Renal Agenesis, Hypoplasia, and Dysplasia

Renal agenesis, which may be unilateral or bilateral, results from failure of the metanephric duct to fuse with the metanephrogenic mesodermal tissue. Although unilateral anomalies have been described more frequently, this simply may reflect the incompatibility of bilateral agenesis with postnatal life.^24,26–28 Brown et al.²⁸ described a foal with bilateral renal agenesis in which severe azotemia was detected shortly after birth. Bilateral ureteral dysgenesis and cryptorchidism, agenesis of the right adrenal gland, and atresia ani accompanied the renal agenesis in this foal. Unilateral defects may be incidental findings in otherwise healthy horses²⁹ or may be detectable during examination of the reproductive tract, because many horses have associated anomalies of that system. Occasionally, unilateral agenesis may result in clinical renal disease if a problem arises in the contralateral kidney. Johnson et al.²⁷ described a 4-year-old Quarter Horse with unilateral renal agenesis and a ureterolith causing contralateral hydronephrosis. The gelding was presented for weight loss, pollakiuria, and stranguria. In addition to the renal anomaly, unilateral agenesis of the ipsilateral testicle also was found on necropsy. Renal agenesis may be a familial disorder in several species.^25,30 Although no information is available to suggest a hereditary basis in horses, one probably should discourage repeat matings after detecting such an anomaly.

One diagnoses renal hypoplasia when one kidney is at least 50% smaller than normal or when the total renal mass is decreased by more than one third.²⁵ Renal hypoplasia is a quantitative defect caused by a reduced mass of metanephrogenic tissue or by incomplete induction of nephron formation by the metanephric duct. The condition may be confused with renal dysplasia. Unilateral renal hypoplasia usually is associated with contralateral hypertrophy and normal renal function, whereas bilateral hypoplasia generally leads to chronic renal failure (CRF).^25,30 Andrews et al.³¹ described bilateral renal hypoplasia in a foal presented after death and in three young horses with CRF that had poor growth from birth. Anomalies in these four horses were limited to the upper urinary tract.

Renal dysplasia is disorganized development of renal tissue caused by anomalous differentiation, intrauterine ureteral obstruction, fetal viral infection, or teratogens.^25,32 Bilateral dysplasia usually leads to renal failure. In general, dysplastic kidneys are normal in size unless concurrent hypoplasia exists or the animal lives for months to years before developing renal failure. Roberts and Kelly³³ reported a case of bilateral renal dysplasia in a 19-month-old pony gelding. The pony was presented for weight loss over a 3-month period, and clinicopathologic assessment revealed CRF. A small, firm, and nodular left kidney was palpable per rectum. At necropsy, the kidneys weighed 280 g each (33% smaller than normal for body weight) and were nodular. Renal dysplasia was suspected because glomeruli in the collapsed areas of the kidneys were small, tubules were immature, and inflammatory cells were scant. Six similar cases of bilateral renal dysplasia resulted in CRF in horses from 2 months to 7 years of age.^34–38 Small kidneys with increased echogenicity and an indistinct corticomedullary junction were typical ultrasonographic findings,^36–38 and these findings were corroborated by computed tomography in one Miniature Horse foal.³⁸ At necropsy, kidneys were typically small and irregular, the cortex and medulla were not well-delineated, and immature glomeruli and primitive tubules were found on histologic examination (Figure 19-5). Renal dysplasia also may cause renal failure in neonates. For example, Zicker et al.³⁹ reported a case of renal dysplasia in a 2-day-old Quarter Horse foal presented for diarrhea and depression. Clinicopathologic assessment revealed azotemia, hyponatremia, hypochloremia, and urinary sodium wastage. At necropsy, the kidneys were normal in size (380 g), but histologic examination revealed immature glomeruli, hypoplastic tubules and vasa recta, and extensive myxomatous connective tissue occupying 90% of the total medullary volume. Finally, renal dysplasia also may be a unilateral problem that does not result in renal failure. Jones et al.⁴⁰ found ureteropelvic polyps to be the cause of unilateral hydronephrosis and renal dysplasia in a Trakehner colt. Poor growth and hematuria for several weeks were the presenting complaints. Renal function remained normal for 8 months after nephrectomy until the colt developed a severe bout of colic, prompting euthanasia. Ureteral obstruction by the polyps was the suggested cause of renal dysplasia, because urinary tract obstruction has been found in a large percentage of cases of human renal dysplasia.³²

FIGURE 19-5 A, Longitudinal section of the right kidney from a 7-year-old Arabian gelding with renal dysplasia shows focal, irregular thinning of the cortex (arrowheads) resulting in a nodular surface and poor delineation of the corticomedullary junction. B, Histologic section of same kidney (Masson trichrome stain; original magnification ×35) reveals an immature glomerulus (large arrowhead) and primitive tubules (arrows) surrounded by persistent mesenchyme.

