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Controversies in Selection of Epoetin Dosages

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Epoetin (recombinant human erythropoietin) is now a widely available though expensive treatment for the anaemia of chronic renal failure, and is effective in more than 95% of patients. Complications of epoetin in this context include hypertension in a third of cases, including hypertensive encephalopathy in a few, and thrombosis of shunts or vascular access devices. Fears that epoetin would cause progression of renal failure have not generally been confirmed, but hyperkalaemia may be a problem in the initial phase of treatment. Epoetin is up to twice as effective when administered subcutaneously rather than intravenously. Responding patients will normally do so within 3 months of starting epoetin. Failures to respond are usually due to iron deficiency or intercurrent disease. Other diseases associated with anaemia and an inappropriately low serum epoetin level include prematurity, the anaemia of cancer and rheumatoid arthritis. The baseline serum endogenous erythropoietin may provide a guide to response in some of these cases. Some encouraging results are being published. Situations where the serum erythropoietin levels are normal or elevated where epoetin has been employed include boosting of haematocrit presurgery as an adjunct to autologous blood donation, treatment of anaemic patients with myelodysplastic syndromes, and improvement of athletic performances.

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References

  1. Goldberg MA, Dunning SP, Bunn HF. Regulation of the erythropoietin gene: evidence that oxygen sensor is a heme protein. Science 1988; 242: 1412–5.

    Article  PubMed  CAS  Google Scholar 

  2. Sawyer ST, Krantz SB, Sawada K. Receptors for erythropoietin in mouse and human erythroid cells and placenta. Blood 1989; 74: 103–9.

    PubMed  CAS  Google Scholar 

  3. Gregory CJ, Eaves AC. Three stages of erythropoietic cell differentiation distinguished by a number of physical and biological properties. Blood 1978; 51: 527–37.

    PubMed  CAS  Google Scholar 

  4. Eaves AC, Eaves CJ. Erythropoiesis in culture. Clin Haematol 1984; 13: 371–9.

    PubMed  CAS  Google Scholar 

  5. Spivak JL, Barnes DC, Fuchs E, et al. Serum immunoreactive erythropoietin in HIV-infected patients. JAMA 1989; 261: 3104–7.

    Article  PubMed  CAS  Google Scholar 

  6. Egrie JC, Eschbach JW, McGuire T, et al. Pharmacokinetics of recombinant human erythropoietin zadministered to hemodialysis patients. Pharmacokinetics of recombinant human erythropoietin (r-HuEPO) administered to hemodialysis (HD) patients. Kidney Int 1988; 33: 262.

    Google Scholar 

  7. Salmonson T, Danielson BG, Wikstrom B. Pharmacokinetics and pharmacodynamics of recombinant human erythropoietin after s.c. and I.V. administration [abstract]. XXVIth EDTA Congress: Gothenburg, Sweden; 1989: 210.

  8. Besarab A. Optimizing epoetin therapy in end-stage renal disease: the case for subcutaneous administration. Am J Kidney Dis 1993; 22: 13–22.

    PubMed  CAS  Google Scholar 

  9. Boelaert J, Schurgers M, Matthys E, et al. Recombinant human erythropoietin pharmacokinetics in CAPD patients: comparison of the intravenous, subcutaneous, andintraperitoneal routes. Nephrol Dial Transplant 1988; 3: 493.

    Google Scholar 

  10. Macdougall IC, Roberts DE, Neubert P, et al. Pharmacokinetics and pharmacodynamics of recombinant human erythropoietin in patients on continuous ambulatory peritoneal dialysis. Lancet 1989; 1: 425–7.

    Article  PubMed  CAS  Google Scholar 

  11. Eschbach JW, Egrie JC, Michael R, et al. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin; results of a combined phase I and II clinical trial. N Engl J Med 1987; 316: 73–8.

