The Urinary System

CHAPTER 11


The Urinary System*




Structure of the Kidney


Mammalian kidneys are paired organs present in the retroperitoneum, ventrolateral and adjacent to the lumbar vertebral bodies and their corresponding transverse processes. These complex organs, which function in excretion, metabolism, secretion, and regulation, are susceptible to disease insults that affect the four major anatomic structures of the kidney: the glomeruli, tubules, interstitium, and vasculature. Because of the limited ways that renal tissue can respond to injury and the limited patterns of injury, in severe and prolonged disease the endpoint will be similar—chronic renal disease and failure. Interdependence between components of the nephron also are responsible for producing a narrow range of repeatable injury patterns, which students can come to recognize on gross or histologic assessment.


Macroscopically, kidneys are organized functionally and anatomically into lobules. Each lobule represents collections of nephrons separated by the medullary rays (Fig. 11-1). Renal lobules should not be confused with renal lobes. Each lobe is represented by a renal pyramid (see Fig. 11-1). Among domestic animals, carnivores and horses have unilobar (or unipyramidal) kidneys. Porcine and bovine kidneys are multilobar (or multipyramidal), but only bovine kidneys have external lobation (Fig. 11-2). A diffuse fibrous capsule that in normal kidneys can be easily removed from the renal surface covers the kidneys. The renal parenchyma is divided into a cortex and medulla (Fig. 11-3). The corticomedullary ratio is usually approximately 1 : 2 or 1 : 3 in domestic animals. The ratio varies among species; for example, those adapted to the desert have a far larger medulla and thus a corticomedullary ratio that can approach 1 : 5. Normally the cortex is radially striated and dark red-brown except in mature cats, in which the cortex is often yellow because of the large lipid content of tubular epithelial cells. The renal medulla is pale gray and has either a single renal papilla, as in cats; a fused, crestlike papilla (renal medullary crest), as in dogs, sheep, and horses; or multiple renal papillae, as in pigs and cattle. The medulla generally can be subdivided into an outer zone, that portion of the medulla close to the cortex, and an inner zone, that portion closer to the pelvis. Papillae are surrounded by minor calyces that coalesce to form major calyces, which empty into the renal pelvis, where urine collects before entry into the ureters.





Microscopically, for ease of discussion, the kidney (and nephron) can be divided into four structural units: renal corpuscle (glomerulus and Bowman’s capsule), tubules, interstitium, and vasculature. The functional unit of the kidney is the nephron, which includes the renal corpuscle and renal tubules (the tubular system includes the proximal convoluted tubules, the loop of Henle, and the distal convoluted tubule). The uriniferous tubule is composed of the nephron and the collecting ducts, which are embryologically distinct from the renal tubules (Fig. 11-4). The uriniferous tubule is embedded structurally in the renal interstitium formed by a meshwork composed of stromal cells such as fibroblasts. The interstitium also contains the renal vasculature, which supplies blood first to the glomerulus and then to the renal tubules.




Glomerulus (Glomerular Tufts)


Macroscopically, glomeruli are difficult to detect in the normal kidney but can be accentuated by lesions that allow them to be identified on cut section as randomly distributed granular foci or as red dots throughout the cortex. Microscopically, the glomerulus is a complex, convoluted tuft of fenestrated endothelial-lined capillaries held together by a supporting structure of cells in a glycoprotein matrix, the mesangium (Fig. 11-5). The entire glomerulus is supported by mesangial matrix that is secreted by the mesangial cells, a type of modified pericyte (Fig. 11-6). Mesangial cells are pluripotential mesenchymal cells, which are contractile and phagocytic and capable of synthesizing collagen and mesangial matrix, as well as secreting inflammatory mediators.






Visceral Epithelium (Podocytes)


Visceral epithelial cells (podocytes), aligned on the external surface of the basement membrane, are responsible for synthesis of basement membrane components and have special cytoplasmic processes (foot processes) that are embedded in the lamina rara externa. Negatively charged glycoproteins overlying the endothelial cells and the podocytes contribute to the charge differential of the glomerular basement membrane (GBM). Foot processes from adjacent visceral epithelium interdigitate to form filtration slits between them. Filtration slit diaphragms are composed of nephrin, a cell adhesion molecule of the immunoglobulin superfamily, which controls slit size by its connection to podocyte actin (see Fig. 11-7). The glomerular filtration barrier selectively filters molecules based on size (70,000 Da), electrical charge (the more cationic, the more permeable), and capillary pressure. In summary, both size-dependent and charge-dependent filtration is possible because of the porous structure of capillary walls, which is a function of endothelial fenestrations, a basement membrane formed of type IV collagen, basement membrane anionic glycoproteins, and filtration slits of the visceral epithelium.






