Canine urolithiasis: A look at over urolith submissions to the Canadian Veterinary Urolith Centre from February 1998 to April 2003

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1 ARTICLES Canine urolithiasis: A look at over urolith submissions to the Canadian Veterinary Urolith Centre from February 1998 to April 2003 Doreen M. Houston, Andrew E.P. Moore, Michael G. Favrin, Brent Hoff Abstract The purpose of this study was to report on the age, sex, breed, and mineral composition of canine bladder uroliths submitted to the Canadian Veterinary Urolith Centre between February 1998 and April Each urolith submission was accompanied by a questionnaire. Of the submissions, approximately 43.8% were struvite and 41.5% oxalate. Struvite uroliths were most common in female dogs. Mixed breed dogs predominated, followed by the shih tzu, bichon frise, miniature schnauzer, Lhasa apso, and Yorkshire terrier. Oxalate uroliths were most common in males and in the miniature schnauzer, bichon frise, Lhasa apso, shih tzu, and Yorkshire terrier. Urate uroliths were most common in male Dalmations. Other urolith types, including cystine, xanthine, silica, and calcium phosphate, were less commonly reported. A review of risk factors for the various uroliths is presented, along with some recommendations for treatment and prevention. Résumé Urolithiase canine : vue d ensemble sur plus de urolithes acheminés au Canadian Veterinay Urolith Center entre février 1998 et avril Le but de cette étude était de rapporter l âge, le sexe, la race et la composition minérale de urolithes retrouvés dans des vessies de chiens et soumis au Canadian Veterinary Urolith Center entre février 1998 et avril La soumission de chaque urolithe était accompagnée d un questionnaire. Approximativement 43,8 % des soumissions concernaient des lithiases phospho-ammoniaco-magnésiennes et 41,5 % des oxalates. Les lithiases phospho-ammoniaco-magnésiennes étaient plus fréquentes chez les chiennes. Les chiens de races croisées étaient les plus nombreux suivis par les Shihs Tzus, Bichons à poil frisé, Schnauzers nains, Lhassa Apsos et Yorkshires terriers. Les lithiases d oxalates étaient plus fré quentes chez les mâles et chez les Schnauzers nains, Bichons à poil frisé, Lhassas Apsos, Shihs Tzus et Yorkshires terriers. Les lithiases d urates étaient plus fréquentes chez les Dalmatiens mâles. Les autres types de lithiases dont celles de cystine, xanthine, silicate et de phosphate de calcium étaient moins souvent rapportées. Une revue des facteurs de risques associés aux différents urolithes est présentée ainsi que certaines recommandations concernant le traitement et la prévention. (Traduit par Docteur André Blouin) Can Vet J 2004;45: Introduction The Canadian Veterinary Urolith Centre (CVUC), located in Guelph, Ontario, Canada, opened in February The CVUC is a collaborative effort between Veterinary Medical Diets and the University of Guelph; it has quantitatively analyzed over submissions. Of these, 5484 were submissions from cats and were from dogs. Submissions to the CVUC have been received from all parts of Canada, including 29% from western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba), 45% from Ontario, Veterinary Medical Diets, 67 Watson Road South, Guelph, Ontario N1H 6H8 (Houston); Laboratory Services, University of Guelph, Guelph, Ontario (Moore, Favrin, Hoff). Address all correspondence and reprint requests to Dr. Doreen M. Houston; dhouston@medi-cal.ca 18% from Québec, and 8% from eastern Canada (Nova Scotia, New Brunswick, Prince Edward Island, and Newfoundland). The purpose of this paper is to report on the number and mineral composition of bladder uroliths, passed or surgically removed, from Canadian dogs over a 5-year period. A review of predisposing factors for urolith formation is presented. Materials and methods A computer-assisted search of data from questionnaires submitted to the CVUC was used to compile information about all canine urinary calculi analyzed between February 1, 1998, and April 1, The age, sex, and breed of affected dogs were recorded. The uroliths analyzed had been surgically removed or were voided. To determine the mineral composition, each Can Vet J Volume 45, March