    Article  PubMed  CAS  Google Scholar 

  12. Eschbach JW, Adamson JW. Recombinant human erythropoietin: implications for nephrology. Am J Kidney Dis 1988; XI: 203–9.

    Google Scholar 

  13. Paganini EP, Miller T, Eschbach J, et al. A prospective randomized multicenter study of subcutaneous erythropoietin administration [abstract 54P]. J Am Soc Nephrol 1991; 2: 348.

    Google Scholar 

  14. Bommer J, Sambtleben W, Koch KM, et al. Variations of recombinant human erythropoietin application in hemodialysis patients. In: Baldamus CA, Scigalla P, Wieczorek L, et al., editors. Erythropoietin: from molecular structure to clinical application. Contrib Nephrol 1989; 76: 149–58.

    Google Scholar 

  15. Zehnder C, Blumberg A. Behandlung der Anämie von Hämodialysepatienten mit rekombinantem humanem Erythropoietin: Vergleich zwischen intravenöser und subkutaner Verabreichum. Schweiz Med Wochenschr 1990; 120: 217–20.

    PubMed  CAS  Google Scholar 

  16. Eschbach JW, Kelly MR, Haley, et al. Treatment of the anemia of progressive renal failure with recombinant human erythropoietin. N Engl J Med 1989; 321: 158–63.

    Article  PubMed  CAS  Google Scholar 

  17. Muirhead N, Churchill DN, Goldstein M, et al. Comparison of subcutaneous and intravenous recombinant human erythropoietin for anemia in hemodialysis patients with significant comorbid disease. Am J Nephrol 1992; 12: 303–10.

    Article  PubMed  CAS  Google Scholar 

  18. Zachée P, Van Rompuy W. Correcting the Anemia of end-stage renal failure with recombinant human erythropoietin (r-HuEPO); the Benelux experience. Erythropoiesis 1994; 5: 51–7.

    Google Scholar 

  19. Zachée P, Roba M, Daelemans R, et al. Recombinant human erythropoietin dosage requirements over the years. Nephrol Dial Transplant 1993; 8: 374–5.

    PubMed  Google Scholar 

  20. Eschbach JW, Abolukhadi MH, Browne JK. Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial. Ann Intern Med 1988; 111: 992–1000.

    Google Scholar 

  21. Rao DS, Shih M, Mohini R. Effect of serum parathyroid hormoneand bone marrow fibrosis on the response to erythropoietin in uremia. N Engl J Med 1993; 328: 171–5.

    Article  PubMed  CAS  Google Scholar 

  22. Zachée P, Chew SL, Daelemans R, et al. Erythropoietin resistance due to vitamin B12 deficiency. Am J Nephrol 1992; 12: 188–91.

    Article  PubMed  Google Scholar 

  23. Driieke TB. Resistance to recombinant human erythropoietin in hemodialysis patients. Am J Nephrol 1990; 10: 34–9.

    Article  Google Scholar 

  24. Koene RA, Frenken LA. Role of rHuEPO in treatment of uremic anemia prior to end-stage renal disease. Kidney Int 1992; Suppl. 38:S142.

  25. Lim VS, Kirchner PT, Fangman J, et al. The safety and efficacy of maintenance therapy of recombinant human erythropoietin in patients with renal insufficiency. Am J Kidney Dis 1989; 14: 496–506.

    PubMed  CAS  Google Scholar 

  26. Levin N, Lazarus JM, Nissenson AR. National cooperative rHu erythropoietin study in patients with chronic renal failure — an interim report. Am J Kidney Dis 1993; 22 Suppl. 1: 3.

    PubMed  CAS  Google Scholar 

  27. Muirhead N. Recombinant human erythropoietin patient dosing algorithm. Semin Nephrol 1990; 10 Suppl. 1: 59–65.

    PubMed  CAS  Google Scholar 

  28. Maier RF, Obladen M, Scigalla P, et al. The effect of epoietin beta (recombinant human erythropoietin) on the need for transfusion in very-low-birth-weight infants. N Engl J Med 1994; 330: 1173–8.

