Homer Smith: his contribution to the practice of nephrology.
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Adult↗
Biomedical subjects
J Neugarten
Publications and source records attributed to J Neugarten.
Estradiol inhibits mesangial cell-mediated oxidation of low-density lipoprotein.
It has been suggested that hyperlipidemia may contribute to the progression of renal disease via the deleterious effects of oxidized low-density lipoprotein (LDL) on the glomerular mesangium. Because estrogens possess potent antioxidant activity, we sought to determine whether sex hormones influence the oxidation of LDL by mesangial cells. Rat mesangial cells were incubated with LDL (200 micrograms/ml), and the extent of lipid oxidation was assessed by the generation of thiobarbituric acid reactive substances (TBARS), by increased electrophoretic mobility, and by enhanced uptake of mesangial cell-modified LDL by macrophages. A progressive rise in TBARS and an increase in electrophoretic mobility was observed on incubation of LDL with mesangial cells. Coincubation with estradiol (10 mumol/L) reduced TBARS generation by 46% at 36 hours (p < 0.01) and reversed the increase in relative electrophoretic mobility (1.25 +/- 0.07 vs 1.01 +/- 0.03, p < 0.05). LDL that had been oxidized by mesangial cells in the presence of estradiol (10 mumol/L) showed reduced uptake by macrophages when compared with LDL that had been oxidized by mesangial cells in the absence of estradiol (14 +/- 2 pmol/10(6) cells per hour vs 22 +/- 3 pmol/10(6) cells per hour, p < 0.05). In contrast, neither testosterone nor estrone had any effect on these parameters. We conclude that estradiol, by virtue of its antioxidant properties, inhibits mesangial cell-mediated oxidation of LDL and reduces the uptake of mesangial cell-modified LDL by macrophages.
Animals↗
The impact of gender on renal transplantation.
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Female↗
Combined antihypertensive and lipid-lowering therapy in experimental glomerulonephritis.
We examined the interrelation between systemic hypertension, hyperlipidemia, and progressive renal injury in experimental glomerulonephritis. Induction of nephrotoxic serum nephritis in Sprague-Dawley rats led to systemic hypertension and hyperlipidemia. Four groups of rats were studied over a 16-week period: (1) untreated nephritic rats; (2) nephritic rats treated with hydralazine, reserpine, and lasix (AH); (3) nephritic rats treated with lovastatin (4 mg/kg) (Lova); and (4) nephritic rats treated with combined antihypertensive/lipid-lowering therapy (AH/Lova). Systolic blood pressure rose progressively in untreated rats (152 +/- 4 mm Hg at 16 weeks). Blood pressure was reduced by antihypertensive therapy (P < .001) (108 +/- 2 mm Hg in the AH group and 111 +/- 3 mm Hg in the AH/Lova group) but remained elevated in animals treated with lovastatin alone (P > .05) (156 +/- 3 mm Hg in the Lova group). Serum cholesterol rose progressively in untreated rats (3.70 +/- 0.85 mmol/L [143 +/- 33 mg/dL] at 16 weeks). The rise in serum cholesterol was prevented by lovastatin therapy (P < .001) (2.22 +/- 0.41 mmol/L [86 +/- 16 mg/dL] in the Lova group and 2.09 +/- 0.52 mmol/L [81 +/- 2 mg/dL] in the AH/Lova group) but not antihypertensive therapy (P > .05) (2.92 +/- 0.65 mmol/L [113 +/- 25 mg/dL] in the AH group). Proteinuria was reduced by antihypertensive therapy (P < .001) and lipid-lowering therapy (P < .05) (16-week values: 1.069 +/- 0.167 g/d in untreated rats, 0.663 +/- 0.164 g/d in the Lova group, 0.392 +/- 0.051 g/d in the AH group, and 0.176 +/- 0.035 g/d in the AH/Lova group).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Medical complications of cocaine: changes in pattern of use and spectrum of complications.
