Nutrition and Urolithiasis

UROLITH FORMATION

Urolithiasis is a common cause of disease in dogs and cats and affects the upper and lower urinary tracts. Medical dissolution and preventative protocols are available for urolithiasis and dietary modification is an important part. Urolith formation occurs when urine is oversatured with the calculogenic minerals. Risk factors include breed, gender, age, diet, metabolic status, and chemical composition of urine. Although microscopic crystalluria likely precedes urolith formation, not all animals with crystalluria form uroliths and uroliths can be present without crystalluria. Once urolith formation has been initiated, the urolith nidus must be retained within the urinary tract, and the urinary environment must favor continued precipitation of minerals, aggregation of these minerals, and growth of the urolith. Alterations in balance between urine concentrations of calculogenic substances and calculogenic inhibitors result in initiation and growth of uroliths. ¹

Struvite

Struvite is magnesium ammonium phosphate hexahydrate and can occur as a consequence of a bacterial urinary tract infection (infection-induced struvite) or without a urinary tract infection (sterile struvite). Infection-induced struvite occurs commonly in dogs and occasionally in cats, while sterile struvite occurs commonly in cats and rarely in dogs. ^{2 –4}

Infection-induced struvite

Infection-induced struvite uroliths form as a consequence of a bacterial urinary tract infection with a microbe that produces urease; Staphylococcus spp occur most commonly. Microbial urease results in oversaturation of urine with struvite calculogenic substances by metabolizing urea to ammonia, producing alkaluria, altering the ionization state of phosphorous, and increasing urinary inflammatory proteins and cells that are incorporated into the urolith. ² Infection-induced struvite uroliths can be dissolved by administering an appropriate antimicrobial agent and feeding a diet to decrease urine to an undersaturated state with regards to struvite. Such a diet is, in comparison with adult maintenance diets, relatively lower in protein resulting in less available urinary urea for microbial urease metabolism, lower in phosphorous, lower in magnesium, acidifying, and diuresing. ^2,3,4,5 The antimicrobial agent must be administered until dissolution is documented to occur. Average time of dissolution is approximately 2 months. Prevention of infection-induced struvite uroliths is accomplished by preventing, controlling, and treating bacterial urinary tract infections. Although diets formulated to decrease urinary saturation with struvite are available, they have limited usefulness and indication because it is the infection with a urease-producing microbe that causes infection-induced struvite urolith formation.

Sterile struvite

Sterile struvite uroliths form typically in 1-10 year old cats ⁶ , although they have been reported to occur rarely in dogs. ³ Sterile struvite uroliths form because of dietary influence on urine composition as well as innate risks for urolith formation. Experimentally, magnesium phosphate and struvite uroliths formed in healthy cats consuming calculogenic diets containing 0.15 to 1.0% magnesium (dry matter basis). ^4,5,6,7 These data are difficult to interpret, however, because the amount of magnesium consumption by cats in these studies may be different in than cats that spontaneously form sterile struvite uroliths consuming commercial diets due to differences in caloric density, palatability, and digestibility. The influence of magnesium on struvite formation depends on urine pH8 and influence of ions, minerals, and other components in urine. ⁹ Alkaluria is associated with increased risk for struvite formation. ^10,11 In a clinical study including 20 cats with naturally occurring struvite urocystoliths and no detectable bacterial urinary tract infection, the mean urinary pH at the time of diagnosis was 6.9 ± O.4. ¹² An additional factor is water intake and urine volume. Consumption of increased quantities of water may result in lowering concentrations of calculogenic substances in urine, thus, decreasing risk of urolith formation. ¹³ Consumption of small quantities of food frequently rather than one or two large meals per day is associated with production of more acidic urine and a lesser degree of struvite crystalluria by cats. ^{14 15} Sterile struvite uroliths can be dissolved by feeding a diet that is restricted in magnesium, phosphorous, and protein, and that induces aciduria relative to adult maintenance cat foods. ¹² In a clinical study including 22 cats with sterile struvite urocystoliths, urocystoliths dissolved in 20 cats in a mean of 36.2 ± 26.6 days (range, 14 to 141 days). ¹² The cats were fed a high-moisture (canned), calorically dense diet containing 0.058% magnesium (dry matter basis) and increased sodium chloride (0.79% dry matter basis) that induced a urine pH of approximately 6.0. Prevention of sterile struvite uroliths involves inducing a urine pH less than approximately 6.5, increasing urine volume, and decreasing excretion of magnesium, ammonium, and phosphorous.

Calcium Oxalate

Calcium oxalate urolith formation occurs when urine is oversaturated with calcium and oxalate. ¹ In addition to these alterations in activities of ions, large molecular weight proteins occurring in urine, such as nephrocalcin, uropontin, and Tamm-Horsfall mucoprotein, influence calcium oxalate formation. ¹⁶ Hypercalciuria is a significant risk factor, but not necessarily the cause of calcium oxalate urolith formation in human beings, dogs, and cats. ¹⁷ Hypercalciuria can result from excessive intestinal absorption of calcium (Gl hyperabsorption), impaired renal reabsorption of calcium (renal leak), and/or excessive skeletal mobilization of calcium (resorptive). ¹⁸ Hypercalciuria has not been well defined in normocalcemic cats with calcium oxalate uroliths but is thought to occur. Hypercalcemia results in hypercalciuria, which may promote calcium oxalate formation. Approximately 5% of dogs and 35% of cats with calcium oxalate uroliths are hypercalcemic; primary hyperparathyroidism is the most common cause in dogs and idiopathic hypercalcemia is the most common cause in cats.

