Biomedical subjects

B D Myers

Publications and source records attributed to B D Myers.

At least 37 records · Page 2Linked to original sources

PubMed1997

Modeling of progressive glomerular injury in humans with lupus nephritis.

We studied glomerular function longitudinally for 36-120 mo in 21 patients undergoing treatment for diffuse, proliferative lupus nephritis. We determined glomerular filtration rate (GFR) and glomerular oncotic pressure (IIGC) and computed the two-kidney ultrafiltration coefficient (Kf) at 6- to 12-mo intervals. The relationships and cross talk among the three variables over time were then analyzed by eigenfunction regression and canonical correlations. We also performed a morphometric analysis of serial biopsies and computed single-nephron Kf in patent glomeruli at baseline and after 36-94 mo of follow-up. Patients were divisible into progressors (n = 12) or nonprogressors (n = 9) according to the presence or absence, respectively, of an irrevocable decline in GFR over time. Examination of longitudinal variables revealed GFR to be strongly related to Kf in all patients and inversely related to IIGC in progressors. By serial morphometric analysis we observed a threefold increase in the prevalence of global sclerosis in progressors but unchanged prevalence in nonprogressors. Whereas single-nephron Kf of remnant glomeruli increased to supernormal levels in nonprogressors, the absence of this compensatory phenomenon in progressors permitted GFR and Kf to decline in parallel with the declining number of functional glomeruli.

Adolescent↗

PubMed1997

Molecular configuration and glomerular size selectivity in healthy and nephrotic humans.

We studied eight healthy volunteers and eight nephrotic subjects to compare the glomerular sieving coefficients (theta) of dextran, a linear polymer of glucopyranose, with those of Ficoll, a spherical polysucrose. Over a molecular radius (rs) interval of 20-70 A, theta for a given Ficoll was uniformly lower than corresponding theta for a dextran of equivalent rs. For each macromolecular species, the theta of molecules with rs > 50 A was selectively enhanced in nephrotic vs. healthy subjects. Analysis of either dextran or Ficoll sieving curves with pore theory revealed the glomerular barrier to have a bimodal pore size distribution: a lower mode of restrictive pores with a lognormal distribution of radii and an upper mode of large shuntlike pores. Nephrotics differed from controls in that the lower mode was broadened and shifted to pores of smaller mean size, but the prominence of shuntlike pores was enhanced by an order of magnitude. Both the mean radius of restrictive pores and the magnitude of the shunt pathway were substantially smaller when estimated from Ficoll than dextran sieving. We interpret the more realistic values for pore parameters derived from Ficoll than dextran sieving to indicate 1) that the normal glomerular barrier prevents albuminuria by virtue of a combination of both charge- and size-selective properties and 2) that a combined impairment of both barrier charge selectivity and size selectively are required to account for the observed level and composition of proteinuria in our nephrotic subjects.

Adult↗

PubMed1997

Clinical and pathological course of renal disease in non-insulin-dependent diabetes mellitus: the Pima Indian experience.

Non-insulin-dependent diabetes mellitus (NIDDM) and the renal disease attributable to it have been characterized extensively in the Pima Indians, a group of American Indians who form the Gila River Indian Community in Arizona. Both of these diseases are common in this community, and their onset and duration are known with greater certainty than in other populations because research examinations, which include oral glucose tolerance tests and measures of urinary protein excretion, have been performed frequently on most members of the population for the past 30 years. Studies of glomerular structure and hemodynamic function in diabetic Pima Indians indicate that glomerular hyperfiltration often develops at the onset of NIDDM and remains elevated until after overt nephropathy appears. Structurally, the glomeruli in subjects with microalbuminuria are not clearly distinguishable from those in subjects with normoalbuminuria, but macroalbuminuria is characterized by extensive glomerular sclerosis, mesangial expansion, and widening of epithelial cell foot processes that together lead to a rapid decline in the glomerular filtration rate. The decline in glomerular function in subjects with macroalbuminuria is due both to a loss of ultrafiltration surface area and to reduction in glomerular hydraulic permeability.

