Soluble TWEAK and Major Adverse Cardiovascular Events in Patients with CKD

Abstract

Background and objectives Soluble TNF-like weak inducer of apoptosis (sTWEAK) is a proinflammatory cytokine belonging to the TNF superfamily. sTWEAK concentrations have been associated with the presence of CKD and cardiovascular disease (CVD). We hypothesized that sTWEAK levels may relate to a higher prevalence of atherosclerotic plaques, vascular calcification, and cardiovascular outcomes observed in patients with CKD.Design, setting, participants, & measurements A 4-year prospective, multicenter, longitudinal study was conducted in 1058 patients with CKD stages 3-5D (mean age =58613 years old; 665 men) but without any history of CVD from the NEFRONA Study (a study design on the prevalence of surrogate markers of CVD). Anklebrachial index and B-mode ultrasound were performed to detect the presence of carotid and/or femoral atherosclerotic plaques together with biochemical measurements and sTWEAK assessment. Patients were followed for cardiovascular outcomes (follow-up of 3.1361.15 years).Results Patients with more advanced CKD had lower sTWEAK levels. sTWEAK concentrations were independently and negatively associated with carotid intima-media thickness. sTWEAK levels were lower in patients with carotid atherosclerotic plaques but not in those with femoral plaques. After adjustment by confounders, the odds ratio (OR) for presenting carotid atherosclerotic plaques in patients in the lowest versus highest tertile of sTWEAK was 4.18 (95% confidence interval [95% CI], 2.89 to 6.08; P,0.001). Furthermore, sTWEAK levels were lower in patients with calcified carotid atherosclerotic plaques. The OR for presenting calcified carotid plaques was 1.77 (95% CI, 1.06 to 2.93; P=0.02) after multivariable adjustment. After the followup, 41 fatal and 68 nonfatal cardiovascular events occurred. In a Cox model, after controlling for potential confounding factors, patients in the lowest tertile of sTWEAK concentrations had a higher risk of fatal and nonfatal cardiovascular events (hazard ratio [HR], 2.40; 95% CI, 1.33 to 4.33; P=0.004) and cardiovascular mortality (HR, 2.67; 95% CI, 1.05 to 6.76; P=0.04).Conclusions Low sTWEAK levels were associated with the presence of carotid atherosclerotic plaques in patients with CKD. Additionally, lower sTWEAK levels were associated with a higher risk of cardiovascular morbidity and mortality.

Combination of biomarkers of vascular calcification and sTWEAK to predict cardiovascular events in chronic kidney disease

“…independent since it has been demonstrated that TWEAK induces macrophage differentiation into osteoclasts in the presence of OPG, indicating a different mechanism of action (29). Confirming data of previous works (19)(20), we observed that sTWEAK levels are independently associated with CV events in CKD patients.…”

“…In addition, loss-of function experiments have shown that TWEAK increases atherosclerotic plaque calcification (15). Finally, circulating soluble TWEAK (sTWEAK) levels have been associated with cardiovascular outcomes in CKD patients (19)(20).…”

Factors predicting cardiovascular events in chronic kidney disease patients. Role of subclinical atheromatosis extent assessed by vascular ultrasound

“…However, neither traditional risk factors, risk score charts for general population nor emerging risk biomarkers appear to significantly increase the prediction power in this population. [ 2 – 4 ] Thus, classical risk prediction equations underestimate cardiovascular disease risk in adults with CKD [ 5 , 6 ] and new tools for risk prediction in renal patients are urgently needed.…”

TRAIL, OPG, and TWEAK in kidney disease: biomarkers or therapeutic targets?

“…For these reasons, TWEAK has been indicated as predictor of mortality in dialysis and non-dialysis CKD patients, as well as a biomarker of CVD outcomes [215]. Moreover, it has been observed that atherosclerotic burden and atheromatosis progression in CKD patients free of CVD are accompanied by low TWEAK, suggesting that TWEAK could serve as biomarker to predict CVD risk even before clinical manifestations [216,217].…”