Elevated Circulating Interleukin 33 Levels in Stable Renal Transplant Recipients at High Risk for Cardiovascular Events

Abstract

BackgroundThe Major Adverse Cardiovascular Events calculator (CRCRTR-MACE) estimates the burden of cardiovascular risk in renal transplant recipients (RTR). Our recent study of 95 RTR reported the 7-year median risk of cardiovascular events (CVE) to be 9.97%, ranging from 1.93 to 84.27%. Nearly a third (28.4%) of the cohort was above 20% risk for a CVE. Since interleukins (ILs) as part of the inflammatory response may play a role in the pathogenesis of cardiovascular disease (CVD), we extended this study to identify which ILs are associated with high cardiovascular risk in this population.MethodsTwenty-two ILs were measured by multiplexed fluorescent bead-based immunoassay in 95 RTR and 56 normal controls. Stepwise analysis after multivariate determination of significant demographic and inflammatory variables was performed between the high and low-CVD risk groups (which were arbitrarily set at scores <10% and ≥20%, respectively). Normalized data was presented as mean ± SD and non-normalized data as median (minimum–maximum). Significance was measured at <0.05.Results27.5% of the low-risk and 31.3% of the high-risk groups had mean IL levels above the 95 percentile of the normal control levels. In the non-parametric analysis IL-6, 9, 16, 17 and 33 were significantly higher in the high-risk group compared to the control. Univariate analysis (UVA) of the high-risk group identified IL-33 as the only IL that remained significantly higher than the control and low-risk groups (p = 0.000). The percentage of patients with IL-33 levels above the 90 percentile of control value in the low and high-risk groups were 15.6% and 52.0%, respectively (p<0.002). UVA of factors significant to high IL-33 levels included estimated glomerular filtration rate (eGFR), while diabetes mellitus, serum phosphorus, microalbuminuria and age also remained significant in the multivariate analysis.ConclusionCirculating IL-33 level is positively associated with high CRCRTR-MACE score. Diminished eGFR, age, diabetes, serum phosphorus and microalbuminurea demonstrate significant relationship with elevated IL-33 levels, supporting the possible pathognomonic role of IL-33 in the cardiovascular burden in RTR.

Study of Cardiovascular Outcomes in Renal Transplantation: A Prospective, Multicenter Study to Determine the Incidence of Cardiovascular Events in Renal Transplant Recipients in Ontario, Canada

“…Further efforts to define the CV risk profile of renal transplant patients should look beyond the factors considered in our analysis and focus on other potential risk factors that have emerged from recent association studies. 22,23 Finally, as all patients were recruited from the province of Ontario, our findings many not fully reflect the experience in other areas of Canada or in other health care settings.…”

IL-33 and ST2 levels in chronic kidney disease: Associations with inflammation, vascular abnormalities, cardiovascular events, and survival

“…There were few studies conducted regarding IL-33/ST2 and cardiovascular risk in patients with kidney disease. In a study conducted in 95 renal transplant patients by Mansell et al, they found that IL-33 levels were increased in patients with high cardiovascular risk as compared with patients with low cardiovascular risks [ 55 ]. In our study, it was found that increased IL-33 and ST2 levels were associated with endothelial dysfunction, ST2 was one of the predictors of endothelial dysfunction, and both IL-33 and ST2 were predictors of fatal and nonfatal cardiovascular events during the follow-up period of the patients.…”

Inflammation and renal fibrosis: Recent developments on key signaling molecules as potential therapeutic targets

“…Serum IL-33 and sST2 levels were reported to be positively associated with cardiovascular events, vascular injury, and mortality in CKD patients (Gungor et al, 2017). Circulating IL-33 levels are also positively associated with greater risk of adverse cardiovascular events in renal transplant recipients (Mansell et al, 2015). In the mouse, expression levels of IL-33 were found to be increased with renal injury induced by UUO, principally in interstitial myofibroblasts (Chen et al, 2016).…”