Xanthine urolithiasis is uncommon in dogs, with case series giving a prevalence of

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1 1 Xanthine urolithiasis in a Cavalier King Charles Spaniel Gow, A.G. 1, Fairbanks, L.D. 2, Simpson, J.W. 1, Jacinto, A.M.L. 1, Ridyard, A. E. 1 1 Royal (Dick) School of Veterinary Studies, Easter Bush Veterinary Centre, Roslin, Division of Veterinary Clinical Sciences, The University of Edinburgh, Midlothian, EH25 9RG, UK 2 Purine Research Laboratory, GSTS Pathology, St Thomas' Hospital, London, SE1 7EH, UK Xanthine urolithiasis is uncommon in dogs, with case series giving a prevalence of between 0.07 to 0.46%( Houston and Moore 2009; Low and others 2010; Osborne and others 2009). The most common cause of canine xanthinuria is iatrogenic when allopurinol is administered, inhibiting xanthine dehydrogenase (Bartges and Kirk 2008). In humans, primary xanthinuria may be caused by enzyme deficiency or a co-factor abnormality. Xanthine dehydrogenase (XDH) deficiency may be isolated (Type I), due to a missense mutation in the encoding gene for XDH, or in association with aldehyde oxidase deficiency, due to a missense mutation of the MCSU gene. Both are inherited in an autosomal recessive manner (Ichida and others 2001; Levartovsky and others 2000). Humans with these defects may be asymptomatic with incidental hypouricaemia (Holmes and others 1974). Clinical signs, when they occur, are related to muscle deposition of xanthine causing myopathy, or renal dysfunction due to renal deposition (Nyhan 2005). A final cause of primary xanthinuria is an abnormality of the molybdenum cofactor required by xanthine oxidase, aldehyde oxidase and sulphite oxidase. Sulfite oxidase deficiency results in dramatic clinical signs of neonatal seizures and ophthalmic abnormalities (Wadman and others 1983). 1

2 Feline xanthine uroliths appear uncommon in the cat with a prevalence of 0.1% reported in uroliths submitted to the Minnisota Urolith Center (Osborne and others 2004). There are case reports of xanthinuria in 2 domestic short-haired cats and one Himalayan cat (Schweighauser and others 2009; Tsuchida and others 2007; White and others 1997). Single nucleotide polymorphism analysis of the XDH gene in a xanthinuric Himalayan cat suggested it had two distinct alleles, making type I xanthinuria unlikely (Tsuchida and others 2007) Primary xanthinuria appears to be rare in the dog with cases reported in 8 dachshunds, two related Cavalier King Charles Spaniels (CKCS) in the Netherlands, one CKCS each in Germany and Sweden, and one King Charles Spaniel in the UK in which xanthine uroliths were identified post-mortem (Delbarre and others 1969; Flegel and others 1998; Kidder and Chivers 1968; Kucera and others 1997; van Zuilen and others 1997). Of the five cases with clinical information, three presented in terminal renal failure and euthanased and one had no clinical signs, only tested as it was related to a symptomatic dog. The one symptomatic dog with follow-up was asymptomatic for 9 months after medical management (van Zuilen and others 1997). This case is a CKCS in the UK with xanthine urolithiasis and urine purine concentrations after medical management A four-year old entire male CKCS was referred to the R(D)SVS with a history of polydipsia and intermittent strangury The dog was bright, responsive and in good body condition. Abdominal palpation was unremarkable and the bladder was half-full, non-painful and not easily 2

3 53 54 expressible. Rectal and neurological examinations were unremarkable. The external genitalia appeared normal Serum biochemistry analysis showed mild increases in glucose, urea, creatinine and inorganic phosphate concentrations. Urine analysis showed a specific gravity of 1.018, ph of 6.3, a trace of blood on dipstick, sediment examination revealed erythrocytes, occasional leucocytes and epithelial cells. Urinary ultrasonography revealed poor renal cortico-medullary definition multiple small nephroliths bilaterally. The bladder and urethra contained uroliths. All stones were radiolucent. A urinary catheter was passed with slight resistance. On aspiration and bladder agitation, yellow uroliths were aspirated (Figure 1). The catheter was retracted to the distal penis. Flushing, aspiration and bladder agitation were repeated until no further uroliths were retrieved. Microscopic examination of the stones showed them to be similar to urate, however xanthine stones appear identical (Kucera and others 1997). A post-prandial bile acid was within reference range making hepatic insufficiency unlikely. The urolith analysis by University of Minnesota Urolith Center confirmed pure xanthine. Spot urine samples were submitted for purine analysis along with four controls (Table 1). Uric acid was detected in all controls but was not in the CKCS sample. Xanthine and hypoxanthine were detected in the CKCS sample but not in any controls. This was suggestive of a defect in purine metabolism, likely a xanthine dehydrogenase deficiency. Molybdenum cofactor abnormality was unlikely due to the severe clinical signs in humans (Wadman and others 1983). Xanthine myopathy has been reported in a minority of humans with xanthine oxidase deficiency. No clinical signs of myopathy were detected. Ultrasonography of the 3

