Urinary cystatin B differentiates progressive versus stable IRIS Stage 1 chronic kidney disease in dogs

Abstract

Background: Early identification of dogs with progressive vs stable chronic kidney disease (CKD) might afford opportunity for interventions that would slow progression. However, currently no surrogate biomarker reliably predicts CKD progression.

Hypothesis/objectives: Urinary cystatin B (uCysB), a novel kidney injury biomarker, predicts progressive disease in International Renal Interest Society (IRIS) CKD Stage 1.

Animals: Seventy-two dogs, including 20 dogs from 4 university centers with IRIS CKD Stage 1, with IDEXX symmetric dimethylarginine (SDMA) concentration up to 17 μg/dL and no systemic comorbidities, and 52 clinically healthy staff-owned dogs from a fifth university center.

Methods: A multicenter prospective longitudinal study was conducted between 2016 and 2021 to assess uCysB concentration in IRIS CKD Stage 1 and control dogs. Dogs were followed to a maximum of 3 years (control) or 25 months (CKD). Stage 1 IRIS CKD was classified as stable or progressive using the slope of 1/SDMA, calculated from 3 timepoints during the initial 90-day period. Dogs with slope above or below -0.0007 week × dL/μg were classified as stable or progressive, respectively. Mixed effects modeling was used to assess the association between uCysB and progression rate.

Results: Estimates of first visit uCysB results predictive of active ongoing kidney injury based on the mixed effects models were 17 ng/mL for control, 24 ng/mL for stable CKD, and 212 ng/mL for progressive CKD (P < .001).

Conclusions and clinical importance: Urinary cystatin B differentiated stable vs progressive IRIS CKD Stage 1. Identification of dogs with progressive CKD may provide an opportunity for clinicians to intervene early and slow progression rate.

Keywords: biomarker; creatinine; disease monitoring; inverse slope; symmetric dimethylarginine.

FIGURE 1

Urinary cystatin B (uCysB) results of individual dog grouped by disease status. Control and stable chronic kidney disease (CKD) dogs appear to have similar uCysB results. Progressive CKD dogs tend to have higher uCysB results compared to control and stable CKD dogs.

FIGURE 2

Box plot of y‐intercepts calculated from inverse urinary cystatin B (uCysB) vs time linear regressions of individual dogs in each study group. The dependent variable was uCysB and the independent variable was follow‐up time. Although the y‐intercepts for control dogs and stable chronic kidney disease (CKD) dogs were comparable, the y‐intercepts for progressive CKD dogs were consistently higher. Differences in y‐intercepts between groups were detected using Kruskal‐Wallis ANOVA (P < .001).

FIGURE 3

Slopes of log(uCysB) by follow‐up time for individual dogs in each study group. Slopes were estimated using least squares regression for each dog with log(uCysB) as the dependent variable and follow‐up time as the independent variable. Differences among slopes of control, stable chronic kidney disease (CKD) and progressive CKD dogs were detected using Kruskal‐Wallis ANOVA (P = .006).

FIGURE 4

First urinary cystatin B (uCysB) measurements for each dog according to assigned study group. Although only 8 dogs had progressive International Renal Interest Society (IRIS) chronic kidney disease (CKD) Stage 1 at first visit, 6 (75%) had first uCysB results above the reference range of 50, 4 (67%) of which progressed beyond IRIS CKD Stage 1.

FIGURE 5

Results of linear mixed effects model with predicted urinary cystatin B results on simulated data of control and International Renal Interest Society chronic kidney disease Stage 1 dogs. Gray regions represent 1.5 × (SE).