Association between hyporesponsiveness to erythropoiesis-stimulating agents and risk of brain hemorrhage in patients undergoing hemodialysis: the Q-Cohort Study.

BACKGROUND: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is associated with increased risks of all cause and cardiovascular mortality in patients undergoing hemodialysis (HD). However, the impact of the hematopoietic response to ESAs on the development of stroke, including brain hemorrhage and infarction, remains unclear. METHODS: In total, 2886 patients undergoing maintenance HD registered in the Q-Cohort Study who were treated with ESAs were prospectively followed up for 4 years. The hematopoietic response to ESAs was evaluated by the erythropoietin resistance index (ERI), calculated by dividing the weekly dose of ESA by post-HD weight and hemoglobin (U/kg/week/g/dL). The primary outcomes were the incidences of brain hemorrhage and infarction. Patients were divided into quartiles based on their ERI at baseline (Q1, ≤ 4.1; Q2, 4.2-7.0; Q3, 7.1-11.2; and Q4, ≥ 11.3). The risks of brain hemorrhage and infarction were estimated using Cox proportional hazards models, adjusting for potential confounders. RESULTS: During the 4 year follow-up period, 71 patients developed brain hemorrhage and 116 developed brain infarction. In the multivariable analysis, the incidence of brain hemorrhage in the highest quartile (Q4) was significantly higher than that in the lowest quartile (Q1) (hazard ratio [95% confidence interval], 2.18 [1.08-4.42]). However, the association between the ERI and the incidence of brain infarction was not significant. CONCLUSIONS: A higher ERI was associated with an increased risk of brain hemorrhage, but not brain infarction, in patients undergoing maintenance HD. A high ERI is thus an important risk factor for brain hemorrhage in these patients.

Within-patient variation of hemoglobin and reticulocytes: implications for evaluating ESA responsiveness in dialysis patients.

INTRODUCTION: Techniques that assess percent reticulocytes (%retics) or hemoglobin (Hb) to detect erythropoiesis-stimulating agents (ESA) use in athletes may be useful in evaluating ESA responsiveness in dialysis patients. However, within-patient variation, appropriate transformation, or the relationship between the blood draw interval length and analyte variation are untested. METHODS: In a prospective, single-arm trial, we determined Hb and %retics in 30 hemodialysis patients receiving stable ESA doses. Within-patient results were evaluated for variance homogeneity and normality with and without transformation. RESULTS: Square-root transformation (sqrt) of %retics produced the most constant variance (lowest r-value for correlation between sqrt|normalized residuals| and fitted values: 0.018 highest P-value 0.739) compared with log transformation (r = -0.198, P < 0.001) or no transformation (r = 0.215, P < 0.001) and showed the least departure from normality (highest P-value: 0.002 vs. < 0.001 vs. < 0.001, respectively). Hb results did not improve with transformation. Within-patient variance in both %retics and Hb increased with interval length between lab draws (P < 0.001). CONCLUSIONS: Initial assessment of anti-doping tool use in dialysis patient anemia management indicates square-root transformation of %retics and adjustment for time between lab draw intervals for both %retics and Hb will be required.