Canine and Feline Urolithiasis Updates and Challenges

India F. Lane, DVM, MS, EdD, DACVIM Elizabeth M. Lennon, DVM, PhD, DACVIM The University of Tennessee College of Veterinary Medicine

Urolithiasis - General

Urolithiasis is common in both dogs and cats. Urolithiasis likely results from a constellation of predisposing factors that ultimately results in precipitation of excretory metabolites in the urine. These precipitates form crystals which can eventually aggregate into stones.

The most common uroliths in dogs include struvite (magnesium ammonium phosphate), calcium oxalate, cystine, urate, and silica. The most common feline uroliths include feline calcium oxalate and struvite. In addition to being comprised solely of one type, uroliths can also be composed of multiple stone types, which is referred to as a compound stone. For example, the core of a urolith could be formed of calcium oxalate with a struvite urolith shell. The majority of uroliths are present in the urinary bladder at diagnosis (84%). Other sites include the urethra (7%), the kidney (3%), and less than 1% are present in the ureters, although that number has been increasing in recent years.

Urine pH has a significant determining factor on the presence of uroliths. Certain uroliths form in acidic urine, while others form in more basic urine. Calcium oxalate, purine, cystine, silica, and calcium phosphate uroliths form in acidic urine, while infection-induced struvite stones form in basic urine. It is important to recognize that crystalluria (presence of microcrystals in the urine that are observed on urine sediment examination) is not abnormal. Normal individuals can have crystals present in their urine and this does not mean that this animal will form stones. Therefore, it is inappropriate to begin an animal on a prescription diet when crystals alone are noted. However, certain types of crystals can be of diagnostic significance – for example, if ammonium urate crystals are seen on urinalysis, this can be indicative of a portosystemic shunt or other hepatic abnormality.

Updates – Urolith Types

Struvite Uroliths

Struvite uroliths, otherwise known as magnesium ammonium phosphate, are radioopaque stones that are often large in size and there may be many stones. They tend to have a smooth contour and are a variety of shapes. In dogs, struvite uroliths are most commonly infection-induced. Therefore, they occur more commonly in females. They tend to be more common in young adult animals. In cats, struvite stones are most often sterile. They occur equally in males and females, and because they tend to form in alkaline urine, they are associated with a high protein diet.

Infection-induced struvite uroliths occur secondary to urease producing bacteria. These bacteria contain the enzyme urease, which cleaves urea, as a survival mechanism to be able to live in the unfavorable environment of urine. Staphylococcus are the most common urease-producing bacteria that results in urinary tract infection in dogs, but other bacteria such as Proteus, Klebsiella, Pseudomonas, Corynebacterium, and Ureaplasma can produce urease as well. The urease enzyme cleaves urea into ammonia, bicarbonate, and carbonate ion. The bicarbonate and ammonia that is produced are responsible for increasing urine pH, and the ammonia is one of the components of the urolith.

Treatment of struvite uroliths includes elimination of existing uroliths and treatment of urinary tract infection. This can be accomplished by surgical removal, minimally invasive techniques, or by medical dissolution through diet, modification of water intake, and treatment of a urinary tract infection if one is

328 present. If struvite uroliths are highly suspected, medical dissolution is often attempted first since it is a non-invasive method of control. Antibiotics that are appropriate for treatment of the UTI, based on culture, should be administered throughout the course of dissolution. Important components of dietary therapy of struvite uroliths includes a low protein diet to decrease the urinary ammonia, low magnesium, low phosphorus, acidifying diet (to cause acidification of the urine). A high salt diet may also be helpful to increase water intake and create more dilute urine, but this is unproven. The average time to medical dissolution of struvite uroliths is 8-10 weeks. During the dissolution period, the animal should be monitored every 4 weeks, with a urinalysis, culture, and radiographs performed. The urine specific gravity should be maintained at less than 1.015 in dogs and less than 1.035 in cats. Urine cultures should be considered, especially if the stones do not appear to be getting smaller. Treatment should be continued 2- 4 weeks past radiographic resolution, since some smaller stones may not be visible radiographically and could serve as a nidus for further stone growth if not completely dissolved.

