Feline Lower Urinary Tract Disorders (Session 1)
Sterile Cystitis (Session 2)

Tony Buffington United States

Introduction

The terms Feline Urologic Syndrome (FUS) and Feline Lower Urinary Tract Disease (FLUTD) serve as shorthand descriptions of the well-known signs of straining, hematuria, pollakiuria, and inappropriate urination in cats. A recent study suggested that lower urinary tract signs afflict approximately 1.5% of cats presented to private veterinary practices engaged in companion animal medicine. However, FUS and FLUTD do not contain any diagnostic specificity for the many (~30) causes of lower urinary tract signs. Results of university-based studies during the last four decades suggest that most (55% to 69%) cats presented for evaluation of nonobstructive lower urinary tract disorders have idiopathic cystitis, approximately 20% have a urolith (struvite or calcium oxalate), and the rest have a variety of less common problems. For example, during 1993�1995, The Ohio State University (OSU) Veterinary Hospital evaluated 109 cats presented for signs of irritative voiding. Seventy cats had idiopathic cystitis, 15 had a stone (eight struvite and seven calcium oxalate), 12 had an anatomic defect, 12 had a urethral obstruction, 11 had a systemic disease, and 10 had a behavior disorder. Two cats had neoplasia (one also had a struvite stone), one had an unidentified stone (and an anatomic defect), and one had a urinary tract infection.

Urolithiasis

The two most common stone types in cats are struvite and calcium oxalate. Struvite (magnesium ammonium phosphate) urolithiasis and urethral obstruction have been induced experimentally in healthy cats by feeding diets containing three to ten times the amount of magnesium found in commercial cat foods. These studies led to the conclusion that magnesium was a primary cause of naturally occurring struvite urolithiasis in cats. It subsequently was learned that struvite stones in the bladder of healthy cats fed large quantities of magnesium dissolved when the urine pH was reduced to approximately 6.0. These results suggested that magnesium�s effect on struvite formation depended on the urine pH, an idea supported by the finding that the form of magnesium used in previous studies had increased the urine pH.

The research implicating magnesium as a potential cause of urinary stone disease in cats seems to have led cat food manufacturers to restrict the magnesium contents of diets and to add ingredients to promote more acidic urine in an attempt to minimize the struvite-promoting potential of their products. Unfortunately, an increase in the frequency of calcium oxalate urolithiasis appears to have occurred since these modifications began; between 1984 and 1995, the proportion of stones submitted to the University of Minnesota Urolith Center found to be composed of calcium oxalate increased from 2% to 40%. Unfortunately, no epidemiologic studies of urolithiasis in cats are available, so the effects, if any, of diet changes on urinary stone incidence or prevalence are unknown.

In contrast to struvite, experimental diet manipulations that induce calcium oxalate stone formation in healthy cats have not been reported. In fact, the recent increase in the incidence of calcium oxalate stone suggests that some cats are genetically predisposed to form calcium oxalate stones and that diet changes unmasked their predisposition. Previous commercial cat diets that did not restrict magnesium or reduce urine pH may have obscured this susceptibility by resulting in formation of urine in which calcium oxalate stones were unlikely to form. When cat food manufacturers added acid-forming ingredients and reduced the magnesium content of foods to prevent struvite formation, the diets may no longer have protected cats prone to calcium oxalate formation. Thus, cats susceptible to calcium oxalate formation were consuming a �provocative� diet. This situation is somewhat analogous to individuals that cannot digest lactose because of inability to express the lactase enzyme. If no lactose is ingested, they appear normal. Consumption of lactose-containing products, however, promptly and dramatically reveals the absence of the enzyme. Calcium oxalate stone disease in humans has been suggested to occur secondary to such a �powder keg (the susceptible individual) and tinderbox (the provocative environment)� situation. This hypothesis may be even more compelling in cats because the overall occurrence of calcium oxalate urolithiasis in the United States appears to be no greater in cats than it is in humans, despite the fact that much of the cat population consumes similarly formulated diets. Moreover, looking back on earlier studies from this perspective, it seems that struvite stones that were induced to form in the bladder of healthy cats may have led to the misperception that commercial diets were the cause of naturally occurring struvite stone disease. These diets too may only have unmasked cats intrinsically susceptible to struvite stone formation.

