Evaluation of the Efficacy of a Commercial Diet in the Dissolution of Feline Struvite Bladder Uroliths*

Evaluation of the Efficacy of a Commercial Diet in the Dissolution of Feline Struvite Bladder Uroliths* Doreen M. Houston, DVM, DVSc Nancy E. Rinkardt, DVM, DVSc John Hilton, PhD Veterinary Medical Diets 67 Watson Road South Guelph, Ontario Canada N1H 6H8 CLINICAL RELEVANCE Clinical signs of struvite urolithiasis resolved in an average of 19 days in cats fed either a canned or dry urine-acidifying, magnesium-restricted diet, and stones completely dissolved in 31 of 39 cats in an average of 30 days. Stones were surgically removed from five cats, and analysis revealed that these stones were not composed of struvite. The results of this study strongly suggest that the diet will dissolve naturally occurring feline struvite bladder uroliths. INTRODUCTION The prevalence of feline lower urinary tract disease (FLUTD), irrespective of cause, has been reported to be 1.5% to 8%. 1,2 The majority of these cases (>60%) occurred in cats younger than 10 years of age and were identified as idiopathic cystitis. 2,3 An estimated 10% to 20% of cats with FLUTD have urolithiasis or urethral plugs; struvite and calcium oxalate (CaOx) are found in more than 80% of these patients. 2 6 In one study, struvite uroliths were the most common mineral type in domestic shorthair (DSH) and domestic longhair (DLH) cats, with females outnumbering males in struvite urolith submissions. In addition, more than 80% of urethral plugs from male cats contain struvite crystals. 4 For struvite *This study was sponsored by Veterinary Medical Diets, Guelph, Ontario, Canada. uroliths to form, urine must be oversaturated with magnesium, ammonium, and phosphate ions and the urine ph, on average, must be above 6.5. In cats, sterile struvite uroliths occur more commonly than infection-induced struvite uroliths. 7 Historically, surgical removal of struvite uroliths was the only reliable method of treatment. Currently, nonsurgical removal of bladder uroliths in cats via voiding urohydropulsion 8 or dietary dissolution 9 is possible. To the authors knowledge, medical dissolution of naturally occurring feline struvite bladder uroliths has only been reported using a canned, magnesium-restricted, urine-acidifying diet. 9 It has been suggested that cats with struvite urolithiasis should be fed only canned food, as water intake is critical to dissolution and prevention of urolithiasis. 10 Not all cats will eat 187

Veterinary Therapeutics Vol. 5, No. 3, Fall 2004 TABLE 1. Nutrient Composition a of Diet A (Canned) and Diet B (Dry) Diet A Diet B Nutrient (%) (canned) (dry) Moisture 81.3 6.60 Protein 46.52 37.01 Lipid 25.13 19.30 Ash 10.69 6.55 Fiber 2.0 1.61 Carbohydrate (NFE) 17.65 32.10 Protein calories 36.2 30.20 Calcium 1.08 0.97 Phosphorus 1.06 0.97 Magnesium 0.07 0.09 Sodium 1.27 0.37 Potassium 1.0 1.21 Kcal/cup or can 144 397 a Dry matter basis except for moisture content and kcal/cup or can, which are on an as-fed basis. NFE = nitrogen-free extract. currently available canned calculolytic diets, and some cats will not eat canned food of any kind. The purpose of the study reported here was to evaluate the efficacy of a canned a and a dry calculolytic diet (Medi-Cal Dissolution Formula, Veterinary Medical Diets, Guelph, Ontario, Canada) in dissolving naturally occurring struvite bladder uroliths in cats. The influence of the diet on body weight, blood chemistry, and urine parameters (ph and specific gravity) was also evaluated. MATERIALS AND METHODS Treatment Diets Nutritional characteristics of the diets are presented in Table 1 and the diet ingredients in the boxes on page 189. The nutrient composition was determined on a single production batch for the canned and dry diets. The nutrient analysis was conducted by Silliker Canada (Markham, Ontario). All analyses a Available in the United States through Innovative Veterinary Diets. were performed following the Standard Methods of Analysis, Association of Official Analytical Chemists (AOAC, 2000). The energy content was determined directly from a digestibility trial on the same production lot, using the total feces collection method as recommended by the Association of American Feed Control Officials (AAFCO) and conducted by Ontario Nutri Lab (Fergus, Ontario). The canned product was produced on Sept. 12, 2000, by Menu Foods (Mississauga, Ontario), and the dry diet was produced on Oct. 27, 2001, by Del Monte Foods (Elmira, Ontario). Diet A was designed to be meal-fed and promote formation of acidic urine (ph 5.85 to 6.05) with a peak 4-hour postprandial urine ph of 6.45 in meal-fed cats. It contained 14 to 16 mg/100 kcal of magnesium. Diet A was formulated as a chunk with a high-moisture gravy. Diet B was designed to promote formation of acidic urine (ph 5.64 to 6.24) with a peak 4-hour postprandial urine ph of 6.2. The diet contained 14 to 16 mg/100 kcal of magnesium as previously recommended for struvite dissolution and prevention type diets. 5,9,10 Each attending veterinarian was made aware of the characteristics of the diet being fed. Recommendations were made to feed the diets in sufficient quantity (approximately 70 kcal/kg body weight/day) to maintain current body weight. Feeding guidelines based on body weight were provided, and body weight was assessed every 2 weeks. The diet was fed for a maximum of 12 weeks; if the urolith(s) had not dissolved by this time, the case was classified as a treatment failure. Before the study was performed, both the canned and dry diets passed the AAFCO maintenance feeding trials at an approved research facility (DLM Pet Products Research and Development, Terminal Island, CA). This preliminary testing assured maintenance of 188