There are several potential complications of medical dissolution of struvite uroliths, including urethral obstruction, continuing urinary tract signs, side effects of the antimicrobial, failure to dissolve, and problems with the diet. Urethral obstruction can occur if the stones get to a size in which they can enter the urethra, so owners should be warned about the symptoms and emergent nature of urethral obstruction. If the animal was originally presented with lower urinary tract symptoms, these could continue for the duration of treatment. Long-term antibiotic treatment can have unwanted medication side effects. Struvite uroliths can fail to dissolve with medical dissolution, and the therapeutic approach should be reconsidered if the stones are not smaller in 4-6 weeks. Failure of dissolution can include owner noncompliance, persistent urinary tract infection, or a compound stone in which part of the stone is not a type can be dissolved. Lastly, some animals may have an intolerance to the diet. By nature, these diets tend to be high fat to replace the restricted protein, so could cause weight gain or potentially contribute to pancreatitis in a predisposed animal.

Prevention of struvite uroliths includes controlling infection and factors that predispose to urinary tract infection, as well as increasing water intake to maintain more dilute urine that will not favor crystal formation.

Calcium oxalate uroliths

Calcium oxalate uroliths are increasing in incidence and comprise 40-50% of all uroliths. They are > 85% of all nephroliths and ureteroliths. Calcium oxalate uroliths are radiodense, usually small and round, and can have an irregular surface. There are often not more than a dozen stones. Increased calcium in the urine is a risk factor for calcium oxalate uroliths. This can result from 1) bone resorption of calcium, 2) hyperabsorption from the gastrointestinal tract, 3) hypercalcemia, or 4) renal leak calciuria, in which increased amounts of calcium are lost into the urine because of a defect in tubular resorption. Breeds that are predisposed to calcium oxalate urolithiasis include miniature Schnauzers, Lhasa apsos, Yorkshire terriers, and Bichon frises. In cats, Siamese and Ragdoll cats are predisposed.

In cats, aciduria is a common finding. Crystals are not present in about half of patients with calcium oxalate uroliths. Cats often have chronic kidney disease concurrently.

Treatment of calcium oxalate uroliths is limited to surgical or minimally invasive removal (see below). Medical dissolution is not effective.

Urate uroliths

Urate urolithiasis (ammonium urate) comprise 5-8% of all uroliths. They are composed of ammonium urate. Dalmatians have a strong genetic predisposition, and 60% of all urate uroliths occur in Dalmatians. English bulldogs are also predisposed. Urate uroliths are also more common in puppies less than one year. Urate uroliths can also occur secondary to liver disease and portosystemic shunt, so liver function should be investigated in animals that are found to have urate uroliths. Urate uroliths are usually

329 radiolucent, so contrast radiography or ultrasound is necessary to detect them. They are usually small, smooth, green or brown, and round, and multiple stones are often present.

Dalmatians have defective transporters for uric acid, so they cannot reabsorb it in the proximal tubule and they cannot transport it to the liver for breakdown, so they end up with higher levels of uric acid in their blood and urine than other dogs. This results in increased risk of ammonium urate uroliths.

Dogs with severe hepatic disease or portosystemic shunts are also at risk of formation of urate uroliths. Uric acid is normally broken down to allantoin in the liver, but if the hepatic enzyme uricase is not able to break this down, due to loss of hepatic mass or portosystemic shunt, increased uric acid in the serum and urine can result. In the case of portosystemic shunt, urate uroliths are usually seen prior to one year of age and other signs of portosystemic shunt are usually present (small breed dog, poor doer, +/- hepatic encephalopathy).

Dogs with urate urolithiasis will usually have acidic urine on urinalysis. Urate or amorphous crystals may be present on urine sediment examination.

Treatment of urate uroliths includes removal of the stones either through surgery, a minimally invasive approach, or by medical dissolution. Results of medical dissolution are variable. Roughly 1/3 will have complete dissolution, 1/3 will have partial dissolution, of which 50% are then small enough to retrieve nonsurgically, and the remaining 1/3 will have an increase in the size or number of stones. Medical dissolution is accomplished through a combination of a xanthine oxidase inhibitor such as allopurinol in combination with a purine-restricted diet. Therapy should maintain a high urine pH. Medical dissolution is usually unsuccessful in dogs with portosystemic shunts, so surgical removal is recommended and the shunt must be addressed surgically.

Allopurinol, a xanthine oxidase inhibitor, is used to decrease the production of uric acid. This medication is excreted by the kidneys, so should be dose-reduced in azotemic animals. Side effects are rare in dogs, but those reported in humans include vomiting, rash, leukopenia, thrombocytopenia, vasculitis, and hepatitis. Because allopurinol blocks the breakdown of xanthine, it can predispose to xanthine uroliths, especially in dogs that do not have dietary purine restriction.

