An age-matched case-control study was initiated to determine the major risk factors associated with CKD in cats and dogs and to determine what clinical signs cat and dog owners observed before their veterinarian diagnosed their pet with CKD. When compared to controls, the feline cases were more likely to have had polydipsia and polyuria in the year before the owners' cats were diagnosed with CKD. In the dogs, increased water intake, increased urination, small size and a recent history of weight loss and bad breath were noticed by the dog owners before veterinary CKD diagnosis. Dog owners recognized abnormal drinking and urination behavior over half a year before their pet's veterinary diagnosis with CKD, and they recognized weight loss almost 4 months before CKD diagnosis. Bad breath was noticed 1.2 years before recognition of CKD by a veterinarian. Given that earlier CKD diagnosis should have been possible in most cases, clinical trials should proceed to measure the efficacy of early interventions.
Chronic kidney disease (CKD) has been reported in 9.6% of cats examined at Purdue’s teaching hospital, and recently we reported kidney diseases affecting 7.6% (361/4,731) of the feline caseload at four U.S. university teaching hospitals [
The clinical course of CKD is progressive and irreversible, with eventual uremia and azotaemia [
Dietary modification has been the principle intervention attempted to retard the progression of CKD [
In this regard, one of our objectives was to determine the risk factors and/or early signs of CKD that were noticed by the owners before their pet received a veterinary diagnosis of CKD. If early detection by owners and confirmation by primary care veterinarians are possible, then the next step would be to conduct blinded clinical trials to determine the efficacy of CKD intervention. Another objective was to identify risk factors for CKD that might elucidate possible causal factors and enable primary prevention.
Because age is such an important CKD determinant, cases and controls were matched on the basis of age and secondarily on year of veterinary treatment. All cases and age-matched controls were taken from the 2006–2008 caseload of Michigan State University’s (MSU) Veterinary Teaching hospital (VTH). Cases were selected if they met all of the following three criteria: (
After exclusion of research animals or animals presented for spay/neuter clinics, feline and canine patients from 2006–2008 were eligible for selection as controls. Controls were matched to cases on the basis of species (feline or canine), animal age, and by the time of treatment at the hospital. Within species, age, and date groups, controls were selected as having the nearest patient number to the case’s patient number. (Case numbers were sequentially assigned when each animal is first presented for treatment.) One control and a backup control were selected for each case, but the backup control was only contacted if the first control did not respond to the survey. It was confirmed from the hospital’s medical records that the controls had no record of any renal disease. Additionally, two questions on the survey requested information regarding the existence of any renal disease, and potential controls were excluded from the study if there was any indication that the control cat or dog had ever had any renal disease.
The feline risk factor survey was written and reviewed by the authors and a specialist in companion animal veterinary internal medicine. Some survey directions for the cases and controls were worded slightly differently to acknowledge the fact that the control cats had never been diagnosed with CKD and to ensure that case owners understood that we were asking only about observations before their pet’s first veterinarian-confirmed diagnosis with CKD. For the controls, pet owners were queried about observations before the CKD onset date in their matched case so that both case and control owners were being asked to recall events from the same number of months in the past. The owners of feline cases and controls were mailed a survey and recontacted in about 1 month with a 2nd mailed survey. About one month after the 2nd mailing, nonrespondents were called on the telephone and asked to return the survey and offered an additional mailed survey. Messages were left on answering machines if the pet owner did not answer the phone.
After completion of the feline data in the summer of 2009, the risk factor survey was modified for administration to canine cases and controls, which began in the fall of 2009. Like the feline survey, the canine survey asked about the existence of various risk factors (observations, conditions, and diseases) occurring before the time of diagnosis in the case, but also asked the case owners to estimate how many years and months before the CKD diagnosis the risk factor was first noticed. Dog owners were asked to estimate the number of pounds of body weight which their pet was over or under its ideal weight at 4, 3, 2, and 1 years before the time of CKD diagnosis in the case.