Ingredient Panel for Diet A Water Sufficient For Processing, Beef, Chicken, Meat By-Products, Chicken Liver, Salmon, Starch, Wheat Gluten, Guar Gum, Minerals (Calcium Sulphate, Salt, Sodium Acid Pyrophosphate, Sodium Bisulphate, Ferrous Sulphate, Iron Bioplex, Zinc Oxide, Zinc Bioplex, Manganous Oxide, Copper Sulphate, Copper Bioplex, Calcium Iodate and Organic Selenium), Caramel, Fructo- Oligosaccharides, Carrageenan, Taurine, Vitamins (Vitamin E, Vitamin C, Thiamine Mononitrate, Niacin, Inositol, Beta-Carotene, Vitamin A, Biotin, D-Calcium Pantothenate, Riboflavin, Pyridoxine Hydrochloride, Vitamin D 3, Folic Acid, Vitamin B 12 and Menadione Sodium Bisulfite Complex), L- Carnitine and L-Glutamine body condition, normal blood gas status (acid base balance), and laboratory parameters (hemoglobin, packed cell volume, serum alkaline phosphatase [ALP], serum albumin, and whole blood taurine within the allowance for normal variation according to AAFCO standards) in healthy cats fed the diets for 26 weeks. In separate trials, both the canned and the dry diets were fed to 20 healthy cats (10 fed canned and 10 fed dry) for 2 weeks; at the end of the study, urine was collected and tested for relative supersaturation (RSS) by the University of Tennessee College of Veterinary Medicine (Knoxville, TN). RSS is determined by measuring urine concentrations of several analytes, including sodium, calcium, oxalate, and magnesium. These values were entered into a computer program (EQUIL 89d, Department of Molecular Biology and Biochemistry, College of Medicine, University of Florida, Gainesville, FL). An RSS of less than 1 indicates that the diet should both dissolve and help prevent the formation of struvite crystals and/or stones. 11,12 Ingredient Panel for Diet B Corn Gluten Meal, Brewers Rice, Chicken Meal, Chicken Fat (Preserved with Mixed Tocopherols, Rosemary Extract, Citric Acid and Lecithin), Corn, Dried Whole Egg, Liver Digest, Gravy Mix, Cranberry Meal, Herring Oil, Beet Pulp, Brewers Yeast, Flax Meal, Minerals (Potassium Chloride, Calcium Sulphate, Phosphoric Acid, Zinc Oxide, Zinc Bioplex, Ferrous Sulphate, Iron Bioplex, Manganous Oxide, Copper Sulphate, Copper Bioplex, Calcium Iodate and Organic Selenium), DL-Methionine, Fructo- Oligosaccharides, Taurine, Vitamins (Choline Chloride, Vitamin E, Niacin, Inositol, Vitamin C, Thiamine Mononitrate, D- Calcium Pantothenate, Riboflavin, Pyridoxine Hydrochloride, Beta-Carotene, Vitamin A, Folic Acid, Menadione Sodium Bisulfite Complex, Biotin, Vitamin B 12 and Vitamin D 3 ), L-Carnitine and L-Glutamine Both the canned and the dry diets had RSS values less than 1. Selection of Cases All the cats in this prospective study were client owned, and owners gave their informed consent for their cats to be included in the study. None of the cats included were being fed a diet designed to dissolve struvite bladder uroliths. The cats were housed in their home environments for the duration of the study. All veterinary clinics in Canada were invited to participate, and 35 accepted. Based on a previous study in which struvite uroliths dissolved in approximately 5 to 6 weeks and assuming a power of 0.8, a minimum of 10 to 12 cats were needed for each diet trial. 9,13 The authors elected to include 15 cases of struvite uroliths for each of the two diet trials. Sixteen cats were originally entered in the canned trial (15 of 189

