Autoantibodies to Erythropoietin Receptor and Clinical Outcomes in Patients With Type 2 Diabetes and CKD: A Post Hoc Analysis of CREDENCE Trial

Abstract

IntroductionAuto-antibodies to erythropoietin receptor (anti-EPOR antibodies) have been identified in patients with various kidney diseases. However, data in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) is limited. We assessed the prevalence of anti-EPOR antibodies and their association with clinical outcomes in this population. MethodsThe CREDENCE randomized patients with T2D and CKD to canagliflozin or placebo. Serum anti-EPOR antibodies, the exposure of interest, were measured using enzyme-linked immunosorbent assay. The primary outcome was doubling of serum creatinine, end-stage kidney disease, or death from kidney or cardiovascular causes. Secondary outcomes included cardiovascular and all-cause mortality. Multivariable Cox-regression models estimated associations between anti-EPOR antibodies and outcomes. The effects of canagliflozin on hemoglobin and hematocrit stratified by the presence of anti-EPOR antibodies were assessed with a repeated measures mixed effects model. ResultsOf 2600 participants with available biosamples, 191 (7.3%) were positive for anti-EPOR antibodies. Higher baseline anti-EPOR antibodies were associated with increased risk of primary outcome (HR per 1-SD increase 1.12 [95%CI 1.01, 1.24], p=0.04), cardiovascular death (HR 1.27 [1.08, 1.48], p<0.01) and all-cause mortality (HR 1.26 [1.11, 1.43], p<0.01). During follow-up, canagliflozin, compared to placebo, increased hemoglobin and hematocrit by 7.0g/L (6.2, 7.9) and 2.4% (2.2, 2.7), respectively. These effects were consistent across patients with and without anti-EPOR antibodies (P-interaction=0.39 and 0.70). ConclusionIn patients with T2D and CKD, anti-EPOR antibodies were associated with the composite kidney and cardiovascular outcome, as well as cardiovascular and all-cause mortality. Canagliflozin increased hemoglobin and hematocrit regardless of anti-EPOR antibodies.