb of the thin segment of the loop toward the renal papilla and moves back toward the corticomedullary junction within the ascending limb of the thin segment. The osmotic gradients of the medulla are established along the axis of the loop of Henle. • Vasa recta, form loops parallel to the loop of Henle. They act as countercurrent exchangers of water and solutes between the descending part (arteriolae rectae) and ascending part (venulae rectae) of the vasa recta. The vasa recta help to maintain the osmotic gradient of the medulla. • Collecting duct in the medulla acts as an osmoticequilibrating device. Modified ultrafiltrate in the collecting ducts can be further equilibrated with the hyperosmotic medullary interstitium. The level of equilibration d epends on activation of ADH-dependent water channels (AQP-2).A standing gradient of ion concentration produces hyperosmotic urine by a countercurrent multiplier effect. The loop of Henle creates and maintains a gradient of ion concentration in the medullary interstitium that increases from the corticomedullary junction to the renal papilla. As noted above, the thin descending limb of the loop of Henle is freely permeable to water, whereas the ascending limb of the loop of Henle is impermeable to water. Further, the thin a scending limb cells add Na and Cl to the interstitium. Because water cannot leave the thin ascending limb, the interstitium becomes hyperosmotic relative to the luminal contents. Although some of the Cl and Na of the interstitium diffuses back into the nephron at the thin descending limb, the ions are transported out again in the thin ascending limb and distal straight tubule (thick ascending limb). This produces the countercurrent multiplier effect. Thus, the concentration of NaCl in the interstitium gradually increases down the length of the loop of Henle and, consequently, through the thickness of the medulla from the corticomedullary junction to the papilla.Vasa recta containing descending arterioles and ascending venules act as countercurrent exchangers. For an understanding of the countercurrent exchange mechanism, it is necessary to resume the description of the renal circulation at the point at which the efferent arteriole leaves the renal corpuscle. The efferent arteriolesof the renal corpuscles of most of the cortex branch to form the capillary network that surrounds the tubular portions of the nephron in the cortex, the peritubular capillary network. The efferent arterioles of the juxtamedullary renal corpuscles form several unbranched a rterioles that descend into the medullary pyramid. These arteriolae rectaemake a hairpin turn deep in the medullary

pyramid and ascend as the venulae rectae. Together, the descending arterioles and the ascending venules are called the vasa recta. The arteriolae rectae form capillary plexuses lined by fenestrated endothelium that supply the tubular structures at the various levels of the medullary pyramid.Interaction between collecting ducts, loops of Henle, and vasa recta is required for concentrating urine by the countercurrent exchange mechanism. Because the thick ascending limb of the loop of Henle has a high level of transport activity and because it is impermeable to water, the modified ultrafiltrate that ultimately reaches the distal convoluted tubule is hyposmotic. When ADH is present, the distal convoluted tubules, the collecting tubules, and the collecting ducts are highly permeable to water. Therefore, within the cortex, in which the interstitium is isosmotic with blood, the modified ultrafiltrate within the distal convoluted tubule equilibrates and becomes isosmotic, partly by loss of water to the interstitium and partly by addition of ions other than Naand Clto the ultrafiltrate. In the medulla, increasing amounts of water leave the ultrafiltrate as the collecting ducts pass through the increasingly hyperosmotic interstitium on their course to the papillae. As noted previously, the vasa rectae also form loops in the medulla that parallel the loop of Henle. This arrangement ensures that the vessels provide circulation to the medulla without disturbing the osmotic gradient established by transport of Cl in the epithelium of the ascending limb of the loop of Henle. The vasa recta form a countercurrent exchange system in the following manner: Both the arterial and venous sides of the loop are thin-walled vessels that form plexuses of fenestrated capillaries at all levels in the medulla. As the arterialvessels descend through the medulla, the blood loses water to the interstitium and gains salt from the interstitium so that at the tip of the loop, deep in the medulla, the blood is essentially in equilibrium with the hyperosmotic interstitial fluid. As the venous vessels ascend toward the corticomedullary junction, the process is reversed (i.e., the hyperosmotic blood loses salt to the interstitium and gains water from the interstitium). This passive countercurrent exchange of water and salt between the blood and the interstitium occurs without expenditure of energy by the endothelial cells. The energy that drives this system is the same energy that drives the multiplier system, namely, the movement of Na and Cl out of the cells of the wateri mpermeable ascending limb of the loop of Henle. The countercurrent exchange system and other movements of molecules in different parts of the nephron are shown in Figure 20.23.