(From Ronen N, van Amstel SR, Nesbit JW et al: Renal dysplasia in two adult horses: clinical and pathological aspects, Vet Rec 132:269, 1993.)

Renal Cysts

One or more renal cysts occasionally are discovered as incidental findings on necropsy examination. The cysts may arise from any portion of the nephron but more often occur in the cortex than in the medulla. The pathogenesis is not known, but a defect in the basement membrane that allows tubular dilation is suspected. Renal cysts vary in size from microscopic to as large as the organ itself and routinely have a clear to slightly opaque wall and contain a thin, clear fluid. Congenital cysts are differentiated easily from acquired cysts (after obstruction) by the extensive scarring that accompanies the latter. Renal cysts also may develop as a consequence of drug therapy (i.e., long-acting corticosteroids) or exposure to certain chemicals.^25,30

Polycystic Kidney Disease, Glomerulocystic Disease, and Other Hereditary Nephropathies

Polycystic kidney disease (PKD) is a disorder in which numerous, variably sized cysts are found throughout the cortex and medulla. With glomerulocystic disease, cysts are microscopic and limited to Bowman’s spaces. Cysts of the bile duct and pancreas also may occur with PKD, and both conditions have been described in stillbirths in many species, including foals.²⁵ The two major types of human PKD are (1) a rare congenital or infantile form inherited as an autosomal recessive trait (which may be found in stillbirths) and (2) a more common adult form inherited as an autosomal dominant trait that leads to renal insufficiency in later life in association with dramatically enlarged, cystic kidneys.^41,42 The latter form of PKD develops because of mutations in genes encoding for polycystins, integral membrane proteins responsible for cell-to-cell interaction.⁴³ Autosomal dominant PKD also has been documented in Persian cats and related breeds and in bull terriers.^44–46 The genetic defect in Persian cats is thought to be similar to the most common defect in human beings (PKD1 gene) and leads to end-stage renal disease by 3 to 10 years of age.⁴⁵ As in human beings, the disorder is detectable by renal ultrasonographic screening of juvenile cats and preventable by avoiding subsequent mating of affected animals. Nevertheless, because of heavy inbreeding the prevalence of PKD in Persian cats and related breeds is between 40% and 50%.^44,45

Ramsey et al.⁴⁷ described polycystic kidneys in a 9-year-old Thoroughbred mare that exhibited anorexia and weight loss. Clinicopathologic assessment revealed CRF, and euthanasia was performed. At necropsy, the kidneys were grossly enlarged and each weighed 12 kg (Figure 19-6). A similar case of bilateral PKD was described in a 15-year-old pony with a 4-week history of hematuria and moderate weight loss. Evaluation revealed azotemia and presence of large masses in the area of both kidneys on rectal examination, and dramatically enlarged polycystic kidneys weighing 11.4 and 9.1 kg, respectively, were found at necropsy.⁴⁸ Bertone et al.⁴⁹ reported a third case of adult PKD in a 10-year-old Paint gelding with weight loss. The horse was mildly azotemic, and several 2- to 15-cm diameter cysts were imaged in both kidneys during ultrasonographic examination. In human beings, polycystic kidneys are believed to result in renal failure as cysts expand (sometimes under pressure) and compress adjacent normal renal tissue. Altered compliance of tubular basement membranes and proliferation of renal tubular epithelium result in outflow obstruction and proximal ballooning, leading to renal cyst formation.⁴² In some human cases, pressure within cysts may be 5 to 10 times higher than surrounding interstitial tissue pressures. Bertone et al.⁴⁹ found no increase in pressure in several cysts catheterized percutaneously in a gelding with PKD, but differences in sodium concentrations suggested that the sampled cysts had arisen from different segments of the renal tubule. Euthanasia was performed after a prolonged hospital course (235 days), and the kidneys were not grossly enlarged except where distorted by large cysts. Although not well documented, PKD has been described anecdotally in two additional Paint horses, suggesting that an inherited form of PKD may occur in that breed. A recent report also documented PKD in an 11-year-old Andalusian gelding.⁵⁰

FIGURE 19-6 Longitudinal section of the left kidney (35 cm long, 25 cm wide, 20 cm deep, and weighing 12 kg) from a 9-year-old Thoroughbred mare with polycystic kidneys. A calculus is located in the renal pelvis, and the arrow demonstrates the only grossly normal-looking renal parenchyma.

(From Ramsey G, Rothwell TLW, Gibson KT et al: Polycystic kidneys in an adult horse, Equine Vet J 19:243, 1987.)