Veterinary Therapeutics Vol. 5, No. 3, Fall 2004 which were ultimately defined as struvite cases) and 23 in the dry food trial (17 of which were ultimately defined as struvite cases). Inclusion of cases ended when 15 in each trial showed total dissolution of the urolith(s). Extra cases were originally included in both studies to account for owner compliance issues, food refusal, and diet failure (uroliths that failed to dissolve within 12 weeks on the diet). The canned diet was ready for clinical trial before the dry diet was. Consequently, the canned diet (diet A) trial was initiated in January to October 2001 and the dry diet (diet B) trial from January to October 2002. The cats did not have a choice of diet fed. Guelph, Laboratory Services Division, Guelph, Ontario) confirmed that the stones were composed of 100% magnesium ammonium phosphate before these three cats were entered in the study. In all other cases, a high index of suspicion for struvite urolithiasis was based on radiographic confirmation of radiodense bladder stone(s), average urine ph values of 6.5 or higher, and either detectable struvite crystalluria or no crystalluria. Cats with a urine ph below 6.5 but with other evidence of struvite urolithiasis were also included. No control group was used in this study. Based on results of historical information, physical examination, complete blood cell Cats were selected on the basis of clinical signs of FLUTD, positive radiographic findings, and supportive urinalysis results. Cats were selected on the basis of clinical signs of FLUTD (hematuria, inappropriate urination, stranguria, dysuria), positive radiographic findings (radiodense bladder uroliths), and supportive urinalysis results. Male cats with urethral plugs and cats with crystalluria but no stones were not included. Because of the sodium content of the canned diet and the acidifying nature of both diets, cats younger than 1 year of age and cats with significant cardiac, renal, thyroid, or hypertensive disorders were not included. Cats with hypercalcemia may have had CaOx urolithiasis and were excluded. Pregnant and lactating cats were also excluded. In three cats (one male cat with a perineal urethrostomy and two female cats), multiple small stones were visible on radiographs of the bladder and urethra. Some of these stones were collected by voiding hydropulsion or passed in urine; quantitative analysis at the Canadian Veterinary Urolith Centre (University of count (CBC; performed in-house), and serum biochemical analysis (total protein, albumin, ALP, alanine transaminase [ALT], urea, creatinine, sodium, potassium, chloride, calcium, and phosphorus; performed at a commercial veterinary laboratory), all of the cats were considered to be healthy, other than the presence of FLUTD. Samples for biochemical analysis from cats on the canned diet were submitted to Vita-Tech Veterinary Laboratory Services (Markham, Ontario), as were samples from 12 of the 15 cats on the dry diet; samples from the remaining three cats were submitted to Central Veterinary Pathology Lab (Edmonton, Alberta, Canada) for biochemical analysis. Samples submitted to Vita-Tech were analyzed by use of reagent kits and an automated biochemical analyzer (Hitachi 917 System, Roche Diagnostics, Boul Armande-Frappier, Lavelle, Quebec, Canada). Samples submitted to Central Veterinary Pathology Lab were analyzed by use of 190

reagent kits and a chemistry analyzer (Dade Dimension XL, Dade Dehring, Deerfield, IL). Successful dissolution of the urolith(s) within 12 weeks of feeding the diet was classified as treatment success. Failure of the urolith to dissolve within 12 weeks of feeding the diet was classified as a treatment failure, and surgical removal and quantitative analysis of the urolith(s) were performed. Antimicrobials Cats with confirmed or suspected urinary tract infections were given antibiotics at the discretion of the attending veterinarians. Because bacteria may remain viable within the nidus of the urolith, antibiotic treatment, if initiated, was recommended to continue until 1 month beyond radiographic evidence of urolith dissolution. 14 Case Evaluation and Follow-Up Recommendations were made to evaluate the cats every 2 weeks after the initial evaluation until 4 weeks after urolith dissolution; evaluation consisted of a clinical history and physical examination, including body weight, urinalysis, radiography, and blood chemistries. Serum was obtained by centrifugation of whole blood and analyzed for concentrations of total protein, albumin, ALP, ALT, urea, creatinine, sodium, potassium, chloride, calcium, and phosphorus. A complete urinalysis was conducted on samples obtained by cystocentesis or free flow. It was recommended that urine ph be determined immediately upon urine collection. Urinary ph was determined using a ph electrode where available (cases 4A, 4B, and 6B); otherwise urine ph was measured by indicator strips (colorimetric dyes). Urine samples for ph determination were obtained at different times of the day, regardless of time of feeding. It was recommended that urine be examined immediately upon collection. Routine urinalysis was performed in-clinic, and no measures other than refrigeration (for urine cultures) were used to preserve the sample. For urine culture, bacterial colony counts greater than 1,000/ml were interpreted as evidence of urinary tract infection. Culture and sensitivity testing of urine samples were performed by either Vita-Tech Veterinary Laboratory Services or Central Veterinary Pathology Lab. Cats confirmed to have urinary tract infections were to be retested at the next recheck (2 weeks later). Uroliths were not classified as being infection induced or sterile, and bacteria were not tested for the presence of urease. Survey abdominal radiography (lateral and ventrodorsal projections) was performed in all cases. Radiographs were interpreted by the attending veterinarians and by two of the authors. In two cases in which urolith dissolution was unclear, a board-certified radiologist reviewed the radiographs. Resolution of clinical signs was determined by the attending clinician upon consultation with the owner during the recheck. Statistical Analysis Measurements were categorized as pretreatment (before diet initiation) and posttreatment (after 4 to 6 weeks on the diet). The differences in categorical variables (sex, breed, presence of crystals) were compared using contingency tables with chi-square test when appropriate. Differences in continuous variables (e.g., age, biochemical analytes) between the groups at the beginning of the trial were compared using a t test. The effect of diet on body weight and clinical chemistry before and after treatment was tested using a split-plot analysis of variance (ANOVA), with cat, diet, and period of time as factors. 15 In cats with struvite uroliths, the effect of diet on urine specific gravity and urine ph was examined using a split-plot ANOVA, with cat, diet, and week (i.e., weeks 0, 2, 4, and 6) as factors. 15 In cats with struvite uroliths, the effect 191

