Effects of hydrochlorothiazide and diet in dogs with calcium oxalate urolithiasis

OBJECTIVE: To determine whether hydrochlorothiazide (HCTZ) reduces urinary calcium excretion in dogs with calcium oxalate urolithiasis. DESIGN: Original study. ANIMALS: 8 dogs with calcium oxalate urolithiasis. PROCEDURE: 4 treatment protocols were evaluated in each dog (a low calcium, low protein diet designed to prevent calcium oxalate urolith formation with and without administration of HCTZ [2 mg/kg (0.9 mg/lb) of body weight, PO, q 12 h] and a maintenance diet with higher quantities of protein and calcium with and without administration of HCTZ). At the end of each 2-week treatment period, 24-hour urine samples were collected. Blood samples were collected during the midpoint of each urine collection period. Analysis of variance was performed to evaluate the effects of HCTZ and diet on urine and serum analytes. RESULTS: Hydrochlorothiazide significantly decreased urine calcium and potassium concentration and excretion. Hydrochlorothiazide also significantly decreased serum potassium concentration. Compared with the maintenance diet, the urolith prevention diet significantly decreased urine calcium and oxalic acid concentration and excretion. Dogs consuming the urolith prevention diet had significantly lower serum concentrations of albumin and urea nitrogen. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of HCTZ decreased urine calcium excretion in dogs with a history of calcium oxalate urolith formation. The greatest reduction in urine calcium concentration and excretion was achieved when dogs received HCTZ and the urolith prevention diet. Results of this study suggest that the hypocalciuric effect of HCTZ will minimize recurrence of calcium oxalate urolith formation in dogs; however, long-term controlled clinical trials are needed to confirm the safety and effectiveness of HCTZ.     

Evaluation of urinary and serum metabolites in Asian small-clawed otters (Aonyx cinerea) with calcium oxalate urolithiasis.

Baseline renal function data was collected during 24-hr periods of feeding and fasting from three male and three female adult Asian small-clawed otters (Aonyx cinerea) with calcium oxalate urolithiasis. Urine was analyzed for calcium, phosphorus, and oxalate, and urinalyses were performed. There was no evidence of glucosuria, which has been previously reported in Asian small-clawed otters with urolithiasis. Urinary oxalate levels were quite high when compared with those of dogs and humans without uroliths, and the ratio of urinary oxalate to calcium was close to 1:1 during periods of food consumption. There was no significant difference in urinary oxalate excretion between the fed and fasting states. Urinary calcium excretion was five times greater during feeding than during fasting. Calcium levels were higher in the otters than those reported for dogs without uroliths but were similar to those for normal humans. Water consumption and urine production were significantly higher during periods of food consumption. Serum chemistry analyses and electrolyte levels were also determined. There was no evidence of hypercalcemia. Fractional clearance of calcium and phosphorus and endogenous creatinine clearance were significantly higher during food consumption than during fasting. Parathyroid hormone levels were similar to those reported for dogs and cats. Serum 25-hydroxy-vitamin D was slightly lower in the otters than in dogs.     

Nutrient intake and urine composition in calcium oxalate stone-forming dogs: comparison with healthy dogs and impact of dietary modification

Nutrient intake and urine composition were analyzed in calcium oxalate (CaOx)stone-forming and healthy control dogs to identify factors that contribute to CaOx urolithiasis. Stone-forming dogs had significantly lower intake of sodium, calcium, potassium, and phosphorus and significantly higher urinary calcium and oxalate concentrations, calcium excretion, and CaOx relative supersaturation (RSS). Feeding a diet used in the treatment of canine lower urinary tract disease for 1 month was associated with increased intake of moisture, sodium, and fat; reduced intake of potassium and calcium; and decreased urinary calcium and oxalate concentrations, calcium excretion, and CaOx RSS. No clinical signs of disease recurrence were observed in the stone-forming dogs when the diet was fed for an additional 11 months. The results suggest that hypercalciuria and hyperoxaluria contribute to the formation of CaOx uroliths in dogs and show that dietary modifications can alter this process.     

