Specific Diseases

5. Specific Diseases

Feline Idiopathic Cystitis

The diagnosis of FIC requires documentation of signs of chronic irritative voiding (dysuria, hematuria, pollakiuria, inappropriate urination), sterile urine, negative imaging studies, and cystoscopic observation of submucosal petechial hemorrhages (glomerulations). In addition, there may be increased urinary bladder permeability, decreased urine concentrations of glycosaminoglycans, increased mucosal vascularity, erosions, ulcerations, edema, fibrosis, and neurogenic inflammation (Buffington et al, 1994; 1996b; 1999a; Buffington & Chew 1999b; Buffington & Pacak, 2001; Buffington, 2002; 2004; Westropp et al, 2002; 2003; Pereira et al, 2004).

Epidemiology

Cats with FIC tend to be young to mid-age (<10 years) and otherwise healthy. Male and females are affected and many of the predisposed cats eat dry food exclusively (Buffington et al, 1997; Jones et al, 1997; Markwell et al, 1998; Buffington, 2002). A significant number have high urine specific gravities.

Management

One of the cornerstones of therapy is to identify and relieve the stressors in the cat's environment. Potential sources of stress include environmental aspects such as other cats, changes in weather, lack of activity, litter box placement, litter type, diet, owner work schedule, and the addition or removal of people or animals. Stress can be managed by providing the cat with hiding places and equipment such as climbing posts and toys that can be chased and caught which allow the cat to express predatory behavior (www.indoorcat.org/: The Indoor Cat Initiative 2006, Buffington et al, 1994;1999b; 2006a,b; Buffington, 2002; Cameron et al, 2004).

Diet plays an important role in the pathophysiology and treatment of interstitial cystitis. An abrupt change or frequent changes in diet has been associated with the recurrence of clinical signs. Therefore, it is reasonable to limit the frequency of diet changes in sensitive cats (Buffington et al, 1994; 1996b; 2006a,b; Jones et al, 1997).

Urine dilution is thought to help cats with FIC because it decreases the concentration of substances in urine that may be irritating to the bladder mucosa. In one study, cats with FIC were significantly more likely to eat dry pet food exclusively (59%) compared with cats in the general population (19%) (Buffington et al, 1997). In a one year, non-randomized prospective study of 46 cats with FIC, feeding a moist therapeutic food specifically designed to promote lower urinary tract health was associated with significant improvement compared with feeding a dry diet. At the end of the one year study, the recurrence of clinical signs in cats eating the moist food was significantly less (11% of 18 cats), compared with cats eating the dry food (39% of 28 cats) (Markwell et al, 1999a) (Figure 19). Compared with the cats consuming the dry food, the urine specific gravity was significantly less in the cats eating the moist food. The mean urine specific gravity ranged from 1.032 - 1.041 in the cats eating the moist food compared to 1.051 - 1.052 in the cats eating the dry food.

Figure 19. Recurrence rates of feline idiopathic cystitis on moist versus dry diet (Adapted from Markwell et al, 1999a).

Highly acidifying diets are not recommended as highly acid urine may increase sensory nerve fiber transmission in the bladder and increase pain perception (Chew & Buffington, 2003).

In some cases, additional therapy may be indicated. Cats naturally release pheromones during facial rubbing when they feel content in their environment. A synthetic analogue of a naturally occurring feline facial pheromone may help decrease anxiety-related behaviors in some cats (Chew et al, 1998; Mills & Mills, 2001; Gunn-Moore & Cameron, 2004). Although a number of additional treatments have been advocated over the years, none, except diet, have been clinically proven to make a significant difference. Additional therapeutic options will likely evolve to decrease central noradrenergic drive and normalize the responsiveness of the stress response system in these sensitive cats (Buffington et al, 1999a; 2006a,b; Buffington, 2004). In the interim, a number of drugs have been suggested including amitriptyline and pentosan polysulfates (glycosaminoglycan or GAG replenishment agents) (Chew et al, 1998; Buffington et al, 1999a; 2006a,b; Buffington & Chew, 1999b; Buffington, 2002; Kraiger et al, 2003; Kruger et al, 2003; Gunn-Moore & Shenoy, 2004; Mealey et al, 2004).

Clinical signs resolve spontaneously in as many as 85% of cats with FIC within 2 - 3 days, regardless of therapy. However, about 40 - 50% of these cats will relapse within 12 months, and some will have multiple recurrences (Markwell et al, 1998; 1999a; Kruger, 2003).

Urethral Plugs

Relief of urinary tract obstruction and reestablishment of urine flow is mandatory in a cat with urethral obstruction. In addition, correction of fluid, electrolyte and acid-base imbalances associated with the obstruction and post-renal azotemia are needed. A number of excellent references are available on the emergency management of uretheral obstruction (Osborne et al, 2000; Westropp et al, 2005).

Uroliths

Universal Risk Factors: Relative Supersaturation

Urine supersaturation is the driving force for the formation of crystals within the urinary tract. More than 40 years ago, human researchers began exploring ways of evaluating urine parameters and predicting urolithiasis risk. This led to a research methodology called Relative Supersaturation (RSS) ratio, a technique first introduced in human medicine in 1960’s by Dr. W.G. Robertson (Nordin & Robertson, 1966). The measurement of the RSS predicts the crystallization potential of that urine. This technique has become the gold standard for urine evaluation in human patients (Pak et al, 1977).

The ability to predict the crystallization potential of urine is a useful tool for clinicians and researchers who wish to develop therapeutic interventions for patients with urolithiasis. In the late 1990’s, Dr Robertson began collaborative work with scientists at the Waltham Centre for Pet Nutrition (WCPN) to validate the relative supersaturation ratio for use in dog and cat urine and a number of publications have now appeared in the veterinary literature on the technique and interpretation thereof (Smith et al, 1998; Markwell et al, 1999b; Robertson et al, 2002).

In order to study urine parameters using RSS, it is necessary to obtain complete urine collections over a 2 to 5 day-period. The urine is analyzed for the concentration of 10 solutes (calcium, magnesium, sodium, potassium, ammonium, phosphate, citrate, sulfate, oxalate and uric acid) and the urine pH (Robertson et al, 2002). The number of interactive complexes that could occur between these ions, together with activity coefficients of the salts is calculated and the activity product determined. The activity product is an indicator of the likelihood of a urolith forming. The activity product is divided by the thermodynamic solubility product of the crystal and the resultant RSS ratio is produced. (The thermodynamic solubility product is the activity product at which a urolith will remain static and not grow or dissolve.)