Albuminuria↗

PubMed1997

Course of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus.

The course of renal disease attributable to non-insulin-dependent diabetes mellitus (NIDDM) has been characterized extensively in the Pima Indians of Arizona. Studies in this population indicate that the glomerular filtration rate often increases at the onset of NIDDM and remains elevated as long as normal urinary albumin excretion (< 30 mg albumin/g creatinine) or microalbuminuria (30-299 mg albumin/g creatinine) persist. After the development of macroalbuminuria (> or = 300 mg albumin/g creatinine), the glomerular filtration rate declines at least as rapidly as reported in subjects with insulin-dependent diabetes. Morphologic examination of kidney tissue reveals extensive glomerular sclerosis, mesangial expansion, and widening of epithelial cell foot processes and the glomerular basement membrane in the subjects with macroalbuminuria, but not in those with normo- or microalbuminuria. These findings suggest that substantial structural damage to the kidney occurs at or about the time that macroalbuminuria develops, and the decline in glomerular function in those with macroalbuminuria is due to a loss of ultrafiltration surface area and a reduction in glomerular hydraulic permeability.

Albuminuria↗

PubMed1996

Development and progression of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus. Diabetic Renal Disease Study Group.

BACKGROUND: Non-insulin-dependent diabetes mellitus (NIDDM) is a major cause of end-stage renal disease. However, the course and determinants of renal failure in this type of diabetes have not been clearly defined. METHODS: We studied glomerular function at intervals of 6 to 12 months for 4 years in 194 Pima Indians selected to represent different stages in the development and progression of diabetic renal disease. Initially, 31 subjects had normal glucose tolerance, 29 had impaired glucose tolerance, 30 had newly diagnosed diabetes, and 104 had had diabetes for five years or more; of these 104, 20 had normal albumin excretion, 50 had microalbuminuria, and 34 had macroalbuminuria. The glomerular filtration rate, renal plasma flow, urinary albumin excretion, and blood pressure were measured at each examination. RESULTS: Initially, the mean (+/-SE) glomerular filtration rate was 143+/-7 ml per minute in subjects with newly diagnosed diabetes, 155+/-7 ml per minute in those with microalbuminuria, and 124+/-7 ml per minute in those with macroalbuminuria; these values were 16 percent, 26 percent, and 1 percent higher, respectively, than in the subjects with normal glucose tolerance (123+/-4 ml per minute). During four years of follow-up, the glomerular filtration rate increased by 18 percent in the subjects who initially had newly diagnosed diabetes (P=0.008); the rate declined by 3 percent in those with microalbuminuria at base line (P=0.29) and by 35 percent in those with macroalbuminuria (P<0.001). Higher base-line blood pressure predicted increasing urinary albumin excretion (P=0.006), and higher base-line urinary albumin excretion predicted a decline in the glomerular filtration rate (P<0.001). The initial glomerular filtration rate did not predict worsening albuminuria. CONCLUSIONS: The glomerular filtration rate is elevated at the onset of NIDDM and remains so while normal albumin excretion or microalbuminuria persists. It declines progressively after the development of macroalbuminuria.

Adolescent↗

PubMed1996

Mechanism of the antiproteinuric effect of cyclosporine in membranous nephropathy.

