The nature of the glomerular injury in minimal change and focal sclerosing glomerulopathies.

Glomerular barrier function was evaluated in 12 healthy human volunteers and in 16 proteinuric patients in whom the nephrotic syndrome was associated with alteration of glomerular epithelial cells alone (minimal change nephropathy [MCN]) or in combination with focal glomerular sclerosis (FGS). We determined the glomerular sieving coefficient for each of nine narrow dextran fractions (Einstein Stoke radius [ESR] = 30 to 46 A), and directly measured, or indirectly estimated, values for the determinants of glomerular ultrafiltration. These quantities were then subjected to analysis based on an hydrodynamic theory of solute transport through an isoporous membrane. The results indicate that relative to normal subjects, effective pore radius is reduced from 59 to 55 and 53 A in McN and FGS, respectively; while the ratio, pore area to pore length (a measure of pore density) is correspondingly reduced from 21.7 X 10(6) to 10.1 X 10(6) and 4.7 X 10(6) cm. respectively, We suggest that collapse of the anionic glomerular membrane matrix in these proteinuric disorders may lead to pore shrinkage and reduced pore density, but that reduced electrostatic repulsion of anionic albumin (ESR = 36 A) facilitates its permeation into Bowman's space. The qualitatively similar disorder of glomerular barrier function in MCN and FGS is consistent with a unitary pathogenesis, but may represent a nonspecific response to depletion of glomerular polyanion.

Dynamics of glomerular ultrafiltration following open-heart surgery.

To elucidate how individual determinants might lower the rate of glomerular ultrafiltration (GFR) in some patients following cardiac surgery, we performed hemodynamic measurements and clearance of inulin (as a measure of GFR), PAH (as a measure of effective renal plasma flow [ERPF]), and dextran-40. Two groups of 17 patients each were distinguished by the presence or absence of prerenal azotemia. Glomerular hypofiltration (GFR = 21 +/- 2 vs. 76 +/- 6 ml/min/1.73 m2, P less than 0.001) in the former was accompanied by depressed left ventricular function, arterial pressure, and ERPF (152 +/- 26 vs. 317 +/- 32 ml/min/1.73 m2, P less than 0.001). To determine if factors beside ERPF play a role in lowering GFR, we calculated the efferent oncotic pressure (pie). Failure of GFR to change over a 24-hour period despite increases in ERPF suggested that both patient groups were at filtration pressure disequilibrium (FPD). This condition permits calculation of a unique glomerular ultrafiltration coefficient (Kf). Over a range of pressures for transcapillary hydraulic pressure (deltaP), such that 3 less than or equal to (deltaP - pie) less than or equal to 10 mm Hg (to simulate FPD), Kf was less than 0.08 ml . sec-1 . mm Hg-1 . 1.73 m-2 in azotemic, but exceeded this value in nonazotemic patients. Although a selective reduction of Kf is predicted to lower the fractional clearance of dextrans, these were significant elevated in azotemic relative to nonazotemic patients (molecular radii 30 - 40 A). A theoretical analysis of the latter data suggests that over the foregoing range of FPD, a 15 to 30% decline in deltaP combined with a 30 to 0% reduction in Kf from values in nonazotemic patients best explains the experimental findings in azotemic patients.

Minimal change nephropathy: an electrochemical disorder of the glomerular membrane.

To investigate the mechanism of proteinuria in minimal change nephropathy, the renal handling of dextrans was studied in seven nephrotic patients with this disorder. Although the urinary excretion of albumin was greatly increased, the urinary excretion and fractional clearance of dextrans (Einstein-Stokes radius (ESR), range 20 to 48 A) were depressed relative to those in nonproteinuric healthy volunteers. This suggests that mean glomerular pore size or pore density was reduced. Uptake of colloidal iron by glomeruli obtained from these patients by needle biopsy was diminished, suggesting loss of glomerular polyanion. Since the fractional clearance of dextrans similar in size to albumin was depressed, not increased, it is proposed that the lack of electrostatic interaction between the glomerular capillaries and polyanionic plasma albumin (ESR = 36 A) accounts for the selective albuminuria which characterizes minimal change nephropathy.

Pathophysiology of hemodynamically mediated acute renal failure in man.

