Erythropoietin, iron depletion, and relative thrombocytosis: A possible explanation for hemoglobin-survival paradox in hemodialysis

Background: High doses of human recombinant erythropoietin (rHuEPO) to achieve hemoglobin levels greater than 13 g/dL in patients with chronic kidney disease appear to be associated with increased mortality. Study Design: We conducted logistic regression and survival analyses in a retrospective cohort of long-term hemodialysis patients to examine the hypothesis that the induced iron depletion with resultant relative thrombocytosis may be a possible contributor to the link between the high rHuEPO dose-associated hemoglobin level of 13 g/dL or greater and mortality. Setting & Participants: The national database of a large dialysis organization (DaVita) with 40,787 long-term hemodialysis patients during July to December 2001 and their survival up to July 2004 were examined. Predictors: Hemoglobin level, platelet count, and administered rHuEPO dose during each calendar quarter. Outcomes & Other Measurements: Case-mix-adjusted 3-year all-cause mortality and measures of iron stores, including serum ferritin and iron saturation ratio. Results: Higher platelet count was associated with lower iron stores and greater prescribed rHuEPO dose. Compared with a hemoglobin level of 12 to 13 g/dL, a hemoglobin level of 13 g/dL or greater was associated with increased mortality in the presence of relative thrombocytosis, ie, platelet count of 300,000/mu L or greater (case-mix-adjusted death-rate ratio, 1.21; 95% confidence limits, 1.02 to 1.44; P = 0.03) as opposed to the absence of relative thrombocytosis (death-rate ratio, 1.04; 95% confidence limits, 0.98 to 1.08; P = 0.1). A prescribed rHuEPO dose greater than 20,000 U/wk was associated with a greater likelihood of iron depletion (iron saturation ratio < 20%) and relative thrombocytosis (case-mix-adjusted odds ratio, 2.53; 95% confidence limits, 2.37 to 2.69; and 1.36; 95% confidence limits, 1.30 to 1.42, respectively; P < 0.001) and increased mortality during 3 years (death-rate ratio, 1.59; 95% confidence limits, 1.54 to 1.65; P < 0.001). Limitations: Our results may incorporate uncontrolled confounding. Achieved hemoglobin level may have different mortality predictability than targeted hemoglobin level. Conclusions: Iron depletion and associated relative thrombocytosis might contribute to increased mortality when administering high rHuEPO doses to achieve hemoglobin levels of 13 g/dL or greater in long-term hemodialysis patients. Randomized trials are needed to test these observational associations.