section epub:type=”chapter” id=”c0003″ role=”doc-chapter”> After studying this chapter, the student should be able to: The kidneys are bean-shaped and are located on the posterior abdominal wall in the area known as the retroperitoneum (Fig. 3.1). An adult human kidney has a mass of approximately 150 g and measures roughly 12.5 cm in length, 6 cm in width, and 2.5 cm in depth. When observed in cross-section, two distinct areas of the kidney are apparent: the cortex and the medulla. The outer cortex layer is approximately 1.4 cm thick and is granular in macroscopic appearance. Because all of the glomeruli are located in the outer cortex, the cortex is the exclusive site of the plasma filtration process. The inner layer, the medulla, consists of renal tissue shaped into pyramids. The apex of each of these pyramids is called a papilla; each contains a papillary duct that opens into a cavity called a calyx. The normal human kidney consists of about 12 minor calyces, which join together to form two to three major calyces. Each calyx acts as a funnel to receive urine from the collecting tubules and pass it into the renal pelvis. The funnel-shaped renal pelvis emerges from the indented region of each kidney and narrows to join with the ureter, a fibromuscular tube that is approximately 25 cm long. One ureter extends down from each kidney and connects to the base of the bladder, a muscular sac that is shaped like a three-sided pyramid. The apex of this “bladder pyramid” is oriented downward and is where the urethra originates and extends to the exterior of the body. To review briefly, urine forms as the plasma ultrafiltrate passes through the renal tubules (nephrons) that reside in the renal cortex and the medulla. Thereafter, the urine is transferred via minor and major calyces to the renal pelvis, where peristaltic activity of smooth muscles moves the urine down the ureters into the bladder. The bladder serves as a holding tank for temporary urine storage until it is voided by urination. When approximately 150 mL of urine accumulates, a nerve reflex is initiated. Unless a person overrides the urge to urinate (i.e., the micturition reflex), simultaneous contraction of the bladder muscles and relaxation of the urinary sphincter will result in the passage of urine through the urethra. The urethra, a canal connecting the bladder to the body exterior, is approximately 4 cm long in women and approximately 24 cm long in men. Note that when an individual is healthy, the composition of urine is not altered appreciably at any point after its introduction into the minor and major calyces. The calyces and subsequent anatomic structures serve only as a conveyance for urine, which is the primary excretory product of the kidneys. Each kidney contains approximately 1.3 million nephrons, which are the functional units or tubules of the kidney. A nephron is composed of five distinct areas, each playing an important part in the formation and final composition of the urine. Fig. 3.2 shows a nephron, its component parts, and their physical interrelationships. The glomerulus consists of a capillary tuft surrounded by a thin epithelial layer of cells known as Bowman’s capsule. Bowman’s capsule is actually the originating end of a renal tubule, and its lumen is referred to as Bowman’s space. The plasma ultrafiltrate of low-molecular-weight solutes initially collects in Bowman’s space because of the hydrostatic pressure difference between the capillary lumen and Bowman’s space. The proximal convoluted tubule begins at the glomerulus and extends from it in a circuitous route through the cortex. Eventually the tubule straightens and turns downward, entering the medulla to become the loop of Henle. The loop of Henle has anatomically distinct areas: thin descending and ascending limbs that include a sharp hairpin turn, and thick descending and ascending limbs that are actually straight portions of the proximal and distal tubules (Box 3.1). Upon reentry into the cortex at the macula densa—adjacent to the glomerulus—the straight distal tubule becomes the distal convoluted tubule. Anatomically up to this point, each nephron is structurally and functionally distinct. After this point, the distal convoluted tubules join to a “shared” collecting tubule or duct that conveys the urine produced in several nephrons through the medulla for a second time. These collecting tubules fuse to become the larger papillary ducts that empty into the calyces of the renal pyramids and finally into the renal pelvis. From the renal pelvis, the urine passes to the bladder to await excretion through the urethra. The kidneys require a rich blood supply to execute their primary function of regulating the internal environment of the body. In fact, despite their mass of only 300 g, or 0.5% of the total body mass, the kidneys receive 25% of the total cardiac output. This high degree of perfusion reflects the direct relationship of the kidney’s functional ability to its blood supply. Each kidney is supplied by a single renal artery that originates from the aorta. As the renal artery successively divides, it forms a distinct vascular arrangement unique to and specifically adapted for the functions of the kidney. The kidney is the only human organ in which an arteriole subdivides into a capillary bed, becomes an arteriole again, and then for a second time subdivides into a capillary network. In addition, the renal arterioles are primarily end arteries that supply specific areas of renal tissue and do not interconnect. Therefore disruption in the supply of blood at the afferent arteriole or the glomerulus will dramatically and detrimentally alter the functioning