Abstract
Idiopathic feline lower urinary tract disease (FLUTD) is a common clinical entity where different treatments, for example glycosaminoglycans (GAGs) such as pentosan polysulphate (PPS), are advocated. However, few treatments have been investigated by well-controlled clinical trials. This paper compares the use of PPS in FLUTD compared to placebo. Of the 18 cats in the experiment, nine were treated with PPS and nine were treated with placebo with subcutaneous injections of 3 mg/kg PPS or placebo day 1, 2, 5 and 10. The study was double-blind, randomised and placebo-controlled. Revaluation was performed after 5 and 10 days, 2 weeks, 2, 6 and 12 months. There were no statistically significant differences concerning clinical signs between groups during treatment or at re-evaluation, except for pretreatment stressful events where PPS-treated cats had experienced significantly more stressful events compared to cats treated with placebo before entering the study. Six cats (33%) showed recurrence of clinical signs during the entire study period, and only one of these cats had more than one recurrent episode. One cat (placebo) was euthanased 7 days after initial treatment because of recurrence of clinical signs. Another cat (placebo) was euthanased due to other reasons after 6 months. At 2 weeks two cats (placebo and PPS) showed clinical signs. At 2 months re-evaluation one cat showed mild clinical signs. At 6 and 12 months all remaining 16 cats were healthy. Idiopathic, non-obstructive FLUTD is a self-limiting disease with good short-term and excellent long-term prognosis without treatment. Whether or not PPS may be beneficial in a subpopulation of cats with continuous or frequently recurring clinical signs may be elucidated in forthcoming double-blind, randomised and placebo-controlled trials including only this subpopulation of cats.
Feline lower urinary tract disease (FLUTD) includes a variety of symptoms, such as haematuria, pollakiuria, stranguria, periuria and painful voiding of urine. The known causes for FLUTD include bladder stones, urethral plugs, bacterial infections, viral infections and neoplasia. The most frequent bladder stones in cats are composed of struvite or calcium oxalate. Urethral plugs are usually formed from mucus based sludge within the bladder, which may or may not contain crystals. Bacterial infections are considered to be rare in cats with FLUTD, and when present, usually secondary to other conditions. 1,2 Neoplasia of the bladder is uncommon in cats, but transitional cell carcinoma may occur. 3 In this paper, idiopathic FLUTD (iFLUTD) is defined as haematuria, pollakiuria, stranguria, periuria and painful voiding of urine in the absence of a known cause.
If submucosal petechial haemorrhages are evident at cystoscopy or vesicotomy it is suggested that the term feline interstitial cystitis (FIC) should be used. 4 The syndrome in cats is characterised by chronic, irritative voiding signs, sterile and cytologically normal urine and cystoscopic observation of submucosal petechial haemorrhages is similar to idiopathic cystitis (IC) in humans. 5 In humans, interstitial cystitis is defined as a non-malignant, inflammatory disorder of unknown cause characterised by lower abdominal pain, dysuria, pyuria, haematuria, proteinuria, distinctive cystoscopic lesions called glomerulation and low urine glycosaminoglycan (GAG) concentrations. 6 Most cases of FIC are self-limiting and resolve in 1 or 2 weeks, but many cats will have recurrent episodes, varying in frequency and severity. 1 Although the aetiology of FIC is not well understood, theories include bacterial and viral infections, autoimmune diseases, urinary toxins, stress, neurogenic factors mast cell-mediated inflammation, or a combination of these causes. 5 The suggested treatments for FIC and iFLUTD in cats include a variety of environmental and dietary alterations as well as pharmacological interventions.
The mucosal surface of the bladder is lined with a thin layer of protective mucus containing a specific GAG, GP-51, which helps prevent bacteria and crystals adhering to the bladder wall. 1 Some cats with FIC have been shown to have a reduced concentrations of GAGs within this protective layer. 5 GAG replacement therapy has been used with some success in humans with FIC. 7,8 The assumption is that exogenous GAG will be excreted into the urine and attach to the defective urothelium, thereby decreasing bladder permeability. 7,8 Pentosan polysulphate (PPS: Cartrophen vet, Biopharm Australia, NSW, Australia), a semi-synthetic GAG, inhibits and modulates pro-inflammatory mediators such as histamine, serotonin and enzymes such as elastase, hyaluronidase and cathepsins. PPS also has anti-arthritic chondroprotective properties, and is used as a treatment for osteoarthritis in dogs. 9 Oral GAG replacement using PPS has been used in humans with IC with unrewarding results. 10 In a randomised, placebo-controlled, double-blind, multi-centred 3-month clinical trial in 136 human patients, oral PPS had no effect over placebo. 10 It has recently been shown that only 6% of orally administered PPS is excreted in the urine. Eighty-four percent is excreted in faeces as intact PPS indicating that it is very poorly absorbed when given orally. 11
The purpose of this study was to determine if PPS administered parenterally in cats with signs of idiopathic lower urinary tract disease may have beneficial short- and long-term effects, compared to placebo.