In addition to PKD, a variety of other hereditary nephropathies have been described in human beings.⁴⁸ Similar disorders are starting to be recognized in domestic animals, including hereditary nephritis in bull terriers, Samoyeds, and English cocker spaniels. Analogous to Alport’s syndrome in human beings, a defective molecular structure of type IV collagen, an important component of the glomerular basement membrane (GBM), appears to be the cause of hereditary nephritis in these dog breeds.⁴⁶ Similarly, a syndrome of renal tubular dysplasia with autosomal recessive pattern of inheritance recently has been described in a population of highly inbred Japanese black cattle,^51–53 as has a syndrome of suspected hereditary renal oxalosis in Beefmaster calves.⁵⁴ Similar hereditary nephropathies are likely to occur in horses; however, to date the only one documented is a syndrome of nephrogenic diabetes insipidus in Thoroughbreds.⁵⁵

Vascular Anomalies

Anomalies of the vascular supply to the equine urinary tract are rare but may result in hematuria, hemoglobinuria, partial ureteral obstruction, or hydronephrosis.^30,56 Latimer, Magnus, and Duncan⁵⁷ described a distal aortic aneurysm and associated extrarenal arterioureteral fistula in a 5-month-old colt presented for intermittent hematuria, colic, and lameness. Partial ureteral obstruction and hydronephrosis were observed on the affected side. Intrarenal vascular anomalies, termed renal arteriovenous malformations, are similarly rare (reported frequency of 0.04% in human beings).⁵⁸ Interestingly, these vascular malformations may be silent until later in life, when varying degrees of hematuria and flank pain may ensue. The anomalous vessels are often tortuous and may be enlarged focally and devoid of elastic tissue. Hematuria and hemoglobinuria are thought to arise from areas where the anomalous vessels lie close to the collecting system.^58,59 With vascular anomalies, one should attempt to determine the extent of the defect (unilateral or bilateral) via ultrasonographic examination, contrast radiographic studies, or cystoscopy (visualization that hematuria is coming from only one ureteral orifice). When a unilateral defect is documented in the absence of azotemia, unilateral nephrectomy or selective renal embolization has been recommended to prevent possible fatal exsanguination through the urinary tract^56,57; however, one may consider conservative treatment if the urinary tract bleeding is minor and has not resulted in anemia.

A large vascular anomaly resulting in transient hemoglobinuria has been reported in a Quarter Horse colt.⁶⁰ Over several weeks the large anomalous vascular structure (Figure 19-7) spontaneously filled with a thrombus so that specific treatment (a nephrectomy) was not pursued. Severe adult-onset, idiopathic renal hemorrhage also has been described in horses.⁶¹ Whether this latter syndrome may have been a consequence of congenital renal vascular malformations has not been determined (see Hematuria section later in this chapter). Occasionally gross hematuria with passage of blood clots can accompany omphalitis or bladder rupture.⁶² One usually can detect these problems during ultrasonographic examination of the umbilical structures and sometimes can image tissue echogenicity within the bladder that is attributable to a blood clot.

FIGURE 19-7 Ultrasonographic image of the right kidney of a 9-day-old Quarter Horse colt shows a 2×3-cm hypoechoic cavity on a dorsal oblique view. A, A swirling pattern, similar in appearance to blood in the ventricles of the heart, was consistent with an arteriovenous malformation. B, In a selective nephrogram of the right kidney of the same colt at 20 days of age, immediately after injection of contrast, a dilated vascular space was demonstrated (contrast appears dark because of reverse gray scale) and the renal cortical tissue abaxial to this structure appeared to have reduced capillary phase contrast.

(From Schott HC, Barbee DD, Hines MT et al: Renal arteriovenous malformation in a Quarter horse foal, J Vet Intern Med 10:204, 1996.)

Pendulant Kidney

A pendulant kidney is a rare anomaly in the horse.⁶³ Rectal examination reveals an extremely mobile kidney attached to the dorsal body wall by a thin band of tissue. Although a pendulous kidney could result from extreme weight loss, hydronephrosis, or perirenal trauma, the condition usually is thought to be congenital. The abnormality is an incidental finding unless displacement or rotation leads to partial or complete ureteral obstruction. As an example, the author has palpated the entire right kidney of one mare immediately craniad of the pelvic canal, and ultrasonographic imaging revealed normal size and structure of the anomalously located kidney.

Ectopic Ureter

Although ureteral ectopia occurs rarely in the horse,⁶⁴ the condition is the most commonly reported developmental anomaly of the equine urinary tract.^64–82 Ectopic ureters may develop when (1) the ureteric bud (metanephric duct) fails to be incorporated into the urogenital sinus or fails to migrate craniad to the bladder neck or (2) the mesonephric duct fails to regress. In the former case, the ectopic ureter opens near the urethral papilla in females or into the pelvic urethra near the colliculus seminalis in males, whereas in the latter, the ureter may open anywhere along the vagina, cervix, or uterus (but only in females because this portion of the mesonephric duct becomes the wolffian duct system in males). In 118 reported cases of ectopic ureter in horses, 105 (89%) were females^{65-68,72-77,79-82}; however, this sex distribution may reflect easier recognition in females of the presenting complaint of urinary incontinence rather than a true sex predilection. Incontinence is recognized more often in females because urine entering the pelvic urethra in males may pass retrograde into the bladder. Although a genetic predisposition for ectopic ureter exists for several dog breeds,⁸³ no breed predilection has been established in horses. However, Quarter Horses may be at greater risk because the condition has been reported in five Quarter Horses, three Standardbreds, two Thoroughbreds, two Appaloosas, an Arabian, a Clydesdale, a Shire, a Fresian, a Foxtrotter, and a Warmblood. The author also has seen the condition in two Quarter Horse fillies (one unilateral and one bilateral), yielding a total of 20 cases.

