Abstract
Urolithiasis, although a relatively common clinical entity in humans and domestic carnivores, has been infrequently reported in native Australian marsupials. Calcium oxalate urolithiasis has not previously been reported in macropods. We report the occurrence of predominantly calcium oxalate urolithiasis in four captive macropods in a large urban zoo. Two of the cases presented with obstructive urethropathy and, in the other two cases, uroliths were discovered incidentally at necropsy. The approach to the two clinical cases was based on the first principles of management of obstructive uropathy in domestic animals modified to accommodate some of the unique aspects of macropods. Potential causes of calcium oxalate urolithiasis and strategies for risk reduction in macropods are discussed.
Case Studies
Case 1
A 49.5-kg, 7-yr-old, castrated male red kangaroo (Macropus rufus) presented with sudden onset inappetence and restlessness. Dribbling of urine and frequent cloacal grooming were observed. The animal was anesthetized with 100 µg/kg IM medetomidine (Domitor, Novartis Animal Health Australasia Pty Ltd; NSW, Australia) and 3 mg/kg IM ketamine (Ketamil, Ilium Veterinary Products; NSW, Australia) and maintained on isoflurane (Forthane, Abbott Australasia; NSW, Australia) and oxygen delivered by mask.
A blood sample was taken and intravenous fluid therapy was initiated. Abdominal radiography revealed abundant intra-intestinal gas. Although the animal's conformation precluded bladder palpation, abdominal ultrasonography revealed bladder distension. A dorsoventral pelvic radiograph with the beam directed obliquely from cranial to caudal revealed an irregular radiodense mass, just caudal to the ischial arch slightly to the left of the midline. A gritty mass was palpated within the pelvic urethra via a digital rectal examination, just anterior to the level of the anus. A diagnosis of obstructive urethral urolithiasis was made. Serosanguinous urine (1.8 L) was aspirated from the bladder by cystocentesis and an attempt was made to pass a urinary catheter. The catheter could not be passed beyond a point approximately 4 cm proximal to the external urethral orifice. This point was several cm distal to the level of the palpable urethral obstruction. Urohydropropulsion was unsuccessful in dislodging the urolith.
Abdominocentesis revealed free fluid in the abdominal cavity and a decision was made to euthanize the animal. Hematology was unremarkable, the white cell count was 12x109/L. A PCV of 42% was assessed to be slightly elevated reflecting dehydration. Serum biochemistry and electrolyte concentrations were within normal ranges. Urinalysis revealed pyuria, hematuria, and amorphous phosphates and USG was 1.033. Uroperitoneum and an associated diffuse peritonitis were confirmed during postmortem examination. A single, irregular urolith was retrieved from the urethra. The bladder was markedly distended and there was significant segmental transmural necrosis. A urinary catheter could not be advanced beyond the penile urethra at necropsy and dissection of the structure revealed that the catheter was consistently lodging in a dorsal diverticulum of the urethra, 4 cm proximal to the external urethral orifice. No additional uroliths were found. Analysis of the urolith by semi-quantitative methods revealed it to be 55% calcium, 10% oxalate, 5% phosphate, 2% magnesium and 28% organic constituents.
Case 2
A captive, castrated male, 32.2-kg, 9-yr-old western grey kangaroo (Macropus fulginosus) was noted to be depressed, weak and ataxic. There was clinical dehydration and a pain response to abdominal palpation. The animal was premedicated with 15 mg diazepam IM (Pamlin Injection, Parnell Laboratories Aust Pty Ltd; NSW, Australia) and anesthesia was induced and maintained with isoflurane and oxygen administered by mask.
A blood sample was taken and intravenous fluid therapy with 0.9% sodium chloride initiated. Antibiotic therapy was also initiated with 350 mg amoxicillin/clavulanic acid IM (Clavulox Injectable, Pfizer Animal Health; NSW, Australia). A hard obstruction was palpable in the penile urethra 8 cm proximal to the external urethral orifice, just caudal to the ischial arch. A urinary catheter could not be passed beyond a point 4 cm proximal to the external urethral orifice. Ultrasonography revealed an apparently intact bladder, partially filled with urine. The animal was moderately azotemic (BUN 35 mmol/L), dehydrated (PCV 56%, TPP 81 g/L) and had elevated serum concentrations of CK (3,178 mmol/L). A smooth yellow/grey bean-shaped calculus was removed from the urethra surgically. The penis was extended caudally and a longitudinal midline approach made from the ventral aspect over the urolith. The surgical wound was left open to granulate. The animal was not observed to pass urine over the ensuing 24 h and the animal subsequently died.
