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

Akihiko Koshino; Brendon L Neuen; Megumi Oshima; Tadashi Toyama; Akinori Hara; Clare Arnott; Bruce Neal; Meg Jardine; Sunil V Badve; Kenneth W Mahaffey; Carol Pollock; Michael K Hansen; Takashi Wada; Hiddo J L Heerspink

doi:10.1016/j.ekir.2023.11.024

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

Kidney Int Rep. 2023 Dec 1;9(2):347-355. doi: 10.1016/j.ekir.2023.11.024. eCollection 2024 Feb.

Authors

Akihiko Koshino^{1

2}, Brendon L Neuen³, Megumi Oshima², Tadashi Toyama², Akinori Hara², Clare Arnott^{3

4}, Bruce Neal^{3

5}, Meg Jardine^{3

6

7}, Sunil V Badve^{3

8

9}, Kenneth W Mahaffey¹⁰, Carol Pollock^{11

12}, Michael K Hansen¹³, Takashi Wada², Hiddo J L Heerspink^{1

3

9}

Affiliations

¹ Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
² Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan.
³ The George Institute for Global Health, University of New South Wales Sydney, Sydney, New South Wales, Australia.
⁴ Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
⁵ School of Public Health, Imperial College London, UK.
⁶ NHMRC Clinical Trials Centre, University of Sydney, New South Wales, Australia.
⁷ Concord Repatriation General Hospital, Sydney, New South Wales, Australia.
⁸ Department of Nephrology, St George Hospital, Sydney, New South Wales, Australia.
⁹ University of New South Wales, Sydney, New South Wales, Australia.
¹⁰ Stanford Center for Clinical Research, Stanford University School of Medicine, Stanford, California, USA.
¹¹ Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, New South Wales, Australia.
¹² Royal North Shore Hospital, St Leonards, New South Wales, Australia.
¹³ Janssen Research and Development, LLC, Spring House, Pennsylvania, USA.

Abstract

Introduction: Autoantibodies 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.

Methods: The 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 (CV) causes. Secondary outcomes included CV 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.

Results: Of 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 (hazard ratio [HR] per 1-SD increase = 1.12, 95% confidence interval [CI] = 1.01-1.24, P = 0.04), with CV death (HR = 1.27, 95% CI = 1.08-1.48, P < 0.01) and all-cause mortality (HR = 1.26, 95% CI = 1.11-1.43, P < 0.01). During follow-up, canagliflozin, compared to placebo, increased hemoglobin and hematocrit by 7.0 g/l (95% CI = 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 = 0.24 and 0.36, respectively).

Conclusion: In patients with T2D and CKD, anti-EPOR antibodies were associated with the composite kidney and CV outcome, as well as CV and all-cause mortality. Canagliflozin increased hemoglobin and hematocrit regardless of anti-EPOR antibodies.

Keywords: SGLT2 inhibitor; anemia; biomarker; cardiovascular; kidney; mortality.