PROGRESSION OF OVERT NEPHROPATHY IN NON-INSULIN-DEPENDENT DIABETES

The detection of overt albuminuria (> 300 mg/g creatinine) in the abse nce of azotemia was used to diagnose early nephropathy in 34 Pima Indi ans with NIDDM of 16 +/- 1 years duration. Differential solute clearan ces were performed serially to define the course of the glomerular inj ury over 48 months. At baseline, the GFR (107 +/- 5 ml/min), filtratio n fraction and sieving coefficients of relatively permeant dextrans (< 52 Angstrom) were all depressed below corresponding values in 20 norm oalbuminuric Pima Indians with a similar duration of NIDDM. Over the e nsuing 48 months the GFR (-34%) and filtration fraction (-13%) in the nephropathic patients declined further. The sieving coefficients of la rge, nearly impermeant dextrans (> 56 Angstrom radius) increased selec tively and fractional clearances of albumin and IgG increased correspo ndingly by > 10-fold. Analysis of the findings with pore theory reveal ed: (1) a progressive decline in pore density and the ultrafiltration coefficient (K-f); and (2) broadening of glomerular pore-size distribu tion that resulted in greater prominence of large pores (> 70 Angstrom radius). We conclude that increasing loss of intrinsic ultrafiltratio n capacity is the predominant cause of the early and progressive decli ne in GFR that follows the development of nephropathy in NIDDM. We spe culate that progressive impairment of barrier size-selectivity contrib utes to but does not fully account for the increasingly heavy proteinu ria that is observed early in the course of this disorder.