The RSS is unique for each crystal type. RSS can be used to define three different zones of urine saturation: undersaturated, metastable or oversaturated. Each of these zones has different implications for the risk of urolith formation (Figure 20). The higher the RSS, the greater the risk of crystal formation, and with low RSS values, the risk of crystal formation is much less likely (Robertson et al, 2002).

Figure 20. Urine relative supersaturation.

A RSS less than one means that the urine is undersaturated and that crystals will not form. In a complex media such as urine, it is possible to have a RSS above one without spontaneous precipitation of crystals (Markwell et al, 1999b). This is due to electrical fields (ionic strength) induced by the numerous ions in solution and the presence of inhibitors of crystallization. Both prevent the free fractions of minerals (e.g. calcium and oxalate) to interact to form crystals. This level of supersaturation is qualified as metastable supersaturation. At this level of saturation, calcium oxalate crystals will not spontaneously form, but might occur in the presence of a nucleus. In the zone of metastable supersaturation, crystals, and thus uroliths, will not dissolve.

At higher levels of minerals in the urine, crystals will form spontaneously within minutes to hours. This is the labile supersaturation zone. The limit between metastable and labile supersaturation is called the formation product. Kinetic precipitation studies in urine have shown that the RSS for the formation product for struvite is 2.5 and for calcium oxalate is 12 (Table 5 & Table 6).

Universal Management

Stimulate Diuresis

The easiest way of reducing supersaturation and indeed, one of the simplest and most effective treatments for all causes of FLUTD, is to increase urine volume and promote diuresis. There is a great deal of evidence in cats that low urine volume as well as urine concentration are risk factors for urolith formation. High urine volumes will actually reduce the risk of urolith formation by increasing the frequency of micturition, which helps remove any free crystals, proteinaceous material and debris from the urinary tract. In addition, urine dilution and increased urinary flow is known to help cats with urolithiasis and urethral plugs as it reduces the concentration of lithogenic substances and reduces the time available for urinary solutes to form crystals or stones.

To stimulate diuresis, drinking must be encouraged (Table 7). Cats when fed two identical diets except for their moisture content tend to consume less water, to urinate less frequently and to produce less, but more concentrated urine on the lower moisture diet (Burger et al, 1980). An increase in water turnover can be achieved by feeding diets that contain 70 - 85% moisture (canned, pouch, tray), by increasing feeding frequency (increasing number of meals/day), by increasing the sodium chloride content of the diet, or by adding water to the diet (Dumon et al, 1999).

The water intake of a cat is significantly influenced by the number of meals per day. Kirschvink et al (2005) reported that that water intake increased from 72 mL/cat/day to 95 mL/cat/day by feeding three meals rather than one meal per day (Table 8).

The digestibility of the diet will influence the absolute amount of water available to dilute urine. Less digestible diets have been associated with increased fecal water loss (Table 9). The increased loss of water into the feces decreases the amount of water absorbed and subsequently excreted in the urine. The risk of urolithiasis increases the more concentrated the urine. Therefore, cats with lower urinary tract disease should be fed highly digestible diets to minimize fecal water loss.

Increased dietary sodium content has been used to increase water intake and cause subsequent urine dilution in cats. The effectiveness of dietary sodium on increasing urine volume was clearly shown in a study by Biourge et al (2001). Healthy cats fed 1.1 g NaCl/1000 kcal had a mean urine volume of 11 ± 5 mL/kg/day. Urine volume increased significantly to 20 ± 7 mL/kg/day when the dietary sodium intake was increased to 2.5 g NaCl/1000 kcal.

Effect of Dietary Sodium on Urinary Calcium Excretion

Historically, there has been controversy about the use of sodium chloride to stimulate thirst and diuresis, as it could also potentially affect urinary calcium excretion, blood pressure and renal disease (Osborne et al, 2000). However, recent studies in cats have refuted this theory, and support the use of moderate increases in sodium to help maintain urinary tract health.

In studies by Devois et al (2000a, b), it was shown that a sodium intake of 1.04% DMB was associated with an increase in 24 hour calcium excretion and urine output. However, as urinary output increased by 100%, the sodium intake resulted in similar calcium and lower oxalate urinary concentrations compared with a sodium intake of 0.30 - 0.39% DMB. Due to the significant effect of sodium on urine volume, increasing dietary NaCl does not increase the urinary calcium oxalate RSS and therefore does not increase the risk for calcium oxalate urolith formation. The results of this study is supported by epidemiological studies that report that diets with a salt content of 1.43 - 3.70 g/1000 kcal have a decreased risk of calcium oxalate urolith formation compared with diets containing 0.48 - 0.77 g/1000 kcal (Lekcharoensuk et al, 2001b).

Hawthorne & Markwell (2004) evaluated the effect of the dietary sodium content of 23 commercially available extruded diets on water intake and urine composition in 55 healthy adult cats. Cats fed diets containing higher levels of dietary sodium content had significantly higher water intake and urine volume (Figure 21), and significantly lower urine specific gravity (Figure 22), and calcium oxalate RSS values (Figure 23) compared to cats fed lower sodium diets. Urinary calcium concentration did not differ significantly between cats fed the moderate and lower sodium diets. The results of this study indicate that dietary sodium concentrations up to 4 g/1000 kcal did not increase the urine calcium concentrations in cats, but did however, increase water turnover and urine volume compared to cat foods with sodium content less than 1.75 g/1000 kcal.

Zu et al (2006) evaluated the effect of dietary sodium content on water intake, urine volume, urine specific gravity, mineral excretion, relative supersaturation and activity product ratios of calcium oxalate and struvite in nine healthy cats. Increasing sodium content from 0.4 to 1.2% DMB was associated with a significant increase in urine volume. Increased dietary sodium did not increase calcium excretion in these healthy cats.

Figure 21. Influence of the dietary sodium content on mean daily water intake and urine volume in cats (Data adapted from Hawthorne & Markwell, 2004).

Figure 22. Influence of the dietary sodium content on mean daily urine specific gravity in cats (Data adapted from Hawthorne & Markwell, 2004).

Figure 23. Influence of the dietary sodium content on mean calcium oxalate rss in cats (Data adapted from Hawthorne & Markwell, 2004).

