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.

Fig. 11-1 Schematic diagram, kidney, dorsal section, dog. (Based on Schaller O, Constantinescu GM, eds: Illustrated veterinary anatomical nomenclature, Stuttgart, Germany, 2007, Enke Verlag.)

Fig. 11-2 Schematic diagram, kidney, dorsal surface and partial dorsal section, cow. (Based on Schaller O, Constantinescu GM, eds: Illustrated veterinary anatomical nomenclature, Stuttgart, Germany, 2007, Enke Verlag.)

Fig. 11-3 Schematic diagram, kidney.
A, Dorsal section through hilus, pig. B, Transverse section through hilus, dog. (Based on Schaller O, Constantinescu GM, eds: Illustrated veterinary anatomical nomenclature, Stuttgart, Germany, 2007, Enke Verlag.)

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.

Fig. 11-4 Schematic diagram of the uriniferous tubule. (From Kierszenbaum AL: Histology and cell biology: an introduction to pathology, ed 2, St Louis, 2007, Mosby.)

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.

Interstitium

Macroscopically, the interstitium consists of a relatively scant connective tissue stroma, primarily present as a reticular meshwork found around and between uriniferous tubules. Microscopically, fibroblasts and connective tissue provide most of the interstitial tissue support. Glycosaminoglycans secreted as part of the extracellular matrix (ECM) increase with age and ischemic damage. Cells in the interstitium, particularly in the medulla, are responsible for local production of prostaglandins. Blood vessels, nerves, and lymphatic vessels are present in the renal interstitium.

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.

Fig. 11-8 Schematic diagram of the vasculature of the kidney. (From Kierszenbaum AL: Histology and cell biology: an introduction to pathology, ed 2, St Louis, 2007, Mosby.)

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.

Fig. 11-9 Schematic diagram of the renin-angiotensin-aldosterone system. (From Kierszenbaum AL: Histology and cell biology: an introduction to pathology, ed 2, St Louis, 2007, Mosby.)

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).

Fig. 11-10 Schematic diagram of the counter-current multiplier and exchanger. (From Kierszenbaum AL: Histology and cell biology: an introduction to pathology, ed 2, St Louis, 2007, Mosby.)

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:

• Leakage of tubular ultrafiltrate from damaged tubules across disrupted basement membranes into the renal interstitium.

• Intratubular obstruction resulting from sloughed necrotic epithelium.

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:

• Ascending disease, such as pyelonephritis

• Intraluminal toxic metabolites derived from glomerular filtrate

• Ischemia (Fig. 11-11)

Fig. 11-11 Schematic diagram of ischemic renal failure.
A wide spectrum of clinical conditions can result in a generalized or localized reduction in renal blood flow, thus increasing the likelihood of ischemic acute renal failure. The most common condition leading to ischemic acute renal failure is severe and sustained prerenal azotemia. Kidney ischemia and acute renal failure are often the result of a combination of factors. (Redrawn from Thadhani R, Pascual M, Bonventre JV: N Engl J Med 334(22):1448-1460, 1996.)

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:

• Decreased ultrafiltration

• Intratubular obstruction

• Fluid back leak

• Intrarenal vasoconstriction

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

• Decreased renal perfusion

• Decreased glomerular filtration

• Ischemic tubular damage

• Toxic tubular damage

• Obstructive renal tubular damage

• Tubulointerstitial inflammation, edema, or fibrosis

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:

• Intravascular accumulation of other metabolic wastes such as guanidines, phenolic acids, and large molecular weight alcohols (example: myoinositol)

• Reduced blood pH (metabolic acidosis)

• Alterations in plasma ion concentrations, particularly potassium, calcium, and phosphate

• Hypertension

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:

• When the glomerular filtration rate is chronically reduced to less than 25% of normal, phosphorus is no longer adequately secreted by the kidneys and hyperphosphatemia results.

• Because of the mass law interactions between serum calcium and phosphorus, ionized calcium concentration in serum is reduced as a result of precipitation of calcium and phosphorus.

