Biomedical subjects
Publications and source records attributed to F C Luft.
To assess the effects of vancomycin on the kidney, we gave rats doses of 10, 50, 100, 200, and 400 mg/kg per day. Creatinine clearance and urine protein excretion did not differ significantly from the control values. Urine osmolality was unchanged. Mild histological changes occurred in rats given the highest dose. We conclude that although histopathological changes occurred at high doses, vancomycin does not alter renal function in rats.
To establish dosage recommendations, moxalactam elimination kinetics were studied in six anephric patients during hemodialysis and in four anephric patients during the interdialytic period. After a single 1-g intravenous bolus injection, moxalactam elimination half-life was 18.0 plus or minus 0.6 h with a volume of distribution of 20.2 plus or minus 3.6 liters and a plasma clearance of 12.8 plus or minus 2.0 ml/min in four nondialyzed patients. Moxalactam elimination half-life was decreased to 2.7 plus or minus 0.2 h during hemodialysis in six patients. After 4 h, 48.5% of the dose was recovered in the dialysate. The maintenance dose of moxalactam should be decreased to 15% of a normal dose in patients with creatinine clearances less than 10 ml/min, and 50% of a loading dose should be given after hemodialysis.
To elucidate the relationship between the renal regulation of sodium and calcium excretion at extremes of sodium intake, we studied 6 normal men ingesting a fixed, 400 mg/day calcium intake and four levels of sodium intake from 10 to 1,500 mEq/day. Serum ionized calcium was not influenced by sodium intake. Blood pressure and cardiac index increased modestly. Urinary calcium excretion increased to 262 +/- 53 mg/day (mean +/- SE). Plasma norepinephrine concentration, serum PTH levels, hematocrit, total serum protein concentrations and CO2 content decreased with increasing sodium intake. Urinary cAMP increased as sodium intake was raised from 10 to 300 mEq/day, but subsequently decreased to basal values. Urinary calcium and sodium excretion were related (p less than 0.001) in a nonlinear fashion as were the fractional excretions of these cations (p less than 0.001). The filtered calcium load and the fractional calcium excretion were directly and linearly related (p less than 0.001). We conclude that the effect of sodium intake on urinary calcium excretion principally reflects changes in the filtered calcium load rather than changes in renal sodium handling. Calcium homeostasis at extremes of sodium intake does not appear to be critically dependent upon PTH-mediated mechanisms. The data suggest that the proximal tubule has a remarkable capacity to dissociate calcium resorption from that of sodium.
To examine the effect of T lymphocyte deficiency on the course of immune complex nephritis, we studied renal function and structure in Swiss albino nude and non-nude mice following injection of heterologous protein. Four groups of 22 mice each (two nude and two non-nude) received either apoferritin 2 mg or saline daily for 10 weeks. Nude mice were maintained in a gnotobiotic environment. Non-nude mice receiving apoferritin developed proteinuria and had increased cellularity within glomeruli compared to either nude mice receiving apoferritin or to control groups (p less than 0.05). Of 22 non-nude mice receiving apoferritin, 16 had glomerular immune deposits by electron and immunofluorescent microscopy while 9 of 22 counterpart nude mice receiving apoferritin had such deposits. Non-nude mice more commonly showed membraneous deposits. Nude and non-nude mice receiving saline had no glomerular deposits. These preliminary data suggest that T lymphocytes may play a significant role in the development of immune complex nephritis.
To identify any relationship between diabetes mellitus and high salt intake in the production of hypertension, we studied the effect of a regular and high salt diet on blood pressure in rats made diabetic with alloxan. The diabetic animals developed marked hyperglycemia, glycosuria, and azotemia out of proportion to changes in glomerular filtration rate. Non-diabetic rats and diabetic rats on a high salt intake in excess of 14 mEq/day developed modest but significant increases in blood pressure, while diabetic rats on a regular diet did not. We conclude that diabetic rats have no greater susceptibility to salt-induced hypertension than rats receiving only salt. Although it is possible that dehydration may have served to attenuate blood pressure increases in our diabetic animals, the diabetic state per se does not appear to result in severe hypertension in the rat regardless of sodium intake.
