American Journal of Kidney Diseases

Epoetin requirements predict mortality in hemodialysis patients

      Background: Anemia is a frequent complication of end-stage renal disease. Poor responsiveness to epoetin therapy hampers the management of anemia. Escalating epoetin doses often are used to overcome epoetin resistance. The objective of this study is to examine the relationship between epoetin dose requirements and mortality. Methods: Using United States Renal Data System administrative claims data, we conducted a retrospective cohort study of 94,569 prevalent hemodialysis patients in 2000 and 2001. A Cox proportional hazard regression analysis, adjusted for baseline variables, and a 5-knot cubic regression spline were used to model the dose-response relationship between epoetin and all-cause mortality. Results: Significant interpatient variation exists in epoetin dose requirements to attain defined hematocrit levels. For every hematocrit cohort studied, patients administered higher doses of epoetin had significantly lower hematocrit values and greater mortality rates. Using the cubic spline function, a significant nonlinear relationship between increased epoetin dose and mortality was found regardless of hematocrit (P < 0.0001), with the steepest increase in relative risk for death found after the 72.5th dose percentile. Conclusion: Epoetin dose requirement is an independent predictor of total mortality in hemodialysis patients after adjustment for hematocrit. Poor responders who continue to have low hematocrit values despite the administration of high epoetin doses may not necessarily benefit from more epoetin, but perhaps should be considered for other adjunctive therapies. In contrast to conventional wisdom, this study suggests that epoetin dosing requirements could provide important prognostic information beyond that predicted by hematocrit alone.

