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Compendium October 2009 (Vol 31, No 10)

Urate Urolithiasis

by John McCue, DVM, DACVIM (Small Animal Internal Medicine, Neurology), Cathy Langston, DVM, DACVIM (Small Animal Internal Medicine), Douglas Palma, DVM, DACVIM (Small Animal Internal Medicine), Kelly Gisselman, DVM, DACVIM (Small Animal Internal Medicine)

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    Abstract

    Urate uroliths belong to the purine family of uroliths and are the third most common urolith type in dogs and cats. In dalmatians, an autosomal recessive trait is responsible for hyperuricosuria and a predisposition to urate urolithiasis. In other dog breeds and in cats, urate uroliths are predominantly associated with liver disease, specifically portosystemic vascular anomalies. Idiopathic urate uroliths may occur in animals without liver disease. Ammonium urate uroliths are most common. Urate uroliths are amenable to medical dissolution. This article reviews the pathogenesis and management of urate urolithiasis.

    Urate and xanthine uroliths belong to the family of naturally occurring purine uroliths. Ammonium urate, a salt of uric acid, is the most common substance in urate uroliths.1 Urate uroliths are the third most common type of urolith in dogs but account for only 5% to 8% of uroliths submitted for analysis.2,3 A genetic predisposition has been documented in dalmatians and is suspected in English bulldogs.1,3 Other breeds reported to be overrepresented include the Yorkshire terrier, miniature schnauzer, shih tzu, and Russian black terrier.3,4 Urate uroliths are also associated with portovascular anomalies, although they can occur with any severe hepatic dysfunction.5 Similar to dogs, the prevalence of urate-containing uroliths in cats is low; however, these uroliths constitute the third most common feline urolith type submitted for analysis.6,7 Siamese cats may be predisposed.6,7 The pathogenesis in cats (with the exception of portosystemic vascular anomalies) remains unclear.8

    Pathogenesis

    Ingested protein and endogenous protein turnover are sources of purines, which are metabolized to hypoxanthine. Through the action of xanthine oxidase, hypoxanthine is converted to xanthine and uric acid (FIGURE 1). In most mammals, uric acid is converted to allantoin by the action of hepatic uricase, and only scant amounts of uric acid are excreted in urine.1 Allantoin is very soluble compared with uric acid.1 Uric acid excreted in the urine may complex with various cations (e.g., ammonium, sodium) to form urate salts. Ammonium is exceptional in its ability to precipitate uric acid in the form of ammonium urate9 (FIGURE 2). As urine becomes supersaturated with urate salts, urate uroliths may form.

    Whether uric acid complexes with other substances to form a less soluble salt depends on several factors. Hyperuricosuria is one factor implicated in the development of urate urolithiasis. Other factors include increased renal excretion or microbial urease production of ammonium ions, aciduria, and the presence of promoters (e.g., cellular debris, crystals) or lack of inhibitors (e.g., urinary glycoproteins) of urolith formation.1

    Dalmatians

    It is hypothesized that despite adequate concentrations of hepatic uricase, dalmatians have a defect in transmembrane transport of uric acid in hepatocytes and renal tubular cells.10 Early studies have shown that the hepatic membrane transport defect plays a significant role in hyperuricosuria in this breed.10 As a result, these dogs have a higher serum concentration of uric acid, and filtered uric acid is poorly reabsorbed in the renal tubules.10

    Although dalmatians exhibit relative hyperuricosuria, not all form uroliths.1 Urate urolith-forming dalmatians have been shown to excrete higher levels of uric acid in their urine; however, the pathogenesis in urolith-forming dogs is multifactorial.1,6,9-11 Approximately 92% to 97% of the urate uroliths from dalmatians that are submitted for analysis are from male dogs11,12 (FIGURE 2). The estimated prevalence of urate urolithiasis in male dalmatians ranges from 27% to 34%.13 Differences in anatomy, genetic factors, and urine composition are thought to account for the disparity in incidence between male and female dalmatians. In general, the urethra of female dogs is shorter and wider than that of males, which may allow small stones to be voided before detectable clinical signs develop. In one large, retrospective analysis of breed-related data for stone formation,14 male dalmatians were shown, in general, to have a significantly increased risk of urolith formation compared with females. Differences in the relative levels of inhibitors or promoters of calculogenesis may also exist between the sexes.15

