Feline idiopathic cystitis refers to naturally occurring LUT disease of unknown etiology.1 It is the most common cause of hematuria, dysuria, pollakiuria, and periuria in male and female cats and may be complicated by urethral obstruction in some affected male cats.1–7 During the past 4 decades, more than 70 agents or procedures have been recommended for treatment and prevention of FIC8,9; yet, few of these proposed treatments have been evaluated in controlled clinical trials.10–14,a Debate surrounding the efficacy of many treatments is complicated by the self-limiting nature of clinical signs associated with most episodes of idiopathic cystitis.10,14–16 Clinical signs of hematuria, dysuria, pollakiuria, and periuria frequently subside within 2 to 7 days without treatment in most cats with acute nonobstructive idiopathic cystitis.3,10–12,14–16 However, it is also evident that LUT signs may recur after variable amounts of time in a substantial number of affected cats.3,10–12,15,16,a It is estimated that between 40% and 65% of cats with idiopathic cystitis will have ≥ 1 recurrence of signs within 1 to 2 years.3,10–12,15,16,a The risk of recurrent episodes of FIC seems to decrease with increasing age.12,15,16
Targeted nutritional interventions may potentially influence expression of FIC and its sequelae by decreasing urine concentrations of proinflammatory mediators and crystallogenic minerals, increasing urine concentrations of anti-inflammatory or proresolving lipid mediators and crystallization inhibitors, increasing solubility of crystalloids in urine, decreasing retention of crystals within the LUT, restoring defective components of the urothelial barrier, and influencing environment-induced or cat-related behavioral risk factors (eg, anxiety).11,13,17–21,a,b To our knowledge, only 2 studies11,13 evaluating the safety and efficacy of nutritional interventions on preventing FIC have been reported. Results of 1 nonrandomized nonblinded study13 of diet moisture content were interpreted to suggest that cats consuming a canned urinary-acidifying food had a lower rate of recurrence of idiopathic cystitis than cats consuming a dry urinary-acidifying food. In a subsequent randomized placebo-controlled, masked study11 of the nutraceutical glucosamine, investigators did not identify significant differences in owner-assessed frequency and severity of recurrent clinical signs of idiopathic cystitis between glucosamine-treated cats and control cats receiving the placebo treatment.
More recently, several multipurpose prevention foods for cats have been developed that are intended to simultaneously manage the combination of risk factors associated with idiopathic cystitis and with struvite- and calcium oxalate–induced LUT disorders.19,22,b Multipurpose prevention foods have the advantages of allowing long-term feeding of a single maintenance food to simultaneously manage multiple risk factors for LUT disorders that may occur at various life stages. However, the effects of multipurpose prevention foods have not been evaluated in cats with idiopathic cystitis. The purpose of the study reported here was to evaluate the safety and efficacy of a manufactured multipurpose cystitis-prevention food on the recurrence of LUT signs in cats with acute nonobstructive idiopathic cystitis.
Materials and Methods
Selection of animals—Client-owned cats were enrolled between June 2009 and October 2010 following written approval of validated informed client consent. Cats with LUT signs (eg, dysuria, gross hematuria, pollakiuria, stranguria, and periuria) were recruited from the greater Lansing, Mich, and Saint Paul and Minneapolis metroplex for participation in ≥ 1 clinical trial.22 Following a telephone interview, clients were offered the opportunity to bring candidate cats to the Veterinary Teaching Hospital at Michigan State University or the Veterinary Medical Center at the University of Minnesota for further evaluation.
Enrollment eligibility for the study was determined on the basis of a defined medical history and findings on physical examination, CBC, serum biochemical analysis, FeLV and FIV testing, urinalysis including a pH determination by meter,c quantitative aerobic bacterial culture of urine, survey abdominal radiography, and abdominal ultrasonography. If needed, cats were sedated with butorphanol (0.2 to 0.4 mg/kg [0.09 to 0.18 mg/lb]) and acepromazine (0.02 to 0.1 mg/kg [0.009 to 0.045 mg/lb]) administered IM to facilitate sample collection and diagnostic imaging.
Cats of either sex and any breed were eligible for study inclusion if they were neutered, 1 to 8 years of age, housed indoors, and current on routine vaccinations and had an acute episode of nonobstructive idiopathic cystitis that included ≥ 2 of the following LUT signs within the preceding 7 days: gross hematuria, dysuria, pollakiuria, stranguria, or periuria of ≥ 24 hours’ duration. A diagnosis of FIC was made by exclusion of other potential causes of LUT signs to the extent they were detectable by the defined database.8
Cats were excluded from the study if they had another detectable cause of LUT signs other than idiopathic cystitis, urethral obstruction, structural abnormalities of the spinal cord or vertebral column, major organ disease (eg, azotemia, liver disease, and anemia), persistent LUT signs of > 14 days’ duration, a pattern of voiding on vertical surfaces, or resided in a home with > 1 additional cat. Cats were also excluded if within the previous 7 days they received antimicrobials, antihistamines, corticosteroids, NSAIDs, anticholinergics, antidepressants, urinary acidifiers, glycosaminoglycans, diuretics, dimethyl sulfoxide, cyclophosphamide, or any other medication used to treat interstitial cystitis in humans.23 In addition, cats were not eligible if they received any vitamin or nutritional supplements or were treated with injectable long-acting corticosteroids or polysulfated glycosaminoglycans within 30 days before enrollment.
All aspects of the study were paid for by the study grant. Clients received remuneration to help compensate for their time and travel expenses associated with study participation. All study procedures were approved by the Institutional Care and Animal Use Committees at each participating institution and the funding agency.