Forty-one patients with a nephrotic syndrome and biopsy-proven membranous nephropathy were administered a 3 to 6-month course of cyclosporine (CsA;4 to 5 mg/kg per day). Differential solute clearances were used to evaluate glomerular function, before and after therapy. CsA lowered median proteinuria by 56%, from 7.3 to 3.2 g/24 h (P < 0.0001). Corresponding mean increments in serum albumin, immunoglobulin G, and oncotic pressure values were 31, 32, and 26%, respectively (all P < 0.0001). Arterial pressure, GFR, and renal plasma flow remained constant, but CsA restored the dextran-sieving curve toward normal, lowering the computed fraction of shunt-like pores by 25% (P < 0.05). In 14 instances, a cross-over design was used to randomly assign patients to 3 months of CsA versus 3 months of enalapril (10 to 30 mg daily), separated by a 1-month washout interval. Although enalapril lowered arterial pressure by 8 mm Hg (P < 0.01), it had no effect on proteinuria, plasma protein composition, filtration dynamics, or dextran sieving (all P = not significant). CsA dependence of proteinuria, indicated by relapsing nephrosis after CsA withdrawal, required additional courses of CsA to maintain proteinuria subnephrotic in most patients. In six patients with declining GFR during prolonged CsA treatment, a repeat biopsy showed more prominent immune deposits and a thicker glomerular basement membrane than at baseline. It was concluded that: (1) CsA lowers proteinuria in MN in part, by enhancing barrier size-selectivity; (2) lack of comparable efficacy of enalapril suggests that the antiproteinuric effect of CsA is related to its immuno-suppressive rather than glomerulodepressor properties; but (3) judged by repeat biopsy, CsA does not prevent continuing autoantibody formation in this disorder.

Adolescent↗

PubMed1995

Progression of overt nephropathy in non-insulin-dependent diabetes.

The detection of overt albuminuria (> 300 mg/g creatinine) in the absence of azotemia was used to diagnose early nephropathy in 34 Pima Indians with NIDDM of 16 +/- 1 years duration. Differential solute clearances were performed serially to define the course of the glomerular injury over 48 months. At baseline, the GFR (107 +/- 5 ml/min), filtration fraction and sieving coefficients of relatively permeant dextrans (< 52 A) were all depressed below corresponding values in 20 normoalbuminuric Pima Indians with a similar duration of NIDDM. Over the ensuing 48 months the GFR (-34%) and filtration fraction (-13%) in the nephropathic patients declined further. The sieving coefficients of large, nearly impermeant dextrans (> 56 A radius) increased selectively and fractional clearances of albumin and IgG increased correspondingly by > 10-fold. Analysis of the findings with pore theory revealed: (1) a progressive decline in pore density and the ultrafiltration coefficient (Kf); and (2) broadening of glomerular pore-size distribution that resulted in greater prominence of large pores (> 70 A radius). We conclude that increasing loss of intrinsic ultrafiltration capacity is the predominant cause of the early and progressive decline in GFR that follows the development of nephropathy in NIDDM. We speculate that progressive impairment of barrier size-selectivity contributes to but does not fully account for the increasingly heavy proteinuria that is observed early in the course of this disorder.

Adolescent↗

PubMed1995

Postischemic injury, delayed function and Na+/K(+)-ATPase distribution in the transplanted kidney.

We evaluated the postischemic renal injury in 22 patients undergoing renal transplantation. Renal tissue obtained 45 to 60 minutes after reperfusion of the allograft was stained with specific antibodies against the delta subunit of Na+/K(+)-ATPase, fodrin and ankyrin. The distribution of each cytoskeletal protein was analyzed by laser confocal microscopy. Subsequent allograft function was assessed on two occasions, 1 to 3 and 36 hours post-reperfusion, respectively. Recipients were divided into two groups: those who achieved a normal GFR on post-transplant day 3 (group 1, N = 12) and those with persistent hypofiltration (group 2, N = 10). Patients of both groups exhibited impaired sodium reabsorption and isosthenuria one to three hours postoperatively, but these abnormalities persisted on day 3 only in group 2 subjects with persistent hypofiltration. Abnormalities of Na+/K(+)-ATPase, ankyrin and fodrin were confined to proximal tubule cells and were marked only in the subjects of group 2. They consisted of redistribution of each cytoskeletal protein from the basolateral membrane to the cytoplasm. We conclude that postischemic injury to a renal allograft results in a loss of polarity of proximal tubule cells. We propose that ensuing impairment of proximal sodium reabsorption could activate tubuloglomerular feedback, thereby contributing to the protracted hypofiltration that characterizes this form of postischemic, acute renal failure.

