Association between high-dose erythropoiesis-stimulating agents, inflammatory biomarkers, and soluble erythropoietin receptors

<p>Abstract</p> <p>Background</p> <p>High-dose erythropoiesis-stimulating agents (ESA) for anemia of chronic kidney disease (CKD) have been associated with adverse clinical outcomes and do not always improve erythropoiesis. We hypothesized that high-dose ESA requirement would be associated with elevated inflammatory biomarkers, decreased adipokines, and increased circulating, endogenous soluble erythropoietin receptors (sEpoR).</p> <p>Methods</p> <p>A cross-sectional cohort of anemic 32 CKD participants receiving ESA were enrolled at a single center and cytokine profiles, adipokines, and sEpoR were compared between participants stratified by ESA dose requirement (usual-dose darbepoetin-α (< 1 μg/kg/week) and high-dose (≥1 μg/kg/week)).</p> <p>Results</p> <p>Baseline characteristics were similar between groups; however, hemoglobin was lower among participants on high-dose (1.4 μg/kg/week) vs usual-dose (0.5 μg/kg/week) ESA.</p> <p>In adjusted analyses, high-dose ESA was associated with an increased odds for elevations in c-reactive protein and interleukin-6 (p < 0.05 for both). There was no correlation between high-dose ESA and adipokines. Higher ESA dose correlated with higher levels of sEpoR (r_s= 0.39, p = 0.03). In adjusted analyses, higher ESA dose (per μcg/kg/week) was associated with a 53% greater odds of sEpoR being above the median (p < 0.05).</p> <p>Conclusion</p> <p>High-dose ESA requirement among anemic CKD participants was associated with elevated inflammatory biomarkers and higher levels of circulating sEpoR, an inhibitor of erythropoiesis. Further research confirming these findings is warranted.</p> <p>Trial registration</p> <p>Clinicaltrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00526747">NCT00526747</a></p

Secondary analysis of the choir trial epoetin-α dose and achieved hemoglobin outcomes

Trials of anemia correction in chronic kidney disease have found either no benefit or detrimental outcomes of higher targets. We did a secondary analysis of patients with chronic kidney disease enrolled in the Correction of Hemoglobin in the Outcomes in Renal Insufficiency trial to measure the potential for competing benefit and harm from achieved hemoglobin and epoetin dose trials. In the 4 month analysis, significantly more patients in the high-hemoglobin compared to the low-hemoglobin arm were unable to achieve target hemoglobin and required high-dose epoetin-alpha. In unadjusted analyses, the inability to achieve a target hemoglobin and high-dose epoetin-alpha were each significantly associated with increased risk of a primary endpoint (death, myocardial infarction, congestive heart failure or stroke). In adjusted models, high-dose epoetin-alpha was associated with a significant increased hazard of a primary endpoint but the risk associated with randomization to the high hemoglobin arm did not suggest a possible mediating effect of higher target via dose. Similar results were seen in the 9 month analysis. Our study demonstrates that patients achieving their target had better outcomes than those who did not; and among subjects who achieved their randomized target, no increased risk associated with the higher hemoglobin goal was detected. Prospective studies are needed to confirm this relationship and determine safe dosing algorithms for patients unable to achieve target hemoglobin

Effect of hemoglobin target on progression of kidney disease: a secondary analysis of the choir (correction of hemoglobin and outcomes in renal insufficiency) trial

BACKGROUND: Conflicting relationships have been described between anemia correction using erythropoiesis-stimulating agents (ESAs) and progression of chronic kidney disease (CKD). This study was undertaken to examine the impact of target hemoglobin on progression of kidney disease in the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) trial. STUDY DESIGN: Secondary analysis of a randomized controlled trial SETTING AND PARTICIPANTS: 1432 participants with CKD and anemia INTERVENTION: Participants were randomized to target hemoglobin of 13.5 vs 11.3 gm/dL with the use of epoetin-alfa. OUTCOMES AND MEASUREMENTS: Cox regression was used to estimate hazard ratios for progression of CKD (a composite of doubling of creatinine, initiation of renal replacement therapy (RRT), or death). Interactions between hemoglobin target and select baseline variables (estimated glomerular filtration rate (eGFR), proteinuria, diabetes, heart failure, and smoking history) were also examined. RESULTS: Participants randomized to higher hemoglobin targets experienced a shorter time to progression of kidney disease in both univariate (HR, 1.25; 95% CI, 1.03–1.52; p=0.02) and multivariable models (HR, 1.22; 95% CI, 1.00–1.48; p=0.05). These differences were attributable to higher rates of RRT and death among participants in the high hemoglobin arm. Hemoglobin target did not interact with eGFR, proteinuria, diabetes, or heart failure (p>0.05 for all). In the multivariable model, hemoglobin target interacted with tobacco use (p=0.04) such that the higher target had a greater risk of CKD progression among participants that currently smoked (HR, 2.50; 95% CI, 1.23–5.09; p=0.01) which was not present among those who did not currently smoke (HR, 1.15; 95% CI 0.93–1.41; p=0.2). LIMITATIONS: A post-hoc analysis and thus cause- effect cannot be determined. CONCLUSIONS: These results suggest that high hemoglobin target is associated with a greater risk of progression of CKD. This risk may be augmented by concurrent smoking. Further defining the mechanism of injury may provide insight into methods to optimize outcomes in anemia management