Hint 25

Water permeability of the epithelium of the collecting ducts is regulated by antidiuretic hormone (ADH, vasopressin), a hormone produced in the hypothalamus and released from the posterior lobe of the pituitary gland. ADH increases the permeability of the collecting duct to water, thereby producing more-concentrated urine. At the molecular level, ADH acts on ADH-regulated water channels, aquaporin 2 (AQP-2), located in the epithelium of the terminal portion of the distal convoluted tubule and in the epithelium of the collecting tubules and ducts. However, the action of ADH is more significant in the collecting tubules and collecting ducts. ADH binds to receptors on the cells of these tubules and triggers the following actions: • Translocation of the AQP-2–containing intracytoplasmic vesicles into the apical cell surface—a shortterm effect. This results in an increased number of available AQP-2 channels at the cell surface, thus increasing water permeability of the epithelium. • Synthesis of AQPs-2and their insertion into the apical cell membrane—a long-term effectAn increase in plasma osmolality or a decrease in blood volume stimulates release of ADH, as does nicotine. In the absence of ADH, copious, dilute urine is produced. This condition is called central diabetes insipidus (CDI). Recent studies indicate that mutation of two genes encoding AQP-2 and ADH receptors is responsible for a form of CDI called nephrogenic diabetes insipidus. In this disease, the kidney does not respond to ADH because of defective AQP-2 and ADH receptor proteins synthesized by the collecting tubule and duct epithelial cells. Excess water consumption can also inhibit ADH release, thereby promoting the production of a large volume of hyposmotic urine. Increased secretion of ADH can produce an extremely hyperosmotic urine, thereby conserving water in the body. Inadequate consumption of water or loss of water because of sweating, vomiting, or diarrhea stimulates release of ADH. This leads to an increase in the permeability of the epithelium of the distal and collecting tubules and promotes the production of a small volume of hyperosmotic urine.

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BLOOD SUPPLY

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Y Some aspects of the blood supply of the kidney have been described in relation to specific functions (i.e., glomerular filtration, control of blood pressure, and countercurrent exchange). It remains, however, to provide an overall description of the blood supply of the kidney. Each kidney receives a large branch from the abdominal aorta, called the renal artery. The renal artery branches within the renal sinus and sends interlobar arteries into the substance of the kidney (Fig. 20.24). These arteries travel between the pyramids as far as the cortex and then turn to follow an arched course along the base of the pyramid between the medulla and the cortex. Thus, these interlobar arteries are designated arcuate arteries. Interlobular arteries branch from the arcuate arteries and ascend through the cortex toward the capsule. Although the boundaries between lobules are not distinct, the interlobular a rteries, when included in a section cut perpendicular to the vessel, are located midway between adjacent medullary rays, traveling in the cortical labyrinth. As they traverse the cortex toward the capsule, the interlobular arteries give off branches, the afferent arterioles, one to each glomerulus. A single afferent arteriole may spring directly from the interlobular artery, or a common stem from the interlobular artery may branch to form several afferent arterioles. Some interlobular arteries terminate near the periphery of the cortex, whereas others enter the kidney capsule to provide its arterial supply.Afferent arterioles give rise to the capillaries that form the glomerulus. The glomerular capillaries reunite to form an efferent arteriole that, in turn, gives rise to a second network of capillaries, the peritubular capillaries. The arrangement of these capillaries differs according to whether they originate from cortical or juxtamedullary glomeruli. • Efferent arterioles from cortical glomeruli lead into a peritubular capillary network that surrounds the local uriniferous tubules (G1 and G2, Fig. 20.24). • Efferent arterioles from juxtamedullary glomeruli descend into the medulla alongside the loop of Henle; they break up into smaller vessels that continue toward the apex of the pyramid but make hairpin turns at various levels treturn as straight vessels toward the base of the pyramid (see G3, Fig. 20.24). Thus, the efferent arterioles from the juxtamedullary glomeruli give rise to vasa recta involved in the countercurrent exchange system and their peritubular capillary network. These vessels are described in the explanation of the countercurrent exchange system (page 721). Generally, venous flow in the kidney follows a reverse course to arterial flow, with the veins running in parallel with the corresponding arteries (see Fig. 20.24). Thus, • Peritubular cortical capillaries drain into interlobular veins, which in turn drain into arcuate veins, interlobar veins, and the renal vein. • The medullary vascular network drains into arcuate veins and so forth. • Peritubular capillaries near the kidney surface and capillaries of the capsule drain into stellate veins (so calledfor their pattern of distribution when viewed from the kidney surface), which drain into interlobular veins , and so forth. LYMPHATIC VESSELSThe kidneys contain two major networks of lymphatic vessels. These networks are not usually visible in routine histologic sections but can be demonstrated by experimental methods. One network is located in the outer regions of the cortex and drains into larger lymphatic vessels in the capsule. The other network is located more deeply in the substance of the kidney and drains into large lymphatic vessels in the renal sinus. There are numerous anastomoses between the two lymphatic networks. NERVE SUPPLY The fibers that form the renal plexus are derived mostly from the sympathetic division of the autonomic nervous system. They cause contraction of vascular smooth muscle and consequent vasoconstriction. • Constriction of the afferent arterioles to the glomeruli reduces the filtration rate and decreases the production of urine. • Constriction of the efferent arterioles from the glomeruli increases the filtration rate and increases the production of urine. • Loss of sympathetic innervation leads to increased urinary output. It is evident, however, that the extrinsic nerve supply is not necessary for normal renal function. Although the nerve fibers to the kidney are cut during renal transplantation, transplanted kidneys subsequently function normally.

