The urinary system is essential for homeostasis. Essential functions include The urinary system includes the paired kidneys and ureters, urinary bladder, and urethra. Essentially, dissolved materials in the liquid fraction of blood (plasma) are formed into a filtrate by the action of the kidneys. Once this filtrate is created, some additional materials are added (secretion), but others are recovered (reabsorption). The liquid that makes it through the microscopic tubular nephrons to the pelvis of the kidney and into the urinary bladder exits the body as urine. Urine is typically slightly acidic (∼pH 6.0), but its volume and composition vary markedly depending on metabolism, diet, and the need to produce either dilute or concentrated urine to maintain extracellular fluid volume and osmolarity. Let’s now consider some of the detailed anatomy of this system, beginning with the kidneys. We’ll use the ovine kidney to characterize some of the major features. In their normal retroperitoneal position, the kidneys are located between the 12th thoracic and third lumbar vertebrae. They are held in place by the peritoneum and are in contact with adjacent visceral and surrounded by a layer of adipose tissue. Consequently, the kidneys are generally well protected. The outermost renal fascia anchors the kidney to the peritoneum, while the center layer of adipose tissue provides support and cushioning. The innermost connective tissue layer is the renal capsule. It is directly adjacent to the outer surface of the kidney parenchymal tissue. The photograph provided in Figure 16.1 shows a bisected preserved sheep kidney. A portion of the thin but tough renal capsule is indicated. This specimen and companion drawing illustrate major macroscopic features of the kidney. However, as we’ll soon see, the ultimate work of filtration and reabsorption is done by complex multicellular tubules called nephrons only visible microscopically. These functional units of the kidney are in lobules within distinct zones or regions of the kidney that can be grossly distinguished. The outer region or zone, the cortex, lies over the inner region called the medulla and a central area called the renal pelvis or hilus. This central area is the location for the entrance and exit of the renal vein and artery as well as the origin of the ureter, which conducts urine to the bladder. The model illustrated in Figure 16.2 provides a three‐dimensional representation of these structures. Figure 16.3 gives a “flow” diagram to link blood flow and corresponding urine production in the kidney. Briefly, the renal artery and vein branch at nearly right angles to supply each of the kidneys. As each of these vessels approaches the hilus, they branch into smaller segmental arteries, named because they supply blood to sectors or segments of the mass of the kidney tissue. Each of the segmental arteries divides to create lobar arteries that divide to yield interlobar arteries that pass between the pyramids of the medulla toward the kidney cortex. Near the boundary between the cortex and medulla, the interlobar arteries branch into the arching arcuate arteries (hence the name) along the bases of the medullary pyramids. Small interlobular arteries radiate outward to supply cortical tissue. Most of the blood (∼90%) that enters the kidney supplies the cortical tissue. Not surprisingly, this is the region where the bulk of the nephrons are located. The veins trace essentially the same pathway in reverse (Fig. 16.4). Fig. 16.1 Bisected preserved sheep kidney. Red latex fills much of the renal pelvis or hilus. The cortex is the outer rim of parenchymal tissue (brackets), and the medulla occurs in the region between the renal pelvis and cortex. A portion of the protective renal capsule is evident as a thin, membrane‐like material. The dotted line outlines the region of a renal pyramid. Among the domestic species, swine and large ruminants have kidneys that are described as multipyramidal or multilobar. In these cases, a papilla (essentially the tip of the pyramid) projects into the space of a minor calyx, and this is continuous with the ureters. Unipyramidal or unilobar kidneys occur in most carnivores, small ruminants, and horses. The kidney (of the cat, for example) consists of one lobe that results from the fusion of several lobes during development. A single broad ridge or crest created by the fusion of the papillae is associated with an expanded internal portion of the ureters, which spreads over the internal surface of the renal pelvis (Banks, 1983). Under usual circumstances, blood flow to the kidney is impressive, averaging 25% of cardiac output. As blood enters the renal artery, it progresses as outlined in Figure 16.3. The essential feature is that blood eventually passes into the tufts of capillaries that constitute the renal corpuscle (a surrounding structure called Bowman’s capsule + the tuft of capillaries) that is connected with the first segment of the nephron (proximal convoluted tubule (PCT)). Fig. 16.2 Model of kidney. The model illustrated in this photograph demonstrates in greater detail the gross anatomy of the kidney. The renal vein (1 and blue arrow) and artery (2 and red arrow) are evident in the region of the renal pelvis, as is the ureter (3). The funnel‐like structures that feed the exiting ureter are the major (4) (closest to the ureter) and minor calyces (5). These structures capture filtrate from the tips of the renal pyramids as shown in the cutaway region. An example of a renal pyramid is illustrated by the dotted lines in Figure 16.1 and Figure 16.2. Fig. 16.3 Kidney blood flow. The group of progressive vessels (left to right) is the arterial branches (tan boxes) that ultimately supply the capillaries of the glomerulus where filtration takes place to supply fluid that enters the lumen of the nephron. Elements of the blood that are not filtered (cells and large proteins) and that are not filtered leave the capillaries of the glomerulus and enter the venous circuit to exit the kidney via the renal vein (green boxes). Fig. 16.4 Kidney blood supply. This stylized drawing illustrates some of the blood supply to kidney parenchymal tissue. SA, segmental artery; IA, interlobar arteries; AR, arcuate arteries; and INA, interlobular arteries. The function of the kidney is tied to the nephrons. Each nephron consists of the glomerulus (the tuft of blood vessels) and glomerular capsule (often called Bowman’s capsule). This tuft or knot of capillaries has an afferent (toward) and efferent (away) arteriole. Blood that enters is subjected to filtration and osmotic pressure that acts to force some of the liquid of the blood between the endothelial cells into the space surrounded by Bowman’s capsule. Blood cells, larger molecules, and the remaining liquid exit the tuft of capillaries via the efferent arteriole. Liquid that passes out of the capillaries into the space of Bowman’s capsule enters the first segment of the tubular portion of the nephron called the PCT. This segment of the nephron gets its name because the tube is very highly coiled (convoluted) and is the closest to the site of filtrate formation (proximal). In sequence, the remaining parts of the nephron are the portion of the PCT leading to the thin or descending limb of the LH, the ascending LH, the distal convoluted tubule (DCT), and the collecting duct (CD). The ends of the CDs are located at the tips of the renal pyramids. This means that liquid that exits the nephrons at this point enters the ureter, passes to the bladder, and is lost as urine. Nephrons occur in two classes. The majority class (cortical) is located primarily within the kidney cortex. However, the juxtamedullary nephrons are arranged near the boundary between the cortex and medulla so that the LH for these nephrons passes deep into the medullary region. As we’ll soon see, these nephrons play an especially important role in the regulation of blood osmolarity. Figure 16.5 illustrates the orientation of nephrons within the kidney tissue. Notice that the branches from the arcuate vessels (paired artery and vein that arch over the boundary between the cortex and medulla) supply the interlobular arteries that ultimately supply the efferent arterioles of the glomerulus. These appear as circular white balls in the photograph. The two classes of nephrons (cortical) and the longer juxtamedullary nephrons are also illustrated in this photograph. The large, branched structure in the center illustrates a CD, which, as the name suggests, collects effluent from the DCT of numerous nephrons as it traverses along the length of the renal pyramid. Further detail of the structure of the glomerulus and the initial segment of the nephron is shown in Figure 16.6. Figure 16.7 provides a drawing to illustrate the components of a nephron and the associated blood supply to the glomerulus. The mammalian kidney is the best‐understood osmoregulatory organ in the animal kingdom, thanks to extensive research over the past 40 years. Activities linked with the mammalian kidney include several functions that are tied with other organs in lower vertebrates, for example, the skin, bladder, and gills of fishes or the salt glands of many reptiles and birds. This perhaps explains the serious nature of kidney disease or defects in our animals. In short, there is no substitute for a healthy, well‐functioning urinary system. As we have indicated in prior sections, structure and function are closely allied. The kidney and especially the elegant arrangement of the sections of the nephron, associated blood supply, and, finally, the creation of a continuously maintained osmotic gradient within the tissue of the renal medulla are critical to kidney function. The nephron is a highly convoluted but nonetheless simple tube composed of a single layer of epithelial cells. The tube is essentially closed at the proximal end because of the tuft of capillaries and filtered fluid leaving Bowman’s capsule, but it is open at its distal