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Urethral Disease and Obstructive Uropathy
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Urethral disease usually induces urinary incontinence or obstruction and produces characteristic clinical signs, including dysuria, stranguria, hematuria, pollakiuria, and urethral discharge. Urethral disease may be congenital or acquired and cause a functional or mechanical lesion (Table 70-1).
The urethra is the tube that conveys urine from the urinary bladder to the exterior of the body . The male urethra is divided into prostatic, membranous, and spongiose or penile portions [1,2]. The prostatic portion extends from the urinary bladder to the caudal edge of the prostate, where the membranous portion begins. The membranous portion ends at the point of the bulb of the penis, where the spongiose portion continues to the external urethral orifice [1,2]. The vascular erectile tissue of the spongiose portion is continuous with the corpus spongiosum of the penis.1 The female urethra corresponds to that portion of the male urethra cranial to the prostate . The urethral mucosa is thrown into folds (rugae) that disappear with urethral distention. A prominent dorsomedian fold remains, known as the dorsal urethral crest [1,2]. In the male, the colliculus seminalis, an oval enlargement located in the middle of the urethral crest that projects into the urethral lumen, contains the minute openings of the uterus masculinus and is closely associated with the deferent ducts, which open on either side [1,2].
The wall consists of four layers, mucosa, submucosa, muscularis, and adventia. The mucosa of both male and female urethras is predominantly transitional epithelium; it gradually changes to stratified squamous epithelium near the external urethral orifice. Stratified cuboidal, stratified columnar, or simple columnar epithelium is interspersed between these two sites [2,3].
The propria submucosa consists of loose connective tissue with many elastic fibers and smooth muscle cells. The urethra in bitches is 68% to 78% connective tissue by volume . Diffuse lymphatic tissue and nodules are also present in dogs [2,3]. Male cats also have simple tubular urethral glands . Cavernous spaces in the submucosa and lamina propria along the entire length of the male and female urethra give the appearance of erectile tissue [1-3]. The quantity and size of cavernous spaces increase in the penile urethra where it becomes the corpus spongiosum .
The urethral muscle is composed of three inner layers of smooth muscle and an outer layer of striated muscle and is continuous proximally with the detrusor muscle of the urinary bladder wall . The amount of smooth versus striated muscle varies at sites along the urethra. In females, the proximal urethra is predominantly smooth muscle with a thick inner circular layer interspersed with thin, oblique fibers  and covered by a thin outer longitudinal layer . Proximal smooth muscle has sphincter-like properties but is not a true anatomic sphincter and not under conscious control. Distally, the smooth muscle fibers become intermixed with striated muscle fibers and are replaced principally by circular striated bundles and a few longitudinal fibers. Terminally, a thin layer of circular smooth muscle lies on the inner side of predominant striated muscle bundles . In males, smooth muscle predominates in the proximal urethra and striated muscle becomes dominant in the post-prostatic urethra . In bitches, skeletal muscles is located in the distal half of the urethra . Unlike dogs, cats have well organized circular and longitudinal smooth muscle fibers in the proximal urethra which shorten and widen the urethra during voiding . Female cats have skeletal muscle in the distal third of the urethra . The distal striated urethral muscle is functionally more efficient in males than in females and is under voluntary control . Smooth muscles in the lower urinary tract are electrically coupled, exhibit spontaneous action potentials, contract when stretched, and are under autonomic control. Urethral muscle is surrounded by an adventitia of loose or dense irregular connective tissue .
The blood supply to the urethra is by branches of the internal pudendal artery and vein . Nerves leaving the pelvic and sacral plexuses (pelvic, pudendal, and hypogastric nerves) control functions involving the urethra . Lymphatic drainage occurs through the medial iliac (formerly external iliac), hypogastric (formerly internal iliac), and sacral lymph nodes .
The primary functions of the urethra are (1) to maintain continence by providing resistance to urine flow in the nonvoiding state , (2) to allow unhindered passage of urine during urinations , and (3) to contribute to the normal host defenses against urinary tract infection [10,11].
Micturition and Continence
Urinary continence is maintained by smooth and striated muscle tone, urethral wall elastic tension, and intra-abdominal pressure and is influenced by urethral length. During voiding, simultaneous contraction of the urinary bladder and relaxation of the urethra allow urination . It is triggered either by reflex or voluntarily. In reflex micturition, bladder afferent fibers excite neurons that project to the brainstem and activate the micturition center in the rostral pons and inhibit sympathetic preganglionic fibers that prevent voiding. Commands from the micturition center reach the sacral spinal cord through a reticulospinal pathway . In voluntary micturition, the external sphincter is voluntarily relaxed by cortical inhibition of the pudendal nerve, which allows urine to flow through the meatus. With either mechanism, contraction of the destrusor muscle causes a vigorous discharge of the mechanoreceptors in the urinary bladder wall, which further activate the supraspinal loop and cause complete emptying of the urinary bladder . During these phases, the urethra and the urinary bladder function interdependently and rely on the cerebral cortex for voluntary control [9,12,14].