Postmortem examination of the animal revealed marked distension and necrosis of the bladder wall, hydronephrosis of the left kidney and multiple red foci within the renal cortices. There was a small volume of serosanguinous urine within the abdominal cavity and a diffuse peritonitis. There was marked distension and necrosis of the bladder, which contained sanguinous urine. Crystals were not evident upon microscopic examination of urine sediment. Attempts to pass a urinary catheter at necropsy demonstrated the presence of a similar urethral diverticulum as described in the animal described above. Histopathology revealed pyelonephritis and an acute necrotizing enteritis. Bacterial culture of several organs identified the presence of E. coli and Aeromonas hydrophila, supporting a diagnosis of terminal septicemia. The calculus was composed of 75% calcium, 10% oxalate, 5% magnesium, 5% phosphate and 5% organic material.
Case 3
A female, red-necked wallaby (Macropus rufogriseus banksianus) was euthanatized due to poor body condition and progression of mandibular osteomyelitis despite an intensive 5-wk course of antibiotic therapy. Repeated hematologic and serum biochemistry analyses had revealed no abnormal findings. In addition to right mandibular osteomyelitis, postmortem examination revealed bilateral nephropathy. Both kidneys had undulating capsular surfaces with multiple small white, fibrous foci. On cut section, the renal medullae were thickened and white, surrounding a series of irregularly shaped stones. The ureters were patent and no stones were evident within the lower urinary tract. Histologic examination of the renal parenchyma revealed multifocally extensive renal interstitial fibrosis, multifocal glomerular sclerosis, and mild nonsuppurative interstitial nephritis. Analysis of the calculus by semi-quantitative methods revealed it to be 40% calcium, 5% magnesium, and 20% oxalate.
Case 4
A female, eastern grey kangaroo (Macropus giganteus giganteus) was euthanatized due to failure to respond to a 16-wk regimen to treat a necrotizing soft tissue injury to the right antebrachium and secondary ulceration of the left plantar tarsal footpad. The animal's wounds were debrided and topically treated during a series of weekly general anesthetics. The kangaroo had also received several courses of parenteral and oral antibiotic therapy. In addition to the wounds noted above, necropsy revealed unilateral irregularity of the capsular surface of the left kidney, pallor and fibrosis of the left renal cortex, bilateral renal medullary fibrosis, and bilateral distension of the renal pelvises with large, firm, tan irregularly shaped concretions. Serum removed from blood collected during the necropsy contained concentrations of urea, creatinine and phosphorus within normal ranges.
Discussion
Urinary calculi form as a result of the precipitation and concretion of salts within the urinary tract. Generally, an individual is predisposed to the precipitation of specific salts where they are present in relative excess, exceeding the capacity of urine to maintain them in a state of supersaturation. Additional risk factors may also be involved in the pathogenesis of urolithiasis.
The pathogenesis of calcium oxalate urolithiasis has been most extensively studied in humans and domestic dogs. In humans, hypercalciuria and/or hyperoxaluria are significant predisposing factors, whereas affected dogs are more likely to have hypercalciuria with normoxaluria.5,7
Generally, hyperoxaluria may occur secondary to:
- Increased production of metabolic oxalate. Heritable disorders of glycine metabolism in humans have been described that result in hyperoxaluria.1
- Increased intake of oxalate-containing foodstuffs (e.g., oxalate-associated disease in ruminants is usually associated with the ingestion of oxalate-rich herbage6).
