Soluble TWEAK Plasma Levels as a Novel Biomarker of Endothelial Function in Patients with Chronic Kidney Disease

Abstract

Background and objectives: Recently, we showed that soluble TNF-like weak inducer of apoptosis (sTWEAK) plasma levels are diminished in hemodialysis patients and had additive effects with IL-6 on survival. Because sTWEAK plasma level has been associated with the presence of chronic kidney disease (CKD) and cardiovascular disease, we hypothesized that in patients with CKD, sTWEAK levels may relate to the increased prevalence of endothelial dysfunction that usually accompanies the decline of estimated GFR (eGFR).Design, setting, participants, & measurements: We studied 295 patients with different stages of nondiabetic CKD (52% male; age 47 ؎ 12 yr), testing the association between sTWEAK plasma levels and CKD stage and the relationship between flow-mediated dilation (FMD) and sTWEAK concentrations. Fifty-five healthy volunteers (51% male; age 47 ؎ 11 yr) served as matched control subjects.Results: A gradual decrease in FMD was observed as eGFR decreased. Compared with healthy control subjects, sTWEAK plasma levels were diminished in all stages of CKD and correlated strongly with eGFR. FMD levels were associated with sTWEAK concentrations in univariate analysis. This association persisted after multivariate adjustment for eGFR levels, high-sensitivity C-reactive protein, diastolic BP, and sTWEAK, all of which were found to be significant and independent contributors to FMD.Conclusions: A decline in eGFR is accompanied by gradual reductions in sTWEAK plasma levels. Because sTWEAK strongly and independently correlated with FMD, our study suggests novel links between sTWEAK and endothelial dysfunction in patients with CKD.

The Relationships between Serum sTWEAK, FGF-23 Levels, and Carotid Atherosclerosis in Renal Transplant Patients

“…Alike in non-renal individuals, 6 studies have shown that low sTWEAK levels are related to atherosclerosis, endothelial dysfunction, and prediction of cardiovascular events in non-CKD patients and nondialyzed CKD stages. 7,8 Confusingly, high levels have also been shown to relate to atherosclerosis, vascular calcification, and mortality in dialysis individuals, 9,10 suggesting a dual or time-differential effect that agrees nevertheless with observations in non-CKD patients. 11 Fibroblast growth factor-23 (FGF-23) is an emerging mediator of the vascular calcification process.…”

“…FGF-23 is a hormone that is secreted from osteoblasts with phosphaturic effects. FGF-23 levels progressively increase as CKD advances 8 and is restored following a successful transplantation. 15 Several studies have investigated the relationship between FGF-23 and carotid atherosclerosis in dialysis patients; reporting controversial results.…”

“…6 Yilmaz et al demonstrated that decrease in sTWEAK levels accompany the increase in kidney failure level and that sTWEAK levels are inversely related to endothelial dysfunction. 8 Additionally, Carrero et al demonstrated that increased sTWEAK levels cause an increase in mortality by stimulating inflammation in dialysis patients. 9 These studies proposed that TWEAK may either increase the inflammatory activity or be preventive against extreme inflammation depending upon its interaction with tissue receptors and also its expression and secretion may be decreased in atherosclerotic situations.…”

Combined Therapy with Renin-Angiotensin System and Calcium Channel Blockers in Type 2 Diabetic Hypertensive Patients with Proteinuria

“…Unexpectedly, lower plasma sTWEAK has been reported in subjects with subclinical atherosclerosis, diabetic subjects, CKD patients (18 -20,36), and in this study. In CKD patients, sTWEAK appeared to be robustly and negatively associated with ED (19), and sTWEAK plasma concentrations were good prognosticators of all-cause and CVD mortality in patients undergoing hemodialysis (18). Interestingly, in patients with chronic stable heart failure, reduced sTWEAK levels predicted an adverse prognosis independently of established risk markers such as the N-terminal prohormone of brain natriuretic peptide (37) and contributed to improve the prediction of coronary artery disease (38).…”

“…Binding of TWEAK to its receptor, Fn14 (13), mediates multiple biologic effects such as cellular growth, proliferation, and migration; osteoclastogenesis; angiogenesis; and apoptosis (15)(16)(17). sTWEAK plasma levels decrease with impaired renal function and associate with the aggravation of the endothelial function and the mortality risk (18,19). In the same line, diminished sTWEAK levels have been reported in patients with subclinical atherosclerosis (20).…”