Tubules


The renal tubular system (in the order of flow of urine) consists of a proximal tubule, loop of Henle, and distal tubule (see Fig. 11-4). The tubules connect to the renal pelvis at the distal end of the collecting ducts, and the whole structure, including the renal corpuscle, renal tubules, and collecting ducts is referred to as the uriniferous tubule (see Fig. 11-4). Macroscopically, the proximal and distal convoluted tubules are linked by the loop of Henle, which is divided into a descending and an ascending limb. The wall of the descending limb and initial portion of the ascending limb is thin (permeable), whereas the cortical portion of the ascending limb is thick (impermeable). Microscopically, the proximal tubule is lined by columnar epithelial cells that have a microvillous (brush) border. This arrangement greatly increases their absorptive surface, and their numerous intracellular mitochondria supply energy for the various secretory and absorptive functions. Distal tubules, collecting tubules, and the loop of Henle are lined by cuboidal epithelial cells that contribute to the concentration of urine by absorptive and secretory activities.




Vasculature


Macroscopically, knowledge of the normal renal blood supply is important in understanding the pathogenesis and distribution of various renal lesions, especially renal infarcts. The kidneys receive blood primarily through the renal artery. An interlobar artery extends along the boundary of each renal lobe (renal column) and then branches at right angles to form an arcuate artery that runs along the corticomedullary junction (Fig. 11-8). Interlobular arteries branch from the arcuate artery and extend into the cortex. They have no anastomoses, making them susceptible to focal ischemic necrosis (infarct) as in any organ with end arteries.



Microscopically, interlobular arteries have small branches that become afferent glomerular arterioles, which enter the renal corpuscle and subsequently exit at the vascular pole as efferent glomerular arterioles (see Fig. 11-8). Efferent arterioles supply the blood for the extensive network of capillaries that surround the cortical and medullary tubular system of the kidneys, known as the peritubular capillary network. The latter surrounds cortical segments of the tubules and then drains into the interlobular vein, arcuate vein, interlobar vein, and ultimately the renal vein. Additionally, the vasa recta are formed from the deeper portions of the peritubular network and descend into the medulla and around the lower portions of the loop of Henle before ascending to the cortex and emptying into venous vessels that connect to the interlobular and arcuate veins. The vasa recta parallel the descending and ascending limbs of the loop of Henle and the collecting ducts (see Fig. 11-4). Hence the blood supply to the tubules depends on passage through the glomerular vessels.



Function of the Kidney


The kidney has the following five basic functions:



• Formation of urine for the purpose of elimination of metabolic wastes.


• Acid-base regulation, predominantly through reclamation of bicarbonate from the glomerular filtrate.


• Conservation of water through reabsorption by the proximal convoluted tubules, the countercurrent mechanism of the loop of Henle, antidiuretic hormone (ADH) activity in the distal tubules, and the urea gradient in the medulla. The tubular system is capable of absorbing up to 99% of the water in the glomerular filtrate.


• Maintenance of normal extracellular potassium ion concentration through passive reabsorption in the proximal tubules and tubular secretion in the distal tubules under the influence of aldosterone.


• Control of endocrine function through three hormonal axes: renin-angiotensin (see Fig. 11-8), most importantly, but also erythropoietin and vitamin D. Erythropoietin, produced in the kidneys in response to reduced oxygen tension, is released into the blood and stimulates bone marrow to produce erythrocytes. Vitamin D is converted in the kidneys to its most active form (1,25-dihydroxycholecalciferol [calcitriol]), which facilitates calcium absorption by the intestine.