In horses with ureteral ectopia, urinary incontinence is generally apparent from birth, and affected animals are presented for extensive scalding of the hindlimbs. With unilateral ectopia, horses also void normally, because the other ureter enters the bladder in the appropriate location. Renal function is usually normal, but the affected ureter may be greatly dilated. Urine pooling in the vagina and uterus was a complicating factor in one case.⁷³ To determine the site of the ectopic ureteral orifice (or orifices), one initially visually examines the vestibule and vagina (using a blade speculum) to look for intermittent urine flow from the area of the urethral papilla. Ectopic ureteral openings usually are not apparent unless urine flow is visible. Endoscopy may be helpful in females (while inflating the vestibule and vagina with air and using a hand to form a seal at the vulva) and is required in males to visualize the ectopic ureteral opening. Intravesical placement of methylene blue dye was performed in one filly to provide evidence for ureteral ectopia. Continued dribbling of clear urine (from the ectopic ureter) followed by passage of blue, discolored urine indicated that only one ureter emptied into the bladder but provided no information on the location of the opening of the ectopic ureter.⁶⁶ Intravenous administration of dyes—including sodium fluorescein (10 mg/kg IV; yellow-green), indigotindisulfonate (indigo carmine, 0.25 mg/kg IV; blue-purple), azosulfamide (2.0 mg/kg IV; red), or phenolsulfonphthalein (1.0 mg/kg IV; red)—to discolor the urine may help locate ectopic ureteral openings.⁸⁴ Contrast radiography (excretory urography or retrograde contrast studies via catheterization of the bladder and ureters) has been used to detail renal architecture and the course of the ureters in some affected animals; however, results of intravenous urograms are frequently inconclusive in foals weighing more than 50 kg (contrast agent is poorly imaged). In a recent report, ultrasound-guided pyelography, in which contrast agent was injected directly into the renal pelvis using a spinal needle, proved to be a more effective technique than imaging after intravenous administration of contrast agent to detail the course of an ectopic ureter, and one should consider this technique in future cases.⁸²

Treatment has included ureterocystostomy (surgical reimplantation of the ectopic ureter or ureters into the bladder) or unilateral nephrectomy. Before surgery, one must determine whether the condition is unilateral or bilateral, which side is affected if unilateral, and whether urinary tract infection (UTI) is present. Further, one should attempt to rule out other anomalies, especially of the reproductive tract. If the problem is bilateral (8 of 20 cases), then one should establish the presence of a normal micturition response by measuring the intravesicular pressure response to progressive distention until the fluid infused is voided spontaneously. This procedure provides an estimate of bladder volume and ensures competency of the urethral sphincter before reimplantation. Among 14 cases in which surgical correction was pursued, ureterocystostomy was successful in establishing a functional urinary system in nine published cases^∗ and one foal seen by the author, but four died of postoperative complications.^68,75,82 In contrast, all four cases treated by unilateral nephrectomy had a favorable outcome.^72,73,79 Because affected ureters often are dilated and tortuous, surgical reimplantation can be difficult and may not result in a functional ureteral orifice. Consequently, when the problem is unilateral, nephrectomy of the affected side may be the preferred treatment option.^85,86

Ureteral Defects or Tears (Ureterorrhexis)

Retroperitoneal accumulation of urine and uroperitoneum has been described in seven foals with unilateral or bilateral ureteral defects^87–93 and has been observed in three additional foals by the author. These included seven male and three female foals of several breeds (five Standardbreds, two Thoroughbreds, one Belgian, one Oldenburg, and one Appaloosa). Clinical signs (decreased nursing, depression, abdominal distention, diarrhea, and muscle twitching or other signs of neuromuscular irritability) and clinicopathologic abnormalities (hyponatremia, hyperkalemia, hypochloremia, and azotemia) are similar to those in horses with bladder rupture but may have a slightly later onset (4 to 16 days of age). Mild protrusion of the vagina may occur in fillies in which the peritoneum has remained intact.⁹⁴ In affected foals, ultrasonographic examination may reveal dilation of the renal pelvis and affected ureter, as well as fluid accumulation around the kidneys or farther caudad within the retroperitoneal space. As with ectopic ureters, excretory urography generally has been an unrewarding diagnostic procedure, but contrast pyelography was used successfully to image leakage of contrast agent from a proximal ureteral defect in a recent report.⁹³ Contrast radiography has not been pursued routinely because exploratory celiotomy generally was performed shortly after a diagnosis of uroperitoneum. Catheterization of the ureters via a cystotomy and retrograde injection of methylene blue allowed localization of the defect (or defects), and surgical correction was performed successfully in four cases by suturing the defect around an indwelling catheter.^89,90,93 Although ascending UTI should be an expected complication with a stent, repair of a defect in one foal without use of an indwelling catheter resulted in further urine leakage from the ureter, prompting a nephrectomy 4 days after the initial surgery.⁹¹ Of the remaining five foals, one died after three unsuccessful attempts at surgical repair,⁸⁸ and euthanasia was performed in four cases without attempting repair.^87,92