- Inappropriately increased intestinal uptake of dietary oxalate, as occurs secondary to many enteric diseases in humans.7
- Inappropriately increased renal tubular excretion of oxalate. A cytoplasmic membrane defect in humans that causes abnormal transport of oxalate across renal tubular cells resulting in a persistent mild hyperoxaluria has been described.4
Although hypercalciuria occurs secondary to diseases characterized by hypercalcemia, canine hypercalciuria is more commonly associated with normocalcemia. In dogs, normocalcemic hypercalciuria is usually due to intestinal hyperabsorption of calcium ('absorption hypercalciuria') wherein hypercalciuria is only present postprandially.5 Less commonly, canine normocalcemic hypercalciuria is associated with a failure of appropriate renal reabsorption of calcium in the distal tubule ('renal leak hypercalciuria') wherein hypercalciuria is consistently present.5
Although it is not currently known whether macropods are susceptible to hypercalciuria or hyperoxaluria by means of the mechanisms outlined above, it is likely that a urinary excess of one or both of these salts was involved in the development of urolithiasis in the cases described here. Captive macropods are often fed rations relatively high in calcium and vitamin D which may predispose them to absorption hypercalciuria and the subsequent development of calcium oxalate urolithiasis. Additional known predisposing factors for human calcium oxalate urolithiasis include reduced urine volume, hyperuricosuria, low urinary pH and low urinary levels of various crystallization inhibitors including citrate and magnesium.5 Desquamated epithelial cells are common nidi for the formation of uroliths and conditions that result in increased epithelial desquamation (e.g., hypovitaminosis A) may also increase the likelihood of urolithiasis where other predisposing conditions are present. The presence of greater than normal levels of urinary mucoprotein, as may occur in animals on a high concentrate/low roughage ration, may also favor the development of urolithiasis in predisposed individuals. It is suspected that some of these factors may also involve in the development of calcium oxalate urolithiasis in captive macropods.
The clinical consequences of urolithiasis are due to urinary tract mucosal damage and bacterial infection. More serious consequences arise when uroliths obstruct urine outflow resulting in postrenal azotemia. Unrelieved total obstruction to urine outflow results in acute renal failure and death. The male urethra is longer, more tortuous and narrower than the female and, in domestic animals, obstructive urethral urolithiasis occurs almost exclusively in males. Prepubescent castration retards urethral development and increases the risk of obstruction in predisposed individuals. Captive male macropods, particularly the larger species, are commonly castrated as subadults for management reasons and would consequently be expected to be more susceptible to obstructive urolithiasis.
Captive female macropods are susceptible to the formation of uroliths, yet obstruction of the lower urinary tract has not been observed in affected female animals. Although the two macropods with uroliths in the renal pelves did not suffer from obstructive uropathy, the presence of uroliths was associated with morphologic lesions in the renal parenchyma, most notably interstitial fibrosis. The presence of uroliths within the renal pelvis has the potential to result in hydronephrosis, or predispose the animal to pyelonephritis.
Diagnosis of uncomplicated urolithiasis in domestic animals is based on observation of clinical signs of urinary tract infection (UTI), confirmation of UTI by urinalysis and demonstration of the presence of uroliths by plain and/or contrast radiography. Crystalluria may be observed upon microscopic examination of urine sediment. Signs of UTI were not observed in animals 1 and 2 prior to obstruction, which may reflect the difficulties inherent in observing the micturition habits of captive macropods. The onset of urethral obstruction in both these animals was characterized by anuria, bladder distension and abdominal discomfort, all signs typical of urinary outflow obstruction in domestic animals. Conventional abdominal radiographic views were of no value in making a diagnosis in these animals due to the tissue mass surrounding the hips and pelvis in macropods of this size. A ventrodorsal pelvic radiographic view directed obliquely from cranial to caudal permitted visualisation of the urolith in animal 1. The uroliths in animals 1 and 2 were palpable per rectum allowing a definitive diagnosis to be made antemortem. It is interesting to note that hematologic and serum biochemical parameters belied the severity of the pathologic changes in these animals. This is contrary to the situation in domestic animals where total urinary obstruction is characterized by rapid and marked elevations in serum concentrations of blood urea nitrogen, creatinine and potassium. Azotemia was not present in animal 1 despite the severity of the clinical presentation and advanced pathology observed at necropsy. The severe renal pathology present in animal 2 was accompanied by only a moderate azotemia. Hyperkalemia was not a feature of either case.
