Background: Erythropoiesis-stimulating agent (ESA) resistance remains incompletely understood among hemodialysis (HD) patients. Method: A retrospective, multicenter study was designed to analyze data from 1,934 patients followed for up to two years. The outcome measure was the erythropoietin resistance index (ERI), defined as erythropoietin dosage over a week divided by the post-HD weight and hemoglobin value. Results: Multivariate analysis revealed albumin, Kt/V, transferrin saturation, statin use and male gender to be inversely related to ERI, whereas parathyroid hormone and angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) use were associated with higher ESA resistance. ERI was statistically lower in patients with higher levels of albumin (p < 0.001) and with higher transferrin saturation levels (p < 0.05). Discussion: The results allow for a better understanding of predictors of erythropoietin resistance among HD patients including not extensively studied factors such as statin and ACEI/ARB use.

1.
Eschbach JW: The anemia of chronic renal failure: pathophysiology and the effects of recombinant erythropoietin. Kidney Int 1989;35:134–148.
2.
Delano BG: Improvements in quality of life following treatment with r-huEPO in anemic hemodialysis patients. Am J Kidney Dis 1989;14:14–18.
3.
Macdougall IC: Poor response to erythropoietin: practical guidelines on investigation and management. Nephrol Dial Transplant 1995;10:607–614.
4.
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.
5.
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;316:73–78.
6.
Rao DS, Shih MS, Mohini R: Effect of serum parathyroid hormone and bone marrow fibrosis on the response to erythropoietin in uremia. N Engl J Med 1993;328:171–175.
7.
Besarab A, Amin N, Ahsan M, Vogel SE, Zazuwa G, Frinak S, Zazra JJ, Anandan JV, Gupta A: Optimization of epoetin therapy with intravenous iron therapy in hemodialysis patients. J Am Soc Nephrol 2000;11:530–538.
8.
Horl WH, Jacobs C, Macdougall IC, Valderrabano F, Parrondo I, Thompson K, Carveth BG: European best practice guidelines 14–16: inadequate response to epoetin. Nephrol Dial Transplant 2000;15 Suppl 4:43–50.
9.
Agarwal R, Davis JL, Smith L: Serum albumin is strongly associated with erythropoietin sensitivity in hemodialysis patients. Clin J Am Soc Nephrol 2008;3:98–104.
10.
Grutzmacher P, Ehmer B, Messinger D, Kulbe KD, Scigalla P: Effect of aluminum overload on the bone marrow response to recombinant human erythropoietin. Contrib Nephrol. Basel, Karger, 1989, vol 76, pp 315–321.
11.
Madore F, Lowrie EG, Brugnara C, Lew NL, Lazarus JM, Bridges K, Owen WF: Anemia in hemodialysis patients: variables affecting this outcome predictor. J Am Soc Nephrol 1997;8:1921–1929.
12.
Ifudu O, Feldman J, Friedman EA: The intensity of hemodialysis and the response to erythropoietin in patients with end-stage renal disease. N Engl J Med 1996;334:420–425.
13.
Bonnet J, McPherson R, Tedgui A, Simoneau D, Nozza A, Martineau P, Davignon J: Comparative effects of 10-mg versus 80-mg atorvastatin on high-sensitivity C-reactive protein in patients with stable coronary artery disease: results of the CAP (Comparative Atorvastatin Pleiotropic Effects) study. Clin Ther 2008;30:2298–2313.
14.
Chiang CK, Yang SY, Peng YS, Hsu SP, Pai MF, Huang JW, Hung KY, Wu KD: Atorvastatin increases erythropoietin-stimulating agent hyporesponsiveness in maintenance hemodialysis patients: role of anti-inflammation effects. Am J Nephrol 2009;29:392–397.
15.
Sirken G, Kung SC, Raja R: Decreased erythropoietin requirements in maintenance hemodialysis patients with statin therapy. ASAIO J 2003;49:422–425.
16.
Albitar S, Genin R, Fen-Chong M, Serveaux MO, Bourgeon B: High dose enalapril impairs the response to erythropoietin treatment in haemodialysis patients. Nephrol Dial Transplant 1998;13:1206–1210.
17.
Zhang Y, Thamer M, Stefanik K, Kaufman J, Cotter DJ: Epoetin requirements predict mortality in hemodialysis patients. Am J Kidney Dis 2004;44:866–876.
18.
