Unmasking erythroid suppression: the hidden culprit in renal anemia pathogenesis.

To analyze erythropoietin (EPO) secretion and bone marrow proliferation under conditions of renal anemia with varying degrees of kidney injury. First, A cross-sectional analysis compared serum erythropoietin (EPO) and erythropoietin receptor (EPOR) levels between patients with early-stage chronic kidney disease (CKD stages 1-2) and those with advanced CKD (stage 5) who had not undergone hemodialysis or received EPO therapy (CKD5 + nonHD). Bone marrow hyperplasia of two patients from each group was analyzed using Wright-Giemsa staining. Second, two C57BL/6 mouse models of progressive renal anemia were established using adenine gavage with or without unilateral pedicle ligation (8M‑N: control; 8M‑M: adenine + sham; 8M‑NM: adenine + ligation). Renal and hepatic EPO expression, bone marrow EPOR and CD71 levels, CpG island methylation in the EPO promoter, and erythroid differentiation by flow cytometry were analyzed. etc. Compared to CKD stage 1-2 patients, the CKD5 + nonHD group showed significantly lower hemoglobin, eGFR, and higher creatinine and BUN levels (p < 0.001). Serum EPO concentrations showed no significant differences between patient groups or experimental mouse groups with varying degrees of kidney injury (p > 0.05). However, the proportion of nucleated cells to mature erythrocytes and erythroid precursors to bone marrow nucleated cells were markedly reduced in CKD5 + nonHD patients compared to CKD1-2 patients (p < 0.05). In animal models with progressive kidney injury (normal controls, adenine + sham, and adenine + unilateral pedicle ligation), serum creatinine, renal fibrosis as assessed by MASSON/PASM staining, CpG island methylation in the EPO promoter and hepatic EPO expression were gradually elevated (p < 0.05). In contrast, hemoglobin, hematocrit, and marrow EPOR/CD71 levels and the proportions of Ter119+ nucleated erythroid cells declined progressively with worsening renal injury (8M-N > 8M-M > 8M-NM, p < 0.001), and the proportions of CD44low/CD711ow late erythroid precursors within Ter119+ nucleated erythroid cells was significantly reduced in 8M-NM (p < 0.001). In renal anemia, compensatory EPO production from extrarenal tissues may partially offsets the reduction in systemic EPO levels. However, bone marrow proliferation, particularly erythroid hematopoiesis, is significantly impaired, highlighting the critical impact of reduced erythropoiesis on anemia progression.