Diabetic Nephropathy: The Proteinuria Hypothesis

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Abstract
Background/Aims: Proteinuria, nearly a universal finding in progressive kidney disease, has been the subject of frequent recent analyses in the renal literature. Proteinuria is a hallmark of diabetic nephropathy: microalbuminuria is the principal early predictor for progression of diabetic glomerulopathy, and proteinuria may be viewed as a measure of the severity and promoter of progression of nephropathy. Methods: This article critically reviews for the first time the full scope of diabetic proteinuria – complex molecular mechanisms, natural history, and analysis of treatment trials – in order to address the validity of ‘the proteinuria hypothesis’, i.e., that diabetic proteinuria is a modifiable determinant of renal progression. This hypothesis is analyzed in detail, including recent studies on the primary therapy of diabetic nephropathy, renin-angiotensin blockade. Results: As fully developed, this hypothesis consists of three postulates: that higher amounts of proteinuria predict progressive loss of function, that proteinuria reduction correlates with slowing progression, and that proteinuria is a surrogate endpoint for clinical trials. The latter postulate has not before been adequately linked to growing information about the first two postulates as they apply to diabetic kidney disease. Conclusion: While diabetic nephropathy is a disease model for the potential use of proteinuria as a surrogate marker for renal progression, this shift in perspective will require prospective data from additional clinical trials, particularly of non-renin-angiotensin blocking drugs, to be complete.