A tubular injury characterized by intraluminal obstruction and transtubular backleak of glomerular filtrate occurs in experimental acute renal failure (ARF) in animals. To determine whether these alterations also occur in human ARF, we studied 44 patients developing nonoliguric ARF following cardiac surgery. The delay in appearance of i.v. administered inulin in urine (Tu) was used as a measure of tubular fluid flow rate. Tu was not longer in 13 ARF patients than it was in control subjects (7.2 vs 9.0 min), suggesting that at least a subpopulation of tubules was widely patent. The fractional urinary dextran clearance profile (thetaD; radii, 20 to 40 A) was then determined in 20 patients with sustained ARF in whom inulin clearance averaged 11 +/- 1 ml/min/1.73 m2. A mass conservation model, which assumes that thetaD in Bowman's space in ARF is the same as that measured in controls, when applied to the experimental observations revealed that, on the average, 42% of filtered inulin was lost by transtubular backleak. A similar fractional inulin backleak (38%) persisted in 11 additional patients in whom ARF had begun to recover and in whom inulin clearance averaged 26 +/- 3 ml/min/1.73 m2. These findings suggest that in hemodynamically-mediated and nonoliguric ARF, (1) tubular obstruction is not homogeneous, and (2) backleak of glomerular filtrate contributes to but does not fully account for depression of inulin clearance.

Proteinuria and functional characteristics of the glomerular barrier in diabetic nephropathy.

Fractional clearances of uncharged dextran 40 and anionic proteins were performed in an attempt to elucidate the defect in glomerular barrier function responsible for heavy proteinuria in diabetic nephropathy. Notwithstanding urinary albumin excretion (UalbV) at 3634 +/- 608 microgram/min, the fractional clearance for dextran molecules with Einstein-Stokes radii (r) between 22 and 36 A was depressed in 12 patients with advanced diabetic nephropathy, which suggests a reduction in mean glomerular pore size or density. Equivalent restriction to transglomerular passage of dextrans with a r < 36 A in 7 patients with minimal change nephropathy was associated with a similarly enhanced proteinuria (UalbV, 3333 +/ 759 microgram/min). The dissociation between fractional clearances for neutral and anionic macromolecules in both disorders is consistent with loss of glomerular electrostatic charge. In diabetic nephropathy, however, the fractional clearances for large dextrans and test proteins considerably exceeded corresponding values in minimal change nephropathy when r greater than or equal to 36 A. Furthermore, the fractional clearances for test proteins were two orders of magnitude smaller than that for equivalent-sized dextrans in minimal change nephropathy, whereas this difference was much less in diabetic nephropathy. Thus, a selective increase in transglomerular passage of large molecules and a progressive loss of ability to discriminate between large molecules of different configuration distinguish the glomerular capillary wall in diabetic nephropathy from that in minimal change nephropathy.

Albuminuria and the permselective properties of the glomerulus in cardiac failure.

Fractional dextran clearances (theta D) were used to ascertain whether the albuminuria accompanying cardiac failure (CF) has a hemodynamic basis. In 17 patients with grade-IV CF in whom GFR and effective renal plasma flow (ERPF) were depressed to 58 +/- 7 and 215 +/- 20 ml/min/1.73 m2, respectively, theta D was elevated relative to normal control subjects over the Stokes-Einstein radius (r) interval of 28 to 46 Angstrom. For dextran of equivalent size to albumin (r = 36 Angstrom), the rate of urinary excretion (UD36V) was not increased because elevated theta D36 was offset by the depressed GFR. In contrast, urinary albumin excretion (UalbV) was increased to 82 +/- 35 microgram/min. Thus, for albuminuria in CF to have the hemodynamic basis suggested by elevation of theta D requires that (I) the fractional clearance for anionic albumin be disproportionately enhanced relative to uncharged dextran by reduced glomerular plasma flow and/or (2) that glomerular electrostatic barrier function be impaired in CF. In seven patients with minimal change nephropathy, UD36V was similar to that in CF, but UalbV was 40 times greater than that in CF. Thus, if glomerular electrostatic barrier function is impaired in CF, such dysfunction is trivial by comparison with minimal change nephropathy.

Acute renal failure following cardiac surgery.

In a prospective 6 month study of 204 patients requiring cardiac operations, five (2.5 percent) developed acute renal failure (ARF) and five (2.5 percent) had documented renal dysfunction (RD). Preoperative left ventricular dysfunction and prolonged cardiopulmonary bypass (CPB) were important predictors of subsequent RD/ARF; CPB pressure per se was not. Physiological and clinical studies in 51 selected patients studied over an 18 month period documented the effectiveness of low flow, low pressure CPB in preserving postoperative renal function. Twenty-two patients with nonazotemic postoperative courses demonstrated moderate depression of cardiac function while the glomerular filtration rate (GFR) was normal (98 +/- 30 ml./min/1.73 M.2) within 24 hours of operation. Seventeen high risk patients developed AFF (65 percent mortality rate) and 12 experienced severe RD without ARF (17 percent mortality). ARF (65 percent mortality rate) and 12 experienced severe RD without ARF (17 percent mortality). Eleven patients with ARF and 11 with RD were studied in the early postoperative period; at this time, all 22 patients demonstrated RD with equivalent severe depression of cardiac and renal function. Superposition of further hemodynamic or toxic insults upon ischemic kidneys was usually necessary for ARF to occur.