Impact of Extended-hours Hemodialysis on Erythropoietin Resistance and Clinical Outcomes

Anemia management is a critical component of care in maintenance dialysis patients, with erythropoiesis-stimulating agents (ESAs) widely used as a mainstay therapy. However, responsiveness to ESAs varies among individuals, and elevated erythropoietin resistance index (ERI), a key indicator of treatment efficacy, has been reported to be associated with increased mortality when. Several studies suggest that extended-hours hemodialysis (HD) contributed to lower ERI values and improved survival outcomes compared to conventional HD, though the underlying mechanisms remain unclear. This study aimed to explore the relationship between iron metabolism markers—ferritin and transferrin saturation (TSAT)—and ERI in patients undergoing extended-hours HD versus conventional HD. Furthermore, given the limited evidence directly comparing ERI and prognosis in extended-hours HD, we investigated the association between ERI and clinical outcomes in this setting to clarify its prognostic significance.

Maintenance HD patients who received either extended-hours HD or conventional HD between January and March 2020 were enrolled, with a follow-up duration of 36 months. Patients who experienced a bleeding event within one month were excluded. The ERI was calculated by dividing the weekly dose of ESA (IU/week) into units by the post-dialysis body weight (kg) and hemoglobin (Hb) concentration (g/dL). Linear associations between ERI and ferritin or TSAT were assessed using multivariable linear regression, while nonlinear relationships were evaluated using restricted cubic spline analysis (RCS). The association between ERI and clinical outcomes was examined using Cox proportional hazards model.

A total of 356 patients were included in the analysis, comprising 169 patients undergoing extended-hours HD (69% male, mean age 66 years, Hb 11.0 g/dL, ferritin 50.9 ng/mL, TSAT 20.1%, ERI 6.0 IU･dL/g･kg/week) and 187 patients receiving conventional HD (63% male, mean age 72 years, Hb 11.2 g/dL, ferritin 89.7 ng/mL, TSAT 23.7%, ERI 12.5 IU・dL/g・kg/week). Multivariable regression analysis demonstrated a statistical association between extended-hours HD and lower ERI after adjusting for potential confounding factors. RCS analysis revealed that at high ferritin levels, both extended-hours and conventional HD were associated with reduced ERI values, in contrast, at low ferritin levels, the ERI elevation seen with conventional HD was not observed with extended-hours HD (Figure 1). A similar pattern was observed in relation to TSAT (Figure 2). In the Cox proportional hazards model incorporating restricted cubic spline analysis, lower ERI in extended-hours HD group was significantly associated with improved survival outcomes (Figure 3).

Extended-hours HD was significantly associated with lower ERI and improved survival outcomes, despite having lower serum ferritin and TSAT levels compared to conventional HD. Notably, RCS analysis indicated that, under conditions of low ferritin or low TSAT, ERI increased in conventional HD, but did not increase in extended-hours HD. These findings suggest that extended-hours HD may favorably modulate iron metabolism and enhance erythropoietic responsiveness, which could, at least in part, contribute to its observed survival benefit.