Micropuncture Studies of the Mechanisms of Normal and Pathologic Albuminuria

129

Differential solute clearances were used to characterize glomerular function in 20 Pima Indians with noninsulin-dependent diabetes mellitus (NIDDM) of < 3 yr duration. 28 Pima Indians with normal glucose tolerance served as controls. In the diabetic group, the glomerular filtration rate (GFR, iothalamate clearance) exceeded the control value by 15% (140±6 vs. 122±5 ml/min, P < 0.01). A corresponding 12% increase in renal plasma flow (RPF) was not statistically significant and did not account fully for the observed hyperfiltration, suggesting a concomitant elevation of the ultrafiltration pressure or coefficient. The median albumin excretion ratio in NIDDM exceeded control by almost twofold (10.1 vs. 5.8 mg/g creatinine), a trend which just failed to achieve statistical significance (P = 0.06). Fractional clearances of dextrans of broad size distribution were also elevated in diabetic subjects, significantly so for larger dextrans of between 48 and 60 A radius. A theoretical analysis of dextran transport through a heteroporous membrane revealed glomerular pores in NIDDM to be uniformly shifted towards pores of larger size than in controls. We conclude that an impairment of barrier size selectivity combined with high GFR elevates the filtered protein load in NIDDM of recent onset. We propose that enhanced transglomerular trafficking of protein may predispose to sclerosis of glomeruli in those Pima Indians with NIDDM who ultimately develop diabetic nephropathy. (J. Clin. Invest. 1991. 88:524-530.) Key words: hyperfiltration * barrier size-selectivity * transmembrane protein shunting. heteroporous membrane models Introduction Considerable evidence in experimental animals and some indirect evidence in humans suggests that the development ofinsu-

Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Glomerular function in Pima Indians with noninsulin-dependent diabetes mellitus of recent onset.

Myers

Nelson²,

Williams³

et al. 1991

129

“…The corresponding range of IgG excreted in Assuming minor or negligible fractional protein reabsorption at the high filtered protein loads that characterized the experimental population, the fractional clearances of the test proteins should approach their glomerular sieving coefficients and reflect, with reasonable accuracy, the extent to which the glomerular capillary wall had become hyperpermeable to each protein (22). Accordingly, the relationship of the fractional clearances of albumin and IgG to the GFR in individual patients illustrated in Fig.…”

Section: Methodsmentioning

confidence: 99%

Nature of the glomerular capillary injury in human membranous glomerulopathy.

Shemesh¹,

Ross²,

Deen³

et al. 1986

A differential solute clearance technique was used to evaluate glomerular capillary wall function in 20 patients with membranous glomerulopathy and massive proteinuria. The clearance of inulin, the filtration fraction, and the fractional clearance of uncharged dextrans of a radius of 28-48 A were depressed significantly below control values in 20 healthy volunteers (P < 0.01). In contrast, the fractional clearance of dextrans of radius >50 A was elevated markedly. A theoretical model of solute transport that depicts the major portion of the glomerular capillary wall as an isoporous membrane and the minor portion as a nondiscriminatory shunt pathway revealed the calculated gomerular ultrafiltration coefficient to be five times lower and mean pore radius of the major membrane component to be 4 A smaller than control values. However, the fraction of filtrate volume permeating the shunt pathway was three-to fourfold above control values and correlated strongly in individual patients with the fractional clearance of albumin (r = 0.76) and of IgG (r = 0.80). Lowering renal plasma flow by 24% during indomethacin therapy in seven patients resulted in a 74% reduction in proteinuria accompanied by a corresponding diminution of filtrate formed through the shunt pathway. Morphometric analysis ofglomerular ultrastructure revealed the magnitude of depression of the glomerular filtration rate and of urinary protein leakage to be related strongly to changes in the epithelial layer of the glomerular capillary wall, but not to the density of subepithelial immune deposits. We conclude (a) that glomerular capillaries in membranous glomerulopathy are characterized by a loss of ultrafiltration capacity and of barrier size-selectivity, and (b) that subepithelial immune deposits do not provide a structural basis for these functional alterations.

“…With the exception of a small increase to 1.6±0.2 Atg/min of IgG excretion in group I, there was no significant change in urinary protein excretion rate after the meal (Table IV). However, micropuncture studies in the rat have revealed that at the high filtered loads observed in group II subjects, the fraction of filtered protein taken up by endocytosis into proximal tubular cells is minor (27). Ifthis is true also for man, the fractional clearance ofeach protein should approach its sieving coefficient under these circumstances.…”

Section: Excretory Responsementioning

confidence: 99%

Functional response of healthy and diseased glomeruli to a large, protein-rich meal.

Chan¹,

Cheng²,

Keil³

et al. 1988

119

Differential solute clearances and hormone assays were used to characterize the effect of a large, protein-rich meal (1.5 g/kg) on glomerular function in 12 healthy volunteers (group I) and 12 patients with chronic glomerular disease (group II). Changes from baseline during 3 h after the meal included an elevation of plasma osmolality, progressive urinary concentration, and increasingly positive fluid balance. Plasma renin activity and arginine vasopressin levels (measured in group II only) increased significantly. Nevertheless, the rate of peak postmeal renal plasma flow became elevated by 13 and 33% in groups I and II, respectively. Corresponding peak increases in postmeal glomerular filtration rate exceeded baseline by 10 and 16%. In the proteinuric subjects of group II the fractional clearances of albumin, IgG and uncharged dextrans in the radius interval 36-54 A, declined significantly after the meal. A similar depression of the fractional dextran-clearance profile was observed also in group I. Applying the fractional clearances of relatively permeant dextrans (radii < 44 A) to a model of hindered solute transport through an isoporous membrane, we estimate that transmembrane hydraulic pressure difference increased by 12% in group I and by between 0 to 12% in group II after protein ingestion. We conclude (i) that oral protein ingestion increases glomerular ultrafiltration pressure and rate in both normal and diseased glomeruli, (ii) that this hemodynamic response may be mediated in part by the glomerulopressor hormones angiotensin II and arginine vasopressin, and (iii) that the foregoing hemodynamic changes exert no acute adverse effect on glomerular barrier size-selectivity.