Micturition involves coordination of autonomic and somatic afferent and efferent activities. Postganglionic sympathetic innervation is via the hypogastric nerve, with preganglionic branches from the first and second lumbar spinal cord segments (L1, L2) in dogs or the second and third segments (L2, L3) in cats [12,14]. Parasympathetic innervation via the pelvic nerve originates from the first, second, and third sacral spinal cord segments (S1, S2, S3) [12,14]. Somatic innervation of the striated urethral muscle is via the pudendal nerve originating from sacral cord segments S1 to S3 [12,14]. Autonomic sympathetic impulses are mediated by acetylcholine at preganglionic synapses and norepinephrine at postganglionic synapses. Norepinephrine excites both alpha receptors (for contraction of smooth muscle; excites trigone and internal urethral sphincter) and beta receptors (for relaxation of smooth muscle; inhibits detrusor muscle) [12,14]. Autonomic parasympathetic impulses activate cholinergic receptors of the urinary bladder and induce contraction of the detrusor smooth muscle [12,14]. The somatic innervation of the striated urethral muscle involves a single synapse between the motor nerve and the muscle, mediated by acetylcholine [12,14].
Sympathetic autonomic activity dominates the storage phase: β-adrenergic stimulation facilitates relaxation of the detrusor muscle and α-adrenergic stimulation produces contraction of the trigone and proximal urethral smooth muscle to maintain continence. There is also α-adrenergic-mediated inhibition of parasympathetic transmission, decreasing cholinergic stimulation of the detrusor muscle and allowing relaxation [8,12].
The primary adrenergic receptor within the prostatic urethra is the α1A subtype (which is responsive to phenylephrine in a dose-dependent manner) . The striated urethral muscle plays a minimal role in maintaining continence, but somatic stimulation can cause temporary rapid contraction should increase resistance to urine flow be required [8,12]. The fibroelastic tissue of the urethra is also responsible for a significant component of resting urethral tone [8,12].
The voiding phase is dominated by parasympathetic autonomic activity. Distention of the urinary bladder stimulates preganglionic parasympathetic sensory receptors through the pelvic nerve and initiates the micturition reflex . Transmission through the parasympathetic ganglia in the pelvic plexus to postganglionic fibers stimulates the detrusor muscle and produces a wave of depolarization and subsequent strong, complete contraction of the urinary bladder. Simultaneously, sympathetic inhibition of the trigone and proximal urethra via the hypogastric nerve allows the smooth muscle to relax . Pelvic nerve sensory neurons also send collaterals to inhibit interneurons in the sacral spinal cord. These in turn inhibit cell bodies of the pudendal nerve innervating the striated external urethral muscle . When the urinary bladder is empty, discharges from the pelvic nerve cease, allowing for loss of inhibition of the hypogastric nerve (sympathetic) and the pudendal nerves (somatic) and closure of the urethra .
Central control of micturition resides in the brain stem, at the level of the pons, and receives sensory stimulus from stretch and pain receptors in the urinary bladder. Voluntary control of the brain stem micturition center includes the cerebral cortex, basal ganglia, thalamus, and cerebellum, and these components exert mostly an inhibitory influence over micturition .
The Role of the Urethra in Host Defense
Some of the natural defense mechanisms of the urinary tract to prevent infection include the length of the urethra, the high pressure zones within the urethra, urethral and ureteral peristalsis, the vesicoureteral flaps that prevent urine reflux from the urinary bladder into the ureters, and the extensive renal blood supply and flow [10,15]. Other host defenses include the antimicrobial properties of urine, renal defenses, and systemic defenses. Most of the urinary tract is sterile; however, bacteria normally reside in the lower genitourinary tract. In dogs, these bacteria include species of Staphylococcus, Streptococcus, Corynebacterium, Pasteurella, Proteus, Klebsiella, Mycoplasma, Escherichia coli and others . This resident population of bacteria may decrease establishment of a uropathogen or may emerge as a uropathogen if normal host defenses are altered. The uropathogenicity of each organism varies. The majority of urinary tract infections (UTI) result from ascending migration of pathogens . The most common canine uropathogens are Escherichia coli (44.1%), Staphylococcus spp (11.6%), Proteus (9.3%), Klebsiella spp (9.1%), Enterococcus spp (8.0%) and Streptococcus spp (5.4%) . The identification of bacteria in the urine is not indicative of a urinary tract infection. An infection exists if a high number of bacteria exist in a properly collected and cultured sample . The urethra contributes to the local host defenses involving normal micturition, anatomic barriers, and mucosal defense barriers.
Mechanical washout induced by unimpeded frequent and complete voiding of an adequate urine volume inhibits bacterial colonization of the urinary tract by rapidly eliminating organisms that reach the proximal urethra and urinary bladder . Urination also reduces the microbial population of urethral mucosa by flushing the urethra with sterile urine. Washout is aided by distention of the urethra, which obliterates mucosal folds that could harbor bacteria . The effectiveness of voiding depends on the rate of urine production, the frequency and completeness of voiding, and the rate of bacterial proliferation . Urine composition also helps to prevent infections. Urine contains substances that inhibit bacterial colonization, including a high urea concentration, organic acids, low molecular weight carbohydrates and Tamm-Horsfall mucoprotein [10,15]. Cell-mediated and humoral immunity within the urine or urinary tract also give protection [10,15]. Antimicrobial properties of urine include extreme high or low urine pH, hyperosmolality, high urea concentration, organic acids, low molecular weight carbohydrates, Tamm-Horsfall mucoproteins, and perhaps others [10,15].
