Objectives of Presentation

Following this presentation, the attendee should be able to:

• Describe minerals that form uroliths in dogs and cats.
• Describe mechanism(s) of urolith formation.
• Describe management of urolithiasis including medical dissolution, minimally invasive procedures, and preventative measures.

Evolving Understanding or Urolith Formation and Assessment

Formation of uroliths is not a disease, but rather a complication of several disorders.¹ A common denominator of urolithiasis is that urine can, from time to time, be oversaturated with one or more crystal precursors resulting in formation of crystals.

Urolith formation, dissolution, and prevention involves complex physical processes including:

1.  Supersaturation resulting in crystal formation.

2.  Effects of inhibitors of crystallization and inhibitors of crystal aggregation and growth.

3.  Crystalloid complexors.

4.  Effects of promoters of crystal aggregation and growth.

5.  Effects of noncrystalline matrix.²

Assessment of urolith formation risk and response to therapy is difficult and has been based on results of epidemiological studies, measurement of urinary mineral concentrations,^3,4 and urinary pH. Because supersaturation of urine with stone-forming substances is necessary for stones to form, measurement of urine saturation is a more accurate means of assessing risk of stone formation, Determining the relative supersaturation (RSS)of a urolith-forming substance in urine is one technique.⁵ RSS values are limited by the fact that the constants used for these calculations have not been measured in the patient’s urine and it may overestimate activity of different minerals, and tend to underestimate risk of urolith formation. Activity product ratios (APR) are another method although an exact measurement of supersaturation is not obtained. APR does not eliminate errors associated with effect of unknown factors; however, since the same urine sample is analyzed before and after equilibration with seed crystals, the same type of error occurs in evaluation and errors cancel. APR overestimates under saturation, underestimates supersaturation, and correctly measures saturation. One limitation of APR determination is the assumption that urine has reached the stability for the salt following incubation.⁶ Limited studies utilizing urine saturation testing have been performed in veterinary medicine, and few have been performed in dogs or cats that are urolith-formers and no studies exist that compares estimates of urinary saturation with recurrence rates of uroliths. Urinary supersaturation represents a risk for urolith formation, but there is overlap between urolith-forming animals and healthy, non-urolith-forming animals.⁷

Clinical Application to Dogs and Cats

• Urinary saturation is the most important, but not the only, driving force for crystallization and urolith formation.
• Several methods exist for estimating urinary saturation; however, none of them adequately describe what is occurring naturally in the biological system (urinary tract).
• Determination of RSS and APR give different results and information. Determination of RSS is a valuable and reasonably reliable technique for estimating urinary saturation; however, it (a) is influenced by concentration of analytes measured, which, in turn, is influenced by urine volume, and (b) it does not account for urinary constituents that are not measured including the influence of inhibitors. Because it is influenced by urine volume, methods designed to increase urine volume (e.g., feeding canned foods, administration of diuretics, and stimulating water consumption by increased levels of dietary sodium) would be expected to lower the relative supersaturation; however, clinical studies in urolith forming dogs and cats are lacking. APR does not give an exact estimation of the supersaturation; however, because a patient’s urine is used pre- and post­incubation with seed crystals, this technique does account for unmeasured urinary constituents and the influence of inhibitors.
• Medical dissolution of uroliths is accomplished by inducing a state of under saturation of urine with the minerals that formed the uroliths.
• Medical prevention of uroliths is accomplished by inducing a state of under saturation of urine or at least a state of saturation at the lower end of the metastability limit.
• Despite use of estimates of urinary saturation, there are no published studies in urolith-forming dogs and cats that validate their prediction of urolith recurrence.
• Means to decrease urinary saturation include increasing urine volume thereby decreasing concentrations of calculogenic substances and decreasing dietary intake of calculogenic substances. Despite these measures, they do not guarantee prevention of urolith recurrence in all patients demonstrating that urolith formation is a complex process and many questions remain unanswered.

