Early low-dose erythropoiesis-stimulating agent therapy and progression of moderate chronic kidney disease: a randomized, placebo-controlled trial.

Background: It is unknown whether early intervention with low-dose erythropoiesis-stimulating agents (ESAs) in non-anaemic patients delays progression of chronic kidney disease (CKD). Methods: In a single-blind, 24-month trial, adults with estimated glomerular filtration rate (eGFR) 30­59 mL/min/1.73 m2 and either Type 2 diabetes mellitus or previous kidney transplantation were randomized to low-dose continuous erythropoiesis receptor activator (CERA; monthly dose 30­75 µg; n = 115) or placebo (n = 120). The primary endpoint was the annual change in eGFR (abbreviated Modification of Diet in Renal Disease formula). Results: Mean (standard deviation) eGFR was 40.7 (9.8) mL/min/1.73 m2 versus 39.8 (9.2) mL/min/1.73 m2 at baseline for CERA and placebo, respectively, and 39.0 (11.6) g/dL versus 39.7 (10.6) g/dL at the final visit. The median (interquartile range) annual reduction in eGFR was 0.5 (−2.2, 3.8) mL/min/1.73 m2 with CERA versus 0.4 (−2.0, 3.2) mL/min/1.73 m2 with placebo (P = 0.657). No significant difference in the annual change in eGFR was observed between treatment groups in the subpopulations with Type 2 diabetes or kidney transplant. Adverse events with a suspected relation to study drug occurred in 22.0% and 16.2% of patients randomized to CERA or placebo, respectively, and adverse events led to study drug discontinuation in 11.0% and 8.5% of patients. Conclusions: Patients with moderate CKD and Type 2 diabetes or previous kidney transplantation showed stable renal function that was unaffected by administration of low-dose ESA. In addition, there was no clinically meaningful effect of 2-year low-dose ESA treatment on albuminuria, an important surrogate marker of kidney injury.

Once-Monthly Continuous Erythropoietin Receptor Activator (C.E.R.A.) in Patients with Hemodialysis-Dependent Chronic Kidney Disease: Pooled Data from Phase III Trials.

INTRODUCTION: Erythropoiesis-stimulating agents and iron are commonly used in patients with chronic kidney disease with the aim of correcting anemia and maintaining stable hemoglobin levels. We analyzed pooled data from 13 studies with similar designs included in the Umbrella Continuous Erythropoietin Receptor Activator (C.E.R.A.) program to investigate the effects of continuous erythropoiesis receptor activator in clinically relevant subgroups of patients with chronic kidney disease and to determine whether the efficacy and safety outcomes demonstrated in the overall chronic kidney disease population are maintained in specific subgroups. METHODS: Data from 13 Phase III trials set up with similar design were retrospectively pooled for this analysis. Patients with chronic kidney disease who had previously been receiving epoetin or darbepoetin were switched to continuous erythropoiesis receptor activator once-monthly after a 4- to 8-week screening period. Patients entered a 16-week continuous erythropoiesis receptor activator dose-titration period followed by an 8-week evaluation period. In total, 2060 patients were included in the analysis. Subgroups were defined based on: hemoglobin target range [lower (10.0-12.0 g/dL)/upper (10.5-13.0 g/dL)], gender (female/male), age (<65/≥65), baseline N-terminal pro-B-type natriuretic peptide levels (<5000/≥5000), cardiovascular risk factors (diabetes/cardiac/vascular/none). RESULTS: Across all subgroups analyzed, switching from shorter-acting erythropoiesis-stimulating agents to continuous erythropoiesis receptor activator once-monthly maintained stable hemoglobin concentrations in a high proportion of patients (78%), with only moderate hemoglobin fluctuations and a low number of dose changes. The safety profile across subgroups was as expected based on pre-existing risk factors; observed increases in adverse events were attributable to underlying risk factors rather than study drug. CONCLUSIONS: This retrospective analysis of 13 trials showed that continuous erythropoiesis receptor activator once-monthly maintained stable hemoglobin levels across a number of clinically relevant patient subgroups, including those with higher inherent cardiovascular risk. The safety profile was consistent with that previously established in the chronic kidney disease population. CLINICALTRIALS. GOV IDENTIFIERS: NCT00413894/NCT00545571/NCT00517413/NCT00560404/NCT00882713/NCT00550680/NCT00576303/NCT00660023/NCT00717821/NCT00642850/NCT00605293/NCT00661505/NCT00699348. FUNDING: F. Hoffmann-La Roche Ltd, Basel, Switzerland.