Effect of Dietary Sodium on Urinary RSS Values

The calculation of RSS from the urine of cats fed a specific diet can be used to study the effect of that diet on the crystallization potential of urine (Markwell et al, 1999b; Robertson, 2002). Studies have confirmed that increasing the dietary intake of sodium significantly reduces the RSS of struvite and calcium oxalate in healthy cats (Figure 24, Figure 25) (Tournier et al, 2006a; Xu et al, 2006). Tournier et al (2006a) evaluated 11 extruded diets with a sodium content ranging from 0.44% to 1.56% DMB on urinary parameters in healthy cats. A significant linear correlation was found between dietary sodium and calcium oxalate RSS, demonstrating that increasing dietary sodium content significantly decreases calcium oxalate RSS in cats by increasing urine volume and thus urine dilution. Increased moisture intake has also been shown to reduce calcium oxalate RSS in urolith former cats (Lulich et al, 2004).

Figure 24. Dietary sodium content is very effective at reducing the rss for struvite in healthy cats. (Royal Canin Research Center 2005; internal data collected during a 2 year-period).

Figure 25. Relationship between dietary sodium and calcium oxalate (CaOx) RSS in healthy cats. (Biourge, 2007).

Effect of Dietary Sodium on Blood Pressure and Renal Function

As in humans, the long term risks of increased (1.75 to 3.25 g/1000 kcal) dietary NaCl intake on the health of cats are controversial. The levels of dietary NaCl that will stimulate diuresis do not appear to affect blood pressure in healthy pets, in cats with early renal disease as well as in feline models of renal failure (Buranakarl et al, 2004; Luckschander et al, 2004; Cowgill et al, 2007). More over, an epidemiological study concluded that feeding cats’ higher level of Na among other nutrients reduced the odds of suffering from chronic renal failure (Hughes et al, 2002).

Short-term feeding of high-sodium foods (1.02% Na versus 0.46% DMB) to young, healthy cats for 14 days was associated with a significantly increased water intake and decreased urine specific gravity without increasing systolic blood pressure (Figure 26). Blood pressure measurements remained within the reference range throughout the study in all 10 cats (Luckschander et al, 2004). The results of this study suggests that feeding a diet with moderately increased salt content increases water intake and causes diuresis without increasing systolic blood pressure in healthy adult young cats.

Figure 26. The effect of sodium chloride on systolic blood pressure in healthy adult cats. (Data adapted from Luckschander et al, 2004).

Cowgill et al (2007) evaluated the effect of dietary sodium concentration on renal function in adult cats. There were no differences in plasma creatinine, BUN or glomerular filtration rate (GFR, assessed by 10-hour pharmacokinetic analysis of exogenous plasma creatinine clearance) when cats were fed 0.22% versus 1.3% sodium diets. These data suggest that extremes of dietary salt have no short-term effect on renal function in healthy cats.

Buranakarl et al (2004) evaluated the effect of salt intake on blood pressure in cats with induced azotemia similar in degree to IRIS Stages II and III in cats. Salt intake had no effect on blood pressure. Further, the lowest level of salt intake was associated with the lowest values for GFR, inappropriate hypokalemic kaliuresis and activation of the renin-angiotensin-aldosterone system. The results of this study suggest that, similar to healthy cats, cats with induced renal disease are not salt sensitive.

Adjusting Urine pH

Adjusting urine pH via dietary manipulation or medical means can be very effective in the management of some but not all uroliths (Figure 27). Urine acidification markedly increases struvite solubility and is essential in the medical dissolution of these uroliths (Stevenson et al, 2000; Smith et al, 2001). In contrast, urine alkalinization is important in increasing the solubility of metabolic uroliths including some urate uroliths and cystine uroliths. Alkalinization above 7.5 is not recommended as this may contribute to calcium phosphate urolithiasis. Calcium oxalate uroliths appear at any urine pH and to date, medical dissolution is impossible.

The effect of urine pH on the risk of forming crystals, and as a method of treatment or prevention will be discussed further as it relates to individual uroliths.

Figure 27. Solubility and PH (personnal communication with Dr WG Robertson).

Struvite

Risk Factors

Unlike dogs, the majority of struvite (magnesium ammonium phosphate hexahydrate; Mg NH4 P04 6H20) uroliths in cats are sterile (Buffington et al, 1997; Lekcharoensuk et al, 2000;2001a; Cannon et al, 2007). Struvite uroliths form when the urine becomes supersaturated with magnesium, ammonium, and phosphorus and when the urine pH is greater than 6.5. Struvite crystals are more soluble when the urine pH is less than 6.5 and crystallization is unlikely to occur when the pH is less than 6.3. However, pH is less critical when food promotes diuresis and urine dilution as it is the case with wet food (Figure 28).

Figure 28. The association between urine pH and RSS for struvite in feline urine (Royal Canin Research Center 2005; internal data collected during a 2 year-period).

A case-control study reported that diets with the highest magnesium, phosphorus, calcium, chloride and fiber, moderate protein and low fat content were associated with an increased risk of struvite urolithiasis (Lekcharoensuk et al, 2001b).

Magnesium - Diets containing 0.15 to 1.0% magnesium on a dry matter basis were associated with the formation of struvite uroliths (Lekcharoensuk et al, 2001b). However, the magnesium effect depends on the form of magnesium and on the urine pH (Tarttelin, 1987; Buffington et al, 1990; Reed et al, 2000a). Buffington et al. (1990) reported that cats fed 0.5% magnesium as MgCl2 did not form struvite uroliths whereas cats that were fed 0.5% magnesium as MgO did form struvite uroliths (Table 10). The difference in susceptibility to struvite formation was due to magnesium oxide promoting the formation of alkaline urine whereas magnesium chloride promoted the formation of a protective acidic urine.

Phosphorus - Cats fed diets high in phosphorus (3.17 - 4.70 g/1000 kcal) were almost four times as likely to develop struvite uroliths compared to cats fed diets with 0.85 - 1.76 g/1000 kcal phosphorus (Lekcharoensuk et al, 2001b). High dietary intake of phosphorus enhances urinary phosphorus excretion and therefore, promotes superaturation of urine with magnesium, ammonium, and phosphate (Finco et al, 1989).

Management

Elimination of the Urinary Tract Infection - Although not common, infection-induced struvite uroliths require a combination of an appropriate antimicrobial and dissolution dietary therapy (see below).

Antibiotic therapy should be based on culture and sensitivity determination of urine obtained by cystocentesis. Antibiotic therapy should be continued for one month following radiographic resolution of the urolith/s, as viable bacteria may remain in the urolith and uroliths may be too small or too lucent to see on radiographs post dissolution.

