Hemoglobin (HB) correction with roxadustat is associated with improved iron homeostasis in patients with non-dialysis-dependent CKD (NDD-CKD)

Background: Anemia in CKD is multifactorial, with contributions from reduced erythropoietin production and hepcidin-induced functional iron deficiency. Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, treats anemia by enhancing erythropoietin synthesis and increasing iron availability via reducing hepcidin and increasing iron transport. We assessed the effect of roxadustat on iron parameters in patients with NDD-CKD. Methods: Patients were randomized to double-blind roxadustat or placebo in 3 pivotal NDD-CKD trials. Oral iron was administered without restriction per discretion of the treating physician, and intravenous (IV) iron use was limited to rescue therapy. Mean changes from baseline (BL) in Hb, hepcidin, and iron parameters were evaluated. Pooled results are reported. Results: Overall, 4277 patients were evaluated (roxadustat N=2391; placebo N=1886). Mean eGFR was 20 ml/min/1.73 m2 in both groups. Roxadustat was superior to placebo in increasing mean Hb from BL (9.1 g/dL for both groups) averaged over Weeks 28-52: 1.9 vs 0.2 g/dL (P<0.0001). IV iron use was required in 2.1% of roxadustat vs 4.8% of placebo patients during the first 52 weeks after randomization. Roxadustat reduced hepcidin and increased both transferrin and serum iron (Figure). Reductions in ferritin and transferrin saturation occurred predominantly in patients with the highest BL values of these parameters when assessed by quartile (>328 μg/L and >35%, respectively). Conclusions: Roxadustat increased both serum iron and iron-carrying capacity (transferrin) while simultaneously inducing erythropoiesis and correcting anemia in patients with NDD-CKD, without the need for regular IV iron supplementation.