How would you manage cystine urocystoliths in a female Siamese cat?

Recently a colleague in private practice asked me for advice about how to treat cystine bladder stones formed by a 5.5 year-old, spayed female Siamese cat. Although textbooks that he consulted contained information about cystine urolithiasis in dogs, he was unable to find recommendations for this disorder in cats. How would you manage this case?

Photo 1: Photograph of multiple cystine urocystoliths removed from a 2-year-old female domestic shorthair cat.

Epidemiology

Unlike canine cystine uroliths, which most commonly are encountered in male dogs, feline cystine uroliths occur in males and females with equal frequency. In our experience, the mean age of cats at the time of diagnosis of cystine uroliths was 3.4 years (age range = 4 months to 12.2 years). Approximately 65 percent of cats were of the domestic shorthair breed and 20 percent were Siamese. One was a Maine Coon, one was a Korat, and two were domestic longhair cats.

Quantitative analysis of feline cystine uroliths submitted to the Minnesota Urolith Center revealed that most are pure. Pure cystine urocystoliths are usually ovoid and smooth (Photo 1, p. 16S). They typically have a light yellow to reddish brown color and vary in diameter from 0.5 mm to several centimeters. All uroliths submitted to the Minnesota Urolith Center were initially obtained from the lower urinary tract (~65 percent of samples came from the bladder, ~5 percent came from the bladder and urethra, ~5 percent came from the urethra, and ~25 percent of samples were voided). The number of uroliths in each patient varied from one to more than 100. Radiodense renoliths subsequently developed in two cats that initially had only urocystoliths.

Etiopathogenesis

Cystine is a nonessential sulfur-containing amino acid that is normally present in low concentrations in plasma. Normally it is freely filtered by glomeruli. Most filtered cystine is then actively reabsorbed by the proximal tubules. Cystinuria is characterized by impaired reabsorption of cystine and other amino acids by the renal tubules. Based on results of studies in humans and dogs, it is likely that feline cystinuria is an inborn error of metabolism. Empirical observations suggest that there may be an association between cystinuria and the Siamese breed. Evaluation of urine amino acid profiles of three affected cats revealed increased levels of arginine, lysine, and ornithine in addition to cystine. This pattern of aminoaciduria may be remembered with the acronym COLA (cystine, ornithine, lysine, and arginine). The major causes of morbidity and mortality recognized in association with cystinuria are sequelae of urolith formation. Because not all cystinuric cats form crystals or uroliths, cystinuria is a predisposing rather than a sole cause of cystine urolith formation.

Clinical findings

The initial clinical signs of affected cats are nonspecific (e.g. hematuria, dysuria, pollakiuria and/or urethral obstruction). They are typical of feline lower tract disease due to any cause.

The solubility of cystine in urine is pH dependent. It is relatively insoluble in acid urine, but becomes more soluble in alkaline urine. Although cystine is less soluble in acid than alkaline urine, the urine pH of affected cats may vary from 6.0 to 8.0. Detection of flat colorless hexagonal cystine crystals is a characteristic finding in urine samples collected from cats with cystine urocystoliths (Photo 2). The six sides of cystine crystals may or may not be equal, and the crystals tend to aggregate and may appear layered. Caution: Cystine crystals are not constantly present in cats with cystinuria or cystine uroliths.

Photo 2: Photomicrograph of aggregates of cystine crystals in sediment of urine collected from a 1-year-old female domestic shorthair cat. 40x = original magnification.

The radiodensity of cystine uroliths compared to soft tissue is similar to struvite, but less than calcium oxalate and calcium phosphate. Thus, when of sufficient size, cystine uroliths can be detected by survey radiography.

Double contrast cystography is more sensitive in detecting small cystine urocystoliths than either survey radiography and or most techniques of ultrasonography. Cystine uroliths appear radiolucent when surrounded by, but not completely submerged in, radiopaque contrast medium. Survey radiography may be insensitive in detecting cystine urethroliths. Positive contrast urethrography may be required to detect and localize cystine uroliths that have passed into the urethral lumen. Although uroliths can be detected by ultrasonography, this method does not provide information about the degree of their radiodensity or shape. Evaluation of the density and shape of uroliths by survey radiography often provides useful information in predicting their mineral type.