Influence of prednisolone on urinary calcium oxalate and struvite relative supersaturation in healthy young adult female domestic shorthaired cats

Prednisolone (10 mg PO q24h) or placebo was administered to healthy cats for 2 weeks in a masked, placebo-controlled, crossover-design study, and 24-hour urine samples were collected. When cats received prednisolone, 24-hour urine pH was lower and 24-hour urine excretion of creatinine, magnesium, phosphate, and potassium was higher than when cats received placebo. No significant difference was found in urinary relative supersaturation for calcium oxalate (CaOx) or struvite between treatment groups. Prednisolone administration did not induce diuresis, nor was it associated with increased calcium excretion or urinary saturation for CaOx in these healthy cats. Results of this study, however, should not be extrapolated to cats that form CaOx uroliths associated with idiopathic hypercalcemia.     

Urinary excretion of advanced glycation end products in dogs and cats

The present study was conducted with privately owned dogs and cats to investigate whether a relationship exists between the dietary AGEs and the urinary excretion of AGEs, as indication of possible effective absorption of those compounds in the intestinal tract of pet carnivores. For this purpose, data were collected from both raw fed and dry processed food (DPF) fed to dogs and cats, through spot urine sampling and questionnaires. Raw pet food (RF, low in AGE diets) was fed as a primary food source to 29 dogs and DPF to 28 dogs. Cats were categorized into 3 groups, which were RF (n = 15), DPF (n = 14) and dry and wet processed pet food (DWF, n = 25). Urinary-free carboxymethyllysine (CML), carboxyethyllysine (CEL) and lysinoalanine (LAL) were analysed using ultrahigh-performance liquid chromatography (UHPLC)—mass spectrometry, and were standardized for variable urine concentration by expressing the AGE concentrations as a ratio to urine creatinine (Ucr) concentration (µg/µmol Ucr). Urinary excretion of CML, CEL and LAL in dogs fed with DPF was 2.03, 2.14 and 3 times higher compared to dogs fed with RF (p < .005). Similar to the dogs, a significant difference in CML:Ucr, CEL:Ucr and LAL:Ucr between the three diet groups was observed in cats (p-overall < 0.005, ANOVA), in which the RF fed group excreted less AGEs than the other groups. Linear regression coefficients and SE of CML:Ucr, CEL:Ucr and LAL:Ucr showed that body weight and neuter status were significantly correlated with CML and CEL excretion, but not to LAL excretion. Our results revealed a significant correlation between dietary AGEs and urinary excretion of free CML, CEL and LAL, and also showed that endogenous formation of these AGEs occurs in both dogs and cats under physiological conditions.     

Urine metabolite values in fed and nonfed clinically normal beagles.

Twenty-four-hour excretion of urine metabolites was determined in 33 clinically normal Beagles during periods of consumption of a standard diet and when food was withheld. The goal was to determine normal canine values for urine analytes incriminated in the genesis of calcium oxalate uroliths. During periods when dogs consumed food, dairy urinary excretion of calcium, uric acid, sodium, potassium, magnesium, ammonium, and hydrogen ions were significantly (P = 0.0004, 0.0038, 0.001, 0.0001, 0.0004, 0.0001, and 0.024, respectively) higher than when food was withheld. Urinary excretion of phosphorus, oxalate, and citrate were not significantly different between samples obtained during periods of food consumption and when food was withheld. Male dogs excreted significantly higher quantities of urine oxalate than females during fed (P = 0.003) and nonfed (P = 0.003) conditions. When food was withheld, urinary uric acid excretion was significantly higher in males than females (P = 0.01). Females excreted significantly more urine calcium than males when food was withheld (P = 0.003). Our results indicated that dietary conditions influence the quantity of sodium, potassium, calcium, magnesium, and uric acid excreted in the urine of clinically normal dogs; therefore, dietary conditions should be considered when measuring the concentration of these analytes in urine.     