Data was entered into a spreadsheet and proof read with a second person. The data was then moved to SAS for analysis. (SAS 9.1.3 Cary, NC. USA) Categorical variables were analyzed by SAS proc logistic for a matched-pair case-control study, producing an odds ratio with 95% confidence intervals. Odds ratios were considered statistically significant at
Each of the canine dichotomous variables was evaluated independently as described above for its association with CKD. Variables found statistically significant at
Our survey response rate was 55% (92 completed pairs/168 selected pairs) for the cats and 51% (120/236) for the dogs. The cats with CKD average 15 years of age (SD = 5.0), and the dogs averaged 9.9 years of age (SD = 3.9).
The odds ratios for dichotomous variables are shown in Table
Feline-matched case-control odds ratios for dichotomous owner-reported risk factors for CKD, with lower (LC) and upper (UC) 95% confidence limits.
Risk factor description | Odds ratio | LC | UC |
---|---|---|---|
Being female | .91 | .49 | 1.7 |
Being neutered | — | — | — |
Excessive thirst or drinking more than a usual amount of water1 | 4.6 | 2.0 | 10 |
Urinating more frequently than usual1 | 4.0 | 1.5 | 11 |
Urinating larger volume than usual1 | 7.5 | 1.7 | 33 |
Urinating in the wrong place (not in the litter box or outside)1 | .47 | .19 | 1.1 |
Unexplained weight loss1 | 1.6 | .90 | 3.0 |
Visible loss of muscle/strength 1 | 1.0 | .42 | 2.4 |
Unexplained weight gain1 | — | — | — |
Decreased appetite1 | 1.4 | .76 | 2.7 |
Refusal to eat for | 1.8 | .74 | 4.7 |
Vomiting (more frequent, not just hairballs)1 | 1.1 | .64 | 2.1 |
Lethargic (excessive sleeping, fatigue, low-energy)1 | 1.2 | .60 | 2.5 |
Constipation1 | .88 | .32 | 2.4 |
Excessive gas (flatulence)1 | — | — | — |
Dental problems1 | 1.0 | .43 | 2.3 |
Gum problems (oral ulcers, etc.)1 | .83 | .25 | 2.7 |
Excessive plaque or tartar on teeth1 | .90 | .37 | 2.2 |
Bad breath1 | .90 | .37 | 2.2 |
Excessive skin or coat odor1 | .57 | .11 | 4.0 |
Abnormal or poor hair coat1 | .79 | .36 | 1.7 |
Pale mucous membranes (eyes, mouth, etc.)1 | .33 | .067 | 1.7 |
Eye problems or changes1 | .55 | .20 | 1.5 |
Mobility problems (stiffness or limping)1 | 1.2 | .51 | 2.9 |
Loss of vision1 | .20 | .023 | 1.7 |
Loss of hearing1 | .60 | .14 | 2.5 |
Never had teeth professionally cleaned | .96 | .55 | 1.7 |
Water always available2 | — | — | — |
Having water refill only once per day2 | .52 | .25 | 1.1 |
Cat was outside at least some of the time2 | .84 | .43 | 1.6 |
Sometimes exposed to other cats2 | .71 | .32 | 1.6 |
Some exposure to house mice2 | .66 | .37 | 1.2 |
Lower urinary tract disease (including infection, stones, cystitis, plugged, etc.)2 | 1.5 | .72 | 3.1 |
Neurological disease2 | .67 | .11 | 4.0 |
Seizures2 | 1.0 | .14 | 7.1 |
Liver problems2 | .20 | .023 | 1.7 |
Dental problems2 | .87 | .41 | 1.8 |
Behavioral problems2 | .63 | .20 | 1.9 |
Neoplasm (cancer)2 | .43 | .11 | 1.7 |
Eye disease2 | 1.3 | .34 | 4.7 |
Glaucoma2 | — | — | — |
Ear infections or other ear problems2 | .57 | .17 | 2.0 |
Frequent vomiting (not just hairballs)2 | .81 | .39 | 1.7 |
Gastrointestinal problems 2 | 1.2 | .39 | 3.5 |
Parasitic problems2 | 2.5 | .49 | 13 |
Reproductive problems2 | — | — | — |
Obesity2 | .93 | .44 | 2.0 |
Diabetes2 | 2.0 | .37 | 11 |
Hyperthyroidism2 | 4.5 | .97 | 21 |
Musculoskeletal (muscles, bones)2 | .33 | .035 | 3.2 |
Hip dysplasia2 | — | — | — |
Dermatologic (skin diseases)2 | 1.2 | .37 | 3.9 |
Cardiovascular diseases (heart disease)2 | .75 | .26 | 2.2 |
Osteodystrophy2 | — | — | — |
1Observations in the one year before the CKD diagnosis in the case.
