Signalment:  

1-month-old male Cape buffalo, (Syncerus caffer caffer).The calf was part of a small herd in a large field enclosure at a zoological park. It was noted to be depressed and slow for 5 days and was briefly caught for examination, collection of blood and fecal samples for diagnostic testing, and empirical treatment with a non-steroidal anti-inflammatory drug, antibiotics and an anthelmintic. The calf was found dead the next day. 

Gross Description:  

The calf was 42 kg and had adequate adipose stores. In both kidneys, the renal papillae were streaked with pale yellow, finely granular material. Similar material was also present in variable amounts in calices and pelvices as sand-like to 2-3 mm diameter, rough, irregular, friable stones. The urinary bladder was distended with thin, cloudy, off-white urine.

Histopathologic Description:

Kidney: The calices are dilated and contain abundant irregular, rounded, lamellated, basophilic concretions (nephroliths), which are partially composed of and mixed with refractile, birefringent, brown to green crystalline material. These concretions and crystals are mixed with neutrophils and cellular debris and multifocally disrupt the renal papillae and urothelium of the calices, which is variably attenuated or hyperplastic. Throughout the section, tubules are frequently dilated and contain pale eosinophilic hyaline casts, coarse granular eosinophilic debris, sloughed necrotic epithelial cells, neutrophils, or lamellated concretions of amphophilic, wispy, radiating, predominantly non-birefringent material similar to that in the calices. The tubular epithelium is often attenuated, necrotic or disrupted by the embedded concretions, which are sometimes covered with a layer of epithelium. There is multifocal mild fibrosis in the interstitium, and glomeruli are diffusely subjectively small. 

Morphologic Diagnosis:  

Kidneys: Severe diffuse chronic nephrolithiasis with myriad intra-tubular and intra-calices calculi and crystals, tubular ectasia, hyaline and cellular casts, interstitial fibrosis, hypoplastic glomeruli and mild neutrophilic pyelonephritis.

Lab Results:  

Serum Chemistry	Value	Reference Range	Units
Albumin	3.7	2.8-3.8	g/dL
Total Protein	7.7	6.7-8.8	g/dL
Globulin	4.0	3.3-6.3	g/dL
BUN	148	10-23	mg/dL
Creatinine	10.3	0.7-1.2	mg/dL
Cholesterol	310	157-393	mg/dL
Glucose	246	41-74	mg/dL
Calcium	6.7	9.1-11.3	mg/dL
Phosphorus	14.8	5.1-8.7	mg/dL
Chloride	132	93-100	mEq/L
Potassium	5.6	4.1-5.5	mEq/L
Sodium	157	136-148	mEq/L
Alk Phos	225	23-96	U/L
ALT	11	15-43	U/L
Total Bilirubin	0.4	0.0-0.2	mg/dL

CBC	Value	Reference Range	Units
HCT	31	24-38	%
WBC	19.4	5.3-14.9	K/uL
Neutrophils	16498	2200-8073	per ul
Lymphocytes	2328	1431-8694	per ul
Monocytes	582	0-774	per ul
Eosinophils	0		per ul
Basophils	0		per ul
Platelets	1692		K/ul

Kidney stone analysis (Minnesota Urolith Center): 100% xanthine

Condition:  

Nephrolithiasis

Contributor Comment:  

This case is typical of xanthine urolithiasis, though this condition has not previously been reported in Cape buffalo. Small stones in the kidneys were composed of 100% xanthine by quantitative stone analysis. Accumulation of xanthine crystals and stones in renal tubules and calices results in obstruction, progressive tubular damage, and eventually renal failure. Xanthine urolithiasis is very rare in animals but has been described in Japanese Black calves, a Galician Blond beef calf, sheep, certain breeds of dogs (e.g. Cavalier King Charles Spaniels, Dachshunds), and cats.(1,3,6,7) The disease in this buffalo calf was very similar to cases of xanthine nephrolithiasis in domestic cattle, in which calves present between 1 and 6 months of age with renal failure.(1,4) The variably-sized, yellow to brown stones can be present in the kidneys, ureters, and bladder and are radiolucent. Diagnosis is based on stone analysis. In this case, other supporting findings included myriad small, spiculate crystals on examination of urine sediment and failure of the renal concretions to stain with von Kossa and Alizarin Red in histologic sections. 