Veterinary Therapeutics Vol. 5, No. 3, Fall 2004 TABLE 2. Signalment and Weight of 16 Cats on Diet Trial A Case Age (yr) Sex Breed Weight (kg) 1 9 SF DSH 7.25 2 3 SF DSH 5.8 3 3 CM DSH 3.95 4 2 CM DSH 7.5 5 8 CM DSH 4.9 6 3 CM DLH 6.5 7 6 SF DSH 8.8 8 13 SF DSH 5.1 9 8 CM DSH 6.6 10 10 SF DSH 5.5 11 4 SF DLH 4.9 12 1.25 CM DSH 5.5 13 6 CM DSH 3.7 14 10 SF DSH 5.45 15 13 CM DSH 6 16 10 SF DSH 4.2 Average 6.83 ± 3.84 5.73 ± 1.36 CM = castrated male; DLH = domestic longhair; DSH = domestic shorthair; SF = spayed female. of diet, sex, number of uroliths, and presence of crystalluria on the time to urolith dissolution and resolution of clinical signs was assessed using Kaplan-Meier survival analysis. 16 The clinical chemistry data were categorized as normal or outside the normal reference range. The differences in pre- and posttreatment data were then compared using a contingency table with a Fisher s exact test. 17 When values outside the normal reference range occurred at only one time point, a binomial probability model was constructed to assess for significance. Differences were considered significant when P <.05. RESULTS A total of 39 cats were entered in the two diet trials 16 cats consumed the canned diet, and 23 consumed the dry diet. Signalment and weight information of the study cats are summarized in Tables 2 (diet A) and 3 (diet B). Bladder uroliths dissolved completely in 31 of 39 (79%) cases; these cases are considered to have been struvite uroliths and are classified as responders. In one case (13B; a 1-year-old spayed female DSH), multiple stones dissolved by week 6; however, one last stone did not dissolve by week 12 and was voided. Stone analysis revealed a mineral composition of 90% struvite and 10% CaOx monohydrate. This case was included in the study but not in the analysis of resolution of clinical signs. Two cases (1B and 20B) were dropped from the trial because of food refusal and owner noncompliance and are not included in any analysis. Urolith(s) did not dissolve in five cases (11A, 5B, 6B, 19B, and 22B), and these stones were surgically removed and analyzed at the Canadian Veterinary Urolith Centre (Table 4). Of the 37 cats eating the dissolution diet, there were no significant differences in age, weight, breed, or sex between the two groups. The mean age of all cats was 5.89 ± 3.89 years (range: 1 13 years), and the average weight of all cats was 5.50 ± 1.31 kg (range: 2.8 8.8 kg); there were 13 castrated males and 24 spayed females. The breeds included DSH (26 of 37 cats), DLH (eight of 192

TABLE 3. Signalment and Weight of 23 Cats on Diet Trial B Case Age (yr) Sex Breed Weight (kg) 1 4.5 SF DSH 4.1 2 6 SF DMH 4.4 3 5 CM DSH 6 4 6 SF DLH 4 5 3 SF Siamese mix 2.8 6 13 CM DSH 4.8 7 2 SF DSH 5.5 8 1.5 SF DMH 3.8 9 8 SF DSH 8.36 10 2 SF DLH 4 11 4 SF DSH 7 12 6 SF DSH 5.5 13 1 SF DSH 5.3 14 7 SF DSH 6.6 15 4 SF DSH 6.14 16 1 SF DLH 3.9 17 11 SF DSH 5.43 18 1 CM DLH 6.2 19 5 CM DSH 4.65 20 3 SF DLH 4.9 21 8 SF DLH 5.3 22 7 CM DLH 6.1 23 7 SF DSH 6 Average 5.04 ± 3.17 5.25 ± 1.24 CM = castrated male; DLH = domestic longhair; DMH = domestic medium-hair; DSH = domestic shorthair; SF = spayed female. TABLE 4. Cases of Surgically Removed Urolith(s) Case Age (yr) Sex Breed Urolith Analysis 11A 4 SF DLH 100% Ammonium acid urate 5B 3 SF Siamese mix 100% Ammonium acid urate 6B 13 CM DSH Calcified tissue 19B 5 CM DSH Calcium oxalate monohydrate (stone 50%, shell 100%, surface 30%) and calcium oxalate dihydrate (stone 50%, surface 70%) 22B 7 CM DLH Calcium oxalate monohydrate (nidus 50%, shell 100%) and ammonium acid urate (nidus 50%, stone 100%, surface 100%) CM = castrated male; DLH = domestic longhair; DSH = domestic shorthair; SF = spayed female. 193