Calculolytic Diets to Dissolve Struvite Uroliths - Pure struvite uroliths can be dissolved by the administration of a diet that promotes an increased urine volume and a urine pH less than 6.3 (Osborne et al, 1990a; Houston et al, 2004). The diet should have a controlled magnesium level and create an RSS value less than one (undersaturated zone). The diet should contain adequate quantities of sodium to promote water intake and the formation of dilute urine. Sterile struvite uroliths do not need adjunctive antibiotic therapy.

The efficacy of a canned, magnesium-restricted, urine acidifying, salt-supplemented diet designed to dissolve struvite urolithiasis was shown in 1990 (Osborne et al, 1990a). More recently, the efficacy of a canned and dry moderately magnesium restricted diet specifically designed to promote the formation of acidic urine, with a RSS value less than one for the dissolution of feline struvite urolithiasis has been reported by Houston et al (2004). In this study of 30 cats, the mean time required for dissolution of struvite uroliths was 26 days on the canned diet and 34 days on the dry diet (Figure 29a and Figure 29b).

Figure 29a. Lateral radiograph of the abdomen of a cat. The arrow points to a large, single urolith. (© D. Houston).

Figure 29b. Lateral radiograph of the abdomen of a cat four weeks after institution of a struvite dissolution diet. The previously noted urolith (Figure 29A) has completely dissolved. (© D. Houston).

It is recommended that dissolution therapy should continue for 1 month after radiographic documentation of struvite dissolution. If the urolith does not dissolve, the wrong mineral type or a complex mineral type may be involved.

Prevention of Recurrence - The recurrence rate for struvite uroliths has been reported as 2.7% with a mean recurrence time of 20 months (Albasan et al, 2006). Therefore, following dissolution or mechanical removal of struvite uroliths, a diet designed to help prevent recurrence is recommended. The diet should have a RSS in the undersaturated to metastable range, a urine pH less than 6.5 and should either be high in moisture (canned, pouch, or tray product) or designed to encourage diuresis (enhanced with sodium chloride).

Drug Therapy - Urinary acidifying agents such as ammonium chloride or DL methionine are not necessary provided an appropriate urine acidifying diet is used.

Figure 30. Four struvite uroliths removed from the bladder of a cat. Typical round to wafer or disc-shaped struvite uroliths. (© Andrew Moore, CVUC, Guelph, Ontario, Canada).

Figure 31. A collection of feline struvite uroliths showing variability in appearance. (© Andrew Moore, CVUC, Guelph, Ontario, Canada).

Monitoring - The efficacy of therapy should be monitored with urinalysis (pH, urine specific gravity, sediment examination) at two weeks, four weeks and then every three to six months. Not all cats with uroliths shed crystals, therefore abdominal radiography should be obtained every three to six months to monitor for early urolith recurrence.

Calcium Oxalate (Figure 32)

Risk Factors

The mean age at diagnosis of calcium oxalate urolithiasis in cats is 7.8 years, with a range of 2 - 18 years. The risk for calcium oxalate urolith formation increases with age. One study reported a bimodal age distribution peaking at 5 and 12 years. The highest risk for developing calcium oxalate uroliths appears to be from 7 - 10 year of age. Smith et al (1998), reported that senior cats (mean age 10.6 ± 1.3 years) produced urine that had significantly lower struvite RSS values (0.72 ± 0.58 vs. 4.98 ± 4.03) and significantly higher calcium oxalate RSS values (3.45 ± 1.62 vs. 0.91 ± 0.87) when compared to a group of younger (4.1 ± 1.0 years) cats. The senior cats had a significantly lower urine pH, compared to the younger cats (6.1 ± 0.2 vs. 6.4 ± 0.2, respectively). The decrease in urine pH in the senior cats may partially explain the increased risk for forming calcium oxalate uroliths with age (Smith et al, 1998).

Figure 32. Typical appearance of feline calcium oxalate uroliths. (© Andrew Moore, CVUC, Guelph, Ontario, Canada).

Genetic and gender differences, inactivity, obesity, and environment have been associated with an increased risk for developing calcium oxalate uroliths (Lekcharoensuk et al, 2001b). Male cats (55%) are more commonly affected and are 1.5 times more likely to develop calcium oxalate uroliths compared to female cats. The Burmese, Himalayan, and Persian breeds have an increased risk of developing calcium oxalate urolithiasis, suggesting that genetic factors may contribute to the formation of calcium oxalate uroliths. Indoor housing has been reported as a risk factor for calcium oxalate urolithiasis (Kirk et al, 1995; Jones et al, 1997; Gerber et al, 2005).

In humans, hyperoxaluria occurs as a result of at least two types of inherited errors of metabolism, both resulting in increased oxalate production and recurrent calcium oxalate urolithiasis (Williams & Wilson, 1990). Inherited primary hyperoxaluria (L-glyceric aciduria), a deficiency of hepatic dglycerate dehydrogenase, an enzyme required for metabolism of oxalic acid precursors, has been reported in cats but the clinical manifestations of this metabolic disorder have been related to weakness and acute onset of renal failure, not calcium oxalate urolithiasis (McKerrell et al, 1989; De Lorenzi et al, 2005).

The explanation for the increased risk of calcium oxalate uroliths in cats from 1984 to 2002 is not clear although the widespread use of severely magnesium-restricted, urine-acidifying diets to control struvite uroliths has been implicated (Kirk et al, 1995; McClain et al, 1995; Thumachai et al, 1996; Osborne et al, 1996c; Lekcharoensuk et al, 2000; 2001a,b). However, many cats are fed acidifying diets and yet few appear to develop hypercalcemia, metabolic acidosis, and calcium oxalate urolithiasis. Therefore additional factors such as gastrointestinal hyperabsorption or increased renal excretion of calcium and/or oxalate may be important in susceptible cats.

Acidosis - Lekcharoensuk et al (2000) reported that cats fed diets formulated to produce a urine pH between 5.99 and 6.15 were three times as likely to develop calcium oxalate uroliths. Persistent aciduria may be associated with low-grade metabolic acidosis, which promotes bone mobilization of carbonate and phosphorus to buffer hydrogen ions (Figure 33). Simultaneous mobilization of calcium coupled with inhibition of renal tubular reabsorption of calcium, results in increased urinary excretion of calcium. Increased urinary calcium excretion has been reported in clinically normal cats fed diets supplemented with urinary acidifiers (Fettman et al, 1992). In five cats with hypercalcemia and calcium oxalate uroliths, discontinuation of the acidifying diets or urinary acidifiers was associated with normalization of serum calcium concentration (McClain et al, 1999).