Diet—Cats entering the study were randomly assigned to be fed either a cystitis-prevention food or a control food. A blocked randomization procedure was used to equally partition cats between study foods.24 Selection of either wet or dry formulations of study foods was by owner preference. Prevention and control foods differed in antioxidant, fatty acid, and mineral (calcium, phosphorous, and magnesium) profiles, but not substantially in the amount of protein, fat, carbohydrate, or caloric density (Appendix). The multipurpose prevention food was a commercially available manufactured feline foodd designed for struvite prevention and dissolution and calcium oxalate prevention.22 In addition to controlled mineral content, the prevention food contained increased concentrations of the antioxidants vitamin E and β-carotene and the long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid. Fish oil was the principle source of supplemental omega-3 fatty acids in the wet and dry prevention food. The control food was custom manufactured and formulated to meet or exceed the Association of American Feed Control Officials standards for adult cats with mineral concentrations and a targeted neutral urine pH designed to mimic common commercially available feline maintenance foods.
The clinical care team and clients were masked as to which food the cat was assigned to be fed; both foods were identical in appearance, form, and packaging. Study foods were distinguished by a color-coded square on the front cover of each sealed package. Each food was manufactured, analyzed for its nutrient content, and packaged with its appropriate color code prior to shipment to the clinical study centers. Food was dispensed to the owner at the end of the first appointment. A suggested daily quantity of food to maintain the cat's current body weight was calculated, and owners were advised to feed the assigned food exclusively to maintain body condition.25 Study foods were introduced over a 7-day transition period. If an enrolled cat would have access to a healthy housemate's food, sufficient study food was dispensed to feed both cats.
Regardless of food assignment, all owners were instructed to provide an ample source of fresh clean drinking water for their cat and received a standardized information handout with recommendations for litter box management; sensory stimulation; provision of scratching posts, hiding places, climbing structures, and widow perches; and enhancement of caregiver-cat interactions.9,26 Short-term opioid analgesic treatment with buprenorphine (0.015 mg/kg [0.007 mg/lb], PO between the gum and cheek, q 8 to 12 h) or butorphanol (0.2 mg/kg, PO, q 12 h) was permitted during the study and was offered to all patients with recurrences associated with signs of pain (eg, vocalization during urination and prolonged stranguria).
Outcomes—Owners were instructed to monitor the presence of 5 clinical signs and record their observations daily. The 5 signs monitored were dysuria (vocalizing resulting from painful urination), hematuria (presence of pink color or overt blood in the urine), periuria (urinating in inappropriate places in the house or outside of the litter box), pollakiuria (increased frequency of urination, compared with the cat's normal behavior), and stranguria (persistent but nonproductive straining or posturing to urinate). Owners were asked to indicate whether they were present when the cat urinated and observed the sign (yes or no). If the owner observed ≥ 2 LUT signs in a 24-hour period, they were instructed to return to the hospital immediately for reevaluation of their cat, even if it was prior to their next scheduled appointment.
In addition to daily observation, cats were monitored over time for secondary and adverse effects (eg, urethral obstruction, changes in serum biochemical analysis results, and weight loss or gain) associated with treatment and for any changes in the home environment. All owners were required to return their cats to the hospital at 1, 3, 6, 9, and 12 months for regularly scheduled reevaluations consisting of a physical examination, body weight measurement, body condition score determination, urinalysis including urine pH as determined by a meter,c and bacteriologic culture of urine. Survey abdominal radiography was repeated at 6 and 12 months, and abdominal ultrasonography was repeated at 12 months. Serum biochemical analysis and CBC were repeated at 12 months, and the results were compared with initial values. If at any time cats became ill during the study, clients were instructed to return immediately for veterinary care even if it was prior to their next scheduled appointment.
Criteria for withdrawal from the study were determined by the cat owner and the investigator. Cat owners could voluntarily withdraw their cat from the study at any time for any reason. Investigators dismissed cats if delayed laboratory results unavailable during the initial appointment were inconsistent with a diagnosis of idiopathic cystitis (eg, positive results of bacteriologic culture of urine) or additional diseases were identified. Cats were also dismissed from the study if they did not consume the food or were fed foods other than the study foods, received medications other than those allowed during the study, or developed adverse events or health problems necessitating care that confounded the study protocol.
With respect to food effect, the primary endpoint was the number of recurrent episodes in which a cat had multiple (≥ 2 concurrent) LUT signs within a day (ie, defined as a multiple-sign day) for the duration of treatment. Multiple-sign days were identified on the basis of information that had been recorded in each owner's daily record. The rationale for the use of a multiple-sign day approach was formed from the concept that FIC may initiate clinical signs, but behavioral factors may maintain and perpetuate some signs despite resolution of cystitis.27 Furthermore, recent studies28,29 have documented that periuria is a nonspecific response to a variety of external environmental stressors in healthy cats as well as in cats with chronic idiopathic cystitis.
Because of the possibility of relatedness, consecutive multiple-sign days were considered as a single episode. Similarly, multiple-sign days that were separated by 1 day in which the cat had no signs or only had a single LUT sign were also considered contiguous and were counted as a single episode. An episode concluded when there were ≥ 2 consecutive days without multiple LUT signs. For the purposes of analysis, episodes were considered independent if there was a 2-day gap between events. The rationale for this definition of independent events was formed from our observations that pollakiuria and dysuria resolve in < 2 days in most cats with acute nonobstructive idiopathic cystitis. In 1 study14 of 6 cats with acute idiopathic cystitis given a placebo and hospitalized for 10 days, dysuria resolved in a median of 1.5 days. Similarly, in another study12 of 15 cats with acute idiopathic cystitis treated with a placebo and hospitalized for 8 days, pollakiuria resolved in a median of 1 day. Considering that most episodes resolved in < 2 days, we hypothesized that a similar period without clinical signs would be indicative of a new event. To our knowledge, studies investigating a correlation between recurrent events have not been reported. Nevertheless, to test the robustness of our results, data were also analyzed on the basis of 4- and 7-day clinical sign–free intervals between events to assess the assumption of independence (data not shown). Significant results concerning efficacy of the diets were found to be identical irrespective of the duration of the interval between events. For the present report, we have chosen to include only results from the analysis of the data with a 2-day interepisode interval, which is more representative of the absolute number of days that clinical signs were observed in affected cats.
