title: Endothelial cell autoantibodies in predicting declining renal function, end-stage renal disease, or death in adult type 2 diabetic nephropathy.
abstract: Albuminuria is a strong predictor of diabetic nephropathy chronic kidney disease outcomes. Yet, therapeutic albuminuria-lowering has not consistently translated into a reduction in clinical events suggesting the involvement of additional pathogenic factors. Our hypothesis is that anti-endothelial cell autoantibodies play a role in development and progression in diabetic nephropathy. We determined anti-endothelial cell antibody (AECA) bioactivity in protein A-elutes of baseline plasma in 305 participants in the VA NEPHRON-D study, a randomized trial of angiotensin receptor blocker (ARB) or dual ARB plus angiotensin-converting enzyme inhibitor therapy in type 2 diabetes with proteinuric nephropathy. Thirty-eight percent (117/305) of participants had significantly reduced endothelial cell survival ( ≤80%) in the IgG fraction of plasma. A VA NEPHRON-D primary endpoint [end-stage renal disease (ESRD), significant reduction in estimated glomerular filtration rate, or death] was experienced by 58 individuals. In adjusted Cox regression analysis, there was a significant interaction effect of baseline anti-endothelial cell-mediated cell survival and albuminuria on the hazard rate (HR) for primary composite endpoint (P = 0.017). Participants lacking strongly inhibitory antibodies with albuminuria ≥1 g/g creatinine had a significantly increased primary event hazard ratio, 3.41 - 95% confidence intervals (CI 1.84-6.33; P < 0.001) compared to those lacking strongly inhibitory antibodies with lower baseline albuminuria ( <1 g/g creatinine). These results suggest that anti-endothelial cell antibodies interact significantly with albuminuria in predicting the composite endpoint of death, ESRD, or substantial decline in renal function in older, adult type 2 diabetic nephropathy.
authors.affiliation: Medical Service, Department of Veterans Affairs New Jersey Health Care System , East Orange, NJ , USA ; Rutgers-Robert Wood Johnson Medical School , New Brunswick, NJ , USA.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Zimering
authors.affiliation: West Haven Cooperative Studies Program Coordinating Center, Connecticut Veterans Healthcare System , West Haven, CT , USA.
authors.forename: Jane H
authors.initials: JH
authors.lastname: Zhang
authors.affiliation: West Haven Cooperative Studies Program Coordinating Center, Connecticut Veterans Healthcare System , West Haven, CT , USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Guarino
authors.affiliation: Veterans Affairs Hospital , Hines, IL , USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Emanuele
authors.affiliation: Baylor University Medical Center, Baylor Heart and Vascular Institute, Baylor Jack and Jane Hamilton Heart and Vascular Hospital , Dallas, TX , USA ; The Heart Hospital , Plano, TX , USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: McCullough
authors.affiliation: Veterans Affairs Medical Center , Pittsburgh, PA , USA.
authors.forename: Linda F
authors.initials: LF
authors.lastname: Fried
keywords: autoantibodies; chronic kidney disease; endothelium; nephropathy; type 2 diabetes