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        • Eschbach J.W.
        • Adamson J.W.
        Anaemia of end-stage renal disease (ESRD).
        Kidney Int. 1985; 28: 1-5
        • Coladonato J.A.
        • Frankenfield D.L.
        • Reddan D.N.
        • et al.
        Trends in anemia management among US hemodialysis patients.
        J Am Soc Nephrol. 2002; 13: 1288-1295
        • Adamson J.W.
        • Eschbach J.W.
        Management of the anaemia of chronic renal failure with recombinant erythropoietin.
        QJM. 1989; 73: 1093-1101
        • Eschbach J.W.
        • Abdulhadi M.H.
        • Browne J.K.
        • et al.
        Recombinant human erythropoietin in anemic patients with end-stage renal disease.
        Ann Intern Med. 1989; 111: 992-1000
        • Besarab A.
        • Bolton W.K.
        • Browne J.K.
        • 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
      1. US Renal Data System. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD2003
        • National Kidney Foundation
        K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease, Update 2000.
        Am J Kidney Dis. 2001; 37: S182-S238
        • Thamer M.
        • Richard C.M.
        • Klinkmann J.
        • Ivanovich P.
        • Lang G.
        • Cotter D.J.
        Use of clinical guidelines for treatment of anemia among hemodialysis patients.
        Artif Organs. 2000; 24: 91-94
        • Ma J.Z.
        • Ebben J.
        • Xia H.
        • Collins A.J.
        Hematocrit level and associated mortality in hemodialysis patients.
        J Am Soc Nephrol. 1999; 10: 610-619
        • Collins A.J.
        • Li S.
        • St Peter W.
        • et al.
        Death, hospitalization, and economic associations among incident hemodialysis patients with hematocrit values of 36 to 39%.
        J Am Soc Nephrol. 2001; 12: 2465-2473
        • Ofsthun N.
        • Labrecque J.
        • Lacson E.
        • Keen M.
        • Lazarus J.M.
        The effects of higher hemoglobin levels on mortality and hospitalization in hemodialysis patients.
        Kidney Int. 2003; 63: 1908-1914
        • Li S.
        • Collins A.J.
        Association of hematocrit value with cardiovascular morbidity and mortality in incident hemodialysis patients.
        Kidney Int. 2004; 65: 626-633
        • Fishbane S.
        Hyporesponsiveness to recombinant human erythropoietin in dialysis patients.
        Dial Transplant. 2000; 29: 545-581
        • Eschbach J.W.
        • Varma A.
        • Stivelman J.C.
        Is it time for a paradigm shift? Is erythropoietin deficiency still the main cause of renal anaemia?.
        Nephrol Dial Transplant. 2002; 17: S2-S7
        • Gunnell J.
        • Yeun J.Y.
        • Depner T.A.
        • Kaysen G.A.
        Acute-phase response predicts erythropoietin resistance in hemodialysis and peritoneal dialysis patients.
        Am J Kidney Dis. 1999; 33: 63-72
        • Ifudu O.
        • Feldman J.
        • Friedman E.A.
        The intensity of hemodialysis and the response to erythropoietin in patients with end-stage renal disease.
        N Engl J Med. 1996; 334: 420-425
        • Barany P.
        • Filho J.D.
        • 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
        • Kalantar-Zadeh K.
        • Kopple J.D.
        • Block G.
        • Humphreys M.H.
        A malnutrition-inflammation score is correlated with morbidity and mortality in maintenance hemodialysis patients.
        Am J Kidney Dis. 2001; 38: 1251-1263
        • Li S.
        • Foley R.N.
        • Gilbertson D.T.
        • Liu J.
        • Collins A.J.
        Clinical factors associated with achieving K/DOQI hemoglobin targets in hemodialysis patients.
        Int Urol Nephrol. 2003; 35: 399-405
        • Van Manen J.G.
        • Korevaar J.C.
        • Dekker F.W.
        • Boeschoten E.W.
        • Bossuyt P.M.M.
        • Krediet R.T.
        How to adjust for comorbidity in survival studies in ESRD patients.
        Am J Kidney Dis. 2002; 40: 82-89
        • Charlson M.E.
        • Pompei P.
        • Ales K.L.
        • MacKenzie C.R.
        A new method of classifying prognostic comorbidity in longitudinal studies.
        J Chronic Dis. 1987; 40: 373-383
        • Durrleman S.
        • Simon R.
        Flexible regression models with cubic splines.
        Stat Med. 1989; 8: 551-561
        • Heinzl H.
        • Kaider A.
        Gaining more flexibility in Cox proportional hazards regression models with cubic spline functions.
        Comput Methods Programs Biomed. 1997; 54: 201-208
        • Gordis L.
        in: ed 2. Saunders, Philadelphia, PA2000: 42-44
        • Eschbach J.W.
        Anemia management in chronic kidney disease.
        J Am Soc Nephrol. 2002; 13: 1412-1414
        • Cotter D.
        Does the evidence for anemia treatment support a survival benefit?.
        Arch Intern Med. 2003; 163: 2395-2396
        • Eschbach J.W.
        • Kelly M.R.
        • Haley N.R.
        • Abels R.I.
        • Adamson J.W.
        Treatment of the anemia of progressive renal failure with recombinant human erythropoietin.
        N Engl J Med. 1989; 321: 158-163
        • Tarng D.C.
        • Huang T.P.
        • Chen T.W.
        • Yang W.C.
        Erythropoietin hyporesponsiveness.
        Kidney Int Suppl. 1999; 69: S107-S118
        • Kalantar-Zadeh K.
        • McAllister C.J.
        • Lehn R.S.
        • Lee G.H.
        • Nissenson A.R.
        • Kopple J.D.
        Effect of malnutrition-inflammation complex syndrome on EPO hyporesponsiveness in maintenance hemodialysis patients.
        Am J Kidney Dis. 2003; 42: 761-773
        • Cotter D.J.
        • 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 (in press)
        • Vaziri N.D.
        Cardiovascular effects of erythropoietin and anemia correction.
        Curr Opin Nephrol Hypertens. 2001; 10: 633-637
      2. Epogen (epoetin alfa) Full Prescribing Information for Physicians. Amgen Inc, Thousand Oaks, CA1999
        • Eschbach J.W.
        • Egrie J.C.
        • Downing M.R.
        • Browne J.K.
        • Adamson J.W.
        Correction of the anemia of end-stage renal disease with recombinant human erythropoietin.
        N Engl J Med. 1987; 316: 73-78
        • Furuland J.
        • Linde T.
        • Ahlmen J.
        • Christensson A.
        • Strombom U.
        • Danielson B.G.
        A randomized controlled trial of haemoglobin normalization with epoetin alfa in pre-dialysis and dialysis patients.
        Nephrol Dial Transplant. 2003; 18: 353-361
        • Keven K.
        • Kutlay S.
        • Nergizoglu G.
        • Erturk S.
        Randomized, crossover study of the effect of vitamin C on EPO response in hemodialysis patients.
        Am J Kidney Dis. 2003; 41: 1233-1239
        • Eschbach J.W.
        • Glenny R.
        • Robertson T.
        • et al.
        Normalizing the hematocrit in hemodialysis patients with EPO improves quality of life and is safe.
        J Am Soc Nephrol. 1993; 4: 4
        • Foley R.N.
        • Parfrey P.S.
        • Morgan J.
        • et al.
        Effect of hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy.
        Kidney Int. 2000; 58: 1325-1335
        • Richardson D.
        Clinical factors influencing sensitivity and response to epoetin.
        Nephrol Dial Transplant. 2002; 17: S53-S59
        • Movilli E.
        • Cancarini G.C.
        • Vizzardi V.
        • et al.
        Epoetin requirement does not depend on dialysis dose when Kt/V > 1.33 in patients on regular dialysis treatment with cellulosic membranes and adequate iron stores.
        J Nephrol. 2003; 16: 546-551
        • Odabas A.R.
        • Cetinkaya R.
        • Selcuk Y.
        • Keles S.
        • Bilen H.
        The effect of high dose losartan on erythropoietin resistance in patients undergoing haemodialysis.
        Panminerva Med. 2003; 45: 59-62
        • Signorello L.B.
        • McLaughlin J.K.
        • Lipworth L.
        • Friis S.
        • Sorensen H.T.
        • Blot W.J.
        Confounding by indication in epidemiologic studies of commonly used analgesics.
        Am J Ther. 2002; 9: 199-205
        • Sehgal A.R.
        • Snow R.J.
        • Singer M.E.
        • et al.
        Barriers to adequate delivery of hemodialysis.
        Am J Kidney Dis. 1998; 31: 593-601
        • Kalantar-Zadeh K.
        • Kopple J.D.
        • Block G.
        • Humphreys M.H.
        Association among SF36 quality of life measures and nutrition, hospitalization, and mortality in hemodialysis.
        J Am Soc Nephrol. 2001; 12: 2797-2806

