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/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).

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.

Index Words: Anemia, thrombocytosis, iron stores, hemodialysis population, erythropoiesis-stimulating agent, malnutrition-inflammation-cachexia syndrome (MICS)