The frequency of urolithiasis does not appear to be greater in cats than in either dogs or humans, so no modification of the diet is necessary before the formation of the first stone. Therapy of cats with a stone includes acute treatment to remove or dissolve the stone and chronic therapy to reduce the risk of recurrence. Urinalysis or urinary tract imaging cannot identify the type of stone. Moreover, both false-positive and false-negative results in the urinalysis can occur. For example, hematuria found in a specimen collected by cystocentesis may be caused by trauma during collection as well as a stone. The presence or absence of crystals also can be confusing. Many cats with bladder stones do not have crystalluria. Indeed, they may not show any signs of stone disease. Moreover, healthy cats can have crystals in their urine, and some 10% of cats with a stone have crystals of different composition from the stone. Increased urine pH, previously thought to be caused by diet or urinary tract infection, also can rise above 7.0 due to the stress of travel and examination. Moreover, urine pH measured by dipstick and by pH meter do not agree well; a dipstick reading of 6.5 can occur with meter readings from 5.8 to 7.0. Thus, none of these parameters is diagnostic for stones. Radiography can be used to identify the presence of radiodense (struvite and calcium oxalate) uroliths. Ultrasound can be used to detect the presence of a stone regardless of its radiodensity if it is sufficiently large.

Stone-specific treatment recommendations can be based on quantitative stone analysis when stone material from spontaneous voiding, catheter aspiration, voiding urohydroexpulsion or surgery can be obtained for analysis. Consumption of a canned (but not dry), magnesium-restricted, urine acidifying diet has been shown to dissolve naturally occurring struvite calculi. However, no medical regimen has been shown to successfully dissolve calcium oxalate uroliths, so surgery is recommended for these patients. When the stone type is unknown, the choice of medical or surgical therapy is offered to the client after the risks and benefits have been explained.

All cats that have formed a stone are at increased risk for recurrence. Decreasing the concentration of potential stone-forming minerals in their urine and increasing their voiding frequency are primary therapy to reduce the risk of formation of a new stone. In a recent case series at The Ohio State University Veterinary Hospital, it was found that all cats with a urinary bladder stone consumed dry food. Of the eight cats with struvite stones, three were fed veterinary foods designed to dissolve or prevent formation of struvite stones, and one of the seven cats with calcium oxalate stones was fed a veterinary food recommended for cats with calcium oxalate stones. These results provide strong evidence that patients with urolithiasis should not consume dry diets.

Increased water intake is the cornerstone of therapy for urolithiasis in both human and veterinary medicine. When a urolith is diagnosed, the patient should be encouraged to consume enough water in canned foods or moistened dry foods and drinking to increase urine volume until the urine specific gravity is ~1.020. In addition to dilution of the urine, some stone-specific alterations may be useful. Although a decreased risk of recurrence of oxalate stones related to diet change has never been documented in cats, changing to a diet that is less acidifying and that has not been magnesium-restricted seems reasonable, as long as the resulting urine specific gravity is ~1.020. Many pet food manufacturers offer diets designed to reduce the probability of stone formation. These diets have been tested in healthy cats, and it is hoped that they will prove effective in cats with naturally occurring stone disease. Unfortunately, the frequency of recurrence of stone formation in cats is not known, so the safety, efficacy, and cost-effectiveness of these diets cannot yet be determined. Research to answer these questions is sorely needed.

Because so many American cat diets have been modified to restrict the formation of struvite, acidifying agents such as ammonium chloride or d,l-methionine should not be routinely prescribed for cats with struvite crystalluria. These agents only impose an additional source of acid that may contribute to the development of metabolic acidosis. Acidifying agents are contraindicated in cats with calcium oxalate urolithiasis and have no known value in the treatment of cats suffering from other lower urinary tract disorders.