Secondary endpoints with respect to food effects were the number of recurrent episodes of a single LUT sign (pollakiuria, periuria, hematuria, dysuria, and stranguria), results of clinicopathologic evaluations, and frequency of adverse events. Analyses of recurrent episodes of individual signs used the same 2-day clinical sign–free interval to distinguish between episodes as used for the analysis of multiple-sign days.
Statistical analysis—The Fisher exact test, Mann-Whitney rank sum test, and unpaired t test were used for univariate analyses of pretreatment population characteristics to identify significant differences between cats fed prevention food and cats fed control food. Normality of the distribution of continuous quantitative variables was evaluated with the Kolmogorov-Smirnov test. Continuous quantitative variables that were not normally distributed (mean age, body condition score, and duration of current event) were evaluated with nonparametric analyses. Data are presented as mean ± SD unless otherwise noted. For analyses of responses to treatment, the primary outcome variable was the number of recurrent episodes of multiple-sign days. Secondary outcome variables included the number of recurrent episodes of single-sign days, results of clinicopathologic evaluations, and frequency of adverse events.
The number of recurrent episodes of multiple-sign days or single-sign days were analyzed as a binomial proportion of the number episodes out of the total number of days a cat was in the study (ie, incidence rate) in a generalized linear model.30 Residuals were examined.e Formulation (wet vs dry) was not included as a variable in outcome analysis because of the nonrandomized nature of formulation assignment (ie, owner preference) and likelihood that results would be confounded by preexisting formulation effects. For reporting purposes, incidence rates are expressed as episodes/1,000 cat days.
Serum biochemical analysis and CBC data were analyzed by means of repeated-measures ANOVA for a factorial arrangement of 2 foods, 2 formulations, and 2 time points. A compound symmetry covariance structure was fit to the data to account for a correlation between the 2 time points. Urinalysis data were also analyzed by means of repeated-measures ANOVA. Because there were 6 time points for urine data, the Akaike information criterion fit statistic was used to select the best covariance structure to account for a correlation between the repeated measures.31 For both the hematologic and urine data, Kenward-Rogers adjustment was used to correct for inflation of the F statistics and downward bias in the SEs.30 All data were analyzed with a commercial statistical software package.f Values of P ≤ 0.05 were considered significant.
Results
Thirty-one male and female cats ranging in age from 1 to 8 years were enrolled. Nine cats (4 males and 5 females) were assigned to receive a wet cystitis-prevention food, 6 (3 males and 3 females) dry cystitis-prevention food, 11 (9 males and 2 females) dry control food, and 5 (4 male and 1 female) wet control food. Selection of wet or dry formulation was by owner preference. Owners selected the same formulation of study food for 12 of 15 cats fed dry food exclusively prior to enrollment and for the 1 cat fed wet food exclusively. For cats fed a mixture of dry and wet formulations prior to enrollment, 8 of 15 owners selected dry study food formulations and 7 selected wet study food formulations. Four cats fed prevention food and 2 cats fed control food were excluded from analysis because of noncompliance (1 cat fed prevention food and 1 cat fed control food), adverse events (vomiting in 1 cat fed prevention food and diarrhea in 1 cat fed control food), food refusal (1 cat fed prevention food), and voluntary withdrawal (1 cat fed prevention food). The remaining 11 cats fed prevention food and 14 cats fed control food were included in analyses (Table 1).
Pretreatment characteristics at the time of study enrollment of 25 cats with acute nonobstructive idiopathic cystitis randomly assigned to receive a cystitis-prevention food or control food.
| Characteristic | Prevention food (n = 11) | Control food (n = 14) | P value |
|---|---|---|---|
| Food formulation | |||
| Dry | 6 | 5 | 0.69 |
| Wet | 9 | 5 | |
| Sex | |||
| Female | 6 | 3 | 0.12 |
| Male | 5 | 11 | |
| Age (y) | 4.4 ± 2.46 | 4.4 ± 2.59 | 0.85 |
| Body weight (kg) | 5.2 ± 1.1 | 5.4 ± 1.5 | 0.65 |
| BCS (scale 1–5) | 3.6 ± 0.7 | 3.4 ± 0.6 | 0.98 |
| Multicat home | 6 | 8 | 1.00 |
| Prior LUT signs | 10 | 8 | 0.09 |
| Duration of current event (d) | 5.4 ± 4.93 | 5.8 ± 4.98 | 0.92 |
| Periuria | 11 | 13 | 1.0 |
| Pollakiuria | 7 | 11 | 0.66 |
| Gross hematuria | 7 | 8 | 1.0 |
| Dysuria | 4 | 5 | 1.0 |
| Stranguria | 3 | 7 | 0.41 |
| Urine specific gravity | 1.052 ± 0.019 | 1.049 ± 0.013 | 0.65 |
| Urine pH | 6.6 ± 0.6 | 6.4 ± 0.4 | 0.41 |
| Hematuria (> 5 RBCs/hpf) | 6 | 8 | 1.0 |
| Pyuria (> 5 WBCs/hpf) | 0 | 0 | 1.0 |
| Struvite crystalluria | 1 | 1 | 1.0 |
Values are number of cats or mean ± SD. Thirty-one cats with acute nonobstructive idiopathic cystitis were enrolled in the study. Four cats fed prevention food and 2 cats fed control food were excluded from analysis because of noncompliance (1 cat fed prevention food and 1 cat fed control food), adverse events (vomiting in 1 cat fed prevention food and diarrhea in 1 cat fed control food), food refusal (1 cat fed prevention food), and voluntary withdrawal (1 cat fed prevention food). Twenty-five cats, 11 fed prevention food and 14 fed control food, were included in analyses.