The relative effects of supplemental dietary calcium and oxalate on urine composition and calcium oxalate relative supersaturation in healthy adult dogs

The aim of this study was to establish the relative effects of dietary calcium and oxalate (in the form of oxalic acid) on the composition of urine produced by healthy adult Cairn Terriers and Miniature Schnauzers. A nutritionally complete dry dog food was fed to 7 dogs (4 Cairn terriers and 3 Miniature schnauzers) for 24 weeks. The dogs were fed the diet alone, or supplemented with six different combinations of dietary calcium (as carbonate and sulphate) and oxalate (as oxalic acid) commonly found in dry commercially prepared dog foods. Urine pH, volume, specific gravity, and concentrations of 12 analytes were measured for each dog; urinary relative supersaturation (RSS) with calcium oxalate (CaOx) was calculated from these values. The effects of supplemental calcium and oxalate were established using two-way analysis of variance and multiple range tests (least significant difference); P<0.05 was considered significant. The lowest level of dietary calcium and oxalate resulted in the lowest CaOx RSS. The high calcium, low oxalate diet resulted in the highest CaOx RSS, a low calcium diet with increased dietary oxalate also tended to increase CaOx RSS although results were highly variable. Urinary calcium concentration increased significantly with dietary calcium; urinary oxalate increased, although inconsistently, with dietary oxalic acid only when dietary calcium was low. Measures to reduce both calcium and oxalate should be considered when implementing dietary changes to reduce the risk of calcium oxalate formation in dogs. A reduction in dietary calcium without a concomitant decrease in dietary oxalate may increase the risk of CaOx crystallisation in susceptible dogs.     

Effects of dietary supplementation with sodium chloride on urinary relative supersaturation with calcium oxalate in healthy dogs

OBJECTIVE: To evaluate the effect of dietary supplementation with sodium chloride (NaCl) on urinary calcium excretion, urine calcium concentration, and urinary relative supersaturation (RSS) with calcium oxalate (CaOx). ANIMALS: 6 adult female healthy Beagles. PROCEDURE: By use of a crossover study design, a canned diet designed to decrease CaOx urolith recurrence with and without supplemental NaCl (i.e., 1.2% and 0.24% sodium on a dry-matter basis, respectively) was fed to dogs for 6 weeks. Every 14 days, 24-hour urine samples were collected. Concentrations of lithogenic substances and urine pH were used to calculate values of urinary RSS with CaOx. RESULTS: When dogs consumed a diet supplemented with NaCl, 24-hour urine volume and 24-hour urine calcium excretion increased. Dietary supplementation with NaCl was not associated with a change in urine calcium concentration. However, urine oxalate acid concentrations and values of urinary RSS with CaOx were significantly lower after feeding the NaCI-supplemented diet for 28 days. CONCLUSIONS AND CLINICAL RELEVANCE: Dietary supplementation with NaCl in a urolith-prevention diet decreased the propensity for CaOx crystallization in the urine of healthy adult Beagles. However, until long-term studies evaluating the efficacy and safety of dietary supplementation with NaCl in dogs with CaOx urolithiasis are preformed, we suggest that dietary supplementation with NaCl be used cautiously.     

Effects of chlorothiazide on urinary excretion of calcium in clinically normal dogs.

Administration of thiazide diuretics has been recommended to prevent calcium oxalate urolith development in dogs. To evaluate the effects of thiazide diuretics in dogs, 24-hour urine excretion of calcium was measured in 6 clinically normal Beagles after administration of chlorothiazide (CTZ) for 2 weeks, administration of CTZ for 10 weeks, and administration of calcium carbonate and CTZ for 2 weeks. Compared with baseline values, 24-hour urine calcium excretion did not decrease after CTZ administration. When CTZ was given at a high dosage (130 mg/kg of body weight), urinary calcium excretion was significantly (P < 0.04) higher than baseline values. Based on these observations, we do not recommend CTZ for treatment or prevention of canine calcium oxalate urolithiasis.     

Influence of hydrochlorothiazide on urinary calcium oxalate relative supersaturation in healthy young adult female domestic shorthaired cats

Hydrochlorothiazide (1 mg/kg PO q12h) or placebo was administered to healthy cats for 2 weeks in a masked, placebo-controlled, crossover-design study, and 24-hour urine samples were collected. When cats received hydrochlorothiazide, 24-hour urine volume, ammonia, chloride, creatinine, magnesium, oxalic acid, phosphate, potassium, and sodium were significantly higher than when cats received placebo. Hydrochlorothiazide was associated with significantly lower urinary saturation for calcium oxalate, but no difference was found in 24-hour urine calcium and citrate, urinary saturation for struvite, or blood ionized calcium. Hydrochlorothiazide decreased urinary saturation for calcium oxalate and could be useful in managing cats with calcium oxalate uroliths. Results of this study, however, should not be extrapolated to cats that form calcium oxalate uroliths.     

