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Pretransplantation erythropoiesis-stimulating agent hyporesponsiveness is associated with increased kidney allograft failure and mortality.

ABSTRACT: Poor response to erythropoiesis-stimulating agents (ESA) is associated with morbidity and mortality among dialysis patients. It is unclear whether the risk associated with poor ESA response during dialysis extends beyond kidney transplantation. We examined pretransplantation ESA response and its effect on allograft failure and mortality.The cohort included all adult Medicare recipients from the U.S. Renal Data System who had received a kidney transplant during years 2000 to 2007 and had at least 6 months of hemodialysis immediately before transplantation. ESA hyporesponsiveness was primarily defined as a monthly ESA dose of 75,000 units or higher and hematocrit 33% or less for at least 3 consecutive months in the pretransplantation period. Crude and adjusted Cox proportional hazards models and Kaplan-Meier methods were used to estimate the effect of ESA hyporesponsiveness on allograft failure and all-cause mortality.The study group consisted of 36,450 patients; 1004 exhibited hyporesponsiveness. The adjusted hazard ratios (95% confidence interval) for allograft failure and mortality after transplantation were 1.23 (1.10-1.42) and 1.61 (1.43-1.81), respectively, supporting that poor ESA response during hemodialysis is associated with adverse posttransplantation outcomes.ESA hyporesponsiveness may be useful in identifying potential allograft recipients who are at high risk for subsequent morbidity and mortality and may benefit from more intensive pretransplantation and posttransplantation monitoring.

SUBMITTER: Costa NA

PROVIDER: S-EPMC4089212 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Pretransplantation erythropoiesis-stimulating agent hyporesponsiveness is associated with increased kidney allograft failure and mortality.

Costa Nadiesda A NA Kshirsagar Abhijit V AV Wang Lily L Detwiler Randal K RK Brookhart M Alan MA

Transplantation 20131101 9

<h4>Background</h4>Poor response to erythropoiesis-stimulating agents (ESA) is associated with morbidity and mortality among dialysis patients. It is unclear whether the risk associated with poor ESA response during dialysis extends beyond kidney transplantation. We examined pretransplantation ESA response and its effect on allograft failure and mortality.<h4>Methods</h4>The cohort included all adult Medicare recipients from the U.S. Renal Data System who had received a kidney transplant during ...[more]

PMID: 23982339

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Project description:Rationale & objectiveSince the change in erythropoiesis-stimulating agent (ESA) labeling and bundling of dialysis services in the United States, few studies have addressed the clinical importance of ESA hyporesponsiveness and none have considered health care resource use in this population. We aimed to further explore ESA hyporesponsiveness and its consequences.Study designRetrospective observational cohort study.Setting & participantsUS Renal Data System Medicare participants receiving dialysis with a minimum 6 months of continuous ESA use from 2012 to 2014.PredictorsErythropoietin resistance index (≥2.0 U/kg/wk/g/L) and ESA dose were used to identify ESA hyporesponders and hyporesponsive subgroups: isolated, intermittent, and chronic.OutcomesAssociations between ESA responsiveness and mortality, cardiovascular hospitalization rates, and health care resource use were evaluated and compared across subgroups.Analytical approachBaseline characteristics were compared using Wilcoxon rank sum tests for continuous variables and χ2 tests for categorical variables. Incidence rates of health care resource use were modeled using an unadjusted and adjusted generalized linear model.ResultsOf 834,115 dialysis patients in the CROWNWeb database, 38,891 ESA hyporesponders and 59,412 normoresponders met all inclusion criteria. Compared with normoresponders, hyporesponders were younger women, weighed less, and had longer durations of dialysis (all P < 0.001). Hyporesponders received 3.8-fold higher ESA doses (mean, 94,831 U/mo) and erythropoietin resistance index was almost 5 times higher than in normoresponders. Hyporesponders had lower hemoglobin levels and parathyroid hormone levels > 800 pg/mL, and iron deficiency was present in 26.5% versus 10.9% in normoresponders. One-year mortality was higher among hypo- compared with normoresponders (25.3% vs 22.6%). Hyporesponders also had significantly higher rates of hospitalization for cardiovascular events, emergency department visits, inpatient stays, home health agency visits, skilled nursing facility, and hospice days.LimitationsOnly US Medicare patients were included and different hyporesponder definitions may have influenced the results.ConclusionsThis study explored ESA hyporesponsiveness using new definitions and incorporated clinical and economic outcomes. It established that ESA-hyporesponsive dialysis patients had higher mortality, cardiovascular hospitalization rates, and health care costs as compared with ESA-normoresponsive patients.