    An autosomal recessive mode of inheritance controlled by a single autosomal gene pair (CFA03) was recently demonstrated for hyperuricosuria in dalmatians.16 However, it is not yet clear that this genetic marker will help breeders in identifying urolith-forming dogs.16

    Other Breeds

    In non-dalmatian breeds, most uric acid is metabolized in the liver to allantoin. The small amount of uric acid that is filtered at the glomeruli is largely reabsorbed by the proximal tubules, and trace amounts are excreted in the urine. Relatively little is known about naturally occurring urate urolithiasis in non-dalmatian breeds of dogs.17 Among these, English bulldogs have the highest incidence.3,18 Mildly elevated serum uric acid levels have been documented in English bulldogs with urate urolithiasis and normal hepatic function.1

    Hepatic Dysfunction

    Hepatic insufficiency and portovascular anomalies can predispose dogs and cats to urate urolithiasis by reducing hepatic conversion of uric acid to allantoin and of ammonia to urea. Urate urolithiasis is a common finding in patients with portovascular anomalies, but it is infrequently associated with hepatic insufficiency due to other causes.5

    Diagnosis

    Clinical Signs

    Clinical signs are usually referable to the level of the urinary tract affected and are indistinguishable from those of other lower urinary tract disease. Signs consistent with hepatic encephalopathy or liver failure may be noted if urate stones are a consequence of hepatic dysfunction.1,5 The average age at which urate urolithiasis is detected in dalmatians is 4.5 years (range: <1 to 16 years).14

    Laboratory Evaluation

    The results of a complete blood count and serum biochemical profile are usually normal. Azotemia, metabolic acidosis, and hyperkalemia are common in cases of obstructive uropathy. Changes compatible with concurrent liver dysfunction may be present. Alkaline phosphatase and alanine aminotransferase activities may be normal or increased and albumin and glucose levels may be decreased. Increased fasting and postprandial bile acid levels and/or increased plasma ammonia concentrations are concurrent findings in animals with portovascular anomalies.5 Urinalysis may reveal urate crystalluria. This finding should be considered abnormal in cats and non-dalmatian dogs1,17; however, urate crystalluria is not synonymous with urate urolithiasis. The chemical composition of a removed urolith can be confirmed by submission to a reference laboratory for quantitative analysis. Quantitative analysis can provide definitive information about mineral composition and guide therapy. Reference laboratories should be contacted for specific sample handling and submission instructions. In addition to urinalysis, urine should be submitted for culture to rule out concurrent infection as a complicating factor in management.

    Imaging

    Approximately 97% of urate uroliths are found in the bladder or urethra, with only 3% found in the kidneys or ureters.3 The stones are radiolucent, usually small (range: <1 mm to 1.5 cm), and round or ovoid. These characteristics lead to a 20% false-negative detection rate with survey radiography.19 Larger stones and those mixed with other components (particularly secondary infection-induced struvite) may be more visible. Double-contrast cystography is the best method for determining the size, shape, and number of stones. This technique has a detection rate of 78% for stones >1.0 mm and allows urethral calculi to be visualized.20 Ultrasonography may be used to visualize urate uroliths in the bladder or kidney. Ureteroliths often require excretory urography for detection.1,19

    Treatment

    Diet

    Urate uroliths are often amenable to dissolution through a combination of dietary modification, urine alkalization, and control of secondary infections (FIGURE 3). Protein (particularly purine) restriction is the foundation of medical management. Currently, two veterinary diets are marketed for this purpose in dogs. These diets are formulated to maintain alkaline urine. Protein restriction indirectly alters renal medullary tonicity by lowering blood urea nitrogen (BUN) content, which limits concentrating ability. Feeding a canned diet or adding water to dry formulations further increases urine volume. Diets severely restricted in protein content are contraindicated in growing or lactating animals. Recipes for homemade diets and modifications of commercially available formulas have been published, but their effectiveness has not been established.1,21

    Urine Alkalinization

    Urine pH is an important modifier of urate solubility. The optimum target range for urine pH is 7.0 to 7.5.1,8-10,19 Urine pH values >7.5 may predispose dogs to the formation of calcium phosphate uroliths.1,19 Additional agents are used when optimal urine pH is not achieved with diet alone (FIGURE 3). Potassium citrate (initial dose: 40 to 90 mg/kg PO q12h) is the preferred agent. Deposition of calcium phosphate over existing uroliths may complicate dissolution.

