Canine and Feline Urolithiasis: Pathophysiology, Epidemiology and Management

Uroliths are organized concretions found in the urinary tract that contain primarily organic or inorganic crystalloid (ionic component of crystals) and a much smaller amount of organic matrix. When urine becomes supersaturated with minerals, and other parameters are conducive to crystallization, minerals can precipitate and individual crystals can be observed in the urine. Crystalluria does not mean that the patient is at risk for urolithiasis. Crystalluria is not a disease and no particular treatment is necessary unless a urolith is currently present or a urolith or urethral plug has formed in the past.

Supersaturation of urine with crystalloids depends on the interaction of dozens of crystalloid species formed by common mineral elements in the urine derived from the amount of each solute ingested and excreted in the volume of urine produced [1]. Organic molecule contributions, such as protein inhibitors or promoters of crystallization, may also influence crystal and stone formation [2]. Urine samples should be analyzed within 1 hour of collection to minimize temperature- and time-dependent in vitro crystallization [3].

Urine pH also affects crystal formation: Struvite, calcium carbonate, and calcium phosphate are less soluble in alkaline urine; cystine, uric acid, and silica are less soluble in acid urine. Depending on which salt of uric acid is present, the solubility of the urate stone may be pH dependent. For example, ammonium urate is more soluble in an alkaline pH, but other salts of uric acid may not be influenced by urine pH to the same extent. Further research is required to properly identify the exact salts present in these calculi. Urine pH does not appear to have a major effect on the solubility of calcium oxalate (CaOx), and CaOx calculi can be observed over a wide spectrum of urine pH. In addition to urinary pH, factors that predispose to urinary stasis play an important role in urolithiasis, because crystals that remain in the urinary tract for a sufficient time to allow aggregation may allow urolith formation.

Relative Supersaturation

The most frequently reported method for evaluating the crystallization potential in canine and/or feline urine is the calculation of relative supersaturation (RSS) [4-6], although many other methods of assessment have been reported in humans [7-9]. Concentrations of lithogenic substances and urine pH are used to calculate the urinary RSS values for particular crystal types. A validated computer program is used to calculate the concentrations of numerous soluble ion complexes and the activity products of the stone-forming ion complexes [6]. The RSS for a particular crystal type is then calculated from the ratios of the activity products to the thermodynamic solubility products for each complex. A RSS less than 1 indicates that the urine is undersaturated with the ion complex evaluated, whereas a RSS greater than 1 indicates that the urine is supersaturated with the ion complex evaluated.

Imaging the Animal with Urolithiasis

Radiographs should be taken prior to stone removal and should include the entire urinary tract. CaOx, apatite, struvite, and silica stones are generally radiopaque. Most urate and cystine stones cannot be identified on plain radiography. Immediately after stone removal, additional radiographs should be assessed to be certain that no stones were inadvertently missed. CaOx stones oftentimes occur as multiple, small calculi and can be difficult to flush from the urethra. Contrast studies or ultrasound should be used to determine the presence or absence of residual urate or cystine stones after surgery. Periodic imaging (every 3 to 4 months) is essential to monitor for recurrent urolithiasis. This will enable the clinician to institute non-invasive therapy while stones are small and surgical interventions may be prevented.

Removal of Calculi

Removal of cystic calculi can be performed by various methods. Oftentimes, a cystotomy is performed. If clinically warranted, at the time of stone removal, a bladder biopsy can be obtained for histologic evaluation and culture. Alternatively, for larger cystic calculi in dogs and cats, laser lithotripsy is available at some referral institutions. Holmium:YAG laser lithotripsy can fragment stones by means of a photothermal process and the laser energy is absorbed in less than 0.5 mm of fluid, making it safe for urologic procedures [10]. The Ho:YAG laser has been reported to fragment all types of canine uroliths in vitro [11], but more studies are needed to evaluate the time required to fragment canine and feline stones in vivo. Once the stones are fragmented, a basket can be inserted through the cystoscope and the largest fragment can be grasped to ensure that it will pass easily through the urethra. The larger pieces should be included for stone analysis to properly identify all the layers of the stone. This is important to subsequently initiate proper management strategies. All other fragments can be removed by voiding urohydropropulsion. Urohydropropulsion is also useful when the animal presents with small cystic calculi. If "sand and debris" or even small stones (3 to 5 mm) are seen in the urinary bladder, surgery is often not necessary and voiding urohydropropulsion may be a less invasive procedure for stone removal. For a complete review of this technique, the reader is referred to the literature [12].