A functional high-pressure zone in the mid-urethra of female dogs, corresponding to an area of smooth and striated muscle, has been hypothesized to inhibit the migration of bacteria along the urethra . Surface characteristics of the urethral epithelium differ in the proximal and distal urethra and correlate, respectively, with absence or presence of bacteria. The normally sterile proximal urethra contains longitudinal folds called microplicae, which flatten when the lumen expands. The distal urethra contains microplicae, but it also has randomly arranged fingerlike projections called microvilli . Urethral peristalsis, beginning in the proximal urethra and moving distally, may be important in maintaining unidirectional urine flow and inhibiting ascension of bacteria . The incidence of cystitis is lower in males than in females, perhaps because of the gram-positive and gram-negative bactericidal fraction of prostatic fluid . Nevertheless, in some dogs the prostate may act as a reservoir for bacteria . In addition, the longer male urethra may provide greater resistance to bacterial access to the proximal urethra and urinary bladder .
Mucosal Defense Barriers
Urinary tract mucosal defense barriers prevent bacterial migration and colonization. These barriers include a glycosaminoglycan layer, antibodies, intrinsic mucosal antimicrobial properties, cell exfoliation, and bacterial interference by commensal microbes of the distal urethra and distal genital tract . Bacterial adherence to urethral epithelial surface is essential to subsequent tissue invasion and colonization . The normal negative electric charge of both the bacterial cell wall and the urethral epithelium tends to repel the bacteria and prevent contact. Bacterial adherence is achieved by molecular bonding between molecular structures known as adhesins and specific receptor sites on the urethral epithelial surface . Adhesins are present on bacterial cell wall fimbriae of gram-negative bacteria or on fibrillae of gram-positive bacteria. Although the mucosa has few direct antibacterial properties, a surface mucopolysaccharide glycosaminoglycan layer provides a barrier to bacterial adherence . The urethral mucosa may also produce secretory immunoglobulin A (IgA) . Most of the IgA in the urine originates from this source and inhibits bacterial ascent from the urethra to the urinary bladder . Disruption of the surface glycosaminoglycan layer by acid or povidone-iodine, allows bacterial adherence to the urethral epithelium . Exfoliation of urethral epithelial cells is a natural phenomenon that may be accelerated by abnormal conditions. This may expedite the removal of bacteria from the urethra during voiding .
Loss of normal urethral function usually results in urinary incontinence or obstruction. Urinary incontinence occurs when the intravesicular pressure exceeds the intraurethral pressure, resulting in uncontrolled loss of urine from the body. Incontinence may also occur owing to anatomic abnormalities that bypass the normal continence mechanisms (ectopic ureters). Such urinary incontinence is primarily caused by incompetence, and may be non-neurogenic or neurogenic. Urethral dysfunction causing urinary tract obstruction may be functional (neurogenic) or mechanical (intraluminal or extraluminal obstruction or loss of integrity). Urethral disease may also affect the ability of the urethra to contribute to host defenses against UTI. UTI is often a concurrent finding with urethral dysfunction, causing either incontinence or obstruction.
Non-Neurogenic Urethral Dysfunction as a Cause of Incontinence
Congenital or acquired urethral abnormalities may result in incontinence, including urethral malformations and conditions that cause urethral incompetence. In addition, urethral obstruction that leads to urinary bladder overdistention may cause detrusor damage and atony leading to overflow incontinence.
Congenital urethral disorders are infrequent. Urethral agenesis, urethral duplication, hypospadias, epispadias, diverticula, stricture, fistula, urethral ectopia, hermaphroditism, and pseudohermaphroditism have been reported. These conditions sometimes result in incontinence or abnormal flow of urine from the urethra.
Ectopic ureters may be associated with anatomic and functional abnormalities of the bladder and urethra [18,19]. Anatomic abnormalities of the urethra and vaginal vestibule are common in dogs with ectopic ureters and may result in continued incontinence after surgical repair if they are not treated concurrently. Urethral troughs, fenestrations, tenting, striping, and the intramural ureter in the dorsal urethral wall may affect the ability of the urethra to generate adequate closure pressure [18,19]. Congenital urethral incompetence that does not resolve after surgical treatment for ectopic ureters may also be a result of persistent ureteral malpositioning, vestibulovaginal malformation, or a congenital neuromuscular deficit on the proximal urethra.
For a discussion of acquired urethral incompetence see Chapter 69: Canine Urethral Sphincter Mechanism Incompetence.
Paradoxical Urinary Incontinence
Paradoxical urinary incontinence mimics urethral obstruction without a physical obstruction . Affected animals have a large urinary bladder and attempt to urinate without success. They may develop postrenal azotemia and uremia. Obstruction is believed to be caused by spastic contraction and inflammation secondary to chronic urethritis . It is difficult to catheterize awake animals but anesthetized animals are catheterized without impedence. As the urinary bladder fills, intravesicular pressure eventually exceeds the resistance caused by the urethral lesion, resulting in urinary incontinence.
Chronic inflammation of the lower urinary tract may produce a syndrome of incontinence characterized by frequent, uncontrolled, involuntary detrusor contractions. It is a disorder of the storage phase of urination and is often referred to as urge incontinence. Inflammation of the urethra may be infectious or noninfectious. Urethritis is not a common clinical entity and is often associated with other urogenital inflammatory diseases, including prostatitis, cystitis, and vaginitis . Noninfectious causes of urethritis, including trauma, chemicals, neoplasms, and urolithiasis, may predispose to bacterial urethritis. The normal urethra is not sterile, and resident bacteria normally populate the distal urethra . Infectious urethritis may also occur secondary to infection elsewhere in the urogenital tract (e.g., cystitis, prostatitis, or vaginitis) . Catheterization may induce urethritis through trauma, bacterial contamination, and reaction to the material of an indwelling catheter .