    Xanthine oxidase inhibitors are used to decrease uric acid production. Allopurinol, a synthetic isomer of hypoxanthine, is a potent inhibitor of xanthine oxidase22 that inhibits the conversion of hypoxanthine to xanthine and of xanthine to uric acid. Its biotransformation takes place primarily in the liver.22 Allopurinol is poorly bound to plasma proteins and is excreted primarily by the kidneys; therefore, it should be used cautiously in animals with hepatic or renal dysfunction. Its half-life in dogs is approximately 2.5 hours. The bioavailability of allopurinol is not affected by food.

    The initial dose of allopurinol is 15 mg/kg PO bid for 4 weeks, at which time, the size, shape, and number of calculi should be reevaluated. The level of uric acid excretion in the urine may be used to guide dose adjustments after the first month. Measurement of urinary uric acid excretion over 24 hours (target level: <300 mg urate/24 hr) gives the most accurate value; however, it is difficult to obtain a complete 24-hour urine collection.23 Single urinary uric acid:creatinine ratios can be used to document a decrease in uric acid excretion.24

    On average, urate cystoliths dissolve over 3.5 months (range: 1 to 18 months) when a combination of diet, pH modification, and xanthine oxidase inhibition is used.1 In male dogs, dissolving cystoliths may move into the urethra and cause clinical signs of obstruction. Retrograde urohydropropulsion can be used to relieve obstructions.21

    Allopurinol should not be used in patients with portosystemic shunts.5 Decreased hepatic metabolism may result in a prolonged half-life and adverse effects, including augmented xanthine oxidase inhibition that causes xanthine urolithiasis. Allopurinol is also an inhibitor of the hepatic microsomal P450 system and should be used judiciously with other drugs that depend on biotransformation in the liver.25 Adverse effects noted in people include skin rash, gastrointestinal disturbances, thrombocytopenia, vasculitis, and hepatitis with other immune-mediated reactions. Many of these reactions were noted in people with existing renal dysfunction.26 There is only one report of potential immune-mediated hemolytic anemia and trigeminal neuropathy in a dog.26

    Allopurinol should be used only in conjunction with a protein-restricted diet. Excessive purine precursors in the diet may predispose patients to xanthinuria and the formation of xanthine uroliths.27 If xanthine urolithiasis occurs, allopurinol should be discontinued for 1 to 2 months while dietary therapy and urine alkalinization is continued to allow the uroliths to dissolve. Xanthine exhibits solubility characteristics similar to those of urate in alkaline urine. Following resolution of xanthine urolithiasis, allopurinol can be reintroduced with a 25% reduction in dose.

    In patients with cystic uroliths that are smaller in diameter than the distended urethra, voiding urohydropulsion or catheter-assisted retrieval may be used to retrieve remaining uroliths and monitor therapy1 (FIGURE 3).

    Infection Control

    Any existing urinary tract infection should be eliminated. Infections are generally considered to be secondary to urolith-induced trauma or to catheterization or other invasive procedures.28

    Nonmedical Management

    If medical dissolution is not pursued, surgical and nonsurgical options are available. Surgery is the most definitive method of treatment.1 Surgical attenuation is recommended for definitive treatment of identified cystic calculi.5 In patients with portosystemic shunts, correction of the shunt may result in spontaneous dissolution of urate uroliths if hepatic perfusion is reestablished. If shunt correction is contraindicated, dietary management is recommended.5

