Abstract
CASE DESCRIPTION AS-year-old male Dwarf rabbit and 4-year-old female Mini-Rex rabbit were evaluated because of anorexia and urine scalding of the perineum.
CLINICAL FINDINGS Abdominal radiography revealed a diffuse increase in the opacity of the urinary bladder attributable to urinary sludge. In 1 rabbit, abdominal ultrasonography revealed several mass-like lesions protruding from the mucosal surface into the lumen of the urinary bladder. Rabbits were anesthetized, and cystoscopy was performed with a rigid 2.7-mm, 30° endoscope. Histologic analysis of tissue samples obtained through the cystoscope operating channel revealed findings consistent with polypoid cystitis.
TREATMENT AND OUTCOME To remove the urinary sludge from each rabbit, the urinary bladder was filled with sterile saline (0.9% NaCl) solution and emptied with a gentle massage several times until the ejected fluid was transparent. Rabbits were treated with NSAIDs, antimicrobials (chosen following microbial culture of urine and antimicrobial susceptibility testing), bathing of the perineum, and a low-calcium diet. The male rabbit died of unrelated causes 18 months later; postmortem examination findings confirmed the polypoid cystitis. The female rabbit remained disease free through to last follow-up (12 months after initial evaluation).
CLINICAL RELEVANCE This was the first report of polypoid cystitis in pet rabbits. Although ultrasonographic findings supported this diagnosis, a definitive diagnosis was achieved through cystoscopy and lesion biopsy. Treatments administered were intended to reduce the potential sources of irritation. Research is needed to investigate the effectiveness of the applied interventions and the association between excessive urinary calcium excretion and polyploid cystitis in rabbits.
A 5-year-old 2.2-kg (4.84-lb) castrated male Dwarf rabbit (rabbit 1) was brought to the Clinica per Animali Esotici in Rome, Italy, because the owner noticed loosening of the hair in the perineum and signs of anorexia during the previous 24-hour period. The rabbit was fed a commercial mixed formula (pellets and seeds), with limited access to vegetables and hay. It had reportedly been producing unusually milky urine for a few weeks prior to evaluation. Physical examination revealed that the rabbit was overweight (body condition score, 4/5),1 had mild pododermatitis in both hind limbs, and had severe scalding of the perineum, consistent with moist dermatitis.2 No other abnormalities were detected.
A CBC and serum biochemical analysis were performed. Results were within published ranges for pet rabbits,3 except for a high serum total calcium concentration (14.0 mg/dL; reference range, 5.6 to 12.5 mg/dL). Abdominal radiography revealed an increase in the opacity of the urinary bladder (Figure 1). Abdominal ultrasonography was performed by use of a linear 8- to 18-MHz ultrasound probe,a with the rabbit manually restrained. Findings indicated an over-distended bladder filled with hyperechoic particulate material. At this point, the differential diagnoses included bacterial cystitis, cystitis secondary to trauma from the urinary crystals, and urothelial neoplasia of the urinary bladder.
Lateral abdominal radiographic (A and B) and sagittal caudoabdominal ultrasonographic (C and D) images of pet rabbits with polypoid cystitis. A—Radiopaque material is visible in the urinary bladder of a 5-year-old 2.2-kg (4.84-lb) castrated male Dwarf rabbit (rabbit 1). Inset is a photograph showing the macroscopic sand-like appearance of the urinary sludge. B—Same rabbit as in panel A, immediately after endoscopy-assisted lavage of the urinary bladder. C—Ultrasonographic appearance of the urinary bladder in a 4-year-old 0.9-kg (1.98 lb) sexually intact female Mini-Rex rabbit (rabbit 2). Notice several mucosal protrusions into the lumen. D—Appearance of the urinary bladder of the rabbit in panel C 3 months after the cystoscopy and lavage procedure. No mucosal lesions are visible.
Citation: Journal of the American Veterinary Medical Association 251, 1; 10.2460/javma.251.1.84
A urine sample was obtained via ultrasound-guided cystocentesis. Urinalysis revealed the presence of calcium oxalate, calcium phosphate, and triple phosphate crystals. Results of bacterial culture of urine and antimicrobial susceptibility testing indicated multidrug-resistant Proteus spp.
