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

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

doi:10.1371/journal.pone.0147328

Cited by 27 publications

(18 citation statements)

References 32 publications

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“…A recent study examined the relationship between iron markers, such as transferrin saturation and ferritin levels, and ESA responsiveness. Finding from the study highlighted that transferrin saturation, but not ferritin, was statistically associated to ESA hyporesponsiveness [20]. On the hand, in our study, transferrin saturation covariate was excluded from the analysis, due to the high proportion of missing values (> 50%).…”

Section: Discussionmentioning

confidence: 84%

In search of potential predictors of erythropoiesis-stimulating agents (ESAs) hyporesponsiveness: a population-based study

et al. 2019

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Background Evidences show that around 20% of biosimilar or originator erythropoiesis-stimulating agents (ESAs) users are hyporesponsive. Controversial post-marketing data exist on the predictors of ESA hyporesponsiveness. The aim of this study was to identify predictors of ESA hyporesponsiveness in patients with chronic kidney disease (CKD) or cancer in clinical practice. Methods During the years 2009–2015, a multi-center, population-based, cohort study was conducted using claims databases of Treviso and Caserta Local Health Units (LHUs). All incident ESA users were characterized at baseline and the differences between the baseline hemoglobin (Hb) value, that is the Hb registered within 30 days prior to the first ESA dispensing (index date, ID) and each outcome Hb value (registered between 30 and 180 days after ID) were calculated and defined as delta Hb (ΔHb). Incident ESA users were defined as hyporesponsive if, during follow-up, they registered at least one ΔHb < 0 g/dL. Including all potential predictors of ESA hyporesponsiveness and stratifying by indication for use, univariate and multivariate binary logistic regression models and Receiver Operating Characteristic (ROC) curves were carried out. Results `In general, 1080 incident ESA users (CKD: 57.0%; cancer: 43.0%) were identified. In CKD, predictors of ESA hyporesponsiveness were C-reactive protein (OR = 1.2, 95% CI: 1.0–1.5; P-value = 0.060) and high levels of baseline Hb (OR = 1.7, 95% CI: 1.2–2.2; P-value< 0,001), the latter being also predictor of ESA hyporesponsiveness in cancer (OR = 1.7, 95% CI: 1.1–2.4; P-value = 0.007). Both in CKD and in cancer, the type of ESA, biosimilar or originator, was not a predictor of ESA hyporesponsiveness. In CKD, concomitant use of iron preparations (OR = 0.3, 95% CI: 0.2–0.7; P-value = 0.002) and of high dosage of angiotensin-converting enzyme inhibitors/angiotensin II-receptor blockers (OR = 0.5, 95% CI: 0.3–0.9; P-value = 0.022) were protective factors against ESA hyporesponsiveness. Conclusions The study confirmed traditional potential predictors of hyporesponsiveness to ESA. The use of biosimilar or originator ESA was not a predictor of hyporesponsiveness in an outpatient setting from two large Italian areas. A better knowledge of the predictors of ESA response would allow a better anemia management to improve patients’ quality of life.

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Section: Discussionmentioning

confidence: 84%

In search of potential predictors of erythropoiesis-stimulating agents (ESAs) hyporesponsiveness: a population-based study

et al. 2019

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“…Although we did not evaluate hepcidin levels in this study, we have previously reported that serum hepcidin levels in MHD patient are significantly higher than those of healthy volunteers, and serum hepcidin in these patients was closely associated with serum ferritin levels [17]. Moreover, elevated serum hepcidin levels in chronic kidney disease patients (not on dialysis) with <TSAT 20% and ferritin levels �40 ng/mL have been reported [18]. Therefore, it is possible that serum hepcidin levels in patients with dysutalization iron for erythropoiesis might be higher than in other patient groups.…”

Section: Iron Utilization For Erythropoiesis and Adverse Events In Hmmentioning

confidence: 75%

“…The Drive study [7] reported that iron administration in patients with dysutilization of iron for erythropoiesis might attenuate the responsiveness to ESA and increase Hb levels. However, we have previously reported that, among patients with hyporesponsiveness to ESA and patients with higher ferritin level (>100 ng/mL), those treated with higher doses of intravenous iron showed a higher risk of composite events (e.g., CCVD, infection, hospitalization, and death) [18]. We recently demonstrated that a high risk of death and/or adverse events was associated with a consistently high ferritin level, large fluctuations in ferritin levels and high doses of intravenous iron [9] in MHD patients.…”