Effect of cation–anion balance in feed on urine pH in rabbits in comparison with other species

In the present investigation, the impact of diet composition on urine pH in rabbits was compared with previous studies on rabbits, cats, dogs, pigs and horses. A total of 13 dwarf rabbits were fed six different diets with a cation–anion balance (CAB) between ?39 and +320 mmol/kg dry matter (DM) using ammonium chloride (NH₄Cl) as an acidifier. CAB was calculated as follows: CAB (mmol/kg DM) = 49.9*Ca + 82.3*Mg +43.5*Na + 25.6*K ? 59*P ? 62.4*S ? 28.2*Cl; minerals in g/kg DM. Urine, faeces and blood were collected. Urine pH ranged from 5.26 ± 0.22 at a CAB of ?39 mmol/kg DM to 8.56 ± 0.24 at a CAB of +320 mmol/kg DM. A low CAB in the feed reduced blood pH and blood base excess significantly. Renal excretion of Ca, P, Na and Mg and water was significantly higher in rabbits eating acidifying diets. In comparison with other species, rabbits reacted to acidifying diets in a similar way as cats, dogs and pigs. Rabbits on a mildly alkalizing diet, however, had a trend to higher urine pH than other monogastric species on such diets (cats, dogs, pigs, horses).     

Effects of dietary potassium citrate supplementation on urine pH and urinary relative supersaturation of calcium oxalate and struvite in healthy dogs

OBJECTIVE: To assess the effect of dietary potassium citrate supplementation on the urinary pH, relative supersaturation of calcium oxalate and struvite (defined as the activity product/solubility product of the substance), and concentrations of magnesium, ammonium, phosphate, citrate, calcium, and oxalate in dogs. ANIMALS: 12 healthy adult dogs. PROCEDURE: Canned dog food was fed to dogs for 37 days. Dogs were randomly allocated to 3 groups and fed test diets for a period of 8 days. Study periods were separated by 6-day intervals. During each study period the dogs were fed either standard diet solus (control) or standard diet plus 1 of 2 types of potassium citrate supplements (150 mg potassium citrate/kg of body weight/d) twice daily. Urinary pH, volume and specific gravity, relative supersaturation of calcium oxalate and struvite, and concentrations of magnesium, ammonium, phosphate, calcium, oxalate, and citrate were assessed for each treatment. RESULTS: Mean urine pH was not significantly affected by dietary potassium citrate supplementation, although urine pH did increase by 0.2 pH units with supplementation. Diets containing potassium citrate maintained a higher urine pH for a longer part of the day than control diet. Three Miniature Schnauzers had a significantly lower urinary relative calcium oxalate supersaturation when fed a diet supplemented with potassium citrate, compared with control diet. CONCLUSIONS AND CLINICAL RELEVANCE: Dietary potassium citrate supplementation has limited effects on urinary variables in most healthy dogs, although supplementation results in maintenance of a higher urine pH later in the day. Consequently, if supplementation is introduced, dogs should be fed twice daily and potassium citrate should be given with both meals or with the evening meal only.     

Calcium oxalate stones in feline littermates.

Two feline littermates were diagnosed with calcium oxalate uroliths. Both had been maintained on a commercially available dry diet with reduced magnesium and urine acidifying properties. One female littermate was diagnosed by visualising the stones by radiographs while the second littermate, also female, became blocked when one of the uroliths lodged in the urethra. Two other, unrelated cats in the household, of similar age and raised under the same conditions, did not develop calcium oxalate uroliths.     