Xanthine is a metabolite of purines normally converted to uric acid by xanthine oxidase. Xanthinuria and xanthine urolithiasis result from loss of function of this enzyme, which can be the result of a primary enzyme defect inherited as an autosomal recessive condition or from secondary inhibition of enzyme function.(3,7) Cases of the secondary form are most often caused by treatment with allopurinol, an inhibitor of xanthine oxidase, and are thus most commonly seen in Dalmatian dogs treated for urate urolithiasis.(2,3) Dietary deficiency of molybdenum, a component of an essential cofactor of xanthine oxidase, was thought to account for xanthine urolithiasis in sheep.(3) The Cape buffalo calf in this report had not been treated with allopurinol and had normal levels of molybdenum on postmortem analysis of liver. It is therefore thought to have had a primary (hereditary) form of the disease, similar to cases in domestic cattle.(1,4,8) A half-sibling of this calf (same sire, different dam) had previously died at 2 months of age with nearly identical lesions, although stone analysis was not performed in that case. Four prior calves from the same dam and sire were unaffected. Characterization of the hypothesized genetic defect in this group of Cape buffalo has not yet been attempted.

JPC Diagnosis:  

Kidney: Nephrolithiasis, intracalyceal and intratubular, moderate to severe, with mild suppurative pyelonephritis, tubular proteinosis and tubular necrosis.

Conference Comment:  

Urolithiasis, a condition frequently encountered in domestic animal species, refers to the presence of calculi within urinary passages. Calculi can form in any part of the urinary system from the kidneys to the urethra. Due to the length and narrow diameter of the penile urethra, impaction secondary to urethral calculi is common in males, especially at the ischial arch, the sigmoid flexure in ruminants, the vermiform appendage in rams, and the proximal end of the os penis in dogs. Calculi are grossly visible concretions of precipitated mineral, urinary proteins and debris, while urethral plugs are composed of aggregates of sandy sludge with a higher proportion of organic material that tend to conform to the shape of the urinary cavity that they fill. Urolith formation is influenced by familial, congenital and pathophysiologic factors including urinary pH, relative dehydration, infection, anatomic abnormalities, foreign bodies (such as grass awns) and drug administration. The supersaturation of urine with stone-forming salts is an important precursor to urolith nucleation.(3) Crystal precipitation and aggregation also play a role in the development of urolithiasis, although crystalluria without calculus formation is a fairly common finding and the factors that promote/prevent the formation of uroliths are complicated and poorly understood. Horse urine, for instance, is normally supersaturated with calcium carbonate and crystalluria is a normal finding on equine urinalysis, yet horses rarely develop urinary calculi.(5)

The important types of urinary calculi in various species are listed in table 1; it is also worthwhile to remember that many uroliths are of mixed composition (although one mineral may predominate). Silica calculi are a significant cause of urinary tract obstruction in pastured ruminants and are occasionally seen in male dogs, especially German shepherds and old English sheepdogs or dogs receiving a ration high in plant-derived ingredients (i.e. corn gluten or rice/soybean hulls). They are hard, white to dark brown, radiopaque and spherical/ovoid (in the urinary bladder) or angular/irregular (when in renal calyces) with a friable core.(3)

Struvite calculi are composed of magnesium ammonium phosphate hexahydrate; historically, they were inappropriately identified as triple phosphate calculi. Grossly, these radiopaque stones appear white to gray, chalky, smooth and easily fractured. They typically contain additional compounds such as calcium phosphate (which often forms a shell around the struvite), ammonium urate, oxalate or carbonate.(3) Struvites are most important in dogs, cats and ruminants where they are commonly associated with infection. Ureases produced by bacteria such as Staphylococcus spp. or Proteus spp. increase the urine pH, which decreases struvite solubility, thus favoring the formation of calculi. Miniature schnauzers appear predisposed, probably due to a familial susceptibility to urinary tract infections. Sterile struvite urolithiasis has been reported in a line of English cocker spaniels and beagles. The formation of struvite calculi within the urinary bladder of cats is one manifestation of an idiopathic condition known as feline lower urinary tract disease (FLUTD); Russian blues, Himalayans, Persians and castrated/spayed males and females are predisposed. Of note, struvite crystalluria is often seen in cats even without calculi; the reasons for this phenomenon are poorly understood. It should also be noted that amorphous urethral plugs containing Tamm-Horsfall mucoprotein, albumin, globulins, cellular debris and struvite crystals are a much more important cause of urethral obstruction in male cats, typically associated with concurrent urinary tract inflammation. Struvite calculi also occur in feedlot steers and sheep on a high grain ration. Much like cats, obstruction in ruminants is typically due to formation of a gritty sludge, rather than discrete calculi, while a high phosphate diet predisposes sheep to struvite urolithiasis.(3,5)

