Progression of diabetic nephropathy: role of plasma homocysteine and plasminogen activator inhibitor-1

Among patients with diabetic nephropathy, the decline in glomerular filtration rate (GFR) varies substantially, ranging from 2 to 20 mL/min per year. Identification of predictors of progression in diabetic nephropathy is important. Plasma total homocysteine (tHcy) rises with urinary albumin excretion rate in diabetes, and plasminogen activator inhibitor-1 (PAI-1) has been correlated with increased matrix accumulation in various glomerulopathies. In this prospective observational cohort study, we evaluated the importance of baseline tHcy and PAI-1 as predictors of the rate of decline in GFR. Baseline tHcy and PAI-1 were measured in 157 type 1 diabetic patients with diabetic nephropathy (92 men; mean age, 41 +/- 10 years; mean diabetes duration, 27 +/- 8 years; median GFR, 80 mL/min/1.73 m(2) [range, 23 to 143 mL/min/1.73 m(2)]). Hereafter, GFR was measured yearly with a plasma clearance technique for at least 3 years (median, 7 years [range, 3.0 to 8.3 years]). The mean rate of decline in GFR was 3.7 +/- 0.3 mL/min per year. A linear regression analysis revealed a borderline significant relationship between rate of decline in GFR and tHcy (P = 0.069) and PAI-1 (P = 0.087). Analysis of the rate of decline in GFR and tertiles of tHcy and PAI-1 revealed that increasing levels of tHcy were correlated with a significantly faster decline in GFR (P = 0.025), whereas increasing levels of PAI-1 were not. After adjustment for other well-established risk factors for progression of nephropathy in a multiple linear regression analysis, however, neither tHcy levels nor PAI-1 levels were independent predictors of rate of decline in GFR.