Acute urethritis may induce stranguria or pollakiuria . Gross hematuria may be present at the beginning of micturition. Urethral discharge must be differentiated from preputial or vaginal discharge . Chronic urethritis may lead to urethral incompetence owing to fibrotic changes in the tissue. Similarly, infiltrative diseases such as neoplasms or granulomatous urethritis may also cause urethral incompetence [22,23]. As the intravesicular pressure increases, the damaged or diseased urethra is unable to prevent the flow of urine, and urinary incontinence results. Chronic urethritis with stricture or infiltrative disease can progress to cause urethral obstruction (see discussion of mechanical urethral obstruction later in this chapter) [22,23].
Neurogenic Urethral Dysfunction as a Cause of Incontinence
Lesions of the sacral spinal cord, sacral roots, or pudendal nerve decrease urethral pressure. Urethral muscle hypotonicity is commonly associated with lower motor neuron lesions at or caudal to the level of the L5 vertebrae (L6 in the cat). These lesions damage the sacral spinal cord segments or nerve roots (pudendal nerve and pelvic nerve) . Detrusor areflexia, with or without complete loss of urethral tone, usually results. With complete lesions, the striated urethral muscle is denervated but the hypogastric nerve innervating the proximal urethral smooth muscle remains intact, because it originates from lumbar spinal cord segments . The sacral lesion abolishes normal sensory input from the stretch receptors in the detrusor muscle. As a result, the proximal urethral smooth muscle does not relax in response to the increased pressure of urinary bladder filling and remains fixed . Manual expression of the urinary bladder may be easy or may meet resistance. Once the urinary bladder fills, the intravesicular pressure overcomes the proximal urethral smooth muscle resistance and overflow incontinence results. Some pain receptors in the hypogastric nerve may remain intact, and the animal may show discomfort and make unsuccessful attempts to urinate .
Consequences of Urethral Incompetence
Urinary incontinence owing to urethral dysfunction results in urine soiling of the environment and pet, particularly causing skin irritation and scalding of the hind limbs, perineum, and ventral abdomen [10,15]. Overdistention of the urinary bladder may damage the muscle cells and also cause separation of the tight junctions between the detrusor muscle fibers, preventing excitation-contraction coupling (see discussion of consequences of chronic urethral obstruction later in this chapter). Increased capacity and incomplete emptying of the urinary bladder can result in large amounts of residual urine and predispose to recurrent urinary tract infection. Bacterial elimination from the urinary bladder is impaired after overdistention of the urinary bladder. Possible consequences of UTI include septicemia, discospondylitis, urolithiasis, incontinence, prostatitis, pyelonephritis, renal failure, and urinary bladder neoplasms. Long-standing urinary bladder distention and chronic UTI cause hypertrophy, hyperplasia, and connective tissue infiltration of the urinary bladder wall or urethra. This results in poor contractile function of these structures, and it reduces the capacity of the urinary bladder, thereby exacerbating the problem of urinary incontinence.
Urethral obstruction may be mechanical or functional. Diseases of the urethra frequently result in partial or complete obstruction of urine outflow. Calculi, neoplasia, granuloma, stricture, or urethral malpositioning can cause urethral obstruction. Occasionally, neurologic disease, prostatic disease, or blood clots may cause obstruction. The condition may be life-threatening and animals should be evaluated for hyperkalemia and metabolic acidosis. Total obstruction is an emergency as it quickly leads to uremia (two to three days) and death (three to six days) if untreated. Additionally, urethral obstruction can result in prolonged bladder distention, which causes temporary or permanent detrusor contractile dysfunction.
Functional Urethral Obstruction
Functional obstruction results from failure of coordination of urethral relaxation with detrusor contraction. Upper motor lesions of the urinary bladder with spinal lesions above L5 affect the suprasacral spinal cord segments . The micturition reflex is lost, and detrusor areflexia with hypertonus of the urethra is the result of lack of inhibition of the hypogastric and pudendal nerves . The urethral hypertonus causes increased resistance to urine flow, and manual urinary bladder expression is difficult. The animal does not perceive vesicle fullness, owing to loss of conscious sensation and cerebral motor control . Micturition can be initiated by spinal reflexes, and a reflex bladder may develop over several days to weeks after the injury . Once a threshold bladder capacity is reached, a "myotactic-like" reflex is initiated via stretch receptors in the bladder wall. These receptors send afferent impulses via the pelvic nerve to the sacral spinal cord. Depolarization of the pelvic nerve efferents contracts the detrusor muscle, but voiding is interrupted, involuntary, and incomplete, owing to failure of urethral relaxation .
Partial suprasacral lesions may result in inappropriate contraction or relaxation failure of the urethral muscle, coincident with detrusor contraction. This condition is termed detrusor-urethral or reflex dyssynergia. The animal makes voluntary attempts to urinate but micturition is incomplete, giving the appearance of mechanical urethral obstruction . The major resistance to urine flow is where the distal striated urethral muscle overlaps the proximal smooth muscle--approximately in the mid-urethra of females and the postprostatic membranous urethra of males. The primary cause of obstruction is thought to be over-discharge of the sympathetic nerve impulses to both the smooth and striated urethral muscle, causing increased intraurethral pressure during attempts at voiding . Abnormalities of the somatic innervation to the urethral striated muscle may also contribute to the dyssynergia. Accompanying problems might include urinary tract infection, bladder atony, prostatic enlargement, urolithiasis, and priapism [26,27].