Serum cobalamin, urine methylmalonic acid, and plasma total homocysteine concentrations in Border Collies and dogs of other breeds

Objective-To determine reference ranges for serum cobalamin (Cbl), urine methylmalonic acid (uMMA), and plasma total homocysteine (tHcys) concentrations and to compare values for healthy control dogs with values for Border Collies (BCs), a breed in which hereditary cobalamin deficiency has been identified. Animals-113 BCs, 35 healthy control dogs fed a typical diet, and 12 healthy dogs fed a bone and raw food diet exclusively. Procedures-Urine and blood samples were obtained from each dog and Cbl, uMMA, and tHcys concentrations were determined. Results-Reference ranges for Cbl (261 to 1,001 ng/L), uMMA (0 to 4.2 mmol/mol of creatinine), and tHcys (4.3 to 18.4 μmol/L) concentrations were determined. Four BCs had a Cbl concentration lower than the assay detection limit (150 ng/L); median uMMA and tHcys concentrations in these dogs were 4,064 mmol/mol of creatinine and 51.5 μmol/L, respectively. Clinical abnormalities included stunted growth, lethargy, anemia, and proteinuria. Abnormalities improved after administration of cobalamin. Of the 109 healthy BCs with Cbl and tHcys concentrations within reference ranges, 41 (37.6%) had a high uMMA concentration (range, 5 to 360 mmol/mol). Results for dogs fed raw food were similar to those for control dogs. Conclusions and Clinical Relevance-Hereditary cobalamin deficiency is a rare disease with various clinical signs. The finding of methylmalonic aciduria in healthy eucobalaminemic BCs and BCs with clinical signs of Cbl deficiency was surprising and indicated these dogs may have defects in intracellular processing of Cbl or intestinal Cbl malabsorption, respectively. Studies investigating Cbl absorption and metabolic pathways are warranted.     

Effects of anionic salts in a pre-partum dairy ration on calcium metabolism

The effects of anionic salts in the transition diet on serum and urine calcium at calving and on peripartal health, subsequent milk production and fertility performance were studied in a well-managed, high-producing Friesland dairy herd. Over a period of a year, approximately 21 days before the expected date of calving, 28 pre-partum heifers and 44 multiparous dry cows were randomly allocated within parity to 1 of 2 transition diets, designated control and experimental anionic diets. The anionic diet contained the same quantities of the basic transition ration fed to the control group as well as a standard anionic salt mixture containing 118 g NH4Cl, 36 g (NH4)2SO4 and 68 g MgSO4 (total 222 g) per animal per day. This reduced the DCAD to -11.68 mEq/100 g dietary dry matter compared to +13.57 for the control diet. Blood and urine were randomly sampled from 7 to 8 animals within each category within 3 hours post-partum. Serum calcium (total and ionised) and creatinine, urine calcium and creatinine and the fractional clearance of calcium were assessed. Relevant clinical, milk production, and fertility data were collected. The total serum calcium (2.07 versus 1.60 mmol/l), serum ionised calcium (1.12 vs 1.02 mmol/l), urine calcium (0.92 vs 0.10 mmol/l) and the fractional clearance of calcium (1.88 vs 0.09%) were significantly higher(P <0.01) at calving for multiparous cows fed the anionic diet compared to those fed the control diet. In the primiparous cows there were no significant differences in serum calcium levels. However, the urine calcium (1.07 vs 0.43 mmol/l) and the fractional clearance of calcium was higher (1.75 vs 0.45%) in cows fed the anionic diet (P <0.05 and 0.01 respectively). These results illustrated that there were benefits, although no differences were demonstrated with respect to health, milk production or fertility. The supplementation of diets with anionic salts in the last 2-3 weeks before calving has the potential to significantly improve parturient calcium homeostasis.     

The effect of urine acidification on calcium oxalate relative supersaturation in cats