When to perform surgery in cats with ureteroliths is often a topic of debate among surgeons and internists. Results from a larger retrospective study of ureteral calculi in cats suggests that medical and surgical management are associated with high morbidity and mortality rates [13]. Medical management with aggressive fluid diuresis, parenteral diuretic therapy, analgesia, and even hemodialysis is recommended prior to any surgical intervention. When the ureteral calculus remains lodged in the ureter, despite medical therapy, and is causing renal compromise or significant discomfort to the cat, surgery should be performed to remove the obstruction. Ureterotomy or ureteroneocystostomy can be done to remove the ureterolith, with the latter procedure performed most often when the ureterolith is in the distal third of the ureter. Recurrent ureterolithiasis is reported to be as high as 40% in cats that were evaluated with serial abdominal imaging. Most of the ureteroliths we analyze at our laboratory are CaOx [14], but we have noted an increased incidence of dried solidified blood calculi in the ureters of cats [15].

Struvite Urolithiasis in Dogs

Struvite-containing calculi comprise about 45% of all canine uroliths analyzed at the UC-Davis Urinary Stone Analysis Laboratory. Almost three quarters of all struvite calculi occurred in female dogs. A strong statistical association between the female sex and increased risk of struvite-containing calculi in dogs has been documented [16]. An increased risk for struvite-containing calculi has been reported in Cocker spaniels, springer spaniels, and Labrador retrievers. A lower risk for struvite-containing calculi in dogs that were subject to stone formation was noted in both sexes of Dalmatians, Pomeranians, and Maltese [17]. We have reported a trend change in the proportion of canine urinary calculi composed of struvite from 1981 to 2001 [18]. For both sexes, a 20-year statistically significant decrease was observed in the proportion of calculus specimens that contained struvite. This decrease in proportion was greater in males than in females. The change in trend may depend on breed, age, gender, and on the interaction among these three factors.

Struvite uroliths are most commonly found in the lower urinary tract, but occasionally are found in the renal pelves and ureters. Struvite uroliths come in a variety of shapes and sizes and other minerals such as calcium and phosphate can be incorporated into the stone because of secondary urine pH changes.

In dogs, virtually all struvite calculi are infection-induced, and the causative organism is usually Staphylococcus intermedius or, less commonly, Proteus mirabilis. These bacteria have the ability to hydrolyze urea into ammonia, bicarbonate, and carbonate. The resulting increase in the urine pH results in urinary supersaturation of the ions. The elevated pH is also thought to be a contributory factor in causing damage to the underlying uroepithelial glycosaminoglycan layer. It has been reported in humans, that non-urease-producing bacteria, may also influence the formation of urinary stones [19], but this has not been evaluated in dogs. Occasionally, in the absence of infection, the urine can become supersaturated with the minerals that compose struvite uroliths, and stone formation can occur in the absence of infection. The solubility of struvite increases when the urine pH is less than 6.8.

Struvite Urolithiasis in Cats

Based on previously published epidemiology studies, struvite was the most common stone reported in cats until approximately 1993, when the incidence of CaOx began to increase [20]. Between 1998 and 2003, struvite was the second most common stone type at another laboratory [21]. We have also noted that struvite is the second most common mineral type found in calculi submitted to the UC-Davis Urinary Stone Analysis Laboratory, and the number of struvite stones has significantly decreased when evaluating the past 15 years [22]. However, the proportion of struvite stones analyzed in the past few years appears to be increasing, whereas the proportion of CaOx-containing uroliths is declining (Fig. 66.1). We have noted a change in feline urolithiasis trends beginning in 1993, when 53% of the stones contained CaOx, while only 47% contained struvite. The proportion of CaOx-containing uroliths continued to increase over the next 8 years, while the proportion of struvite-containing uroliths decreased during that same period. Stones not containing CaOx or struvite appeared to be static during that same period. One hypothesis for this apparent change in trend could be that less highly acidifying diets are being prescribed by veterinarians, but diet histories were not available from these records to confirm or deny this hypothesis.

Figure 66.1. Average of struvite and calcium oxalate stones in cats over 3 years.

