Erythropoietin, Iron Depletion, and Relative Thrombocytosis: A Possible Explanation for Hemoglobin-Survival Paradox in Hemodialysis
Received 17 January 2008; accepted 12 May 2008. published online 01 September 2008.
Refers to article:
Normalization of Hemoglobin in Patients With CKD May Cause Harm: But What Is the Mechanism?
T.J. Littlewood
American Journal of Kidney Diseases
October 2008 (Vol. 52, Issue 4, Pages 642-644) Full Text |
Full-Text PDF (68 KB)
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.
1Harold Simmons Center for Kidney Disease Research and Epidemiology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA
2Department of Epidemiology, UCLA School of Public Health, Los Angeles, CA
8Division of Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, CA
Address correspondence to Kamyar Kalantar-Zadeh, MD, MPH, PhD, Harold Simmons Center for Kidney Disease Research and Epidemiology, LABioMed at Harbor-UCLA Medical Center, 1124 West Carson St, C1-Annex, Torrance, CA 90509-2910
ABSTRACT