Evolving Management of Urolithiasis

In 2016, the ACVIM released a consensus on management of urolithiasis in dogs and cats, which is available as an open source document at www.acvim.org and summarized.⁸

Lower Urinary Tract Uroliths

Struvite uroliths (i.e., moderately radiopaque uroliths in dogs with alkaline urine and a urinary tract infection caused by urease-producing bacteria (such as Staphylococcus spp.), and moderately radiopaque uroliths in cats with approximately neutral urine pH) should be medically dissolved unless: 1) medications or dissolution foods cannot be administered or are contraindicated, 2) uroliths cannot be adequately bathed in modified urine (e.g., urinary obstruction, large solitary urocystoliths occupying almost all of the urinary bladder), or 3) uncontrollable infection despite appropriate medical management and owner compliance. Medical dissolution for struvite uroliths is highly effective and infection-induced struvite usually dissolve in 8 weeks while sterile struvite dissolve in less than 2–5 weeks.^9,10 Urocystoliths small enough to pass through the urethra should be removed by medical dissolution, voiding urohydropropulsion, basket retrieval, or other extraction procedures that do not involve surgical intervention. Urocystoliths too large to pass through the urethra should be removed by medical dissolution, intracorporeal laser lithotripsy, or percutaneous cystolithotomy.^11,12 Consider medical dissolution of urate uroliths before removal. Hyperuricosuria, concentrated urine, and acidic urine are the predominant factors driving urate urolith formation.¹³ In most dogs and cats, uric acid is transported to the liver where it is metabolized by uricase to allantoin. A defective uric acid transporter (i.e., SLC2A9 genetic mutation) and hepatic porto-vascular anomalies are common causes for hyperuricosuria and urate urolithiasis.¹⁴ However, for some animals, especially cats, the cause(s) for hyperuricosuria and urate urolith formation remains idiopathic. Dissolution of urate uroliths in dogs usually is accomplished within 4 weeks by feeding a purine-restricted, alkalinizing, diuretic diet, and administering a xanthine oxidase inhibitor (i.e., allopurinol: 15 mg/kg PO q12h).¹³ Dissolution has not been possible in cats or in dogs and cats with uncorrected liver disease. Cystine uroliths form, in part, because of decreased proximal tubular reabsorption of cystine. Consumption of a decreased protein, urine-alkalinizing, canned food a with 2-mercaptopropionylglycine at a dosage of 15–20 mg/kg PO q12h successfully dissolves cystine stones.¹⁵ Cystine solubility increases with increasing urine pH. In vitro studies that achieved a urine pH >7.5 increased efficacy of thiol-binding drugs to solubilize cystine in the urine. Administration of 2-mercaptopropionylglycinewithout modifying the diet is associated with dissolution.^15,16 Dissolution should be attempted cautiously in cats because of intolerance of 2-mercaptopropionylglycine. Dogs and cats without clinical signs but with non-dissolvable uroliths too large to pass into the urethra or too irregular to cause urethral obstruction need only periodic monitoring and appropriate client education. With the onset of clinical signs (e.g., hematuria, dysuria, UTI, urolith removal should be considered. Educate clients about clinical signs of urinary obstruction. In order to minimize patient discomfort and unnecessary damage to healthy tissues, nonsurgical removal methods (e.g., dissolution, basket retrieval, lithotripsy, percutaneous cystolithotomy) should be considered for nonclinical urocystoliths that are likely to cause urinary obstruction. Urethroliths should be managed by intracorporeal lithotripsy and basket retrieval.¹⁷ In male dogs and cats urethroliths can be urohydropropulsed retrograde back into the bladder and retrieved by percutaneous cystolithotomy or cystotomy.¹⁸ Urethrostomy can be considered to minimize future urethral obstruction in highly recurrent stone-forming animals. Rigid adherence to strategies to prevent urolith recurrence, however, should be considered first. Because of the high frequency of morbidity and adverse effects associated with urethral surgery, urethral surgeries are discouraged except under few circumstances.