2Observations in all years before the CKD diagnosis in the case.
Feline-Analysis of Continuous variables regarding observations before the diagnosis of CKD in the Case, analyzed by matched
Lifetime description of diet before diagnosis of ckd in the case | Case mean | Control mean | Paired |
---|---|---|---|
Lifetime % of diet-dry food1 | 72 | 73 | .84 |
Lifetime % of diet-wet food1 | 24 | 24 | .84 |
Lifetime % of diet-table scraps1 | 2.2 | 1.5 | .45 |
Lifetime % of diet-moist (bag or pouch)1 | 1.2 | 2.2 | .48 |
Lifetime % of diet-hunting1 | .86 | .72 | .78 |
Dry food percent2,3 | .95 | 1.0 | .10 |
Wet food percent2,3 | .54 | .63 | .24 |
Table scraps percent2,3 | .21 | .25 | .67 |
Moist food percent2,3 | .072 | .053 | .52 |
Hunted food percent2,3 | .47 | .18 | .08 |
Mature diet percent2,3 | .47 | .42 | .29 |
% of years outside2,3 | 8.12 | 13 | .14 |
Water available2 (1 = sometimes, 2 = usually, 3 = always) | 39 | 38 | .74 |
Avg number of other cats contacted2 | 1.6 | 1.8 | .40 |
1Asked of owner regarding the cat’s lifetime experience.
2Tabulated from the owner’s account of each year of the cat’s life.
3This percent of lifetime diet was calculated from the owner’s assessment of the cat’s diet during each year of its life.
A variable for the difference in weight (in units of 10 Kg) between the case and its matched control was found to be a significant predictor of CKD at
Cases were reportedly overweight by 1.5, 1.2, 1.2, and
Canine-matched case-control odds ratios for dichotomous owner-reported risk factors for CKD, with lower (LC) and upper (UC) 95% confidence limits.
Risk factor description | Odds ratio | LC | UC | Yrs1 noticed before Dx (SD) |
---|---|---|---|---|
Being female | .968 | .59 | 1.6 | |
Being neutered | .55 | .20 | 1.5 | |
Excessive thirst or drinking more than a usual amount of water: (x_thrst) | 4.4 | 2.3 | 8.4 | .74 (2.1) |
Urinating more frequently than usual: (Ur_more) | 4.7 | 2.2 | 10 | .71 (2.2) |
Urinating larger volume than usual: (Ur_large) | 3.8 | 1.6 | 9.4 | .51 (2.0) |
Urinating in the wrong place: (Ur_acc) | 2.7 | 1.4 | 5.4 | .60 (1.8) |
Unexplained weight loss: (Wgtloss) | 9.5 | 3.4 | 27 | .38 (1.8) |
Visible loss of muscle/strength | 2.0 | .90 | 4.5 | |
Unexplained weight gain | 3.0 | .81 | 11 | |
Decreased appetite: (Dec_ap) | 5.1 | 2.5 | 10 | .43 (1.5) |
Refusal to eat for | 11.7 | 3.6 | 38 | .22 (1.2) |
Vomiting (more frequently than other dogs): (Vomit) | 3.5 | 1.4 | 8.7 | .45 (2.0) |
Lethargic (excessive sleeping, fatigue, low-energy): (Leth) | 2.3 | 1.2 | 4.2 | .16 (.45) |
Constipation | 1.7 | .40 | 7.0 | |
Excessive gas (flatulence) | 1.6 | .52 | 4.9 | |
Dental problems | 1.6 | .64 | 3.9 | |
Gum problems (oral ulcers, etc.) | 4.0 | .45 | 36 | |