At surgery or necropsy a single defect was found in six foals, whereas bilateral defects were found in four foals and multiple defects were apparent in one ureter. In most cases the defects have been located in the proximal third of the ureter near the kidney. Interestingly, distended, tortuous ureters, occasionally accompanied by hydronephrosis, also were described in three affected foals,^88,91,93 and distal obstruction of the ureters at the bladder was suspected in two of these cases, prompting ureteroneocystostomy. Although several reports suggest that these ureteral defects may be anomalies of development, the actual cause of these ureteral defects is not known. Traumatic disruption was suggested in the initial report in which histologic examination of the margins of the defect revealed hemorrhage and proliferation of immature connective tissue.⁸⁷ A traumatic cause was further supported by a subsequent report in which histologic examination of the defects revealed absence of transitional epithelium and inflammation in a foal that had been attacked by dogs.⁹² Inflammation and granulation tissue also were visible in the apparently obstructed distal ureter in one of the foals with ureteral distention, again suggesting an acquired lesion. Blunt abdominal trauma, often sustained during automobile accidents, can cause retroperitoneal accumulation of urine and uroperitoneum in human beings.⁹⁵ Disruption of the ureter is usually near the kidney, and this complication of trauma may not be recognized for several days after injury. In one foal evaluated by the author, multiple rib fractures found at necropsy suggested that these ureteral tears actually could be a complication of foaling trauma.

Rectourethral and Rectovaginal Fistulae

If the urorectal fold fails to separate completely the primitive hindgut from the urogenital sinus, then a rectourethral fistula may be found in a colt or a rectovaginal fistula or a persistent cloaca may be found in a filly.⁹⁶ These anomalies are rare in horses and when present usually are associated with atresia ani and other anomalies, including agenesis of the coccygeal vertebrae and tail, scoliosis, adherence of the tail to the anal sphincter area, angular limb deformities, and microphthalmia.^{70,71,97–102} Affected foals usually are presented for atresia ani, although one also may observe signs of colic and straining. Evidence for a fistula is passage of fecal material from the vulva or urethra. In fillies one may detect rectovaginal fistulae by digital palpation of the dorsal vestibule and vagina, but in colts a definitive diagnosis usually requires contrast radiographic procedures such as a barium enema or a retrograde urethrogram (Figure 19-8). Surgical correction of atresia ani and fistulae has been performed successfully in several foals, but multiple surgical procedures may be required. Because ascending UTI may be a complication, one should submit a sample of urine collected via bladder catheterization (preferably during surgery) for bacterial culture.⁹⁶ In human beings the evidence suggests that these anomalies are hereditary, and in one report several foals born with atresia ani were sired by the same stallion.⁹⁷ Consequently, affected horses should not be used for breeding after surgical correction of the anomalies.

FIGURE 19-8 A positive contrast urethrogram in a 3-day-old burro that had atresia ani and intermittent passage of fecal material from the urethra. A catheter passed via the urethra and contrast agent injected into the catheter resulted in accumulation of a large amount of contrast agent in the rectum and a lesser amount in the intrapelvic portion of the urethra. A small amount of contrast agent is visible in the urethrorectal fistula (arrow).

A urethrorectal fistula resulting in passage of urine from the anus also has been described in a 3-year-old Thoroughbred gelding.¹⁰³ The fistula in this gelding was thought to be acquired after trauma or straining because no other developmental problems were detected and the edges of the defect were irregular and inflamed when examined with a speculum inserted into the rectum.

Bladder Defects

Uroperitoneum may result from bladder rupture during parturition in foals (most commonly males)¹⁰⁴ or as a consequence of urachal leakage after infection of the umbilical structures.^105,106 In addition, Wellington described uroperitoneum in two foals that were full brothers.¹⁰⁷ Urine entered the abdomen from a dorsal defect in both colts, and smooth margins to the defects combined with a lack of appreciable inflammation provided evidence in favor of anomalous development rather than trauma. Other authors have suggested that some cases of uroperitoneum likely are associated with anomalous bladder defects because of the size, location, or lack of apparent inflammation of the margins of the defects.^70,108–111 For example, Bain¹⁰⁸ described uroperitoneum in a foal in which the ventral portion of the bladder was absent between the lateral ligaments (umbilical artery remnants) from the umbilicus to the urethra.