Idiopathic Cystitis

Idiopathic cystitis (IC) is a noninfectious inflammatory lower urinary tract disease. Diagnosis of idiopathic cystitis is based on the presence of chronic lower urinary tract signs (dysuria, pollakiuria, hematuria, urination in inappropriate locations), sterile urine, and failure to find a more objective cause for this clinical picture after appropriate lower urinary tract diagnostic procedures (including plain and contrast radiography or ultrasonography). The diagnosis of IC is thus a diagnosis of exclusion. Because the underlying cause(s) of this disorder are unknown, treatment recommendations must necessarily be tentative.

Signs of lower urinary tract disease in cats with non-obstructive IC often resolve spontaneously within a couple of weeks regardless of treatment, so most treatments attempt to prevent subsequent recurrence of clinical signs. Stress seems to be very important in the development of flares in cats with IC and may be important in precipitating the first episode of signs in susceptible animals. Unfortunately, stress is difficult to quantitate; potential �stressors� in a cat's life may include changes in the environment, weather, activity, use of the litter pan, food intake, owner work schedule, additions or subtractions from the household population of humans or animals, and other factors. Regimens to reduce stress may prove essential in the management of cats with IC. To reduce environmental stress, it is recommended that the patient be provided with places to hide and opportunities to express the natural predatory behavior of cats. These opportunities can include climbing posts and toys that can be chased and caught. Many other behavioral strategies are available to be considered.

Clinical experience suggests that diet change can result in recurrence of signs of IC in some patients. Many years ago, only one veterinary food was marketed for treatment of struvite urolithiasis and prevention of lower urinary tract signs. Signs often resolved around the time of institution of this diet, and some clinicians observed that signs recurred when owners switched cats on this diet to other foods. More recently, it has been observed that signs often resolve for a time regardless of treatment. Moreover, with the advent of many similarly formulated veterinary and commercial foods marketed for use in cats with signs of lower urinary tract disease, signs sometimes recur when cats are switched from any of these foods to another one of them. These observations suggest that the change itself may result in recurrence of signs. This hypothesis is strengthened by the observation that some cats with signs of lower urinary tract disease appear to be sensitive to a variety of environmental stimuli. Pending further study to test this hypothesis, limiting the frequency of dietary changes in this group of patients may be prudent.

The OSU Veterinary Hospital recently reported that signs of lower urinary tract disease recurred in only 11% of cats with IC during one year of feeding the canned formulation of a veterinary food designed to result in production of acidic urine. Recurrence occurred in 39% of cats fed the dry form of the food, suggesting that constancy, composition, and consistency all may be important, though the mechanisms remain to be determined. Interestingly, the urine specific gravity of cats fed the dry form was usually greater than 1.050, whereas that of cats fed the canned diet usually was less than 1.040. In addition to water, diet-related decreases in urine magnesium, and/or increases in urine calcium, potassium, and/or hydrogen ion concentrations all could influence activity of sensory nerve fibers in the urothelium. Unfortunately, most of these effects have been studied using in vitro experimental systems. The effects of urine electrolyte content on signs of lower urinary tract disease have not been adequately studied but may be important in treating some patients. Additionally, the differences in texture between dry and canned diets could play a role, though this too has yet to be studied.

Recently, a feline pheromone that exerts a calming effect on cats has become available to veterinarians. This product (Feliway^� Ceva, France)�a synthetic analogue of a naturally occurring feline facial pheromone�was developed in an effort to decrease anxiety-related behaviors of cats. Cats release pheromones during facial rubbing when they feel comfortable with their environment. Although not specifically tested in cats with IC, treatment with this pheromone has been reported to reduce the amount of anxiety experienced by cats in unfamiliar circumstances, a response that may be helpful to these patients and their owners.