In 2000, the University of Minnesota Urolith Center reported that the foreign shorthair, ragdoll, Chartreux, Oriental shorthair, domestic shorthair, and Himalayan were breeds at risk for the formation of struvite calculi [20]. The Rex, Burmese, Abyssinian, Russian blue, Birman, Siamese, and mixed breed cats had a significantly lower risk of developing struvite uroliths. Table 66-1 provides a table of relative breed risks for struvite and CaOx formation that we have seen at The UC-Davis Urinary Stone Analysis Laboratory [22]. The bladder is the most common site for struvite urolith retrieval, and approximately 90% of the struvite uroliths submitted to our laboratory are removed from this site. Struvite stones were also submitted after being removed from the urethra (7%) and the upper urinary tract (0.34%) or after the stones were voided (2.5%). Ureteral stone submittals have significantly increased over the past 15 years [22].

In cats, struvite stone formation usually occurs in sterile urine. This is in contrast to dogs in which struvite stones are usually associated with a urease-producing bacterial infection. Epidemiologic studies on diet and struvite formation in cats have been published [23], but the pathophysiology of struvite urolith formation in cats is not yet completely understood. Struvite urolith formation likely results from a combination of breed, sex, and dietary factors. Struvite is more soluble in slightly acidic urine (pH < 6.8). Therefore, factors that may be associated with the formation of alkaline urine (e.g., family history of struvite stones, a diet low in animal protein, or distal renal tubular acidosis) should also be considered in cats with struvite urolithiasis.

Calcium Oxalate Urolithiasis in Dogs and Cats

The exact mechanism of CaOx stone formation is unknown and likely involves interrelationships among gender, genetics, breed, diet, and environmental factors. In either species with proven or suspected CaOx urolithiasis, serum should be evaluated to assess the calcium concentrations. Elevated calcium from various causes (neoplastic, primary, or secondary hyperparathyroidism, or idiopathic hypercalcemia in cats) can predispose the animal to CaOx stone formation. In humans, approximately 75% of kidney stones are composed predominantly of CaOx, and oxalate metabolism is thought to play a crucial role in stone development. Hyperoxaluria can occur from increased dietary intake as well as a loss or diminished activity of oxalate-degrading bacteria in the colon (Oxalobacter formigenes) [24]. Primary hyperoxaluria type I is an inborn error of glyoxylate metabolism and can lead to marked increases in hepatic oxalate production in humans [25]. Human beings are also much more prone to developing nephrolithiasis, particularly in industrialized nations, whereas bladder stones are found most frequently in developing countries [26] (as well as in dogs and cats). Although urinary supersaturation with crystals is implicated in stone formation in humans, several studies have investigated the possibility that the urine is not the initial site of stone development. A vascular etiology for nephrolithiasis in humans has been proposed [26], suggesting that vascular abnormalities (e.g., hypertensive vascular injury, atherosclerosis) can lead to Randall's plaques (papillary lesions that are usually associated with calcium and phosphate or CaOx) [27]. Stoller et al., hypothesized that the primary event in CaOx nephrolithiasis in humans may begin in the vascular bed at the tip of the renal papilla. Still other studies have investigated a role for elevated lipids in CaOx urolith formation in rats and humans [28]. Therefore, the primary site of urolithiasis may be unrelated to urinary stasis, infection, or other secondary causes for urinary stones, and novel treatment regimens may need to be investigated. No studies investigating these disorders or hypotheses have been published for cats and dogs and what, if any, relationships can be made between these species remains to be seen.

CaOx is one of the most common mineral types present in specimens of calculi that are obtained from dogs. The incidence of CaOx stones appears to be increasing over the past 20 years (with a reciprocal decrease in the proportion of struvite uroliths) [18]. CaOx calculi appear to be more common in older, castrated male dogs [16,29]. Other risk factors for CaOx uroliths in dogs include obesity [29] and breed. Several small-breed dogs, including the miniature schnauzer, a breed that is recognized to also be at risk for hypertriglyceridemia, have a higher risk of CaOx urolith formation. Elevated cholesterol [26] and triglycerides have been evaluated in other species with CaOx uroliths, and research in rats suggests that elevated lipids may play a role in CaOx urolith formation [26,28]. However, the pathogenesis of stone formation in dogs and cats may differ from that in rats and humans.

