American Journal of Kidney Diseases
Volume 52, Issue 4 , Pages 727-736 , October 2008

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

  • Elani Streja, MPH

      Affiliations

    • Harold Simmons Center for Kidney Disease Research and Epidemiology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA
    • Department of Epidemiology, UCLA School of Public Health, Los Angeles, CA
  • ,
  • Csaba P. Kovesdy, MD

      Affiliations

    • Salem VA Medical Center, Salem, VA
  • ,
  • Sander Greenland, DrPH

      Affiliations

    • Department of Epidemiology, UCLA School of Public Health, Los Angeles, CA
  • ,
  • Joel D. Kopple, MD

      Affiliations

    • Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA
    • David Geffen School of Medicine at UCLA, Los Angeles, CA
    • Department of Family Health, UCLA School of Public Health, Los Angeles, CA
  • ,
  • Charles J. McAllister, MD

      Affiliations

    • DaVita, Inc, El Segundo, Los Angeles, CA
  • ,
  • Allen R. Nissenson, MD

      Affiliations

    • David Geffen School of Medicine at UCLA, Los Angeles, CA
    • Division of Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, CA
  • ,
  • Kamyar Kalantar-Zadeh, MD, MPH, PhD

      Affiliations

    • Harold Simmons Center for Kidney Disease Research and Epidemiology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA
    • Department of Epidemiology, UCLA School of Public Health, Los Angeles, CA
    • Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA
    • David Geffen School of Medicine at UCLA, Los Angeles, CA
    • Corresponding Author InformationAddress 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

Received 17 January 2008 ,Accepted 12 May 2008.