• Reduced ionized serum calcium stimulates parathyroid hormone (PTH) secretion, causing calcium release from the readily mobilizable calcium stores in the bone and from osteoclastic bone resorption.

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:

BOX 11-1 Portals of Entry to the Kidney

Ascending From Ureter

• Extension from lower urinary tract secondary to gastrointestinal content contamination (diarrhea) (females primarily)

• Extension from lower urinary tract secondary to genital tract contamination (pyometra) (females exclusively)

• Extension from lower urinary tract secondary to dermal contamination (perivulvar dermatitis)

• Targets tubules and interstitium primarily

Hematogenous

• Localization within corticomedullary vessels

• Septic—embolic nephritis

• Nonseptic necrosis with infarction

• Localization within large renal vasculature

• Massive infarction

• Localization within glomerular tufts

• Localization within interstitial vessels

• Targets glomeruli, tubules, interstitium, and vasculature

Direct Penetration

• Activation of products in proximal tubules—necrosis

• Presence of heavy metal—mercury, cadmium

• Crystalline oversaturation

• Direct toxic action—cisplatin

• Targets tubules

• Hematogenous

• Ascending from ureter

• Glomerular filtrate

• Direct penetration

Renal Corpuscle

Hematogenous

As in all visceral organs, the sustaining blood supply can provide a portal of hematogenous entry for infectious organisms, which in the kidney can lead to glomerular localization or embolic nephritis.

Tubules

Glomerular Filtrate

Substances secreted into the glomerular filtrate can produce localized trauma to tubular lining cells such as crystalline salt oversaturation (e.g., oxalate crystals). Filtered preformed toxins or metabolized substances processed by the tubular lining epithelium exert their effect principally on the proximal tubular epithelium.

Ascending Injury

Ascension from the exterior via the urethra and urinary bladder is relatively unique in that few body systems have an opening to the exterior, and these are rarely blind-ended as in the urinary system. Thus ascending infection from the exterior can localize and be perpetuated in the kidneys. Common etiologic agents in this process, such as bacteria, may originate from the exterior skin surface and the adjacent orifices of the intestinal tract or the genital tract.

Hematogenous (Interstitial Capillaries and Vasa Recta)

The luminal and abluminal surfaces of epithelial cells lining renal tubules can be exposed to systemic blood-borne (hematogenous) toxins that are secreted via peritubular capillaries into the interstitial and/or luminal fluid, respectively.

Interstitium

Hematogenous

The interstitium can be entered most successfully by the associated interstitial blood supply, allowing for interstitial localization of blood-borne pathogens, similar to those seen with glomerular blood-borne infections.

Ascending Injury

See previous section on Tubules.

Lymphoid Nodules

Although often present as aggregates or less commonly as nodules, lymphoid infiltrates within the interstitium are not normal but the result of previous insults typically from infectious etiologies, such as Leptospirosis, or as a result of ascension secondary to long-standing pyelonephritis.

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:

• Localization within large renal vasculature. Massive infarction of the kidney is the result of large-bore renal vessel disease.

• Localization within corticomedullary vessels. In the case of associated bacterial spread, septic embolic nephritis can occur. In those examples in which the embolus is nonseptic, the result is infarctive necrosis.

• Localization within glomerular tufts. In this example, the lesions are localized to the vasculature of the small vessels within the glomerular tuft.

• Localization within interstitial vessels. In this example, the lesions are localized to necrosis of interstitial tissues and tubules.

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).

BOX 11-2 Renal Defense Mechanisms Against Injury and Infectious Agents

• Barrier system—glomerular basement membrane (GBM)

• Monocyte-macrophage system—glomerular mesangium

Renal Corpuscle

Glomerular Basement Membrane

The most important of these barrier systems is the glomerular filtration membrane (see Fig. 11-7). The glomerular membrane is structurally adept at separating substances based on size and charge. 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. This inherent function of the glomerulus can also protect other regions of the nephron from damage by circulating inflammatory cells and their cytokines, as well as infectious agents that are present in the systemic circulation (i.e., bacteria in bacteremia).