Function of the Glomerular Basement Membrane


The GBM is structurally adept at separating substances based on size and charge. Additionally, the glomerulus is equipped with its own specialized mesangial cells, a component of the monocyte-macrophage system (see Figs. 11-6 and 11-7). Both size-dependent and charge-dependent filtration is possible because of the porous structure of capillary walls, which is a function of endothelial fenestrations, a basement membrane formed of type IV collagen, basement membrane anionic glycoproteins, and filtration slits of visceral epithelium. In addition to the principal glomerular function of plasma filtration, glomerular functions also include regulation of blood pressure by means of secreting vasopressor agents and/or hormones, regulation of peritubular blood flow, regulation of tubular metabolism, and removal of macromolecules from circulation by the glomerular mesangium. Integral to these functions is the juxtaglomerular apparatus, which functions in tubuloglomerular feedback by autoregulating renal blood flow and glomerular filtration rate. The juxtaglomerular apparatus is composed of four components: (1) an afferent arteriole whose smooth muscle is modified to form myoepithelial cells, which are the juxtaglomerular cells that secrete renin; (2) an efferent arteriole; (3) the macula densa; and (4) the extraglomerular mesangium. Renin, produced by cells of the juxtaglomerular apparatus, stimulates the production of angiotensin I from circulating angiotensinogen. The angiotensin-converting enzyme in the macula densa converts angiotensin I to angiotensin II, which then functions to constrict afferent renal arterioles; maintain renal blood pressure; stimulate aldosterone secretion from the adrenal gland, thus increasing sodium (Na+) reabsorption; and stimulate ADH release (Fig. 11-9). ADH principally increases the permeability of collecting tubules to water and increases the permeability of the medullary region to urea.




Function of the Proximal Tubules


A key function of the proximal tubules is to reabsorb Na+, chloride (Cl), potassium (K+), albumin, glucose, water, and bicarbonate. This is facilitated by luminal brush border, basolateral infoldings, magnesium-dependent Na+ and K+ pumps, and transport proteins. The proximal tubule is continuous with the loop of Henle that is in close physiologic and anatomic association with the peritubular capillary network (within the cortex) and the vasa recta (within the medulla). The loop of Henle, via a countercurrent mechanism and Na+/K+-adenosine phosphatase (ATPase) pumps, absorbs Na+ and Cl ions, producing a hypotonic filtrate that flows into the next portion of the nephron—the distal convoluted tubule. Here, water is reabsorbed from the tubule into the interstitium because of a solute concentration gradient and by the effects of ADH. The filtrate is further concentrated in the collecting ducts by water and sodium reabsorption by a Na+/K+-ATPase pump and additional water reabsorption into the medullary interstitium by a urea gradient. Intercalated cells of the collecting tubule regulate acid-base balance and reabsorb potassium. Thus the final excretory product, urine, is formed (Fig. 11-10).




Renal Failure (Loss of Function)


Renal failure occurs when one or more of the functions previously listed are altered. When renal functional capacity is abruptly impaired (loss of 75%), such that the kidneys fail to carry out their normal metabolic and endocrine functions, acute renal failure can ensue. It is important to remember that the glomerulus, tubules, collecting ducts, and capillary blood supply in each nephron are closely interrelated, both anatomically and functionally. The fluid that filters through the glomerulus into Bowman’s space is called glomerular filtrate, and it arises after passage through the glomerular filtration barrier. This ultrafiltrate of plasma (primary urine), which contains water, salts, ions, glucose, and albumin, passes into the capsular space (Bowman’s space) and then empties into the proximal convoluted tubule at the urinary pole to traverse through and be acted on by the tubular system. Alterations in tubular structure or function influence glomerular structure and function and vice versa. For example, necrosis or atrophy of renal tubules results in loss of function of the affected nephrons and secondary atrophy of the glomerulus. In addition, because most of the capillary blood supply to tubules is through postglomerular capillaries, a reduction in glomerular blood flow consequently reduces the blood supply to the tubules.



Acute Renal Failure: Acute renal failure can be caused by (1) tubular necrosis from infectious agents, such as bacteria (Leptospira spp., Escherichia coli, Streptococcus spp., Staphylococcus spp., and Proteus spp.) or viruses (infectious canine hepatitis virus, canine distemper virus, and canine herpesvirus); (2) obstructive nephropathy from urolithiasis, transitional cell neoplasms of the lower urinary system, or trauma; (3) renal ischemia with tubular necrosis from occlusive vasculitis/vasculopathy caused by bacteria, bacterial toxins, or tumor emboli; (4) tubular necrosis from nephrotoxic drugs, such as aminoglycoside-based antimicrobial drugs or antineoplastic drugs; and/or (5) tubular necrosis from chemicals, such as ethylene glycol and heavy metals.