Section: Iron Administration In Patients With Dysutalization Of Iron mentioning

confidence: 92%

Low transferrin saturation (TSAT) and high ferritin levels are significant predictors for cerebrovascular and cardiovascular disease and death in maintenance hemodialysis patients

et al. 2020

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Patients with high serum ferritin and low transferrin saturation (TSAT) levels could be considered as presenting with dysutilization of iron for erythropoiesis. However, the long-term safety of iron administration in these patients has not been well established. An observational multicenter study was performed over 3 years. In 805 patients undergoing maintenance hemodialysis (MHD), we defined dysutilization of iron for erythropoiesis in patients with lower TSAT (<20%) and higher ferritin (�100 ng/mL) levels. A time-dependent Cox hazard model was used for the evaluation of the association between dysutilization of iron for erythropoiesis and adverse events and survival. Patients with low TSAT levels showed an increased risk of cerebrovascular and cardiovascular disease (CCVD) and death compared to patients with normal or higher TSAT levels. Patients with low ferritin and high TSAT levels had a significantly lower risk of CCVD and death compared with patients with high ferritin and low TSAT levels. Higher TSAT levels were associated with male gender, age, the absence of diabetes, low levels of high-sensitivity CRP, and low β2 microglobulin levels, but not with intravenous iron administration or ferritin levels. Although patients with low TSAT levels had a significantly higher risk of CCVD or death, high TSAT levels were not linked with iron administration. Patients, who were suspected of dysutilization of iron for erythropoiesis, had a higher risk of CCVD and death. The administration of iron should be performed cautiously for improving TSAT levels, as iron administration could sustain TSAT levels for a short term.

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“…Several studies have demonstrated an association between EPO hyporesponsiveness and poor clinical outcomes, such as anemia, heart failure, and increased cardiovascular and all-cause mortality [11, 12]. The ERI is a sensitive evaluation index of EPO responsiveness and can predict composite events (CVD, infection, hospitalization, or death) [13] and all-cause mortality in MHD patients [14, 15]. Our study demonstrated that ERI values were from 2.26 to 32.61 IU/week (g/dL) –1 /kg, and the mean ERI value was (12.67 ± 6.17) IU/week (g/dL) –1 /kg.…”

Section: Discussionmentioning

confidence: 99%

Association between Serum Magnesium and Erythropoietin Responsiveness in Hemodialysis Patients: A Cross-Sectional Study

Song

et al. 2019

Kidney Blood Press Res

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Background/Aims: As shown in the China Health and Nutrition Survey, serum magnesium is associated with anemia. However, the roles of magnesium in anemia and erythropoietin (EPO) responsiveness remain unclear in maintenance hemodialysis (MHD) patients. This study aims to investigate the level of serum magnesium and its relationship with EPO responsiveness in MHD patients. Methods: A total of 307 MHD patients were recruited for this survey. Laboratory data and anthropometrics were collected. EPO responsiveness was evaluated by the erythropoietin resistance index (ERI). The subjects were divided into 3 groups according to serum magnesium concentrations (group A, the lowest tertile; group B, the middle tertiles; and group C, the highest tertile). Multivariate logistic regressions were conducted to evaluate the factors that may be associated with EPO responsiveness. Results: The mean serum magnesium level was significantly higher than normal levels in MHD patients, while no hypomagnesemia was observed. A multivariate logistic regression model revealed that high-sensitivity C-reactive protein, intact parathyroid hormone, serum albumin, and magnesium levels were correlated with a high ERI. The OR of a high ERI was found to be 2.57 (95% CI 1.330–4.975, p = 0.005) for group A and 1.66 (95% CI 0.878––3.140, p > 0.05) for group B compared with the OR for group C. Conclusion: Serum magnesium levels were higher than normal levels in MHD patients. A high serum magnesium level was correlated with good EPO responsiveness and was therefore suggested to be a protective factor for EPO hyporesponsiveness.

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

Cited by 27 publications

References 32 publications

In search of potential predictors of erythropoiesis-stimulating agents (ESAs) hyporesponsiveness: a population-based study

In search of potential predictors of erythropoiesis-stimulating agents (ESAs) hyporesponsiveness: a population-based study

Low transferrin saturation (TSAT) and high ferritin levels are significant predictors for cerebrovascular and cardiovascular disease and death in maintenance hemodialysis patients

Association between Serum Magnesium and Erythropoietin Responsiveness in Hemodialysis Patients: A Cross-Sectional Study

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