Utilization of several genetic models (twins, families of monozygotic twins, characterized hypertensives and normotensive first-degree-relatives of essential hypertensives) has permitted us to probe for evidence of genetic mediation of several components of the blood pressure control system in humans. These studies have identified evidence for genetic mediation of systolic blood pressure in a cross-sectional study of normotensive subjects covering a wide age span. Further, this effect was independent of body size. The twin model, studied under conditions of sodium loading and sodium and volume depletion, demonstrated a genetic component in the response of plasma renin activity, aldosterone, norepinephrine and renal sodium excretion to these maneuvers. Among hypertensive subjects and unexpected abnormality in the distribution of a specific MNS blood group pattern was seen in renal vascular hypertensives. This may provide a new genetic marker for identifying individuals at increased risk to develop this abnormality.
Twenty-six patients with renal vascular hypertension were treated with percutaneous transluminal dilatation. Twenty-one were followed for more than 1 year; 18 underwent repeat angiography. Recurrence of stenosis was shown angiographically in one of six patients with fibromuscular disease and in 12 of 12 patients with atherosclerotic disease. The procedure was more likely to result in cure of hypertension (six of 10) in patients with fibromuscular disease than in patients with atherosclerotic disease (one of 16). Although percutaneous transluminal angioplasty provides the advantages of simplicity, reduced cost, and probably reduced risk, long-term utility of the procedure remains to be established. A prospective randomized trial, establishment of a registry, or both would serve this purpose.
Previous micropuncture experiments have shown that gentamicin reduces the glomerular Kf even at low doses. Light and transmission electron microscopy have failed to provide evidence of structural alterations to explain the observed decreases in Kf. To elucidate and effects of gentamicin on glomerular ultrastructure, we used both scanning and transmission electron microscopy to study the glomeruli of rats given gentamicin at 4 and 40 mg/kg/day for 10 days, as well as 20 mg/kg/day for 4 weeks. Observations were also made during recovery from gentamicin-induced renal injury. Scanning and transmission electron microscopy revealed that gentamicin induced striking reductions in endothelial fenestral diameter, density, and area. These changes were not appreciated by light microscopy. By quantitative measurements, the reductions in endothelial fenestral area were found to be parallel to the previously observed reduction in Kf. During recovery, the morphological alterations improved pari passu with functional recovery. Contrary to observations in other models of acute renal failure, gentamicin-induced glomerular injury was unique in that the visceral epithelial surface was not affected. The mechanisms by which gentamicin induces alterations in glomerular ultrastructure remain to be defined.
There is a need for nonpharmacologic approaches to hypertension treatment, particularly in those patients with mild elevations in blood pressure. Evidence suggests that development of hypertension is related to excess sodium ingestion in many people and that sodium restriction provides simple, safe, and effective therapy. Dietary sodium restriction should be considered as initial and adjunctive therapy for hypertensive persons, particularly those who are receiving thiazide diuretics. Although validated methods of estimating dietary sodium intake are not yet established, overnight urinary collections provide a convenient approach. Chemical chloride strips may greatly facilitate compliance.
In addition to being tubular nephrotoxins, the aminoglycosides are known to injure the glomerular endothelium by decreasing the diameter and density of endothelial fenestrae. To determine whether or not these changes correlate with the rank order of toxicity we compared in rats the effects of netilmicin, tobramycin, and amikacin on renal function, tubular and glomerular ultrastructure, at 10 and 25 times the recommended human dose. According to measurements of glomerular filtration rate their rank order of toxicity, in increasing severity was: netilmicin, tobramycin, and amikacin. The same order of effect was observed on glomerular ultrastructure. Thus glomerular structural changes correspond to glomerular functional changes in this model.
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Mezlocillin kinetics was examined in 28 adult subjects with varying renal function. Mezlocillin 3 gm, was infused over 30 min. Mean peak plasma concentrations ranged from 204 to 253 mg/I. When the area under the curve (AUC) was plotted against creatinine clearance (CCr), the relationship found was expressed by the equation AUC = 656e(-0.01)(CCr). From this relationship a dosage nonogram was derived describing a power function with the following equaton: Dose fraction = 1.32--e(-0.01)(CCr). Therapeutic guidelines are suggested.