We sought to determine whether changes in patterns of cocaine use, characterized by widespread abuse of cocaine alkaloid, have altered the nature and severity of medical complications over the past decade. Infectious complications, almost invariably associated with intravenous use, accounted for nearly all hospital admissions in the early 1980s. Cardiovascular, neurologic and psychiatric complications rose dramatically after 1987 both in absolute number and as a proportion of total complications. This rise parallelled increases in the absolute number and proportion of hospitalized patients smoking cocaine alkaloid or using intranasal cocaine, both disproportionately associated with non-infectious complications. While infectious complications were often local in nature, serious neurologic and cardiovascular sequelae were observed. These data indicate that changes in patterns of cocaine use have altered the nature and increased the severity of medical complications with a shift from infectious to cardiovascular, neurologic and psychiatric complications which may be life-threatening and associated with substantial morbidity.
Administration, Intranasal↗
Preferential binding of oxidized LDL to rat glomeruli in vivo and cultured mesangial cells in vitro.
Hyperlipidemia may contribute to the pathogenesis of glomerular sclerosis. We therefore compared binding and uptake of native LDL and oxidized LDL (Ox-LDL) to cultured mesangial cells (MC) and the resulting effects on prostaglandin generation and cell proliferation. Ox-LDL, prepared from native LDL by incubation with copper, was bound to MC in a concentration dependent manner with a four- to fivefold increase in binding over LDL. In competition binding experiments Ox-LDL competed to 90% with LDL for binding sites, but LDL only displaced Ox-LDL to 15%. Furthermore polyinosinic acid, which blocks binding of Ox-LDL to macrophages, inhibited binding of Ox-LDL but not that of LDL to MC. Mesangial cells also preferentially took up Ox-LDL over LDL, and Ox-LDL resulted in higher [14C] oleate incorporation into cholesteryl esters than LDL, findings consistent with different handling of Ox-LDL and LDL by MC. LDL slightly stimulated mesangial cell proliferation at low concentration (10 to 50 micrograms/ml of LDL) returning to control levels at 100 and 250 micrograms/ml. In contrast Ox-LDL inhibited cell proliferation in a concentration-dependent manner, starting at concentrations as low as 10 to 25 micrograms/ml of Ox-LDL. Direct observations of mesangial cells by phase contrast microscopy confirmed the cytotoxic effects of Ox-LDL. Addition of Ox-LDL to mesangial cells resulted in a concentration-dependent increase in PGE2 synthesis within one hour, while at this time point LDL had no significant effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Dietary protein restriction and glomerular permselectivity in nephrotoxic serum nephritis.
We have previously demonstrated that long-term dietary protein restriction ameliorates proteinuria and limits glomerular structural injury in rats with nephrotoxic serum nephritis. In the present study, we examined the influence of short-term dietary protein restriction on glomerular permselectivity. As compared to nephritic rats maintained on a normal protein diet, whole kidney and single nephron hemodynamics were lower in nephritic rats subjected to dietary protein restriction of three days duration (glomerular filtration rate: 0.79 +/- 0.10 vs. 1.46 +/- 0.11 ml/min, P less than 0.003; renal plasma flow rate: 2.50 +/- 0.34 vs. 3.96 +/- 0.38 ml/min, P less than 0.02; glomerular capillary pressure: 44 +/- 1 vs. 53 +/- 1 mm Hg, P less than 0.002; proteinuria: 77 +/- 15 vs. 224 +/- 14 mg/24 hr, P less than 0.01). This was associated with a rise in afferent resistance, from 2.99 +/- 0.77 to 5.45 +/- 0.94 dyn.sec.cm-5, NS. In nephritic rats maintained on 24% protein, fractional clearances were elevated above control values for neutral dextrans with molecular radii exceeding 50 A but were depressed for those with molecular radii below 30 A (P less than 0.05). Dietary protein restriction elevated the fractional clearances of dextrans with radii less than 30 A while depressing the fractional clearances of dextrans with radii greater than 50 A (P less than 0.05). The proportion of glomerular filtrate permeating the shunt pathway was elevated above control values in nephritic rats on the 24% protein diet but declined in those fed the low protein diet (NSN-24%: 0.86%; NSN-6%: 0.31%; control: 0.19%).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Protective effects of specific platelet-activating factor receptor antagonists in experimental glomerulonephritis.