2 Table 1. Urolith composition and sex of top 6 canine pure breed submissions Urolith composition Calcium Calcium Oxalate Struvite Urates Phosphate Breed Sex a Number of Stones n % n % n % n % Miniature schnauzer M F Shih tzu M F Bichon frise M F Lhasa apso M F Dalmation M F Yorkshire terrier M F Totals a M castrated male; F spayed female layer of each specimen was analyzed by optical crystallography, using polarized light microscopy. If additional clarification was needed, another quantitative technique was used (X-ray microanalysis, Fourier transform infrared spectroscopy, or scanning electron microscopy). All 4 quantitative techniques are available at the CVUC. As previously described, uroliths containing at least 70% of a single mineral were classified as that type (1). Only uroliths with 1 mineral type or a prominent mineral type were included. This represents the majority of submissions (1). For purposes of this paper, the terms calcium oxalate or oxalate include calcium oxalate monohydrate, calcium oxalate dihydrate, or both. The term urate includes the salts of uric acid (ammonium, potassium, and sodium acid urate), as previously established (2). Calcium phosphate includes apatite, brushite, and carbonate forms. Results Uroliths composed of struvite (magnesium ammonium phosphate hexahydrate) were those most commonly analyzed, with 7287 (43.8%) submissions. Oxalate submissions were a close second, numbering 6904 (41.5%). Other types of uroliths were reported infrequently: urate 797 (4.8%), calcium phosphate 360 (2.2%), silica 155 (0.9%), cystine 59 (0.4%), xanthine 9 (0.05%), and mixed content 1076 (6.5%). Females outnumbered males by approximately 12:1 in struvite stone submissions when all breeds, including mixed breed dogs, were considered. The average age for a female dog with a struvite urolith was 5.7 y (median age 5 y, with a range of 2 mo to 17 y) and 6.0 y for a male dog (median age of 6 y, with a range of 2 mo to 18 y). Female mixed breed dogs (1860) were most commonly presented with struvite uroliths. Pure breeds of dogs with frequent submissions of struvite uroliths included the female shih tzu, bichon frise, miniature schnauzer, Lhasa apso, and Yorkshire terrier (Table 1). In each of these breeds, females outnumbered males by 16:1 in struvite urolith submissions. Struvite uroliths were either single or multiple and of variable size. Figures 1A and 1B reveal a large struvite bladder urolith seen on radiographs (Figure 1A) and after surgical removal (Figure 1B) from a mature spayed female border collie cross. This stone weighed an amazing 0.6 kg and measured 12.5 cm long by 7.5 cm wide. Like most struvite stones, it was radiodense and easy to visualize. Male dogs outnumbered female dogs by approximately 3:1 in canine calcium oxalate stone submissions when all breeds, including mixed breed dogs, were considered. Oxalate uroliths were found most commonly in male dogs from mixed breeds (910 submissions), followed by the following 6 pure breeds of dogs: miniature schnauzer, bichon frise, Lhasa apso, shih tzu, and Yorkshire terrier. Unlike the other breeds, the female schnauzer appeared to have an almost equal chance of developing an oxalate as a struvite stone (Table 1). The average age for a male dog to present with an oxalate urolith was 8.1 y (median age of 8 y, with a range of 2 mo to 18 y) and 8.4 y for a female dog (median age of 8 y, with a range of 6 mo to 17 y). A total of 797 urate uoliths were submitted to the CVUC. Of these, over 500 were from Dalmations, with males dominating females by approximately 50:1. The only other breeds with at least 30 urate submissions included the shih tzu, miniature schnauzer, English bulldogs (30), and mixed breed dogs (30). In all these cases, males were 2.5 times as likely as females to have a urate urolith. The average age of a male with a urate urolith was 5.5 y (median age of 5 y with a range of 4 mo to 15 y) compared with that of the female at 4.6 y (median age of 4 y with a range of 2 mo to 14 y). Less commonly submitted uroliths included calcium phosphate, silica, cystine, and xanthine. Calcium phosphate submissions (including the brushite, apatite, and carbonate forms) numbered 360. Of these, 205 (56.9%) were from females and 176 (48.9%) were from males. The average age of both female and male dogs with calcium phosphate uroliths was 7.4 y (median age of 7.5 y with a range of 2 mo to 15 y). Seventy-five (20.8%) were from mixed breed dogs, 64 (17.8%) from the shih 226 Can Vet J Volume 45, March 2004

