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ACE-I and ARBs in early diabetic nephropathy
Michael Mauer
University of Minnesota, Minneapolis, mauer002{at}umn.edu
Bernard Zinman
University of Toronto, Toronto, Ontario, Canada
Robert Gardiner
McGill University, Montreal, Quebec, Canada
Keith N Drummond
McGill University, Montreal, Quebec, Canada
Samy Suissa
McGill University, Montreal, Quebec, Canada
Sandra M Donnelly
University of Toronto, Toronto, Ontario, Canada
Trudy D Strand
University of Minnesota, Minneapolis
Michael S Kramer
McGill University, Montreal, Quebec, Canada
Ronald Klein
University of Wisconsin, Stout, Wisconsin, USA
Alan R Sinaiko
University of Minnesota, Minneapolis
Introduction
Antihypertensive treatment of patients with clinical manifestations of diabetic nephropathy, and especially, renin-angiotensin system (RAS) inhibition, slows, but may not fully arrest progression towards end-stage renal disease. Studies using `hard' endpoints such as doubling of serum creatinine, dialysis, or death that are initiated before emergence of any renal functional abnormalities in diabetes, would be of impractical length and size. We therefore undertook a primary prevention study (The Renin-Angiotensin System Study or RASS) to determine if inhibition of the RAS could slow the development of a key diabetic glomerulopathy structural endpoint, increase in mesangial fractional volume (Vv[Mes/glom]).
Methods
This is a parallel group, double-blind, placebo-controlled trial with 285 patients with Type 1 diabetes mellitus (95 per group) randomised to receive the angiotensin-converting enzyme inhibitor, enalapril, the angiotensin II receptor blocker, losartan, or placebo. All patients are normotensive, normoalbuminuric and have normal or increased glomerular filtration rates at study entry. The study is based on primary endpoint of change in Vv(Mes/glom) from baseline to the five-year renal biopsy, with baseline and interval measures of albumin excretion rate, glomerular filtration rate, blood pressure, and glycaemia. Baseline, mid-point, and five-year retinal fundus photography are also performed.
Results
One thousand and sixty-five patients were interviewed, 707 refused participation and 73 were excluded. The target of 285 subjects were randomised and their clinical and demographic characteristics are described. Biopsy complications occurred in 17 (6%), only one of which required hospitalisation. There were no permanent biopsy-related sequelae.
Conclusions
Renal structural variables are reasonable surrogate endpoints for studies of progression of early diabetic nephropathy. Although requiring substantial recruitment effort, diabetic nephropathy primary prevention trials based on change in renal structure are feasible.
Key Words: diabetes • nephropathy • ACE-I • ARBs • study design
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