The present study was undertaken to evaluate the hypothesis that enhanced production of platelet-activating factor (PAF) contributes to the renal hemodynamic alterations and impaired glomerular permselectivity that characterize the heterologous phase of nephrotoxic serum nephritis. Intravenous administration of nephrotoxic gamma globulin to normal rats led to a rapid decline in glomerular filtration rate within 60 min from 1.08 +/- 0.08 to 0.45 +/- 0.12 ml/min/100 g b.wt., P less than .001, and in effective renal plasma flow rate from 2.56 +/- 0.15 to 1.35 +/- 0.21 ml/min/100 g b.wt., P less than .02. Concomitantly, the fractional excretion of protein rose from 3.4 +/- 0.6 X 10(-5) to 11.6 +/- 2.3 X 10(-5), P less than .03. Pretreatment with the specific PAF receptor antagonists WEB 2086 or WEB 2170 significantly ameliorated the impairment in glomerular filtration rate and in effective renal plasma flow rate induced by nephrotoxic globulin. Filtration rate declined by 0.63 +/- 0.12 ml/min/100 g b.wt. 60 min after administration of nephrotoxic globulin, but fell only 0.30 +/- 0.14 ml/min/100 g b.wt. in rats pretreated with WEB 2086, P less than .05 and 0.34 +/- 0.11 ml/min/100 g b.wt. in rats pretreated with WEB 2170, P less than .01. The decline in effective renal plasma flow rate 60 min after administration of nephrotoxic globulin was 1.21 +/- 0.30 ml/min/100 g b.wt., but only 0.86 +/- 0.23 ml/min/100 g b.wt. in rats pretreated with WEB 2086, NS, and 0.52 +/- 0.21 ml/min/100 g b.wt. in rats pretreated with WEB 2170, P less than .003.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Rhabdomyolysis and acute renal failure associated with cocaine abuse.
Cocaine abuse has emerged as a major public health problem among young adults. Illicit use of cocaine has been associated with an increasing array of medical complications. Both traumatic and nontraumatic rhabdomyolysis, often complicated by acute renal failure, has recently been described following cocaine abuse. The present report describes our experience with 15 such patients and serves to further define the spectrum of muscle injury associated with cocaine abuse ranging from the incidental finding of elevated serum levels of muscle enzymes to acute renal failure. Those patients who developed renal failure experienced more severe rhabdomyolysis in association with trauma, seizures or hyperpyrexia.
Acid-Base Equilibrium↗
Thromboxane mediates the renal hemodynamic effects of platelet activating factor.
The mechanism by which platelet-activating factor affects renal hemodynamics is controversial. In the present study we examined the hypothesis that thromboxane mediates the renal hemodynamic response to platelet activating factor (PAF) by determining the effects of pretreatment with a selective thromboxane receptor antagonist. Infusion of platelet-activating factor into the left renal artery of normal rats in a dose that failed to alter mean arterial pressure or blood hematocrit values reduced urinary flow rate from 25.9 +/- 6.3 to 12.6 +/- 1.5 microliters/min (P less than .01), reduced effective renal plasma flow rate from 14.01 +/- 2.09 to 5.42 +/- 2.38 ml/min/kg body weight (P less than .01), reduced glomerular filtration rate from 4.81 +/- 1.00 to 1.68 +/- 0.34 ml/min/kg (P less than .03), and increased the fractional excretion of protein from 0.021 +/- 0.008 to 0.094 +/- 0.005 percent (P less than .05). Pretreatment with the selective thromboxane receptor antagonist SKF 96148 (10 mg/kg) not only prevented PAF-induced reductions in effective renal plasma flow rate and glomerular filtration rate but increased these values (effective renal plasma flow rate: 14.09 +/- 2.76 vs. 16.84 +/- 2.08 ml/min/kg, P less than .05; glomerular filtration rate: 4.42 +/- 0.43 vs. 5.50 +/- 0.59 ml/min/kg, P less than .03) and aborted proteinuria. Pretreatment with indomethacin (2 mg/kg) ameliorated PAF-induced alterations in renal hemodynamics and glomerular permselectivity in the final collection period. Infusion of lyso-PAF, a biologically inactive precursor of PAF, or of indomethacin alone or SKF 96148 alone had no significant effect on measured parameters. These observations suggest that thromboxane mediates the renal hemodynamic and permselective effects of PAF.
Animals↗
Cocaine-induced rhabdomyolysis masquerading as myocardial ischemia.