3 1 from a male bichon frise, 1 from a male sheltie, and 1 from a female mixed breed dog. The average age for a male dog with a xanthine urolith was 6.6 y (median age of 7 y with a range of 4 mo to 9 y) and for a female dog, 6.3 y (median age of 5 y with a range of 5 mo to 9 y). Mixed and compound uroliths accounted for the remaining 1049 submissions. Approximately 80% of thesee were combinations of struvite and calcium phosphate. A small percentage were combinations of oxalate and calcium phosphate (7%), oxalate and struvite (3%), oxalate and silica (3%), and oxalate and urate (3%). Figures 1A and 1B. Large struvite stone occupying bladder (Figure 1A) of a Border collie cross female dog. The stone removed (Figure 1B) was 0.6 kg in weight and measured 12.5 cm long 7.5 cm wide at it widest part. Case, with permission, from Dr. David Condon, Abegweit Animal Hospital, Charlottetown, Prince Edward Island. tzu, 46 (12.7%) from the bichon frise, 37 from the Lhaso apso (10.2%), 25 from the miniature schnauzer (6.9%), and 12 from the Yorkshire terrier (3.3%). Approximately 155 silica submissions were analyzed. Breeds that were represented included mixed (n = 33), shih tzus (n = 20), miniature schnauzer (n = 20), bichon frise (n = 13), and Lhasa apso (n = 12). Males predominated (130 male:25 female). The average age of a female dog with a silica urolith was 8.6 y (median age of 8.8 y with a range of 4 mo to 14 y), that of a male dog was 8.5 y (median age of 8 y with a range of 6 mo to 16 y). Of 59 cystine urolith submissions, approximately 75% were submitted from 5 breeds: the English bulldog (n = 17), Newfoundland (n = 9), Chihuahua (n = 7), rottweiler (n = 5), and Scottish deerhound (n = 3). In all but 1 case (Newfoundland), the dogs were male. The female dog was 4 y of age; the average age of male dogs with a cystine urolith was 4.3 y (median age of 4 y with a range of 6 mo to 10 y). Nine xanthine uroliths were submitted in the period discussed. Four of these (44.4%) were from male Dalmations receiving a xanthine oxidase inhibitor as part of the treatment regime for urate urolithiasis. Of the remaining 5, 2 were from female miniature schnauzers, A B Discussion Struvite uroliths were the most common submission to the CVUC from dogs. Struvite uroliths are the most commonly reported urolith in many studies worldwide (1 8). A strong statistical association in dogs between femalee sex and an increased risk of struvite containing urolithiasis has been demonstrated (1,2,7,8). Most struvite stones in dogs are infection-induced, and female dogs are at the greatest risk for this (1,2,8,9). This is likely due, at least in part, to the anatomy of the female urethra, which is short and wide compared with that of the male (1,2,8,9). Ascending urea-splitting bacteria, such as Staphylococcus spp. (less commonly Proteus spp. and Ureaplasma ), are implicated (2,3,6,9). Urease is an enzyme that, in the presence of water, hydrolyzes urea, a byproduct of amino acid catabolism, producing a high concentration of ammonia and carbonate ions. The ammonia combines with water or the hydrogen ion to produce the ammonium ion. An elevated urinary ph reduces the solubility of magnesium ammonium phosphate and favors precipitation of struvite crystals (9). When a urinary tract infection (UTI) with ureaseproducing microbes occurs in dogs with urine containing a sufficient quantity of urea, hydrolysis of the urea results in hyperammoniuria, even when the ph of the glomerular filtrate and renal tubular fluid is alkaline (1). Struvite uroliths may form in the face of UTIs, even when the animal is on an acidifying diet (1,9). Dogs have been shown to develop struvite uroliths in their lower urinary tracts within 2 wk of the induction of staphylococcal urinary tract infection (10). Althoughh uncommon, the presence of foreign bodies in the bladder can act as a nidus for infection-induced struvite uroliths (11). A small percentage of dogs with struvite urolithiasis have sterile urine. In some of these cases, however, bacteria have