Hyporesponsiveness to Erythropoiesis-Stimulating Agents in Dialysis-Dependent Patients with Anaemia of Chronic Kidney Disease: A Retrospective Observational Study

Abstract

Introduction: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) in patients with anaemia of chronic kidney disease may lead to increased ESA doses to achieve target haemoglobin levels; however, elevated doses may be associated with increased mortality. Furthermore, patients with hyporesponsiveness to ESAs have poorer clinical outcomes than those who respond well to ESAs. Incidence and clinical characteristics of patients with ESA hyporesponsiveness were explored in a real-world setting.

Methods: This was a retrospective study of electronic medical records of adults with stage 5 chronic kidney disease receiving renal replacement therapy and ESA treatment, from 1 January 2015 to 31 December 2021. The primary objective was ESA hyporesponsiveness rate/1000 days, with a hyporesponsive event defined as ESA use at an elevated dose, according to National Institute for Health and Care Excellence (NICE) criteria. Other hyporesponsiveness definitions applied were erythropoietin resistance index-defined ESA hyporesponsiveness (ERI) Kidney Disease Improving Global Outcomes (KDIGO) and a clinical practicality algorithm.

Results: In total, 85,259 patients were included in the analysis; 59.9% were male, median (interquartile range) ESA starting dose was 733.3 (400.0, 1200.0) IU/week and follow-up duration was 2.2 (1.0, 4.2) years. Incidence of ESA hyporesponsiveness varied when applying different definitions; NICE 0.05/1000 days (5.2% of patients), ERI 0.40/1000 days (40.7%), KDIGO 0.15/1000 days (15.4%), and clinical practicality algorithm 0.48/1000 days (47.9%). ESA doses remained higher in hyporesponsive versus responsive patients, yet haemoglobin levels were similar between groups.

Conclusion: The results from this study, which applied multiple hyporesponsiveness definitions to a large, geographically diverse population of patients with anaemia of CKD, showed variation in ESA hyporesponsiveness incidence rates depending on definitions used and higher ESA doses in hyporesponsive versus responsive patients. These results underscore the need for individualised clinical assessment and thorough evaluation when considering ESA dose adjustments to reach haemoglobin targets. Graphical abstract available for this article.

Trial registration: NCT05530291.

Keywords: Anaemia; CKD; Dialysis; Erythropoiesis-stimulating agent; Hyporesponsiveness.

Fig. 1

Study design. ^aThe date of initiation of RRT was available for all patients included in the analysis in case there was a need for distinction between incident/non-incident patients. ^bDefined as the first ESA treatment date within the study period; patients with no relevant information on the ESA start date in the database were excluded from the analysis. ^cEnd of follow-up was earliest date of death, transplantation, dialysis centre change (i.e. moving outside of an FMW facility or an FME facility not using the EuCliD database), loss to follow-up, or end of study. ESA erythropoiesis-stimulating agent, RRT renal replacement therapy

Fig. 2

Kaplan–Meier curve for the occurrence of first ESA hyporesponsive event after ESA initiation (overall population). Right-hand panel presents data points on a larger scale for clarity. Blue areas indicated a 95% Hall–Wellner band. Crosses indicate censored data points. ESA erythropoiesis-stimulating agent

Fig. 3

Mean (left) and median (IQR; right) a ESA dose and b Hb levels over the first 12 months post-ESA initiation (index date) in patients with a NICE ESA hyporesponsive event over the full study period and patients with an ESA response. Left-hand panels show mean values. Right-hand panels show box plots, comprising low whiskers (Q1 − 1.5 × IQR), a box denoting the IQR with median line and high whiskers (Q3 + 1.5 × IQR). ESA erythropoiesis-stimulating agent, Hb haemoglobin, IQR interquartile range, NICE National Institute for Health and Care Excellence, Q quartile