Veterinary Therapeutics Vol. 5, No. 3, Fall 2004 37), domestic medium-hair (DMH; two of 37), and Siamese mix (one of 37). For the 32 cats with struvite urolithiasis, the mean age was 5.80 ± 3.59 years (range: 1 13 years), and the mean body weight was 5.63 ± 1.30 kg (range: 3.7 8.8 kg). The struvite cats entered in diet trial A tended to be older (mean age: 7.02 ± 3.90 years; range: 1.25 13 years), but the difference was not statistically significant (P =.07). The mean age of struvite cats in diet trial B was 4.74 ± 3.00 years (range: 1 11 years). There was no significant difference in body weight between the two groups of cats (P =.54). The breeds of cats with struvite urolithiasis were DSH (n = 24), DMH (n = 2), and DLH (n = 6). There was a significant (P =.04) difference between the number of DSHs in the diet A group (14 of 15) versus diet group an, included hematuria (24 of 37 cats), inappropriate urination (11 of 37), stranguria (seven of 37), dysuria (two of 37), urinary obstruction (three of 37; uroliths submitted for analysis), and a urine odor described as sweet (one of 37). Physical examination revealed no significant abnormalities other than palpable bladder urolith(s) in three cats. The number of bladder uroliths visible on initial radiographs, presence of struvite crystalluria, and time to dissolution of uroliths in cases with struvite urolithiasis are presented in Table 5. Initial evaluation of urine revealed the presence of struvite crystalluria in 18 of 32 (56%) cats with struvite urolithiasis; 14 of 32 (44%) cats did not shed struvite crystals. In the cats that had urolith(s) surgically removed, two (5B and 6B) of five had struvite crystals in the The average time to urolith dissolution for both groups was 4.28 weeks. B (10 of 17). Of the cats with struvite urolithiasis, there were 10 castrated males and 22 spayed females. There was a significant (P =.02) difference between the number of spayed female cats in diet group B (15 of 17, or 88%) versus diet group A (seven of 15, or 47%). Complete diet history was available for 21 of 39 cats in the trial and 18 of 32 cats with struvite urolithiasis. Diets were primarily commercial canned and dry formulations. No cat was eating a diet designed to dissolve struvite uroliths at the time of admission to the study. Approximately 50% of the cats were eating strictly dry commercial cat foods; the remaining cats were fed predominately dry food with some canned food provided either daily or weekly. No specific information on the amounts of dry or canned food consumed was obtained. At the time of presentation, clinical signs, as described by the owner or referring veterinari- initial urinalysis and three of five (11A, 19B, and 22B) did not shed any crystals. No cats had other crystal types identified in the initial urinalysis. The presence of crystalluria was not associated with the presence of struvite urolithiasis, nor was the presence of struvite crystalluria associated with the number of struvite uroliths. In the cats with struvite urolithiasis, six of 15 cats in diet group A had no radiographic evidence of uroliths (i.e., uroliths had dissolved) at the 2-week recheck, five of 15 had no radiographic evidence of uroliths at the 4-week recheck, and four of 15 had no radiographic evidence of uroliths at the 6-week recheck. In diet group B, four of 17 cats had no radiographic evidence of uroliths at the 2-week recheck, two of 17 had no radiographic evidence of uroliths at the 4-week recheck, 10 of 17 had no radiographic evidence of uroliths at the 6-week recheck, and one of 17 had no ra- 194

TABLE 5. Number of Bladder Uroliths, Time to Dissolution, and Presence of Struvite Crystalluria in Cats with Struvite Urolithiasis Case Number of Uroliths Time to Dissolution (wk) Crystalluria? Diet A 1 1 4 No 2 2 4 Yes 3 1 6 Yes 4 1 4 Yes 5 1 2 No 6 1 2 No 7 1 4 Yes 8 1 6 No 9 2 2 Yes 10 Multiple 4 No 12 3 6 No 13 4 2 Yes 14 1 6 Yes 15 Multiple 2 No 16 Multiple 2 Yes Average time to dissolution 3.73 Diet B 2 1 4 No 3 Multiple 6 Yes 4 Multiple 8 Yes 7 1 6 No 8 Multiple 4 No 9 Multiple 2 No 10 2 2 Yes 11 1 6 No 12 1 + sediment 4 Yes 13 Multiple 6 Yes 14 Multiple 6 No 15 Multiple 6 Yes 16 1 2 Yes 17 1 6 Yes 18 1 2 No 21 Multiple 6 Yes 23 Multiple 6 Yes Average time to dissolution 4.82 diographic evidence of uroliths at the 8-week recheck. The average time to dissolution for both groups was 4.28 weeks (30 days). The average time to dissolution was 3.73 weeks (26 days) in the cats in diet group A and 4.82 weeks (34 days) in the cats in diet group B. The time to dissolution tended to be longer in diet group B, but this difference was not statistically significant (P =.066). The time to dissolution tended to be more rapid in males than females, but this difference was also not statistically significant. The time to dissolution did 195

