Abstract

Introduction Oxidative stress (OS) has been associated with cardiovascular disease and adverse survival outcomes in chronic kidney disease and end-stage renal disease patients. In successful renal transplant recipients (RTR), OS remains exacerbated when compared to healthy controls, however, to date no study has assessed whether it may prospectively impact long-term survival. The current study aims to investigate whether the OS biomarker malondialdehyde (MDA) is prospectively associated with long-term risk of cardiovascular mortality in an extensively phenotyped cohort of stable RTR. Materials & Methods Prospective cohort study of stable RTR with a functioning allograft ≥1 year, recruited between 2001 and 2003 in a university setting. Plasma MDA was measured by thiobarbituric acid reaction assay. Associations of circulating MDA with cardiovascular mortality were assessed using Cox regression analyses in the overall RTR cohort and within subgroups of patients according to significant effect-modifiers. For all analyses IBM SPSS software version 23.0 was used. Results In 604 RTR (51±12 years-old, 55% male, at a median of 6.0 [interquartile range (IQR) 2.7– 11.5] years after transplantation), baseline median plasma MDA concentration was 5.38 [IQR, 4.31–6.45] μmol/L. During a median follow-up of 6.4 [IQR, 5.6–6.8] years, 110 (18%) RTR died, 44 (40%) deaths due to cardiovascular causes. An increase in one standard deviation of circulating MDA was positively associated with risk of cardiovascular mortality (hazard ratio [HR] 1.31, (95% confidence interval [95% CI] 1.03–1.67)). This association was independent of adjustment for potential confounders, including immunosuppressive therapy and traditional cardiovascular risk factors. In RTRs with a relatively low plasma vitamin C concentration (<42.5 μmol/L) or relatively low estimated glomerular filtration rate (<45 mL/min/1.73 m2), MDA was associated with a more than two-fold higher risk of cardiovascular mortality (HR 2.22 (95% CI 1.48–3.32), and HR 2.05 (95% CI 1.43–2.92), respectively). Conclusion Circulating MDA is independently associated with higher long-term risk of cardiovascular mortality, particularly in RTR with relatively low plasma vitamin C or renal function. Further studies are warranted to investigate whether OS-targeted interventions may decrease the burden of excess premature cardiovascular mortality in RTR.