BCS = Body condition score. NA = Not applicable.
All cats were reported to have had ≥ 1 multiple-sign days in the week prior to enrollment. Periuria was the most common preenrollment LUT sign reported, followed by pollakiuria, gross hematuria, dysuria, and stranguria (Table 1). Univariate analyses did not identify significant differences between cats fed prevention food and cats fed control food with respect to formulation assignment (wet or dry), age, sex, multi cat household status, body weight, body condition score, history of previous episodes of clinical signs of LUTs, history of previous consumption of prevention diets, clinical signs, and duration of clinical signs prior to enrollment.
Hematuria in the absence of pyuria was the most common pretreatment urinalysis finding (Table 1). Struvite crystalluria was detected in 1 cat assigned to receive the prevention food and 1 cat assigned to receive control food. Univariate analyses did not identify significant differences between cats fed prevention food and cats fed control food with regard to results of pretreatment CBCs, serum biochemical analyses, urinalyses, and urinary bladder ultrasonography.
The median time of study enrollment was 364 days (range, 187 to 400 days) for cats fed prevention food and 352 days (range, 47 to 370 days) for cats fed control food. One cat fed prevention food was voluntarily withdrawn at 189 days because the owner relocated out of state. Of the cats receiving control food, 2 cats were dismissed early at 47 and 49 days because of an episode of urethral obstruction and 1 cat was dismissed at 195 days because of allergic dermatitis. The mean ± SD time of enrollment for cats fed control food (301 ± 115 days) was significantly (P = 0.03) shorter than that of cats fed prevention food (355 ± 58 days). In total, 3,904 cat-days were analyzed for the prevention food group (11 cats) and 4,215 for the control food group (14 cats). All cats were returned for scheduled reevaluations. In addition, 5 of 11 cats fed prevention food were returned for 6 unscheduled visits and 8 of 14 cats fed control food were returned for 13 unscheduled visits.
For all scheduled reevaluations combined, the overall mean urine specific gravity (for all cats and all observations) for cats fed prevention food was 1.052 ± 0.015 (range, 1.011 to 1.078); overall mean urine specific gravity for cats fed control food was 1.049 ± 0.015 (range, 1.010 to 1.078). The mean urine specific gravity across the specific scheduled reevaluation time points for cats fed prevention food ranged from 1.049 ± 0.018 to 1.056 ± 0.012; the mean urine specific gravity for cats fed control food ranged from 1.047 ± 0.017 to 1.051 ± 0.018. Repeated-measures ANOVA revealed that there were no significant differences in mean urine specific gravity between cats fed prevention food and cats fed control food over the course of the study. However, cats consuming wet formulations had a significantly (P < 0.01) lower urine specific gravity than cats consuming dry formulations. There was a significant (P < 0.01) effect of time on urine specific gravity, but the clinical importance of this data was not apparent. No significant interactions between food, formulation, or time were observed.
For all scheduled reevaluations combined, the overall mean urine pH for cats fed prevention food was 6.3 ± 0.4 (range, 5.5 to 7.4); for cats fed control food, the overall mean urine pH was 6.8 ± 0.6 (range, 5.9 to 8.1). The mean urine pH across the specific scheduled reevaluation time points for cats fed prevention food ranged from 6.2 ± 0.4 to 6.3 ± 0.5; the mean urine pH for cats fed control food ranged from 6.6 ± 0.7 to 6.9 ± 0.6. Repeated-measures ANOVA revealed that cats consuming the prevention food had a significantly (P < 0.01) lower urine pH than cats consuming control food. There were no significant effects of formulation or time on urine pH. A significant (P = 0.05) interaction between food and time over the course of the study was observed, but the clinical importance of this data was not apparent.
Microscopic hematuria was observed in urine sediment at some point during treatment in 8 of 11 cats fed prevention food and 13 of 14 cats fed control food. At scheduled reevaluations, the number cats fed prevention food with microscopic hematuria ranged from 2 to 4 of 11 cats; the number cats fed the control food with microscopic hematuria ranged from 1 to 6 of 14 cats. The majority (156/162 [96%]) of urine specimens were collected by cystocentesis. Pyuria (> 5 WBCs/hpf) was not detected in cats fed prevention food; however, mild pyuria (5 to 10 WBCs/hpf) was observed in 4 urine specimens from 3 of 14 cats fed control food. Crystalluria was observed in urine specimens at some point during treatment in 5 of 11 cats fed prevention food and in 9 of 14 cats fed control food. At scheduled reevaluations, the number of cats fed prevention food with crystalluria ranged from 0 to 3 of 11 cats; the number of cats fed the control food with crystalluria ranged from 1 to 4 of 14 cats. Struvite crystals were identified in 6 of 9 and 14 of 15 urine specimens from cats with crystalluria fed prevention food and control food, respectively. Amorphous crystals were reported in 3 of 9 and 1 of 15 of urine specimens from cats fed prevention food and control food, respectively. Of the 19 unscheduled reevaluations for recurrent signs or adverse events, crystalluria was detected in urine sediment for 0 of 11 cats fed prevention food and 2 of 14 cats fed control food (1 struvite crystalluria and 1 amorphous crystalluria). No significant differences were found in the number of cats with hematuria, pyuria, and crystalluria between cats fed prevention food and cats fed control food.
No clinically relevant differences were found in serum biochemical analysis and CBC results between cats fed prevention diet and cats fed control food; all values were within reference ranges.