Veterinary Therapeutics Vol. 5, No. 3, Fall 2004 TABLE 6. Mean (±SD) Urine Specific Gravity (USG) and Urine ph a Pretreatment Posttreatment Diet USG ph USG ph A 1.041 ± 0.01 6.82 ± 0.65 1.037 ± 0.008 6.45 ± 0.58 B 1.039 ± 0.011 7.12 ± 0.72 1.052 ± 0.005 6.07 ± 0.26 a Assessed at 2-wk intervals and for 1 mo beyond urolith dissolution (while the cats were eating the diet). not differ significantly with the number of struvite uroliths (P =.98). Of cats with struvite urolithiasis in diet group A, clinical signs resolved at the 2-week recheck in 11 of 15 cats and at the 4-week recheck in four of 15 cats. Of cats with struvite urolithiasis in diet group B (excluding cat 13B, which passed the last stone at 12 weeks), clinical signs resolved at the 2-week recheck in nine of 16 cats, at the 4-week recheck in six of 16 cats, and at the 6-week recheck in one of 16 cats. In one of these cats (18B), the urolith was apparently dissolved at the 2-week recheck but clinical signs were not resolved until the 4- week recheck. The average time to resolution of clinical signs for both groups was 2.77 weeks (19 days). The average time to resolution of clinical signs was 2.5 weeks (18 days) in diet group A and 3 weeks (21 days) in diet group B. There was no statistically significant difference between the groups (P =.24), nor was the time to resolution of clinical signs associated with the number of struvite uroliths (one versus more than one; P =.46). There was no difference in the time to resolution of clinical signs between the sexes (P =.94). Pre- and posttreatment body weights did not differ between the cats in diet groups A and B (P >.36). There was a decrease in body weight (P <.05) between the pre- and posttreatment period in cats consuming diet A. With respect to urine specific gravity, cats with struvite urolithiasis in diet group A had a significantly higher urine specific gravity than cats in diet group B before treatment. Urine specific gravity decreased significantly in cats in diet group A after treatment and increased significantly in cats in diet group B after treatment (Table 6). With respect to urine ph, cats with struvite urolithiasis in diet group A tended to have a lower urine ph compared with cats in diet group B (P <.05). Urine ph decreased significantly after treatment in both diet groups, with a greater decline in diet group B (P <.001) than diet group A (P <.02) (Table 6). Chemistry values that were found to be abnormal before treatment were rechecked and subsequently found to be within normal limits in all but one cat (13A) in which both pre- and posttreatment calcium levels were mildly elevated. Calcium was the only value that approached significance (P =.055) in the Fisher s exact test for change in pre- versus posttreatment values, with the posttreatment value increased (Table 7). Potassium was significantly decreased in three cats in diet group B after treatment (P <.04) using binomial probability (Table 7). Urine culture was performed in 35 cats. Culture results were positive in 10 of 35 (29%) cats and negative in 25 of 35 (71%). Of the 10 positive urine samples, three samples were collected by cystocentesis and seven as midstream free-flow samples. Most bacteria cultured were Escherichia coli (55.6%) or Enterococcus spp (43%). Twenty-two of 35 cats (63%) were treated with antibiotics; 13 of 35 (37%) never 196

TABLE 7. Mean (±SD) Pretreatment and Posttreatment Serum Calcium and Potassium Levels in 37 Cats Consuming Diets A and B Parameter Diet A Diet B (reference range) Pretreatment Posttreatment Pretreatment Posttreatment Calcium (2 2.6 mmol/l) 2.44 (±0.10) 2.49 (±0.12) 2.43 (±0.10) 2.44 (±0.08) Potassium (4 5.8 mmol/l) 4.79 (±0.29) 4.75 (±0.31) 4.70 (±0.50) 4.50 (±0.48) received antibiotics. Of the 22 cats treated with antibiotics, 10 (45%) received the antibiotics before week 0 (they either received antibiotics before culture results were available or were on antibiotics at the time of culture). Fifteen (68%) of the 22 cats treated with antibiotics received a fluoroquinolone (enrofloxacin or orbifloxacin), and the rest received amoxicillin, amoxicillin clavulanic acid, or a first-generation cephalosporin. Four of the 22 cats were treated with more than one class of antibiotic. DISCUSSION Survey radiographic evidence of dissolution of radiodense bladder uroliths in the cats fed either a canned or dry calculolytic diet is evidence that the mineral composition of the uroliths was struvite. The failure of seven cats to complete the study was primarily due to cat and/or owner compliance issues or to the presence of other minerals within the uroliths (ammonium acid urate and/or CaOx mono- or dihydrate). Struvite bladder uroliths are most often reported in young to middle-aged DSH cats and 1- to 7-year-old DLH cats. 2 6 Previous studies have also reported a predominance of struvite in female cats. 2 6 In the current study, the majority of cats with struvite urolithiasis were DSH and female, with an average age of 5.8 years (range: 1 13 years), which is in agreement with previous studies. The presumptive diagnosis of struvite urolithiasis in cats is usually based on clinical signs, supportive urinalysis results, and radiography. The ability to palpate bladder uroliths was uncommon, as previously reported, and should not be relied on for diagnosis. 9 Supportive urinalysis results previously reported may include a urine ph higher than 6.5, evidence of struvite crystalluria, and the absence of other crystal types. 7,9 In the current study, the average urine ph of cats with struvite urolithiasis was 6.97, although five of 32 cats presented with a urine ph of 6. Assumption of struvite urolithiasis in these five cases was based on the presence of struvite crystals in one cat and stone size (diameters of 2 and 0.6 cm) in two cats. The remaining two cats were entered on the basis of clinical signs and presence of radiographically dense uroliths. Although struvite crystals tend to form at a higher urine ph, they may form at a lower urine ph if there are also increased concentrations of magnesium, ammonium, and phosphate. 18 In dogs, large stone size (>1 cm) indicates a high probability of struvite urolithiasis. 19 To the authors knowledge, this finding has not been reported in cats; however, CaOx uroliths tend to be smaller than struvite uroliths. 7 There are several explanations as to why cats with struvite urolithiasis present with a urine ph of 6. First, urine ph detected by dipstick methodology is not accurate and can be up to 0.9 points off in either direction. 18,20 22 Therefore, the observed ph of 6 may have been falsely decreased. Second, if the urine samples were collected while the cat was fasting, it is possible that a lower urine ph would be seen. 197

Veterinary Therapeutics Vol. 5, No. 3, Fall 2004 As mentioned previously, one criterion for a tentative diagnosis of struvite urolithiasis is the presence of struvite crystals in urine. In the current study, neither the presence of struvite crystalluria nor the number of struvite stones was associated with struvite urolithiasis, as has been previously reported. 9 canned food than dry). Higher urine specific gravity is expected with the consumption of dry food in cats. Theories have been proposed to explain this finding, which appears to be due to the solute and energy content of the diet, not just the moisture content. 24,28 A previous study evaluating a canned calculolytic diet in cats In the current study, neither the presence of struvite crystalluria nor the number of struvite stones was associated with struvite urolithiasis. Five cats that were tentatively diagnosed with struvite urolithiasis did not respond to dietary treatment, and cystotomy was performed. These cases illustrate that although a tentative diagnosis of struvite urolithiasis can be based on supportive urine and radiographic results, these assumptions are not always correct. Struvite crystals may be associated with urease-producing bacteria or may develop in vitro as urine is stored before analysis or while urine is refrigerated. 20,23 Acidification of urine appears to be the most important factor in the dissolution and prevention of struvite urolithiasis in cats. 24 27 Urine ph decreased significantly during consumption of both diets. Diet B was formulated to be more acidifying than diet A, which is consistent with the results seen. Urine ph in this study was not controlled with respect to time of feeding and the methodology employed to measure urine ph. If the evaluation of fasting urine samples and the consistent use of a ph meter had been employed, a lower urine ph may have been observed in both groups of cats. Dissolution tended to occur more rapidly with the canned diet, although the difference was not statistically significant. This may be due to less saturation of the urine with calculogenic substrates (posttreatment urine specific gravity was lower with found that urine specific gravity increased as cats consumed the food, in spite of an increased sodium level in the diet. 9 Results from both the previous study and the study reported here support the conclusion that a lower urine specific gravity may not be as important for dissolution of struvite in cats. In the majority of cases, clinical signs of LUTD subsided before uroliths completely dissolved. This finding has also been reported previously. 9 In one case, signs did not resolve until 2 weeks after apparent urolith dissolution. This may have been a result of a small urolith (<3 mm) that was not detected on radiographs or chronic inflammatory changes in the bladder wall caused by urolithiasis. 29 Cats with struvite urolithiasis may have one or multiple stones of varying sizes. As previously reported, there was no apparent relationship between the time required for dissolution and the number or size of bladder uroliths. 9 Body weight decreased in cats consuming diet A. Although recommendations were made to feed 70 kcal/kg/day, it is likely that these cats did not make the transition to an all canned food diet well, and some weight loss occurred. It is also possible, as suggested in a previous study, 9 that cats lost weight because of the presence of LUTD. In that study, cats 198

gained weight after the diet was discontinued. In the current study, body weight was not assessed after the diet was discontinued and therefore it is unknown whether cats would have gained weight after treatment. However, cats on a previous AAFCO maintenance feeding trial maintained normal body weight. Blood chemistry values found to be abnormal before treatment were rechecked and found to be normal after treatment, with the exception of one cat (13A) in which both preand posttreatment calcium levels were mildly elevated (2.63 mmol/l before treatment vs. 2.7 mmol/l after treatment; reference range: 2 2.6 mmol/l). However, both samples were mildly hemolyzed. Hemolysis interferes with spectrophotometric methods of calcium determination and may have caused a falsely increased level. This cat was accepted into the trial based on the presence of struvite crystals in the initial urinalysis, a urine ph of 7.5, and four radiodense bladder uroliths. The uroliths were dissolved at the 2-week recheck. Calcium was the only value in which changes between pre- and posttreatment values approached significance, with posttreatment values being increased (Table 7). In addition, three cats consuming diet B experienced a decrease in potassium levels after treatment (Table 7). These changes may be a result of the acidifying nature of the diet. Previous studies have shown that when fed on a long-term basis, acidifying diets may lead to metabolic acidosis, causing an increase in blood calcium and a decrease in potassium. 9,30 Decreased potassium was not seen in cats consuming the canned diet, most likely because the dry diet was more acidifying. It is unknown why these changes were not seen during the maintenance feeding trial. AAFCO feeding trials are performed on healthy cats; although the cats in this study were apparently healthy (other than the presence of FLUTD), it is possible that the presence of FLUTD contributed to a lower serum potassium level. The three cats in this current study that experienced a decrease in potassium levels maintained body weight (one gained weight), and their ages were 1, 2, and 8 years. In the study described here, no cultures were positive for Staphylococcus or Proteus and urine cultures were not tested for the presence of urease. It is uncommon for bacteria other than Staphylococcus and Proteus spp to produce urease, 29 and most of the positive urine cultures in the present study were positive for E. coli or Enterococcus spp. It is likely that the documented infections were a result, not the cause, of urolithiasis; it is also possible that samples not collected by cystocentesis may have tested positive because of contamination. In a previous study of feline struvite uroliths, infectioninduced uroliths were more difficult to dissolve than non infection-induced uroliths. 9 In that study, struvite uroliths associated with ureasenegative infection dissolved in a median of 21 days while urease-positive stones dissolved in Acidification of urine appears to be the most important factor in the dissolution and prevention of struvite urolithiasis in cats. 82 days. In the current study, if the uroliths had been infection induced, it is likely that a longer time to dissolution would have been observed. Although most urine samples were cultured, few were found to be positive. Despite this, 63% of these cats received a course of antibiotics. As previously reported, urinary tract in- 199

