Endothelial dysfunction and inflammation predict development of diabetic nephropathy in the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) study

Objective. To evaluate risk factors for progression from persistent microalbuminuria to diabetic nephropathy in the Irbesartan in Patients with Type 2 diabetes and microalbuminuria (IRMA 2) study, including biomarkers of endothelial dysfunction, chronic low-grade inflammation, growth factors and advanced glycation end products (AGE peptides). Methods. IRMA 2 was a 2-year multicentre, randomized, double-blind trial comparing irbesartan (150 and 300 mg once daily) versus placebo. The primary end-point was time to onset of diabetic nephropathy. Samples from a subgroup from the placebo and the 300 mg irbesartan treatment group were used in this post-hoc analysis (n=269, 68%). Nine biomarkers were analysed: high sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), fibrinogen, von Willebrand Factor (vWf), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular cell adhesion molecule-1 (sICAM-1), sE-selectin, transforming growth factor-beta (TGF-beta) and AGE peptides. Mean standard deviation scores (Z-scores) were used to combine biomarker information. Results. In a Cox enter model with combined Z-scores for biomarkers of endothelial dysfunction (vWf, sVCAM-1, sICAM-1, sE-selectin) and for biomarkers of inflammation (hs-CRP, IL-6, fibrinogen), endothelial dysfunction (hazard ratio for a 28% increase (=1 SD) in Z-score) 3.20 (1.56 to 6.56), p=0.001) and UAER (HR for a 75% increase (=1 SD) in UAER) 2.61 (1.30 to 5.23), p=0.007) were found as independent predictors. Independently, IL-6 and vWf predicted the end-point. In addition, endothelial Z-score was associated with progression of albuminuria (p=0.038). Conclusion. Endothelial dysfunction and possibly inflammation are novel predictors of progression to diabetic nephropathy in patients with type 2 diabetes and microalbuminuria independently of traditional risk factors. ClinicalTrials.gov ID: NCT00317915.