Timing-adjusted iron dosing enhances erythropoiesis-stimulating agent-induced erythropoiesis response and iron utilization
Tóm tắt
We recently demonstrated, using an index of recently synthesized hemoglobin, reticulocyte hemoglobin (Ret-Hb), that iron administration remarkably improves hemoglobin (Hb) synthesis during the period of high activation of erythropoiesis induced by the administration of a continuous erythropoietin receptor activator (CERA). We aimed to investigate whether repetition of iron dosing sustains effective erythropoiesis and suppresses iron storage. In a 3-month comparison of monthly CERA administration, 104 hemodialysis patients were randomized into two groups that received 40 mg iron intravenously 3 times; the first-week iron group [n = 51], given iron in the first week after CERA administration, during the period of high activation of erythropoiesis, and the third-week iron group [n = 53], given iron in the third week at the time of mild erythropoiesis activation. Initial mean CERA dosages were 123.5 ± 67.5 μg/month and did not differ between the groups. Hb levels were not different between the groups throughout the study. One-week increases in Ret-Hb levels after CERA administration were higher, during the first and the third month, in the group given iron in the first week compared with the third-week iron group (241.9 ± 63.3 vs. 196.2 ± 82.8 mg/dL, P = 0.004; 227.2 ± 83.5 vs. 187.9 ± 88.7 mg/dL, P = 0.037, respectively). The increase in ferritin levels was suppressed 3 months later in the first-week iron group compared with that of the third-week iron group (22.3 ± 64.0 vs. 69.0 ± 76.6 ng/mL, P = 0.002). Hepcidin levels decreased 1 week after CERA administration in both groups and were not different between the groups. Timing-adjusted iron administration increased the levels of recently produced Hb and iron utilization and suppressed the ferritin levels. The iron administration timing deserves consideration when optimizing the efficiency of erythropoiesis-stimulating agents in patients undergoing hemodialysis.
UMIN000016375
. Registered 29 January 2015.
Tài liệu tham khảo
Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE. The impact of anemia on cardiomyopathy, morbidity and mortality in end-stage renal disease. Am J Kidney Dis. 1996;28:53–61.
Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. 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.
López-Gómez JM, Portolés JM, Aljama P. Factors that condition the response to erythropoietin in patients on hemodialysis and their relation to mortality. Kidney Int Suppl. 2008;111:S75–81.
Fujikawa T, Ikeda Y, Fukuhara S, Akiba T, Akizawa T, Kurokawa K, Saito A. Time-dependent resistance to erythropoiesis-stimulating agent and mortality in hemodialysis patients in the Japan Dialysis Outcomes and Practice Patterns Study. Nephron Clin Pract. 2012;122(1-2):24–32.
Richardson D. Clinical factors influencing sensitivity and response to epoetin. Nephrol Dial Transplant. 2002;l7(Suppl):53–9.
Dru¨eke T. Hyporesponsiveness to recombinant human erythropoietin. Nephrol Dial Transplant. 2001;16:25–8.
Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int. 2012;2:279–335.
Locatelli F, Bárány P, Covic A, De Francisco A, Del Vecchio L, Goldsmith D, Hörl W, London G, Vanholder R, Van Biesen W, ERA-EDTA ERBP Advisory Board. Kidney Disease: Improving Global Outcomes guidelines on anaemia management in chronic kidney disease: a European Renal Best Practice position statement. Nephrol Dial Transplant. 2013;28(6):1346–59.
Tsubakihara Y, Nishi S, Akiba T, Hirakata H, Iseki K, Kubota M, Kuriyama S, Komatsu Y, Suzuki M, Nakai S, Hattori M, Babazono T, Hiramatsu M, Yamamoto H, Bessho M, Akizawa T. 2008 Japanese Society for Dialysis Therapy: guidelines for renal anemia in chronic kidney disease. Ther Apher Dial. 2010;14(3):240–75.
Brewster UC. Intravenous iron therapy in end-stage renal disease. Semin Dial. 2006;19(4):285–90.
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(10):3070–80.
Major A, Mathez–Loic F, Rohling R, Gautschi K, Brugnara C. The effect of intravenous iron on the reticulocyte response to recombinant human erythropoietin. Br J Haematol. 1997;98:292–4.
Kakimoto-Shino M, Toya Y, Kuji T, Fujikawa T, Umemura S. Changes in hepcidin and reticulocyte hemoglobin equivalent levels in response to continuous erythropoietin receptor activator administration in hemodialysis patients: a randomized study. Ther Apher Dial. 2014;18(5):421–6.
Kuji T, Toya Y, Fujikawa T, Kakimoto-Shino M, Nishihara M, Shibata K, Tamura K, Hirawa N, Satta H, Kawata S, Kouguchi N, Umemura S. Acceleration of iron utilization after intravenous iron administration during activated erythropoiesis in hemodialysis patients: a randomized study. Ther Apher Dial. 2015;19(2):131–7.
Thomas L, Franck S, Messinger M, Linssen J, Thome M, Thomas C. Reticulocyte hemoglobin measurement—comparison of two methods in the diagnosis of iron-restricted erythropoiesis. Clin Chem Lab Med. 2005;43:1193–202.
Fishbane S, Galgano C, Langley Jr RC, Canfield W, Maesaka JK. Reticulocyte hemoglobin content in the evaluation of iron status of hemodialysis patients. Kidney Int. 1997;52:217–22.
Goodnough LT, Skikne B, Brugnara C. Erythropoietin, iron, and erythropoiesis. Blood. 2000;96(3):823–33.
Besarab A, Kaiser JW. Frinak S A study of parenteral iron regimens in hemodialysis patients. Am J Kidney Dis. 1999;34(1):21–8.
Pai AB, Conner T, McQuade CR, Olp J, Hicks P. Non-transferrin bound iron, cytokine activation and intracellular reactive oxygen species generation in hemodialysis patients receiving intravenous iron dextran or iron sucrose. Biometals. 2011;24(4):603–13.
Nakanishi T, Kuragano T, Nanami M, Otaki Y, Nonoguchi H, Hasuike Y. Importance of ferritin for optimizing anemia therapy in chronic kidney disease. Am J Nephrol. 2010;32:439–46.
Locatelli F, Aljama P, Bárány P, Canaud B, Carrera F, Eckardt KU, Hörl WH, Macdougal IC, Macleod A, Wiecek A, Cameron S. European Best Practice Guidelines Working Group. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant. 2004;19(Suppl 2):ii1–47.
Ghoti H, Rachmilewitz EA, Simon-Lopez R, Gaber R, Katzir Z, Konen E, Kushnir T, Girelli D, Campostrini N, Fibach E, Goitein O. Evidence for tissue iron overload in long-term hemodialysis patients and the impact of withdrawing parenteral iron. Eur J Haematol. 2012;89(1):87–93.
Swinkels DW, Wetzels JF. Hepcidin: a new tool in the management of anaemia in patients with chronic kidney disease? Nephrol Dial Transplant. 2008;23(8):2450–3.