been isolated from the nidus of the urolith, indicating that bacterial infection of the urinary tract may undergo spontaneous remission after initiating urolith formation (1). Infection-induced struvite is the most frequent type of urolith encountered in immature dogs (1). Other conditions that promote crystalliza- tion of magnesium ammonium phosphate, such as an alkaline urine, diet, and genetic predisposition, may also be associated with struvite calculogenesis (3). As noted earlier, breeds frequently identified with struvite urolithiasis were the miniature schnauzer, bichon frise, shih tzu, Lhasa apso, and Yorkshire terrier, and previous studies have shown similar tendencies (1,7,8,12). In addition, the Pekingese and cocker spaniel Can Vet J Volume 45, March

4 Figure 2. Lateral X-ray of a dog showing bladder stone with multiple ring-like layers. The presence of calcium carbonate in an infection-induced struvite urolith may hinder medical dissolution of struvite uroliths. Case, with permission, from Dr. Susan Purdy, Sackville Animal Clinic, Sackville, New Brunswick. may be at risk (7). It has been suggested that the miniature schnauzer can have an inherited abnormality of local host defenses of the urinary tract that increases its susceptibility to bacterial urinary tract infections (10,13). Hereditary factors thought to be associated with inbreeding have been reported to increase the frequency of struvite uroliths in beagles (14). Ling et al (2) observed an increased risk of struvite calculi in both sexes of cocker spaniels, springer spaniels, and Labrador retrievers. Bartges et al (15) reported recurrent sterile struvite uroliths in 3 related cocker spaniels. Lower risk of struvite calculi in stone-forming dogs was seen in both sexes of Dalmations, Pomeranians, and Maltese terriers (2). One previous study reported no stones in female Great Danes or bull mastiffs (5) and another study reported that English bulldogs had a relatively high occurrence of ammonium urate and cystine stones, but a relative lack of struvite uroliths (8). In the present study, there were no female Great Danes and only 1 female bull mastiff with struvite bladder uroliths. Most large radiodense stones in dogs are infectioninduced struvite uroliths (1). Urocystoliths 10 mm in any dimension are 92% likely to consist of struvite (8); it is rare for any other type of urolith to be 15 mm (8). Medical dissolution of struvite stones is more difficult in dogs than in cats. The high prevalence of infectioninduced struvite, the prevalence of fine concentric laminations with low porosity, and the occasional occurrence of calcium carbonate (also called calcium apatite carbonate or carbonate apatite) or calcium phosphate in struvite uroliths are factors that explain why dietary dissolution is more difficult (1,2,16) (Figure 2). The calcium components are not amenable to medical dissolution. The formation of calcium phosphate or calcium carbonate in the face of a struvite urolith has been reported previously (1). As the urine becomes progressively more alkaline by microbial hydrolysis of urea and dissociation of monobasic hydrogen phosphate (H 2 P0 4- ), an increased concentration of dibasic hydrogen phosphate (HP0 = 4 ) and anionic phosphate (P ) occurs. The latter is then available in increased quantities to combine with calcium excreted in urine to form calcium apatite. With the microbial hydrolysis of urea, the newly generated molecule of carbon dioxide combines with water to form carbonic acid, which, in turn, dissociates to form HC0 3 and H. In a highly alkaline urine, HC0 3 may lose its proton to become C0 = 3, anions of which may displace anions of P0 3-4 in calcium apatite crystals to form carbonate apatite crystals (1). In order for medical dissolution to be effective, protein is reduced in the calculolytic diet and, consequently, a common finding is that urea and albumin are reduced in the serum of dogs fed this diet (17). The diet is also restricted in phosphorus and magnesium and has additional salt (to induce thirst and promote compensatory polyuria). An increase in serum hepatic alkaline phosphatase activity has also been reported in dogs eating a calculolytic diet (17). Concomitantly, hydropic degeneration of hepatocytes