The decision was made to perform cystoscopy to remove the urinary sludge. The rabbit was pre-medicated for the procedure with butorphanol tartrateb (0.2 mg/kg [0.09 mg/lb], SC) and sedated with a combination of ketamine hydrochloridec and dexmedetomidine hydrochlorided (12 and 0.06 mg/kg [5.5 and 0.027 mg/lb], respectively, IM).4–6 A catheter was placed in the left saphenous vein for intraoperative fluid administration. The glottis was endoscopically identified, and endotracheal intubation was performed with a 2.5-mm uncuffed endotracheal tube. The rabbit was then positioned in dorsal recumbency on a platform mounted over the surgical table to permit maneuvering of the endoscope.
A rigid 2.7-mm, 30° endoscopee (covered by a 14.5F operative sheath) with a 5F working channel and 2 stopcocks was used for cystoscopy. Sterile saline (0.9% NaCl) solution was irrigated through the stopcock at a rate of approximately 1 drop/s. The penis was exteriorized manually. The urethra was identified and accessed by applying gentle pressure to the tip of the endoscope during infusion of saline solution. Cystoscopy revealed the urethral mucosa to be hyperemic. Three 2- to 4-mm, white-to-transparent spheroidal masses protruded into the lumen of the urethra at the level of the urethrovesical junction (Figure 2). A diffuse proliferation of white, spheroidal, pedunculated, sessile masses was visible on the urinary bladder mucosa. Biopsy forceps were inserted through the operating channel, and multiple biopsy specimens of the proliferative mucosa were obtained with a 34-cm-long, 5F, flexible biopsy forceps with double-action jaws.f No proliferative lesions were visible on the fundus of the urinary bladder.
Endoscopic views of the urinary bladder in the Dwarf rabbit of Figure 1. A—Multiple, small white-to-transparent, rounded mass-like lesions (arrows) are visible protruding into the lumen of the urethra at the level of the urethrovesical junction. B—Whitish, rounded, pedunculated, sessile mass-like lesions (arrows) are visible on the neck of the urinary bladder. C—Biopsy specimens of the lesions are obtained via biopsy forceps. D—Fundus of the urinary bladder. Notice the lack of proliferative lesions in this area.
Citation: Journal of the American Veterinary Medical Association 251, 1; 10.2460/javma.251.1.84
After collection of biopsy specimens, the urinary bladder was slowly filled with sterile saline solution injected through the irrigation channel and then manually expressed with gentle massage to remove urinary sludge. For this purpose, the endoscope was removed, leaving the protective sheath in place. At the beginning of the lavage procedure, voided urine was white to yellow in color and thick and granular (Figure 1). Lavage of the urinary bladder was performed several times until the voided fluid appeared colorless and transparent. Abdominal radiography was repeated after the procedure, confirming removal of the urinary sludge.
Following the procedure, treatment was initiated with meloxicamg (1 mg/kg [0.45 mg/lb], PO, q 24 h)7 and antimicrobials appropriate for the multidrug-resistant organism identified through bacterial culture and antimicrobial susceptibility testing. By the next day, the rabbit's appetite had clearly improved and it was discharged from the hospital. On discharge, the owner was advised to wash the perineum of the rabbit with a neutral shampoo 3 times/d until the moist dermatitis resolved. As part of long-term management, a low-calcium diet was prescribed, consisting of timothy hay,h romaine lettuce, and timothy hay-based pellets.2,8,9,i
Biopsy samples were fixed in neutral-buffered 10% formalin, routinely processed, and embedded in paraffin. Five-micrometer-thick sections were stained with H&E stain. Microscopic examination revealed findings consistent with mucosal polypoid cystitis, characterized by polyps lined by minimally hyperplastic to attenuated transitional epithelium (Figure 3). The stalks of the polyps were composed of edematous fibrous vascularized tissue and scattered lymphoplasmacytic cells. Within the stroma were cysts lined by transitional epithelial cells. These cysts contained eosinophilic proteinaceous material (cystic glandularis).