    Article  PubMed  CAS  Google Scholar 

  29. Shannon KM, Mentzer WC, Abels RI, et al. Enhancement of erythropoiesis by recombinant human erythropoietin in low birth weight infants: a pilot study. J Pediatr 1992; 120: 586–92.

    Article  PubMed  CAS  Google Scholar 

  30. Carnielli V, Montini G, Da Riol, et al. Effect of high doses of human recombinant erythropoietin on the need for blood transfusions in preterm infants. J Pediatr 1992; 121: 98–102.

    Article  PubMed  CAS  Google Scholar 

  31. American College of Physicians. Practice strategies for elective red blood cell transfusion. Ann Intern Med 1992; 116: 403–5.

    Google Scholar 

  32. Goodnough LT, Price TH, The EPO Study Group. A phase III trial of recombinant human erythropoietin therapy in nonanemic orthopedic patients subjected to aggressive autologous blood phlebotomy: dose, response, toxicity, and efficacy. Transfusion 1994; 34: 66–71.

    Article  PubMed  CAS  Google Scholar 

  33. Goodnough LT, Brittenham G. Limitations of the erythropoietic response to serial phlebotomy: implications for autologous blood donor programs. J Lab Clin Med 1990; 115: 28–35.

    PubMed  CAS  Google Scholar 

  34. Kickler TS, Spivak JL. Effect of repeated whole blood donations on serum immunoreactive erythropoietin levels in autologous donors. JAMA 1988; 260: 65–7.

    Article  PubMed  CAS  Google Scholar 

  35. Mercuriali F, Zanella A, Barosi G, et al. Use of erythropoietin to increase the volume of autologous blood donated by othopedic patients. Transfusion 1993; 33: 55–60.

    Article  PubMed  CAS  Google Scholar 

  36. Watanabe Y, Fuse K, Konishi T, et al. Autologous blood transfusion with recombinant human erythropoietin in heart surgery. Ann Thorac Surg 1992; 54: 479–84.

    Article  PubMed  CAS  Google Scholar 

  37. Biesma DH, Kraaijenhagen RJ, Marx JJM, et al. The efficacy of subcutaneous recombinant human erythropoietin in the correction of phebotomy-induced anemia in autologous blood donors, transfusion 1993; 33: 825–9.

    CAS  Google Scholar 

  38. Kyo S, Omoto R, Hirashima K, et al. Effect of human recombinant erythropoietin on reduction of homologous blood transfusion in open heart surgery: Japanese multi-center study. Circulation 1992; 86 Suppl. II: 413–8.

    Google Scholar 

  39. Levine EA, Gould SA, Rosen AL, et al. Perioperative recombinant human erythropoietin. Surgery 1989; 106: 432–8.

    PubMed  CAS  Google Scholar 

  40. Levine EA, Rosen AL, Sehgal LR, et al. Treatment of acute postoperative anemia with recombinant human erythropoietin. J Trauma 1989; 29: 1134–9.

    Article  PubMed  CAS  Google Scholar 

  41. Rothstein P, Roye D, Verdisco L, et al. Preoperative use of erythropoietin in an adolescent Jehovah’s witness. Anesthesiology 1990; 73: 568–70.

    Article  PubMed  CAS  Google Scholar 

  42. Anderson KE, Groeger DE, Carson RW, et al. Erythropoietin for the treatment of porphyria cutanea tarda in a patient on long-term hemodialysis. N Engl J Med 1990; 322: 315–7.

    Article  PubMed  CAS  Google Scholar 

  43. Hallenberg L, Magnusson B. The etiology of ‘sports anemia’. Acta Med Scand 1984; 216: 147–8.

    Google Scholar 

  44. Biesma DH, Kraaijenhagen RJ, Dalmulder J, et al. Recombinant human erythropoitin in autologous blood donors: a dosefinding study. Br J Haematol 1994; 86: 30–5.