Project description:BackgroundEvidences 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.MethodsDuring 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.ResultsIn 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.ConclusionsThe 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.

Project description:BackgroundEpoetin alfa and darbepoetin alfa are erythropoiesis-stimulating agents (ESAs) indicated for the treatment of anemia in chronic renal failure, including patients on dialysis and patients not on dialysis. Clinical experience demonstrates that the dose conversion ratio (DCR) between epoetin alfa and darbepoetin alfa is nonproportional across the dosing spectrum. However, previous calculations of the dose relationship between epoetin alfa and darbepoetin alfa, described in previous work as the "dose ratio" (DR), (a) used cross-sectional designs (i.e., compared mean doses for patient groups using each ESA) and were therefore vulnerable to confounding or (b) did not adjust for the nonproportional dose relationship. DRs reported in the literature range from 217:1 to 287:1 epoetin alfa (Units [U]):darbepoetin alfa (micrograms [micrograms]). Payers may need a single DCR that accounts for the nonproportional dose relationship to evaluate the economic implications of converting a nondialyzed patient population with chronic kidney disease (CKD) from epoetin alfa to darbepoetin alfa.ObjectiveTo estimate a single mean maintenance DCR between epoetin alfa and darbepoetin alfa in subjects with CKD not receiving dialysis, using methods that take into account the nonproportional dose relationship between the 2 ESAs.MethodsThis was a post-hoc analysis of a subset of patients enrolled in an unpublished, open-label, single arm phase 3 clinical trial (ClinTrial. gov identifier NCT00093977) that was completed in 2006. Although the clinical trial enrolled both dialyzed and nondialyzed patients, the present study used a patient subset comprising nondialyzed patients with CKD previously receiving weekly or every-other-week (Q2W) epoetin alfa who were switched to Q2W darbepoetin alfa to maintain hemoglobin (Hb) levels between 11.0 and 13.0 grams per deciliter. A population mean DCR was estimated using 2 methods: (a) a regression-based method in which the log-transformed (natural logarithm) mean weekly darbepoetin alfa dose over the evaluation period of the study (weeks 25 to 33) was regressed on the log-transformed (natural logarithm) weekly epoetin alfa dose over the 2-week screening period; and (b) a mean ratio method in which the DCR was calculated for each individual patient and then averaged for the study population to give a population-level DCR. Sensitivity analyses estimated the DCR in various subgroups.ResultsOf 1,127 patients enrolled in clinical trial NCT00093977, 567 patients on dialysis were excluded. Of the remaining 560 patients, 104 received weekly or Q2W epoetin alfa, were switched to Q2W darbepoetin alfa, received at least 1 non-zero dose of darbepoetin alfa during the evaluation period, and were included in the DCR calculation for the present study. Analysis of the log-log plot for the regression-based method indicated 2 or more possible regression lines with separate slopes. However, based on our a priori analysis plan to estimate a single DCR for the patient sample, the estimated sample mean maintenance DCR in the regression analysis was 330.6 U epoetin alfa to 1 micrograms darbepoetin alfa. In the mean ratio analysis, the DCR was 375.6 U:1 micrograms. Sensitivity analyses in which DCRs were calculated for different subgroups with different baseline differences identified a variable DCR range of 302-380 U:1 micrograms.ConclusionsThe methodology used in estimating the DCR accounts for the nonproportional dose relationship between epoetin alfa and darbepoetin alfa and may represent an advance over the methods used in previous research. The mean maintenance DCR between the 2 ESAs exceeds a threshold of 300 U:1 micrograms, which is greater than previously reported DRs. This methodology provides payers the means to compare ESA doses in CKD patients not receiving dialysis.

Dataset Information

Pretransplantation erythropoiesis-stimulating agent hyporesponsiveness is associated with increased kidney allograft failure and mortality.

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Pretransplantation erythropoiesis-stimulating agent hyporesponsiveness is associated with increased kidney allograft failure and mortality.

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