Erythroferrone, Hepcidin, and Erythropoietin in Chronic Kidney Disease: Associations with Hemoglobin and Renal Function

<b>Background/Objectives</b>: Chronic kidney disease (CKD) is commonly complicated by anemia resulting from impaired erythropoietin (EPO) production, iron dysregulation, and chronic inflammation. Erythroferrone (ERFE) and hepcidin are key regulators of erythropoiesis and iron metabolism, but their interaction in CKD remains incompletely understood. This study aimed to examine the associations among ERFE, hepcidin, EPO, and hemoglobin, and to determine whether these markers independently relate to anemia severity in CKD. <b>Methods</b>: This cross-sectional case-control study included 126 patients with CKD (stages 2-5) and 33 age- and sex-matched healthy controls. Laboratory parameters, including hemoglobin, ferritin, transferrin saturation (TSAT), EPO, ERFE, hepcidin, and renal indices (eGFR, BUN, creatinine), were analyzed. Group differences were assessed using ANOVA or Kruskal-Wallis tests with post hoc analyses, and trends were evaluated using the Jonckheere-Terpstra test. Age- and sex-adjusted correlations and multivariable linear regression identified independent associations with hemoglobin. <b>Results</b>: Patients with CKD were older (61.2 ± 14.8 vs. 33.4 ± 10.7 years, <i>p</i> < 0.001) and had lower hemoglobin (11.8 ± 1.9 vs. 13.5 ± 1.4 g/dL, <i>p</i> < 0.001) and higher ferritin levels (245 (110-470) vs. 105 (40-240) ng/mL, <i>p</i> = 0.002) compared with controls. eGFR declined progressively across CKD stages (median (IQR): 73 (64-86) to 12 (7-17) mL/min/1.73 m², <i>p</i>-trend < 0.001). ERFE and hepcidin showed increasing trends with advancing CKD (<i>p</i>-trend = 0.031 and 0.047, respectively). Hemoglobin correlated negatively with ERFE (r = -0.40, 95% CI: -0.53 to -0.26, <i>p</i> < 0.001) and positively with eGFR (r = 0.42, 95% CI: 0.28-0.54, <i>p</i> < 0.001). In adjusted regression analysis, ERFE (β = -0.29, 95% CI: -0.41 to -0.18, <i>p</i> < 0.001) and eGFR (β = 0.25, 95% CI: 0.13-0.37, <i>p</i> < 0.001) remained independently associated variables of hemoglobin (adjusted R² = 0.47). <b>Conclusions</b>: Anemia severity in CKD is independently associated with both renal dysfunction and higher ERFE concentrations, suggesting a disrupted ERFE-hepcidin regulatory balance. These findings provide hypothesis-generating insights into the complex interplay between iron metabolism and erythropoiesis in CKD. Validation in larger, multi-center longitudinal studies that include inflammatory markers is warranted.