Owners reported ≥ 1 LUT sign in 9 of 11 cats fed prevention food and all 14 cats fed control food over the entire study period. Pollakiuria and periuria were the most commonly reported LUT signs during treatment in cats fed prevention food as well as cats fed control food (Table 2). A significantly (P = 0.04) lower proportion of cats fed prevention food (2/11) had stranguria, compared with cats fed control food (9/14). There was also a lower proportion of cats fed prevention food (2/11) that had dysuria, compared with cats fed control food (8/14), although the difference was not significant (P = 0.09). In addition, the proportion of cats with pollakiuria, periuria, or hematuria was lower in cats fed prevention food, compared with cats fed control food, although the difference was not significant. The mean incidence rate of episodes of individual signs for hematuria, dysuria, and stranguria was significantly lower in cats fed prevention food, compared with cats fed control food. The mean incidence rates for pollakiuria and periuria episodes were lower in cats fed prevention food, compared with cats fed control food, but this difference was not significant.
Comparisons of the number of cats and mean ± SE incidence rate of LUT signs in 25 cats with acute idiopathic cystitis fed a cystitis-prevention food or control food.
| No. of cats | Mean ± SE incidence rate (episodes/1,000 cat-days) | |||||
|---|---|---|---|---|---|---|
| Episode | Prevention food (n = 11) | Control food (n = 14) | P value | Prevention food (n = 11) | Control food (n = 14) | P value |
| Multiple-sign days* | 4 | 9 | 0.24 | 0.7 ± 0.5 | 5.4 ± 2.4 | 0.01 |
| Pollakiuria† | 6 | 10 | 0.39 | 2.0 ± 0.9 | 5.4 ± 1.9 | 0.09 |
| Periuria† | 8 | 11 | 1.00 | 5.2 ± 2.8 | 10.4 ± 4.8 | 0.33 |
| Gross hematuria† | 3 | 8 | 0.23 | 0.3 ± 0.3 | 3.4 ± 1.6 | 0.01 |
| Dysuria† | 2 | 8 | 0.09 | 0.2 ± 0.2 | 3.1 ± 1.7 | 0.02 |
| Stranguria† | 2 | 9 | 0.04 | 0.2 ± 0.2 | 3.8 ± 1.5 | 0.01 |
One day or ≥ 2 consecutive days with ≥ 2 LUT signs. †One day or ≥ 2 consecutive days with indicated LUT sign.
Four of 11 cats fed prevention food and 9 of 14 cats fed control food had episodes of multiple-sign days. The proportion of cats fed prevention food that had episodes of multiple-sign days (4/11) was lower than that in cats fed control food (9/14); however, this difference was not significant (Table 2). Of the 4 cats fed prevention food with episodes of multiple-sign days, 2 were fed dry food and 2 were fed wet food. Of the 9 cats fed control food with episodes of multiple-sign days, 6 were fed dry food and 3 were fed wet food. Multiple LUT signs were observed for 13 days in cats fed prevention food and for 152 days in cats fed control food. When analyzed as episodes of multiple-sign days, 5 recurrent episodes were observed in 4 cats fed prevention food during 3,904 cat-study days, compared with 47 recurrent episodes observed in 9 cats fed control food during 4,215 cat-study days. Of the 4 cats fed prevention food with recurrent episodes of multiple-sign days, 3 cats had 1 recurrent episode and 1 cat had 2 recurrent episodes; of the 9 cats fed control food with recurrent episodes, 3, 1, 1, 2, 1, and 1 cats had 1, 2, 3, 5, 13, and 16 recurrent episodes, respectively. The mean incidence rate observed in cats fed prevention food was almost 8-fold lower relative to cats fed control food (relative risk, 7.89; 95% confidence interval, 3.58 to 17.36; P = 0.013). The overall incidence rates for recurrent episodes of multiple-sign days were 1.3 episodes/1,000 cat-days for cats fed prevention food and 11.2 episodes/1,000 cat-days for cats fed control food.
Duration of episodes of multiple-sign days ranged from 1 to 8 days (median, 1 day) in cats fed prevention food and from 1 to 13 days (median, 3 days) in cats fed control food. Signs resolved in ≤ 2 days in 4 of 5 (80%) episodes of cats fed prevention food and in 21 of 47 (45%) episodes in cats fed control food. Signs resolved in < 7 days in 4 of 5 (80%) episodes in cats fed prevention food and 43 of 47 (92%) episodes in cats fed control food. One cat fed prevention food had a single episode of 8 days’ duration, whereas single episodes of 10, 11, 12, and 13 days’ duration were observed in cats fed control food. However, the duration of episodes of multiple-sign days did not differ significantly between cats fed prevention food and cats fed control food.
Cats fed prevention food and cats fed control food did not differ significantly in regard to major stressors reported over the course of the study (eg, changes in number of people or pets, moving, remodeling, visitors, or pet sitters during owner absences), availability of window perches and scratching posts, increased number of litter boxes, or change in litter box type or location (Table 3). Opioid analgesics were dispensed at some point during the study to a significantly (P = 0.02) greater proportion of cats fed control food (12/14) than cats fed prevention food (4/11).
Prevalence of environmental factors in 25 cats with acute nonobstructive idiopathic cystitis fed a cystitis-prevention food or control food.
| Factor | Prevention food (n = 11) | Control food (n = 14) | P value |
|---|---|---|---|
| Major stressor* | 6 | 8 | 1.0 |
| Window perch available | 10 | 13 | 1.0 |
| Scratching post available | 7 | 11 | 0.66 |
| Increased number of litter boxes | 4 | 5 | 1.0 |
| Change in litter box location | 3 | 7 | 0.67 |
| Change in type of litter box or litter material | 1 | 3 | 0.60 |
| Opioid analgesic dispensed | 4 | 12 | 0.02 |
Change in number of people or pets in the home, moving, remodeling, visitors (people and other pets), extended owner absence, and care provided by pet sitter.