Figure 33. The effect of metabolic acidosis on urinary calcium excretion.

In one study on cats, the addition of an acidifier to a canned food was associated with a small but significant increase in calcium oxalate RSS. However, this higher RSS was still well below the formation product of 12 (Stevenson et al, 2000). Furthermore, this study demonstrated that it is possible to formulate a very acidifying diet (mean urine pH = 5.8) that will both minimize struvite and calcium oxalate crystallization (Figure 34). When comparing urinary pH and calcium oxalate RSS values associated with various commercial and experimental feline diets, urinary pH appears to be a very poor predictor of calcium oxalate RSS (Figure 35) (Tournier et al, 2006b).

Figure 34. Influence of urinary pH on calcium oxalate and struvite RSS (Adapted from Stevenson et al, 2000).

Figure 35. Urine pH is a poor predictor of the risk of calcium oxalate in feline urine. Data from 125 individual diets (from Tournier et al, 2006b).

Calcium - Hypercalciuria was a consistent abnormality in ten cats with calcium oxalate uroliths (Lulich et al, 2004). Increased intestinal absorption of calcium may occur due to excess dietary calcium, excess vitamin D, or hypophosphatemia. Increased renal excretion of calcium may occur with decreased renal tubular reabsorption (furosemide and corticosteroids), or increased mobilization of calcium from body stores (acidosis, hyperparathyroidism, hyperthyroidism, excessive vitamin D) (Ling et al, 1990; Osborne, 1995a;1996b;2000).

Protein - Diets high in animal protein have been associated with acidosis, increased urinary calcium and oxalate excretion, and decreased urinary citric acid excretion in humans (Holmes et al, 2001; Borghi et al, 2002; Pietrow & Karellas, 2006). Consumption of animal protein by both healthy cats and cats with calcium oxalate urolithiasis is associated with increased water consumption, urine volume, and urinary phosphorus excretion, while calcium excretion is not increased (Funaba et al, 1996; Lekcharoensuk et al, 2001; Lulich at al 2004). High protein diets (105 - 138 g/1000 kcal) were less than half as likely to be associated with calcium oxalate urolith formation as diets low in protein (52 - 80 g/1000 kcal) (Lekcharoensuk et al, 2001b). A case-control study reported that cats fed diets low in moisture and low in protein had an increased risk of calcium oxalate urolithiasis (Lekcharoensuk et al, 2001b). Protein type has also been shown to influence urinary oxalate excretion in cats (Zentek & Schultz, 2004).

Water Consumption - Intravascular volume depletion and concentration of urine volume increases the risk of urine supersaturation with calcium and oxalate. Cats fed diets high in moisture content are about one third as likely to develop calcium oxalate uroliths compared to cats fed diets low in moisture.

Oxalate - Excessive dietary oxalate (e.g., broccoli, spinach, rhubarb, nuts, strawberries) will increase the renal clearance of oxalate and the risk of urolithiasis in humans and such foods are to be avoided in pets (Lulich et al, 1994; Holmes et al, 2001).

A collection of feline calcium oxalate uroliths indicating variability in appearance. Most often, calcium oxalate dehydrate has a speculated appearance (bottom right corner); calcium oxalate monohydrate is often round (bottom left corner). (© Andrew Moore, CVUC, Guelph, Ontario, Canada).

Vitamin C - In humans, although controversial, calcium oxalate uroliths have been associated with excessive consumption of vitamin C and low levels of vitamin B6 (Hughes et al, 1981; Mitwalli, 1989; Curhan et al, 1999). Vitamin C is metabolized to oxalic acid and excreted in urine. The effect of dietary vitamin C supplement on urinary oxalate concentration has been studied in 48 adult American Domestic Short Hair cats (Yu et al, 2005). Cats were fed a nutritionally complete and balanced dry control food for two weeks before they were fed for four weeks, one of four diets containing 40 mg/kg, 78 mg/kg, 106 mg/kg, or 193 mg/kg of vitamin C, respectively. Vitamin C supplementation up to 193 mg/kg did not affect urinary oxalate concentration in the healthy cats.

Vitamin B6 - Vitamin B6 increases the transamination of glyoxylate, an important precursor of oxalic acid, to glycine. Therefore pyridoxine deficiency increases the endogenous production and subsequent excretion of oxalate. Experimentally induced vitamin B6 deficiency resulting in increased urinary oxalate concentrations and oxalate nephrocalcinosis has been reported in kittens (Bai et al, 1989). However, a naturally occurring form of this syndrome has not yet been reported. Supplementation with vitamin B6 does not decrease urinary oxalic acid excretion compared with a diet containing adequate levels of vitamin B6 (Wrigglesworth et al, 1999). Consequently, the ability of supplemental vitamin B6 to reduce urinary oxalic acid excretion in cats with calcium oxalate uroliths consuming diets with adequate quantities of vitamin B6 is unlikely.

Citrate - Urinary citrate deficiency has been suggested to increase the risk of calcium oxalate in humans by increasing the availability of calcium ions to bind with oxalate (Allie-Hamdulay & Rodgers, 2005; Pietrow & Karellas, 2006). Citrate deficiency may be an inherited defect or be secondary to acidosis, which promotes the renal tubular utilization of citrate. If consumption of dietary acid precursors is associated with hypocitraturia in cats, the risk of calcium oxalate uroliths may increase as citrate is an inhibitor of calcium oxalate urolith formation (Lekcharoensuk et al, 2001b).

Magnesium - Magnesium has been reported to be an inhibitor of calcium oxalate urolithiasis in other species (Johansson et al, 1980). In cats, diets with low magnesium content (0.09 - 0.18 g/1000 kcal) are associated with an increased risk of calcium oxalate urolith formation, compared with diets with moderate magnesium content (0.19 - 0.35 g/1000 kcal) (Lekcharoensuk et al, 2001b). Conversely, diets with magnesium contents more than 0.36 g/1000 kcal were associated with an increased risk of calcium oxalate urolithiasis (Lekcharoensuk et al, 2001b). Magnesium contributes to increased urinary calcium loss by increasing blood-ionized calcium concentration and suppressing PTH secretion.