Biological behavior

We have had the opportunity to monitor the biological behavior of cystine urolithiasis in three cystine urolith-forming cats. One neutered female and one neutered male with a perineal urethrostomy have been evaluated for more than 10 years since the date of diagnosis. One neutered female cat has been monitored for seven years since the date of diagnosis. During the initial period of evaluation of these cats, the male with a perineal urethrostomy had 14 recurrent episodes of urocystoliths over a 4.5-year interval. One female had 68 recurrent episodes over a 7-year interval, and the other female had 28 recurrent episodes over a 1.5-year interval. The rate of recurrence of radiographically detectable cystine urocystoliths ranged from two weeks to approximately three months. Recurrent urocystoliths were removed by voiding urohydropropulsion. Two cats subsequently developed nephroliths presumed to be composed of cystine. Urocystoliths stopped forming in both cats after development of nephroliths.

In one cystinuric, arginuric, ornothinuric cat, transient, but severe, hyperammonemia associated with neurologic signs was recognized on three occasions. In this cystinuric cat, concomitant argininuria and ornithinuria likely were of sufficient magnitude on these occasions to cause depletion of urea cycle intermediates predisposing him to hyperammonemia. Recall that if cats do not consume adequate dietary sources of arginine to generate sufficient ornithine for conversion of ammonia and carbon dioxide to urea via the hepatic urea cycle, life-threatening hyperammonemia may result.

Urolith analysis

Quantitative analysis of uroliths provides a definitive diagnosis of cystinuria. Uroliths may be collected with a tropical fish net during the void phase of micturition, by aspiration through a urinary catheter or by voiding urohydropropulsion. Samples may be submitted to the Minnesota Urolith Center for quantitative analysis (FAX: 612-624-0751).

Treatment and prevention

Medical protocols that consistently promote dissolution of cystine uroliths in cats have not yet been developed. Likewise, lithotripsy is very unlikely to be of benefit in the management of cystine uroliths. At this time, surgery is the most reliable method to remove large stones from the urinary bladder.

However, if urocystoliths are detected while they are still small enough to pass through the urethra, they may be removed by voiding urohydropropulsion. We have used voiding urohydropropulsion to control recurrent urocystoliths in two cats (the male cat with a perineal urethrostomy had 12 recurrent episodes, and one female cat had 32 recurrent episodes).

Because cystinuria is an inherited metabolic defect, and because cystine uroliths rapidly recur in a substantial number of stone-forming cats, prophylactic therapy should be considered.

Current recommendations for prevention of recurrence of feline cystine uroliths encompass reduction in the urine concentration of cystine and increasing the solubility of cystine in urine. This strategy can be accomplished by a combination of dietary modification, diuresis and alkalinization of urine.

Diets that promote formation of acidic concentrated urine are risk factors for cystine urolithiasis in susceptible cats. Pending further studies, we recommend moist renal failure diets (such as canned Prescription Diet Feline k/d, Hill's Pet Nutrition) with the goal of increasing urine volume and minimizing formation of acid urine. If dry diets are fed, add liberal quantities of water to them. Strive to achieve a urine specific gravity value less than 1.030.

The solubility of cystine in urine is pH dependent. However, changes in urine pH that do not result in alkalinity are likely to have minimal effect on increasing cystine solubility. Therefore, recommending consumption of high-moisture alkalinizing diets is logical. If necessary, a sufficient quantity of potassium citrate or sodium bicarbonate may be given orally in divided dose to sustain a pH of approximately 7.5.

Data derived from studies of humans with cystinuria suggest that dietary sodium may enhance cystinuria. This information suggests that potassium citrate may be preferable to sodium bicarbonate as a urine alkalinizer. However, further studies are required to evaluate the effect of dietary sodium on urinary excretion of cystine in cats.

N-(2-mercaptopropionyl)-glycine (2-MPG), commonly called Thiola (Mission Pharmacal, San Antonio, Texas) has been successfully used in dogs to reduce urinary cystine concentration. In a 2-year-old spayed female domestic shorthair cat, we have reduced the rate of urocystolith recurrence from two-week intervals to approximately six-week intervals by daily administration of Thiola at an oral dose of 12 to 20 mg/kg given every 12 hours. Evaluation of hemograms and serum biochemistry profiles revealed no adverse events to 2-MPG therapy in this cat. We have successfully used a combination of 2-MPG therapy and voiding urohydropropulsioin to manage 36 recurrent episodes of cystine urocystoliths in this cat for almost four years. However, pending further safety and efficacy studies of Thiola in cats, we emphasize the need for continued caution when considering 2 MPG for treatment of cytine urolithiasis in this species.