Upper Urinary Tract Uroliths

Only problematic nephroliths require treatment such as outflow obst ruction, recurrent infection, pain, and those enlarging to the point of causing renal parenchymal compression, should be considered for removal in dogs and cats. Dissolution only should be considered for nonobstructive nephroliths or if the obstruction can be concomitantly alleviated or bypassed (e.g., urethral stenting). The presence of nephroliths in cats with chronic kidney disease did not significantly affect the progression of renal disease.¹⁹ Treatment for other nephroliths potentially amenable to dissolution should be addressed on a case-by-case basis considering the stability of kidney function and the likelihood of complete removal or dissolution. Approximately 20–30% of upper urinary tract uroliths in dogs are suspected to be struvite for which dissolution should be effective. Rapid control of infection while avoiding surgical urolith extraction should maximally preserve kidney function.²⁰ Dissolution should not be attempted in cats with obstructive upper urinary tract uroliths. Over 90% of nephroliths and ureteroliths in cats are compose d primarily of calcium oxalate. Delaying appropriate care may contribute to an irreversible decrease in kidney function.²⁰ Problematic nephroliths should be removed by 1) dissolution, 2) endoscopic nephrolithotomy (i.e., for nephroliths too large for extracorporeal shock wave lithotripsy and for nephroliths in cats), and 3) extracorporeal shockwave lithotripsy (for nephroliths in dogs only). Extracorporeal shockwave lithotripsy has minimal effects on renal function but is reserved for nephroliths ≤1.5 cm in diameter. Nephroliths >1–1.5 cm often require concurrent ureteral stent placement. A diagnosis of a ureteral obstruction should be based on ultrasonographic findings of hydronephrosis and associated hydroureter proximal to an obstructive ureterolith regardless of the degree of the renal pelvic dilatation. If renal pelvic dilatation is <5 mm, careful imaging is needed to confirm obstruction unless it is associated with concurrent hydroureter proximal to an obstructive urolith. If no obstructive lesion is seen on ultrasound examination, abdominal radiography should be performed concurrently to evaluate for the presence of nephroureteroliths. If ureteroliths are not visualized, a ureteral obstruction is not necessarily excluded, because ureteral strictures are common (>25% of cats). In a study evaluating the causes of hydronephrosis, all renal pelves >13 mm were associated with ureteral obstruction and those >7 mm were likely associated with ureteral obstruction. Partial and complete ureteral obstructions should be managed as an emergency regardless of whether the obstruction is partial or complete. lnterventional procedures, such as ureteral stents and subcutaneous ureteral bypass, have a lower morbidity and mortality rate for ureteral obstruction than do traditional surgical options in both dogs and cats, respectively.²¹ Medical management of stable obstructive ureterolithiasis can be considered for 24–72 hours. Medical treatment should include fluid diuresis and mannitol continuous rate infusion treatment, if tolerated. Alpha adrenergic antagonists and tricyclic antidepressants also have been used with anecdotal reports of improvement in some cases. Medical treatment should not be continued in animals that are persistently oliguric or anuric, hyperkalemic, have progressive azotemia and progressive renal pelvic dilatation; minimally invasive urolith extraction or bypass is needed. Fluid treatment should be closely monitored to prevent overhydration. In dogs, in addition to propulsive treatment for uroliths, broad-spectrum antimicrobials IV (ideally for at least 24 hours before intervention) should be administered. Ureterolith-induced ureteral obstructions should be monitored rather than decompressed when renal pelvic dilatation is ≤3–5 mm, and renal function is stable. Medical management for the treatment of cats with ureteral obstructions is only reported to be effective in 8–13% of cases.²⁰ Because over 25% of ureteral obstructions in cats are associated with concurrent ureteral strictures, success of medical management often is limited. Subcutaneous ureteral bypass or ureteral stenting for ureteral obstructions in cats should be considered the first choice for the best possible outcome. lnterventional options such as ureteral stent placement, extracorporeal shockwave lithotripsy, or both for the treatment of ureteral obstructions in dogs always should be considered and offered to clients. Ureteral stents are associated with the lowest short- and long-term morbidity and mortality rates when compared to all other reported treatment options. Careful assessment of urinalysis (e.g., crystals, urine pH), urine culture results, radiographic appearance, and when possible, quantitative urolith analysis should always be performed. In dogs, suspected struvite ureteroliths should be stented and then dissolved. Suspected obstructed calcium oxalate ureteroliths should be either stented for long-term treatment or stented with concurrent or subsequent extracorporeal shockwave lithotripsy, if necessary. Cystine and urate ureteroliths should be treated by a ureteral stent and concurrent medical and dietary treatment. Ureteral stents in dogs often can be placed endoscopically. Owners should be aware of re-obstruction risks that are most often associated with concurrent ureteral stricture. Knowing the urolith composition will help by employing appropriate medical and dietary treatment to prevent stent encrustation and future urolith formation. If stenting fails, other options such as extracorporeal shock wave lithotripsy and subcutaneous ureteral bypass device placement, or traditional surgery, can be considered. Dogs with ureteral obstruction should have their urine cultured and should be given antimicrobial treatment at the time of diagnosis because of the high incidence of concurrent UTI and pyonephrosis.

