Idiopathic Feline Lower Urinary Tract Diseases: Therapeutic Rights & Wrongs
C.A. Osborne, DVM; J.P. Lulich, DVM; J.M. Kruger, DVM; D.J. Polzin, DVM
Over the past decade, knowledge of specific causes and natural course of feline LUTDs has increased, allowing diagnostic and therapeutic efforts to be directed toward identification and elimination of specific underlying causes. However, there is considerable controversy about symptomatic treatment of idiopathic forms of LUTD in male and female cats. This is not surprising since clinical signs associated with this form of the disease are frequently self-limiting and of short duration. Our observations and those of others suggest that clinical signs of hematuria, dysuria, and pollakiuria in many untreated nonobstructed male and female cats with acute idiopathic LUTD frequently subside within 3 to 7 days. In this setting, any form of therapy might appear to be beneficial, as long as it is not harmful. The self-limiting nature of clinical signs in many cats with idiopathic LUTD underscores the need for controlled prospective double-blind clinical studies to prove the efficacy of various forms of therapy.
The following generalities recommended for treatment of nonobstructive forms of idiopathic feline LUTD have not all been substantiated by experimental and/or clinical investigations. Some recommendations are based on our clinical observations and personal opinion.
Antibiotics have commonly been used for decades as empirical therapy of idiopathic LUTD. However, the infrequency (1 to 3%) with which bacteria have been identified at the onset of clinical signs of LUTDs in young to middle aged cats has been documented. The uselessness of antimicrobial agents in the treatment of a bacteriuric cats with LUTDs has also been documented. Indiscriminate use of antimicrobial agents has been responsible, at least in part, for the emergence of the resistant strains of microbes that populate veterinary hospitals. We do not recommend routine use of antibiotics for management of cats that do not have bacterial UTI.
URINARY TRACT ANTISEPTICS
Urinary tract antiseptics such as methenamine are sometimes used as adjunctive agents for treatment, control, and prevention of bacterial UTI in humans. Although their use is frequently acknowledged in the treatment of bacterial UTI in dogs, and is occasionally mentioned for treatment of LUTDs in cats, their effectiveness has not been substantiated in these species. We do not recommend urinary tract antiseptics to treat idiopathic LUTD.
URINARY TRACT ANALGESICS
Phenazopyridine is commonly used as a urinary tract analgesic in humans. Use of phenazopyridine, alone or in combination with sulfa drugs, is contraindicated in cats because they are very susceptible to dose-related methemoglobinemia and irreversible oxidative changes in hemoglobin, resulting in formation of Heinz bodies and anemia.
Acidification of urine is of value in helping to dissolve or prevent sterile struvite uroliths, but is of unlikely value in treatment of idiopathic LUTD. Many commercially manufactured diets are designed to acidify urine. Iatrogenic over acidification with acidifiers is most likely to occur in cats with pre-existing renal failure, cats consuming acidifying diets, and immature cats. Long term over acidification increases the risk for hypokalemia, renal dysfunction, demineralization of bones, and calcium oxalate urolithiasis. In addition, high doses of methionine may result in Heinz body anemia and methemoglobinemia.
SMOOTH AND SKELETAL MUSCLE ANTISPASMODICS
Cats with inflammation of the lower urinary tract characteristically develop pollakiuria and/or urge incontinence. In both cases, inappropriate voiding of urine usually occurs at low volumes of bladder filling and may be associated with sensations of pain, bladder fullness, and urgency.
Because the exact mechanisms of pollakiuria and urge incontinence are unknown, details about specific therapy are unavailable. Presumably, pollakiuria and urge incontinence result from inflammation induced stimulation of urinary bladder sacral sensory afferents. Sensations of pain and perceptions of fullness and urgency induce a premature micturition reflex and subsequent inappropriate or involuntary voiding of small quantities of urine. Since cholinergic parasympathetic efferents are largely responsible for detrusor contraction, it is logical to consider anticholinergic agents as symptomatic treatment of pollakiuria and urge incontinence. However, the efficacy of these agents in cats with nonobstructive idiopathic LUTD has not been established by properly controlled clinical trials.
The anticholinergic agent propantheline minimizes the force and frequency of uncontrolled detrusor contractions, but has negligible effect on urethral sphincter pressure. In a controlled clinical study of the efficacy of propantheline (7.5 mg given orally on one occasion) in the treatment of naturally occurring hematuria and dysuria in nonobstructed male and female cats, no difference in rate of recovery was observed between cats treated with propantheline and control groups. This is not an unexpected finding, because propantheline represents a symptomatic form of therapy. It is possible that therapy with propantheline of longer duration may have reduced the severity of dysuria. Propantheline may be considered to reduce the severity and frequency of urge incontinence in nonobstructed male and female cats. It has a rapid onset of action. However, care must be used to prevent urinary retention as a result of excessive dosages. Other potential adverse effects include tachycardia, vomiting, and constipation. An empirical dose of 0.25 to 0.5 mg/kg PO q12-24 hr has been suggested. Further studies utilizing appropriate dosages and maintenance intervals are required to substantiate a beneficial effect of propantheline in cats with urge incontinence.