Cotter DJ, Stefanik K, Zhang Y, Thamer M, Scharfstein D, Kaufman J: Hematocrit was not validated as a surrogate end point for survival among epoetin-treated hemodialysis patients. J Clin Epidemiol 2004;57:1086–1095.
19.
Kilpatrick RD, Critchlow CW, Fishbane S, Besarab A, Stehman-Breen C, Krishnan M, Bradbury BD: Greater epoetin alfa responsiveness is associated with improved survival in hemodialysis patients. Clin J Am Soc Nephrol 2008;3:1077–1083.
20.
Regidor DL, Kopple JD, Kovesdy CP, Kilpatrick RD, McAllister CJ, Aronovitz J, Greenland S, Kalantar-Zadeh K: Associations between changes in hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients. J Am Soc Nephrol 2006;17:1181–1191.
21.
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.
22.
Locatelli F, Pisoni RL, Combe C, Bommer J, Andreucci VE, Piera L, Greenwood R, Feldman HI, Port FK, Held PJ: Anaemia in haemodialysis patients of five European countries: association with morbidity and mortality in the dialysis outcomes and practice patterns study (DOPPS). Nephrol Dial Transplant 2004;19:121–132.
23.
Locatelli F, Conte F, Marcelli D: The impact of haematocrit levels and erythropoietin treatment on overall and cardiovascular mortality and morbidity – the experience of the Lombardy Dialysis Registry. Nephrol Dial Transplant 1998;13:1642–1644.
24.
Collins AJ, Li S, St Peter W, Ebben J, Roberts T, Ma JZ, Manning W: Death, hospitalization, and economic associations among incident hemodialysis patients with hematocrit values of 36 to 39%. J Am Soc Nephrol 2001;12:2465–2473.
25.
Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, Schwab SJ, Goodkin DA: 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.
26.
Szczech LA, Barnhart HX, Inrig JK, Reddan DN, Sapp S, Califf RM, Patel UD, Singh AK: Secondary analysis of the choir trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int 2008;74:791–798.
27.
Zhang Y, Thamer M, Cotter D, Kaufman J, Hernan MA: Estimated effect of epoetin dosage on survival among elderly hemodialysis patients in the United States. Clin J Am Soc Nephrol 2009;4:638–644.
28.
Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D: Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355:2085–2098.
29.
Drueke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A: Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006;355:2071–2084.
30.
Kaysen GA, Muller HG, Ding J, Chertow GM: Challenging the validity of the EPO index. Am J Kidney Dis 2006;47:166.
31.
Lopez-Gomez JM, Perez-Flores I, Jofre R, Carretero D, Rodriguez-Benitez P, Villaverde M, Perez-Garcia R, Nassar GM, Niembro E, Ayus JC: Presence of a failed kidney transplant in patients who are on hemodialysis is associated with chronic inflammatory state and erythropoietin resistance. J Am Soc Nephrol 2004;15:2494–2501.
32.
Lopez-Gomez JM, Portoles JM, Aljama P: Factors that condition the response to erythropoietin in patients on hemodialysis and their relation to mortality. Kidney Int Suppl 2008:S75–81.
33.
Ifudu O, Uribarri J, Rajwani I, Vlacich V, Reydel K, Delosreyes G, Friedman EA: Gender modulates responsiveness to recombinant erythropoietin. Am J Kidney Dis 2001;38:518–522.
34.
Reeves WB, Fairman RM, Haurani FI: Influence of hormones on the release of iron by macrophages. J Reticuloendothel Soc 1981;29:173–179.
35.
Deiss A: Iron metabolism in reticuloendothelial cells. Semin Hematol 1983;20:81–90.
36.
Funk DD: Plasma iron turnover in normal subjects. J Nucl Med 1970;11:107–111.
37.
Uchida T, Akitsuki T, Kimura H, Tanaka T, Matsuda S, Kariyone S: Relationship among plasma iron, plasma iron turnover, and reticuloendothelial iron release. Blood 1983;61:799–802.
38.
Locatelli F, Andrulli S, Memoli B, Maffei C, Del Vecchio L, Aterini S, De Simone W, Mandalari A, Brunori G, Amato M, Cianciaruso B, Zoccali C: Nutritional-inflammation status and resistance to erythropoietin therapy in haemodialysis patients. Nephrol Dial Transplant 2006;21:991–998.
39.