Phosphate - Hypophosphatemia may increase the risk of calcium oxalate urolithiasis in cats. The risk of calcium oxalate urolith formation was five times higher in cats fed a diet with 0.85 - 1.76 g/1000 kcal of phosphorus compared with a diet containing 1.77 - 3.16 g/1000 kcal of phosphorus (Lekcharoensuk et al, 2001b). Hypophosphatemia will result in the activation of Vitamin D3 to calcitriol by 1-alpha-hydroxylase in the kidney and cause increased intestinal absorption and renal excretion of calcium. In addition, urinary pyrophosphate has been suggested to be an inhibitor of calcium oxalate urolith formation (Osborne et al, 1995b; Reed et al, 2000b,c). Conversely, diets higher in phosphorus (>3.17 g/1000 kcal) were associated with an increased risk of calcium oxalate urolith formation compared with diets containing moderate levels (1.77 - 3.16 g/1000 kcal) (Lekcharoensuk et al, 2001b).

Sodium - Supplemental sodium chloride has long been suggested to increase urinary calcium excretion in humans. Similar observations have been made in cats. The link between dietary Na and urinary Ca excretion led to the assumption that high salt diets could promote calcium oxalate formation in cats, and thus lead to the recommendation that diets designed for the management of FLUTD should be low in sodium. However, although increased sodium intake increases calcium excretion, calcium concentration does not increase because of the concomitant increase in urine volume and a significant decrease in CaOx RSS is observed (see above, Effect of dietary sodium on urinary calcium excretion). Furthermore, a recent epidemiological study found that increasing dietary sodium reduces the risk of calcium oxalate uroliths in cats (Lekcharoensuk et al, 2001b).

Potassium - Diets low in potassium have been shown to contribute to the risk for calcium oxalate uroliths (Lekcharoensuk et al, 2001b). Potassium-rich diets may be protective against calcium oxalate urolith formation by altering urinary calcium excretion. This has been shown to be true in humans (Lemann et al, 1991).

Management and Prevention of Recurrence

Calcium oxalate uroliths do not respond to medical dissolution. Consequently, cystouroliths must be mechanically removed by voiding urohydropropulsion or surgery. Once removed, preventive measures are indicated as the risk of recurrence is high.

Recurrence rates have been reported as 10.9% with a mean recurrence time of 20 months. The recurrence rate was 1.8 times higher in male compared to female cats (Albasan et al, 2006). Medical protocols are therefore essential to reduce urolith recurrence following removal.

Eliminate Risk Factors - If the cat is hypercalcemic, a complete medical work up is indicated to identify and treat the underlying cause. In many cases, an underlying cause for the hypercalcemia can not be determined.

If the cat is normocalcemic, risk factors for urolithiasis should be identified and controlled. Dry acidifying diets that have not been formulated to increase urine production and drugs that promote excessive urinary calcium excretion (urinary acidifiers, furosemide, etc.) should be avoided. No treats or dietary supplements containing calcium, vitamin D or excessive amounts of vitamin C should be given, as these may promote increased excretion of calcium and/or oxalate (Osborne et al, 1995a).

Dietary Modification - Crystallization of calcium oxalate, the first step in the formation of this urolith cannot occur unless the urine is supersaturated with these crystalloids. Therefore, diets promoting the production of urine that is metastable or undersaturated with calcium oxalate should help prevent reoccurrence. The diet should produce an RSS value significantly less than 12 (ideally less than 5). Augmenting water intake remains a major factor in managing and preventing calcium oxalate urolithiasis (see above: Stimulate diuresis).

Calcium and Oxalate - Studies have clearly shown that the concentrations of dietary calcium and dietary oxalate influence the urinary calcium oxalate RSS (Smith et al, 1998; Markwell et al, 1998a; 1999a,b; Stevenson et al, 2000). Excessive dietary calcium and dietary oxalate should be avoided but calcium oxalate preventive diets should not be calcium or oxalate restricted to any significant degree. Reducing consumption of either one of these constituents could increase the availability of the other constituent for intestinal absorption. In one study of ten cats, reduction in dietary calcium was not associated with increased urinary oxalic acid concentration (Lulich et al, 2004) but in other studies (Lekcharoensuk et al, 2001b), a decreased risk of calcium oxalate urolithiasis was observed in cats fed diets containing moderate quantities of dietary calcium.

Phosphorus, Magnesium, Potassium - Dietary phosphorus should not be restricted or supplemented (Lekchareonesuk et al, 2001b). The severe phosphate restriction may increase urinary calcium excretion, which contributes to urolith formation. Low protein/renal diets are not recommended because they are the lowest phosphorus containing diets.

As both dietary magnesium restriction and magnesium supplementation have been associated with an increased risk of calcium oxalate urolithiasis in cats; diets should neither be severely restricted nor supplemented with magnesium (Osborne et al, 1995a; Lekcharoensuk et al, 2001b).

Urinary pH Recent work in our facility suggests that urine pH is not a good predictor of calcium oxalate saturation in healthy cats (Figure 35). Even though metabolic acidosis will increase urinary calcium concentration (Kirk et al, 1995; McClain et al, 1995; Thumachai et al, 1996; Lekcharoensuk et al, 2000;2001), it is possible to formulate a diet that will induce a urine pH between 5.8 - 6.2 and still induce a RSS CaOx well below 5, thus allowing to prevent both struvite and calcium oxalate crystal formation.

A collection of feline calcium oxalate uroliths. The "Jackstone" like appearance may easily be mistaken for a silica urolith on radiograph. (© Andrew Moore, CVUC, Guelph, Ontario, Canada)

Drug Therapy and Monitoring - Adjunct medical therapies with citrate, thiazide diuretics, and vitamin B6 have been recommended in some cases of persistent calcium oxalate crystalluria or recurrent urolithiasis. Potassium citrate has been useful in humans to prevent recurrent calcium oxalate urolithiasis, via its ability to form soluble salts with calcium (Pietrow & Karellas, 2006). Oral potassium citrate increases the urine pH and may be of use in cases where the urine pH is more acidic than desired, a state that could contribute to hypocitraturia (Osborne et al, 1995b; Lekcharoensuk et al, 2001b).

Hydrochlorothiazide diuretics are used to treat people with calcium oxalate urolithiasis. Hydrochlorothiazide has been shown to decrease the calcium oxalate RSS in healthy adult cats (Hezel et al, 2006). However hydrochlorothiazide administration was associated with increased excretion of potassium, sodium, magnesium, phosphorus and chloride, which could result in whole body depletion with long term administration.