end as it joins the CDs that empty into the renal pelvis. We will explore these relationships by discussing in some detail the cellular structure of the different epithelial cells located along the course of the nephron. To understand the role of the kidney in the long‐term control of blood pressure, blood flow, and stimulation of erythrocyte production, we will describe the importance of a specialized cluster of modified distal convoluted cells called the macula densa and the juxtaglomerular cells in the wall of the afferent arteriole, which together make up the juxtaglomerular apparatus (JGA). In addition, we’ll consider the significance of the network of peritubular capillaries that intertwine around the LH and the curved course of blood flow that mirrors the hairpin bend in the LH called the vasa recta. Fig. 16.5 Organization of nephrons. This photograph of a kidney model illustrates the orientation of microscopic structures within the tissue of a kidney pyramid. Numerous renal glomeruli (white globular structures) populate the renal cortex. Cross‐sectioned glomeruli (arrows) show the funnel‐like arrangement of Bowman’s capsule surrounding the tuft of capillaries and the afferent and efferent arterioles. The coiled tubule immediately exiting the glomerulus is the proximal convoluted tubule. Its path can be traced, as it becomes the descending then ascending loop of Henle. Once back in the region of the glomerulus, the tubular nephron becomes the distal convoluted tubule before it joins the collecting duct (CD). Fig. 16.6 Structure of the glomerulus. This photograph illustrates the cellular structure associated with the glomerulus. The larger vessel on the upper right illustrates the afferent arteriole; the pale‐yellow covering on the surface of the vessel once it enters Bowman’s capsule illustrates a layer of cells called podocytes that support the endothelial cells of the afferent capillary bed. These cells aid in the regulation of the filtration process as discussed in the following. The other half of the tuft of vessels demonstrates the efferent vessels leading to the efferent arteriole. The pale blue layer of cells inside Bowman’s capsule represents the simple squamous epithelial cells that line its internal surface. To the left, these cells give rise to simple cuboidal epithelial cells that constitute the internal lining of the proximal convoluted tubule (PCT). The structure on the extreme right illustrates a cross section of the distal CT. The boxed area represents cells of the wall of the afferent arteriole and adjoining distal CT that comprise a structure called the juxtaglomerular apparatus or JGA. As discussed in the text, the JGA is important in sensing decreases in blood pressure that lead to homeostatic events to restore pressure to normal. Fig. 16.7 Nephron diagram. This simplified diagram illustrates key aspects of a juxtaglomerular nephron. While the convoluted tubules are more extensive, relative orientation is maintained. Notice that the branches of the efferent arteriole that supply the region surrounding the convoluted tubules give rise to the network vessels surrounding the loop of Henle (LH) and the vasa recta, which allows blood from the region of the convoluted tubules to flow around the LH but in the opposite direction of fluid flow within the tubule. This is important because the countercurrent flow allows a steep osmotic gradient that is created by the action of cells of the LH to be maintained within the surrounding interstitial space. In practical terms, this means that fluid that then passes up the ascending LH into the distal convoluted tubule and into the collecting duct transits down the collecting duct (CD) and through this surrounding osmotic gradient. By controlling the degree of permeability of the collecting duct to water, this allows either dilute (water is not recovered from the fluid entering the collecting duct) or concentrated (water follows osmotic forces and leaves the collecting duct lumen) urine to be produced. Three critical processes that contribute to the control of the volume and composition of urine are: (1) filtration of the blood plasma to create ultrafiltrate within the lumen of Bowman’s capsule, (2) tubular reabsorption of water and most of the salts of the ultrafiltrate, and (3) tubular secretion, much of which occurs via active transport. Let us begin by considering factors that control the creation of filtrate. As you might guess, one of the factors that directly impacts the rate of filtration is the blood pressure supplying the glomerulus. This is analogous to the rate of water flow through a sprinkler increasing as the water faucet is opened. Indeed, one of the symptoms of high blood pressure is more frequent urination. The data plotted in Figure 16.8 demonstrate the dramatic nature of this response. Other forces within Bowman’s capsule also influence the rate of filtrate formation. Once filtration has started and fluid begins to collect, the fluid‐filled space