Materials and Methods
Cats
Cats were recruited consecutively as owners sought veterinary care concerning urinary problems at Albano Animal Hospital.
Inclusion criteria consisted of (1) clinical signs, such as stranguria, haematuria, pollakiuria and painful voiding, and (2) absence of positive urine culture for bacteria, (3) absence of concrement detected on ultrasonography, and (4) absence of urethral obstruction. Exclusion criteria consisted of the presence of bladder stones, urethral plugs, positive urine culture for bacteria and moderate to severe presence of urinary crystals.
Procedures
The owners were interviewed using a questionnaire concerning previous and present health status, current clinical signs and their duration, indoor or outdoor living, feeding habits and possible stressful events before onset of clinical signs. Ultrasonographic examination (Philips HDXE11, linear probe L12) included inspection of the bladder wall and measurements of its thickness and the length and width of the bladder. Urine analysis included dipstick for presence of blood, protein, glucose, ketones, microscopic sediment evaluation and bacterial culture (Vetstix, Melet Schloessing Laboratories). Urine was collected via transcutaneous cystocentesis.
Randomisation
The cats were randomly assigned to treatment or placebo. Randomisation was performed according to the regulations of Swedish Medical Product Agency in groups of 10. The assignment of each cat remained unknown to the investigators and owners during the entire study period.
Treatment
The cats were treated with subcutaneous injections of 3 mg/kg PPS or placebo (isotonic saline solution) on days 1, 2, 5 and 10.
Evaluation Schedule
The cats were examined clinically at the time of injections and the owners were interviewed regarding the cats' urination habits using a questionnaire. A telephone interview was made after 2 weeks, 2 and 6 months and 1 year following the beginning of treatment.
Statistical Analysis
All statistical calculations were performed by use of a computerised statistical program (SAS JMP 3.2 and SAS 6.12, SAS Institute, USA). Equal variances between groups were tested using the F-test (variance ratio test). For continuous data that were normally distributed, groups were compared by use of Student's t-test for unpaired data. For categorical data, groups were compared by use of χ2 test, and Fisher's exact test was used when n<5. The minimum level of significance was chosen as P<0.05 (two-tailed). Data are presented as mean±standard deviation (SD) and median.
Ethical Consideration
The study was conducted with informed consent obtained from all owners involved, as well as approval from the Swedish Medical Product Agency and the Swedish Board of Agriculture.
Results
Cats
Nineteen cats were entered into the study. One of the cats was subsequently excluded because of bacterial growth in the urine sample taken at the initial visit. There were nine cats in the treatment group and nine cats in the placebo group. There were no statistically significant differences between groups concerning age, sex, body weight, breed, indoor/outdoor living, feeding, presenting signs and duration of signs, clinical and ultrasonographic examination, urine analysis, or concomitant treatment at initial presentation.
All cats were neutered; nine male and nine female. Ages ranged from 8 months to 12 years (median 62; mean 65±34 months). Body weight ranged from 2.4 to 8.4 kg (median 4.8; mean 4.9±1.3 kg). Nine cats (50%) were considered to be overweight by the examining veterinarian (BW). Breed distribution was 16 (89%) domestic shorthairs, one Persian and one Abyssinian. Five (28%) of the 18 cats were kept exclusively indoors. Eleven cats (61%) were fed predominantely dry cat food and seven cats (39%) were fed predominantely moist cat food. Clinical signs at presentation included stranguria (18 cats), haematuria (nine cats), periuria (11 cats), obvious pain, such as vocalisation while urinating (10 cats), and pollakiuria (16 cats). Duration of signs before presentation ranged from 1 to 14 days (median 3; mean 3.6±3 days). Two cats (one in each group) had previously showed signs of urinary tract disease. Ultrasonographic examination was normal in all but one cat, which showed an irregular mucosal surface of the bladder wall. This cat was euthanased 2 days after the third injection due to recurrent urinary signs. Urine analysis showed the presence of occult blood in all cats. A mild degree of crystals of magnesium ammonium phosphate was found in four cats (one cat in the treatment group and three cats in the placebo group). Six of the cats, three in each group, were treated with non-steroid anti-inflammatory drugs (NSAIDs; tolfenamin acid, Tolfedine, ViaVet, 4 mg/kg orally once daily for 4 days) and two cats, one in each group, received amoxycillin (Vetrimoxin, CEVA Vetpharma) at a dose of 10 mg/kg bid orally for 10 days during the study period.
