Background: Hemodialysis (HD) patients occasionally experience minor asymptomatic elevation in C-reactive protein (CRP) levels, which may be associated with difficulty in managing renal anemia using erythropoiesis-stimulating agents (ESAs). Here, we assessed whether elevation of CRP predicts future incidences of ESA hyporesponsiveness. Methods: A total of 2,956 HD patients lacking ESA hyporesponsiveness and infectious diseases were enrolled, and the association between CRP levels and incidence of ESA hyporesponsiveness was assessed. CRP levels were divided into 4 categories (normal [<1.0 mg/l], mild [1.0≤ CRP <3.0 mg/l], moderate [3.0≤ CRP <10.0 mg/l] and high [≥10.0 mg/l]). The primary outcome was the cumulative incidence of ESA hyporesponsiveness, defined as a failure to achieve hemoglobin level ≥10 g/dl despite receiving high doses of ESAs (≥9,000 U/week recombinant human epoetin [rHuEPO]-α or rHuEPO-β and ≥60 μg/week darbepoetin-α) during 12 months of follow-up. Results: The cumulative incidence of ESA hyporesponsiveness was 134 (4.8%) occurrences over 4 months and 300 (12.4%) over 12 months. The elevated CRP groups had significantly higher incidence of ESA hyporesponsiveness over 4 months of follow-up than the normal reference group (adjusted relative risk [RR] 1.6, 95% CI 1.0-2.6 for moderate; adjusted RR 2.5, 95% CI 1.5-4.1 for high). Furthermore, the association remained consistent even over 12 months (adjusted RR 1.4, 95% CI 1.0-1.8 for moderate; adjusted RR 1.6, 95% CI 1.1-2.4 for high). Conclusions: Elevated CRP levels were associated with future incidence of ESA hyporesponsiveness from low-grade inflammation (3.0≤ CRP <10.0 mg/l).

Macdougall IC, Cooper AC: Erythropoietin resistance: the role of inflammation and pro-inflammatory cytokines. Nephrol Dial Transplant 2002;17(suppl 11):39-43.
Fukuma S, Yamaguchi T, Hashimoto S, Nakai S, Iseki K, Tsubakihara Y, Fukuhara S: 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.
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.
Weiss G, Goodnough LT: Anemia of chronic disease. N Engl J Med 2005;352:1011-1023.
Singh AK, Coyne DW, Shapiro W, Rizkala AR; DRIVE Study Group: Predictors of the response to treatment in anemic hemodialysis patients with high serum ferritin and low transferrin saturation. Kidney Int 2007;71:1163-1171.
Rattanasompattikul M, Molnar MZ, Zaritsky JJ, Hatamizadeh P, Jing J, Norris KC, Kovesdy CP, Kalantar-Zadeh K: Association of malnutrition-inflammation complex and responsiveness to erythropoiesis-stimulating agents in long-term hemodialysis patients. Nephrol Dial Transplant 2013;28:1936-1945.
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.
Icardi A, Paoletti E, De Nicola L, Mazzaferro S, Russo R, Cozzolino M: Renal anaemia and EPO hyporesponsiveness associated with vitamin D deficiency: the potential role of inflammation. Nephrol Dial Transplant 2013;28:1672-1679.
Mrug M, Stopka T, Julian BA, Prchal JF, Prchal JT: Angiotensin II stimulates proliferation of normal early erythroid progenitors. J Clin Invest 1997;100:2310-2314.
Bradbury BD, Critchlow CW, Weir MR, Stewart R, Krishnan M, Hakim RH: Impact of elevated C-reactive protein levels on erythropoiesis-stimulating agent (ESA) dose and responsiveness in hemodialysis patients. Nephrol Dial Transplant 2009;24:919-925.
Inrig JK, Bryskin SK, Patel UD, Arcasoy M, Szczech LA: Association between high-dose erythropoiesis-stimulating agents, inflammatory biomarkers, and soluble erythropoietin receptors. BMC Nephrol 2011;12:67.
He LP, Tang XY, Ling WH, Chen WQ, Chen YM: Early C-reactive protein in the prediction of long-term outcomes after acute coronary syndromes: a meta-analysis of longitudinal studies. Heart 2010;96:339-346.
Bazeley J, Bieber B, Li Y, Morgenstern H, de Sequera P, Combe C, Yamamoto H, Gallagher M, Port FK, Robinson BM: C-reactive protein and prediction of 1-year mortality in prevalent hemodialysis patients. Clin J Am Soc Nephrol 2011;6:2452-2461.
Ridker PM: Cardiology patient page. C-reactive protein: a simple test to help predict risk of heart attack and stroke. Circulation 2003;108:e81-e85.
Kawaguchi T, Tong L, Robinson BM, Sen A, Fukuhara S, Kurokawa K, Canaud B, Lameire N, Port FK, Pisoni RL: C-reactive protein and mortality in hemodialysis patients: the dialysis outcomes and practice patterns study (DOPPS). Nephron Clin Pract 2011;117:c167-c178.
K/DOQI Workgroup: K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am J Kidney Dis 2005;45(4 suppl 3):S1-S153.
Sitter T, Bergner A, Schiffl H: Dialysate related cytokine induction and response to recombinant human erythropoietin in haemodialysis patients. Nephrol Dial Transplant 2000;15:1207-1211.
Nassar GM, Fishbane S, Ayus JC: Occult infection of old nonfunctioning arteriovenous grafts: a novel cause of erythropoietin resistance and chronic inflammation in hemodialysis patients. Kidney Int Suppl 2002;80:49-54.
Chawla LS, Krishnan M: Causes and consequences of inflammation on anemia management in hemodialysis patients. Hemodial Int 2009;13:222-234.
Myers GL, Rifai N, Tracy RP, Roberts WL, Alexander RW, Biasucci LM, Catravas JD, Cole TG, Cooper GR, Khan BV, Kimberly MM, Stein EA, Taubert KA, Warnick GR, Waymack PP: CDC/AHA workshop on markers of inflammation and cardiovascular disease: application to clinical and public health practice: report from the laboratory science discussion group. Circulation 2004;110:e545-e549.
Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith SC Jr, Taubert K, Tracy RP, Vinicor F; Centers for Disease Control and Prevention; American Heart Association: Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the centers for disease control and prevention and the American heart association. Circulation 2003;107:499-511.
Kanwar M, Hashem M, Rosman H, Kamalakannan D, Cheema A, Ali A, Gardin J, Maciejko JJ: Usefulness of clinical evaluation, troponins, and C-reactive protein in predicting mortality among stable hemodialysis patients. Am J Cardiol 2006;98:1283-1287.
Johnson DW, Pollock CA, Macdougall IC: Erythropoiesis-stimulating agent hyporesponsiveness. Nephrology (Carlton) 2007;12:321-330.
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.
Babitt JL, Lin HY: Molecular mechanisms of hepcidin regulation: implications for the anemia of CKD. Am J Kidney Dis 2010;55:726-741.
Malyszko J, Mysliwiec M: Hepcidin in anemia and inflammation in chronic kidney disease. Kidney Blood Press Res 2007;30:15-30.
Haukoos JS, Newgard CD: Advanced statistics: missing data in clinical research - part 1: an introduction and conceptual framework. Acad Emerg Med 2007;14:662-668.
Myers WR: Handling missing data in clinial trials: an overview. Drug Inf J 2000;34:525-533.
Gamble C, Hollis S: Uncertainty method improved on best-worst case analysis in a binary meta-analysis. J Clin Epidemiol 2005;58:579-588.
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