Functionally, acute renal failure can be caused by prerenal (compromised renal perfusion), intrarenal (compromised kidney function), or postrenal (obstruction of the urinary tract) factors. Prerenal factors include reduced renal blood flow, whether secondary to circulatory collapse (shock, severe hypovolemia) or local obstruction of vascular supply (thrombus or lodgement of embolus). Acute tubular necrosis, a form of intrarenal acute renal failure, induces clinical oliguria (decrease in urine production) or anuria (absence of urine production) by one or several mechanisms. These mechanisms include the following:



The latter mechanism is less well accepted, but both mechanisms result in decreased glomerular filtration rate.


Prerenal and intrarenal factors are most responsible for episodes of acute renal failure, with prerenal azotemia and ischemic tubular damage actually being a continuum. Postrenal obstructive diseases are discussed in the lower urinary tract section. Intrarenal disease can target tubules by the following three main mechanisms:



Acute renal failure occurs when the kidney fails to excrete waste products and to maintain fluid and electrolyte homeostasis. The four main pathologic alterations in acute renal failure are as follows:



These alterations can occur after many insults, including the following:



Animals that die of acute renal failure often do so because of the cardiotoxicity of elevated serum potassium, metabolic acidosis, and/or pulmonary edema. Hyperkalemia results from decreased filtration, decreased tubular secretion, and decreased tubular sodium transport. Cell lysis and the extracellular shift of fluid in acidic environments also contribute to the increased serum potassium concentrations. These alterations are reflected clinically by signs, such as polyuria and polydipsia, vomiting and diarrhea, and ammoniacal-smelling breath, and an array of nonrenal lesions described later and can be detected and monitored with biochemical tests of serum, plasma, and urine for azotemia and uremia.



Azotemia and Uremia: Assays for plasma or serum concentrations of urea, creatinine, and the nitrogenous waste products of protein catabolism, are routinely used as indices of diminished renal function. The intravascular increase of these nitrogenous waste products is referred to as azotemia. Renal failure can result in the following:



The result of renal failure is a toxicosis called uremia. Uremia can therefore be defined as a syndrome associated with multisystemic lesions and clinical signs because of renal failure. These multisystemic lesions are discussed in greater detail in the section on Disorders of Domestic Animals.



Chronic Renal Failure: Similar to acute renal failure, chronic renal failure occurs over a longer time duration and results in several additional hematologic and biochemical alterations. In the diseased kidney, production of erythropoietin, a stimulant of erythropoietic maturation, is reduced and contributes to nonregenerative anemia, as does uremia-associated increased erythrocytic fragility. Most animals in renal failure have hyperphosphatemia and low to normal calcium levels, although variations exist, depending on species and stage of the disease. Alterations in calcium-phosphorus metabolism in the uremic animal are a hallmark of chronic renal failure and result from a complex set of events as outlined in the following:



These changes in calcium-phosphorus metabolism are made more severe by the reduced ability of the diseased kidneys to hydroxylate 25-hydroxycholecalciferol to the more active 1,25-dihydroxycholecalciferol (calcitriol), resulting in decreased intestinal absorption of calcium. Calcitriol production is further inhibited by hyperphosphatemia. In addition, calcitriol normally suppresses PTH secretion; therefore reduced calcitriol production further increases PTH secretion. With time, these events lead to parathyroid chief cell hyperplasia (renal secondary hyperparathyroidism), fibrous osteodystrophy (renal osteodystrophy), and soft tissue calcification.


Renal secondary hyperparathyroidism is further thought to perpetuate and enhance renal disease by stimulating nephrocalcinosis (see Fig. 11-31; also see Chapter 12), the process by which renal tubular epithelium is damaged by an increase in intracellular calcium. Calcium is precipitated in mitochondria and in tubular basement membranes. Soft tissue calcification associated with uremia occurs in numerous sites and represents both dystrophic and metastatic calcification. These lesions are discussed in greater detail in the section on Disorders of Domestic Animals.



