Glomerular function in advanced human diabetic nephropathy.

Intrinsic membrane properties of the glomerular capillary wall were evaluated in 20 diabetic patients, who had heavy proteinuria and reduced GFR, and in 15 healthy control subjects. The glomerular sieving coefficients were determined for narrow dextran fractions with molecular radii between 20 and 64 A. GFR determinants were directly measured or indirectly estimated. These quantities were then subjected to a theoretical analysis based upon (1) a mathematical model of glomerular ultrafiltration and (2) a pore model of transmembrane solute transport. The results indicated that in patients with diabetic nephropathy and glomerular ultrafiltration coefficient (0.02 vs. 0.16 ml . sec-1 . mm Hg-1 . 1.73m-2), effective pore area-to-pore length (2.6 x 10(6) vs. 20.0 x 10(6) cm), and mean pore radius (56.8 vs. 58.0 A) are all reduced relative to normal control subjects. It is suggested that (1) hypofiltration in advanced diabetic nephropathy results, in part, from reduction of the surface area available for filtration, while (2) proteinuria is a consequence of either loss of electrostatic barrier function, of isolated focal disruptions within the glomerular filtration barrier, or a combination thereof.

Mechanisms of proteinuria in diabetic nephropathy: a study of glomerular barrier function.

The fractional clearance of neutral dextrans (theta D) with Einstein-Stokes radii between 30 and 64 A was determined in normal subjects (controls, N = 15) and in diabetic patients with heavy proteinuria (advanced nephropathy, N = 16) or trace proteinuria (early nephropathy, N = 8). When plotted on log normal probability coordinates, the correlation between theta D and radius in controls and in early diabetic nephropathy was linear, suggesting that glomerular pores form one population with a normal distribution. In advanced diabetic nephropathy, however, theta D for large molecules (radius greater than 46 A) was elevated and departed from linearity suggesting a bimodal pore size distribution within the glomerular membrane. A mathematical model was devised, which revealed the mean fraction of glomerular filtrate permeating the upper pore mode to be 0.009 +/- 0.002, and the pores to be totally nondiscriminatory toward molecules with radii up to 64 A. We conclude that the development of large pores (or defects) within the glomerular membrane in advanced diabetic nephropathy permits the unrestricted passage of large plasma proteins into the urine.

The nature of the glomerular injury in minimal change and focal sclerosing glomerulopathies.

Glomerular barrier function was evaluated in 12 healthy human volunteers and in 16 proteinuric patients in whom the nephrotic syndrome was associated with alteration of glomerular epithelial cells alone (minimal change nephropathy [MCN]) or in combination with focal glomerular sclerosis (FGS). We determined the glomerular sieving coefficient for each of nine narrow dextran fractions (Einstein Stoke radius [ESR] = 30 to 46 A), and directly measured, or indirectly estimated, values for the determinants of glomerular ultrafiltration. These quantities were then subjected to analysis based on an hydrodynamic theory of solute transport through an isoporous membrane. The results indicate that relative to normal subjects, effective pore radius is reduced from 59 to 55 and 53 A in McN and FGS, respectively; while the ratio, pore area to pore length (a measure of pore density) is correspondingly reduced from 21.7 X 10(6) to 10.1 X 10(6) and 4.7 X 10(6) cm. respectively, We suggest that collapse of the anionic glomerular membrane matrix in these proteinuric disorders may lead to pore shrinkage and reduced pore density, but that reduced electrostatic repulsion of anionic albumin (ESR = 36 A) facilitates its permeation into Bowman's space. The qualitatively similar disorder of glomerular barrier function in MCN and FGS is consistent with a unitary pathogenesis, but may represent a nonspecific response to depletion of glomerular polyanion.