    Voiding urohydropulsion has been described as a means of obtaining stones for analysis and for removing cystic uroliths, when appropriate.19 Retrograde urohydropulsion can be used to temporarily relieve any urethral obstruction while a patient is stabilized for surgery.19,a

    Lithotripsy is a recent addition to the list of management options for urinary calculi in dogs and cats. Shock wave lithotripsy and laser lithotripsy techniques have been described.29-31 Although extracorporeal shock wave lithotripsy (ESWL) is useful in managing nephroliths and ureteroliths, its use for urate uroliths is poorly described, perhaps partly because these uroliths occur infrequently in the upper urinary tract.29 Successful resolution was achieved in two of five dogs with purine uroliths of the upper urinary tract using ESWL.30 ESWL is not currently recommended for treatment of cystic uroliths in dogs and cats.

    Laser lithotripsy has been evaluated for the treatment of ureteral, cystic, and urethral uroliths. Laser lithotripsy has become more widely available and may be more practical than ESWL for veterinary patients. When a holmium:YAG laser is used to fragment uroliths, stone composition does not have a significant effect on fragmentation time.29 Laser fragmentation of urate uroliths can result in uric acid conversion to cyanide.31 The risk of clinical toxicity is considered to be very low, and laser lithotripsy has been used for urate uroliths without complications.30 As more experience is gained with laser lithotripsy and this procedure becomes more widely available at referral institutions, it may replace other therapies for cystic urate urolithiasis.

    Evaluating Response to Medical Therapy

    Periodic evaluation is necessary to assess owner compliance and the rate of urolith dissolution. After the initial enumeration and measurement of uroliths, patients should be reevaluated monthly until uroliths are no longer present. Double-contrast cystography or ultrasonography is usually necessary. Urine pH, specific gravity, and sediment analysis should be evaluated along with BUN to determine the success of medical therapy. If uroliths fail to decrease in size, or if they increase in size during the initial 8 weeks of therapy, the diagnosis should be reevaluated or an alternative management option pursued.1

    Prevention

    The foundation of preventive therapy is increased water consumption and dietary modification (TABLE 1). The aforementioned prescription diets are appropriate for long-term feeding. Feeding of an exclusively canned diet is recommended. Use of ultralow-protein diets has been associated with dilated cardiomyopathy in English bulldogs and a few dalmatians.32,33 Taurine and/or carnitine deficiency may underlie the development of dilated cardiomyopathy in predisposed dogs.32 Oral taurine supplementation has not been definitively shown to affect outcome.33 It has been suggested that English bulldogs be fed a low-protein renal diet instead of an ultralow-protein diet, with allopurinol administered as needed.34 Allopurinol may be continued as maintenance therapy in cases of recurrent urate urolithiasis. Because of the risk of xanthine uroliths with long-term administration, regular monitoring is important.1

    Despite general hyperuricosuria in dalmatians, prescription diets may not be indicated in all patients and should be used on an individual basis.1,8,11,19 Because of the low risk of clinical urate urolithiasis, the rationale for prophylaxis in female dalmatians has been questioned.11 The general recommendation is to limit protein sources that are high in purines in this breed19 (BOX 1). It is suggested that protein consumption be limited to <20% protein on a dry matter basis.1 Given the relatively late onset of clinical signs and multiple factors involved, breeding selection against this trait is difficult.

    Cats

    Urate uroliths are the third most common urolith type in cats, accounting for approximately 6% to 9% of feline uroliths submitted for analysis.6,7 Unlike struvite and calcium oxalate uroliths, the incidence of urate uroliths seems to have remained stable over the past 2 decades. In cats, urate uroliths are found almost exclusively in the bladder, and males and females are equally affected.7 With the exception of portovascular anomalies, the pathogenesis of urate uroliths in cats is unknown. Screening for occult hepatopathy is recommended in all cats with urate-containing uroliths.8,34 Suggested risk factors in cats include the formation of highly acidic, highly concentrated urine associated with diets high in purine precursors.8

    Surgery remains the treatment of choice in cats, as medical dissolution protocols have not been developed for this species. Additional studies of the efficacy and safety of allopurinol in cats are needed. Successful dissolution has been noted only anecdotally. Any concurrent infections should be treated based on culture and sensitivity testing. Prevention is similar to that in dogs and is centered on feeding a low-protein diet, limited in purine precursors, that promotes formation of moderately dilute urine of neutral pH.14 There is no feline equivalent of the canine prescription diets; however, prescription feline diets for the management of renal disease have been used with success. Many of these diets are formulated with potassium citrate. Prevention of recurrence was noted to be >90% with one such diet.34 The addition of supplemental potassium citrate can be used to achieve an appropriate urine pH.