The efficacy and safety of hydrochlorothiazide have not evaluated in cats with calcium oxalate uroliths, hence its use can not be recommended at this time.

Efficacy of therapy should be monitored with urinalysis (pH, urine specific gravity and sediment examination) at two weeks, four weeks and then every three to six months. As not all cats with calcium oxalate uroliths shed crystals, abdominal radiography should be completed every three to six months to reveal urolith recurrence at a time when the uroliths are small enough that voiding urohydropropulsion may be possible.

Managing Renal and Ureteral Uroliths

Controversy exists as how to most effectively manage renal and ureteral uroliths. Kyles et al (2005) reported that 92% of cats with ureterolithiasis were azotemic at the time of presentation, 67% of cats had multiple uroliths, and 63% were affected bilaterally. The high probability of bilateral involvement, concurrent renal insufficiency, and likelihood of reoccurrence limit nephrectomy as a surgical option. Nephrotomy results in the unavoidable destruction of nephrons, hence, this surgery is not recommended unless it is clearly established that the renal uroliths are causing clinically significant disease. Ureterotomy may be indicated for those cats with progressive hydronephrosis and an identifiable ureterolith. Post-operative complications include uroabdomen and ureteral stricture. Alternatively, partially obstructing uroliths can be managed conservatively. The ureterolith will pass into the bladder in 30% of cats managed conservatively (Kyles et al, 2005). Although commonly used in human medicine, lithotripsy has not been established as a routine procedure in the cat.

Calcium Phosphate

Recognition and management of underlying contributing conditions is the first and most important step in the prevention of calcium phosphate urolithiasis. The cat should be assessed for evidence of primary hyperparathyroidism, hypercalcemia, excessive urine concentrations of calcium and/or phosphate, and an inappropriately alkaline urine pH (>7.5). There may also be a previous history of dietary therapy and administration of alkalinizing agents to prevent another urolith type. If a specific underlying disorder is not diagnosed, calcium phosphate uroliths are generally managed similar to strategies used for calcium oxalate urolithiasis. One should, however, be very careful to avoid excessive urine alkalinization, which may occur with some diets used for the prevention of calcium oxalate uroliths.

Urate (Figure 36)

Risk Factors

Urate uroliths are the third most common type of urolith reported in cats. They are composed of uric acid and the monobasic ammonium salt of uric acid (ammonium acid urate). Compared to struvite and calcium oxalate, the prevalence is less than six percent (Osborne et al, 2000; Houston et al, 2004; 2006) and this has not changed significantly in the last two decades. In Canada, ten of 321 (3.1%) ammonium urate submissions were from Siamese cats and nine of 321 (2.8%) were from Egyptian Maus (Houston et al, 2006).

Figure 36. Urate urolith. (© Andrew Moore, CVUC, Guelph, Ontario, Canada).

Urate uroliths may occur in cats with portosystemic shunts or any form of severe hepatic dysfunction. This may be associated with reduced hepatic conversion of ammonia to urea resulting in hyperammonemia. Urate uroliths in cats with portosystemic shunts often contain struvite. Urate uroliths may also occur:

• In cats with urinary tract infections that result in increased urinary ammonia concentrations,
• In cats with metabolic acidosis and highly acidic urine,
• And when cats are fed diets high in purines, such as liver or other organ meats (Osborne et al, 1992a; Ling 1995; Ling & Sorenson, 1995).

In the majority of cases, the exact pathogenesis remains unknown (Cannon et al, 2007).

Treatment

Urate uroliths may be amenable to dietary dissolution, however, there are no published clinical trials on the efficacy of diet for the medical dissolution of feline urate uroliths.

The dietary strategy aims at decreasing the purine content of the diet. As with all urolith types, encouraging water intake and urine dilution by feeding a moist (canned, pouch, tray) diet or adding supplemental water or sodium to the food can help to lower urinary saturation.

Alkalinization of Urine - Alkaline urine contains low levels of ammonia and ammonium ions, and thus alkalinizing the urine will decrease the risk of ammonium urate urolithiasis. Low protein, vegetable based diets have an alkalinizing effect but additional potassium citratemay be needed. The dose should be individualized to maintain a urine pH in the range of 6.8 - 7.2. Alkalinizing the urine above 7.5 should be avoided as this may promote formation of secondary calcium phosphate crystals. If a vegetable based diet is used in a cat, care must be taken to ensure it is adequately balanced to meet the unique needs of the cat.

Xanthine Oxidase Inhibitors - Allopurinol, an inhibitor of xanthine oxidase, the enzyme responsible for catalyzing the conversion of xanthine and hypoxanthine to uric acid has been used in other species to help lower urinary urate excretion. Although a dosage of 9 mg/kg PO per day has been suggested for cats (Plumb, 2002), the efficacy and potential toxicity of allopurinol in cats is unknown and consequently, it’s use in cats is not recommended.

Monitoring

During dissolution, the size of the urolith(s) should be monitored by survey and/or double contrast radiography or ultrasonography every four to six weeks. Following complete dissolution, ultrasound examination (or double contrast cystography) is recommended at least every two months for one year as the risk of recurrence is high. The efficacy of preventative therapy should be also be monitored with urinalysis (pH, urine specific gravity, sediment examination) every three to six months.

Cystine (Figure 37)

Risk Factors

Cystine uroliths occur in cats with cystinuria, an inborn error of metabolism characterized by a defective proximal tubular reabsorption of cystine and other amino acids (ornithine, lysine, arginine) (DiBartola et al, 1991; Osborne et al, 1992a; Ling, 1995; Osborne et al, 1996). No obvious gender or breed predisposition has been reported but the Siamese breed may be at risk (Ling et al, 1990; Osborne et al, 2000; Cannon, 2007). Most cats are middle to older aged (Kruger et al, 1991).

Figure 37. Scanning electron microscope image of a cystine urolith from a cat. (© Andrew Moore, CVUC, Guelph, Ontario, Canada).

Management

Medical protocols that consistently promote the dissolution of cystine uroliths in cats have not yet been developed (Osborne et al, 2000). Small uroliths may be removed by voiding urohydropulsion (Lulich et al, 19993b). Cystotomy is required to remove larger uroliths.

If medical dissolution is attempted, the aim of therapy is to reduce the concentration of cystine in the urine and to increase cystine solubility. This usually requires dietary modification with a methionine-cystine reduced protein diet in combination with a thiol-containing drug.

