Additive Effects of Soluble TWEAK and Inflammation on Mortality in Hemodialysis Patients

Abstract

Background and objectives: Chronic kidney disease (CKD) is characterized by an exceptionally high mortality rate, primarily due to cardiovascular disease. Reduced soluble TNF-like weak inducer of apoptosis (sTWEAK) plasma levels have been reported both in patients with subclinical atherosclerosis and CKD.Design, participants, & measurements: A cross-sectional study was conducted in 218 prevalent patients (121 men; 63 ؎ 14 yr) undergoing hemodialysis (HD). sTWEAK levels in relation with the patients' outcome were studied.Results: sTWEAK plasma levels were 208 [(165 to 272) pg/ml, median interquartile range], significantly lower than healthy controls (P < 0.0001). sTWEAK was negatively associated with inflammatory markers, such as C-reactive protein and IL-6. Overall mortality was assessed after an average follow-up of 31 mo, during which 81 patients died. After controlling for potential confounding variables, patients in the upper tertile of sTWEAK plasma levels had an increased risk of cardiovascular and all-cause mortality. A significant interaction effect between sTWEAK and IL-6 levels was found [synergy index: 2.19 (0.80, 5.93)]. Thus, the association of sTWEAK with mortality was strongest in patients with inflammation (defined as IL-6 > 7.0 pg/ml), in whom high sTWEAK strongly predicted cardiovascular and all-cause mortality. These results were confirmed in a second cohort of HD patients.Conclusions: The concurrent presence of elevated sTWEAK plasma concentrations and an inflammatory environment have additive effects on mortality in HD patients. Further studies on the potential different role of sTWEAK in health and disease are warranted.

Persistent Inflammation as a Catalyst for Other Risk Factors in Chronic Kidney Disease

“…Furthermore, because IL-6 induces the production of Fn14, it has been suggested that a persistently inflamed state may exacerbate the action of TWEAK through increased receptor synthesis (29). Thus, as we observed that simultaneously elevated levels of TWEAK and IL-6 in dialysis patients were associated with significant reductions in IGF-1 and handgrip strength, this combination may lead to muscle catabolism (27).…”

“…They proposed that angiotensin II may stimulate an interaction between the liver and the skeletal muscle because the liver becomes the major source of IL-6 and serum amyloid A. Second, elevated IL-6 and soluble TNF-like weak inducer of apoptosis (TWEAK) levels have additive effects on outcome prognostication ( Figure 2B) (27). TWEAK is a member of the TNF superfamily, which through binding to its receptor Fn14 mediates various biologic effects, including exacerbation of the inflammatory response and muscle-wasting activation through the ubiquitin-proteasome and NF-B pathways (28).…”

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).…”

IL-6 Levels, Nutritional Status, and Mortality in Prevalent Hemodialysis Patients

“…The pathophysiological basis of inflammatory cytokines, and particularly of IL-6-induced PEW, may be increased protein catabolism (19,20) and/or resistance to the anabolic effect of growth hormone, which may contribute to the loss of strength and muscle mass (21); in addition, inflammation may affect appetite and eating behavior (22,23). It was recently suggested that interactions between inflammatory markers and sTWEAK (soluble TNF-like weak inducer of apoptosis) affect the nutritional status of prevalent HD patients; thus, significant reductions in markers of PEW (IGF-1 and handgrip strength) associated with high levels of both IL-6 and sTWEAK may provide an additional link between inflammation and PEW (24). The malignant form of PEW, essentially caused by chronic inflammation in the HD population, is associated with pronounced hypoalbuminemia, markedly increased resting energy expenditure, oxidative stress, and poor clinical outcome, and has been termed as "malnutrition type 2" by Stenvinkel et al (25).…”