Prevention of Uroliths

Removal or bypass of uroliths will not alter the underlying conditions responsible for their formation. The most effective prevention strategies are those that eliminate the underlying cause. For cases in which a cause remains elusive or cannot be altered, minimize pathophysiologic risk factors associated with formation. Nutritional treatment remains a subject of much clinical interest and debate because of epidemiological and pathophysiological data associating nutrient intake with urine saturation and lithogenicity. For all mineral types (except infection-induced struvite), feeding diets high in moisture is one of the cornerstones of urolith prevention strategies. Primary treatment for preventing infection-induced struvite uroliths, which is the most common struvite urolith in dogs, is early identification and elimination of UTI. Eliminating these infections will prevent recurrence of infection-induced struvite uroliths. Foods marketed to treat struvite urolithiasis will not prevent their recurrence but may delay or minimize, urolith burden in the presence of unrecognized UTI. Calcium oxalate urolithiasis in dogs and cats appears to be driven primarily by hypercalciuria in association with either hypercalcemia (e.g., primary hyperparathyroidism, idiopathic hypercalcemia in cats) or normocalcemia.⁶

Selection of effective preventative treatment is challenging because:

1.  Properly designed clinical trials evaluating urolith recurrence have not been published.

2.  The exact mechanisms underlying calcium oxalate urolith formation are not completely understood.

3.  Associative factors identified in epidemiological studies have not been proven to result in disease.

4.  Surrogate endpoints of therapeutic efficacy such as relative supersaturation are mathematical models that may not correlate well with calcium oxalate urolith formation.

