Loss of Glomerular Permselectivity in Type 2 Diabetes Associates With Progression to Kidney Failure

We examined whether defects in glomerular size selectivity in type 2 diabetes are associated with progressive kidney disease. Glomerular filtration rate (GFR) and fractional clearances of dextrans of graded sizes were measured in 185 American Indians. The permselectivity model that best fit the dextran sieving data represented the glomerular capillary as being perforated by small restrictive pores and a parallel population of larger nonrestrictive pores characterized by omega(0), the fraction of total filtrate volume passing through this shunt. The hazard ratio (HR) for kidney failure was expressed per 1-SD increase of omega(0) by Cox regression after adjusting for age, sex, mean arterial pressure, HbA(1c), GFR, and the urine albumin-to-creatinine ratio (ACR). Baseline mean SD age was 43 10 years, HbA(1c) 8.9 2.5%, GFR 147 46 mL/min, and median (interquartile range) ACR 41 (11-230) mg/g. During a median follow-up of 17.7 years, 67 participants developed kidney failure. After adjustment, each 1-SD increment in omega(0) was associated with a higher risk of kidney failure (HR 1.55 [95% CI 1.17, 2.05]). Enhanced transglomerular passage of test macromolecules was associated with progression to kidney failure, independent of albuminuria and GFR, suggesting that mechanisms associated with impaired glomerular permselectivity are important determinants of progressive kidney disease.