American Journal of Kidney Diseases

Erythropoietin, Iron Depletion, and Relative Thrombocytosis: A Possible Explanation for Hemoglobin-Survival Paradox in Hemodialysis

Published:September 01, 2008DOI:


      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.


      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.


      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/μL 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).


      Our results may incorporate uncontrolled confounding. Achieved hemoglobin level may have different mortality predictability than targeted hemoglobin level.


      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.

      Index Words

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      Linked Article

      • Normalization of Hemoglobin in Patients With CKD May Cause Harm: But What Is the Mechanism?
        American Journal of Kidney DiseasesVol. 52Issue 4
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          In this issue of the American Journal of Kidney Diseases, Streja et al1 hypothesize that the increased mortality in patients with kidney failure with hemoglobin levels increased into the normal range by using erythropoietic-stimulating agents (ESAs) is caused by reactive thrombocytosis that, in turn, is caused by iron deficiency. Their study was a retrospective look at more than 40,000 patients with kidney failure receiving outpatient hemodialysis. Relative thrombocytosis (defined as platelet count > 300 × 109/L) was seen in 15% of the patient population and was associated with a 30% greater weekly dose of ESA, lower transferrin saturation, and lower serum ferritin concentration.
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