Adolescent↗

PubMed1995

Endogenous ANP in postischemic acute renal allograft failure.

Circulating atrial natriuretic peptide (ANP) levels and glomerular binding sites for ANP were examined in 23 subjects undergoing renal transplantation. Subjects were divided into two groups, group 1 (n = 12) with prompt and group 2 (n = 11) with delayed allograft function. Sixty to 180 min after graft reperfusion, renovascular resistance was threefold higher and glomerular filtration rate (GFR) depressed by 79% in group 2 vs. group 1. Corresponding median plasma ANP (114 vs. 140 pg/ml) and guanosine 3',5'-cyclic monophosphate (cGMP) levels (22 vs. 28 pmol/ml) were similarly elevated in the two groups [P = not significant (NS)]. Autoradiographic analysis of glomeruli in an allograft biopsy revealed the median density of total receptors (24 vs. 28 fmol/mm3), A receptors (15 vs. 19 fmol/mm3), and C receptors (6 vs. 9 fmol/mm3) for ANP to also be similar in group 2 vs. group 1, respectively (P = NS). By postoperative day 3, allograft GFR averaged only 6 +/- 2 in group 2 vs. 59 +/- 4 ml/min in group 1. Median plasma ANP levels doubled in each group to 262 and 251 pg/ml, respectively (P = NS). However, median values for plasma levels (38 vs. 17 pmol/ml) and the fractional clearance of cGMP (1.9 vs. 1.2) were significantly higher in group 2 than group 1. We conclude that, despite an adequate density of glomerular ANP receptors and enhanced cGMP generation, neither renal vasoconstriction nor hypofiltration is alleviated by a progressive elevation of plasma ANP levels in renal transplant recipients with sustained postischemic injury. We infer that constricted afferent arterioles are unresponsive to the vasorelaxant action of endogenous ANP in this form of postischemic, acute renal failure.

Acute Kidney Injury↗

PubMed1995

Mechanisms of filtration failure during postischemic injury of the human kidney. A study of the reperfused renal allograft.

Postischemic filtration failure in experimental animals results primarily from depression of the transcapillary hydraulic pressure difference (delta P), a quantity that cannot be determined in humans. To circumvent this limitation we determined the GFR and each of its remaining determinants in transplanted kidneys. Findings in 12 allografts that exhibited subsequent normofiltration (group 1) were compared with those in 11 allografts that exhibited persistent hypofiltration (group 2). Determinations were made intraoperatively in the exposed graft after 1-3 h of reperfusion. GFR (6 +/- 2 vs 29 +/- 5 ml/min) and renal plasma flow by Doppler flow meter (140 +/- 30 vs 315 +/- 49 ml/min) were significantly lower in group 2 than group 1. Morphometric analysis of glomeruli obtained by biopsy and a structural hydrodynamic model of viscous flow revealed the glomerular ultrafiltration coefficient to be similar, averaging 3.5 +/- 0.6 and 3.1 +/- 0.2 ml/(min.mmHg) in group 2 vs 1, respectively. Corresponding values for plasma oncotic pressure were also similar, averaging 19 +/- 1 vs 21 +/- 1 mmHg. We next used a mathematical model of glomerular ultrafiltration and a sensitivity analysis to calculate the prevailing range for delta P from the foregoing measured quantities. This revealed delta P to vary from only 20-21 mmHg in group 2 vs 34-45 mmHg in group 1 (P < 0.001). Further morphometric analysis revealed the diameters of Bowman's space and tubular lumens, as well as the percentage of tubular cells that were necrotic or devoid of brush border, to be similar in the two groups. We thus conclude (a) that delta P depression is the predominant cause of hypofiltration in this form of postischemic injury; and (b) that afferent vasoconstriction rather than tubular obstruction is the proximate cause of the delta P depression.