indicated that these biochemical and morphological changes were associated with dietary protein restriction (17). Currently, diets for dissolving struvite uroliths in dogs are high in fat and salt; care must be taken in feeding such diets to dogs with a tendency towards obesity, pancreatitis, hyperlipidemia, or salt-intolerant conditions, such as heart and kidney disease. The canine calculolytic diet is not recommended for immature dogs for more than a few weeks and, if used, body weight, serum albumin concentration, and packed cell volume should be monitored for evidence of protein or calorie malnutritionn (1,16,17). Because bacteria can be trapped within the matrix of a urolith, appropriate antimicrobial treatment must be administered throughout the entire dissolution treatment of struvite uroliths and for 1 mo beyond radiographic dissolution (1). Bacteria are commonly reported in urine of dogs consuming the calculolytic diet and receiving antibiotics. The presumption is that the bacteria are being released from the inner portions of dissolving infection-induced uroliths (1). On average, it takes approximately 14 wk (range of 8 to 20 wk) to dissolve infection-induced struvite uroliths (17); a shorter period of time (3 wk) is reported for sterile struvite uroliths (range of 2 to 4 wk) (1,17,18). Surgical removal may be the most prudent method of stone removal when alll aspects of the specific case are reviewed. If a cystotomy is performed, a piece of bladder mucosa should be submitted for culture and sensitivity testing, as this is a more sensitive procedure than culturing the urine (19). Alternative methods of removal, including voiding hydropulsion, catheter-assisted retrieval, and retrogradee hydropulsion, have been described (20,21). Oxalate uroliths were the second most common urolith reported in this study. Males appeared to be at increased risk compared with females. Dogs with oxalate uroliths tended to be older compared with dogs with struvite uroliths. These age and sex predispositions are similar to what has been reported in other studies (2,5,7,22,23). The breeds identified with an increased frequency for oxalate are similar to those in previous reports (2,5,7,22 24). One study reported that miniature schnauzers had a calcium oxalate urolith frequency 11.8 times greater than did other breeds and that males were at 3 times greater risk than females of developing oxalate uroliths, with the average age being 9 y (24). In another report, male 228 Can Vet J Volume 45, March 2004

5 Dalmations, Labrador retrievers, English bulldogs, cocker spaniels, and golden retrievers had a low prevalence of calculi containing oxalate (5). Although a genetic basis has not been established as a cause of calcium oxalate formation in dogs, differences in mineral metabolism and urine composition may provide an explanation for the increased development of calcium oxalate urolithiasis in certain breeds of dogs. For example, miniature schnauzers urinated significantly less often than Labrador retrievers and also had a lower urine volume (ml/kg BW/d), a significantly higher urine ph, and significantly higher urinary calcium concentrations than Labrador retrievers (25,26). Unlike the situation with struvite uroliths, infection does not appear to be a contributor to oxalate stone formation. Although oxalate crystals can form at any urinary ph, most dogs had urine phs 6.5 at the time of urolith diagnosis. Reported risk factors for canine calcium oxalate urolithiasis may include excess dietary intake of calcium, vitamin D, or vitamin C; disorders contributing to hypercalcemia, such as lymphoma, primary hyperparathyroidism, and defective nephrocalcin; and diets containing high quantities of oxalic acid derivatives (spinach, wheat germ, sweet potatoes, chocolate, nuts) (23,27). As dietary dissolution is not possible for oxalate uroliths, voiding hydropulsion or surgical removal is indicated (20,21). Postsurgical recurrence rates are high, and it is important to open the bladder fully and retrieve all uroliths, and to obtain a radiograph postoperatively to ensure that all uroliths have been removed (27,28). The third most common canine urolith submitted to the CVUC was ammonium urate. The Dalmation is a high-risk breed with