ESA Hyporesponsiveness Is Associated with Adverse Events in Maintenance Hemodialysis (MHD) Patients, But Not with Iron Storage.

Takahiro Kuragano,Akihiko Matsuda,Hideyasu Kiyomoto,Hiroki Hase,Toshiaki Murata,Toru Inoue,Atushi Fukatsu,Shouichi Fujimoto,Yukihiro Itakura,Takeshi Nakanishi,Taiga Hara,Nobuhiko Joki,Osamu Matsumura,Kenichiro Kitamura,Hideharu Abe

doi:10.1371/journal.pone.0147328

Abstract

ObjectiveIt has been reported that hyporesponsiveness to erythropoiesis-stimulating agent (ESA) is associated with adverse events in patients on maintenance hemodialysis (MHD). However, it has not been determined whether higher iron storage is associated with an improved response, including better survival, to ESA.Design and MethodWe measured serum ferritin, hemoglobin (Hb), and transferrin saturation (TSAT) levels every three months for two years in 1,095 MHD patients. The weekly dose of ESA to Hb ratio was also calculated as an index of ESA responsiveness (ERI).ResultsA significant correlation (p<0.001, R = 0.89) between ferritin and Hb was only observed in the patients with ferritin levels <50 ng/mL. High-dose (≥50 mg/week) intravenous iron administration, female sex, low serum albumin, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were significant predictors of a high ERI value (>280); however, serum ferritin and TSAT levels did not predict a higher ERI. In the time-dependent Cox hazard model, the risk for a composite event in the patients with a high ERI (≥280) and a high ferritin level (≥100 ng/mL) was significantly greater (hazard ratio [HR], 2.09, P = 0.033) than that for patients with a high ERI and a low ferritin (<100 ng/mL) level.ConclusionHb was dependent upon ferritin levels in patients with ferritin levels <50 ng/mL but not in patients with ferritin levels ≥50 ng/mL. Patients with hyporesponsiveness to ESA had a greater risk of composite events, but ERI was unrelated to iron storage.

Highlights

Several studies have demonstrated an association between hyporesponsiveness to erythropoiesis-stimulating agents (ESA) and poor clinical outcomes, such as increased cardiovascular morbidity, faster progression to end stage kidney disease and allcause mortality [1,2,3,4]
Patients with hyporesponsiveness to ESA had a greater risk of composite events, but erythropoietin resistance index (ERI) was unrelated to iron storage
We performed a secondary analysis of the patients enrolled in the TRAP study in which we evaluated the relationships among ESA responsiveness, iron storage capacity, and adverse events in maintenance hemodialysis (MHD) patients

Summary

Introduction

Several studies have demonstrated an association between hyporesponsiveness (i.e., resistance) to erythropoiesis-stimulating agents (ESA) and poor clinical outcomes, such as increased cardiovascular morbidity, faster progression to end stage kidney disease and allcause mortality [1,2,3,4]. It has been long demonstrated that the factors affecting ESA hyporesponsiveness and the subsequent need for higher doses of ESA include iron deficiency, chronic hyperparathyroidism, low serum albumin, elevated aluminum level, malnutrition, suboptimal dialysis, and medications, such as angiotensin-converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB) and statins [6,7]. The Dialysis Patients’ Response to Intravenous Iron with Elevated Ferritin (DRIVE) study [9] reported that even in patients with high serum ferritin levels (>800 ng/mL), administration of ferric gluconate reduced the required ESA dose These authors suggested that in the presence of hyporesponsiveness to ESA and repleted iron storage, a higher dose of intravenous iron could overcome functional iron deficiency. In MHD patients with repleted iron storage, it has not been determined whether reducing the dose of ESA, along with a prolonged therapy of high dose intravenous iron therapy, is associated with better survival

Methods

Results

Conclusion