In severely affected patients, analgesics may be indicated. Animal behaviorists have prescribed amitriptyline for some time to help treat inappropriate urination in cats. Amitriptyline possesses several potential therapeutic benefits for cats with IC. These include analgesia, stabilization of mast cell membranes, norepinephrine reuptake inhibition (that results in down-regulation of noradrenergic transmission), anticholinergic effects, and antagonism of both glutamate receptors and sodium channels. Findings in a series of cats with severe IC at OSU Veterinary Hospital suggest that the clinical signs of many cats are remarkably reduced during amitriptyline treatment. Improvement in clinical signs is not always accompanied by improvement in the cystoscopic appearance of the bladder. Controlled studies of the safety of amitriptyline in cats with IC are not available. OSU Veterinary Hospital prescribes the drug to be given orally once daily before the owner retires for the night. The dosage is adjusted between 2.5 mg to 12.5 mg to produce a barely perceptible calming effect on the cat. The reduction in severity of clinical signs can be dramatic in some cats, but little or no beneficial effect is observed in others. Because the long-term safety of amitriptyline in cats has not been well-established, OSU Veterinary Hospital recommends that serum liver enzyme concentration (e.g., ALT, ALP, AST) be evaluated before, one month after institution of therapy, and at least yearly thereafter to assure that the drug has not adversely affected liver function. However, in the experience of the staff of OSU Veterinary Hospital, amitriptyline given at the above dosage is safe for at least two years. Potential side effects include excessive urine retention (anticholinergic effects) and increased concentrations of liver enzymes. Other tricyclics, such as desipramine or nortriptyline, may produce fewer side effects, but these have not yet been tested. OSU staff also has used butorphanol to relieve bladder pain with apparent success in a small number of cats with chronic idiopathic cystitis. Longer-term studies of the effect of chronic pain relief as therapy for idiopathic cystitis are sorely needed. OSU staff has not used NSAIDs in cats with IC, but NSAIDs are of little value in the treatment of IC in humans.

Glycosaminoglycan (GAG) replacement treatment has been used with some success in humans with IC. The assumption is that exogenous GAG will attach to the defective urothelium, thereby decreasing bladder permeability. However, there may be differences in the relative efficacy of the various available GAG. In addition, GAG can exert analgesic and anti-inflammatory effects that might prove useful. A double-blinded placebo-controlled study of a specific GAG treatment for cats with IC is underway in the United States.

Experimental justification for many of these recommendations currently is lacking, which is similar to the situation for most therapies for interstitial cystitis in humans. It is hoped that the interest and controversy generated by the demonstration of the occurrence of IC in more than one species will stimulate further research into the causes and treatments for this painful, debilitating disease. Development of safe and effective protocols for cats with IC will depend on implementation of appropriately designed clinical trials.

Summary

Diet therapy may benefit cats with idiopathic cystitis or a urinary tract stone. Cats with idiopathic cystitis seem to benefit from a canned diet fed once daily, if such a feeding plan is not too stressful to the cat or to the owner. The issues surrounding stress, diet change, and disease are controversial, and further investigation of these relationships is needed. Cats with naturally occurring urolithiasis seem to form stones despite consumption of dry diets that should inhibit their formation. This observation emphasizes the significance of the most important nutrient, water, in the treatment of cats with urolithiasis. Whether veterinary foods designed to treat patients with a stone will reduce the (unknown) rate of stone recurrence remains to be determined.

References

1.  Osborne CA, Lulich JP, Kruger JM. Disorders of feline lower urinary tract I Etiology and Pathophysiology: WB Saunders, 1996.

2.  Thumchai R, Lulich J, Osborne CA, et al. Epizootiologic evaluation of urolithiasis in cats: 3,498 cases (1982-1992). Journal of the American Veterinary Medical Association 1996;208:547-51.

3.  Buffington CAT, Chew DJ. Effects of diets on cats with non-obstructive lower urinary tract diseases: a review. J. Anim. Phsyiol. and Anim. Nutr. 1998;80:120-127.

4.  Buffington CAT, Chew DJ, Woodworth BE. Feline Interstitial Cystitis. Journal of the American Veterinary Medical Association 1999;215:682-687.

5.  Markwell PJ, Buffington CAT, Chew DJ, et al. Clinical evaluation of commercially available urinary acidification diets in the management of idiopathic cystitis in cats. Journal of the American Veterinary Medical Association 1999;214:361-365.

6.  Buffington CAT, Chew DJ. Diet therapy in cats with lower urinary tract disorders. Veterinary Medicine 1999;94:625-630.

7.  Buffington CAT, Chew DJ. Calcium oxalate urolithiasis in cats. Endourology 1999;13:659-663.

Notes