Mechanical Urethral Obstruction
Intraluminal urethral obstruction may result from congenital or acquired urethral strictures, urethroliths, neoplasms, polyps, proliferative urethritis , foreign bodies, blood clots, malpositioning, or penile fractures [20,28-31]. Urethral strictures may form secondary to previous urethral injury such as surgery, urethroliths, external trauma, or urethral catheterization. Urethral uroliths originate in the urinary bladder and cause urethral obstruction more frequently in male dogs, although this is reported in females. The most frequent site of urethral obstruction is the caudal end of the os penis, but uroliths can lodge elsewhere in the urethra. Clinical signs include stranguria and complete inability to urinate.
Primary urethral tumors are reported more frequently in older female dogs. Transitional cell carcinoma and squamous cell carcinoma are most common [32-34]. Other reported tumors include leiomyoma, leiomyosarcoma, prostatic adenocarcinoma, hemangiosarcoma, rhabdomyosarcoma, myxosarcoma, and lymphoma [32-35]. Metastases localize in regional lymph nodes and lungs [32,33,35]. Clinical signs vary and include stranguria associated with partial to complete obstruction. Hematuria and urinary incontinence are also reported .
Proliferative urethritis (granulomatous infiltrative urethritis) is poorly defined in dogs. It is clinically indistinguishable from urethral neoplasms; typical clinical signs are stranguria, hematuria, and urinary obstruction [22,23]. Proliferations are often bands of tissue that are attached to the mucosa on both ends rather than being pedunculated or papillary. The mucosal proliferations can cause a one-way valve effect that causes outflow obstruction but often permits retrograde passage of urethral catheters. The urethra can be palpated as thickened and firm. Older female dogs appear predisposed to proliferative urethritis. The cause is unknown but the tissue reaction may represent a specific, cell-mediated reaction to antigens, organisms, or foreign bodies. Histologic findings include lymphoplasmacytic and neurotrophic inflammation of the urethra [22,23]. The urethral epithelium becomes mildly to moderately hyperplastic. Multifocal, nodular, and coalescing aggregates of lymphocytes, plasma cells, macrophages, and neutrophils are observed in the mucosal and submucosal layers [22,23].
Urethral obstruction in cats with idiopathic lower urinary tract disease may occur. Reasons for obstruction may include urethral inflammatory swelling, muscular spasms, reflex dyssynergia, luminal accumulation of sloughed tissue, inflammatory cells or erythrocytes, and formation of matrix-crystalline plugs .
Extraluminal urethral obstruction can occur secondary to adjacent compressive masses or swelling. Fractures and tumors of the os penis have been reported to cause urethral obstruction [37,38]. Traumatic loss of urethral integrity from poor catheterization technique, pelvic fracture, and gunshot or bite wounds can lead to failure of urine outflow and signs consistent with outflow obstruction.
Consequences of Urethral Obstruction .,39
The consequences of urethral obstruction depend on whether the obstruction is acute or chronic and partial or complete. Partial or early outflow obstruction may not impair renal function sufficiently to cause uremia; however, complete obstruction causes signs of uremia within 24 hours. As functional renal mass decreases or as intravesical, ureteral, and renal pressure increases, urine concentrating ability is lost. Additionally, urethral obstruction may lead to detrusor atony, mucosal damage, urinary tract infection, and urethral or urinary bladder rupture. Acute complete or severe partial obstruction produces postrenal azotemia and uremia that, if not corrected, is fatal in 3 to 6 days. In contrast, chronic partial obstruction causes excessive pressure in the excretory pathway as the urinary bladder's capacity is exceeded. This increase in pressure causes progressive dilatation of the urinary tract, and damage to renal parenchyma may be sufficient to cause chronic renal failure.
Acute Complete Urethral Obstruction
Acute complete urethral obstruction manifests as anuria and results in overdistention of the urinary bladder. Local pressure at the obstruction site damages the muscosa, causing swelling, hemorrhage, and epithelial denudation. Overdistention of the urinary bladder causes similar changes. Outflow obstruction results in increased pressure in the urinary bladder and urethra proximal to the site of obstruction. As intravesicular pressure increases, damage occurs to the urothelium and detrusor muscle. Nerves in the urinary bladder wall are damaged and inflammatory cells infiltrate. The kidneys and ureters are affected if back pressure persists. As the urinary bladder's capacity is exceeded, intraureteral and renal intratubular pressures increase . Normal pressure in the renal pelvis and ureters of the dog ranges from zero to 10 mm Hg . With complete ureteral obstruction during saline diuresis, ureteral pressure in dogs reach 50 to 150 mm Hg within 5 to 15 minutes [42,43]. After 4 hours of obstruction, intratubular pressure declines but can still be as much as 3 times normal [44-46]. The decline in intratubular pressure is thought to result from a reduction in fluid volume in the tubular system because of decreased glomerular filtration rate (GFR), increased tubular reabsorption, or increased capacity of a compliant renal pelvis .
Reduced Glomerular Filtration Rate
The GFR is determined by (1) the net ultrafiltration pressure across the glomerular capillaries (the difference between the hydrostatic pressure in the glomerular capillaries and the sum of the plasma oncotic pressure in the glomerular capillaries plus the hydrostatic pressure in Bowman's space); (2) the permeability of the glomerular capillary wall to water and small solutes; and (3) the surface area of the capillaries.40 Urinary tract obstruction can affect one or more of these factors, significantly decreasing GFR.