homozygosity for a recessive gene that results in defective urate metabolism. Less commonly affected breeds include the English bulldog, miniature schnauzer, shih tzu, and Yorkshire terrier (29 31). Young to mid-age dogs tend to be affected (8). Younger animals with portosystemic vascular shunts are at risk. In a study of 275 Dalmations, the majority (95%) of uroliths were from males (31). In other studies, females were affected with urate urolithiasis more often than males (2,5). In the latter studies, the females were significantly older than were the males. These findings were not documented in the current study. Calcium phosphate uroliths have been reported in a number of breeds, including those at risk for calcium oxalate (Yorkshire terrier, miniature schnauzer, cocker spaniel, shi tzu, bichon frise, and miniature poodle) (32). Silica uroliths are very uncommon, but they have beeen reported in a number of breeds, including the German shepherd and Old English sheepdog (2,33). Our study did not support this finding. As in previous studies, most dogs with silica uroliths were male (2,33). Diets high in cereal grains containing silicates (corn gluten and soybean hulls) have been implicated (33). Cystinuria is an inborn error of metabolism. Breeds reported to be affected include the English bulldog, Newfoundland, dachshund, mastiff, bullmastiff, Australian cattle dog, Scottish deerhound, and others (34 37). Most are young (2 to 5 y) and male, except for the Newfoundland dog in which females appear to be at greater risk (37). In our study, male Newfoundlands with cystine uroliths outnumbered females 8:1. Xanthine uroliths are reported most often following the administration of a xanthine oxidase inhibitor in the management of urate uroliths. Naturally occurring xan- thinuria has been reported in Cavalier King Charles spaniels and in dachshunds (2,38 41). The etiology is thought to be an inborn error of purine metabolism and is more common in males (2,38 41). In the current study, numbers of cases were low and no breed associations (outside of Dalmatians receiving a xanthine oxidase inhibitor) were made. Discussing risk factors for urolith formation with owners of over-represented breeds, monitoring urine, and radiographing on a regular basis (every 2 to 3 mo) may help in early identification, treatment, and prevention of uroliths. Urine should be obtained and ph and sediment recorded and examined within 15 to 60 min of collection. Urinary crystals (both struvite and oxalate) can form in vitro if urine is refrigerated or allowed to sit for prolonged periods. Urine samples should be analyzed within 60 min of collection to minimize temperature- and timedependent effects on in-vitro crystal formation. Presence of crystals observed in stored samples should be validated by reevaluation of fresh urine (42). It is usually recommended that radiographs be taken every 3 to 6 mo in repeat urolith formers (27). 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J Vet Int Med 2001;15: Case LC, Ling GV, Franti CE, Ruby AL, Stevens F, Johnson DL. Cystine-containing urinary calculi in dogs: 102 cases ( ). J Am Vet Med Assoc 1992;201: Bartges JW, Osborne CA, Lulich JP, et al. Prevalence of cystine and urate uroliths in bulldogs and urate uroliths in Dalmations. J Am Vet Med Assoc 1994;204: Casal ML, Giger U, Bovee KC, Patterson DF. Inheritance of cystinuria and renal defect in Newfoundlands. J Am Vet Med Assoc 1995;207: Bartges JW, Osborne CA, Felice LJ. Canine xanthine uroliths: risk factor management. In: Kirk RW, Bonagura JD, eds. Current Veterinary Therapy XI. Philadelphia: WB Saunders 1992: Ling GV, Ruby AL, Harrold DR, Johnson DL. Xanthine-containing urinary calculi in dogs given allopurinol. J Am Vet Med Assoc 1991;198: Van Zuilen CD, Nickel RF, Van Dijk Th, Reijngould DJ. Xanthinuria in a family of Cavalier King Charles spaniels. Vet Q 1997;19: Kucera J, Bulkova T, Rychla R, Jahn P. Bilateral xanthine nephrolithiasis in a dog. J Small Anim Pract 1997;38: Albasan H, Lulich JP, Osborne CA, Lekcharoensuk C, Ulrich LK, Carpenter KA. Effects of storage time and temperature on ph, specific gravity, and crystal formation in urine samples from dogs and cats. J Am Vet Med Assoc 2003;222: Can Vet J Volume 45, March 2004