Veterinary Therapeutics Vol. 5, No. 3, Fall 2004 fection does not appear to be a common cause of LUTD in cats. 3 A recent survey of small animal veterinarians found that most were aware that their use of antimicrobials was inappropriate. 31 In this survey, only 40% of responders considered no antimicrobials as their first choice of treatment in a cat with uncomplicated FLUTD. In the current study, 63% of cats were treated with antimicrobials and the majority of these treatments were not based on the results of urine culture. In addition, 68% of cats treated with antimicrobials were administered a fluoroquinolone. Several recent studies in dogs have shown increasing bacterial resistance to fluoroquinolones. 32 35 To the authors knowledge, similar studies have not been done in cats; however, since bacterial drug resistance is a significant concern in the human field, prudent use of antimicrobial agents in veterinary practice is strongly encouraged. The limitations of this study include the lack of control with respect to collection of samples and follow-up (because the patients were client-owned and were treated at the discretion of the attending veterinarian). Urine ph and evaluation for crystals should be performed immediately following urine collection and preferably with the use of a ph meter. In addition, the study was not blinded to those collecting and interpreting the data. CONCLUSIONS Results of this study provide strong evidence that both a canned and dry urine-acidifying, magnesium-restricted diet will dissolve naturally occurring feline struvite bladder uroliths. The average time to dissolution for both diets was 30 days, and time to dissolution was not influenced by the number of uroliths. REFERENCES 1. Lund EM, Armstrong PJ, Kirk CA, et al: Health status and population characteristics of dogs and cats examined at private veterinary practices in the United States. JAVMA 214(9):1336 1341, 1999. 2. Lekcharoensuk C, Osborne CA, Lulich JP: Epidemiologic study of risk factors for lower urinary tract diseases in cats. JAVMA 218:1429 1435, 2001. 3. Buffington CAT, Chew DJ, Kendall MS, et al: Clinical evaluation of cats with nonobstructive urinary tract diseases. JAVMA 210:46 50, 1997. 4. Houston DM, Moore AE, Favrin MG, Hoff B: Feline urethral plugs and bladder uroliths: A review of 5484 submissions 1998 2003. Can Vet J 44:974 977, 2003. 5. Thumchai R, Lulich JP, Osborne CA, et al: Epizootiologic evaluation of urolithiasis in cats: 3,498 cases (1982 1992). JAVMA 208(4):547 551, 1996. 6. Ling GV, Franti CE, Ruby AL, Johnson DL: Epizootiologic evaluation and quantitative analysis of urinary calculi from 150 cats. JAVMA 196(9):1459 1462, 1990. 7. Osborne CA, Lulich JP, Thumchai R, et al: Feline urolithiasis: Etiology and pathophysiology. Vet Clin North Am Small Anim Pract 26(2):217 232, 1996. 8. Lulich JP, Osborne CA, Carlson M, et al: Nonsurgical removal of urocystoliths in dogs and cats by voiding urohydropropulsion. JAVMA 203:660 663, 1993. 9. Osborne CA, Lulich JP, Kruger JM, et al: Medical dissolution of feline struvite urocystoliths. JAVMA 196(7):1053 1063, 1990. 10. Buffington CAT, Chew DJ: Diet therapy in cats with lower urinary tract disorders. Vet Med July:626 630, 1999. 11. Bartges JW, Osborne CA, Lulich JP, et al: Methods for evaluating treatment of uroliths. Vet Clin North Am Small Anim Pract 29:45 57, 1999. 12. Robertson WG, Jones JS, Heaton MA, et al: Predicting the crystallization potential of urine from cats and dogs with respect to calcium oxalate and magnesium ammonium phosphate (struvite). J Nutr 132:1637S 1641S, 2002. 13. Machin D, Campbell M, Fayers P, Pinol A: Sample Size Tables for Clinical Studies, ed. 2. Oxford, Blackwell Science, 1997, p 315. 14. Labato MA: Managing urolithiasis in cats. Vet Med Sept:708 718, 2001. 15. Gill JL: Repeated measurement: Sensitive tests for experiments with few animals. J Anim Sci 63:943 954, 1986. 16. Collett D: Modelling Survival Data in Medical Research. London, Chapman and Hall, 1994, p 347. 17. Zar JH: Biostatistical Analysis. Englewood Cliffs, NJ, Prentice-Hall, 1974, p 620. 18. Osborne CA, Lulich JP, Ulrich LK, et al: Feline crys- 200

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