As intratubular pressure increases, a decrease occurs in the effective filtration pressure (the difference between intraglomerular capillary pressure and the pressure in Bowman's space or intratubular pressure). This decrease is mainly due to a reduction in hydrostatic pressure in the glomerular capillaries and is accompanied by a marked decrease in renal blood flow after 24 hours' obstruction [47-49]. Progressive preglomerular constriction occurs with obstruction for longer than 5 hours, with a decrease in GFR of approximately 80% after 24 hours' obstruction [50-52]. Obstruction results in heterogeneous nephron function. Some nephrons cease to function and others show decreased GFR; they are, respectively, known as nonfiltering and filtering nephrons . The GFR of outer, cortical nephrons is less affected than that of the inner, juxtamedullary nephrons: after 24 hours' obstruction, decreases are 60% to 70% and 50% of normal, respectively . After 24 hours, GFR decreases further owing to the major vasoconstricting agents thromboxane A2, angiotensin II, and maybe the endothelial-derived relaxing factor . The obstructed kidney may prevent further decrements in GFR by the production of vasodilatory prostaglandins such as prostaglandin E2 and prostacyclin which antagonize the vasoconstrictive effects of thromboxane A2 and angiotensin II . Recovery of GFR following relief of obstruction decreases as the duration of obstruction increases.
During obstructive uropathy, changes in renal blood flow can be divided into 3 phases . During the first phase, 1 to 2 hours after obstruction, renal cortical blood flow actually increases above normal, in association with a decrease in intrarenal resistance and gradually increasing intraureteral pressure [53-57]. However, inner medullary blood flow decreases from the onset of obstruction, reaching less than 30% of normal within 6 hours . The initial increase in blood flow may be the result of augmented production of vasodilatory prostaglandins (prostaglandin E2 [PG E2] and prostacyclin) by the obstructed kidney [59-60]. Increased renal prostaglandin production by the interstitial medullary cells is thought to be the result of a decline in the inner medullary blood flow secondary to the increase in ureteral pressure. The prostaglandin synthesis causes abrupt changes in vascular resistance with an overshoot in renal blood flow, seen in the first phase . During the second phase, 2 to 5 hours after obstruction, the renal blood flow decreases to normal and intraureteral pressure continues to increase. The second phase may be the result of an increase in renal resistance, a direct effect of increasing ureteral pressure on the interstitium. Finally, in the third phase, ureteral pressure begins to decrease but renal blood flow continues to decline progressively with time. The final, chronic phase is the result of an increase in resistance at the preglomerular level . The progressive decrease in blood flow may be a result of increased production of thromboxane A2, a metabolite of arachidonic acid and a powerful vasoconstrictor.40 Persistent renin secretion and angiotensin production may also play a role in vasoconstriction, although the evidence is conflicting [61-62]. Renin initiates the production of angiotensin, a potent vasoconstrictor. Cells of the outer cortical nephrons have a higher concentration of renin than those of the juxtamedullary nephrons . Increased renal nerve activity or high levels of catecholamines at critical sites in the kidney might also contribute to vasoconstriction and decreased renal blood flow [63-65].
Soon after the onset of acute ureteral obstruction, an influx into the kidney occurs of leukocytes, primarily macrophages and T lymphocytes . This influx is associated with a relative depletion of macrophages from the glomeruli. After relief of obstruction, the macrophage and T-lymphocyte infiltrate decreases over days.
The degree and duration of obstruction determine the degree and nature of tubular effects and their recovery . Tubular abnormalities include a concentrating defect, altered reabsorption of solutes and water, and impaired excretion of hydrogen and potassium. Sodium, potassium, phosphate, magnesium, and proton retention may occur during obstruction. Tubular dysfunction may continue after relief of the obstruction owing to tubular damage.
Complete urinary obstruction can lead to death from uremia in 3 to 6 days. Death is a result of combined abnormalities in fluid, electrolyte, and acid-base balances that result in accumulation of metabolic waste products . Characteristically, hyperkalemic metabolic acidosis occurs, and serum phosphorous and calcium values may be elevated. Fractional excretion of potassium increases after relief of obstruction and hypokalemia may occur postobstruction . This may be caused by increased delivery of sodium to the distal tubule where sodium-potassium exchange occurs.
Metabolic acidemia associated with urethral obstruction results from retention of metabolic acids, consumption of bicarbonate to stabilize plasma and compartmental pH, generation of lactate associated with hypovolemia and hypoxia, and decreased conservation of bicarbonate in the obstructive and postobstructive periods .
Direct effects of acidemia include decreased myocardial contractility, stroke volume, and cardiac output; excitable membrane alterations leading to dysrhythmias; central nervous system depression; and dysfunction of metabolic pathways . Indirect effects of acidemia include alterations in transcellular potassium distribution, plasma protein binding, ionization of pharmacologic agents, oxygen transport, tissue catabolism, and increased parasympathetic activity. Whereas animals with urinary tract obstruction have hyperkalemic metabolic acidosis, a urine acidifying defect is apparent and may persist after relief of the obstruction . Two defects have been isolated, a selective aldosterone deficiency and distal renal tubular acidosis, or the two may be combined. Two mechanisms are proposed. First, bicarbonate excretion increases markedly, owing to altered proximal tubule reabsorption . Second, the kidney's ability to acidify urine at distal sites is impaired. The ability of outer cortical nephrons to secrete hydrogen ions appears intact, and the defect is most likely in the collecting duct or juxtamedullary nephrons .