Photomicrographs of endoscopic biopsy specimens from the urinary bladder of rabbit 1 (A) and rabbit 2 (B) in Figure 1 and a tissue specimen obtained after death from the urinary bladder of rabbit 1 (C). A—Polyps appear to be lined by minimally hyperplastic (black arrow) to attenuated (red arrow) transitional epithelium. The polyp stalks are composed of an edematous fibrous vascularized stroma (yellow asterisk) and scattered lymphoplasmacytic cells. Within the stroma are cysts lined by transitional epithelial cells (black asterisks). H&E stain; bar = 100 μm. B—The mucosal polyps are covered by a multifocaly eroded urothelium. The superficial submucosa is moderately edematous, with multifocal areas of dense collagenous stroma, and contains a mild superficial, perivascular to interstitial, predominantly lymphoplasmacytic infiltrate. H&E stain; bar = 60 μm. C—Villous-like projections are covered by transitional epithelium and contain a core of proliferative connective tissue (polypoid cystitis; black arrow). Within the lamina propria, close to or continuous with the mucosal epithelium, are compact nests of transitional epithelium cells (Brunn nests; blue arrows). Cystlike (asterisks) and tubuloglandular-like structures (red arrows) are lined by 1 to several layers of uniform cuboidal to columnar epithelial cells (cystitis cystica and glandularis) that extend deep into the lamina propria. H&E stain; bar = 200 μm.
Citation: Journal of the American Veterinary Medical Association 251, 1; 10.2460/javma.251.1.84
Perineal scalding resolved 4 days after hospital discharge as determined during a follow-up examination. Follow-up radiography and ultrasonography performed 2 weeks after hospital discharge revealed no abnormalities. Five months after the procedure, the rabbit was brought back to the hospital with gastrointestinal stasis and perineal scalding. Abundant radiopaque material was radiographically identified in the urinary bladder. Endoscopic lavage of the urinary bladder was performed again, resulting in clinical improvement. The owner admitted that the rabbit's diet had not been changed as instructed.
Approximately 1.5 years after the first procedure, the rabbit was found dead by its owner. A complete postmortem examination was performed. On gross examination, the wall of the urinary bladder appeared thickened and opaque. Histologic examination of the urinary bladder tissue revealed features of polypoid cystitis and cystitis glandularis with Brunn nests (Figure 3). The cystitis was characterized by the presence of villous-like projections that were covered by transitional epithelium and contained a core of connective tissue infiltrated by multiple coalescing foci of lymphocytes, plasma cells, and rare heterophils, similar to what was observed previously. The Brunn nests were characterized by compact nests of transitional epithelial cells in the lamina propria, close to or continuous with the mucosal epithelium. Other postmortem findings included hepatic necrosis, chronic interstitial nephritis, and peritoneal cysticercosis.
A 4-year-old 0.9-kg (1.98 lb) sexually intact female Mini-Rex rabbit (rabbit 2) was evaluated because of a decrease in food intake. The rabbit had free access to hay, and the owner provided vegetables and a commercial pelleted diet twice per day. Physical examination revealed that the stomach was moderately distended with feed, and a mass was palpable in the caudal portion of the abdomen. Severe scalding of the perineum (moist dermatitis) was also identified. No other abnormalities were detected. Results of a CBC and serum biochemical analysis were unremarkable, except for hypercalcemia (serum total calcium concentration, 15.7 mg/dL) and hyperglycemia (serum glucose concentration, 212 mg/dL; reference range, 75 to 155 mg/dL).
Abdominal radiography revealed an increase in the opacity of the urinary bladder, multifocal mineralization of both renal pelves without evident hydronephrosis, and a well-demarcated opacity of the midcaudal aspect of the abdomen dorsal to the urinary bladder, consistent with an enlarged uterus. Abdominal ultrasonography was performed as for rabbit 1, revealing several mucosal masses protruding into the lumen of the fundus of the urinary bladder (Figure 1) and a fluid-filled and considerably distended uterus. As for rabbit 1, differential diagnoses included bacterial cystitis, cystitis secondary to trauma from the urinary crystals, and urothelial neoplasia of the urinary bladder. Endometrial hyperplasia and adenocarcinoma were differential diagnoses for the uterine changes.10
A urine sample was obtained via ultrasound-guided cystocentesis and submitted for urinalysis. As for rabbit 1, results indicated the presence of calcium oxalate, calcium phosphate, and triple phosphate crystals. Results of bacterial culture of urine and antimicrobial susceptibility indicated multidrug-resistant Enterococcus spp.