Adult↗

PubMed1994

Determination of blood flow to the transplanted kidney. A novel application of phase-contrast, cine magnetic resonance imaging.

There is at present no noninvasive method that reliably measures blood flow in the poorly functioning renal allograft. The present study was designed to evaluate phase-contrast cine magnetic resonance imaging (PC-cine-MRI) for this purpose. We recruited for study 18 patients who had received kidney transplants 13-66 months earlier from closely related living donors. As judged by the glomerular filtration rate, which was elevated for a single kidney (76 +/- 4 ml/min 1.73 m2), allograft function was excellent, permitting the assumption of unimpaired renal extraction of paminohippuric acid (PAH). Allograft blood flow was determined consecutively on the same day, first by the standard PAH clearance technique and they by the product of the velocity of protons and renal vein cross-sectional area using PC-cine-MRI. MRI determinations could not be completed because of claustrophobia in two patients and failure to image the terminus of the allograft vein another two. Comparison of blood flow in the remaining 14 subjects revealed the two techniques to be strongly related (r = 0.91, P < 0.001). On the average, the renal blood flow rate was similar by each method; 732 +/- 62 by PAH clearance and 703 +/- 69 ml/min by PC-cine-MRI, but the agreement among individuals between the two methods was only modest, with a 95% confidence interval of agreement from -214 to +254 ml/min. We conclude that PC-cine-MRI provides a fairly accurate and noninvasive method for determining the rate of blood flow in the transplanted kidney. With further refinement it should permit the role of depressed blood flow in a variety of acute and chronic forms of human allograft dysfunction to be elucidated in humans for the first time.

Glomerular Filtration Rate↗

PubMed1994

Mechanisms of proteinuria in nephrotic humans.

The glomerular capillary wall imposes a remarkably efficient barrier to the passage of proteins the size of albumin and larger. The development of heavy proteinuria signifies impairment of the function of this barrier. Because endogenous proteins of graded size are heterogeneous with respect to their molecular charge and undergo extensive tubular reabsorption, they are not useful for quantifying the extent of barrier dysfunction. An alternative approach is to determine the fractional clearance of uncharged and non-reabsorbable polymers of graded size. When combined with a hydrodynamic theory of solute transport through a heteroporous membrane, the intrinsic properties of healthy and diseased glomerular capillary walls can be inferred. This approach reveals the nephrotic range proteinuria that attends minimal change nephropathy to be associated with impairment of both the size- and charge-selective properties of glomerular capillary walls.

Albumins↗

PubMed1994

The biophysical basis of hypofiltration in nephrotic humans with membranous nephropathy.

Physiologic and morphologic techniques were used to elucidate the determinants of the glomerular filtration rate in 62 nephrotic patients with membranous nephropathy and 104 healthy controls. Renal plasma flow, glomerular filtration rate, afferent oncotic pressure and dextran sieving coefficients were determined. Mathematical models of glomerular filtration were then used to compute likely upper bounds for the ultrafiltration coefficient and pore area/length ratio (a measure of pore density). These upper bounds for each measure of intrinsic ultrafiltration capacity were both depressed by 75% in membranous nephropathy. A corresponding excess of ultrafiltration pressure (versus control), attributable solely to reduced intracapillary oncotic pressure was by 12 mm Hg. Glomerular morphometry revealed peripheral capillary filtration surface area to be enhanced in membranous nephropathy (3.27 x 10(5) vs. 2.03 x 10(5) micron2). However, there was a massive reduction in filtration slit frequency due to epithelial podocyte broadening (336 vs. 1204 slits/mm capillary length) as well as marked thickening of the glomerular basement membrane (1130 vs. 388 nm). We conclude that the latter two findings lower the ultrafiltration coefficient in membranous nephropathy by depressing the hydraulic permeability of the glomerular capillary wall. We propose that this abnormality is solely responsible for the hypofiltration observed in a majority of patients with this disease.