PURPOSE: Cocaine abuse has recently emerged as a major problem among young adults, and is increasingly associated with a variety of medical complications. In view of recent reports demonstrating that illicit cocaine use may cause rhabdomyolysis, we reviewed the collective experience of a university-affiliated medical center to identify patients with cocaine-induced rhabdomyolysis. PATIENTS AND METHODS: Among hospital admissions due to acute cocaine abuse during the period June 1987 through June 1988, we identified seven patients who exhibited biochemical evidence of skeletal muscle injury. Six of these patients presented within one hour of free-basing cocaine with complaints of thoracic skeletal muscle pain. Hospital admission was prompted by the suspicion of myocardial ischemia or infarction. The remaining patient was incidentally found to have an elevated serum level of creatine phosphokinase (CPK) after abusing cocaine and was hospitalized to exclude a cardiac origin. RESULTS: Serum CPK levels in the seven patients rose to a mean peak value of 16.1 +/- 3.6 mu kat/L, and returned toward normal within 72 hours. A cardiac origin for the elevated CPK values was excluded by negative results of determinations of CPK-MB fractions. CONCLUSION: Rhabdomyolysis must be added to the every-growing list of medical complications associated with the illicit use of cocaine. Skeletal muscle injury may be a more common complication of cocaine abuse than has previously been appreciated, escaping medical attention when the clinical manifestations are relatively mild. The importance of recognizing this clinical entity lies in the potential confusion with myocardial ischemia. This point is illustrated by the fact that each of our patients was hospitalized to exclude the possibility of cocaine-induced myocardial infarction. Cardiac ischemia could not be differentiated from skeletal muscle injury solely on the basis of clinical assessment.
Adult↗
Effect of indomethacin on glomerular permselectivity and hemodynamics in nephrotoxic serum nephritis.
The present study was undertaken to determine the effects of prostaglandin synthesis inhibition on glomerular hemodynamics in nephrotoxic serum nephritis and to elucidate the mechanisms by which prostaglandin synthesis inhibition reduces proteinuria in nephritic rats. Dextran sieving studies were performed before and after intravenous administration of indomethacin to control rats and to nephritic rats with heavy proteinuria. Indomethacin did not significantly alter mean arterial pressure, glomerular filtration rate or proteinuria in control rats nor were significant changes in dextran sieving observed. By contrast, in nephritic rats indomethacin significantly reduced glomerular filtration rate (2.58 +/- 0.50 vs. 1.39 +/- 0.27 ml/min, P less than 0.001), proteinuria (0.198 +/- 0.079 vs. 0.048 +/- 0.019 mg/min, P less than 0.05) and filtration rate-corrected proteinuria (0.059 +/- 0.033 vs. 0.031 +/- 0.013 mg/ml GFR, P less than 0.05). The fractional clearance of neutral dextrans with molecular radii exceeding 42 A were elevated above control values in nephritic rats (P less than 0.05). After administration of indomethacin, the fractional clearance of neutral dextrans uniformly declined toward control values and remained elevated only for molecular radii exceeding 54 A. Assessment of glomerular hemodynamics in nephritic rats before and after indomethacin showed significant declines in single nephron filtration rate (31.5 +/- 3.0 vs. 21.2 +/- 2.5 nl/min, P less than 0.02), glomerular plasma flow rate (99.5 +/- 6.7 vs. 68.5 +/- 7.8 nl/min, P less than 0.05) and glomerular ultrafiltration coefficient (0.0430 +/- 0.0033 vs. 0.0339 +/- 0.0032 nl.sec-1.mm Hg-1, p less than 0.05). Indomethacin did not significantly change these parameters in control rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Glomerular size-selective barrier dysfunction in nephrotoxic serum nephritis.
