Background: Evidence suggests hemodialysis (HD) patients with resistance to erythropoiesis-stimulating agents (ESA) have a higher mortality rate. We investigated the association between ESA responsiveness and mortality in our HD population. Methods: A prospective cohort study of chronic HD patients was conducted at Jyoban Hospital in Fukushima, Japan. We collected data on patient demographic factors, comorbidities, dialysis vintage, body weight, ESA dose and hemoglobin concentration, as well as data on known risk factors for ESA hyporesponsiveness. The erythropoietin resistance index (ERI) was calculated by dividing the weekly body-weight-adjusted epoetin dose by the hemoglobin concentration. The association between ESA hyporesponsiveness estimated by the highest tertile of ERI and mortality was investigated by using the Cox proportional hazards model with adjustments for demographic factors, comorbidities, dialysis adequacy and serum biochemical data. Results: A total of 248 patients were included as subjects in the cohort, and their overall 2-year mortality rate was 13.3%. According to the results of the Kaplan-Meier analysis, patients with an ERI in the highest tertile had significantly higher mortality than patients with an ERI in the lower two tertiles (p = 0.0121). The highest ERI tertile was associated with higher all-cause mortality in both the unadjusted hazards model (hazard ratio, HR: 4.429; 95% CI: 1.249-15.704) and the adjusted hazards model (HR: 4.204; 95% CI: 1.173-15.065). Conclusions: A higher degree of resistance to ESA in chronic HD patients is associated with increased mortality.

Keywords:
Erythropoietin, Anemia, End-stage renal disease, Mortality , Hyporesponsiveness, Epoetin
1.
Eschbach JW, Egrie JC, Downing MR, 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;316:73-78.
2.
Macdougall IC, Cooper A: The inflammatory response and epoetin sensitivity. Nephrol Dial Transplant 2002;17(suppl 1):48-52.
3.
Zhang Y, Thamer M, Stefanik K, et al: Epoetin requirements predict mortality in hemodialysis patients. Am J Kidney Dis 2004;44:866-876.
4.
Kilpatrick R, Critchlow C, Fishbane S, et al: Greater epoetin alfa responsiveness is associated with improved survival in hemodialysis patients. Clin J Am Soc Nephrol 2008;3:1077-1083.
5.
Locatelli F, Pisoni R, Combe C, et al: 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.
6.
Robinson BM, Joffe MM, Berns JS, et al: Anemia and mortality in hemodialysis patients: accounting for morbidity and treatment variables updated over time. Kidney Int 2005;68:2323-2330.
7.
Johnson DW, Pollock CA, Macdougall IC: Erythropoiesis-stimulating agent hyporesponsiveness. Nephrology (Carlton) 2007;12:321-330.
8.
KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis 2006;47(suppl 3):S16-S145.
9.
Locatelli F, Aljama P, Bárány P; 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-ii47.
10.
Chung S, Song HC, Shin SJ, et al: Relationship between erythropoietin resistance index and left ventricular mass and function and cardiovascular events in patients on chronic hemodialysis. Hemodial Int 2012;16:181-187.
11.
Daugirdas JT: Second generation logarithmic estimates of single-pool variable volume Kt/V: an analysis of error. J Am Soc Nephrol 1993;4:1205-1213.
12.
Murao N, Ishigai M, Yasuno H, et al: Simple and sensitive quantification of bioactive peptides in biological matrices using liquid chromatography/selected reaction monitoring mass spectrometry coupled with trichloroacetic acid clean-up. Rapid Commun Mass Spectrom 2007;21:4033-4038.
13.
Tsubakihara Y, Nishi S, Akiba T, et al: 2008 Japanese Society for Dialysis Therapy: guidelines for renal anemia in chronic kidney disease. Ther Apher Dial 2010;14:240-275.
14.
Scott DS: Dose conversion from recombinant human erythropoietin to darbepoetin alfa: recommendation from clinical studies. Pharmacotherapy 2002;22:160S-165S.
15.
Kalantar-Zadeh K, Ikizler TA, Block G, Avram MM, Kopple JD: Malnutrition-inflammation complex syndrome in dialysis patients: causes and consequences. Am J Kidney Dis 2003;42:864-881.
16.
López-Gómez JM, Portolés JM, Aljama P: Factors that condition the response to erythropoietin in patients on hemodialysis and their relation mortality. Kidney Int Suppl 2008;111:S75-S81.
17.
Streja E, Kovesdy CP, Molnar MZ, et al. Role of nutritional status and inflammation in higher survival of African American and Hispanic hemodialysis patients. Am J Kidney Dis 2011;57:883-893.
18.
Movilli E, Cancarini GC, Zani R, et al: 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.
19.
Mallick S, Rafiroiu A, Kanthety R, et al: Factors predicting erythropoietin resistance among maintenance hemodialysis patients. Blood Purif 2012;33:238-244.
20.
Yilmaz MI, Solak Y, Covic A, Goldsmith D, Kanbay M: Renal anemia of inflammation: the name is self-explanatory. Blood Purif 2011;32:220-225.
21.
Coyne DW: Hepcidin: clinical utility as a diagnostic tool and therapeutic target. Kidney Int 2011;80:240-244.
22.
Kilpatrick RD, Critchlow CW, Fishbane S, et al: Greater epoetin alfa responsiveness is associated with improved survival in hemodialysis patients. Clin J Am Soc Nephrol 2008;3:1077-1083.
23.
Panichi V, Rosati A, Bigazzi R, et al: Anaemia and resistance to erythropoiesis-stimulating agents as prognostic factors in haemodialysis patients: results from the RISCAVID study. Nephrol Dial Transplant 2011;26:2641-2648.
24.
Fukuma S, Yamaguchi T, Hashimoto S, et al: Erythropoiesis-stimulating agent responsiveness and mortality in hemodialysis patients: results from a cohort study from the dialysis registry in Japan. Am J Kidney Dis 2012;59:108-116.
25.
Nishio A, Chhatkuli BP, Ma JZ, Kalantari K: Higher doses of erythropoietin-stimulating agents and hyporesponsiveness to their effects are associated with increased mortality among prevalent hemodialysis patients. Blood Purif 2013;36:29-36.
26.
Nakai S, Iseki K, Itami N, et al: An overview of regular dialysis treatment in Japan (as of 31 December 2010). Ther Apher Dial 2012;16:483-521.
© 2014 S. Karger AG, Basel
2014
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