Short-Term Erythropoietin Treatment Does Not Substantially Modulate Monocyte Transcriptomes of Patients with Combined Heart and Renal Failure

Kim E Jie,Floor Pepers-De Kort,Yutaka Yasui,Pieter A Doevendans,Karien Van Der Putten,Marianne C Verhaar,Qi Liu,Jaap A Joles,Marloes W Bergevoet,Carlo A Gaillard,Branko Braam,Sebastiaan Wesseling

doi:10.1371/journal.pone.0041339

Abstract

BackgroundCombined heart and renal failure is associated with high cardiovascular morbidity and mortality. Anti-oxidant and anti-inflammatory, non-hematopoietic effects of erythropoietin (EPO) treatment have been proposed. Monocytes may act as biosensors of the systemic environment. We hypothesized that monocyte transcriptomes of patients with cardiorenal syndrome (CRS) reflect the pathophysiology of the CRS and respond to short-term EPO treatment at a recommended dose for treatment of renal anemia.MethodsPatients with CRS and anemia (n = 18) included in the EPOCARES trial were matched to healthy controls (n = 12). Patients were randomized to receive 50 IU/kg/week EPO or not. RNA from CD14+-monocytes was subjected to genome wide expression analysis (Illumina) at baseline and 18 days (3 EPO injections) after enrolment. Transcriptomes from patients were compared to healthy controls and effect of EPO treatment was evaluated within patients.ResultsIn CRS patients, expression of 471 genes, including inflammation and oxidative stress related genes was different from healthy controls. Cluster analysis did not separate patients from healthy controls. The 6 patients with the highest hsCRP levels had more differentially expressed genes than the 6 patients with the lowest hsCRP levels. Analysis of the variation in log2 ratios of all individual 18 patients indicated that 4 of the 18 patients were different from the controls, whereas the other 14 were quite similar. After short-term EPO treatment, every patient clustered to his or her own baseline transcriptome. Two week EPO administration only marginally affected expression profiles on average, however, individual gene responses were variable.ConclusionsIn stable, treated CRS patients with mild anemia, monocyte transcriptomes were modestly altered, and indicated imprints of inflammation and oxidative stress. EPO treatment with a fixed dose has hematopoietic effects, had no appreciable beneficial actions on monocyte transcription profiles, however, could also not be associated with undesirable transcriptional responses.

Highlights

Patients suffering from chronic heart failure (CHF) and concomitant renal failure have increased cardiovascular morbidity and mortality [1]
We have recently described that monocytes from chronic kidney disease (CKD) patients display increased expression of genes coding for suppressors of cytokine signaling proteins [20,21]
Study population characteristics Baseline characteristics of patients with cardiorenal syndrome (CRS) and anemia and age- and gender-matched controls are described in table 1

Summary

Introduction

Patients suffering from chronic heart failure (CHF) and concomitant renal failure have increased cardiovascular morbidity and mortality [1]. Patients have an increased risk for myocardial infarction with higher mortality compared to the general population [2]. This condition in which combined cardiac and renal dysfunction aggravates failure of the individual organs has been described as the cardiorenal syndrome (CRS) [3]. The pathophysiology of renal anemia includes an absolute and/or relative deficiency to erythropoietin (EPO) and a reduced sensitivity to EPO of red-cell lineages. Regarding the former, analogues of the human EPO are available to increase EPO levels. We hypothesized that monocyte transcriptomes of patients with cardiorenal syndrome (CRS) reflect the pathophysiology of the CRS and respond to short-term EPO treatment at a recommended dose for treatment of renal anemia

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Discussion

Conclusion