There is an apparent reciprocal relationship between magnesium ammonium phosphate (MAP, struvite) and calcium oxalate (CaOx) urolithiasis incidence rate in cats. The number of struvite uroliths submitted for analysis over the past 35 years has been decreasing, with an increase in CaOx urolith submissions. Commercial diets aimed to dissolve struvite uroliths are typically acidified, and it has been suggested that dietary acidification increases urinary calcium excretion and the risk of CaOx crystallization. The objective of this study was to assess the effect of urine acidification on the relative supersaturation (RSS) of CaOx in cats, as a representation of crystallization risk. Four diets were extruded to contain identical nutrient contents, but with gradual acidification (0, 0.6, 1.3 and 1.9% sodium bisulphate substituted sodium chloride in diets A, B, C and D respectively). Thirteen adult cats were fed each diet sequentially for a minimum of 10 days. Average urine pH was 6.4, 6.2, 6.0 and 5.9 on diets A, B, C and D respectively (p < 0.0001). Struvite RSS decreased on diets inducing more acidic urine pH (p < 0.0001). Urinary calcium excretion and concentration increased with diets inducing lower urine pH (p < 0.0001), but oxalate excretion and concentration decreased (p < 0.001). CaOx RSS was not different between diets (p = 0.63). These results suggest that a lower diet base excess and resulting urine pH to support struvite dissolution do not increase the risk for CaOx crystallization in the range of urine pH representative of most commercial feline diets. Long-term studies are needed to confirm this.     

Substitution of dietary calcium chloride for calcium carbonate reduces urinary ph and urinary phosphorus excretion in adult cats

Summary

In a 4×4‐vvk cross‐over study, eight adult cats were given four moist diets containing identical amounts of calcium (13.9 mmol/MJ) but with different ratios of calcium carbonate to calcium chloride, the calcium salts providing half of the total dietary calcium. Increasing amounts of calcium chloride were substituted for equimolar amounts of calcium carbonate. Higher intakes of calcium chloride caused significantly lower pH values in postprandial and 24‐h urine samples. The urinary excretion of ammonium and titratable acid rose with increasing calcium chloride intake. The urinary concentrations of calcium and magnesium were not affected by the type of calcium salt, but the urinary excretion and concentration of phosphorus were significantly depressed when the amount of calcium chloride in the diet was increased. The results are discussed in the context of dietary prevention of and therapy for struvite urolithiasis in cats.     

Pet food safety: sodium in pet foods

Healthy dogs and cats appear to be able to adjust to differing amounts of sodium in their diet via the rennin-angiotensin-aldosterone mechanisms. There is no strong evidence that increased dietary sodium increases the risk of hypertension in dogs and cats, and the current recommendation for hypertensive animals is to avoid high dietary salt intake without making a specific effort to restrict it. The prevalence of salt sensitivity and its effect on blood pressure has not been determined for cats or dogs. The ideal amount of sodium in the diet of dogs and cats with cardiac deficiency has not been determined, as increasing may detrimentally increase the extracellular fluid volume, but decreasing it may detrimentally increase the activation of the rennin-angiotensin-aldosterone system. Increased dietary sodium increases urine output and may decrease the risk of forming calcium oxalate uroliths due to the decrease in relative supersaturation of solutes. However, caution should be used in increasing the sodium intake of patients with renal disease as increased dietary sodium may have a negative effect on the kidneys independent of any effect on blood pressure.     

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.     

Comparison of urine composition of healthy Labrador retrievers and miniature schnauzers.

OBJECTIVE: To compare urine composition in Labrador Retrievers (LR) and Miniature Schnauzers (MS) fed the same dog food. ANIMALS: 8 healthy LR (mean [+/- SD] age, 3.1+/-1.7 years) and 8 healthy MS (mean age, 3.7+/-1.3 years). PROCEDURE: A nutritionally complete dry dog food was fed to the dogs for 24 days. Urinary pH, volume, specific gravity, frequency of urination, and urinary concentrations of 12 analytes were measured for each dog; urinary relative supersaturation (RSS) with calcium oxalate and brushite (calcium hydrogen phosphate dihydrate) were calculated from these values. RESULTS: MS urinated significantly less often and had a lower urine volume (ml/kg of body weight per d) and a significantly higher urine pH, compared with LR. Urinary calcium concentration and brushite RSS were significantly higher in the urine of MS. As a result of a high calorie requirement, primarily as a result of high surface area to volume ratio, MS had significantly higher intake (per kg body weight) of dietary minerals, compared with LR. CONCLUSIONS AND CLINICAL RELEVANCE: Differences in urine composition exist between breeds fed the same diet, some of which, including lower urine volume, higher calcium concentration, and higher brushite RSS, may contribute to the high prevalence of calcium oxalate uroliths observed in MS. Differences between breeds should be considered when evaluating strategies for controlling calcium oxalate stone formation.