To examine and compare the effects of tobramycin and gentamicin and glomerular endothelium, these drugs were given to rats at dosages of 80, 40 or 4 mg/kg per day for 10 days, when detailed, quantitative scanning electron microscopic studies of glomerular architecture were performed. Gentamicin caused significant dose-related decreases in endogenous creatinine clearance, but tobramycin did not. Gentamicin administration resulted in a decrease in the diameter and density of endothelial fenestrae at all dosages tested. The changes were dose-dependent and accounted for a decrease in filtration area ranging from 75% at 4 mg/kg per day to 36% at 80 mg/kg per day. Tobramycin administration caused only minor alterations, even at the high dosages, which did not significantly reduce filtration area. Thus, the difference in effect of glomerular filtration rate caused by gentamicin and tobramycin corresponds closely to differences in their effects on glomerular ultrastructure.
The nephrotoxicity of dibekacin was compared with those of gentamicin and amikacin in a rat model. The doses used were 3, 10, and 30 times the suggested human therapeutic dose on a weight basis. Indices of glomerular and tubular function failed to clearly differentiate the drugs. Dibekacin and gentamicin produced equally severe injury to the renal tissue. Slightly less damage occurred with amikacin.
To elucidate morphologic changes in glomeruli of rats made diabetic with alloxan 40 mg/kg, we examined the filtration barrier with light microscopy, transmission (TEM), and scanning electron microscopy (SEM). The rats were killed at 10 or 20 weeks. The presence of diabetes was verified by blood and urine glucose measurements. In vivo perfusion was carried out through the left ventricle with gluteraldehyde in cacodylate buffer. SEM and TEM were performed by conventional techniques. SEM revealed striking changes in both the epithelial and endothelial surfaces which were focal and progressive with time. The epithelial surfaces showed podocyte fusion with areas of frank necrosis. Occasional areas of regeneration were seen. The endothelium showed a loss in number and decrease in size of fenestrae, proliferation of microvilli, and appearance of irregular cellular processes. TEM confirmed the presence of cellular changes. The basement membrane was irregularly thickened and the mesangium was more prominent than in control animals. We conclude that not only is the basement membrane affected by diabetes, but also important endothelial and epithelial cell changes occur as well. These changes are best appreciated by SEM and have not been previously described.
To elucidate the role of the glomerular filtration barrier in the development of nephrotoxic acute renal failure, we produced acute renal failure in rats with either gentamicin or tobramycin. Both drugs evoked changes in the glomerular capillary endothelium. Gentamicin administration resulted in a dose-related decrease in the diameter, density and area of endothelial fenestrae, which was considerably more pronounced than those observed with tobramycin. Prolonged, high-dose gentamicin administration caused a decrease in creatinine clearance, an increase in plasma renin activity and a corresponding decrease in the area available for filtration. These changes reverted with continued drug administration. These results support the notion that morphological alterations in the filtration barrier are responsible for the decrease in filtration observed in acute renal failure. The changes may be at least in part mediated by the renin-angiotensin system.
Over a 4-year period, 94 of 248 patients with end-stage renal disease were evaluated echocardiographically because of clinically suspected pericarditis. The clinical diagnosis was established in 39 patients based on the development of a friction rub at some time during their course. 15 of the 55 patients, in whom the diagnosis of pericarditis could not be established, had a small pericardial effusion. The rest had no pericardial fluid. 15 patients developed pericarditis prior to the initiation of dialysis and all responded to dialysis alone. 4 had no effusions, 3 had small effusions and 8 had moderate or large effusions. In 9 of 24 dialysis patients with pericarditis, a presumptive etiology other than uremia was identified. In these 24 patients, 9 had no effusions, 2 had small effusion and 13 had moderate or large effusions. Only 9 patients, all with moderate or large effusions, required operation. The data suggest that: t1) pericarditis present at the initiation of dialysis regularly resolves with dialysis; (2) specific etiologies are common; (3) small pericardial effusions are common in dialysis patients without pericarditis; (4) pericardial effusions are frequently not present in uremic patients with pericarditis and, (5) the size of the pericardial effusion is of some value in predicting which patients may subsequently require operative intervention.
Heritable influences on venous plasma norepinephrine (PNe) and urinary norepinephrine (UNe) values were examined in normotensive monozygotic and dizygotic twins during volume expansion and contraction. The presence of genetic variance was tested by calculating the within-pair estimate of genetic variance. Significant genetic variance was found to influence PNe during recumbency before and after a 4-h iv infusion of 2 liters saline. Similarly, heritable influences on UNe excretion were observed in a 10-h urine collection after the sodium load. Heritable influences on PNe or UNe were not observed after postural stimulation or volume contraction. The data suggest that sympathetic nervous system activity is influenced by heritable factors which may contribute to the development of hypertension in some individuals.