Excessive plaque or tartar on teeth: (Plaque) | 2.6 | 1.2 | 5.5 | .80 (2.5) |
Bad breath: (Breath) | 2.9 | 1.4 | 6.0 | 1.2 (2.9) |
Excessive skin or coat odor | 2.7 | .71 | 10 | |
Abnormal or poor hair coat | .70 | .30 | 1.6 | |
Pale mucous membranes (eyes, mouth, etc.) | 1.3 | .34 | 4.7 | |
Eye problems or changes | 1.1 | .41 | 3.2 | |
Mobility problems (stiffness or limping) | .62 | .33 | 1.1 | |
Loss of vision | 1.6 | .73 | 3.5 | |
Loss of hearing | 1.1 | .41 | 3.2 | |
Teeth professionally cleaned at least yearly | 1.23 | .73 | 2.1 | |
Water always available | — | — | — | |
Outside more than just for walks | .56 | .26 | 1.2 | |
Frequently exposed to dogs outside the household | .65 | .32 | 1.3 | |
Sometimes or frequently exposed to mice | 1.1 | .53 | 2.2 | |
Inappropriate urination, blood in urine, painful urination, infection, stones, cystitis, plugged, and so forth. | .90 | .37 | 2.2 | |
Neurological disease | .5 | .13 | 2.0 | |
Seizures | 1.4 | .54 | 3.8 | |
Liver problems | 4.5 | .97 | 21 | |
Dental problems | 2.0 | .81 | 5.0 | |
Behavioral problems | 3.0 | .61 | 15 | |
Neoplasm (cancer) | .47 | .19 | 1.1 | |
Eye disease | 1.1 | .41 | 3.2 | |
Glaucoma | 2.0 | .18 | 22 | |
Ear infections or other ear problems | .63 | .33 | 1.2 | |
Gastrointestinal problems | .64 | .25 | 1.6 | |
Parasitic problems | .46 | .16 | 1.3 | |
Reproductive problems | — | — | — | |
Obesity | 1.6 | .77 | 3.3 | |
Diabetes | 2.0 | .18 | 22 | |
Hyperthyroidism | 1.0 | .20 | 5.0 | |
Musculoskeletal (muscles, bones) | .69 | .30 | 1.6 | |
Hip dysplasia | .33 | .07 | 1.7 | |
Dermatologic (skin diseases) | .79 | .40 | 1.6 | |
Cardiovascular diseases (heart disease) | 4.0 | .45 | 36 | |
Osteodystrophy | — | — | — |
1Number of years before veterinary diagnosis when this disease was diagnosed or observation first noticed in the CKD case. Shown only for statistically significant risk factors.
Biologic systems models regarding urinary symptoms (Model 1), weight loss (Model 2) and miscellaneous (Model 3)—adjusted for dog weight1,2,3.
OR | LC | UC | OR | LC | UC | ||
---|---|---|---|---|---|---|---|
Model 1 | |||||||
X_thrst | 5.5 | 2.5 | 12 | Wtkg10 | 1.7 | 1.3 | 2.2 |
Model 2 | |||||||
Wgt_Loss | 5.8 | 1.6 | 21 | Refusal | 8.3 | 1.6 | 43 |
Dec_ap | 3.2 | 1.1 | 8.9 | WtKg10 | 1.6 | 1.2 | 2.2 |
Model 3 | |||||||
Leth | 2.5 | 1.2 | 5.1 | Breath | 2.6 | 1.1 | 6.0 |
WtKg10 | 1.4 | 1.1 | 1.8 |
1OR = Odds ratio estimate with the lower (LC) and upper (UC) 95% confidence interval.
2Variables are defined in Table
3The following variables were evaluated.
Model 1: WtKg10 x_thrst,
Model 2: WtKg10 Wgtloss Dec_ap Refusal
Model 3: WtKg10 Leth
Nonsignificant variables (underlined) were removed.
Combined model1.