4 77 78 hind limb musculature and serum creatine kinase activity were performed and were unremarkable. The dog had no history of allopurinol administration As a xanthine dehydrogenase deficiency was suspected, a proprietary low protein diet (u/d; Hill s Pet Nutrition), to reduce purine excretion and adding water in attempt to reduce the concentration of xanthine in the urine were reccommended, however owner compliance was not absolute with either of these measures. After urolith retrieval the owner stated that the dog's lower urinary tract signs resolved. During the next 11 months however, stranguria recurred on numerous occasions, necessitating repeat catheterization and aspiration. Recurrent urocystoliths and progression of nephrolithiasis was documented by ultrasonography with an organised 22mm nephrolith developing in the left pelvis. Serum phosphate concentrations returned to reference range, likely due to the low phosphate diet: creatinine concentration remained stable. Urine analysis and culture detected an active sediment and growth of Pasturella multocida on one occasion. This responded to potentiated amoxycillin (Synulox; Pfizer). Subsequent culture was negative. Urinary purines were performed on three occasions after dietary modification (Table 1). Eleven months after presentation, the dog was euthanased due to post-surgical complications of nephrolith removal and cystotomy. Postmortem examination was declined by the owner Primary xanthinuria reported in the CKCS is thought to be a genetic defect inherited in an autosomal recessive manner, as in humans (van Zuilen and others 1997). The defect may be a type I or II XDH deficiency. Administration of allopurinol and metabolite analysis would differentiate these; however as this would not alter 4

5 management, and also have required a control population, this was not performed. XDH activity may also be measured in hepatic or intestinal tissue (Nyhan 2005), this was also not ethically justified Xanthine deposition is thought to cause calculogenic pyelonephritis (Bradbury and others 1995; Kucera and others 1997). This case presented with signs of renal failure which is consistent with the four other symptomatic cases reported. In humans, treatment of primary xanthinuria is based on a low purine diet and aggressive hydration (Nyhan 2005). Of 10 cats with xanthine urolithiasis fed an alkalinising diet and having a 2 year follow-up, only one was reported to have clinical recurrence (Osborne and others 2004). In this case, the diet fed was alkalinizing and the urinary ph was 7, the recommended ph for human urine in primary xanthinuria management (Pais and others 2006). In vitro studies and clinical cases have shown minimal dissolution at physiological ph levels therefore at best this is a preventative measure (Pais and others 2006). Although urine specific gravity reduced subsequent to initial presentation, it is unknown whether this was due to improved oral water intake or a deterioration of renal function and poor concentrating ability. In humans, xanthine concentrations below 3 mmol/l are suggested to reduce urolith formation (LD Fairbanks personal communication). This was not consistently achieved and uroliths recurred. Urinary xanthine excretion normalised to creatinine appeared to increase compared to the first measurement. This may have been due to poor dietary compliance Acknowledgements 5

6 A.G. would like to thank Hill s Pet Nutrition for sponsoring his residency, and the owners and referring veterinary practice for their help and co-operation. Table 1: Urinary Purines Animal Case initial analysis Analysis on u/d 1 month Analysis on u/d 2 months Analysis on u/d 4 months Control 1 Control 2 Control 3 Hypoxanthine nd nd nd nd Xanthine nd nd nd nd Uric acid nd nd nd nd Creatinine Ratio of xanthine to creatinine Urine S.G Urine ph nd = not detected Control Table 1 Legend: Urinary Purine analysis at the Purine Research Laboratory, Guy s and St Thomas Hospital, by high-performance liquid chromatography. Spot urinary purines of the case at presentation and three time points during dietary modification. Spot urine from 4 control dogs was also tested Figure 1 Legend: Sample of the uroliths retrieved during catheter aspiration. References BARTGES, J. W. & KIRK, C. A. (2008) Interpreting and Managing Crystaluria. In Kirk's current veterinary therapy. XIV 6

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