Thiol-containing Drugs - These drugs react with cystine by a thiol disulfide exchange reaction, resulting in the formation of a complex that is more soluble in urine than cystine. N-2-mercaptopropionyl-glycine (2-MPG) is recommended at a dosage of 12 - 20 mg/kg q 12 hours (Osborne et al, 2000).

Alkalinization of Urine - The solubility of cystine is pH dependent, being markedly more soluble in alkaline urine. Urine alkalinization may be achieved using a diet that contains potassium citrate or additional potassium citrate may be administered.

Monitoring

During dissolution, the size of the urolith(s) should be monitored by survey and double contrast radiography or ultrasonography every four to six weeks. Following complete dissolution, ultrasound examination (or double contrast cystography) is recommended at least every two months for one year as risk of recurrence is high. Efficacy of therapy should be also be monitored with urinalysis (pH, urine specific gravity, sediment examination) every two to three months.

Xanthine (Figure 38)

Xanthine uroliths are rare and may be due to an inborn error of purine metabolism or arise secondary to the administration of allopurinol. In most cases, no identifying risk factors are observed. There is no apparent breed, age or sex predisposition reported (Osborne et al, 1992a;1996b; White et al, 1997).

Figure 38. Xanthine urolith (scale: 0.1 mm markings). Small xanthine calculi from a 9 month male siamese cross cat. The pale color is atypical; usually they are green or yellow. (© Andrew Moore).

The dietary strategy aims at decreasing the purine content of the diet. As with all urolith types, encouraging water intake and urine dilution by feeding a moist (canned, pouch, tray) diet or adding supplemental water or sodium to the food can help to lower urinary saturation. Allopurinol therapy must be discontinued in the management of urate urolithiasis as it is a contributing factor to xanthine urolith formation.

Silica (Figure 39)

Silica uroliths are uncommon. Based on limited numbers, there is no breed predisposition. In Canada, males outnumbered females in submission (Houston et al, 2006). The pathogenesis, at least in dogs, may involve consumption of an absorbable form of silica in various foods, resulting in urinary silica hyperexcretion. There may be some relationship to the increased use of plantderived ingredients such as fibers and bran in pet foods (Osborne et al, 1995a,b).

Figure 39. Silica urolith. (© Compliments of JL Westropp, Davis, California).

Silica uroliths may be an incidental findings in cats. Surgical removal is indicated if clinical signs of FLUTD are thought to be due to the urolith. Because the initiating and precipitating causes of silica urolithiasis are unknown, only nonspecific dietary recommendations can be made. Empiric recommendations are to change the diet to one with high quality protein and if possible, reduced quantities of plant ingredients. Increased water intake and urine dilution is to be encouraged.

Miscellaneous Uroliths

Potassium magnesium pyrophosphate uroliths have been reported in four Persian cats (Frank et al, 2002). In Canada, a total of 15 potassium magnesium pyrophosphate uroliths have been analyzed at the Canadian Veterinary Urolith Center. Two thirds were identified in male cats. The majority occurred in domestic cats (66.7%). There was one male and one female Himalayan, one male and one female Persian, and one male Maine Coon cat. There were an additional nine uroliths with a nidus of either calcium oxalate (eight) or struvite (one) surrounded by pyrophosphate uroliths or shells. Although the etiology is not definitively known, it is postulated that it is related to some temporary or permanent enzyme dysfunction causing pyrophosphate supersaturation of the urine, which leads to crystallization of the urolith (Frank et al, 2002).

Dried solidified blood uroliths (Figure 40) have been reported in cats in North America (Westropp et al, 2006). Their etiology remains unknown. These uroliths usually do not contain any mineral material and a large number are radio-transparent.

Figure 40. A collection of dried solidified blood uroliths from the bladder of a cat. (© Compliments of JL Westropp, Davis, California).

Because the initiating and precipitating causes of both potassium magnesium pyrophosphate uroliths and dried solidified blood uroliths are unknown, only nonspecific dietary recommendations can be made. Empiric recommendations are to change the diet to one that is highly digestible and low in fiber with high quality protein. Increased water intake and urine dilution is to be encouraged.

Compound Uroliths

Compound uroliths consist of a nidus of one mineral type and a urolith or shell of another mineral type (Figure 41). They form because factors promoting precipitation of one type of urolith supersede earlier factors promoting precipitation of another mineral type. Some mineral types may also function as a nidus for the deposition of another mineral type; for instance, all urolith types predispose to urinary tract infections, which in turn, may result in secondary struvite precipitation (Osborne et al, 2000).

Figure 41. Complex urolith removed from a cat. The urolith was submitted for quantitative analysis: once opened, the nidus was analyzed as ammonium acid urate. The shell was determined to be struvite. (© Andrew Moore, CVUC, Guelph, Ontario, Canada).

The possibility of compound uroliths highlights the need to submit uroliths for quantitative analysis so that the appropriate dietary and medical strategy can be implemented. The dietary strategy aims at managing the factors that lead to the formation of the nidus. As with all urolith types, encouraging water intake and urine dilution by feeding a moist (canned, pouch, tray) diet or adding supplemental water or sodium to the food can help to lower urinary saturation.

Conclusion

Encouraging water intake to enhance urine volume and diuresis is paramount for the management of all cats with clinical signs of lower urinary tract disease. For FIC, urine dilution decreases noxious, irritating substances in the bladder. For urethral plugs, urine dilution and enhanced urine volume will also help decrease the concentration of proteinaceous material and urinary tract debris. For urolithiasis, urine dilution enhances urine volume for a given solute load, reduces saturation, and decreases the concentrations of crystalloids. In addition, increasing urine volume may influence crystal transit time through the urinary tract, thus reducing the potential for crystal growth.

Dietary modification is an important part of the management regimen for cats with urolithiasis, regardless of the cause. Specific dietary recommendations for individual uroliths are dependent on the mineral composition of the urolith. For cats with struvite urolithiasis, control of magnesium and reduction of urine pH through dietary manipulation are necessary to achieve urine which is undersaturated with struvite. For cats with calcium oxalate urolithiasis, attention is paid to the amount of calcium and oxalate precursors in the diet and the goal is to achieve an RSS in the metastable range. Manipulating urinary pH is not effective for the management of calcium oxalate uroliths. For metabolic uroliths (cystine, xanthine, urate), reduced quantities of dietary protein are recommended and urine pH is adjusted to be in the neutral to alkaline range.