Cats can also develop urate uroliths. In cats, investigation of a portosystemic shunt should be performed although liver disease is uncommon in affected cats. Treatment is similar and includes protein restriction, the goal of increasing urine pH, and although unpublished, allopurinol has been used at half of the dose used in dogs.

Urate uroliths have a high recurrence rate, reported to be between 30-50%. They often recur within the first year. About 80% of dogs can be managed with diet alone, but the remaining 10% require additional therapy. About 90% of cats can be managed with diet.

Cystine uroliths

Cystine uroliths occur as a familial disease resulting from a proximal tubular defect in the resorption of cystine resulting in increased urinary excretion of cystine. This defect can occur alone or in combination with other amino acids termed “COLA”: cystine, ornithine, lysine, arginine. Cystine uroliths are less radiodense than struvite or calcium oxalate, but are usually visible on radiographs. They are usually small and round, with a smooth contour and animals usually have less than a dozen stones.

Treatment of cystine uroliths includes dissolution with a low protein diet, urinary alkalinization, and thiol drugs. Cystine solubility increases exponentially when the urine pH is greater than 7.2. Thiol drugs including tiopronin and d-penicillamine can be used, but should not be used in cats.

330 Calcium oxalate uroliths have a high recurrence rate, so animals with these stones should be monitored periodically. If hypercalcemia is present, the underlying cause should be treated. If it cannot be completely resolved, a high fiber diet and potassium citrate should be considered. Dietary therapy is an important preventative strategy. Potassium citrate therapy can help to prevent formation of calcium oxalate uroliths since citrate is an inhibitor of calcium oxalate crystal formation. It is added in most oxalate preventative diets. It should be titrated to maintain urine pH above 7.5.

Thiazide diuretics can be used in animals with recurrent calcium oxalate urolithiasis. These medications decrease urinary calcium excretion by increasing absorption from the tubule. Animals should be monitored for hypercalcemia.

Bisphosphonates such as alendronate (Fosamax) decrease calcium mobilization from bone, so can help to decrease urinary calcium excretion, particularly in animals with hypercalcemia. These medications can cause osteonecrosis, and esophagitis is a common side effect if not carefully administered.

Challenges

How can I avoid a(nother) cystotomy?

In the case of uroliths that are of unknown type or require removal, the most common method for treatment of cystoliths is via cystotomy. However, other options include catheter-assisted retrieval, voiding urohydropropulsion, or cystoscopic retrieval with either a percutaneous cystolithotomy (cystoscopic- assisted cystotomy) or laser lithotripsy in select cases. If the urolith is causing urethral obstruction, retrograde urohydropropulsion is attempted, in which a urinary catheter is placed to the level of the obstruction and saline flush is used to try to push the stone back into the bladder. If a ureteral obstruction is present, a ureteral stent or other method of ureteral bypass is used. Nephroliths are usually simply monitored unless they are causing a problem.

Other minimally invasive techniques include laparascopic and percutaneous approaches to mini- cystotomies.

What can I do about frequent recurrences?

Pseudorecurrence, or failure of complete removal, is a significant problem following stone removal. Postoperative radiographs must always be performed following any method of stone removal, since small stones are easy to miss during cystotomy.

True recurrence is common, however, especially for metabolic uroliths. Recurrence can be fairly rapid – In a recent series of dogs followed for 12 weeks after cystotomy, hyperechoic foci suggestive of tiny, subclinical urolith formation were observed in 11 of 18 (60%) at some point during the period of study. (Mariano et al, 2018) Early sonographic recurrence did not vary by stone type, although most of the recurrences were in calcium oxalate-formers. The clinical significance is not entirely clear, but early institution of monitoring seems wise.

For frequent recurrences, consider:

x For recurrent struvite urolithiasis in dogs, focus on preventing and managing urinary tract infection. x For recurrent calcium oxalate uroliths in dogs, use minimally invasive techniques to remove small, clinical or potentially obstructive uroliths. Consider adding moisture to the feeding plan, potassium citrate or thiazide diuretics. x For recurrent urate uroliths, use minimally invasive techniques to remove small, clinical or potentially obstructive uroliths. Rule out xanthine urolith formation and review allopurinol dosage.