of the associated nephron. Consequently, renal tissue is particularly susceptible to ischemia or infarction. The medulla is especially susceptible because it has no direct arterial blood supply. Should vascular stenosis or an occlusion occur, renal tissue damage will result, and the extent of damage will be dependent on the number and location of the blood vessels involved. An afferent arteriole at the vascular pole supplies blood individually to the glomerulus of each nephron (Fig. 3.3). On entering the glomerulus, the afferent arteriole branches into a capillary tuft, which is related intimately to the epithelial cells of Bowman’s capsule. This branching and anastomosing capillary network comes together to become the efferent arteriole as it leaves the glomerulus. Subsequently, the efferent arteriole branches for a second time into a capillary plexus. The type of nephron that the efferent arteriole services determines the vascular arrangement of this second capillary plexus. Theouter cortical nephrons have short loops of Henle, and the efferent arteriole branches into a fine capillary plexus—the peritubular capillaries—that encompasses the outer cortical tubules entirely. The mid- and deep juxtamedullary nephrons have long loops of Henle. The efferent arterioles of these nephrons first branch into a peritubular capillary bed, which enmeshes the cortical portions of the tubules, and then divide into a series of long, U-shaped vessels, the vasa recta, which descend deep into the renal medulla close to the loops of Henle. The corresponding ascending vasa recta form the beginnings of the venous renal circulation, emerging from deep in the medulla to form venules and drain into the renal veins. The close relationship of the peritubular capillaries and the renal tubules enables the sequential processing and exchange of solutes between the lumen fluid (ultrafiltrate) and the bloodstream throughout the nephron. The unique vascular arrangement of the renal circulation makes it possible for the kidney to function optimally. The comparatively wide-bore afferent arteriole allows for high hydrostatic pressure at the glomerulus. This pressure averages 55 mm Hg, approximately half of the mean arterial blood pressure, and is the driving force behind glomerular filtration. All other capillary beds have a narrower lumen, which causes greater resistance to blood flow and consequently low blood pressure within them. The ultrafiltrate itself also affects the resultant filtration force across the glomerular filtration barrier. The plasma ultrafiltrate already in Bowman’s space exerts a hydrostatic pressure of 15 mm Hg that opposes filtration. In addition, the ultrafiltrate is low in protein and high in water compared with the plasma in the capillary lumen. Hence water that freely passed the filtration barrier seeks to reenter the plasma from Bowman’s space. As a result, an oncotic pressure of 30 mm Hg caused by the higher protein concentration in the plasma opposes glomerular filtration as well. The outcome of these three pressure differences is a net filtration pressure of 10 mm Hg, which favors the formation of a plasma ultrafiltrate in Bowman’s space (Table 3.1). Note that the filtration barrier expends no energy in forming the plasma ultrafiltrate; rather, the cardiac output provides the glomerular capillary blood pressure that drives plasma ultrafiltration. Table 3.1 The afferent and efferent arterioles exit Bowman’s capsule at the vascular pole in proximity to each other. The vascular pole is also the site of the juxtaglomerular apparatus. The morphologically distinct structures that compose the juxtaglomerular apparatus are portions of the afferent and efferent arterioles, the extraglomerular mesangial cells (which are continuous with the supporting mesangium of the glomerulus), and the specialized area of the distal convoluted tubule (known as the macula densa). Characteristically, large quantities of secretory granules containing the enzyme renin are present in the smooth muscle cells of the afferent arteriole located in the juxtaglomerular apparatus. The juxtaglomerular apparatus, which is essentially a small endocrine organ, is the principal producer of renin in the kidney. Renin is an enzyme that when released into the bloodstream in response to decreased blood volume, decreased arterial pressure, sodium depletion, vascular hemorrhage, or increased potassium ultimately forms angiotensin and causes the secretion of aldosterone. Aldosterone secretion stimulates the kidneys to actively retain sodium and passively retain water. As a result, the volume of extracellular fluid expands, the blood pressure increases, and normal potassium levels, as well as normal renal perfusion, are restored. Conversely, an increase in blood volume, an acute increase in blood pressure, or the loss of potassium inhibits renin secretion and enhances sodium excretion (also see Renal Concentrating Mechanism subsection later in this chapter). Because of renin secretion, the juxtaglomerular apparatus and the kidneys play an important role in body fluid homeostasis through their ability to modify blood pressure and fluid balance. Urine formation is the primary excretory function of the kidneys. Urine formation consists of three processes: plasma filtration at the glomeruli followed by reabsorption and secretion of selective components by the renal tubules. Through these processes, the kidneys play an important role in removal of metabolic waste products, regulation of water and electrolytes (e.g., sodium, chloride), and maintenance of the body’s acid-base equilibrium. The kidneys are the true regulators of the body, determining