Evolution of incipient nephropathy in type 2 diabetes mellitus.

  • Lemley K
  • Abdullah I
  • Myers B
 et al. 
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BACKGROUND: We examined the course of glomerular injury in 12 Pima Indians with
long-standing (>8 years) type 2 diabetes mellitus, normal serum creatinine, and
microalbuminuria. They were compared with a group of 10 Pima Indians in Arizona
with new-onset (normoalbuminuria (METHODS: A combination of physiological and morphological techniques was used to
evaluate glomerular function and structure serially on two occasions separated by
a 48-month interval. Clearances of iothalamate and p-aminohippuric acid were used
to determine glomerular filtration rate (GFR) and renal plasma flow,
respectively. Afferent oncotic pressure was determined by membrane osmometry. The
single nephron ultrafiltration coefficient (Kf) was determined 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 (>/=300
mg/g). A 17% decline in GFR between the two examinations from 186 +/- 41 to 155
+/- 50 mL/min (mean +/- SD; P = 0.06) was accompanied by a 17% decline in renal
plasma flow (P = 0.003) and a 6% increase in plasma oncotic pressure (P = 0.02).
Computed 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 surface
area declined significantly, however, from 6.96 +/- 2.53 to 5.51 +/- 1.62 x 105
mm2 (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 Kf 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 revealed that among the determinants
of GFR, only the change in single nephron Kf was related to the corresponding
change in GFR. CONCLUSION: We conclude that a reduction in Kf 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.

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  • K V Lemley

  • I Abdullah

  • B D Myers

  • T W Meyer

  • K Blouch

  • W E Smith

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