Evolution of incipient nephropathy in type 2 diabetes mellitus

Background. We examined the course of glomerular injury in 12 Pima Indians with long-standing (>8 years) type 2 diabetes mellitus, normal serum creati nine, and microalbuminuria. They were compared with a group of 10 Pima Indi ans in Arizona with new-onset (<5 years) type 2 diabetes, normal renal func tion, and normoalbuminuria (<30 mg albumin/g creatinine on random urine spe cimens). Methods. A combination of physiological and morphological techniques was us ed to evaluate glomerular function and structure serially on two occasions separated by a 48-month interval. Clearances of iothalamate and p-aminohipp uric acid were used to determine glomerular filtration rate (GFR) and renal plasma Row, respectively. Afferent oncotic pressure was determined by memb rane osmometry. The single nephron ultrafiltration coefficient (K-t) was de termined by morphometric analysis of glomeruli and mathematical modeling. Results. The urinary albumin-to-creatinine ratio (median + range) increased from 84 (28 to 415) to 260 (31 to 2232) mg/g between the two examinations (P = 0.01), and 6 of 12 patients advanced from incipient (ratio = 30 to 299 mg/g) to overt nephropathy (greater than or equal to 300 mg/g). A 17% decl ine in GFR between the two examinations from 186 +/- 41 to 155 +/- 50 mi/mi n (mean +/- SD: P = 0.06) was accompanied by a 17% decline in renal plasma how (P = 0.003) and a 6% increase in plasma oncotic pressure (P = 0.02). Co mputed glomerular hydraulic permeability was depressed by 13% below control values at both examinations, a result of a widened basement membrane and a reduction in frequency of epithelial filtration slits. The filtration surf ace area declined significantly, however, from 6.96 +/- 2.53 to 5.51 +/- 1. 62 x 10(5) mm(2) (P = 0.01), a change that was accompanied by a significant decline in the number of mesangial cells (P = 0.001), endothelial cells (P = 0.038), and podocytes (P = 0.0005). These changes lowered single nephron K-f by 20% from 16.5 +/- 6.0 to 13.2 +/- 3.6 nL/(minutes + mm Hg) between the two examinations (P = 0.02). Multiple linear regression analysis reveal ed that among the determinants of GFR, only the change in single nephron K- f was related to the corresponding change in GFR. Conclusion. We conclude that a reduction in K-t is the major determinant of a decline in GFR from an elevated toward a normal range as nephropathy in type 2 diabetes advances from an incipient to an overt stage.