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).


CONCLUSIONS
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.
Persson
Frederik
F
Steno Diabetes Center, Gentofte, Denmark. frip@steno.dk
Rossing
Peter
P
Hovind
Peter
P
Stehouwer
Coen D A
CD
Schalkwijk
Casper G
CG
Tarnow
Lise
L
Parving
Hans-Henrik
HH
D000328:Adult; D000368:Aged; D000419:Albuminuria / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology*; D015415:Biomarkers; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000150:complications* / Q000175:diagnosis* / Q000188:drug therapy / Q000503:physiopathology; D018450:Disease Progression; D004727:Endothelium / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000188:drug therapy; D000077405:Irbesartan; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012372:ROC Curve; D013777:Tetrazoles / Q000627:therapeutic use*
D015415:Biomarkers; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000077405:Irbesartan