Efficacy of Reticulocyte Hemoglobin Equivalent-Guided vs. Transferrin Saturation-Guided Iron Supplement Protocol in Patients on Hemodialysis: A Cluster Randomized Controlled Trial

Background: Iron deficiency increases cardiovascular risk and all-cause mortality in hemodialysis patients. However, standard diagnostic tests - serum ferritin and transferrin saturation (TSAT) - have limitations and are costly. Reticulocyte hemoglobin equivalent (RET-He) is a novel, less expensive marker for diagnosing iron deficiency. This study aimed to assess the non-inferiority of RET-He-guided intravenous(IV)iron supplementation compared with TSAT-guided supplementation in hemodialysis patients. Methods: A total of 138 hemodialysis patients from seven centers were randomized into TSAT-guided (n=68) and RET-He-guided (n=70) groups. Both groups received IV iron according to a prespecified protocol. The primary outcome was the erythropoietin resistance index (ERI) at month 3. RET-He was considered non-inferior if the upper bound of the 95% confidence interval (CI) for the between-group difference was ≤160 units/week/mg/dL. Secondary outcomes included death, hospitalization, cardiovascular events, blood transfusion, and infection. Results: Baseline characteristics were similar between groups. At month 3, RET-He-guided was non-inferior to TSAT-guided supplementation in reducing ERI (RET-He: 792.19 ± 371.64 vs. TSAT: 793.65 ± 393.22 units/week/mg/dL; mean difference: –60.65, 95% CI: –217.86 to 96.57). RET-He-guided patients received significantly less iron (498 ± 247 vs. 605 ± 278 mg; p = 0.01). Secondary outcomes were not significantly different between groups. Conclusion: RET-He-guided IV iron supplementation demonstrated non-inferior efficacy in reducing ERI over three months compared with TSAT-guided supplementation and required significantly less iron. RET-He may offer a lower cost for iron management in hemodialysis patients by reducing both laboratory and treatment expenses.