The high recurrence rate of calcium oxalate uroliths warrants a comprehensive approach and regular monitoring. High-moisture (>75% water) foods or adding water to dry food should be recommended. Strive to achieve a urine specific gravity ≤1.020 in dogs and <1.030 in cats Increasing dietary protein from 35% to 57% (dry matter) increased urine calcium concentration by 35% and decreased urine citrate concentration by 45% in cats.²⁶ In dogs and cats with hypercalcemia, correcting or controlling hypercalcemia aids in preventing calcium oxalate urolith recurrence. Doing so is difficult in cats with idiopathic hypercalcemia and no single treatment has been shown to be effective, including glucocorticoids, bisphosphonate administration, or dietary modification using a high-fiber diet with potassium citrate administration.²² Feeding high-sodium (>375 mg/100 kcal) dry foods should not be a recommended as a substitute for high-moisture foods. High-sodium foods increase urinary water excretion, but the effects appear to be short-lived (i.e., 3–6 months).²³ Potassium citrate is an alkalinizing salt that when administered PO and metabolized promotes the excretion of more beneficial alkaline urine. Alkaline urine enhances urinary citrate excretion, which is a chelator of calcium ions. Consider thiazide diuretics for frequently recurrent calcium oxalate uroliths as they enhance the renal tubular reabsorption of filtered calcium. Some recommend the concomitant administration of potassium citrate because thiazide diuretics contribute to urine acidification. A 55% decrease in urinary calcium concentration was reported in urolith-forming dogs that were treated with hydrochlorothiazide at a dosage of 2 mg/kg q12h.²⁴ A 65% decrease in urinary calcium oxalate relative supersaturation was reported in clinically normal cats receiving hydrochlorothiazide at a dosage of 1 mg/kg q12h.²⁵ In order to minimize urate urolith recurrence, decrease urine concentration, promote alkaline urine, and limit purine intake. For dogs with the SLC2A9 mutation, urate urolith recurrence can be minimized by increasing fluid intake, promoting alkaline urine (pH ≥7), and limiting purine intake. In cats and dogs with porto­vascular anomalies, correcting of the vascular anomaly should also be considered, if appropriate. Data in cats are limited, but purine restriction and urine alkalization are recommended. High-moisture (>75% moisture) foods or adding water to dry food is recommended. Strive to achieve a urine specific gravity ≤1.020 in dogs and <1.030 in cats. Additional water consumption to achieve lower urine concentrations of uric acid provides more effective prevention. Urate solubility increases with increasing urine pH.¹³ Decreasing dietary protein has been shown to decrease urinary saturation with ammonium urate in dogs. Selecting an effective food may be difficult because properly controlled studies evaluating urolith recurrence are rare. Consider xanthine oxidase inhibitors for dogs homozygous for genetic hyperuricosuria that have failed therapeutic diet prevention. Use a dosage of 5–7 mg/kg q12–24h to safely prevent urate uroliths. Administration of xanthine oxidase inhibitors should be avoided in dogs that are not receiving decreased purine diets to minimize the risk of xanthine urolith formation. Xanthine oxidase inhibitors have not been formally investigated in cats. In order to minimize cystine urolith recurrence, decrease urine concentration, limit animal protein intake, limit sodium intake, increase urine Ph, and neuter. Newer classification systems for cystinuria have been published recently.²⁶ High-moisture (>75% moisture) foods or adding water to dry food is recommended. Strive to achieve a urine specific gravity ≤1.020 in dogs and <1.030 in cats. Cystine solubility increases with increasing urine pH. In vitro studies that achieved a urine pH >7.5 increased the efficacy of thiol drugs to solubilize cystine in the urine of cystinuric humans. Therefore, potassium citrate or other alkalinizing citrate salts should be administered to dogs and cats with persistently acidic urine. The dosage should achieve a urine pH of approximately 7.5. Diets for the prevention of cystine uroliths should be low in methionine and cystine precursors with adequate amounts of taurine and carnitine. Feeding high-protein diets, particularly those rich in methionine, a cystine precursor, should be avoided in cystinuric dogs. In some forms of cystinuria, neutering has been associated with decreases in cystine concentration because of a suspected androgen-dependent effect, but this effect is not universal. In recurrent cystine urolith formers, add 2 mercaptopropionylglycine to prevention strategies to further lower cystine concentration and increase cystine solubility. Dosages are 15 mg/kg PO q12h.

References

1.  Bartges JW. Urinary saturation testing. In: Bartges J, Polzjn DJ, eds. Nephrology and Urology of Small Animals. Ames, IA: Wiley-Blackwell; 2011:75–85.

2.  Bartges JW, Osborne CA, Lulich JP, et al. Methods for evaluating treatment of uroliths. Vet Clin North Am Small Anim Pract. 1999;29:45–57.

3.  Osborne CA, Polzin DJ, Abdullahi SU, et al. Struvite urolithiasis in animals and man: formation, detection, and dissolution. Adv Vet Sci Comp Med. 1985;29:100–101.

4.  Bartges JW, Osborne CA, Pozin DJ. Recurrent sterile struvite urocystolithiasis in three related Cocker Spaniels. J Am Anim Hosp Assoc. 1992;28:459–469.

5.  Brown C, Purich D. Physical-chemical processes in kidney stone formation. In: Coe F, Favus M, eds. Disorders of Bone and Mineral Metabolism. New York, NY: Raven Press; 1992:613–624.

6.  Robertson WG, Jones JS, Heaton MA, et al. Predicting the crystallization potential of urine from cats and dogs with respect to calcium oxalate and magnesium ammonium phosphate (struvite). J Nutr. 2002;132:1637S–1641S.

7.  Kavanagh JP. Supersaturation and renal precipitation: the key to stone formation? Urol Res. 2006;34:81–85.

8.  Lulich JP, Berent AC, Adams LG, et al. ACVIM small animal consensus recommendations on the treatment and prevention of uroliths in dogs and cats. J Vet Intern Med. 2016;30:1564–1574.