No significant differences were found in the frequency of adverse events reported between cats fed prevention food and cats fed control food. Mean body weight and body condition score did not change significantly from baseline values in cats in either food group over the course of study. Of the 31 cats originally enrolled in the study, gastrointestinal signs (vomiting or diarrhea) were observed in 3 of 15 cats fed prevention food and 1 of 16 cats fed control food. Food refusal was observed in 1 of 15 cats fed prevention food. Nonspecific dermatitis was observed in 1 of 16 cats fed control food. A Staphylococcus urinary tract infection was detected in 1 of 15 cats fed prevention food. Small radiolucent urocystoliths were detected by ultrasonography at the conclusion of the study in 2 of 15 cats fed prevention food. In a male cat fed the dry formulation of the prevention food, subsequent removal and quantitative stone analysisg revealed the urolith to be composed of 100% calcium oxalate. In another female cat fed the wet formulation of the prevention food, urocystoliths collected shortly after the time of diagnosis by voiding hydropropulsion were determined to be composed of 100% magnesium ammonium phosphate. Both cats were subclinically affected at the time of detection and had been so for 314 and 361 days, respectively. Urethral obstruction resulting from a struvite crystalline-matrix urethral plug was observed in a male cat fed the dry formulation of the control food; partial idiopathic urethral obstruction was observed in an additional male cat fed the dry formulation of the control food.
Discussion
Feeding the prevention food, compared with the control food, significantly reduced the incidence rate of recurrent episodes of multiple-sign days and of recurrent episodes of individual signs of hematuria, dysuria, and stranguria in cats with acute nonobstructive idiopathic cystitis in the present study. To our knowledge, this is the first report documenting that significant impact of targeted nutritional intervention on the rate of recurrence of clinical signs associated with FIC. The primary endpoint with respect to food effect was the number of recurrent episodes of multiple-sign days. The use of a multiple-sign day approach throughout the duration of treatment is based on the concept that FIC may initiate clinical signs, but behavioral factors may maintain and perpetuate some LUT signs despite resolution of idiopathic cystitis.27 For example, persistence of periuria may be caused by behavioral disorders acquired as a result of classical conditioning in which litter box use becomes associated with painful urine voiding and cats develop an aversion to litter box use despite resolution of idiopathic cystitis, litter box aversion resulting from increased use and poor hygiene during an episode of cystitis, or discovery of a new substrate preference as a result of cystitis-induced periuria. Furthermore, recent studies28,29 have documented that periuria is a nonspecific response to a variety of unrelated external environmental stressors in healthy cats as well as in cats with chronic idiopathic cystitis. In the absence of a more specific marker of FIC recurrence, we hypothesized that the criterion of ≥ 2 LUT signs would be a more reliable indicator of recurrence and minimize the impact of acquired persistent or nonspecific behaviors on outcome assessment.
In many instances of recurrent signs, results of evaluations were consistent with a diagnosis of recurrent FIC. However, only 13 of 25 (52%) cats with recurrences returned for reevaluation. As a consequence, not all recurrent episodes were comprehensively reevaluated to determine the cause of LUT signs. Given that FIC is an exclusion diagnosis, we cannot absolutely exclude the possibility that other LUT disorders were responsible for clinical signs. For nearly all affected cats, caregivers reported that clinical signs associated with recurrent episodes resolved without additional treatment or with only short-term analgesic administration. The self-limiting nature of LUT signs and lack of additional findings on scheduled reevaluations suggested that recurrent episodes of LUT signs most likely represented recurrent episodes of FIC. Our experience is similar to that reported in a previous study13 of dietary management of idiopathic cystitis in which only 7 of 13 cats with recurring clinical signs were available for reevaluation during an episode of LUT signs. The reasons for inconsistent caregiver compliance with follow-up instructions are unknown. We speculate that for many affected cats, rapid resolution of clinical signs (25/52 [48%] of all episodes resolved in ≤ 2 days) and inconvenience of arranging travel reduced requested unscheduled visits.
Feeding the prevention diet significantly reduced the mean incidence rate of recurrent episodes of multiple-sign days by almost 8-fold (cats fed prevention diet, 0.7 episodes/1,000 cat-days; cats fed control food, 5.4 episodes/1,000 cat-days; relative risk, 7.89). Incidence rate measures the frequency with which new episodes of clinical signs occurred over time in the study population.32 Compared with a simple proportion of affected cats with ≥ 1 recurrent episode, incidence rate has the advantage of allowing assessment of multiple recurrent events in individuals that comprise a population in which individuals were observed for varying durations of time. Our observations and those of others indicate that multiple recurrences in an individual cat is a common and important feature of idiopathic cystitis.3,11,12,15,16 In a study,11 further episodes of LUT signs were observed in 26 of 40 (65%) cats with recurrent idiopathic cystitis treated orally with either glucosamine or a placebo. The median number of recurrences in affected cats was 2.5 (range, 1 to 19).11 However, few studies have evaluated incidence rates of recurrent episodes of LUT signs in cats with idiopathic cystitis. In 2 case reports,15,16 sufficient data were available to calculate individual recurrence incidence rates for 2 cats with idiopathic cystitis. Incidence rates were determined to be 1.9 episodes/1,000 cat-days in a cat fed an acidifying low-magnesium therapeutic food16 and 6.9 episodes/1,000 cat-days in a cat fed a grocery store commercial maintenance food.15 In a controlled clinical trial of short-term amitriptyline treatment for acute idiopathic cystitis, the mean incidence rate was 2.6 episodes/1,000 cat-days for 15 affected cats treated with a placebo.12 However, a variety of therapeutic and nontherapeutic maintenance foods were fed during the 2-year follow-up period in that study. To our knowledge, other studies investigating incidence rates of recurrent episodes of idiopathic cystitis in cats fed exclusively therapeutic or maintenance foods similar in composition to foods used in the present study have not been reported.
