Hyporesponsiveness to erythropoiesis-stimulating agent in non-dialysis-dependent CKD patients: The BRIGHTEN study.

Among non-dialysis-dependent chronic kidney disease (ND-CKD) patients, a low hematopoietic response to erythropoiesis-stimulating agents (ESAs) is a predictor for poor renal and cardiovascular outcome. To assess the method for evaluating hyporesponsiveness to ESA in patients with ND-CKD, a multicenter, prospective, observational study of 1,980 adult patients with ND-CKD with renal anemia was conducted. Darbepoetin alfa (DA) and iron supplement administrations were provided according to the recommendation of the attached document and the guidelines of JSDT (Japanese Society of Dialysis and Transplantation). The primary outcomes were progression of renal dysfunction and major adverse cardiovascular events. ESA responsiveness was assessed using pre-defined candidate formulae. During the mean follow-up period of 96 weeks, renal and cardiovascular disease (CVD) events occurred in 683 (39.6%) and 174 (10.1%) of 1,724 patients, respectively. Among pre-set candidate formulae, the one expressed by dividing the dose of DA by Hb level at the 12-week DA treatment was statistically significant in predicting renal (hazard ratio [HR], 1.449; 95% confidence interval [CI], 1.231-1.705; P<0.0001) and CVD events (HR, 1.719; 95% CI, 1.239-2.386; P = 0.0010). The optimum cut-off values for both events were close to 5.2. In conclusion, hyporesponsiveness to ESA in ND-CKD cases, which is associated with a risk for renal and CVD events, may be evaluated practicably as the dose of DA divided by the Hb level at the 12-week DA treatment, and the cut-off value of this index is 5.2. A search for the causes of poor response and measures for them should be recommended in such patients. Trial registration: ClinicalTrials. gov Identifier: NCT02136563; UMIN Clinical Trial Registry Identifier: UMIN000013464.
Competing Interests: Dr Narita reported receiving lecture fee and grant from Kyowa Kirin (KK). Dr Hayashi reported receiving honoraria from KK. Dr Maruyama received honoraria and subsidies or donation from KK. Dr Masaki reported receiving lecture fee and grant from KK. Dr Nangaku reported receiving honoraria, manuscript fees, and subsidies or donations from KK. Dr Nishino reported receiving lecture fee and grant from KK. Dr Sofue reported receiving grant from KK. Dr Takashi Wada reported receiving honoraria and subsidies or donation from KK. Dr Hase reported receiving honoraria from KK. Dr Yamamoto reported receiving honoraria and manuscript fees from KK. Dr Takehiko Wada reported receiving honoraria from KK. Dr Akizawa received honoraria and manuscript fees from KK. Dr Tsubakihara received honoraria from KK. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
(Copyright: © 2022 Narita et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)