Sequela after Release of Obstruction
The decrease of GFR associated with 24 to 36 hours of obstruction is completely reversible . Most early alterations in the kidney are functional and do not result in permanent loss of nephrons . Complete obstruction for more than 6 days does result in permanent loss of nephrons . Dogs with unilateral ureteral obstruction showed 39% recovery of renal function after 2 weeks of obstruction, 10% after 4 weeks, and 2% after 6 weeks . Urinary tract obstruction, even after release, alters the kidney's ability to modulate water and electrolyte excretion. One of the first abnormalities in kidney function following obstruction is a decrease in the urinary concentrating ability. Following release of urinary tract obstruction a dramatic loss of water and solute occurs, a phenomenon referred to a postobstructive diuresis [40,41]. The factors presumed to be involved in the concentrating defect of obstructive uropathy include decreased removal of solute from the thick ascending limb of the loop of Henle, decreased total number of juxtamedullary nephrons, washout of solutes from the medulla owing to increased medullary blood flow, and decreased hydro-osmotic response of the cortical collecting duct to antidiuretic hormone .
Factors contributing to this phenomenon include the volume status of the animal before release of the obstruction. Animals often receive intravenous fluids and undergo volume expansion. In part, the increased urine flow and sodium excretion after release of obstruction is a physiologic response to volume expansion . Accumulation of urea and other relatively nonabsorbable solutes during obstruction can promote solute diuresis and result in loss of much sodium and water after release .
The inappropriate increase in urine output after urinary obstruction release may also result from an intrinsic defect in renal tubular function. Studies have demonstrated a defect along the proximal and distal tubules of outer cortical nephrons and to the level of the loop of Henle in the juxtamedullary nephrons [51,67]. Other studies suggest the medullary collecting duct may be the site of altered water and sodium reabsorption .
The medullary interstitial cells, responsible for prostaglandin synthesis, show proliferative changes by 5 days after obstruction . Increased medullary prostaglandin synthesis decreases the reabsorption of sodium chloride by the medullary ascending limb of the loop of Henle and the medullary solute content . Increased prostaglandin secretion may also increase blood flow in the vasa recta and cause persistent increase in blood flow in the vasa recta and cause persistent washout of the medulla. A decrease in medullary solute content has the end result of decreasing the diffusion of water out of the collecting duct .
An increase in medullary prostaglandin production may antagonize the effect of vasopressin, reducing the permeability of the collecting tubules to water and contributing to the decrease of urine osmolality . After obstruction, vasopressin-dependent cAMP production may also be impaired [71,72].
Chronic Urethral Obstruction
Chronic partial obstruction is not immediately life threatening but results in pathologic changes in the urinary bladder, ureters, and kidneys. Chronic overdistention of the urinary bladder owing to resistance to urinary outflow may cause varying degrees of hydroureter and hydronephrosis.
During the early phases of obstruction, functional and morphologic changes in the ureter and renal pelvis include muscular hypertrophy and hyperplasia. Later, collagen and elastic connective tissue are produced by the smooth muscle cells, which impair myogenic impulse transmission and disrupts normal peristalsis .
Structural renal changes during hydronephrosis can result in chronic renal failure. Experimental urethral obstruction in the rat, rabbit, and dog cause initial changes in the proximal tubules, which show a transient dilatation over several days, and then undergo atrophy . By 14 days postobstruction, there is progressive dilatation of the distal and collecting tubules with atrophy of the proximal tubular cells . By 28 days, medullary thickness is reduced by 50%, and dilatation and atrophy of the distal and collecting tubules continues . The cortex becomes thinner and the proximal tubules are markedly atrophic. Glomerular changes are noted after 28 days. By 8 weeks, only a thin parenchymal strip of connective tissue and small glomeruli remains .
During chronic hydronephrosis with high intratubular pressures, 80% to 90% of the urine is reabsorbed into the tubules and exits via the renal veins . A small portion of urine is reabsorbed into the hilar lymphatic vessels, and some fluid is extravasated into the perirenal spaces .
Chronic Urinary Bladder Distention
Urinary bladder outlet obstruction with distention produces significant alterations in detrusor structure and function . Chronic urinary bladder outlet obstruction causes increased thickness of the urinary bladder wall owing to muscle hypertrophy, hyperplasia, and collagen deposition by the smooth muscle cells . Hypertrophy is the predominant response to moderate obstruction, whereas hyperplasia with more collagen deposition is the predominate response to severe obstruction .
Although the urinary bladder enlarges, its compliance and capacity decrease . This is demonstrated by a sharp incline in the filling limb of the cystometrogram . Chronic obstruction results in reduced detrusor contractility and evidence of partial denervation is reported [75-77]. Postjunctional supersensitivity secondary to partial denervation contributes to detrusor instability [75,76], characterized by frequent, inappropriate detrusor contractions. Obstruction can cause rapid changes, and muscarinic receptor density is reduced by 50% after 24 hours' distention . The defect in contractile mechanism is not solely due to low muscarinic receptor density . Other factors in reduced contractility include a decrease in the myofilaments of hypertrophic smooth muscle cells; weak contractions of hyperplastic, immature muscle cells; weak contractions of hyperplastic, immature muscle cells ; increased noncontractile elements in the urinary bladder wall ; and decreased propagation of action potentials through the detrusor muscle secondary to intercellular disruption . Electron microscopy studies of rabbit detrusor muscle after urinary bladder distention have shown acute disruption of intercellular junctions with secondary intercellular fibrosis . Two months after urinary bladder distention, intracellular separation of the cytoplasm from the plasma membrane of the detrusor muscle fibers was demonstrated . Results of another study question whether these changes are significant and really represent" disruption" of junctions. Gosling and coworkers reported similar findings in distended bladders and those of normal control subjects.81 They proposed that these junctions represent normal "intermediate" junctions, as opposed to "close" or tight junctions. In their study, neither junction type was affected by distention .