Adolescent↗

PubMed1994

Renal artery blood flow: quantitation with phase-contrast MR imaging with and without breath holding.

PURPOSE: To compare the accuracy of 16-frame cine phase-contrast (PC) magnetic resonance (MR) imaging with those of two breath-hold PC techniques in the measurement of renal artery blood flow. MATERIALS AND METHODS: In vitro flow measurements were performed in a segment of harvested human artery embedded in gel. For the cine PC acquisition, respiratory motion was simulated. In eight subjects with recently obtained para-amino-hippurate-clearance renal blood flow data, renal artery flow measurements were subsequently performed with two breath-hold imaging techniques and with cine PC imaging during shallow respiration. RESULTS: Breath-hold sequences were significantly more accurate than conventional cine PC sequences both in vitro (P < .005) and in vivo (P < .05). Cine PC imaging tended to overestimate flow (in vivo mean, 24.47% +/- 9.94), reflecting artifactual enlargement of the apparent vessel size. CONCLUSION: Reliable blood flow measurements in the renal artery are possible with breath-hold PC MR imaging.

Adult↗

PubMed1994

Structural basis for reduced glomerular filtration capacity in nephrotic humans.

Previous studies have established that in a variety of human glomerulopathies the reduced glomerular filtration rate (GFR) is due to a marked lowering of the ultrafiltration coefficient (Kf). To identify the factors which lower Kf, we measured the filtering surface area per glomerulus, filtration slit frequency, basement membrane thickness, and GFR and its determinants in patients with minimal change and membraneous nephropathies and in age-matched healthy controls. Overall values of Kf for the two kidneys were calculated from GFR, renal plasma flow rate, systemic colloid osmotic pressure, and three assumed values for the transcapillary pressure difference. "Experimental" values of the glomerular hydraulic permeability (kexp) were then calculated from Kf, glomerular filtering surface area, and estimates of the total number of nephrons of the two kidneys. Independent estimates of the glomerular hydraulic permeability (kmodel) were obtained using a recent mathematical model that is based on analyses of viscous flow through the various structural components of the glomerular capillary wall. Individual values of basement membrane thickness and filtration slit frequency were used as inputs in this model. The results indicate that the reductions of Kf in both nephropathies can be attributed entirely to reduced glomerular hydraulic permeability. The mean values of kexp and kmodel were very similar in both disorders and much smaller in the nephrotic groups than in healthy controls. There was good agreement between kexp and kmodel for any given group of subjects. It was shown that, in both groups of nephrotics, filtration slit frequency was a more important determinant of the water flow resistance than was basement membrane thickness. The decrease in filtration slit frequency observed in both disorders caused the average path length for the filtrate to increase, thereby explaining the decreased hydraulic permeability.

Adolescent↗

PubMed1994

Determinants of glomerular hypofiltration in nephrotic patients with minimal change nephropathy.

