The impact of chronic kidney disease and short-term treatment with rosiglitazone on plasma cell-free DNA levels.

Amanda L Mcguire,Timothy J J Inglis,Nadia Urosevic,Doris T Chan,Gursharan Dogra,Aron Chakera

doi:10.1155/2014/643189

Abstract

Patients with chronic kidney disease (CKD) are at increased risk of cardiovascular disease. Circulating free nucleic acids, known as cell-free DNA (cfDNA), have been proposed as a novel biomarker of cardiovascular risk. The impact of renal impairment on cfDNA levels and whether cfDNA is associated with endothelial dysfunction and inflammation in CKD has not been systematically studied. We analysed cfDNA concentrations from patients with varying degrees of CKD. In addition, to determine whether there is a relationship between cfDNA, inflammation, and endothelial dysfunction in CKD, levels of proinflammatory cytokines and von Willebrand Factor (vWF) were measured in patients treated with the peroxisome proliferator-activated receptor gamma agonist rosiglitazone or placebo for 8 weeks. cfDNA levels were not increased with renal impairment or associated with the degree of renal dysfunction (P = 0.5). Treatment with rosiglitazone for 8 weeks, but not placebo, was more likely to lead to a reduction in cfDNA levels (P = 0.046); however, the absolute changes in cfDNA concentrations during treatment were not statistically significant (P > 0.05). cfDNA levels correlated with markers of endothelial dysfunction (hsCRP P = 0.0497) and vWF (P = 0.0005). In conclusion, cell-free DNA levels are not influenced by renal impairment but do reflect endothelial dysfunction in patients with CKD.

Highlights

Patients with renal impairment have an elevated risk of cardiovascular disease, which increases as renal function declines [1, 2]
We report the largest study to date analysing the effect of renal impairment on circulating cell-free DNA (cfDNA) levels and demonstrate that, even in the presence of advanced kidney disease, levels of cfDNA are equivalent to those reported in healthy controls and that apoptotic cfDNA fragments are not present
In the REVERT trial, short-term rosiglitazone therapy significantly lowered insulin resistance, high sensitivity C-reactive protein, and von Willebrand factor [15], suggesting that PPARγ agonists may reduce endothelial dysfunction in patients with chronic kidney disease (CKD). In keeping with this hypothesis, we demonstrated that patients who received rosiglitazone were more likely to show a decrease in cfDNA levels after 8 weeks than those who received placebo and that cfDNA levels correlated to levels of vWF and cfDNA, established markers of endothelial dysfunction [40, 41]

Summary

Introduction

Patients with renal impairment have an elevated risk of cardiovascular disease, which increases as renal function declines [1, 2]. As chronic kidney disease (CKD) is considered a proinflammatory state [12, 13], we hypothesised that cfDNA levels would be elevated in patients with renal impairment and PPAR Research that treatments that decreased endothelial dysfunction would reduce cfDNA levels. To answer these questions, we measured plasma cfDNA levels in 127 patients with a wide range of renal impairment (CKD stages 2–5) who participated in two randomized controlled trials that investigated vascular function and inflammation in patients with CKD [14, 15]. To determine if there was a link between cfDNA levels and endothelial dysfunction and inflammation in CKD [17,18,19,20], we measured concentrations of cfDNA and inflammatory cytokines in 70 patients treated with either placebo or the peroxisome proliferator-activated receptor gamma (PPARγ) agonist rosiglitazone for 8 weeks [15]

Methods

Results

Discussion

Conclusion