Fifteen cats were treated with all four injections, whereas two cats received three injections (placebo) and one cat received two injections (PPS). There was one statistically significant difference (P=0.0023) between groups, as nine cats (100%) in the treatment group and two (22%) of cats in the placebo group were considered by the owners as having been exposed to stressful events before onset of clinical signs.
Revaluation
All 18 cats were re-evaluated day 5 (day of third injection) after initial treatment. Two cats (both in the placebo group) were euthanased during the re-evaluation period, 7 days after the first injection due to recurrence of lower urinary tract disease, and after 6 months due to unrelated medical problems. Sixteen cats remained in the study during the entire study period, ie, 12 months.
Day 5: One (placebo) of 18 cats showed signs of lower urinary tract disease, such as stranguria, haematuria, pollakiuria and pain during voiding. Clinical examination was normal in all cats.
Day 10: All 17 cats were asymptomatic and clinical examination was normal.
Day 14: One cat (placebo, same cat as day 5) showed stranguria, haematuria, pollakiuria, and painful voiding, and another cat (PPS) displayed haematuria and painful voiding. All remaining 15 cats were asymptomatic according to owners questioned via telephone.
2 Months: One cat (PPS) showed pollakiuria. None of the other 16 cats displayed any signs of urinary tract disease.
6 Months: None of 16 cats had recurrence of lower urinary tract disease.
12 Months: None of 16 cats had recurrence of lower urinary tract disease.
Two cats (one from each group) showed signs of LUTD in between the pre-determined re-evaluation dates, 3 and 9 months after initial treatment. In total, 5 of 18 cats (27%) showed recurrence of clinical signs during the entire study period, and only one of these cats had more than one episode.
There were no statistically significant differences between groups on re-evaluation.
Discussion
Few treatments for idiopathic non-obstructive FLUTD have been investigated by well-controlled clinical trials. As iFLUTD is often self-limiting, many treatments may appear effective. The present study shows that in the majority of cats (89%) with signs of iFLUTD, clinical signs resolved spontaneously and the frequency of recurrent clinical signs was low. As there was no statistically significant difference between the group of cats treated with PPS and the placebo group in either short-term or long-term follow-up, PPS cannot be recommended for use in iFLUTD. However, as only six cats (33%) showed recurrence of clinical signs and only one of these cats had more than one episode, the possible beneficial effects of PPS in cats with continuous or frequently recurrent clinical signs could not be evaluated in this study. Our data are supported by the finding that daily oral administration of glycosamine for 6 months was not beneficial in a randomised, double-blinded, placebo-controlled trial of 40 cats with FIC, where 65% showed recurrence of signs with a mean of five recurrences per cat. 12 The apparent difference in recurrence rate compared to our study may stem from difference in inclusion criteria, particularly as the present trial included mainly cats presented for the first time whereas in the study by Gunn Moore et al 12 only cats with at least two previous episodes of clinical signs were included and cats with urethral obstruction were not actively excluded.
Risk factors commonly reported to be associated with iFLUTD include indoor living, obesity, male sex, pure breed and stressful events. 13 In the present study, 28% cats were kept strictly indoors, 50% of cats were overweight, 50% were male and only 11% were pure breed. Sixty-two percent of cats had, according to owners, been exposed to stressful events before onset of clinical signs in this study.
The roles of analgesia and anti-inflammatory drugs have been debated in the treatment of iFLUTD. In the present study, NSAIDs were given to seven cats (39%) for 1–4 days after onset of clinical signs. As there was no difference in outcome between cats treated and untreated cats, the short-term use of NSAID does not seem beneficial in our population of cats. A double-blinded placebo-controlled trial of orally administered anti-inflammatory doses of prednisolone showed no clinical benefit in adult male and female cats with iFLUTD. 14
In conclusion, idiopathic, non-obstructive FLUTD is a self-limiting disease with good short-term and excellent long-term prognosis without treatment. Whether or not PPS may be beneficial in a subpopulation of cats with continuous or frequently recurring clinical signs may be elucidated in forthcoming double-blind, randomised and placebo-controlled trials including only this subpopulation of cats.
Acknowledgements
The authors thank Dr Claes-Göran Sjösten and N-vet for supplying pentosan polysulphate and placebo used in the trial.
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