CaOx stones are the most common urolith type found in people, and during the past 15 years the incidence of CaOx urolith formation has been increasing in cats [20]. CaOx stones are composed of calcium oxalate monohydrate (whewellite) or calcium oxalate dihydrate (weddellite). The exact cause of CaOx stone formation in the cat is unknown. The concern regarding struvite stone disease in cats seems to have led pet food manufacturers to restrict the magnesium content of feline diets and has also resulted in the formulation of diets with greater urinary acidifying potential. Unfortunately, an increase in the frequency of CaOx urolithiasis appears to have occurred since these dietary modifications began. Between 1984 and 1995 the percentage of stones submitted to the University of Minnesota Urolith Center that were found to be composed of CaOx increased from 2% to 40% [30]. We reported a similar trend from our laboratory [14]. Although dietary acidification can enhance the solubility of struvite crystals in the urine of cats, it also promotes the release of calcium carbonate from bone as a metabolic buffer, and hypercalciuria results [31]. Results have shown that differences in age, sex, breed, and reproductive status did not contribute to the apparent reciprocal relationship between occurrences of CaOx and struvite uroliths in cats [20]. However, as mentioned earlier in the struvite section, we, and others [21] have also noted a decrease in the proportion of CaOx stones submitted over the past few years. CaOx uroliths can occur anywhere in the urinary tract, and when ureteroliths are present in cats, the mineral composition is likely to be CaOx. Approximately 73% of CaOx stones we analyzed from cats were removed from the bladder, 7.3% were removed from the ureter(s), 4.3% were removed from the kidney(s), 13% were removed from the urethra and 2% were voided. Most of the time, if CaOx stones were removed from the urethra or voided, stones were also located elsewhere in the urinary tract.

Cat breeds reported to be at higher risk for CaOx urolithiasis include the ragdoll, British shorthair, foreign shorthair, Himalayan, Havana brown, Scottish fold, Persian, and exotic shorthair. The Birman, Abyssinian, Siamese, and mixed breed cats were at significantly lower risk for developing CaOx uroliths [20]. As mentioned, cats with CaOx urolithiasis are generally older than cats with struvite urolithiasis. Cats between 7 and 10 years of age are reported to be 67 times more likely to develop CaOx uroliths than are cats between one and two years of age [20]. Male cats were reported to be 1.5 times more likely to develop CaOx uroliths than were female cats, while neutered cats were seven times more likely to develop CaOx uroliths as compared with sexually intact cats.

Urate Urolithiasis in Dalmatian Dogs

Unlike most other breeds of dogs, Dalmatian dogs have well described alterations in purine metabolism that lead to the excretion of urate (salts of uric acid) or, much less commonly, uric acid in the urine rather than the more soluble metabolite, allantoin [32]. In Dalmatians, the liver does not completely oxidize available uric acid, even though it contains a sufficient concentration of uricase, the enzyme necessary to convert uric acid to allantoin. It is hypothesized that the hepatic cellular membranes are partially impermeable to uric acid [33]. In addition, Dalmatians are reported to excrete excessive amounts of uric acid from the kidneys, which is the result of a combination of reduced tubular reabsorptive capacity and increased tubular secretion [34]. Increased uric acid excretion appears to be a risk factor for urate stones, but not the only cause. All Dalmatians excrete relatively high amounts of uric acid (400 to 600 mg of uric acid per day as compared with 10 to 60 mg per day in non-Dalmatian dogs); however, not all Dalmatians form urate stones. It is likely that a combination of breed and other factors, such as a lack of urinary inhibitors [35], may play a role in the pathogenesis of urate stone formation. It has been reported that most Dalmatians that form calculi are males [17]. Reasons for this sex difference could be that there is a contributing X-linked genetic trait, or that stones become lodged in the smaller diameter urethra of male dogs. Genetic studies have reported that the mode of inheritance is not X-linked and the prevalence of the clinical disease in male Dalmatians ranges from 26% to 34% [32].

Depending on which salt of uric acid is present, the solubility of the urate stone may be pH dependent. For example, ammonium urate is more soluble in an alkaline pH, but other salts of uric acid may not be influenced by urine pH to the same extent. Further research is required to properly identify the exact salts present in these calculi.

Urate Urolithiasis in Non-Dalmatian Dogs

A high incidence of ammonium urate stones have been reported in dogs with portal vascular anomalies. Portal vascular shunts provide communication between systemic vasculature and the systemic circulation, bypassing the liver and resulting in decreased hepatic function. As a result, uric acid accumulates and may predispose the animals to urate stone formation. It is hypothesized that surgically correcting the underlying problem and eliminating the hyperuricosuria can prevent urate stone prevention for dogs with portovascular anomalies. Allopurinol is generally not recommended in dogs with portovascular anomalies, because of alterations in metabolism of this drug.

