Thresholds of iron markers for iron deficiency erythropoiesis—finding of the Japanese nationwide dialysis registry

Reportedly, serum ferritin levels are much lower in Japanese hemodialysis (HD) patients than their Western counterparts. Therefore, the cutoff values of ferritin and transferrin saturation (TSAT) for iron deficiency might differ from other countries. We conducted a cross-sectional observational study using the Japanese nationwide registry data. We enrolled 142,339 maintenance HD patients and assessed the association between these markers, hemoglobin (Hb), and erythropoiesis-stimulating agent (ESA) resistance index (ERI) utilizing restricted cubic spline analyses. Median ferritin and TSAT levels were 73 (IQR: 31-158) ng/ml and 23.7 (16.8-32.0)%, respectively. These lower ferritin ranges may possibly stem from a lower inflammatory state in Japanese patients, as shown in median CRP of 1.0 mg/l. An adjusted nonlinear association between Hb and TSAT showed that Hb levels drop with the decrease in TSAT below 20%, regardless of serum ferritin levels, suggesting the absolute iron deficiency cutoff as 20% for TSAT. In patients with TSAT >20%, the association between Hb and ferritin levels is nearly flat, whereas in patients with TSAT <20%, ferritin <50 ng/ml was associated with low Hb. In long-acting ESAs-users with TSAT >20%, U-shaped relationship was observed between ERI and ferritin with the bottom of ERI around 100 ng/ml of ferritin, possibly because high ferritin levels reflected an inflamed state leading to hyporesponsiveness to ESA. The patient subgroup with TSAT <20% and ferritin >100 ng/ml had significantly higher ERIs compared with the subgroup with TSAT >20% and ferritin <100 ng/ml, implying that TSAT, rather than ferritin, should be a primary iron marker predicting ESA response.