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y. URETER, URINARY BLADDER, AND URETHRA

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All excretory passages, except the urethra, have the same general organization. On leaving the collecting ducts at the area cribrosa, the urine enters a series of structures that do not modify it but are specialized to store and pass the urine to the exterior of the body. The urine flows sequentially to a minor calyx, a major calyx, and the renal pelvis, and leaves each kidney through the ureter to the urinary bladder, where it is stored. The urine is finally voided through the urethra. All of these excretory passages, except the urethra, have the same general structures, namely, a mucosa (lined by transitional epithelium), muscularis, and adventitia (or, in some regions, a serosa).Transitional epithelium lines the calyces, ureters, bladder, and the initial segment of the urethra. Transitional epithelium (urothelium) lines the excretory passages leading from the kidney. This stratified epithelium is essentially impermeable to salts and water. The epithelium begins in the minor calyces as two cell layers and increases to an apparent four to five layers in the ureter (Fig. 20.25) and as many as six or more layers in the empty bladder. However,

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muscular sheets. Peristaltic contractions of the smooth muscle move the urine from the minor calyces through the ureter to the bladder. Ureters Each ureter conducts urine from the renal pelvis to the urinary bladder and is approximately 24 to 34 cm long. The distal part of the ureter enters the urinary bladder and follows an oblique path through the wall of the bladder. Transitional epithelium (urothelium)lines the luminal surface of the wall of the ureter. The remainder of the wall is composed of smooth muscle and connective tissue. The smoothmuscle is arranged in three layers: an inner longitudinal layer, a middle circular layer, and an outer longitudinal layer (Plate 78, page 736). However, the outer longitudinal layer is present only at the distal end of the ureter. Usually, the ureter is embedded in the retroperitoneal adipose tissue. The adipose tissue, vessels, and nerves form the adventitia of the ureter. As the bladder distends with urine, the openings of the ureters are compressed, reducing the possibility of reflux of urine into the ureters. Contraction of the smooth muscle of the bladder wall also compresses the openings of the ureters into the bladder. This action helps prevent the spread of infection from the bladder and urethra, frequent sites of chronic infection (particularly in females), to the kidney. In the terminal portion of the ureters, a thick outer layer of longitudinal muscle is present in addition to the two listed above, particularly in the portion of the ureter that passes through the bladder wall. Most descriptions of the bladder musculature indicate that this longitudinal layer continues into the wall of the bladder to form a principal component of its wall. The smooth muscle of the bladder, however, is not as clearly separated into distinctive layers.

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mm