Other canine breeds (without hepatic dysfunction) have been reported to have an increased incidence for urate urolithiasis, particularly the English bulldog. The pathogenesis of the urate stone formation in this breed has not been determined and evaluation of eight male English bulldogs with stones revealed mild elevation in serum uric acid concentrations. Hepatic function was normal when assessed [33]. The miniature schnauzer, Shih Tzu, and Yorkshire terriers [33], and perhaps the Russian black terrier [36], are also over represented.

Feline Urate Urolithiasis

We have evaluated the mineral composition of 4933 feline uroliths submitted to the UC-Davis Urinary Stone Analysis Laboratory from 1986 to 2003. Of these, 10.4% contained urate. Approximately half of these stones were composed of 100% urate. Others were mixed with struvite or CaOx, and of these, 49% were from female cats and 51% were from males. When evaluating data from our laboratory, the incidence of urate calculi in cats does not appear to have changed over the past 20 years; therefore, the occurrence of these calculi does not appear to be influenced by the dietary changes that occurred to minimize struvite stone formation. CaOx may be a secondary component of some urate stones, and urate stones found in cats with portosystemic shunts often also contain struvite [30]. Often, the pathophysiology of urate urolith formation in cats is unknown.

Cystine and Silica Urolithiasis in Dogs and Cats

Cystine uroliths account for a small percentage of uroliths we analyze at the UC-Davis Urinary Stone Analysis Laboratory. Other laboratories in the United States also report this stone type infrequently [37]. Cystinuria can occur in some dogs and cats and appears to be a heterogeneous disease. Cystinuria is an inherited renal transport disorder characterized by excessive urinary excretion of cystine as well as the other dibasic amino acids ornithine, arginine, and lysine. Dibasic aminoaciduria has also been reported with cystinuria. Concurrent excess carnitine has also been reported in the urine of five dogs with cystinuria that were studied [38]. The molecular basis of cystinuria has been investigated in Newfoundland dogs, and the cloning and sequencing of the canine SLC3A1 gene (the amino acid transport gene) and the identification of a nonsense mutation in exon 2 of this gene have been reported [39]. Cystine is insoluble in urine and the solubility of this amino acid decreases further in acidic urine. Generally cystine uroliths are not visible on plain radiography, unless they are exceptionally large. Cystine uroliths are rare in cats; they accounted for only 0.2% of uroliths from cats at the Minnesota Urolith Center [40] and 0.15% of the feline uroliths analyzed at our laboratory.

A diet that is high in moisture and reduced in dietary protein has the potential for minimizing the recurrence of stone formation in dogs with cystine uroliths. If protein is restricted in a dog excreting excessive sulfur amino acids, taurine supplementation is recommended. The effects of sodium on cystine excretion have not been evaluated in dogs, however, sodium has been reported to enhance cystinuria in humans [41]. The thiol-containing drugs (e.g., n-(2-mercaptopropionyl)-glycine (2-MPG)) can decrease the concentration of cystine in the urine by participating in a thiol-disulfide exchange reaction. In one retrospective study of 88 dogs [42], the most common breeds with cystine urolithiasis were dachshunds, Tibetan spaniels, and basset hounds. Cystine excretion appeared to decrease as the animal aged. According to this study in dogs with recurrent cystine urolithiasis, dissolution was induced by increasing the tiopronin dosage to 40 mg/kg body weight per day. Adverse effects were found using the thiol-containing drugs and included aggressiveness and myopathy. All signs disappeared when treatment was stopped. In addition to the use of the thiol-containing drugs, increasing water intake should also be initiated.

Silica urolithiasis is uncommon in dogs and rare in cats. These uroliths account for approximately 0.1 to 2.0% of the uroliths seen each year from the Minnesota Urolith Center [43] as well as from the UC-Davis Urinary Stone Analysis Laboratory. Most dogs with silica uroliths are older, and male dogs appear to be predisposed. The most common breeds associated with silica urolithiasis at our laboratory include the German shepherd, Labrador retriever, and Australian shepherd. The hypothesized pathophysiology of silica stones is reviewed nicely elsewhere and the reader is referred to the literature for information pertaining to management [43].