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Biomedical subjects

W M Bennett

Publications and source records attributed to W M Bennett.

At least 163 records · Page 9Linked to original sources
PubMed1989

A new proposal for the mechanism of cyclosporine A nephrotoxicity. Inhibition of renal microsomal protein chain elongation following in vivo cyclosporine A.

In this paper, we report experiments examining the effect of cyclosporine A on "run-off" translation in microsomes isolated from tissues of Sprague-Dawley rats. In microsomes isolated from rat brain, kidney and thymus, cyclosporine A added in vitro in concentrations of up to 100 micrograms/ml did not reduce [3H]L-leucine incorporation relative to controls. A small dose-dependent reduction in [3H]leucine incorporation was observed in microsomes isolated from rat liver when cyclosporine A was added in high concentrations (5 and 6% at 25 and 100 micrograms/ml). However, when cyclosporine A was injected at 50 mg/kg/day for 10 days, [3H]L-leucine incorporation was inhibited 99.9% in microsomes isolated from kidney. The oral administration of cyclosporine A at 50 mg/kg/day for 6-10 days produced a 75% inhibition of incorporation by isolated renal microsomes. These changes were observed in the absence of measurable reductions in "run-off" transcription measured as [3H]UTP incorporation by renal nuclei exposed to cyclosporine A in concentrations of up to 100 micrograms/ml in vitro or isolated from animals given oral cyclosporine A at 50 mg/kg/day for 6 days. Cross-over experiments were performed using microsomes and microsomal supernatant fractions (cell saps) from tissues of animals treated with cyclosporine A and control vehicle. Renal cell sap from cyclosporine A treated animals inhibited [3H]L-leucine incorporation by microsomes isolated from the kidneys or other tissues of animals treated with control vehicle. These experiments demonstrated that a translation inhibitor was present in the cell sap of cyclosporine A treated animals which could directly block translation elongation in microsomes from control animals. When renal cell sap from both control and cyclosporine A treated animals was added to control microsomes, inhibition was still prominent, suggesting the presence of an inhibitor rather than the absence of an elongation factor. Oral administration of cyclosporine A at 50 mg/kg/day for 6 days depressed renal microsomal [3H]L-leucine incorporation equally in male and female rats to 25% of control. The dose-response relationship for microsomal protein synthesis inhibition after 6 days of oral cyclosporine A administration was: 5 mg/kg, 73.7% of control; 10 mg/kg, 64.1% of control; 25 mg/kg, 54.9% of control and 50 mg/kg, 24.1% of control. Renal microsomal protein synthesis following oral cyclosporine A at 50 mg/kg/day was reduced to 54% of control by day 2 and was maximally inhibited at 25-30% of control by day 4.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Mesangiocapillary glomerulonephritis type II (dense-deposit disease): clinical features of progressive disease.

Twenty-seven patients presenting to the Royal Melbourne Hospital between 1968 and 1988 with mesangiocapillary glomerulonephritis type II with intramembranous dense deposits (dense-deposit disease, DDD) are analyzed. Patients were divided into two groups on the basis of whether renal function deteriorated (14 patients) or remained stable (13 patients). At presentation or during the course of the disease, heavy proteinuria, macroscopic hematuria, and high quantitative urinary red cell or white cell counts characterized patients with progressive disease. Patients with crescents on their initial renal biopsy or with large numbers of polymorphs in glomerular capillaries corresponding with sterile pyuria were more likely to have deterioration of renal function. The average time from onset of symptoms to development of end-stage renal disease was over 16 years. The patient's clinical course could not be anticipated by serum complement profiles, the presence of C3 nephritic factor, or partial lipodystrophy. Pregnancy did not affect the course of the disease. Six patients underwent renal transplantation and the disease recurred on renal biopsy in four. However, only two individuals lost renal allografts due to recurrent DDD.

Adolescent↗
PubMed1989

Lovastatin in the treatment of multifactorial hyperlipidemia associated with proteinuria.