Cystoscopy and lavage of the urinary bladder were performed in a similar manner as for rabbit 1 to remove the urinary sludge and rule out urinary bladder neoplasia. During this procedure, the urinary papilla was easily identified in the vagina and accessed by means of gentle pressure during infusion of saline solution. No abnormalities were detected in the urethra. However, the lumen of the urinary bladder contained polypoid masses that gave the mucosal surface a corrugated appearance. Biopsy specimens of the masses were obtained as for rabbit 1. Immediately after cystoscopy, ovariohysterovaginectomy was performed.
Following surgery, treatments were initiated and discharge instructions were provided to the owner as for rabbit 1. Histologic examination of biopsy specimens prepared as for rabbit 1 revealed findings consistent with mucosal polypoid cystitis. The mucosal polyps were covered by a multifocally eroded urothelium. The superficial submucosa was moderately edematous and congested and contained a mild superficial, perivascular to interstitial, predominantly lymphoplasmacytic infiltrate (Figure 3).
The rabbit recovered from the surgery without complication, began eating the next day, and was discharged from the hospital. Over the next 2 weeks, the moist dermatitis gradually resolved as determined by weekly examinations. Follow-up abdominal ultrasonography was performed 3 months after hospital discharge and did not reveal proliferative lesions of the urinary bladder mucosa (Figure 1). At the last ultrasonographic follow-up examination performed 4 months after initial evaluation, the rabbit was disease free.
Discussion
A systematic search of the literature (Supplemental Appendix S1, available at http://avmajournals.avma.org/doi/suppl/10.2460/javma.251.1.84) confirmed that the present report represents the first description of polypoid cystitis in pet rabbits. This condition should be considered as a differential diagnosis for rabbits with masses of the urinary bladder lumen or rabbits with chronic urinary sludge. Biopsy specimens were easily and safely obtained from the rabbits by transurethral cystoscopy, assisting in the diagnosis.
The term polypoid cystitis was first used to describe an uncommon disease of the urinary bladder in humans, characterized by inflammation of the bladder mucosa and development of single or multiple polypoid masses without histologic evidence of neoplasia.11 Since then, the condition, also known as papillomatous or papillary cystitis, has been sporadically reported in humans12 and other animals, including dogs13 and ruminants.14,15 Although the exact etiology of polypoid cystitis is unknown, it is presumed to involve an inflammatory and hyperplastic reaction to chronic irritation of the bladder mucosa.16,17
In humans, polypoid cystitis is associated with the use of indwelling catheters.16,18 In 1 report,16 most (n = 34) of the lesions identified in 50 patients were located on the posterior aspect of the bladder wall, corresponding to the site of the catheter tip. More recent evidence indicates that polypoid cystitis may also develop in humans with no recent history of urinary bladder catheterization.19 In a case series17 involving 17 dogs with polypoid cystitis, none had received an indwelling urinary catheter prior to evaluation. The authors of that report17 concluded that the causative factors in dogs are different from those in humans.
Neither rabbit of the present report had a prior history of catheterization or surgery of the urinary bladder. However, both rabbits had urinary bladder sludge. Compared with other mammals, rabbits have a unique process for calcium metabolism.20 Excess calcium in the diet is absorbed, leading to a high plasma calcium concentration, and excess amounts of absorbed calcium are excreted in the urine.20 In other mammals, the calcium absorption rate in the intestine may be physiologically downregulated during periods of high calcium intake. High urinary calcium concentration secondary to consumption of a high-calcium diet (eg, alfalfa) is associated with urinary sludge formation.21 A high-calcium diet, dehydration, and urine retention have been suggested to result in large amounts of calcium carbonate precipitate forming a thick sludge in the urinary bladder, causing urethral irritation and dysfunction.9 We believe that excessive excretion of urinary calcium and subsequent chronic inflammation caused by stagnation of the sludgy urine provided a trigger for the lesions identified in the urinary bladders of the rabbits of the present report. Clearly, it was not possible to exclude that other inflammatory stimuli were responsible for the development of hyperplasia and polyps.