which substances to retain and which to excrete, regardless of what has been ingested or produced. The kidneys process approximately 180,000 mL (125 mL/min) of filtered plasma each day into a final urine volume of 600 to 1800 mL. The largest component of urine is water. The principal solutes present are urea, chloride, sodium, and potassium, followed by phosphate, sulfate, creatinine, and uric acid. Other substances initially in the ultrafiltrate, such as glucose, bicarbonate, and albumin, are essentially completely reabsorbed by the tubules. Consequently, the urine of normal healthy individuals does not contain these solutes in significant amounts. Table 3.2 presents a comparison of selected solutes initially filtered by the glomerulus and the quantity actually excreted after passage through the nephrons. Because normal urine output is approximately 1200 mL (approximately 1% of the filtered plasma volume), 99% of the ultrafiltrate that initially collects in Bowman’s space is actually reabsorbed. In addition, the nephrons of the kidneys extensively and selectively reabsorb and secrete solutes as the ultrafiltrate passes through them. Table 3.2 aAverage 24-hour urine volume; glomerular filtration rate of 125 mL/min. The glomerulus is a tuft of capillaries encircled by and intimately related to Bowman’s capsule, the thin epithelium-lined proximal end of a renal tubule. The glomerulus forms a barrier that is specifically designed for plasma ultrafiltration. Although this glomerular filtration barrier almost completely excludes proteins larger than albumin (molecular weight, 67,000 daltons), it is extremely permeable to water and low-molecular-weight solutes. From the capillary lumen to Bowman’s space, where the plasma filtrate first collects, four structural components are apparent by electron microscopy: the mesangium, consisting of mesangial cells and a matrix; the fenestrated endothelial cells of the capillaries; the podocytes or visceral epithelial cells of Bowman’s capsule; and a distinct trilayer basement membrane sandwiched between the podocytes of Bowman’s capsule and the capillary endothelial cells, or between the podocytes and the mesangium (Fig. 3.4). No basement membrane is present between the capillary endothelium and the mesangium; this provides evidence of the role the basement membrane has in ultrafiltration but not in structural anchoring. Knowledge of the structural composition of the glomerulus is important in understanding its function in health and disease. The mesangium, located within the anastomosing lobules of the glomerular tuft, forms the structural core tissue of the glomerulus. The mesangial cells are thought to be of smooth muscle origin, retaining contractility characteristics and a large capability for phagocytosis and pinocytosis, which helps to remove entrapped macromolecules from the filtration barrier. The ability of mesangial cells to contract also suggests a role in regulating glomerular blood flow. The matrix surrounding the mesangial cells is, as mentioned earlier, continuous with the extraglomerular mesangium of the juxtaglomerular apparatus. The capillary endothelial cells of the glomerulus make up the first component of the actual filtration barrier. The endothelium is fenestrated—that is, it has large open pores 50 to 100 nm in diameter. When viewed from the lumen of the capillary, these openings give the endothelium a dotted swiss appearance (Fig. 3.5). In addition, the capillary endothelium possesses a negatively charged coating that repels anionic molecules. The size of the pores and the negative charge of the endothelium play an important role in solute selectivity during plasma ultrafiltration. The second component of the filtration barrier is the basement membrane, which separates the epithelium of the urinary space from the endothelium of the glomerular capillaries. The basement membrane has three layers: the lamina rara interna lies adjacent to the capillary endothelium, the lamina densa (electron dense by electron micrograph) is located centrally, and the lamina rara externa is adjacent to the epithelium of Bowman’s space (Fig. 3.6). The basement membrane consistently courses below the epithelium of Bowman’s space and is absent between the capillary endothelium and the supporting mesangium. As mentioned previously, this trilayer structure is not the basement membrane of the glomerular capillaries; rather, it contributes specifically to the permeability characteristics of the filtration barrier. Composed principally of collagenous and noncollagenous proteins, the basement membrane of the filtration barrier is a matrix with hydrated interstices. Nonpolar collagenous components are concentrated in the lamina densa. An important polar noncollagenous component, heparan sulfate (a polyanionic proteoglycan), is located primarily in the outer lamina rara layers, endowing the layers with their strongly anionic character. On the tubule side of the glomerulus, lining Bowman’s space, are the podocytes. Attached to the glomerular basement membrane, the podocytes constitute the third component of the filtration barrier. The name podocyte means foot cell and relates to their footlike appearance when viewed in cross-section (see Fig. 3.6). The podocytes completely cover the glomerular capillaries with extending fingerlike processes and interdigitate with neighboring podocytes (Fig. 3.7, A and B).However, their processes actually do not touch each other; rather, a consistent space of 20 to 30 nm separates them, forming a snakelike channel that zigzags across the surface of the glomerular capillaries.1 This snakelike channel is called the filtration slit and