The efficacy and safety of lovastatin as a hypolipidemic agent were evaluated in ten adult patients with secondary hypercholesterolemia due to proteinuria (greater than 2 g/d) and (in seven patients) concurrent corticosteroid therapy. Patients were on a low-cholesterol diet throughout the study. After a 4-week baseline period, patients were randomized to receive either placebo or 10 mg lovastatin twice daily for a period of 6 weeks. The dose of lovastatin was increased to 20 mg twice daily for 6 weeks, and 40 mg twice daily for 6 weeks in the latter group. Those patients who received placebo for the first 6 weeks subsequently received 10, 20, and 40 mg of lovastatin twice daily in a stepped dose regimen, with each dose given for 6 weeks. Lovastatin was well tolerated by all patients and none withdrew from the study. Baseline plasma cholesterol concentrations (390 +/- 20 mg/dL; mean +/- SEM) decreased 22% (P less than 0.003) at the lowest dose of 10 mg twice daily, 27% at 20 mg twice daily, and 33% at 40 mg twice daily. Baseline plasma triglycerides decreased by 25% (P less than 0.05) at the highest dosage. Concentrations of low-density lipoprotein (LDL) cholesterol fell by 29%, 34%, and 45% on doses of 10, 20, and 40 mg of lovastatin twice daily. Concentrations of high-density lipoprotein (HDL) cholesterol increased slightly. Serum creatinine concentrations and proteinuria were not affected by lovastatin therapy. We conclude that lovastatin was a well-tolerated and extremely effective hypocholesterolemic agent in patients with persistent secondary hypercholesterolemia associated with proteinuria or proteinuria and concurrent corticosteroid therapy.

Adrenal Cortex Hormones↗
PubMed1989

Sustained depression of the resting metabolic rate after massive weight loss.

To assess potential long-term effects of weight loss on resting metabolic rate (RMR), the RMRs of seven obese women were measured by indirect calorimetry before weight loss, during a protein-sparing modified fast, and for 2 mo while at a stable reduced weight. Body composition was also determined at each interval. RMR significantly decreased 22% (p less than 0.01) with initiation of the modified fast. RMR values during the modified fast and during the maintenance diet at stable reduced weight were not different and all were significantly lower than the prediet RMR. Loss of lean tissue could not account for the decrease because changes in RMR per fat-free mass paralleled the total RMR reduction. A sustained decrement in RMR accompanied weight loss and persisted for greater than or equal to 8 wk despite increased caloric consumption and body weight stabilization.

Adult↗
PubMed1989

Polyaspartic acid prevents experimental aminoglycoside nephrotoxicity.

The influence of the polyamino acid polyaspartic acid (PAA) on experimental aminoglycoside nephrotoxicity was determined. PAA prevented all measured functional and pathologic evidence of gentamicin nephrotoxicity for less than or equal to 27 d of study. All the animals given PAA, either alone or with gentamicin, developed prominent cytoplasmic vacuoles in the cells of the renal proximal convoluted tubules; the vacuoles in rats given just PAA differed from those observed in rats given PAA plus gentamicin. Rats given PAA plus gentamicin accumulated roughly 10 times more renal aminoglycoside as did rats given gentamicin alone. Immunohistochemical localization studies confirmed the presence of increased amounts of gentamicin in the cytoplasm of the tubular cells of animals given gentamicin plus PAA. PAA did not alter the in vitro antimicrobial activity of gentamicin versus Escherichia coli or Pseudomonas aeruginosa. These studies demonstrate the ability of PAA to prevent experimental gentamicin nephrotoxicity.

Animals↗
PubMed1989

Assessing university nephrology training as preparation for community consultative practice.

The authors gathered information about the consultative practice of nephrology in a community environment and used this information to speculate about improvements that could be made in the training of nephrologists in academic medical centers, based on their knowledge of such training. Data were gathered on the specialty affiliations of the physicians who requested 211 consecutive consultations, on the clinical problems encountered, and on the most likely diagnosis for each problem. In some instances the referral patterns, patient mixes, and clinical diagnoses observed in the community-based practice differed significantly from those often emphasized in training programs in academic medical centers. Such differences may be unintentionally reinforced, because the clinical literature in which new findings are reported and validated largely arises from university-type clinical practices. Specific examples of the differences observed and some suggestions for change are given. Although additional research is needed to confirm the findings of this study, and although these findings may not be applicable to other settings or other internal medicine subspecialties, these findings raise questions about the appropriateness of completely university-based training in preparing physicians for practice in a community setting. The authors suggest that cooperation between community hospitals and established university programs could bring about the best opportunities for clinical training.

Community Medicine↗
PubMed1989

Renal cortical mitochondrial integrity in experimental cyclosporine nephrotoxicity.