    Article  PubMed  CAS  Google Scholar 

  45. Rutherford CJ, Schneider TJ, Dempsey H, et al. Efficacy of different dosing regimens for recombinant human erythropoietin in a simulated presurgical setting: the importance of iron availability in optimizing response. Am J Med 1994; 96: 139–45.

    Article  PubMed  CAS  Google Scholar 

  46. Brugnara C, Chambers LA, Malynn E, Golberg MA, Kruskall MS. Red blood cell regeneration induced by subcutaneous recombinant erythropoietin: iron-deficient erythropoiesis in iron-replete subjects. Blood 1993; 81: 956–64.

    PubMed  CAS  Google Scholar 

  47. Vreugdenhil G, Wognum AW, Van Eijk HG, et al. Anaemia in rheumatoid arthritis. The role of iron, vitamin B12 and folic deficiency and erythropoietin responsiveness. Ann Rheum Dis 1990; 49 (2): 93–8.

    Article  PubMed  CAS  Google Scholar 

  48. Miller CB, Jones RJ, Piantadosi S, et al. Decreased erythropoietin response in patients with anemia of cancer. N Engl J Med 1990; 322: 1689–92.

    Article  PubMed  CAS  Google Scholar 

  49. Spivak JL. Cancer-related anemia: its causes and characteristics. Semin Oncol 1994; 21: 3–8.

    PubMed  CAS  Google Scholar 

  50. Miller CB, Jones RJ, Zahurak ML, et al. Impaired erythropoietin response to anemia after bone marrow transplantation. Blood 1992; 80: 2677–82.

    PubMed  CAS  Google Scholar 

  51. Verhoef GEG, Zachée P, Ferrant A, et al. Recombinant human erythropoietin for the treatment of anemia in the myelodysplastic syndromes: a clinical and erythrokinetic assessment. Ann Hematol 1992; 64: 16–21.

    Article  PubMed  CAS  Google Scholar 

  52. Verhoef GEG, Zachée P, Demuynck H, et al. Measurements of serum cytokines levels in patients with myelodysplastic syndromes (MDS). Proceedings of the 24th Congress of the International Society of Haematology. Br J Haematol 1992: 362.

  53. Fischl M, Galpin JE, Levine JD, et al. Recombinant human erythropoietin for patients with AIDS treated with zidovudine. N Engl J Med 1990; 322: 1488–93.

    Article  PubMed  CAS  Google Scholar 

  54. Hellström E, Birgegard G, Carlsson M, et al. Treatment of myelodysplastic syndromes with a combination of granulocyte colony-stimulating factor and erythropoietin. In: Bauer C, Koch KM, Singalla P, et al., editors. Erythropoietin molecular physiology and clinical applications. New York: Marcel Dekker Inc., 1993: 331–46.

    Google Scholar 

  55. Bourantas K. High-dose recombinant human erythropoietin and low-dose coticosteroids for treatment of anemia in paroxysmal nocturnal hemoglobinuria. Acta Haematol 1994; 91: 62–5.

    Article  PubMed  CAS  Google Scholar 

  56. Cazzola M, Ponchio L, Beguin Y, et al. Subcutaneous erythropoietin for treatment of refractory anemia in hematologic disorders, results of a Phase I/II clinical trial. Blood 1992; 79: 29–37.

    PubMed  CAS  Google Scholar 

  57. Henry DH. Anaemia in AIDS patients: pathophysiology and therapy. Erythropoiesis 1991; 2: 87–99.

    Google Scholar 

  58. Henry DH. Recombinant human erythropoietin in the treatment of the anemia associated with solid tumors. In: Bauer C, Koch KM, Singalla P, et al., editors. Erythropoietin molecular physiology and clinical applications. New York: Marcel Dekker Inc., 1993: 293–8.