Other smooth [oxybutin (0.5 to 1.25 mg/cat PO q8-12 hr), prazosin (0.03 mg/kg IV), phenoxybenzamine (2.5 to 7.5 mg/cat PO q12-24 hr), acepromazine] and skeletal [dantrolene (0.5 to 2.0 mg/kg PO q8 hr, diazepam (1.0 to 2.5 PO q8-12 hr) muscle antispasmodics have been recommended for symptomatic management of urethrospasm associated with LUTD. Although some of these pharmacologic agents produce significant decreases in intraurethral pressure in normal male cats and cats with naturally occurring urethral obstruction, the role of urethral smooth or skeletal muscle spasm in producing clinical signs associated with idiopathic forms of feline LUTD is unknown. In a limited study of 6 male cats with urethral obstruction due to unspecified causes, intraurethral pressures prior to administration of antispasmodics were not significantly different from those of normal nonobstructed male cats. Similar studies in cats with idiopathic forms of LUTD have not been performed. On the basis of available data, we are unable to routinely recommend smooth and skeletal muscle antispasmodics to treat cats with idiopathic LUTD.
It is reasonable to assume that most cats with idiopathic LUTD have an inflammatory lesion of the lower urinary tract. Hematuria is indicative of (but not pathognomonic of) inflammation; dysuria indicates involvement of the lower urinary tract. The specific cause(s) of inflammation in cats with idiopathic diseases are as yet unknown. Lack of specific therapy for cats with idiopathic causes of hematuria and dysuria has stimulated many to question the value of anti-inflammatory agents to reduce the severity of clinical signs.
Use of glucocorticoids to minimize dysuria and hematuria associated with inflammation in cats with idiopathic LUTD is logical. To test this logic, we conducted a double-blind, controlled therapeutic trial utilizing male and female adult cats with previously untreated idiopathic LUTD. Six symptomatic cats selected randomly were given 1.0 mg/kg of prednisolone orally, twice each day for 10 days; and six symptomatic cats were given a placebo. In both groups, clinical signs subsided in a mean of 1 to 2 days, and in both groups hematuria and pyuria subsided in approximately 2 to 5 days.
Piroxicam, a nonsteroidal anti-inflammatory drug, has been empirically suggested to reduce dysuria and pollakiuria in cats with idiopathic LUTD. The empirical dose is 0.3 mg/kg PO q24 hr. Pending double-blind controlled clinical trials, it is not possible to make recommendations about the safety and efficacy of this drug.
Amitriptyline (Elavil), a tricyclic antidepressant and anxiolytic drug with anticholinergic, antihistaminic, anti-alpha-adrenergic, anti-inflammatory, and analgesic properties, has been used extensively for treatment of interstitial cystitis in humans. Despite amitriptyline's popularity, its exact mechanism of action and its therapeutic value in managing patients with interstitial cystitis is unknown.
Amitriptyline has been advocated for symptomatic therapy of idiopathic feline LUTD. The empirical dose is 2.5 to 12.5 mg/cat PO q24 hr. Anecdotal reports and limited data suggest that administration of amitriptyline to some cats with chronic idiopathic forms of LUTD was associated with amelioration of clinical signs. Consequently, amitriptyline has gained popularity as an agent for symptomatic therapy of idiopathic feline LUTD. Recently, a double blind controlled clinical trial designed to evaluate the effectiveness of amitriptyline (daily dose of 5 mg for 7 days) in cats with idiopathic LUTD was performed. Results revealed that short-term therapy had no benefit in context of resolution of pollakiuria and hematuria, and was associated with an increased risk of recurrence.
Adverse events reported in cats treated with amitriptyline include sedation, urine retention, constipation, weight gain, increased serum bilirubin and ALT values, neutropenia, and thrombocytopenia. We don't recommend amitriptyline to treat acute self-limiting episodes of idiopathic LUTD.
Transitional epithelium of the urinary tract is covered by a thin layer of hydrated extracellular macromolecules called glycosaminoglycans (GAGs). Major classes of biologically important GAGs include hyaluronic acid, heparan sulfate, heparin, chondroitin 4-sulfate, chondroitin 6-sulfate, dermatan sulfate, and keratan sulfate. Urothelial GAGs: 1) prevent adherence of microorganisms and crystals to the bladder, and 2) limit transepithelial movement of urine proteins and other ionic and nonionic solutes. Quantitative or qualitative defects in surface GAGs and subsequent increased urothelial permeability have been hypothesized to be a causative factor in the pathogenesis of feline idiopathic LUTD and human interstitial cystitis.
Oral or intravesicular administration of pentosan polysulfate sodium (Elmiron), a semi-synthetic low molecular weight heparin GAG analogue, is often used to manage human interstitial cystitis. Pentosan polysulfate reinforced urothelial GAGs and reduced transitional cell injury. Remission of symptoms was observed in 28 to 40% of human interstitial cystitis patients treated with oral or intravesicular pentosan polysulfate compared to only 13 to 20 % remission in patients treated with a placebo. Adverse events uncommonly recognized in humans treated with pentosan polysulfate include prolongation of prothrombin time, epistaxis, gingival bleeding, alopecia, abdominal pain, diarrhea, and nausea. In cats, the empirical dose extrapolated from human studies is 2 to 10 mg/kg PO q12 hr. However, evaluation of the safety and efficacy of pentosan polysulfate, or other GAG preparations, for treatment of feline idiopathic LUTD by controlled clinical trials have not yet been reported. Although treatment with drugs designed to restore the GAG lining of the urinary tract is logical, it is not possible to make recommendations at this time.
INCREASED PRODUCTION OF LESS CONCENTRATED URINE
Results of preliminary clinical studies have been interpreted to suggest that canned dietary formulations may reduce recurrence of clinical signs of idiopathic LUTD. Although a specific mechanism was not specified, reduced concentrations of potentially harmful solutes was suggested as one possibility.
References are available upon request.