covers only about 3% of the total glomerular basement membrane area. The slit is lined with a distinct extracellular structure known as the slit diaphragm. The substructure of the slit diaphragm consists of regularly arranged subunits with rectangular open spaces about the size of an albumin molecule. Often the slit diaphragm is considered part of the basement membrane, although it is distinctly separate and actually lies on the basement membrane. Podocytes are metabolically active cells. They contain numerous organelles and extensive lysosomal elements that correlate directly with their extensive phagocytic ability. Macromolecules that are unable to proceed through the slit diaphragm or return to the capillary lumen are rapidly phagocytized by podocytes to prevent occlusion of the filtration barrier. Similar to the capillary endothelium, all surfaces of the podocytes, filtration slits, and slit diaphragms that line the urinary space are covered with a thick, negatively charged coating. In review, the three distinct structures that compose the glomerular filtration barrier are (1) the capillary endothelium with its large open pores, (2) the trilayer basement membrane, and (3) the filtration diaphragms located between the podocytes (epithelium) of Bowman’s space. Each component maintains an anionic charge on its cellular surface or within it, and each component is essential for proper functioning of the filtration barrier. The selectivity of the filtration barrier is based on the molecular size and charge of the solute. Water and small solutes rapidly pass through the filtration barrier with little or no resistance. In contrast, larger plasma molecules must overcome the negative charge present on the endothelium and must be able to pass through the endothelial pores, which are 50 to 100 nm in diameter.1 The shield of negativity of the endothelium successfully repels most plasma proteins, thereby preventing the filtration barrier from becoming congested with them. However, neutral and cationic molecules readily pass through the filtration barrier if they do not exceed the size restriction imposed by the basement membrane. To penetrate the basement membrane and the slit diaphragm, neutral and cationic molecules must possess an effective molecular radius of less than 4 nm. The successful passage of molecules with diameters larger than 4 nm decreases with increasing size. However, molecules with diameters greater than 8 nm typically are not capable of glomerular filtration.2 Albumin has an effective radius of 3.6 nm and a molecular weight of approximately 67,000 daltons.3 If the shield of negativity that permeates the basement membrane and the filtration slits is not present, albumin would readily pass through the filtration barrier. This is evidenced in glomerular diseases in which loss of the shield of negativity (e.g., lipoid nephrosis) or an alteration in the filtration barrier structure (e.g., glomerulonephritis) results in proteinuria and hematuria. The initial ultrafiltrate present in Bowman’s space differs from the plasma in that it lacks the blood cells and plasma proteins larger than albumin (including any protein-bound substances). The normal filtration rate of approximately 125 mL/min depends on body size and is discussed at length in the section on glomerular filtration tests. Any condition that modifies glomerular blood flow, hydrostatic or oncotic pressures across the glomerular filtration barrier, or the structural integrity of the glomerulus will affect the glomerular filtration rate and ultimately the amount of urine produced. The epithelium that lines the renal tubules changes throughout the five distinct areas of the nephron. Looking at the diverse and specialized epithelial characteristics of each segment aids in understanding the various processes that take place. Once the glomerular ultrafiltrate has been formed in Bowman’s space, hydrostatic pressure alone moves the ultrafiltrate through the remaining tubular portions of the nephrons. Each tubular portion has a distinctively different epithelium, which relates directly to the unique processes that occur there. The first section, the proximal tubule, consists of a large convoluted portion (pars convoluta) followed by a straight portion (pars recta). The cells of the proximal tubule are tall and extensively interdigitate with each other (Fig. 3.8). These intercellular interdigitations serve to increase the overall cellular surface area and are characteristic of salt-transporting epithelia. The luminal surfaces of these cells have a brush border because of the abundant number of microvilli present (typical of absorbing epithelia as in the small intestine). These densely packed microvilli, by greatly increasing the luminal surface area, provide a maximal area for filtrate reabsorption. In addition, the proximal tubular cells have numerous mitochondria (evidence of their high metabolic activity) and are abundant in the enzymes necessary for active transport of various solutes.
The Kidney
Key Terms1
Renal Anatomy
Renal Circulation
Force
Magnitude
Hydrostatic (blood pressure)
+55 mm Hg
Hydrostatic (ultrafiltrate in Bowman’s space)
−15 mm Hg
Oncotic (protein in blood and not in ultrafiltrate)
−30 mm Hg
Net pressure
+10 mm Hg
Renal Physiology
Urine Formation
Component
Initial Ultrafiltrate, mmol
Final Urine, mmol
Percent Reabsorbed
Water (1.2 La)
9,500,000.00
67,000.00
99.3
Urea
910.00
400.00
44.0
Chloride
37,000.00
185.00
99.5
Sodium
32,500.00
130.00
99.6
Potassium
986.00
70.00
92.9
Glucoseb
900.00
0.72
100.0
Albumin
0.02
0.001
95.0
Glomerulus
Tubules
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The Kidney
Learning Objectives
