Role of Plasma Homocysteine and Plasminogen Activator Inhibitor-1 in the Progression of Diabetic Nephropathy

Abstract

Diabetic nephropathy is a progressive disease and a leading cause of end stage renal disease. However, the decline in glomerular filtration rate (GFR) varies substantially between patients, ranging from 2 to 20 ml/min/year. Thus, identification of predictors of progression in diabetic nephropathy is of importance. Plasma total homocysteine (tHcy) rises with urinary albumin rate in diabetes, and plasminogen activator inhibitor-1 (PAI-1) has been correlated to increased matrix accumulation in various glomerulopathies. The aim of the present prospective observational cohort study was to evaluate the importance of baseline tHcy and PAI-1 as predictors of the rate of decline in GFR. At baseline tHcy and PAI-1 were measured in 157 type 1 diabetic patients with diabetic nephropathy (92 males, age 41 ± 10 years, diabetes duration 28 ± 8 years, GFR (median (range)) 80 (23–143) ml/min/1.73 m2). Hereafter, GFR was measured yearly with a plasma clearance technique for at least 3 years, median 7 (range 3.0 to 8.3) years. The mean rate of decline in GFR was 3.7 (0.3) ml/min/year. A linear regression analysis revealed a borderline significant relation between rate of decline in GFR and tHcy (p=0.069) and PAI-1 (p=0.087), respectively. Analyzing rate of decline in GFR and ter-tiles of tHcy and PAI-1, increasing levels of tHcy was correlated with a faster decline in GFR, p=0.025, whereas PAI-1 was not. However, after adjustment for other risk factors for progression of nephropathy, i.e. progression promoters, in a multiple linear regression analysis, neither tHcy nor PAI-1 was independent predictors of rate of decline in GFR. Our study demonstrates a relation between plasma tHcy and the rate of decline in GFR. Plasma tHcy and PAI-1 were, however, not found to be independent predictors of progression in diabetic nephropathy after adjustment for other well established progression promoters.