Although the proportion of cats fed prevention food that had recurrent episodes was lower than that of cats fed control food, the difference was not significant. Proportional outcome has been traditionally used as a principle variable to assess therapeutic efficacy of agents advocated for the management of FIC.3,10–13,33,a Proportional outcome expresses the fraction of cats with a recurrence in a population, whereas incidence rate measures the frequency of recurrences over time. These 2 types of observations are not mutually exclusive, but complementary in assessing the frequency of recurrences. Discordance between proportional outcome and incidence rate in the present study may be related to differences between cats fed prevention food and cats fed control food in the prevalence of risk factors for recurrence of LUT signs. Few studies have investigated risk factors for recurrent FIC. In a previous study12 of cats with acute idiopathic cystitis, a higher number of pretreatment episodes of LUT signs were associated with a significantly increased risk of recurrent episodes, whereas increasing age was associated with a significantly decreased risk of recurrence. In the present study, the mean age of cats fed prevention food and cats fed control food were virtually identical. Furthermore, there were a substantially greater number of cats with previous episodes of LUT signs in the prevention food group, compared with the control group. More likely, the disparity between proportional outcome and incidence rate was the result of a limited sample size. The small sample size in the present study increases the probability of type II statistical error and the risk of false-negative results.34 Further studies with a larger sample size are essential to identify external and internal risk factors for recurrent FIC.
In addition to frequency, duration of episodes is another important dimension of recurrent events. In the present study, resolution of recurrent episodes of multiple-sign days occurred in ≤ 2 days for 4 of 5 (80%) episodes in cats fed prevention food and for 21 of 47 (45%) episodes in cats fed control food; however, by 7 days, 4 of 5 (80%) episodes were resolved in cats fed prevention food and 43 of 47 (92%) episodes were resolved in cats fed control food. Our observations are similar to those reported in other studies3,10–12,14 in which most episodes of LUT signs in cats with idiopathic cystitis resolved in ≤ 7 days. The duration of recurrent episodes of multiple-sign days in the present study was substantially, albeit not significantly, shorter in cats fed prevention food, compared with cats fed control food.
Despite significant effects of food on recurrence rates, the specific food components responsible for the beneficial food effect were not determined. The prevention food was modestly reduced in mineral content, produced a more acidic urine pH, and contained higher concentrations of antioxidants and omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) and lower concentrations of omega-6 fatty acids than the control food (Appendix). Whereas there is no available evidence supporting a benefit to urine acidification or magnesium restriction in cats with idiopathic cystitis, we hypothesize that beneficial effects of the prevention food were most likely the result of the anti-inflammatory effects associated with increased concentrations of antioxidants and the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid.35–37 However, proof of this hypothesis requires further investigations to confirm and characterize the specific therapeutic roles of long-chain omega-3 fatty acids and antioxidants in the management of FIC.
Although the proportions of cats with pollakiuria, periuria, dysuria, gross hematuria, and stranguria were substantially lower for cats fed prevention food, compared with cats fed control food, only the proportions of cats with stranguria were significantly lower in cats fed prevention food. However, mean incidence rates for episodes of gross hematuria, dysuria, and stranguria were significantly lower for cats fed prevention food, compared with rates for cats fed control food. In addition, incidence rates for recurrent episodes of pollakiuria or periuria were lower in cats fed prevention food, compared with cats fed control food; however, these differences were not significant. The reasons for unapparent food effects on episodes of pollakiuria and periuria are unknown but may be related to acquired elimination behaviors,27 nonspecific response to external stressors,28,29 observer bias, or limited statistical power for this aspect of the study. Lower statistical power is likely the result of various combinations of small sample size, variation in results, and a smaller than anticipated treatment effect.34
Moist foods are commonly recommended for managing cats with idiopathic cystitis.11,13,19 In previous studies,11,13 significantly lower frequency of recurrences and significant improvements in mean health scores were attributed to feeding wet foods to affected cats. Other studies3,12,38 have not identified significant effects of formulation (wet vs dry) on expression of FIC. However, the design of the present study precluded meaningful assessment of the role of food formulation in recurrence of FIC. Selection of wet or dry formulation was by owner preference, not by randomization. Consequently, any formulation effects observed in our study were likely confounded by the effects of the formulation fed prior to enrollment.
Other management and environmental factors may have potentially influenced outcomes. It has been reported that social and environmental stressors and certain management practices may be risk factors for recurrence of FIC.3,18,38 The present study was not designed to evaluate the effect of environment enrichment and management practices on recurrences of LUT signs. However, information collected over the course of study suggested that cats fed prevention food and cats fed control food were similar in the proportion of cats that had major stressful events and that had access to window perches and scratching posts. Increases in litter box number and changes in litter box location, litter box style, and litter substrate were reported more frequently in cats fed control food; however, these differences were not significant. On the basis of these observations, it seems unlikely that differences in environmental factors and management practices account for the differences in food effects on recurrences of LUT signs observed in the present study.
Crystalluria was uncommonly observed in cats fed prevention food and cats fed control food during the course of the study. When present, struvite was the predominant crystal type observed in urine sediment from both cats fed prevention food and cats fed control food; calcium oxalate crystalluria was not observed in cats of either food group. Although the prevalence of crystalluria was higher in cats fed control food, differences between prevention and control foods were not significant. It is interesting that struvite crystalluria was observed in cats fed prevention food despite the fact that the prevention diet was designed to promote urine undersaturation for struvite (relative supersaturation < 1)b and has been shown to effectively dissolve presumed struvite uroliths in 7 to 52 days.22 However, our observations are similar to other studies13,39–41 in which struvite crystalluria was observed in cats fed low-magnesium, urine-acidifying foods. Observation of struvite crystalluria in some cats fed prevention food may be related to episodic variations in urine pH associated with the time of eating, method of feeding, amount of food consumed, and travel to the hospital.39,42–45
Obstructive uropathy was observed in 2 male cats fed control food: 1 with struvite crystalline-matrix urethral plug-induced obstruction and another with partial idiopathic obstruction. Our observations in the present study are consistent with the notion that male cats with active episodes of idiopathic cystitis are at risk for urethral obstruction.3,16,21 Although episodes of urethral obstruction were not observed in male cats fed prevention food, lack of quantitative measures of crystal and matrix production and limited sample size preclude formulation of meaningful conclusions regarding the efficacy of the prevention food in reducing the risk of urethral obstruction.