Anomalous fusion of the bladder to the inner umbilical ring (absence of the urachus) has been described in one foal.¹¹² The malformation precluded normal contraction and evacuation of the bladder, and a megavesica—a greatly enlarged bladder—developed. The clinical appearance was similar to that of uroperitoneum, and surgical separation of the bladder from the umbilical ring restored normal anatomic and functional integrity of the bladder. A similar case with a greatly distended bladder was reported in a foal evaluated for abdominal distention⁷⁰ that was attributed to an adhesion of the bladder to the urachus or umbilical remnant. An enlarged, flaccid bladder also was described in a foal undergoing exploratory celiotomy for suspected urinary tract disruption.¹⁰⁵ Adhesions to the abdominal wall were not reported, and the foal survived after the surgery during which 50% of the distended bladder was resected. In addition to bladder distention, persistent attachment of the bladder to the area of the umbilicus via a urachal remnant was reported to cause pollakiuria and dysuria in a 15-month-old Thoroughbred filly.¹¹³ The author also has seen postpartum bladder rupture in a mare in which a persistent urachal attachment was suspected to be a contributing factor.

Excessive bladder distention or megavesica has been described further in four stillborn foals¹¹⁴ and one neonatal foal.¹¹⁵ In the latter foal and in another report,¹¹⁶ chronic bladder distention appeared to lead to loss of smooth muscle in the dorsal bladder wall and replacement with collagen. The result was bladder rupture during parturition. Although these reports are similar to an early report by Rooney¹⁰⁴ describing the dorsal bladder wall as the anatomic weak link and likely area for rupture, they differ in that chronic distention of the bladder in utero with smooth muscle loss is not recognized in more typical bladder ruptures in neonatal foals. Why bladder distention should occur in utero without obstruction of the lower tract (not found in these cases) is not clear. Although an excessively long umbilical cord (longer than 85 cm) may lead to urachal obstruction,^114,117 urine produced in utero alternatively could drain into the amniotic cavity via the urethra. Thus this form of megavesica remains poorly characterized and poorly understood.

Bladder distention also is recognized in some foals with hypoxic-ischemic encephalopathy. Affected foals may posture to urinate frequently, and ultrasonographic examination may reveal an enlarged bladder or incomplete bladder emptying. In recumbent foals, one may note abdominal distention, and temporary use of an indwelling bladder catheter to keep the bladder empty is helpful; however, ascending UTI may be a complication. Cystometrography would be useful to assess detrusor function in affected foals, but no reports describe use of this diagnostic test in equine neonates. Although administration of cholinergic drugs (e.g., bethanechol) to improve detrusor function or α-adrenergic blockers (e.g., phenoxybenzamine, acepromazine) to decrease urethral sphincter tone has been described anecdotally to be of benefit, no reports describe the efficacy of these medications in foals with this problem.

Some neonatal foals examined for abdominal pain are apparently unable to urinate normally. Ultrasound examination will reveal a normal gastrointestinal tract and a greatly enlarged but intact urinary bladder. These foals can be treated with indwelling urinary catheters for 2 to 3 days along with phenazopyridine (4 mg/kg PO every 8 to 12 hours) for 5 to 7 days.¹¹⁸ Phenazopyridine acts a local analgesic on the lower urinary tract and may relieve spasm or allow better relaxation of the bladder sphincters and promote normal micturition.

Patent Urachus

The urachus is the conduit through which fetal urine passes from the bladder into the allantoic cavity. Normally, the urachus closes at the time of parturition, but incomplete closure is the most common malformation of the equine urinary tract. Patent urachus occurs more commonly in foals than in other domestic species.³⁰ Greater than average length or partial torsion of the umbilical cord has been suggested to cause tension on the attachment of the umbilical cord to the body wall. The result is dilation of the urachus and subsequent failure to close at birth.^{70,71,114,117,119} Patent urachus results in a persistently moist umbilicus after birth, from which urine may leak as drips or as a stream during micturition. One must distinguish this malformation from septic omphalitis, which also can result in urine leakage from the umbilicus within a few hours to days after birth. Ultrasound examination of the umbilical remnants is indicated to rule out or monitor for concurrent omphalophlebitis. Patent urachus has been referred to as a congenital problem and the latter as an acquired problem, but both may result in urine leakage from the urachus from birth. Neither is life threatening, but local sepsis often is accompanied by more severe illness, including septicemia or localized infection, particularly in joints.