Urinary bladder outlet obstruction also alters the metabolic function of the urinary bladder, which may contribute to altered contractility . After 2 weeks of obstruction, urinary bladder tissue showed a decrease in aerobic metabolism and an increase in anaerobic metabolism . The ability of the urinary bladder to maintain a contraction and empty may be directly related to aerobic metabolism. Subsequently, the decrease in aerobic metabolism, even in the presence of increased anaerobic metabolism, may contribute to the decreased ability of the obstructed urinary bladder to empty . Another study found that urinary bladder tissue shows a marked decrease in ATP concentration after obstruction, which may be attributed to the ischemic conditions created by distention . Distention of the dog's urinary bladder for 2 hours reduced blood flow in the mucosa, muscularis, and total bladder tissue by 25% to 30% in each component . In addition, the increase in connective tissue in the urinary bladder wall lowers the overall intracellular concentration of ATP in the smooth muscle .
Sequelae after Release of Chronic Obstruction
Outflow obstruction predisposes to bacterial infections. Contributing factors include catheterization, urine stasis, vesicoureteral reflux and pre-existing infections. Detrusor atony and urethral swelling or spasm may contribute to urine stasis .
After release of chronic urinary obstruction, postobstruction diuresis and concentrating defects are observed. The amount of function recovered depends on the duration of obstruction . Release of obstruction within 6 days may allow full return of function. Release after 14 days may restore 50% to 65% function. Release after 30 days of obstruction may restore up to 30% of function. Obstruction for more than 4 weeks may result in permanent damage .
Postobstruction renal failure may occur as a result of renal parenchymal loss owing to sustained increased intrarenal pressure, cytokine production by infiltrating leukocytes, electrolyte imbalances, fibrosis of damaged renal parenchyma, and renal ischemia owing to dehydration . Death may be associated with fluid and electrolyte imbalances as a result of cardiopulmonary failure.
Urethral prolapse is an eversion or prolapse of mucosa from the tip of the penis. Dogs present for signs of preputial or penile bleeding. It is seen most often in young male brachycephalic dogs and can be associated with sexual excitement or stranguria associated with urethral infection or urolithiasis [83,84]. The exact cause is unknown but theories speculate a genetic predisposition or an increased abdominal pressure secondary to chronic upper airway obstruction . In people, poor attachment between the muscle layers of the urethra associated with episodic increases in abdominal pressure is proposed as a cause .
Urethral injury may be associated with catheterization, obstruction or external trauma, especially abdominal, pelvic, or perineal trauma. Types of trauma include urethral contusions, tears, avulsion, or os penis fracture. Contusions may be asymptomatic or may cause hematuria, dysuria, and pollakiuria. Those with tears or avulsion may be unable to urinate or may have hematuria. Trauma resulting in disruption of urethral integrity results in urine leaking into the surrounding tissues or abdomen, causing a chemical-type irritation. Leakage into the subcutaneous tissues results in severe swelling, discoloration, and sometimes tissue necrosis. Urine contact with tissues for more than 12 to 24 hours results in inflammation, edema, and cellulitis, which delays healing and promotes fibrosis . Uroabdomen results in profound dehydration, life-threatening hyperkalemia, severe postrenal azotemia, chemical peritonitis, and metabolic acidosis . Manifestations of uroabdomen include lethargy, anorexia, vomiting, dehydration, abdominal distention, and pain. Additional complications of uretheral injury include stricture formation and urinary incontinence.
Urine is hyperosmolar and an accumulation in the abdominal cavity creates a concentration gradient across the peritoneum from the extracellular fluid compartment to the abdominal cavity. Large molecules such as creatinine pull water into the abdomen whereas smaller solutes such as urea and electrolytes (potassium) diffuse into the extracellular fluid compartment. Sodium and chloride diffuse into the abdomen. Dehydration results from a combination of fluid shifts, fluid losses from vomiting, and a decrease in fluid intake. Dehydration leads to a decrease in glomerular filtration and a subsequent decrease in excretion of urea and creatinine. Retention of urine in the abdomen with accumulation of excretory products also results in increased serum urea and creatinine. The body's normal buffer system is depleted as hydrogen retained in abdominal urine is reabsorbed through peritoneal capillaries, leading to metabolic acidosis. The production of lactic acid secondary to poor tissue perfusion resulting from dehydration and hypovolemic shock also contribute to metabolic acidosis.
Urine accumulation in the abdomen causes a chemical peritonitis that results in functional ileus and pain. Septic peritonitis may occur if a urinary tract infection existed or a penetrating injury had occurred. Peritonitis contributes to a shift of fluid from the extracellular space into the abdomen with a concurrent loss of albumin into the abdominal effusion .
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Affiliation of the authors at the time of publication
School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA.