Effects of Diet on Urine Composition of Cats With Calcium Oxalate Urolithiasis
Ten client-owned cats with calcium oxalate (CaOx) urolithiasis were evaluated to determine the effect of diet on urine CaOx saturation. Two dietary treatments were evaluated in each cat: the diet consumed just prior to urolith detection and a canned diet formulated to prevent CaOx uroliths. This study revealed that hypercalciuria is a consistent abnormality in cats with CaOx urolith formation. When urolith-forming cats consumed a diet formulated to prevent urolith formation, activity product ratios for CaOx (which estimate the degree to which urine is saturated with CaOx) were significantly lower. These results suggest that consumption of an appropriately formulated urolith-prevention diet will reduce recurrence of CaOx urolithiasis.
Introduction
Over the past two decades, the Minnesota Urolith Center (MUC) has observed substantial increases in the number of cats with calcium oxalate (CaOx) uroliths. For instance, in 1981, quantitative mineral analysis was performed on uroliths from 69 cats, and only one cat had a urolith composed of CaOx.1 However, in 1999, uroliths were analyzed from 5091 cats, of which 2800 (55%) cats had uroliths composed of CaOx.2
It has been proposed that treatments designed to minimize the formation of struvite uroliths have resulted in an increase in the occurrence of CaOx uroliths.3–5 One reason for this speculation is that dietary-induced urine acidification, which promotes dissolution and prevention of sterile struvite uroliths, also promotes hypercalciuria, a risk factor for CaOx urolith formation.6 On the basis of these observations and results of studies in other species, diets formulated to reduce urine acidity have been recommended to minimize recurrence of CaOx urolith formation in cats.78
Evaluation of the impact of diets designed to minimize CaOx urolith recurrence requires knowledge of CaOx urolith recurrence rates. However, the biological behavior of CaOx urolith recurrence in cats has not yet been systematically evaluated by prospective clinical studies. Once all uroliths have been removed from the lower urinary tract, it has been the authors’ clinical experience that CaOx uroliths usually recur within a few months to a few years. Therefore, it is apparent that controlled clinical studies designed to evaluate the effectiveness of diets in minimizing CaOx urolith recurrence should span several years.
Alternative methods designed to predict the likelihood of crystal formation based on measurement of the types and quantities of calculogenic substances in urine are often used, because they require a relatively short time to assess the probable efficacy of urolith-preventive diets. In humans, measurement of activity product ratios is one method frequently used to evaluate the efficacy of various types of medical treatments for CaOx urolithiasis.9–12 An estimate of the degree to which urine is saturated with CaOx can be determined with the aid of a computer program that calculates activity products.10 The activity product is derived from evaluation of several physiochemical properties of urine such as the concentration of several analytes (including calcium, oxalic acid, citric acid, sodium, uric acid, phosphorus, potassium, and magnesium), urine pH, temperature, and ionic strength.
The authors hypothesized that appropriate dietary changes (e.g., reducing calcium, oxalic acid, and sodium; adding potassium citrate to promote formation of neutral urine pH, increased moisture) would minimize risk factors known to be associated with CaOx urolith recurrence in cats with a history of CaOx uroliths. To evaluate this hypothesis, the authors compared activity product ratios of urine from urolith-forming cats while they were consuming the diet fed to them prior to the time of urolith detection, with activity product ratios from a different time when a diet formulated to prevent CaOx uroliths was being fed.
Materials and Methods
Study Population
Ten cats with CaOx uroliths were evaluated. Cats were selected on the basis of quantitative evaluation of uroliths submitted to the MUC by practitioners in the Minneapolis-Saint Paul metropolitan area. Only cats with uroliths composed of 100% CaOx were included. The mineral composition of uroliths was determined by optical crystallography. At the time of the study, no hypercalcemia, renal failure, bacterial urinary tract infection, or uroliths were detected in any cat by serum biochemical analysis, urinalysis, urine culture for aerobic bacteria, and survey radiography. Cats were excluded from this study if they had received glucocorticoids or calcium supplements within the past 2 years.
Experimental Design
To minimize differences attributable to individual cats or time, a crossover design was used to evaluate the effect of diet on urine activity product ratios for CaOx. Two groups of diets were evaluated: the diet each cat consumed prior to urolith detection and a canned diet formulated to prevent CaOx urolith formation.a Seven brands of diets were consumed by cats just prior to detection of uroliths, and all seven brands were dry kibble. The manufacturers provided data on the key nutrient content of these diets. The quantities of each dietary component in the seven diets were compiled and expressed as a median and range [Table 1]. These values were compared to the dietary components in the urolith-prevention diet. Because diets fed prior to urolith detection were offered free choice to each cat, the same pattern of feeding was followed throughout the study. The canned urolith-prevention diet was also provided free choice, and fresh food was replenished twice daily. The order in which the two diet groups were fed to each cat was randomly assigned. Each diet was fed to cats for 8 weeks prior to evaluation of urine activity product ratios.
Sample Collection
Cats lived with their owners except during the 72-hour urine-collection periods. At the end of each 8-week treatment period, cats returned to the veterinary hospital associated with MUC for collection of urine and blood. Prior to collection of timed urine samples, urine was collected by cystocentesis for a complete urinalysis and culture for aerobic bacteria. At the beginning of each timed collection period, urine voiding was induced by manual compression of the urinary bladder sufficient to stimulate micturition. If cats did not voluntarily void urine within 60 minutes, the urinary bladder was emptied via cystocentesis. Cats were then placed in cages with special litter pans that allowed collection of urine independent of feces. Voided urine was collected every 6 hours and stored in capped receptacles at 4°C. Cats were offered unlimited food and water that was replaced twice a day. At the end of each 72-hour urine collection, urine remaining in the bladder was collected by induced voiding or cystocentesis.
Blood samples were collected from the jugular vein of each cat during the midpoint of 72-hour urine collections. Serum was harvested from samples by standard procedures within 30 minutes of collection and stored for approximately 12 hours at 4°C until analyzed.b An aliquot of each serum sample was separately stored at −90°C for determination of parathyroid hormone (PTH) and 25-hydroxycholecalciferol concentrations.c Ionized calcium was determined from venous blood aspirated into syringes containing dry lithium heparin.d
Sample Analysis
Urine concentrations of creatinine, sodium, potassium, and chloride were determined with an automated serum biochemistry analyzer.b Urine concentrations of calcium, magnesium, and phosphorus were measured by atomic absorption spectrophotometry.e Urine oxalic acid concentrations were determined by solid-phase extraction followed by ion exchange chromatography, and citric acid concentrations were determined colorimetrically.13 Urine uric acid concentrations were determined by high liquid pressure chromatography.14 Urine specific gravity (USG) was measured with a refractometer.
Activity product ratios for CaOx in urine were determined by incubating 15-mL aliquots of the 72-hour urine sample with 150 mg of CaOx monohydrate seed crystals in sealed 25-mL flasks. Flasks were placed in a reciprocating water bath shaker at 38°C and 60 revolutions per minute for 48 hours. Urine pH was adjusted at 12-hour intervals to the original pH ±0.1 unit by addition of either 0.1 molar hydrogen chloride or 0.1 sodium hydroxide. After the incubation period, contents of each flask were passed through a 0.22-μm filter to remove crystals that would otherwise interfere with measurement of analytes. Concentrations of urinary analytes were measured as previously described and entered into a microcomputer-based program for calculation of relative saturation values.10 Activity product ratios were calculated by dividing relative saturation values for CaOx before incubation with seed crystals, by the relative saturation values for CaOx after incubation with seed crystals.
Statistical Analysis
Student’s t-test for paired samples was used to evaluate statistical differences in values between the two dietary treatments.15 The assumption of normality was tested with the Wilk-Shapiro statistic.16 When data was not normally distributed, statistical differences were assessed using a non-parametric method (Wilcoxon’s signed rank test) for paired samples.17 Analyses were performed using a commercially available statistical software program.f P values <0.05 were considered significant.
Results
Ten cats (Persian [n=1], Scottish fold [n=1], and mixed-breed cats [n=8]) with CaOx urolithiasis were evaluated. Eight of the 10 cats were castrated males; two were spayed females. The cats were 7.7±4.7 years of age and weighed 5.77±2.0 kg. No cat developed a urinary tract infection during the study. Mean USG when cats consumed the canned urolith-prevention diet (mean±standard deviation [SD], 1.043±0.011) was similar to USG when the same cats consumed the dry diet associated with urolith formation (mean±SD, 1.043±0.012). Compared to cats consuming the diet associated with urolith formation for 8 weeks (mean±SD, 5.78±2.0 kg), cats consuming the urolith-prevention diet for 8 weeks weighed 0.13 kg less (mean±SD, 5.65±1.8 kg), but the difference was not significant (P=0.18). Calcium oxalate crystalluria was detected twice; it occurred only when cats consumed diets associated with urolith formation.