produces hydrostatic pressure against the endothelial cell from outside the capillaries. You can imagine this as the difference between filling an empty water bucket with a hose compared with pushing the hose to the bottom of a barrel that is already filled. The water coming from the hose is counteracted by the force of the water already in the barrel. In addition, the osmotic properties of the blood and newly created filtrate impact the rate of water movement across the capillary cells. This means that despite a typical hydrostatic pressure of about 55 mm Hg at the level of the afferent arteriole, the combination of competing forces produces a net filtration force of about +10 mm Hg. Regardless of this seemingly small pressure differential, because of the very large number of glomeruli in each kidney, that is, typically 2–4 million (depending on the species), this produces an enormous degree of filtration. For a 70‐kg primate, the average glomerular filtration rate (GFR) is 125 mL per minute. As a crude estimate, let us assume that blood volume equals 10% of body weight and that the blood is 50% plasma. This results in a blood volume of 7 kg. Let us further estimate that 1 kg = 1 L. This then would yield a blood volume of 7 L or 3.5 L of blood plasma. Because the plasma is mostly water, at a normal rate of GFR, it would only take 28 minutes for the entire plasma volume to be filtered. In other words, without mechanisms to minimize urine production, the entire plasma volume would be lost in about 30 minutes. This staggering calculation highlights not only the degree of filtration but also the significance of the actions of the kidney in recovering most filtered water and important nutrients. In addition to the hydrostatic pressure within the glomerulus, these capillaries are also structurally designed to maximize bulk fluid flow. Specifically, they are fenestrated. Compared with capillaries in other regions of the body, the endothelial cells contain numerous large pores, so permeability is about 100 times greater than for other capillary beds. Despite the benefit of enhanced fluid filtration, it is also important that large macromolecules within the blood are not filtered. Thus, the basement membrane surrounding the endothelial cells contains collagen and numerous negatively charged glycoproteins. This acts to repel albumin and other serum proteins. There are also specialized cells called podocytes that cover the outer surface of the endothelial cells. The podocytes send out numerous pseudopodia that create processes called pedicels that interdigitate to create filtration slits. Filtrate driven by hydrostatic pressure passes through the pores of the endothelial cells, through the basement membrane, and then through these filtration slits. These three layers effectively act as a kind of molecular sieve so that small molecules and water readily pass into the lumen of Bowman’s capsule, but essentially all proteins are excluded from the filtrate based on charge and/or molecular size. There is a bulk flow of water through the glomerulus so that small, dissolved ions, sugars, amino acids, urea, and most other small molecules enter the filtrate. Table 16.1 illustrates the relationship between molecular weight and the transfer of several common blood components into kidney filtrate. Fig. 16.8 Urine formation and blood pressure. The relationship between renal blood pressure and the rate of urine formation is evident. Table 16.1 Relationship between molecular weight and properties of selected substances and urinary filtration. Adapted from Eckert Animal Physiology, Edition 5. The composition of the filtrate is similar to that of blood plasma with the exception of the protein content, but the composition of urine is very different; thus, it is apparent that both the volume and composition of the filtrate are markedly altered as it passes through the segments of the nephron. Essentially, the kidneys filter blood plasma and then reabsorb needed materials from the ultrafiltrate. In fact, nearly most of the water and most critical nutrients are recovered before the fluid reaches the end of the PCTs. The activity of the cells of the PCT is reflected by the structure of the cells. Specifically, these cuboidal epithelial cells have plentiful mitochondria and rough endoplasmic reticulum (RER) as well as numerous apical microvilli. These attributes provide for the synthesis of abundant amounts of ATP, much of which is needed to power active transport mechanisms to recover important nutrients that should not appear in urine. In short, ATP is expended either directly or indirectly in transferring ions (and other molecules) across the epithelium against a concentration gradient. Ionic gradients that are developed depend on the activity of three classes of ATPases or protein pumps. ATPases were discussed generally in Chapter 3. These are quite complex components of cell membranes in many organisms. They are composed of membrane domains as well as catalytic