    Google Scholar 

  59. Henry DH, Abels RI. Recombinant erythropoietin in the treatment of cancer and chemotherapy-induced anemia: results of double-blind and open-label follow-up studies. Semin Oncol 1994; 21: 21–8.

    PubMed  CAS  Google Scholar 

  60. Kleasson S, Ringden O, Ljungan P, et al. Reduced blood transfusions requirements after allogeneic bone marrow transplantation: results of a randomised, double-blind study with highdose erythropoietin. Bone Marrow Transplant 1994; 13: 397–402.

    Google Scholar 

  61. Kurzrock R, Talpaz M, Gutterman JU. Very low doses of GM-CSF administered alone or with erythropoietin in aplastic anemia. Am J Med 1992; 93: 41–8.

    Article  PubMed  CAS  Google Scholar 

  62. Ludwig H, Fritz E, Leitgeb C, et al. Erythropoietin treatment for chronic anemia of selected hematological malignancies and solid tumors. Ann Oncol 1993; 4: 161–7.

    PubMed  CAS  Google Scholar 

  63. Miller CB, Mills SR. Anemia associated with cisplatin chemotherapy, In: Bauer C, Koch KM, Singalla P, et al., editors. Erythropoietin molecular physiology and clinical applications. New York: Marcel Dekker Inc., 1993: 299–308.

  64. Mittelman M, Lessin LS. Clinical application of recombinant erythropoietin in myelodysplasia [letter]. Hematol Oncol Clin North Am 1994; 8: 993.

    PubMed  CAS  Google Scholar 

  65. Pincus T, Olsen NJ, Russell J, et al. Multicenter study of recombinant human erythropoietin in correction of anemia in rheumatoid arthritis. Am J Med 1990; 89: 161–8.

    Article  PubMed  CAS  Google Scholar 

  66. Miller CB, Platanias LC, Mills SR, et al. Phase I-II trial of erythropoietin in the treatment of cisplatin-associated anemia. J Natl Cancer Inst 1992; 84: 98–103.

    Article  PubMed  CAS  Google Scholar 

  67. Oster W, Herrmann F, Gamm H, et al. Erythropoietin for treatment of anemia of malignancy associated with neoplastic bone marrow infiltration. J Clin Oncol 1990; 8: 956–62.

    PubMed  CAS  Google Scholar 

  68. Laporte JP, Woler M, Gorin NC, et al. Efficacy of recombinant human erythropoietin in the treatment of refractory anemias without excess of blasts in myelodysplastic syndromes. Leuk Lymphoma 1994; 12: 307–14.

    Article  PubMed  Google Scholar 

  69. Bessho M, Jinnai I, Matsuda A, et al. Improvement of anemia by recombinant erythropoitin in patients with myelodysplastic syndromes and aplastic anemia. Int J Cell Cloning 1990; 8: 445–58.

    Article  PubMed  CAS  Google Scholar 

  70. Yoshida Y, Anzai N, Kawabata H, et al. Serial changes in endogenous erythropoietin levels in patients with myelodysplastic syndromes and aplastic anemia undergoing erythropoietin treatment. Ann Hematol 1993; 66: 175–80.

    Google Scholar 

  71. Verhoef GEG, Demuynck H, Zachée P, et al. Treatment of myelodysplastic syndromes (MDS) with the combination of interleukin-3 and erythropoietin. Blood 1993; 82 SUPPL 1–377a.

    Google Scholar 

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  1. Division of Haematology, University of Leuven, Leuven, Belgium

    Pierre Zachée

  2. Division of Nephrology and Haematology, General Hospital Stuivenberg, Lange Beeldekenstraat 267, B-2060, Antwerp, Belgium

    Pierre Zachée

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Zachée, P. Controversies in Selection of Epoetin Dosages. Drugs 49, 536–547 (1995). https://doi.org/10.2165/00003495-199549040-00004

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