When results from the two dietary treatments were compared, mean urine activity product ratios for CaOx were significantly lower (P=0.006) during consumption of the urolith-prevention diet [see Figure]. These observations were consistent with the significant reduction in urine excretion and concentration of calcium that occurred during consumption of the same diet [Table 2]. Unexpectedly, the mean urine concentration of citric acid, a chelating agent of CaOx, was lower during consumption of the urolith-prevention diet; however, the difference was not significant (P=0.55). Significant differences between diet groups were not detected in 72-hour urine oxalic acid concentration, urine pH, and urine volume. Although the urolith-prevention diet contained substantially more moisture than the other foods, USG of urine from timed collections was not significantly different between the two dietary treatments. In contrast, consumption of the urolith-prevention diet was associated with significant reductions in urinary concentrations of sodium, potassium, and chloride.
Serum concentrations of albumin, alkaline phosphatase (ALP), alanine transaminase (ALT), amylase, aspartate transaminase (AST), total bilirubin, urea nitrogen, cholesterol, total carbon dioxide, calcium, creatinine, glucose, magnesium, phosphorus, potassium, sodium, and total protein remained within normal reference ranges irrespective of the diet consumed.18 Nonetheless, serum concentrations of phosphorus and ALP were lower (P=0.015 and P=0.014, respectively), and ALT was higher (P=0.016) during consumption of the urolith-prevention diet.
Consumption of the two types of diets did not result in any significant differences in serum concentrations of ionized calcium, PTH, or 25-hydroxycholecalciferol [Table 3]. However, three cats had abnormally increased concentrations of ionized calcium (>1.4 mmol/L; reference range, 0.4 to 1.4 mmol/L) during consumption of the diet associated with urolith formation, and one cat had an increased value during consumption of the urolith-prevention diet. Two cats had abnormally increased concentrations of PTH (>4 pmol/L) during consumption of the diet associated with urolith formation, and two cats had increased concentrations of PTH during consumption of the urolith-prevention diet. The cats with increased serum ionized calcium concentrations were not the same cats that had increased serum PTH concentrations.
Discussion
To the authors’ knowledge, this is the first study reporting the concentrations of urinary analytes in a group of cats with CaOx urolithiasis. Although formation of CaOx uroliths is associated with a complex and incompletely understood sequence of events, it is accepted that initial crystal formation and subsequent crystal growth are at least partly a reflection of urine supersaturation.9 Therefore, therapy that reduces supersaturation of urine with calculogenic substances should minimize urolith recurrence. Compared to diets consumed at the time of detection of CaOx uroliths, consumption of the urolith-prevention diet by the cats in this study reduced urinary CaOx supersaturation by 59%. Because supersaturation of urine with calculogenic minerals is a risk factor for CaOx urolith formation, these results suggest that consumption of the urolith-prevention diet will reduce CaOx urolith recurrence.
In humans, reduced concentrations of calcium and oxalic acid and increased concentrations of citric acid, magnesium, and sodium are associated with reduced supersaturation of urine with CaOx.91019 In the study reported here, there were no significant differences in urinary concentrations of oxalic acid, citric acid, and magnesium associated with consumption of the two groups of diets. Urine concentration of sodium was significantly lower during consumption of the urolith-prevention diet. This difference parallels the lower sodium content of the urolith-prevention diet compared to the diets associated with urolith formation. Increased dietary sodium may appear inappropriate, because sodium promotes urinary calcium excretion. However, in one study, when cats consumed diets containing higher sodium (0.91 g compared to 0.43 g/100 g of diet), CaOx supersaturation decreased even though calcium excretion increased.20 It is plausible to assume that the effects of oral sodium on water intake and its diluting effect on urine calcium concentration were relatively greater than the effect of sodium on promoting urine calcium excretion. Despite differences in dietary sodium intake and urine sodium excretion, consumption of the canned urolith-prevention diet significantly lowered the urinary concentration of calcium without a significant change in USG. The effect of additional water in the canned urolith-prevention diet on urine concentration may have been matched by the effect of higher sodium in the dry diets associated with urolith formation. Based on these results, it is apparent that the lower activity product ratios for CaOx associated with consumption of the urolith-prevention diet was primarily a function of the diet’s ability to reduce the urinary concentration of calcium.
A question to consider is how differences in the composition of the diets evaluated in this study might have influenced urinary calcium concentration. One dietary component that may have affected the urinary concentration of calcium is protein. In this study, the urolith-prevention diet contained the highest quantity of protein per Kcal of food. However, results of several studies in humans suggest that increased protein consumption increases the risk for CaOx uroliths by promoting mobilization of calcium from bone, increasing glomerular filtration of calcium, and reducing renal tubular resorption of calcium.21–24 In cats, however, consumption of increased quantities of dietary protein may be associated with other factors that modify urine calcium concentration. For example, an epidemiological study evaluating effects of dietary factors on the risk of CaOx uroliths in cats revealed that high-protein diets (10.5 to 13.8 g/100 kcal) were less than half as likely to be associated with CaOx urolith formation as diets low in protein (5.2 to 8 g/100 kcal).3 In another study, increased consumption of animal protein by healthy cats was associated with increased water consumption and urine volume.25 Similar mechanisms may have contributed to the increased urine volume and lower concentration of calcium observed in the present study.