Tessitore N, Solero GP, Lippi G, Bassi A, Faccini GB, Bedogna V, Gammaro L, Brocco G, Restivo G, Bernich P, Lupo A, Maschio G: The role of iron status markers in predicting response to intravenous iron in haemodialysis patients on maintenance erythropoietin. Nephrol Dial Transplant 2001;16:1416–1423.
40.
NKF-DOQI Clinical Practice Guidelines for the Treatment of Anemia of Chronic Renal Failure: National kidney foundation-dialysis outcomes quality initiative. Am J Kidney Dis 1997;30:S192–240.
41.
Locatelli F, Aljama P, Barany P, Canaud B, Carrera F, Eckardt KU, Horl WH, Macdougal IC, Macleod A, Wiecek A, Cameron S: 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.
42.
KDOQI Clinical Practice Guideline and Clinical Practice Recommendations For Anemia in Chronic Kidney Disease: 2007 update of hemoglobin target. Am J Kidney Dis 2007;50:471–530.
43.
Kapoian T, O’Mara NB, Singh AK, Moran J, Rizkala AR, Geronemus R, Kopelman RC, Dahl NV, Coyne DW: Ferric gluconate reduces epoetin requirements in hemodialysis patients with elevated ferritin. J Am Soc Nephrol 2008;19:372–379.
44.
Movilli E, Cancarini GC, Zani R, Camerini C, Sandrini M, Maiorca R: Adequacy of dialysis reduces the doses of recombinant erythropoietin independently from the use of biocompatible membranes in haemodialysis patients. Nephrol Dial Transplant 2001;16:111–114.
45.
Ishani A, Weinhandl E, Zhao Z, Gilbertson DT, Collins AJ, Yusuf S, Herzog CA: Angiotensin-converting enzyme inhibitor as a risk factor for the development of anemia, and the impact of incident anemia on mortality in patients with left ventricular dysfunction. J Am Coll Cardiol 2005;45:391–399.
46.
Herrlin B, Nyquist O, Sylven C: Induction of a reduction in haemoglobin concentration by enalapril in stable, moderate heart failure: a double blind study. Br Heart J 1991;66:199–205.
47.
Sizeland PC, Bailey RR, Lynn KL, Robson RA: Anemia and angiotensin-converting enzyme inhibition in renal transplant recipients. J Cardiovasc Pharmacol 1990;16(suppl 7):S117–S119.
48.
Vlahakos DV, Canzanello VJ, Madaio MP, Madias NE: Enalapril-associated anemia in renal transplant recipients treated for hypertension. Am J Kidney Dis 1991;17:199–205.
49.
Hirakata H, Onoyama K, Hori K, Fujishima M: Participation of the renin-angiotensin system in the captopril-induced worsening of anemia in chronic hemodialysis patients. Clin Nephrol 1986;26:27–32.
50.
Gould AB, Goodman SA: Effect of an angiotensin-converting enzyme inhibitor on blood pressure and erythropoiesis in rats. Eur J Pharmacol 1990;181:225–234.
51.
Schwenk MH, Jumani AQ, Rosenberg CR, Kulogowski JE, Charytan C, Spinowitz BS: Potential angiotensin-converting enzyme inhibitor-epoetin alfa interaction in patients receiving chronic hemodialysis. Pharmacotherapy 1998;18:627–630.
52.
Cruz DN, Perazella MA, Abu-Alfa AK, Mahnensmith RL: Angiotensin-converting enzyme inhibitor therapy in chronic hemodialysis patients: any evidence of erythropoietin resistance? Am J Kidney Dis 1996;28:535–540.
53.
Conlon PJ, Albers F, Butterly D, Schwab SJ: ACE inhibitors do not affect erythropoietin efficacy in haemodialysis patients. Nephrol Dial Transplant 1994;9:1358.
54.
Erturk S, Ates K, Duman N, Karatan O, Erbay B, Ertug E: Unresponsiveness to recombinant human erythropoietin in haemodialysis patients: possible implications of angiotensin-converting enzyme inhibitors. Nephrol Dial Transplant 1996;11:396–397.
55.
Miller CB, Jones RJ, Piantadosi S, Abeloff MD, Spivak JL: Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med 1990;322:1689–1692.
56.
Gaweda AE, Goldsmith LJ, Brier ME, Aronoff GR: Iron, inflammation, dialysis adequacy, nutritional status, and hyperparathyroidism modify erythropoietic response. Clin J Am Soc Nephrol 2010;5:576–581.
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