We have previously reported amelioration of heavy proteinuria, vascular sclerosis and glomerular structural damage by antihypertensive therapy in nephrotoxic serum nephritis (NSN). In the present study, we examine glomerular permselectivity in this hypertensive form of NSN and the effect of hypertension treatment on size-selective barrier function. Mean arterial pressure was maintained at normotensive levels (mean 123 +/- 3 mm Hg) with a combination of hydralazine, hydrochlorthiazide and reserpine in 7 nephritic rats, while 10 untreated rats remained hypertensive (mean 165 +/- 4 mm Hg). At six weeks, glomerular filtration rate was reduced in untreated rats (mean 0.54 ml/min) but was preserved in those rendered normotensive (mean 1.71 ml/min), P less than 0.02). Twenty-four-hour urinary protein excretion, mean 371 +/- 74 mg in hypertensive nephritic rats, was markedly reduced in rats on the antihypertensive regimen to a mean of 120 +/- 17 mg (P less than 0.02), as was 24-hour urinary gamma-globulin excretion (mean 35 +/- 9 mg in untreated vs. 16 +/- 2 mg in treated). Fractional clearances of tritiated polydisperse neutral dextrans were significantly enhanced for molecular radii exceeding 50 angstroms in hypertensive animals, indicative of a loss of glomerular size permselectivity. Rats on antihypertensive therapy did not develop such a size selective defect. Thus, hypertensive rats with nephrotoxic serum nephritis develop "gaps" in the glomerular basement membrane which allow the excretion of large molecular weight neutral dextrans and gamma-globulin. This defect in glomerular permselectivity can be averted with antihypertensive therapy.
Animals↗
Nephrotoxic serum nephritis with hypertension: perfusion pressure and permselectivity.
We examined the effect of acute reduction in renal perfusion pressure on proteinuria and glomerular permselectivity in a model of nephrotoxic serum nephritis which is characterized by hypertension, heavy proteinuria and severe structural injury. Sequential dextran sieving studies were performed after two weeks of nephritis in 10 uninephrectomized rats at their basal elevated blood pressure levels (154 +/- 3 mm Hg) and at lowered renal perfusion pressure of 105 to 110 mm Hg, achieved by adjusting a ligature around the aorta above the origin of the renal artery. Glomerular filtration rate (GFR) decreased from 1.35 +/- 0.24 to 0.95 +/- 0.19 ml/min (P less than 0.002), while urinary protein excretion (factored for filtration rate) declined from 0.69 +/- 0.2 to 0.39 +/- 0.1 mg per ml GFR (P less than 0.002) at the lower perfusion pressure. A companion protocol documented a modest reduction in renal plasma flow (RPF) from 4.96 +/- 0.48 to 4.44 +/- 0.63 ml/min (P less than 0.05) and a decline in glomerular transcapillary hydraulic pressure difference (delta P) from 43 to 33 mm Hg (P less than 0.001) during the ligature maneuver. In the hypertensive state, fractional clearances of neutral dextrans (theta ND) with molecular radii exceeding 40 A were elevated in nephritic rats as compared to uninephrectomized non-nephritic controls. With reduction in renal perfusion pressure. Theta ND uniformly declined toward control values and remained significantly elevated only for molecular radii exceeding 55 A. The calculated fraction of glomerular filtrate passing through a non-size discriminatory shunt, pathway was 0.93% during the hypertensive period and was reduced at lower perfusion pressures to 0.52% (to be compared to 0.19% in controls).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Hypertension and renal diseases.
Experimental data are summarized that provide evidence that enhanced transmission of systemic hypertension to the glomerulus occurs in the setting of reduced renal mass. It is proposed that similar adaptive glomerular hemodynamic alterations occur in parenchymal renal disease in humans, favoring the development of intraorgan hypertension. Accelerated vascular and glomerular damage and functional deterioration result. Treatment of systemic hypertension with agents that reduce glomerular capillary pressure has been shown to ameliorate the manifestations of experimental glomerular disease. The importance of preventing hemodynamic injury to the arterioles and glomerular capillaries in the management of human renal disease is stressed.
Animals↗
The existence of a protracted course in crescentic glomerulonephritis.
We describe a spectrum of clinical and morphologic features which may occur in idiopathic crescentic glomerulonephritis. Of note are patients who pursue a more indolent course to renal failure in contrast to typical rapidly progressive glomerulonephritis (RPGN). Patients following this protracted course have an insidious presentation with hematuria and renal insufficiency, and at the time of renal biopsy (usually after many months of clinical illness) show less extensive involvement with crescents, which are often in both cellular and fibrous stages. This form of crescentic glomerulonephritis is further distinguished from RPGN by frequent hypertension and the nephrotic syndrome, the absence of oligo-anuria and progression to renal failure over many months or even years.
Adolescent↗
Role of hypertension in the evolution of renal diseases.
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Animals↗