      Linked Article

      • In Reply
        American Journal of Kidney DiseasesVol. 51Issue 5
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          In our analysis,1 we sought to evaluate the sensitivity of previously reported epoetin alfa (EPO) dose-mortality associations2,3 to: (1) more comprehensive adjustment for confounding, and (2) use of time-dependent exposure and covariate measures. In these previous analyses,2,3 data on important confounding variables (eg, albumin) were unavailable, and cross-sectional exposure measures were evaluated, ignoring EPO dose changes over time.
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      • Relative Mortality and Epoetin Alfa Dose in Hemodialysis Patients
        American Journal of Kidney DiseasesVol. 51Issue 5
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          The paper by Bradbury et al1 confirms our previous findings indicating that time-dependent confounding between epoetin dose, achieved hematocrit, and level of sickness for individual patients exists and is complex. Similar to hematocrit, epoetin dose requirement has an important role and must be considered in models that predict patient mortality, as clearly shown in our analyses published in the Journal of Clinical Epidemiology2 and the American Journal of Kidney Diseases.3 We applaud the authors for considering exposure as a possible explanatory factor.
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      • Relative Mortality and Epoetin Alfa Dose Among Hemodialysis Patients
        American Journal of Kidney DiseasesVol. 51Issue 5
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          Bradbury et al1 found higher epoetin doses were associated with improved survival or a neutral effect using lagged time-dependent analyses, contrary to previous association studies2 and randomized trials.3,4 They report administered epoetin dose declines from approximately 21,000 units per week 8 weeks before death to approximately 8,000 units per week 3 weeks before death and attribute this to missed doses from hospitalization as they collected only in-center data. However, the increasing rate of missed doses cannot account for the dramatic decline.
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      • In Reply
        American Journal of Kidney DiseasesVol. 51Issue 5
        • Preview
          The purpose of our analysis1was to evaluate the sensitivity of previously reported epoetin alfa (EPO) dose-mortality associations2,3 from observational studies to comprehensive adjustment for confounding and time-varying assessments of EPO dose and hemoglobin levels. We observed marked changes in hazard ratio estimates versus previous analyses, suggesting that previous analyses2,3 were biased away from the null. We did not state that our results were definitive. Rather, we suggested that confounding needs to be better addressed in future observational studies of EPO dose and mortality.
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