General principles of treatment of obstructive urolithiasis are rapid decompression of the bladder to restore renal function and fluid therapy to address hydration, electrolyte and acid base derangements. Ideally, bladder decompression is achieved by restoration of urethral patency by removal of the urolith, either by passage of urinary catheter or hydropropulsion.3 Where urethral patency cannot be restored by these means, the bladder is emptied by cystocentesis and the patient prepared for surgical removal of the uroliths. Attempts to pass a urinary catheter in normal male macropods are seldom successful. Although the difficulty has been attributed to the presence of a sigmoid flexure in the fibroelastic male macropod penis, in the cases described here catheterization was prevented when the catheter consistently passed into a dorsal diverticulum of the urethra, located 4 cm from the external urethral orifice.
In animals 1 and 2, urethral obstruction occurred at the level of the ischial arch. In dogs this would be an indication for perineal urethrotomy.2 The macropod penis is positioned caudal to the scrotum within the cloaca relatively close to the pelvic symphysis. Consequently, a surgical approach via the penis is necessary for obstructions at this level in macropods. The postoperative death of the animal precluded the opportunity to assess the technique employed in case 2 for urethrotomy.
Conclusions
Although this paper documents the occurrence of obstructive and incidental calcium oxalate urolithiasis in macropods, it is unknown whether these uroliths were formed as a result of hyperoxaluria, hypercalciuria or other factors.
Until further studies define specific predisposing factors for calcium oxalate urolithiasis in captive macropods, it would seem prudent to address those aspects of husbandry that are likely to result in crystalluria and the subsequent concretion of urine crystals into uroliths. Oxalate-containing foodstuffs should be avoided and food items that are high in vitamin D and calcium should be limited. Fresh herbage or vegetables should be made available to ensure all animals have an adequate vitamin A intake. Care should be taken to ensure that all animals in an enclosure have access to water ad lib in order to maintain an optimum urine output. Urinalysis should be performed as part of the routine macropod veterinary examination for the early detection of crystalluria.
Urethral obstruction in macropods is investigated and managed according to the principles applied to domestic animals. Ultrasonography is useful for demonstration of bladder distension as the conformation of large macropods makes bladder palpation difficult. Similarly, radiography of the pelvic cavity may be problematic due to the large tissue mass. Oblique radiographic views may be more useful in these animals for the demonstration of uroliths in the pelvic urethra. The penile and pelvic urethra should be palpated as far proximally as possible to exclude the possibility of uroliths that are not readily visible on radiographic examination.
Catheterization is unlikely to be successful in restoring urethral patency in macropods and cystocentesis will usually be necessary for bladder decompression. Biochemical parameters such as BUN, creatinine and serum potassium may not be as sensitive indicators of the extent and duration of renal failure in macropods with acute urine outflow obstruction as in domestic species. Urethrotomy is likely to be necessary for re-establishment of urethral patency in affected macropods and surgery should be undertaken with consideration of the genital conformation of these animals.
Literature Cited
1. Danpure, C.J. et al. 2001. Primary hyperoxaluria. In: Scriver CR (ed) The Metabolic and Molecular Basis for Inherited Disease. Vol 2. McGraw Hill, New York: 3323–3367.
2. Dean, P.W. et al. 1990. Canine urethrotomy and urethrostomy. Compend. Contin. Educ. Pract. Vet. 12(11):1541–1554.
3. Fossum, T.W. and C.S. Hedlund. 2002. Surgery of the bladder and urethra. In: Small Animal Surgery. Mosby Inc., St Louis: 572–609.
4. Gambaro, et al. 1995. Erythrocyte transmembrane flux and renal clearance of oxalate in idiopathic calcium nephrolithiasis. Kidney Int. 48(5):1549–1552.
5. Lulich, J.P. et al. 1989. Canine calcium oxalate urolithiasis; detection, treatment and prevention. In: Kirk RW (ed) Current Veterinary Therapy X. Small Animal Practice.
6. Radostits, O.H. et al. 2000. Diseases of the urinary system; urolithiasis in ruminants. In: Veterinary Medicine; A Textbook of the Diseases of Cattle, Sheep, Pigs, Goats and Horses. WB Saunders Company Ltd. pp 493–498.
7. Smith, L.H. 1990. The pathophysiology and medical management of urolithiasis. Seminars in Nephrology. 10(1):31–52.