Portals of Entry



Kidney as a Whole


The urinary system and especially the kidney can be exposed to injurious stimuli and agents via a number of routes (Box 11-1), including the following:






Tubules







Vasculature


As in all visceral organs, the sustaining blood supply can provide a portal of hematogenous entry for infectious organisms, which in the case of the kidney principally leads to arterial localization at one of several gradated sites as follows:




Defense Mechanisms


Defense mechanisms unique to the renal system have evolved to counteract the routes of typical exposure to injurious agents and include those localized to the renal corpuscle, tubules, interstitium, and vasculature (Box 11-2).




Renal Corpuscle








Responses to Injury


The response of the urinary system to injury is the response of each of its components—kidney, ureter, bladder, and urethra—to injury. Additionally, components within the kidney, such as the renal corpuscle, tubules, interstitium, and vasculature, have their own unique responses to injury. Responses to injury are described sequentially in this section and are summarized in Box 11-3.




Responses of the Kidney to Injury


The functional unit of the kidney is the nephron, and damage to any component of the nephron (renal corpuscle and tubules) results in diminished function and progressive damage to the kidney. Renal disease can be best summarized by dividing it into general tissue responses that affect the primary anatomic components: glomeruli, tubules, interstitium, and vasculature. In the early stages of disease, specific anatomic components may be targeted by specific insults: glomeruli in immune-mediated disease and tubules in toxin-induced necrosis. But in the more chronic stages of disease, the kidney undergoes changes related to nephron loss that are not specific to the original cause but are considered common end-stage responses to many injurious stimuli.



Renal Corpuscle


Primary glomerular damage often occurs as a result of deposition of immune complexes, entrapment of thromboemboli and bacterial emboli, or direct viral or bacterial infection of glomerular components. Such insults are reflected morphologically by necrosis, thickening of membranes, or infiltration of leukocytes, and functionally by reduced vascular perfusion. Continued or severe injury can result in chronic changes characterized at first by atrophy and fibrosis of the glomerular tuft (sclerosis) and secondarily by atrophy of renal tubules, as the nephron dies. Similar chronic glomerular changes can result from reduced blood flow or chronic loss of tubular function.


Damage to the glomerular filtration barrier can result from several causes and produce a variety of clinical signs. The major clinical finding of glomerular disease is the leakage of various low molecular weight (small molecule size) proteins, such as albumin, into the glomerular filtrate. As a result, large quantities of albumin overload the protein reabsorption capabilities of the proximal convoluted tubular epithelium to such an extent that protein-rich glomerular filtrate accumulates in the variably dilated tubular lumina and protein subsequently appears in the urine. Renal diseases that result in proteinuria are called protein-losing nephropathies. Protein-losing nephropathy is one of several causes of severe hypoproteinemia in animals. Prolonged, severe renal protein loss results in hypoproteinemia, reduced plasma colloid osmotic (oncotic) pressure, and loss of antithrombin III. The nephrotic syndrome is further characterized by generalized edema, ascites, pleural effusion, and hypercholesterolemia.


The functions of the glomerulus listed in the following are affected by processes that injure it in disease:



The pathophysiologic mechanisms of glomerular injury from infectious or chemical insults have been summarized by the following three theories:



The intact nephron hypothesis proposes that damage to any portion of the nephron affects the entire nephron function. This is seen when glomerular damage interferes with peritubular blood flow and results in decreased tubular resorption or secretion. Not all nephron damage is irreversible, for example, renal tubular epithelium can regenerate but whole nephrons are not capable of regeneration. Thus the outcomes for the nephrons vary from hypertrophy to repair.


Unlike the intact nephron hypothesis, the hyperfiltration hypothesis helps explain the progressive nature of glomerular disease. Glomerular hyperfiltration is a result of increased hydrostatic pressure that damages delicate glomerular capillaries and in cases of prolonged hypertension produces a sustained repeating deleterious effect on the glomerulus, ultimately resulting in glomerulosclerosis. Increased dietary protein can produce a transient increase in glomerular hyperfiltration and if persistent can result in glomerulosclerosis. There may be a species effect, as dogs that undergo experimental hyperfiltration are much less prone to development of progressive glomerular disease than are rats.


The theory of complex deposition is derived from the fact that glomeruli are the primary site for removal of macromolecules (principally immune complex) from the circulation. Complexes may be deposited in subepithelial, subendothelial, or mesangial locations. These immune complexes are capable of triggering a sequence of inflammatory responses including the following:


Sep 17, 2016 | Posted by in GENERAL | Comments Off on The Urinary System
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