    Conclusion

    Urate and xanthine uroliths are generally uncommon, except in dalmatians. Ultrasonography and double-contrast cystography are the best imaging techniques for diagnosing these radiopaque calculi. The presence of urate uroliths or crystalluria in a breed that is not predisposed should prompt evaluation for a portosystemic shunt. Urate uroliths are generally small and may be removed by dissolution, nonsurgical, or surgical techniques. Purine- and protein-restricted diets that alkalinize the urine are recommended for dissolution, as well as for prevention in male dalmatians. Allopurinol is used in some cases to aid dissolution and prevention.

    To Learn More

    This article is part of a series on the pathogenesis and treatment of urolithiasis. The first article is titled, "Diagnosis of Urolithiasis" (August 2008).

    Downloadable PDF

    1. Bartges JW, Osborne CA, Lulich JP, et al. Canine urate urolithiasis: etiopathogenesis, diagnosis, and management. Vet Clin North Am Small Anim Pract 1999;29(1):161-191.

    2. Osborne CA, Lulich JP, Polzin DJ, et al. Analysis of 77,000 canine uroliths. Perspectives from the Minnesota Urolith Center. Vet Clin North Am Small Anim Pract 1999;29:17-38.

    3. Houston DM, Moore AE, Favrin MG, et al. Canine urolithiasis: a look at over 16,000 urolith submissions to the Canadian Veterinary Urolith Centre from February 1998 to April 2003. Can Vet J 2004;45(3):225-230.

    4. Bende B, Nemeth T. High prevalence of urate urolithiasis in the Russian black terrier. Vet Rec 2004;155(8):239-240.

    5. Bartges JW, Cornelius LM, Osborne CA. Ammonium urate uroliths in dogs with portosystemic shunts. In: Bonagura JD, ed. Kirk's Current Veterinary Therapy XIII. Philadelphia: WB Saunders; 2000:872.

    6. Houston DM, Moore AEP, Favrin MG, et al. Feline urethral plugs and bladder uroliths: a review of 5484 submissions (1998-2003). Can Vet J 2003;44:974-977.

    7. Cannon AB, Westropp JL, Ruby AL, et al. Evaluation of trends in urolith composition in cats: 5,230 cases (1985-2004). JAVMA 2007;231:570-576.

    8. Osborne CA. Diseases of the lower urinary tract. In: Finco DR, Osborne CA, eds. Canine and Feline Urology and Nephrology. Baltimore: Lippincott Williams and Wilkins; 1995:822-833.

    9. Sorenson JL, Ling GV. Diagnosis, prevention, and treatment of urate urolithiasis in dalmatians. JAVMA 1993;203(6):863-869.

    10. Sorenson JL, Ling GV. Metabolic and genetic aspects of urate urolithiasis in dalmatians. JAVMA 1993;203(6):857-862.

    11. Albasan H, Lulich JP, Osborne CA, et al. Evaluation of the association between sex and risk of forming urate uroliths in dalmatians. JAVMA 2005;227(4):565-569.

    12. Ling GV, Franti CE, Ruby AL, et al. Urolithiasis in dogs I: mineral prevalence and interrelations of mineral composition, age, and sex. Am J Vet Res 1998;59:624-629.

    13. Bannasch DL, Ling GV, Bea J, et al. Inheritance of urinary calculi in the dalmatian. J Vet Intern Med 2004;18:483-487.

    14. Ling GV, Franti CE, Ruby Al, et al. Urolithiasis in dogs II: breed prevalence and interrelations of breed, sex, age, and mineral composition. Am J Vet Res 1998;59(5):630-642.