Oxalate calculi tend to develop as large, solitary, white to yellow bladder stones covered with sharp spines. They are composed of calcium oxalate monohydrate or calcium oxalate dihydrate, and although the pathogenesis is poorly understood, it likely involves some combination of hypercalciuria and hyperoxaluria. The major causes of hypercalcemia/hypercalciuria are briefly discussed in WSC 2013-2014, conference 13, case 3. Oxalic acid may be ingested in some foods or synthesized from glyoxylic and ascorbic acid. The formation of calcium oxalate uroliths is inhibited by dietary magnesium, which forms soluble complexes with oxalate, and citrate, which forms a similar complex with calcium. Oxalate uroliths are the second most common type of calculi encountered in dogs and have been associated with hyperparathyroidism, hypercalcemia, hyperadrenocorticism and exogenous steroid administration. Male miniature schnauzers, bichon frises, lhasa apsos, Yorkshire terriers, shih tzus and miniature poodles are predisposed. The prevalence of oxalate urolithiasis is increasing in cats and is likely related to dietary factors, although the specifics are not clear. Since oxalate is metabolized in the rumen, oxalate calculi are not generally considered important in ruminants; however, they are reported in sheep grazing grain stubble, although the source of the oxalates in these cases remains unknown.(3,5)

Uric acid and urates are products of purine metabolism; calculi usually contain ammonium urate in combination with uric acid and phosphate. Uric acid/urate calculi are typically multiple, hard, laminated green-brown, radiodense spherical stones found within the urinary bladder. Urate stones are rarely reported in swine and cats but are most common in Dalmation dogs. In neonatal pigs in a negative energy balance, there is increased production of purine catabolites, which also predispose the formation of urate calculi. Urate urolithiasis in Dalmations results from an autosomal recessive defect in the hepatic uptake of uric acid, leading to its incomplete metabolism and accumulation. This defective transport system also inhibits tubular reabsorption of uric acid from the glomerular filtrate, resulting in urine that is supersaturated with urates.(3,5)

Xanthine is another purine metabolite, which, as noted by the contributor, is normally degraded via xanthine oxidase to uric acid. Xanthine stones are irregular, yellow to brown-red, laminated, friable and radiolucent.(3,5) This interesting case provides an excellent example of an uncommon condition (xanthine urolithiasis) in an unusual species. The contributor provides a thorough description of the gross pathology, histology, clinical-pathology and pathogenesis of xanthine urolithiasis in veterinary medicine. 

Table 1. Composition of urinary calculi in select domestic animal species.(3)

Species	Common Types	Uncommon Types
Ox	Silica Struvite Carbonate	Xanthine
Sheep	Silica Struvite Oxalate Clover stones Carbonate	Xanthine
Dog	Struvite Oxalate Purines (urate, uric acid, xanthine)	Silica Cystine Calcium phosphate
Cat	Struvite Oxalate	Urate Cystine
Horse*	Carbonate
Pig*		Urate (neonates)

* urinary calculi are uncommon in horses and rare in swine

References:

1. Hayashi M, Ide Y, Shoya S. Observation of xanthinuria and xanthine calculosis in beef calves. Jap J Vet Sci. 1979;41:505-510.

2. Ling GV, Ruby AL, Harrold DR, Johnson DL. Xanthine-containing urinary calculi in dogs given allopurinol. J Am Vet Assoc. 1991;198:1935-1940.

3. Maxie MG, Newman SJ. Urinary system. In: Maxie MG, ed. Jubb, Kennedy and Palmers Pathology of Domestic Animals. Vol 2. 5th ed. Edinburgh, UK: Elsevier Limited; 2007:508-514.

4. Miranda M, Rigueira L, Suarez ML, et al. Xanthine nephrolithiasis in a Galician blond beef calf. J Vet Med Sci.2010;72(7);921-923.

5. Newman SJ. The urinary system. In: Zachary JF, McGavin MD, eds. Pathologic Basis of Veterinary Disease. 5th ed. St. Louis: Elsevier; 2012:643-645.

6. Tsuchida S, Kagi A, Koyama H, Tagawa M. Xanthine urolithiasis in a cat: a case report and evaluation of a candidate gene for xanthine dehydrogenase. J Feline Med Surg. 2007;9:503-508.

7. Van Zuilen CD, Nickel RF, van Dijk TH, Reijngoud D-J. Xanthinuria in a family of Cavalier King Charles spaniels. Vet Quart. 1997;19:172-174.

8. Watanabe T, Ihara N, Itoh T, Fujita T, Sugimoto Y. Deletion mutation in Drosophila ma-l homologous, putative molybdopterin cofactor sulfurase gene is associated with bovine xanthinuria type II. J Biol Chem. 2000;275(29);21789-21792.

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3-1. Kidney

3-2. Kidney

3-3. Kidney

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