and regulatory subunits located on the cytoplasmic face of the membrane. For example, protons (H+) from electron transport in the mitochondria pass through the F‐ATPase system that powers ATP synthesis within the internal membranes of the mitochondria. The proton V‐ATPase pump utilizes the hydrolysis of ATP to transport protons out of the cell or across membranes to generate an electrochemical gradient. These gradients then can serve many functions, for example, by acting via cotransport to direct the movement of ions through specific channels, via symporters, or via antiporters as described in earlier chapters. V‐ATPase pumps have a phosphorylated intermediate form of the transport protein. This feature is important because it adds an element of control to the activity of the pump. In other words, changes in molecules (hormone receptors, e.g.) that impact the degree of phosphorylation of this intermediate protein have a direct impact on the functionality of the transporter. Three subclasses of this type of ATPase pump include the Na+/K+ P‐ATPase pump discussed in relation to nerve function, the Ca2+ P‐ATPase pump that is involved in muscle contraction, and the H+/K+ pump that is involved in acidification of gastric juices and kidney cell activity. Table 16.2 provides a summary of some of the features of these pumps. Therefore, how are these pumps specifically involved in kidney function? The Na+/K+ P‐ATPase pumps, located on the basolateral membranes of the tubular epithelial cells, regulate intracellular sodium levels, and thereby, cell volume by moving sodium out of the cell into extracellular fluid. If the cell also has K+ channels in the apical membrane, then K+ ions will be excreted into the extracellular fluid if the electrochemical gradient is maintained in the appropriate direction (Fig. 16.9). If there are K+ channels in the basolateral membrane, then there will be K+ movement between intra‐ and extracellular compartments that is driven by the Na+/K+ ATPase pump. These mechanisms are involved in the overall secretion of K+ and recovery of Na+ by the cells of the nephron. Table 16.2 Features of three major classes of ATPase pumps. Fig. 16.9 Distal tubule ion transport. In the distal convoluted tubule and collecting duct of the nephron, the cells secrete K+ into the filtrate. Na+/K+ ATPase pumps in the basolateral membrane actively transport K+ into the cell, where it then passes down its concentration gradient and exits from the apical end of the cell into the lumen. This allows the recovery of Na+ essentially in exchange for the elimination of K+. While it is critical that appropriate quantities of sodium and potassium be recovered from kidney filtrate to maintain the osmolarity of body fluids, the Na+/K+ ATPase pumps either directly or indirectly support the movement of many substances. For example, if the apical membrane of the tubular cells contains Na+/glucose or Na+/2Cl−/K+ symporters, then the activity of these pumps can control the uptake of glucose, K+, or Cl−. This is just what selectively happens within specific sections of the nephron. If the Na+/2Cl−/K+ pump is in the basolateral membrane of the cell, its activity can drive the uptake of Cl− from the extracellular fluid (to be secreted into the filtrate). Specifically, the presence of chloride channels or pores in the apical membrane of the cell allows the passage of higher concentrations of chloride out of the cell and into the filtrate. Figure 16.10 illustrates the histological appearance of the renal corpuscle as well as several cross‐sectioned profiles of parts of a nephron. At first, it may seem confusing. The larger rounded structures are the renal corpuscles, and the various tubules are sections through proximal or DCTs, perhaps an ascending or descending LH or CDs. Other tubelike structures include the network of peritubular capillaries. Remember the name of the beginning and ending section of the nephron: convoluted tubule. Because of its highly coiled, curving structure, a given histological section from the kidney might well exhibit many profiles of the same tubular structure as it is cut at various places. However, there are distinct structural features that allow the identification of proximal versus convoluted tubules, or differences between LH and CDs, for that matter. One simple feature that allows a quick orientation is the presence of renal corpuscles. If these structures are present, then the tissue section was taken from either within the cortex or the tissue in the boundary between the cortex and medulla. The appearance of long parallel arrays of simple tubes is a major indication that the tissue section was prepared from a sample collected deeper into the renal medulla, perhaps near the apex of a renal pyramid. These tubules likely represent the walls of the ascending or descending LH of the juxtamedullary nephrons, peritubular capillaries, or numerous CDs. Fig. 16.10 Nephron histology. Panel (A) gives a low‐power survey image of