331 When should I worry about nephroliths?

In dogs, any type of stone can be found in the upper tract. However the most common upper tract uroliths are calcium oxalate, followed by struvite and urate. Large, infection-induced nephroliths and ureteroliths are occasionally encountered in dogs with upper urinary tract infections.

In cats, most (> 70%) upper urinary tract uroliths in cats are also calcium oxalate in composition. Small, multiple stones are common, usually found in both kidneys and/or ureters. Small ureteroliths appear to migrate over time in cats; it is unknown how many cats have passed and voided smaller uroliths prior to diagnosis. Approximately 15% of cats had concurrent lower tract uroliths in one retrospective analysis. Middle-aged to older cats are most often affected. Purebred cats, including Siamese, Persians, Burmese and Himalayans, appear to be at increased risk for formation of nephroliths. In many cats, renal size is asymmetrical, with one kidney small (end-stage or nonfunctional) and the remaining kidney large due to compensatory hypertrophy or hydronephrosis. Some have hypothesized that the small kidney was previously obstructed and reached end-stage status without detection.

Most upper urinary tract uroliths in dogs are asymptomatic, discovered as incidental findings when radiographs are performed for other reasons (vomiting, back pain, etc.). Nephroliths are often found in dogs with who are evaluated for lower urinary tract signs as well. Other signs may include: x Pain? Although pain or painful episodes are often described in the history of dogs with upper urinary tract stones, the cause of abdominal or back pain is likely due to problems other than urolithiasis. Dogs appear much less painful than cats or people with kidney or ureteral stones. x Persistent infection? Nephroliths can serve as a nidus for recurrent or relapsing urinary tract infections, which may be detected by urinalysis or because of lower tract signs. Severe illness can be observed in dogs with nephroliths and acute pyelonephritis. x Chronic kidney disease? Nephroliths are commonly found in cats with chronic kidney disease. There also appears to be an association between uroliths in any location and CKD in cats. Nonobstructive nephroliths don’t appear to significantly impact long term outcome of CKD. x Persistent hematuria, especially microscopic hematuria may be associated with upper tract uroliths. Although probably of minimal significance regarding blood loss or symptomatology, dried blood clots have been documented as a cause of ureteral obstruction in cats.

Most nephroliths do not require direct treatment. Principles of management include:

x Monitor and prevent further growth. Cats or dogs with asymptomatic or nonobstructive calcium oxalate nephroliths can be managed with medical strategies formulated to prevent additional nephrolith growth. x Manage concurrent urinary tract infection: Treated as a complicated UTI based on culture and susceptibility results. x Struvite nephroliths can be dissolved using medical protocols. The time required for complete dissolution may be prolonged (2 to 11 months) for upper tract stones as they are not bathed in urine in the same fashion as bladder stones. There is a small risk of ureteral obstruction as the stone dissolves to a smaller size.

Indications for Direct Intervention: Indications for specific intervention include obstruction of urine flow, recurrent infection, progressive nephrolith enlargement (especially if accompanied by reductions in renal function), and possibly, to protect a solitary functional kidney. x Extracorporeal Shock Wave Lithotripsy has been fairly successful in dogs; one or two treatments are required and availability is limited. x Surgery: Nephroliths are usually approached by nephrotomy or pyelolithotomy. x Percutaneous approaches are commonly done in people, where a rigid scope is placed in the kidney to remove or to pulverize stones. Some techniques have been employed in small animals.

332 What about ureteroliths?

Ureteroliths can become obstructive in cats (and occasionally in dogs) and have become the most common cause of acute azotemia in cats today. Acute pain or illness is observed when previously non- obstructive uroliths migrate and completely obstruct urine flow.

Acute azotemia is expected with bilateral obstruction, or acute unilateral obstruction of a sole functional kidney (usually when the other kidney has already failed). Most often these cats are lethargic, anorectic, and may appear painful or exhibit vomiting. Cats may exhibit atypical aggression, perhaps because of abdominal pain. Severely uremic cats can appear moribund, hypothermic and hyperkalemic, similar to a cat with advanced urethral obstruction.

