The link between circulating markers of endothelial function and proteinuria in patients with primary glomerulonephritis

Introduction: It is well-established that there is an increase in the incidence of cardiovascular mortality in patients with proteinuric renal disease. The magnitude of the increase in risk is unlikely to be explained by traditional risk factors for cardiovascular disease alone. Proteinuria itself may constitute an additional risk factor, and proteinuric patients are known to have a degree of endothelial dysfunction. The nature of this relationship between proteinuria and endothelial function is the subject of intense investigation. Aim: The aim of this study was to examine the relationship between proteinuria and endothelial dysfunction, as reflected by serum von Willebrand factor (vWF), and the soluble cell adhesion molecules VCAM and ICAM, in patients with primary glomerulonephritis (GN). A secondary aim was to discern whether any relationship could be explained by renal function, lipid profile, inflammation or blood pressure. Methods: A cross-sectional study was undertaken in consecutive patients attending a general nephrology clinic with biopsy-proven primary GN. Patients with end-stage renal disease (ESRD), those on immunosuppressive drugs, or with intercurrent infective illnesses were excluded. Blood pressure and body mass index were recorded. Routine lab assays were undertaken for serum creatinine, lipid profile, and 24-hour urinary protein (U_Prot). Additional serum samples were stored at -80 °C for subsequent measurement of vWF, VCAM, ICAM and sensitive C reactive protein (sCRP). Results: Data were collected from 129 (86 male) patients. Mean (standard deviation) estimated creatinine clearance was 64 (32) ml/min, and median (interquartile range) 24-hour proteinuria was 1.1 (0.22 - 2.9) g. Mean vWF was 173 (68) IU/dl, median VCAM, ICAM and sCRP were 594(410-708) ng/ml, 235 (208-286) ng/ml, and 2.33 (0.83 - 5.68) mg/l, respectively. There was a significant positive correlation between vWF and U_Prot (Spearman rank correlation, r = 0.41, p < 0.001). When split into tertiles, according to U_Prot (0 - 500 mg, 500 - 2,000 mg, and > 2,000 mg), there was a significant, stepwise increase in mean vWF (p<0.001), log VCAM (p<0.001), and log ICAM (p=0.002). On multivariate analysis with vWF as the continuous dependent variable, U_Prot, age, total cholesterol and sCRP were the only significantly independent correlates (model-adjusted R₂ = 33%). Conclusion: In patients with primary GN, there is a significant association between endothelial activation as reflected by vWF, VCAM, or ICAM and increasing proteinuria. Elevations in vWF, as well as being related to classical risk factors, are associated with increases in total proteinuria and low-grade inflammation. Thus, future prospective studies should examine the extent to which vWF and other circulating markers of endothelial activation predict coronary heart disease risk in patients with proteinuric renal disease.