Background
In renal transplant recipients (RTRs), cardiovascular mortality is the most common cause of long-term renal graft loss. Oxidative stress (OS) has been associated with cardiovascular disease and is known to be enhanced in RTRs. We aimed to prospectively investigate whether the concentration of the OS biomarker malondialdehyde (MDA) is associated with long-term risk of cardiovascular mortality in a large cohort of RTRs.
Methods
The plasma MDA concentration was measured using the thiobarbituric acid reaction assay in 604 extensively phenotyped RTRs with a functioning allograft for ≥1 year. To analyse whether plasma MDA concentration was independently associated with the risk for cardiovascular mortality, we performed Cox proportional hazards regression analyses according to significant effect modiers. In addition, pre-specified effect modification analyses was performed in which known cardiovascular risk factors (e.g. eGFR, proteinuria, diabetes mellitus, smoking status) or variables associated with oxidative status (e.g. plasma ascorbic acid concentration) were tested.
Results
Median circulating MDA concentration at baseline was 5.38 [interquartile range (IQR) 4.31–6.45] μmol/L. During a follow-up period of 6.4 (IQR 5.6–6.8) years, 110 (18%) RTRs died, with 40% of deaths due to cardiovascular causes. MDA concentration was significantly associated with the risk for cardiovascular mortality {hazard ratio [HR] 1.31 [95% confidence interval (CI) 1.03–1.67] per
1-SD increment}, independent of adjustment for potential confounders, including renal function, immunosup pressive therapy, smoking status and blood pressure. Further adjustment for the cardiovascular risk factors listed in the Framingham score and those proposed by the WHO, patients cardiovascular history and immunosuppressive therapy did not materially alter the associafition (Table 1).
Competing risk analyses showed that MDA concentration, although consistently associated with cardiovascular mortality, was not associated with the competing event non-cardiovascular mortality, and posterior adjustments did not alter this result (Table 1).
The positive association between plasma MDA concentration and the risk for cardiovascular mortality was stronger among patients with relatively lower eGFR [HR 2.09 (95% CI 1.45‒3.00) per 1 SD increase; P < 0.001] compared with the overall RTR population (Figure 1).
Conclusions
Circulating MDA concentration is independently associated with long-term risk for cardiovascular mortality, particularly in RTRs with relatively lower ascorbic acid concentrations or renal function. This association was modified by circulating ascorbic acid concentration, with a stronger association between MDA concentration and cardiovascular mortality risk among patients with relatively lower concentrations of ascorbic acid. Further studies are warranted to elucidate whether OS-targeted interventions could decrease cardiovascular mortality in RTRs.
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