The function of renal cortical mitochondria isolated from rats with cyclosporine nephrotoxicity was studied. Renal cortical mitochondria were isolated from 5 male Fischer rats after 14 days of daily intraperitoneal administration of CsA, 25 mg/kg body wt. Compared with the mitochondrial function of 5 pair-fed control rats receiving vehicle alone, state 3 respiration (ADP-dependent) using several substrates was mildly depressed only with pyruvate-malate supported respiration (27 +/- 3 vs. 36 +/- 2 nmol O2/min/mg protein; P less than 0.05). The Ca2+ accumulation rate was slightly reduced (354 +/- 14 vs. 416 +/- 18 nmol/min/mg protein; P less than 0.025) while the cytochrome enzyme concentrations were not different from controls. Respiratory control ratios were not affected (CsA group: 9.5 +/- 2.8, control group: 8.9 +/- 2.3; glutamate-malate as substrates). These minor alterations in mitochondrial function occurred in the presence of severe depression in the glomerular filtration rate and renal morphologic changes commonly seen with CsA administration. Moreover, there was no increase in enzymuria. These results indicate that CsA has minor effects on the respiratory function of renal cortical mitochondria. The severe depression in the glomerular filtration rate is out of proportion to these minor alterations in mitochondrial function. These findings argue against a prominent role for a direct toxic action of CsA on tubular cells in the pathogenesis of acute cyclosporine-induced renal dysfunction.

Animals↗
PubMed1989

Mechanisms of aminoglycoside nephrotoxicity.

Aminoglycosides continue to be widely used for the treatment of serious Gram-negative infections. Ten to fifteen per cent of all courses of therapy are complicated by declines in renal function, despite close monitoring of serum drug levels. The proposed pathogenesis and biochemical mechanisms of renal dysfunction caused by these commonly used therapeutic agents are discussed.

Aminoglycosides↗
PubMed1989

Treatment of IgA nephropathy with eicosapentanoic acid (EPA): a two-year prospective trial.

Thirty-seven patients with biopsy proven mesangial IgA nephropathy were prospectively allocated to either two years of treatment with eicosapentanoic acid (EPA) 10 g per day or no treatment. At entry treated and untreated patients with renal dysfunction (Group A) or patients with normal serum creatinine less than 0.12 mmol/l (Group B) did not differ in serum creatinine, creatinine clearance, urinary protein excretion, or quantitative urinary red cell counts. Compliance with EPA therapy was excellent as assessed by plasma fatty acid profiles. At the end of the trial creatinine clearance in treated patients had gone from 80 +/- 16 to 57 +/- 17 ml/min (p less than 0.05) and in untreated patients from 76 +/- 18 to 55 +/- 14 (p less than 0.05). There were no beneficial effects in either Group A or Group B patients. The only two patients who had improvement in renal function were in the EPA treatment group. Although no side effects of treatment were noted, EPA does not alter the course of established mesangial IgA nephropathy.

Adult↗
PubMed1989

Use of antimicrobial agents in renal failure.

Many antimicrobial agents are excreted primarily by the kidneys, and hence, to avoid toxicity and maintain efficacy, dosage adjustments are necessary. After estimating a patient's creatinine clearance, an appropriate dosage adjustment is easily accomplished. The adjustments for aminoglycosides are simplified by the use of a suggested once-daily, or once every other day dosage regimen.

Aminoglycosides↗
PubMed1988

Renal function 27 years after unilateral nephrectomy for related donor kidney transplantation.

Renal function in a living related kidney donor was evaluated 27 years after unilateral nephrectomy. The patient was normotensive and had no significant proteinuria. Creatinine was 0.8 mg. per dl. and creatinine clearance was 88 ml. per minute per 1.73 m.2 or 152 per cent of the single kidney pre-nephrectomy value. Tubular function assessed by the ability to lower urinary pH in response to an acid load was normal. Biopsy of the transplanted kidney 18 years after donation was histologically normal. This case represents one of the longest followup evaluations of a living related donor reported to date and it argues against any adverse effects of organ donation on the function of the remaining kidney.

Adult↗
PubMed1988

The use of OKT3 in cadaveric renal transplantation for rejection that is unresponsive to conventional anti-rejection therapy.

Thirty-one recipients of cadaver kidney transplants were given OKT3 monoclonal anti-T cell antibody for rejection treatment after conventional therapy had failed. Seventy-four percent of steroid or steroid and antithymocyte globulin (ATG) resistant rejections reversed with a standard course of OKT3. Rejections reversed in 85% of 26 patients treated within 90 days of transplantation. Late rejections treated more than 90 days after transplantation were poorly responsive to OKT3 and graft survival for this group of five patients was poor (20%). However, for those patients treated with OKT3 for early resistant rejection, actuarial 4-year graft survival was 66%. Actuarial 4-year patient survival was 97%, and the incidence of serious infection was low. Acute rejections in cadaver transplantation are common and a small percentage of rejections are resistant to steroids and ATG. OKT3 has proven to be useful for reversing these resistant rejections without causing significant morbidity from infection or death.

Adolescent↗