Variable | OR | LC | UC | Sig |
---|---|---|---|---|
Dec_ap | 4.5 | 1.7 | 12 | .003 |
Breath | 3.6 | 1.1 | 12 | .034 |
Wgtloss | 9.4 | 2.1 | 43 | .004 |
X_thrst | 5.6 | 2.0 | 16 | .001 |
KgWt10 | 1.6 | 1.2 | 2.3 | .004 |
1Variables are defined in Table
Max-rescaled
Canine-analysis of continuous variables regarding observations before the diagnosis of CKD in the case, analyzed by matched
Lifetime description of diet before diagnosis of CKD in the case | Case mean | Control mean | Paired |
---|---|---|---|
Age in years | 9.9 | 10 | .061 |
Lifetime % of diet-dry food | 75 | 82 | .042 |
Lifetime % of diet-wet food | 14 | 8.4 | .047 |
Lifetime % of diet-table scraps | 10 | 9.2 | .74 |
Lifetime % of diet-moist (bag or pouch) | 1.7 | .76 | .22 |
Food for all ages (last 2 yrs of life)1 | 51 | 49 | .66 |
Mature diet (last 2 yrs of life)1 | 24 | 26 | .57 |
Diet for overweight (last 2 yrs of life)1 | 6.8 | 6.3 | .85 |
Weight in kg1 | 20 | 28 | .00 |
1Percent of diet of this type during the last 2 years of life.
The feline and canine surveys repeatedly stressed that we were only asking about observations made before the veterinary diagnosis of CKD in the cases or, for controls, the onset date we provided for their matched case. As such, recall bias should have been minimized in that the owners of both cases and controls were asked to remember events from an equal distance into the past. We acknowledge that the evaluation of so many risk factors involves multiple comparisons that must certainly affect the validity of the generated confidence intervals, however this was a hypothesis-generating study for which no causal associations should be implied or assumed.
When compared to their matched controls, the feline cases were more likely to have had polydipsia and polyuria in the years before their cat was diagnosed with CKD. This suggests that earlier diagnosis and intervention may have been possible if these pet owners had been taught to recognize the early signs of CKD. Given the progressive nature of the disease and the demonstrated correlation between clinical chemistry and survival times, it is reasonable to hypothesize that interventions would be most effective if initiated as early as possible in the clinical course of the disease [
Our desire for a specific diagnosis (inclusion criteria 2 and 3) reduced the study sample size such that, when coupled with a return rate of 55%, we only had 92 completed pairs for analysis. Another unexpected challenge to statistical power was that many of the risk factors were quite rare in the study population. Therefore, there are several risk factors that have reasonably high odds ratios, but failed to reach statistical significance in that the OR confidence interval included 1.0.
The association with hyperthyroidism had a high odds ratio (4.5). Although both hyperthyroidism and CKD are strongly associated with age, the cases and controls were matched for age, so age cannot explain this observed association. It is possible that cats for which clinical pathology results were obtained were more likely to have been diagnosed with both hyperthyroidism and CKD, which are both very common in older cats.
There was a nonsignificant finding that the percent of diet from hunting might be positively associated with CKD, and further investigation may be warranted. This question was asked because infectious or toxicologic agents associated with hunting, such as hantavirus in rodents, may contribute to renal destruction as a hidden cause of CKD.
Most significant variables related to polydipsia, polyuria, recent weight loss, small body size, and periodontal disease. Controls were somewhat more likely to get a greater percentage of their diet from dry dog food, but this was most likely a result of their averaging about 8 kg more than their matched cases. The two-variable models shown in Table
Model 1 in Table
The combined final model (Table
Polzin et al. [
A small body size was an extremely important predictor of CKD in dogs, such that future studies should consider matching on body size (or breed) as well as age. We found that our cases averaged 8 kg less weight than controls. This was the current weight or weight 2 months before death for dogs that were deceased. We also found that a lower body weight was a significant predictor of CKD in all of our multivariable models (Tables
If CKD can be recognized sufficiently early in its clinical course, there are several prospects for intervention which presumably would be the most effective if introduced as early as possible during the clinical course of the disease. Dietary modification has been reported to retard the development of CKD in dogs and cats [
In cats, it has been recommended that serum phosphate and parathyroid hormone be monitored, and phosphate-restricted dietary management and intestinal phosphate binders be used to retard the progression of CKD and accompanying hyperparathyroidism [
High rates of gingivitis and periodontal disease have been reported in humans with chronic kidney disease [
This paper was funded by Hills Pet Nutrition, Inc.