The urolith-prevention diet also contained a greater quantity of moisture than the other diets. Studies designed to evaluate the effect of water consumption in humans with CaOx uroliths revealed that additional water consumption significantly reduced activity product ratios for CaOx in urine.1226 In a case-controlled study designed to evaluate dietary risk factors in 173 cats with CaOx uroliths, moisture content of the diet was inversely related to urolith formation.3 Logically, a high fluid intake would inhibit CaOx urolith formation by reducing urinary concentrations of calcium and oxalic acid. In the present study, the higher moisture content of the urolith-prevention diet may have contributed to a reduction in CaOx supersaturation by similar mechanisms. However, the authors recognize that although 24-hour urine volume was greater during consumption of the urolith-prevention diet, the difference was not statistically significant.
Another factor that may have influenced the urinary concentration of calcium was the calcium content of the diet. Compared to the diets associated with urolith formation, the urolith-prevention diet contained lower quantities of calcium. Hypercalciuria is a well-documented risk factor for CaOx urolithiasis in dogs and humans.2728 Compared to healthy cats, the CaOx urolith-forming cats in the present study were hypercalciuric.29–31 Cats normally maintain calcium homeostasis by renal excretion of excessive calcium absorbed from the intestinal tract; therefore, the hypothesis that reduction of dietary calcium intake would result in a reduced risk for CaOx urolith formation is logical. However, the benefits of dietary calcium restriction have been recently challenged. Results of an epidemiological study revealed that cats consuming diets with the lowest amounts of calcium (0.1 to 0.2 g/100 kcal) had significantly greater risk for CaOx urolith formation than cats consuming diets with higher levels of calcium (0.21 to 0.37 g/100 kcal).3 Results of recent epidemiological studies of dietary habits of humans revealed similar findings.3233 The beneficial effect of increased dietary calcium in reducing the risk of CaOx urolith formation has been thought to be related to interactions of dietary calcium and dietary oxalic acid in the intestinal lumen. When sufficient dietary calcium is available in the intestinal lumen, it combines with oxalic acid to form nonabsorbable complexes of CaOx, which in turn results in reduction of intestinal absorption and renal excretion of calcium and oxalic acid. However, if dietary calcium is reduced without a concomitant reduction in dietary oxalic acid, intestinal absorption and urinary excretion of oxalic acid may increase. Increases in the urinary concentration of oxalic acid appear to be a greater risk factor for CaOx urolith formation than equivalent increases in urinary calcium concentration, because smaller increments of oxalic acid are required for formation of insoluble CaOx.34 In the study reported here, reduction in dietary calcium during consumption of the urolith-prevention diet was not associated with increased urinary oxalic acid concentration. Similar findings were reported in CaOx urolith-forming dogs consuming diets with lower quantities of calcium.35 These observations suggest that diets can be formulated with smaller amounts calcium without adversely raising urinary concentrations of oxalic acid.
Conclusion
Results of this study indicate that hypercalciuria is associated with CaOx uroliths in cats. The results also indicate that urine supersaturation with CaOx can be reduced by appropriate dietary modifications, which, in turn, may reduce the risk for CaOx urolith formation. Although specifically formulated diets can reduce CaOx supersaturation, additional studies evaluating urolith recurrence are needed to confirm the clinical relevance and effectiveness of dietary therapy to prevent CaOx urolith recurrence in cats.
Prescription Diet Feline c/d-oxl; Hill’s Pet Nutrition, Inc., Topeka, KS
Synchron Clinical System CX-7 Delta; Beckman Instruments, Inc., Brea, CA
Animal Health Diagnostic Laboratory, Lansing, MI
Marquest Gaslyte arterial blood sampler; Marquest Medical Products, Inc., Englewood, CO
SpectrAA Systems; Varian Techtron PTY, Limited, Victoria, Australia
SAS/STAT user’s guide, version 6, 4th ed.; SAS Institute, Inc., Cary, NC
Citation: Journal of the American Animal Hospital Association 40, 3; 10.5326/0400185
Effect of diets on urine activity product ratios for calcium oxalate in 10 cats with a history of calcium oxalate urolithiasis.