The congenital patent urachus traditionally has been treated with frequent (two to four times daily) chemical cauterization of the urachus with swabs dipped in a concentrated phenol or 7% iodine solution or with silver nitrate applicators.⁶⁹ Because the urachus may close spontaneously in a number of cases, and because these agents desiccate and irritate tissue (and may predispose to infection), the rationale for this approach has been questioned.¹¹⁹ In a study comparing the effects of disinfectant solutions on the bacterial flora of the umbilicus of normal foals, use of a 7% iodine solution was observed to cause rapid desiccation of the umbilical tissue and subsequent development of a patent urachus when the stump fell off a few days later.¹²⁰ Chlorhexidine diacetate (0.5%) appears to be more effective than 1% to 2% iodine solutions in reducing umbilical bacterial counts. Chlorhexidine is less irritating to tissue, binds to the stratum corneum, and has prolonged antiseptic effects.¹²⁰ The use of caustic or irritating solutions for routine umbilical dipping or treatment of patent urachus should probably be avoided because it may lead to localized necrosis and infection that may actually result in umbilical infections.

Consequently, in the absence of apparent infection, no local treatment may be indicated specifically, but affected foals frequently are given antibiotics prophylactically. For acquired patency (which may be associated with local infection, cachexia, or septicemia), broad spectrum antibiotic therapy is indicated, and resolution of the systemic disease may be accompanied by elimination of the umbilical infection and closure of the urachus. Most cases of patent urachus without septic omphalophlebitis will resolve with supportive care, routine umbilical disinfection, and antibiotic therapy. Empiric antibiotic therapy with antibiotics that are eliminated (and concentrated) in urine, such as potentiated sulfonamides, cephalosporins, aminoglycosides, or penicillins usually provides adequate antimicrobial protection with uncomplicated patent urachus in otherwise healthy foals. Chemical cauterization is contraindicated with local sepsis because it may increase the risk of urachal rupture and development of uroperitoneum.¹²¹ If one observes no decrease in urine leakage after 5 to 7 days of medical therapy, or if ultrasonography reveals abnormalities of multiple structures in the umbilicus,^122,123 then surgical exploration and resection of the urachus and umbilical vessels may be indicated. In a retrospective study of 16 foals treated for sepsis of umbilical cord remnants, six of nine (67%) survived after surgical resection and antibiotic treatment, whereas only three of seven (43%) survived after antibiotic treatment alone.¹²⁴ Although this series of 16 foals often is cited in support of surgical intervention, one should note that the series studied a small number of foals and that the cases were evaluated over 10 years (1975-1985), during which time many aspects of neonatal care improved. In a more recent retrospective report of 33 foals with umbilical remnant infections, no difference in survival was observed between foals treated with antibiotics combined with surgical resection or with antibiotic therapy alone.¹²³ Further, emphasis was placed on the insensitivity of palpation of the umbilicus in detection of umbilical remnant infection (compared with ultrasonographic examination) and the poor outcome of cases in which the umbilical vein was involved. In addition to the possibility of omphalitis leading to urachal rupture and development of uroperitoneum, urachal leakage also may occur into the abdominal musculature and subcutaneous tissues and lead to swelling and cellulitis of the ventral abdominal wall.¹²⁵ Both instances require surgical intervention. Finally, trauma or tearing of the urachus also can lead to umbilical evagination of the urinary bladder,¹²⁶ which can result in partial or complete obstruction of urine flow, and surgical correction is indicated.

Urea Metabolism

A molecule of urea is produced in the liver from two ammonium ions that are liberated during catabolism of amino acids. For each urea molecule the carbon atom is derived from bicarbonate. One ammonium ion is cleaved from an amino acid via an α-ketoglutarate–dependent transamination coupled to oxidative deamination of glutamate. The second ammonium ion is derived from aspartate in the urea cycle.² Urea synthesized in the liver is released into the blood, and clearance by the kidneys represents the major pathway (75% to 100%) of excretion. Extrarenal urea excretion includes losses in sweat and through the gastrointestinal tract. With normal intestinal function, enteric excretion is minimal because of enterohepatic recirculation (reabsorption of ammonia from the degradation of urea by bacterial ureases and subsequent reformation of urea in the liver).³

In human beings, inborn errors of metabolism leading to deficiency of a specific transaminase or of one of the five enzymes of the urea cycle can result in accumulation of ammonia and other intermediates of amino acid catabolism. These disorders typically are inherited as autosomal recessive traits, and the consequence is moderate to severe mental dysfunction because the accumulated intermediates can be toxic to the central nervous system (CNS; i.e., ammonia) or can act as false neurotransmitters (i.e., aromatic amines).¹ Because urea production is limited in these disorders, blood urea nitrogen (BUN) concentration is often low.² Although such defects in metabolism appear to be rare in domestic animals,⁴ development of encephalopathy in association with hyperammonemia has been recognized in horses.^5,6 Furthermore, in one report of two related Morgan weanling fillies, persistent hyperammonemia was suspected to be caused by a defect in a mitochondrial ornithine transporter similar to an autosomal recessive syndrome of hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) in human beings.⁷