Metabolic acidosis promotes hypercalciuria by promoting bone turnover (release of calcium with buffers from bone), increasing serum ionized calcium concentration resulting in increased urinary calcium excretion, and decreased renal tubular reabsorption of calcium. Consumption of diets supplemented with the urinary acidifier ammonium chloride by cats has been associated with increased urinary calcium excretion. ²⁰ Significant aciduria (urine pH < 6.2) may represent a risk factor for calcium oxalate formation because of acidemia and hypercalciuria. In addition, acidic urine alters function and concentration of crystal inhibitors. Low urine pH decreases urinary citrate concentration by increasing renal proximal tubular citrate reabsorption. Acidic urine is known to impair function of macromolecular protein inhibitors. Inhibitors, such as citrate, magnesium, and pyrophosphate, form soluble salts with calcium or oxalic acid and reduce availability of calcium or oxalic acid for precipitation. Other inhibitors, such as Tamm-Horsfall glycoprotein and nephrocalcin, interfere with the ability of calcium and oxalic acid to combine minimizing crystal formation, aggregation, and growth. Oxalic acid is a metabolic end product of ascorbic acid (vitamin C) and several amino acids, such as glycine and serine, derived from dietary sources. Oxalic acid forms soluble salts with sodium and potassium ions, but a relatively insoluble salt with calcium ions. Therefore, any increased urinary concentration of oxalic acid may promote calcium oxalate formation. Decreased urine volume results in increased calcium and oxalic acid saturation and an increased risk for urolith formation. Medical protocols that will promote dissolution of calcium oxalate uroliths are not currently available; therefore, uroliths must be removed physically, either surgically or by voiding urohydropropulsion. ²¹ Nutritional and/or medical protocols should be considered to minimize urolith recurrence or prevent further growth of uroliths remaining in the urinary tract. Coals of dietary prevention include: 1) reducing urine calcium and oxalate concentration, 2) promoting high concentrations and activity of urolith inhibitors, 3) reduce urine acidity, and 4) promote dilute urine.

Dietary modification for prevention of calcium oxalate uroliths in dogs and cats includes inducing diuresis, restricting protein, promoting alkaluria, and restricting calcium. For cats with idiopathic hypercalcemia, feeding a higher fiber diet with supplemental potassium citrate may be effective. ²² Increasing urine volume is a mainstay of preventative therapy for calcium oxalate urolithiasis in human beings. By increasing water intake, urinary concentrations of calculogenic minerals are reduced. In addition, larger urine volumes typically increase urine transit time and voiding frequency, thereby reducing retention time for crystal formation and growth. Feeding cats a canned food is the most practical means of increasing water intake and lowering calcium oxalate urine saturation. Solubility of calcium oxalate in urine is minimally influenced by pH; however, epidemiologic studies consistently identify acidifying diets among the most prominent risk factors for calcium oxalate urolithiasis. ^6,23,24 Furthermore, aciduria promotes hypocitraturia, and functional impairment of endogenous urolith inhibitors. Potassium citrate is often included in diets designed for calcium oxalate prevention. In urine, citric acid combines with calcium to form soluble complexes, thereby reducing ionic calcium concentration. Citric acid also directly inhibits nucleation of calcium and oxalate crystals. Consumption of high levels of sodium may augment renal calcium excretion in human beings. Recent studies in healthy cats and dogs did not find increased urine calcium excretion in response high dietary salt intake. ^{25 26} Urinary magnesium forms complexes with oxalic acid, reducing the amount of oxalic acid available to form calcium oxalate. Studies in cats associate low dietary magnesium with calcium oxalate risk. There are currently, several commercial diets available for dogs and cats that meet these nutritional recommendations.

Urate

Uric acid is one of several biodegradation products of purine nucleotide metabolism. ²⁷ In most dogs and cats, allantoin is the major metabolic end product; it is the most soluble of the purine metabolic products excreted in urine. Ammonium urate is the monobasic ammonium salt of uric acid, and it is the most common form of naturally occurring purine uroliths observed to occur in dogs and cats. ²⁸ Urate uroliths may occur as a consequence of liver disease, specifically a portal vascular anomaly, or without the presence of liver disease, termed idiopathic urate urolithiasis. Urate uroliths occurring in association with portovascular anomalies are most commonly composed of ammonium urate, and often diagnosed before 1 year of age.

There apparently have been few studies of the biological behavior of ammonium urate uroliths in dogs with portal vascular anomalies ^{29 30 31–32} and none in cats. It is logical to hypothesize that elimination of hyperuricuria and reduction of urine ammonium concentration following surgical correction of anomalous shunts would result in spontaneous dissolution of uroliths composed primarily of ammonium urate. Appropriate clinical studies are needed to prove or disprove this hypothesis. Dissolution of urate uroliths in dogs without liver disease is possible using a protein-restricted, alkalinizing diet and allopurinol, although the success rate is approximately 40%. ²⁷ Restricting dietary protein results in lower concentrations of purine precursors that are converted to uric acid. Inducing alkaluria increases solubility of ammonium urate. A similar strategy is used for prevention. Although no studies have been performed evaluating the efficacy or safety of medical dissolution of urate uroliths in cats with idiopathic urate urolithiasis, we have successfully dissolved urate uroliths in cats using a low protein diet and allopurinol. Until further studies are performed to confirm the safety and efficacy of medical dissolution, surgical removal remains the treatment of choice for urate uroliths in cats. Prevention of urate urolith recurrence in cats has been > 90% when using a protein restricted, alkalinizing diet.