Unexpectedly, small urocystoliths were detected by ultrasonography at 12-month reevaluations in 2 subclinically affected cats fed prevention food. In 1 cat fed the dry form, uroliths were found to be composed of calcium oxalate. Composition of the urolith in the second cat fed the wet form was found to be struvite. These events were unforeseen, especially considering that the mineral and urine pH profiles of the prevention diet were designed to promote formation of urine that is undersaturated for struvite (relative supersaturation < 1) and in the metastable saturation zone for calcium oxalate (relative supersaturation between 1 and 12).b Furthermore, consumption of wet food increases water intake, resulting in the formation of less concentrated urine that is less saturated with calculogenic crystalloids.19 The specific lithogenic factors responsible for the formation of small stones observed in these 2 subclinically affected cats are unknown. Potential genetic predispositions and diet- or disease-induced quantitative or qualitative changes in urine pH and concentrations of crystalloids or organic crystallization promoters or inhibitors may have played a role in the formation of uroliths in these cats.46–51 To our knowledge, studies investigating the role of FIC as a risk factor for heterogeneous crystallization and subsequent growth of uroliths have not been reported. Although owners of both cats affirmed compliance, we cannot exclude the possibility that these cats had inadvertent access to other foods.
In conclusion, feeding of a commercially available low-magnesium, urinary-acidifying, omega-3 fatty acid– and antioxidant-enriched prevention food was of benefit for reducing the rate of recurrent episodes of multiple-sign days and episodes of individual LUT signs of hematuria, dysuria, and stranguria in cats with acute idiopathic cystitis. However, significant food effects on recurrence rates of pollakiuria and periuria were not apparent. We emphasize that the present study is limited in that its design precludes meaningful assessment of the role of food formulation (wet vs dry) on recurrence of FIC or the effect of nutrition on cats with chronic forms of the disease.
ABBREVIATIONS
| FIC | Feline idiopathic cystitis |
| LUT | Lower urinary tract |
Chew DJ, Bartges J, Adams L, et al. Randomized, placebo-controlled clinical trial of pentosan polysulfate sodium for treatment of feline interstitial cystitis (asbtr). J Vet Intern Med 2009;23:690.
Gluhek T, Bartges JW, Callens A, et al. Evaluation of 3 struviteoxalate preventive diets in healthy cats (abstr). J Vet Intern Med 2012;26:801.
Corning pH meter 430, Scientific Products Division, Corning Inc, Corning, NY.
Prescription Diet c/d Multicare Feline Dry, Hill's Pet Nutrition Inc, Topeka, Kan.
STUDENTPANEL, SAS, version 9.2 for windows, SAS Institute Inc, Cary, NC.
SAS, version 9.2 for windows, SAS Institute Inc, Cary, NC.
Minnesota Urolith Center, Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minn.
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Appendix
Comparisons of key nutritional components on a dry-matter basis of wet and dry formulations of a cystitis-prevention food and control food fed to cats in the present study.
Comparisons of key nutritional components on a dry-matter basis of wet and dry formulations of a cystitis-prevention food and control food fed to cats in the present study.
| Prevention food | Control food | |||||||
|---|---|---|---|---|---|---|---|---|
| Dry | Wet | Dry | Wet | |||||
| Variable | Value | SD | Value | SD | Value | SD | Value | SD |
| Protein (%) | 36.6 | 0.21 | 44.0 | NA | 34.7 | 0.16 | 44.5 | NA |
| Calcium (%) | 0.7 | 0.02 | 0.9 | 0.04 | 1.4 | 0.08 | 1.3 | 0.05 |
| Phosphorus (%) | 0.7 | 0.03 | 0.9 | 0.02 | 1.2 | 0.05 | 1.2 | 0.05 |
| Magnesium (%) | 0.07 | 0.01 | 0.08 | NA | 0.12 | 0.01 | 0.10 | 0.01 |
| Sodium (%) | 0.3 | 0.01 | 0.3 | NA | 0.3 | 0.01 | 0.5 | 0.01 |
| Potassium (%) | 0.89 | 0.04 | 0.81 | NA | 0.84 | 0.01 | 1.00 | 0.03 |
| Chloride (%) | 0.93 | NA | 0.89 | NA | 0.51 | NA | 0.11 | NA |
| Total n-3 fatty acids (%) | 0.6 | 0.02 | 0.8 | 0.03 | 0.2 | 0.02 | 0.2 | 0.02 |
| Docosahexaenoic acid (%) | 0.15 | 0.01 | 0.18 | < 0.001 | 0.01 | < 0.00 | 0.04 | < 0.001 |
| Eicosapentaenoic acid (%) | 0.22 | 0.01 | 0.27 | < 0.001 | 0.02 | 0.01 | 0.04 | < 0.001 |
| n6:n3 ratio | 5 | NA | 3 | NA | 20 | NA | 20 | NA |
| Vitamin E (U/kg) | 965 | 42 | 1,214 | 55 | 51 | 7 | 106 | 13 |
NA = Not applicable (data from a single analysis of a composite sample).
Values are from analytic data from either a single analysis of a composite sample composed of aliquots taken from 10 points during food production or the mean ± SD of analyses from multiple samples (n > 3; range, 3–49) after production. Chloride concentrations are reported on a dry-matter basis as predicted.