BUN concentration depends on age, diet, rate of urea production, and renal function. For example, a low BUN typically is found in neonatal foals after an anabolic demand for amino acids.⁸ Investigations of nitrogen use in ponies have demonstrated that urea production is proportional to dietary protein content. Similarly, urinary urea excretion increases in proportion with urea production.^9,10 As a result, with increased levels of dietary protein or when urea is supplemented in the diet, BUN may increase twofold or greater.^11–13

In human beings and small animals, BUN is routinely higher in samples collected postprandially because diets are typically high in protein.³ Postprandial elevation of BUN has not been described in horses or other herbivores. However, fasting leads to enhanced protein catabolism to meet energy demands and increased BUN in horses.^14,15 In ponies, however, BUN decreases with fasting.¹⁶ This opposite response suggests differences in the metabolic responses of horses and ponies to anorexia, consistent with a greater capacity of ponies to mobilize and use fat during starvation. Other causes of protein catabolism, including fever, infection, trauma, myositis, burns, and corticosteroid therapy, also can produce an increase in BUN.³ Finally, a decrease in RBF or renal function produces an increase in BUN. The former may occur with dehydration or during periods of anesthesia or exercise; the latter is a reflection of renal disease.³ With short bouts of moderate to intensive exercise, BUN often does not change^13,17; however, during prolonged exercise BUN can increase by 50% or more because of the combined effects of decreased RBF and protein catabolism.^18,19

Most renal nitrogen excretion occurs in the form of urea in urine. One must recognize that urea excretion is completely passive and that the high concentrations achieved in urine are merely a consequence of medullary tonicity produced by the countercurrent-multiplier function of the loop of Henle. Thus although variations in dietary protein intake lead to parallel changes in urea excretion, the idea that low-protein diets decrease the workload on the kidney is a fallacy.³ Urinary urea nitrogen concentrations can vary from as low as 50 mg/dl in neonatal foals or horses with primary polydipsia to greater than 2500 mg/dl in normal horses on high-protein diets. Total daily urea excretion usually ranges between 100 and 300 g per day in horses with normal renal function.

Creatinine Metabolism

Cr is produced by the nonenzymatic, irreversible cyclization and dehydration of creatine. Three amino acids in the kidney, liver, and pancreas are indirectly responsible for its production; subsequently Cr is transported to other organs such as muscle and brain, where it is phosphorylated to store energy in the form of phosphocreatine.^3,20 In human beings, 1.5% to 2% of the creatine pool is converted to Cr daily and results in fairly constant excretion of Cr within a given individual.³ With normal renal function, a direct relationship exists between daily Cr production, serum Cr concentration, and Cr excretion, all three being proportional to total muscle mass. The fact that Cr is 30% higher in male humans than in female humans and that urinary Cr excretion is correlated to body size across a wide range of animal species supports this relationship.^3,21 Cr is excreted principally in urine, but sweat and the gastrointestinal tract are secondary routes of excretion.³ In contrast to urea, enterohepatic recycling of Cr does not occur, and the gastrointestinal tract may represent a major route of excretion when renal function is compromised. For example, in a group of azotemic human patients, between 15% and 65% of radiolabeled Cr was found to be excreted through the intestine.²² Cr excreted by this route is degraded rapidly by bacteria so that little is found in feces.

Like BUN, Cr can vary with age, activity level, and renal function. In contrast, dietary protein intake has little influence on Cr in horses.¹¹ Newborn foals routinely have Cr values 30% to 50% higher than those measured in the mare, and values as high as 20 to 30 mg/dl have been measured in some premature or asphyxiated foals.⁸ These high values may result from limited diffusion of Cr across the placenta. For example, the Cr in equine amniotic fluid collected at term is proportionately much greater than urea nitrogen concentration (Cr, 10.1 mg/dl; urea nitrogen, 38.8 mg/dl).²³ If the foal appears healthy and all other laboratory values are within reference ranges, then a Cr value in the range of 5 to 15 mg/dl should not cause alarm. In most healthy foals with normal renal function, Cr decreases to values below 3.0 mg/dl within the first 3 to 5 days of life.²² After the first few days of life, Cr is usually lower in foals than in adults¹² because of the combined effect of rapid growth and the fact that skeletal muscle comprises a smaller percentage of body weight in foals than in adult horses. Other nonrenal factors that may influence Cr include fasting, rhabdomyolysis or muscle wasting caused by disease, and exercise. Although fasting can increase the measured value for Cr, a substantial portion of this increase actually is due to other compounds (possibly ketones) that increase during fasting and are measured as non-Cr chromagens in the commonly used Jaffe’s colorimetric assay for Cr determination (see Examination of the Urinary System).^12,14,24

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