the tissue from the cortex of the kidney. The larger rounded structures (arrows) are the renal corpuscles. The other abundant circular profiles are cross‐sectioned areas of various segments of nephrons. Most of the profiles would be either proximal or distal convoluted tubules. Panel (B) shows some of the details of a renal corpuscle (outlined by the brackets). Ultrafiltrate flows from this structure into the proximal convoluted tubule (PCT). In this case, by chance, a portion of the tubule that drains this renal corpuscle has been sectioned. The large arrow indicates the direction of flow. Fig. 16.11 Proximal and distal tubules. This image is taken from the renal cortex and shows profiles of proximal (PCT) and distal convoluted tubules (DCT). In both cases the cells are cuboidal, but cells of the PCT are larger and have evidence of stained material along the apical cell surface and evidence of abundant microvilli (arrows). As filtrate enters the PCT, forces begin the recovery of important nutrients, ions, and water. Because of these activities, the structure of the cells of PCT and DCT is distinct. As shown in Figure 16.11, epithelial cells of both PCT and DCT are cuboidal, but the cells of the PCT typically have abundant microvilli and mitochondria. In paraffin‐embedded sections of fixed kidney tissue, the lumenal spaces of the PCT sometimes appear as if the apical ends of the cells are painted. This color and thickness are an indication of stain accumulation on the proteins that coat the microvilli. The remarkable capacity of the nephron to recover important nutrients is illustrated in Figure 16.12. Under normal circumstances, nearly all the glucose and amino acids are recovered from the filtrate before it reaches the LH. The significance of measuring inulin and hippuric acid to understanding kidney function is also indicated. Table 16.3 summarizes the major functions associated with each of the segments of the nephron. In addition to the recovery of dissolved substances, the rate of fluid flow also is dramatically reduced as each of the progressive segments of the nephron is traversed. As indicated earlier, the capacity to regulate the volume of urine produced is critical. As shown in Table 16.4, despite an average rate of filtrate formation of ∼125 mL/min in a 70‐kg primate, urine production is typically only about 1 mL per minute. Just how this regulation takes place will be discussed in subsequent sections. Fig. 16.12 Flow of selected materials. This diagram illustrates the dramatic rate of removal of amino acids and glucose from the ultrafiltrate formed in the glomerulus. By the time fluid enters the loop of Henle, essentially all the amino acids and glucose have been recovered in normal circumstances. When animals are given inulin or hippuric acid, the rate of appearance of these substances can be used to monitor kidney health. For example, inulin that enters the filtrate remains; it is neither reabsorbed nor transported from the peritubular blood (no secretion). This gives a measure of the glomerular filtration rate, or GFR. Hippuric acid, on the other hand, is not recovered, but in addition, all of it in the blood that enters the glomerulus is transported into the filtrate (100% secretion). Thus, the evaluation of hippuric acid concentrations provides a measure of plasma flow rate to the kidney. Table 16.3 Summary of functions of nephron regions. Table 16.4 Rate of fluid flow in regions of the nephron.
16
Urinary System
Anatomy of the Urinary System
Nephron Structure
Mechanisms of Urine Formation
Factors Affecting Filtration
Substance
Molecular Weight
Radius (nm)
Blood/Filtrate Ratio
Water
18
0.11
1.0
Glucose
180
0.36
1.0
Sucrose
342
0.44
1.0
Insulin
5500
1.48
0.98
Ova albumin
43 500
2.85
0.22
Hemoglobin
68 000
3.25
0.03
Serum albumin
69 000
3.55
<0.01
Proximal Convoluted Tubule
Property
H+ F‐ATP Synthase
H+ V‐ATPase
Na+/K+ P‐ATPase
Location
Mitochondria
Plasma membranes (apical)
Plasma membranes (basolateral)
Function
ATP synthesis
Acidification, gradient energy formation
Gradient energy formation
Action
Uses H+ gradient to power ATP synthase
Uses ATP to create H+ gradient
Uses ATP to create gradients for H+, Na+, K+, and Ca2+
Inhibitors
Azide
Bafilomycin
Ouabain 
Region
Function
Glomerulus
Creation of filtrate from blood
Proximal convoluted tubule
Major area for reabsorption of filtrated water and solutes, obligatory water reabsorption
Thin descending limbs of loops of Henle
Maintenance of hypertonicity of medullary tissue via countercurrent system
Thick ascending limbs of loops of Henle
Na+, K+, Cl− reabsorption, creation of osmotic gradient in medullary tissue
Distal convoluted tubule
NaCl reabsorption, facilitative water resorption
Collecting ducts
Final control of excretion of electrolytes and water, regulation of acid–base balance
Region
Rate of Flow (mL/min)
Percent
Glomerulus
124
100
Loop of Henle
50
40
Distal CT
25
20
Collecting duct
12
9
Renal pelvis
1
0.8
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