Angiopoietin-2 levels predict mortality in CKD patients

Background. The pathophysiology of aggravated atherosclerosis in chronic kidney disease (CKD) is still incompletely understood. However, there is an increasing focus on non-traditional risk factors, including endothelial dysfunction. Angiopoietin-2 (Ang-2) impairs endothelial function by inhibiting the binding of Angiopoietin-1 (Ang-1) to their shared receptor Tie2 and is increased in diabetes, hypertension, coronary heart disease and CKD. Furthermore, Ang-2 levels are associated with the prevalent vascular burden of CKD patients. Thus, we aimed to investigate its impact on outcome in CKD, the population most likely to die of cardiovascular events. Methods. We prospectively studied 128 CKD patients [43 CKD Stage 4, 85 CKD Stage 5 (57 haemodialysis, 28 peritoneal dialysis)] over a follow-up period of 4 years. Biochemical and clinical parameters, including objective scoring of vascular calcification (VC) by computed tomography (CT) and arterial stiffness by applanation tonometry (including radial-dorsalis pedis pulse wave velocity (PWVrd)) were recorded. Baseline Ang-1 [enzyme-linked immunosorbent assay (ELISA)], Ang-2 [immunoluminometric assay (ILMA)] and soluble Tie2 (sTie2) (ELISA) levels were measured in this group as well as in 20 healthy controls. Results. Ang-2 values were significantly higher in CKD patients than in controls (2.01 +/- 0.94 versus 1.00 +/- 0.47 ng/mL, P < 0.0001). Furthermore, Ang-2 was significantly higher in dialysis than in Stage 4 CKD patients and correlated with markers of vascular disease [cholesterol, hsCRP, osteoprotegerin (OPG)]. However, elevated Ang-2 was not associated with the degree of VC or with arterial stiffness. Cox-regression analysis detected Ang-2 as an independent predictor of mortality in both unadjusted [hazard ratio (HR) 1.15; P = 0.002] and models adjusted for age and VC (HR 1.14; P = 0.003). Conclusions. Ang-2 levels are associated with systemic markers/mediators of micro-inflammation in CKD patients. Furthermore, elevated Ang-2 levels are strong predictors of long-term mortality, independent of conduit arterial stiffness or VC.