9.  Lulich JP, Kruger JM, Macleay JM, et al. Efficacy of two commercially available, low-magnesium, urine-acidifying dry foods for the dissolution of struvite uroliths in cats. J Am Vet Med Assoc. 2013;243:1147–1153.

10.  Bartges J, Moyers T. Evaluation of d,l-methionine and antimicrobial agents for dissolution of spontaneously-occurring infection-induced struvite urocystoliths in dogs. In: Proceedings of the ACVIM Forum 2010.

11.  Arulpragasam SP, Case JB, Ellison GW. Evaluation of costs and time required for laparoscopic-assisted versus open cystotomy for urinary cystolith removal in dogs: 43 cases (2009–2012). J Am Vet Med Assoc. 2013;243:703–708.

12.  Adams LG, Berent AC, Moore GE, et al. Use of laser lithotripsy for fragmentation of uroliths in dogs: 73 cases (2005–2006). J Am Vet Med Assoc. 2008;232:1680–1687.

13.  Bartges JW, Osborne CA, Lulich JP, et al. Canine urate urolithiasis. Etiopathogenesis diagnosis, and management. Vet Clin North Am Small Anim Pract. 1999;29:161–191, xii–xiii.

14.  Bannasch D, Safra N, Young A, et al. Mutations in the SLC2A9 gene cause hyperuricosuria and hyperuricemia in the dog. PLoS Genet. 2008;4:e1000246.

15.  Osborne CA, Sanderson SL, Lulich JP, et al. Canine cystine urolithiasis. Cause, detection, treatment, and prevention. Vet Clin North Am Small Anim Pract. 1999;29:193–211, xiii.

16.  Hoppe A, Denneberg T. Cystinuria in the dog: clinical studies during 14 years of medical treatment. J Vet Intern Med. 2001;15:361–367.

17.  Lulich JP, Osborne CA, Albasan H, et al. Efficacy and safety of laser lithotripsy in fragmentation of urocystoliths and urethroliths for removal in dogs. J Am Vet Med Assoc. 2009;234:1279–1285.

18.  Osborne CA, Lulich JP, Polzjn DJ. Canine retrograde urohydropropulsion: Lessons from 25 years of experience. Vet Clin North Am Small Anim Pract. 1999;29:267–282.

19.  Ross SJ, Osborne CA, Lekcharoensuk C, et al. A case-control study of the effects of nephrolith1asis in cats with chronic kidney disease. J Am Vet Med Assoc. 2007;230:1854–1859.

20.  Kyles AE, Hardie EM, Wooden BG, et al. Management and outcome of cats with ureteral calculi: 153 cases (1984–2002). J Am Vet Med Assoc. 2005;226:937–944.

21.  Berent A. Indwelling urinary catheters and stents. In: Bartges JW, Polzin DJ, eds. Nephrology and Urology of Small Animals. Ames, IA: Wiley-Blackwell; 2011:329–339.

22.  McClain HM, Barsanti JA, Bartges JW. Hypercalcemia and calcium oxalate urolithiasis in cats: a report of live cases. J Am Anim Hosp Assoc. 1999;35:297–301.

23.  Reynolds BS, Chetboul V, Nguyen P, et al. Effects of dietary salt intake on renal function: a 2-year study in healthy aged cats. J Vet Intern Med. 2013;27:507–515.

24.  Lulich JP, Osborne CA, Lekcharoensuk C, et al. Effects of hydrochlorothiazide and diet in dogs with calcium oxalate urolithiasis. J Am Vet Med Assoc. 2001;218:1583–1586.

25.  Hezel A, Bartges JW, Kirk CA, et al. Influence of hydrochlorothiazide on urinary calcium oxalate relative super saturation in healthy adult cats. J Vet Intern Med. 2006;20:741.

26.  Brons AK, Henthorn PS, Raj K, et al. SLC3A1 and SLC7A9 mutations in autosomal recessive or dominant canine cystinuria: a new classification system. J Vet Intern Med. 2013;27(6):1400–1408.