In children, hypercalciuria may be associated with urinary tract infection.22 An association between large amounts of crystals in the urine and papillary hyperplasia of the urothelium has also been identified in laboratory rabbits.23 The time required for an irritating stimulus to induce such pathological changes is unclear; however, pathological changes described as polypoid cystitis have been identified in humans that had been catheterized for < 1 month.16
In humans, polypoid cystitis is the most common lesion misdiagnosed as papillary urothelial neoplasia.24 Considering the differences in treatment strategy and prognosis for cystitis versus bladder neoplasia, it is important to achieve a definitive diagnosis. Abdominal ultrasonography is a useful ancillary test when polypoid cystitis is suspected. Typical ultrasonographic findings include mucosal projections and polypoid to pedunculated masses of variable size and shape.25 Although no supporting research has been performed, some authors suggest that without histologic examination of biopsy specimens, results of ultrasonography should not be considered diagnostic.25 To obtain diagnostic tissue samples, cystotomy and cystoscopy may be used. For both rabbits of the present report, cystoscopy performed with a rigid endoscope allowed evaluation of the urethral and urinary bladder mucosa and collection of diagnostic biopsy specimens.
The main treatment for polypoid cystitis in humans consists of removing the source of irritation.26 Our method of eliminating the sources of irritation in the 2 rabbits of the present report consisted of removing the sludgy urine by cystoscopic-assisted lavage of the urinary bladder, reducing urinary calcium excretion by feeding a low-calcium diet, and treating the bacterial infection by administration of an antimicrobial chosen on the basis of the antimicrobial resistance pattern of the responsible organism. Although current recommendations for removal of sludgy urine from rabbits consist of catheterization and urohydropropulsion,2 in our experience, catheterization of the urinary bladder in female rabbits under direct endoscopic guidance is easier than blinded catheterization. Furthermore, use of the protective sheath of the endoscope as a catheter allows the passage of thick urine.j For rabbit 1 of the present report, although endoscopic removal of the sludgy urine and supportive treatment alleviated the clinical signs, subsequent necropsy revealed incomplete remission of the polypoid cystitis. The outcome for rabbit 2 was different because luminal masses were no longer ultrasonographically visible 3 months after cystoscopy and lavage of the urinary bladder. Given the lack of clinical signs of abnormal ultrasonographic findings, it was likely that the polypoid cystitis had resolved in that rabbit.
An anecdotal report9 of polypoid cystitis in pet rabbits and a report27 of polypoid cystitis in laboratory rabbits suggest this disorder as a differential diagnosis for hematuria. The 2 pet rabbits of the present report had no signs of hematuria. Instead, both had perineal scalding and urinary sludge. Veterinarians should be aware of the different clinical signs for polypoid cystitis in rabbits.
Although the etiology of polypoid cystitis is unknown, we found that this condition can develop in pet rabbits and that its diagnosis was feasible through cystoscopy and examination of tissue biopsy specimens. Additional research is needed to investigate the possible association between polypoid cystitis and excessive calcium excretion through the urine. Moreover, experimental studies are needed to determine the general effectiveness of the interventions used for the 2 rabbits reported here.
Acknowledgments
The authors have no financial interests with companies that manufacture products used in the management of these cases or with companies that manufacture competing products.
This case report is reported in accordance with the CARE Guidelines for consensus-based clinical case reporting.28
Footnotes
L8–18i, General Electric, Fairfield, Conn.
Dolorex (10 mg/mL), MSD Animal Health Srl, Segrate, Italy.
Dexdomitor (0.5 mg/mL), Orion Pharma, Espoo, Finland.
Ketavet (100 mg/mL), Intervet Productions Srl, Segrate, Italy.
64019 BA, Karl Storz Gmbh and Co, Tuttlingen, Germany.
67161 Z, Karl Storz Gmbh and Co, Tuttlingen, Germany.
Metacam, Boehringer Ingelheim Vetmedica Inc, St Joseph, Mo.
Western timothy hay Oxbow Animal Health, Murdock, Neb.
Urinary tract health formula, Supreme Pet Foods, Hadleigh. Suffolk, England.
Selleri P, Di Girolamo N, Collarile T. Cystoscopy in rabbit: diagnostic and therapeutic applications (abstr), in Proceedings. 10th Annu Meet Assoc Exot Mammal Vet 2012;40–41.
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