Urinary transferrin, high molecular weight proteinuria and the progression of renal disease

Aims. Proteinuria predicts rate of progression in a variety of nephropathies. There is considerable evidence that iron-transferrin is toxic to proximal tubular cells in vitro, and recent clinical work suggests that selectivity of proteinuria influences the outcome of renal disease. The aim of this study was to examine the relationship between the nature of proteinuria and progression of renal disease. Methods. This was a prospective, cross-sectional study in 66 patients with primary glomerulonephritis, diabetic nephropathy and a variety of other renal diseases. Urinary transferrin was measured by sandwich ELISA and correlated with rate of change in estimated creatinine clearance (ECC). Urinary SDS-PAGE was undertaken to divide proteinuria into tertiles according to molecular weight and to quantify the protein in each tertile. The magnitude of each tertile was then correlated with rate of change in ECC over a median period of 20 months. Results. Rate of change of renal function correlated with total proteinuria (r(2) = 18%, p < 0.001) and albuminuria (r(2) = 17%, p < 0.001), but not urinary transferrin (r(2) = 0%, p = 0.235). On univariate analysis high molecular weight proteinuria (r(2) = 21%, p < 0.001), intermediate molecular weight proteinuria (r(2) = 15%, p = 0.001) and low molecular weight proteinuria (r(2) = 10%, p = 0.005) correlated with rate of change in ECC as did total fasting cholesterol (r(2) = 7%, p = 0.003). On multivariate analysis, however, the only independent predictors of rate of change in ECC were high molecular weight proteinuria (r(2) = 19%, p < 0.001), and total fasting cholesterol (r(2) = 5%, p = 0.035). Conclusions. We found no evidence to support the hypothesis that iron-transferrin is important in the development of human renal injury. High molecular weight proteinuria correlates more strongly with rate of progression of renal disease than intermediate molecular weight, low molecular weight or even total proteinuria. This suggests either, that one or more high molecular weight proteins are implicated in causing progressive renal impairment, or that loss of size selectivity at the glomerular basement membrane is associated with accelerated tubulointerstitial damage.