The diagnostic workup is aimed at determining the likely composition, number and sites of uroliths, the structural and functional effects on the urinary tract (especially obstruction), and the most appropriate therapeutic plan. x A CBC, serum biochemical panel, urinalysis and urine culture is indicated. x Survey Radiography. survey radiography is extremely useful for the diagnosis of radioopaque (appearing white) uroliths, to assess renal size and shape, urinary bladder size, and to screen for fluid accumulation in the abdomen or retroperitoneum, suggesting urinary tract rupture. The retroperitoneal space must be carefully reviewed for evidence of small ureteroliths. x Serial abdominal ultrasonography adds to the information gained by radiography. Renal pelvic dilation and ureteral dilation can be picked up by a skilled sonographer even when quite subtle. Dilation may not develop for several days after acute obstruction, however. Multiple sonographic evaluations may be necessary to determine whether a nephrolith or ureterolith is progressively obstructive.It may be impossible to visualize more distal obstructions, or multiple obstructive sites. x Specialized imaging techniques, including excretory urography, computed tomography and antegrade pyelography, may be particularly helpful in characterizing ureteroliths and other ureteral pathology. x Quantitative assessment of individual kidney function is helpful prior to planning surgery or lithotripsy treatment, because structural appearance does not always correlate with function.

Management of ureteroliths is challenging and individualized. Conservative management can be initiated in stable cats. Many ureteroliths will pass into the lower urinary tract over time and can be voided or removed from the urinary bladder. In nonazotemic or mildly azotemic, asymptomatic cats or dogs without evidence of obstruction, a “wait and see” approach is reasonable. However, there is a risk of subtle, chronic damage to the ureter or kidney while waiting; migration can take weeks to months. Regular, serial radiographic and sonographic examinations must be done to determine the rate of change in the urinary tract. Stents (see below) can be placed to maintain urine flow during the waiting period.

Indications for Intervention: Complete or progressive obstruction in a functional kidney. Complete outflow obstruction raises ureteral pressure, which is then transmitted to the proximal tubules and affects renal filtration forces and blood flow. Renal function can deteriorate by 70 – 80% within 2 weeks. Reversibility declines with time, so treatment decisions often need to be made quickly to protect renal function. x Medical strategies: Fluid diuresis may be employed to facilitate migration of small ureteroliths, and is recommended as a first line attempt in cats with obstructive ureteroliths. o Use of smooth muscle relaxants (alpha antagonists), diuretics (particularly mannitol), steroids or non-steroidal anti-inflammatory agents to facilitate ureteral movement is theoretically useful, but the effects of these agents are unproven in cats. o Amitriptyline shows promise for facilitating ureteral stone passage in cats. o It appears reasonable to monitor partially obstructive stones for 2 – 3 days, provided azotemia and pelvic/ureteral dilation is stable or decreasing. However, some ureteroliths may be embedded in diseased, edematous or inflamed ureters and will not move spontaneously. o Pain management is also an important component of treatment.

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x Referral options for intervention: o Temporary nephrostomy tube: allows urine flow while patient is stabilized and definitive procedures are planned. o Surgical approaches: ƒ A modified nephrotomy or pyelolithotomy is employed for nephroliths or proximal ureteroliths. ƒ Resection and reimplantation of the ureters can be effective for surgical management of distal ureteroliths. ƒ Ureterotomy also has been successful for the removal of obstructive ureteroliths in some cats; this approach requires a highly experienced surgical team due to the small size of the feline ureter. o Subcutaneous Ureteral Bypass (SUB): Tubing and a shunting port is used to allow urine to drain from the kidney directly to the bladder for temporary or long-term salvage needs. o Ureteral stents: Alone or in combination with surgical or lithotripsy procedures, stents are tiny tubes placed in the renal pelvis and directed down through the urethra to the bladder, ideally to allow urine drainage while ureteroliths or stone fragments pass down to the bladder and are voided.

Key Points:

x Struvite uroliths can be medically dissolved with appropriate management and monitoring, including control of urinary tract infection in dogs. x Minimally invasive techniques are useful in managing recurrent cystouroliths. x Most nephroliths can be monitored and do not require direct intervention. x Obstructive ureteroliths, evidenced by changes in azotemia and sonographic findings, require intervention. x Ureteral stents or subcutaneous ureteral bypass techniques are becoming preferred choices for managing ureteral stones in cats.

Key Reference:

Lulich, Berent, Adams, Westropp, Bartges, Osborne. ACVIM Small Animal Consensus Recommendations on the Treatment and Prevention of Uroliths in Dogs and Cats. JVIM 30: 1564-1574, 2016.

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