Physiologic and morphologic techniques were used to elucidate the determinants of the GFR in 25 nephrotic patients with minimal change nephropathy. They were divided into two groups according to the finding of either a normal (Group 1, N = 13) or a depressed (Group 2, N = 12) inulin clearance. RPF, afferent oncotic pressure, and dextran sieving coefficients were determined. Mathematical models of glomerular ultrafiltration were then used to compute likely upper bounds for the ultrafiltration coefficient and pore area/length ratio (a measure of pore density). The upper bounds for each measure of intrinsic ultrafiltration capacity were depressed below estimated normal values in healthy controls by 55 and 47% in Group 1 patients and by 86 and 83% in Group 2 patients with minimal change nephropathy. A corresponding excess of ultrafiltration pressure (versus control), attributable solely to reduced intracapillary oncotic pressure, was by 10.8 and 11.5 mm Hg, respectively. Glomerular morphometry revealed peripheral capillary filtration surface area to be preserved in both minimal change nephropathy groups. However, a significant reduction in filtration slit frequency due to epithelial podocyte broadening correlated with the computed ultrafiltration coefficient across the two minimal change nephropathy groups (r = 0.65; P < 0.001). It was concluded that podocyte deformation invariably lowers the ultrafiltration coefficient and pore area/length ratio in minimal change nephropathy but that an offsetting reduction in intracapillary oncotic pressure prevents the GFR from declining in many cases. However, the models presented here predict that the depression of capillary oncotic pressure is insufficient to compensate when the ultrafiltration coefficient is lowered by substantially more than half and that it is in this circumstance that minimal change nephropathy is most likely to be accompanied by glomerular hypofiltration.

Adolescent↗

PubMed1993

Elevated levels of tumor necrosis factor-alpha in the nephrotic syndrome in humans.

To investigate the possible role of cytokines in the mediation of glomerular injury in the nephrotic syndrome, the levels of interleukin (IL)-1 beta, IL-2, interferon (IFN)-alpha, IFN-gamma, and tumor necrosis factor-alpha (TNF-alpha) were measured in patients with primary nephrotic syndrome. These patients had minimal change nephropathy (MCN), focal and segmental glomerulosclerosis (FSGS), or membranous nephropathy (MN) on biopsy. Cytokine levels were assessed by immunoradiometric assays, and specimens consisted of plasma, urine, and the culture supernate of mitogen-stimulated peripheral blood mononuclear cells (PBMC). Only TNF-alpha was found to be significantly elevated, in the plasma and urine of patients with FSGS and MN, above that found in healthy control subjects and patients with MCN. The elevation of TNF-alpha could not be shown to correlate with the length or severity of the nephrotic syndrome or with loss of body mass. IL-1 beta, IL-2, IFN-alpha, and IFN-gamma levels were not elevated. In culture, mitogen-stimulated PBMC from all three groups of nephrotic subjects released an excess of TNF-alpha compared with controls, a response not consistently observed for the other cytokines measured. The findings of this survey of cytokine levels in nephrotic patients support the possibility that TNF-alpha may play a pathogenic role in the induction or maintenance of glomerular barrier dysfunction in humans.

Adolescent↗

PubMed1993

Effects of angiotensin II receptor blockade on remnant glomerular permselectivity.

This study examined the mechanisms by which angiotensin II (Ang II) receptor blockade improves glomerular barrier function in rats with reduced nephron number. Proteinuria was measured at four weeks after 5/6 renal ablation, and rats were then divided into a group which received the Ang II receptor blocker MK954 and a group which received no treatment. Studies performed one week later showed that Ang II receptor blockade reduced proteinuria without altering GFR in renal ablated rats. Micropuncture studies showed that Ang II blockade reduced both mean arterial pressure (142 +/- 7 mm Hg, ablation without treatment; 105 +/- 2 mm Hg, ablation with treatment) and glomerular transcapillary pressure (54 +/- 3 mm Hg, ablation without treatment; 43 +/- 1 mm Hg, ablation with treatment). Dextran sieving studies showed that untreated rats developed a size-selective defect characterized by increased transglomerular passage of neutral dextrans with radii 54 to 76 A and a charge-selective defect characterized by an increased transglomerular passage of anionic dextran sulfate with a radius of approximately 18 A. Ang II blockade reduced fractional clearance values for large neutral dextrans near to values observed in normal rats but had no effect on the fractional clearance of dextran sulfate (0.68 +/- 0.11, ablation without treatment; 0.66 +/- 0.08, ablation with treatment; 0.46 +/- 0.05, normal rats). These findings indicate that reducing Ang II activity improves size-selectivity without affecting charge-selectivity in injured remnant glomeruli.

Angiotensin II↗