    15. Carvalho M, Lulich JP, Osborne CA, Nakagawa Y. Role of urinary inhibitors of crystallization in uric acid nephrolithiasis: dalmatian dog model. Urology 2003;62(3):566-570.

    16. Safra N, Schaible RH, Bannasch DL. Linkage analysis with an interbreed backcross maps dalmatian hyperuricosuria to CFA03. Mamm Genome 2006;17(4):340-345.

    17. Kruger JM, Osborne CA. Etiopathogenesis of uric acid and ammonium urate uroliths in non-dalmatian dogs. Vet Clin North Am Small Anim Pract 1986;16:87-126.

    18. Bartges JW, Osborne CA, Lulich JP, et al. Prevalence of cysteine and urate uroliths in bulldogs and urate uroliths in dalmatians. JAVMA 1994;204(12):1914-1918.

    19. Adams LG, Syme HM. Canine lower urinary tract diseases. In: Ettinger SJ, Feldman E, eds. Textbook of Veterinary Internal Medicine. Philadelphia: WB Saunders; 2006:1850-1874.

    20. Weichselbaum RC, Feeney DA, Jessen CR, et al. Urocytolith detection: comparison of survey, contrast radiographic and ultrasonographic techniques in an in vitro bladder phantom. Vet Radiol Ultrasound 1999;40(4):386-400.

    21. Osborne CA, Bartges JW, Lulich JP, et al. Canine urolithiasis. In: Hand MS, Thatcher CD, Remillard RL, et al, eds. Small Animal Clinical Nutrition. 4th ed. Topeka: Mark Morris Institute; 2000:605-688.

    22. Hande K, Reed E, Chabner B. Allopurinol kinetics. Clin Pharmacol Ther 1978;23(3):598-605.

    23. Bartges JW, Osborne CA, Felice CJ, et al. Reliability of single urine and serum samples for estimation of 24-hour urinary uric acid excretion in six healthy beagles. Am J Vet Res 1994;55:472-476.

    24. Moentk JA, Dibartola SP, Buffington CA. Effect of allopurinol on urine urate-to-creatinine rations in normal dalmatians. JAAHA 1994;30:483-486.

    25. Vessell ES, Passananti GT, Greene FE. Impairment of drug metabolism in man by allopurinol and nortriptyline. New Engl J Med 1970;313:1484-1499.

    26. Pedroia V. Allopurinol-induced immune disorders. Canine Pract 1980;8:19-22.

    27. Bartges JW. Canine xanthine uroliths: risk factor management. In: Kirk RW, Bonagura JD, eds. Kirk's Current Veterinary Therapy IX. Philadelphia: WB Saunders; 1992:900-905.

    28. Lees GE. Bacterial urinary tract infections. Vet Clin North Am Small Anim Pract 1996;26:297-304.

    29. Davidson EB, Ritchey JW, Higbee RD, et al. Laser lithotripsy for treatment of canine uroliths. Vet Surg 2004;33:56-61.

    30. Adams LG. Lithotripsy using shockwaves and lasers. Proc 24th Annu ACVIM Forum 2006:439-441.

    31. Teichman JM, Vassar GJ, Glickman RD, et al. Holmium:YAG lithotripsy: photothermal mechanism converts uric acid calculi to cyanide. J Urol 1998;160:320-324.

    32. Freeman LM, Mitchel KE, Brown DJ, et al. Idiopathic dilated cardiomyopathy in dalmatians: nine cases (1990-1995). JAVMA 1996;209(9):1592-1596.

    33. Freeman LM, Rush JE, Brown DJ, et al. Relationship between circulating and dietary taurine concentrations in dogs with dilated cardiomyopathy. Vet Ther 2001;2(4):370-378.

    34. Bartges J, Kirk C. Nutrition and urolithiasis. Proc 25th Annu ACVIM Forum 2007:13-15.

    aVoiding and retrograde urohydropulsion, along with other methods of removing uroliths, will be described in a future article in this series.

    References »

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