References 

  1. Van Wyck DB, Bailie G, Aronoff G. Just the FAQs: Frequently asked questions about iron and anemia in patients with chronic kidney disease. Am J Kidney Dis. 2002;39:426–432
  2. Locatelli F, Pisoni RL, Akizawa T, et al. Anemia management for hemodialysis patients: Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines and Dialysis Outcomes and Practice Patterns Study (DOPPS) findings. Am J Kidney Dis. 2004;44:27–33
  3. Regidor DL, Kopple JD, Kovesdy CP, et al. Associations between changes in hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients. J Am Soc Nephrol. 2006;17:1181–1191
  4. National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis. 2006;47(suppl 3):S146–S146
  5. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998;339:584–590
  6. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085–2098
  7. Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:2071–2084
  8. Phrommintikul A, Haas SJ, Elsik M, Krum H. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: A meta-analysis. Lancet. 2007;369:381–388
  9. Strippoli GF, Tognoni G, Navaneethan SD, Nicolucci A, Craig JC. Haemoglobin targets: We were wrong, time to move on. Lancet. 2007;369:346–350
  10. Kalantar-Zadeh K, McAllister CJ, Lehn RS, Liu E, Kopple JD. A low serum iron level is a predictor of poor outcome in hemodialysis patients. Am J Kidney Dis. 2004;43:671–684
  11. Kalantar-Zadeh K, Regidor DL, McAllister CJ, Michael B, Warnock DG. Time-dependent associations between iron and mortality in hemodialysis patients. J Am Soc Nephrol. 2005;16:3070–3080
  12. Coyne D. Challenging the boundaries of anemia management: A balanced approach to i.v. iron and EPO therapy. Kidney Int Suppl. 2006;101:S1–S3
  13. Kadikoylu G, Yavasoglu I, Bolaman Z, Senturk T. Platelet parameters in women with iron deficiency anemia. J Natl Med Assoc. 2006;98:398–402
  14. Gurbel PA. The relationship of platelet reactivity to the occurrence of post-stenting ischemic events: Emergence of a new cardiovascular risk factor. Rev Cardiovasc Med. 2006;7(suppl 4):S20–S28
  15. Aljaroudi WA, Halabi AR, Harrington RA. Platelet inhibitor therapy for patients with cardiovascular disease: Looking toward the future. Curr Hematol Rep. 2005;4:397–404
  16. Kalantar-Zadeh K, Kilpatrick RD, McAllister CJ, Greenland S, Kopple JD. Reverse epidemiology of hypertension and cardiovascular death in the hemodialysis population: The 58th annual fall conference and scientific sessions. Hypertension. 2005;45:811–817
  17. Kovesdy CP, Trivedi BK, Kalantar-Zadeh K, Anderson JE. Association of anemia with outcomes in men with moderate and severe chronic kidney disease. Kidney Int. 2006;69:560–564
  18. Barany P, Divino Filho JC, Bergstrom J. High C-reactive protein is a strong predictor of resistance to erythropoietin in hemodialysis patients. Am J Kidney Dis. 1997;29:565–568
  19. Kalantar-Zadeh K, McAllister CJ, Lehn RS, Lee GH, Nissenson AR, Kopple JD. Effect of malnutrition-inflammation complex syndrome on EPO hyporesponsiveness in maintenance hemodialysis patients. Am J Kidney Dis. 2003;42:761–773
  20. Gunnell J, Yeun JY, Depner TA, Kaysen GA. Acute-phase response predicts erythropoietin resistance in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis. 1999;33:63–72
  21. Longenecker JC, Coresh J, Klag MJ, et al. Validation of comorbid conditions on the end-stage renal disease medical evidence report: The CHOICE Study (Choices for Healthy Outcomes in Caring for ESRD). J Am Soc Nephrol. 2000;11:520–529
  22. Kalantar-Zadeh K, Kopple JD, Kilpatrick RD, et al. Association of morbid obesity and weight change over time with cardiovascular survival in hemodialysis population. Am J Kidney Dis. 2005;46:489–500
  23. Kalantar-Zadeh K, Kilpatrick RD, Kuwae N, et al. Revisiting mortality predictability of serum albumin in the dialysis population: Time dependency, longitudinal changes and population-attributable fraction. Nephrol Dial Transplant. 2005;20:1880–1889
  24. Nather A, Mayerhofer K, Grimm C, et al. Thrombocytosis and anaemia in women with recurrent ovarian cancer prior to a second-line chemotherapy. Anticancer Res. 2003;23:2991–2994
  25. Hefler L, Mayerhofer K, Leibman B, et al. Tumor anemia and thrombocytosis in patients with vulvar cancer. Tumour Biol. 2000;21:309–314
  26. Valentini G, Chianese U, Tirri G, Giordano M. Thrombocytosis in progressive generalized sclerosis (scleroderma) and in other rheumatic diseases. Z Rheumatol. 1978;37:233–241
  27. Rodriguez GC, Clarke-Pearson DL, Soper JT, Berchuck A, Synan I, Dodge RK. The negative prognostic implications of thrombocytosis in women with stage IB cervical cancer. Obstet Gynecol. 1994;83:445–448
  28. Sokunbi DO, Wadhwa NK, Suh H. Vascular disease outcome and thrombocytosis in diabetic and nondiabetic end-stage renal disease patients on peritoneal dialysis. Adv Perit Dial. 1994;10:77–80
  29. Dominguez I, Crippa S, Thayer SP, et al. Preoperative platelet count and survival prognosis in resected pancreatic ductal adenocarcinoma. Ann Surg. 2008;247:571–579
  30. Gross S, Keefer V, Newman AJ. The platelets in iron-deficiency anemia (I. The response to oral and parenteral iron). Pediatrics. 1964;34:315–323
  31. Dahl NV, Henry DH, Coyne DW. Thrombosis with erythropoietic stimulating agents—Does iron-deficient erythropoiesis play a role?. Semin Dial. 2008;21:210–211
  32. Franchini M. Platelet count increase following phlebotomy in iron overloaded patients with liver cirrhosis. Hematology. 2003;8:259–262
  33. Tekin D, Yavuzer S, Tekin M, Akar N, Cin S. Possible effects of antioxidant status on increased platelet aggregation in childhood iron-deficiency anemia. Pediatr Int. 2001;43:74–77
  34. Kurekci AE, Atay AA, Sarici SU, Zeybek C, Koseoglu V, Ozcan O. Effect of iron therapy on the whole blood platelet aggregation in infants with iron deficiency anemia. Thromb Res. 2000;97:281–285
  35. Sidi Y, Douer D, Krugliac J, Pinkhas J. Platelet aggregation and adhesiveness in severe iron deficiency due to menorrhage. New Istanbul Contrib Clin Sci. 1978;12:161–165
  36. Youdim MB, Woods HF, Mitchell B, Grahame-Smith DG, Callender S. Human platelet monoamine oxidase activity in iron-deficiency anaemia. Clin Sci Mol Med. 1975;48:289–295
  37. Coyne DW, Kapoian T, Suki W, et al. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: Results of the Dialysis Patients' Response to IV Iron with Elevated Ferritin (DRIVE) Study. J Am Soc Nephrol. 2007;18:975–984
  38. Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant human erythropoietin in anemic patients with end-stage renal disease (Results of a phase III multicenter clinical trial). Ann Intern Med. 1989;111:992–1000
  39. Beguin Y, Loo M, R'Zik S, et al. Effect of recombinant human erythropoietin on platelets in patients with anemia of renal failure: Correlation of platelet count with erythropoietic activity and iron parameters. Eur J Haematol. 1994;53:265–270
  40. Loo M, Beguin Y. The effect of recombinant human erythropoietin on platelet counts is strongly modulated by the adequacy of iron supply. Blood. 1999;93:3286–3293
  41. Murray MJ, Murray AB, Murray MB, Murray CJ. The adverse effect of iron repletion on the course of certain infections. Br Med J. 1978;2:1113–1115

 Originally published online as doi:10.1053/j.ajkd.2008.05.029 on September 2, 2008.

PII: S0272-6386(08)01005-6

doi: 10.1053/j.ajkd.2008.05.029

American Journal of Kidney Diseases
Volume 52, Issue 4 , Pages 727-736 , October 2008