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Biomedical subjects

W M Bennett

Publications and source records attributed to W M Bennett.

At least 217 records · Page 12Linked to original sources
PubMed1986

Comparison of cyclosporine nephrotoxicity with aminoglycoside nephrotoxicity.

Cyclosporine therapy is frequently complicated by dose related nephrotoxicity. In this review, the pharmacology, pathophysiology and clinical features of cyclosporine nephrotoxicity are contrasted with the adverse renal reactions of aminoglycoside antibiotics. From this analysis, it is apparent that these two common nephrotoxins produce renal dysfunction by different mechanisms. Aminoglycosides produce primarily direct toxic effects on the proximal tubular cell while cyclosporine nephrotoxicity is probably predominantly mediated by hemodynamic processes.

Aminoglycosides↗
PubMed1986

Effect of phenobarbital and cimetidine on experimental cyclosporine nephrotoxicity: preliminary observations.

Cyclosporine is metabolized by the hepatic microsomal cytochrome P-450 mixed function oxidases. To determine the effects of inducers and inhibitors of this enzyme on nephrotoxicity, male Fischer 344 rats were treated with cyclosporine in doses of 25 mg/kg and 40 mg/kg by daily gavage for 14 days. Groups of animals were given phenobarbital 75 mg/kg i.p., cimetidine 75 mg/kg i.p., or .9% saline i.p. for 3 days prior to starting cyclosporine and throughout therapy. Animals treated with the oil vehicle for cyclosporine served as controls. Animals receiving cyclosporine together with phenobarbital hat better preservation of glomerular filtration rate than did other cyclosporine-treated animals. Cimetidine did not enhance cyclosporine nephrotoxicity. Direct tubular toxicity was not evident using cortical slice transport of tetraethylammonium, fractional excretion of sodium and light microscopy as markers. If phenobarbital protects from cyclosporine nephrotoxicity because of its enzyme inducing action, it would follow that the parent drug and not a toxic metabolite mediates renal dysfunction. Based on the decreased glomerular filtration rate in the absence of overt tubular damage the major mechanism of cyclosporine nephrotoxicity is probably related to vascular or glomerular effects of the drug.

Animals↗
PubMed1986

Chronic gentamicin nephrotoxicity. Continued tubular injury with preserved glomerular filtration function.

After an initial episode of acute tubular necrosis, apparent resistance to gentamicin nephrotoxicity develops in rats during prolonged drug administration. The authors studied this phenomenon by examining the autoradiographic distribution of 3H-gentamicin and 3H-thymidine during 5 weeks of gentamicin treatment and by analyzing renal structure and function after a 12-week course of treatment. These studies show that regenerating cells exclude gentamicin, but concentrate it again after maturation, and that the rate of thymidine incorporation is still high well after recovery from acute toxic injury. After 12 weeks of gentamicin, the glomerular filtration rate was only modestly diminished, whereas in vitro cortical organic ion transport was substantially impaired. Light and electron microscopy demonstrated all phases of injury and recovery among cells of most proximal tubules and evidence of chronic tubulointerstitial disease. It is concluded that "resistance" to gentamicin is a state of persistent tubular cell injury obscured functionally by preservation of the glomerular filtration rate and histologically by asynchrony of cell necrosis and regeneration.

Acute Kidney Injury↗
PubMed1985

Pediatric cadaver kidney transplants into adults.

During a 5-year period 77 adults received single kidney cadaver transplants from donors 16 months to 16 years old. Cyclosporin immunosuppression was not used. Three recipients had ischemic ureteral complications, 1 of which resulted in allograft loss. Of the kidney grafts 34 were from donors 8 years old or younger, and comparison of renal function was made with the 43 adult recipients of cadaver kidneys from older children. The mean 1-month serum creatinine nadir was significantly higher in the recipients of kidneys from the younger children (2.6 plus or minus 1.6 versus 1.9 plus or minus 0.8 mg./per dl.). There were no statistically significant differences in 1-week dialysis requirement, 1-month kidney graft function or actuarial kidney graft survivals and serum creatinine levels at 3, 6, 12 and 24 months after grafting. Cadaver kidneys from young donors can be transplanted successfully into adults.

Adolescent↗
PubMed1985

Cyst fluid antibiotic concentrations in autosomal-dominant polycystic kidney disease.

Infections involving cysts of patients with autosomal-dominant polycystic kidney disease (PCKD) are often refractory to therapy possibly because of poor penetration of antibiotics into cyst fluid. Ten patients with PCKD had blood urine and cyst fluid sampled at surgery or autopsy for antibiotic concentrations. Cysts were categorized as to their nephron site of origin by cyst fluid sodium concentrations. Drugs active against anaerobes such as metronidazole and clindamycin were present in therapeutic concentrations in both proximal and distal cysts. Ampicillin and trimethoprim-sulfamethoxazole had the best profiles considering likely infecting organisms and the antibiotic concentrations achieved in both type of cysts. It is likely that prolonged therapy with both of these drugs is necessary to insure therapeutic success. Other drugs that can be detected in cysts are lipid soluble, undergo tubular secretion, or have high pKa values. These include erythromycin, vancomycin, and cefotaxime. Aminoglycosides because of their predominant glomerular filtration and thus low filtration rate per single cystic nephron are undetectable in both proximal and distal cysts. Clinically, alternatives to aminoglycosides should be chosen for infected cysts in PCKD.

Adult↗
PubMed1985

Analgesic-associated nephropathy. Unappreciated cause of renal dysfunction.

Analgesic-associated nephropathy is a preventable renal disease that leads to end-stage renal failure when it is not recognized and treated. Patients with this disorder are usually evaluated initially by the family physician, whose awareness of the entity and high degree of clinical suspicion will result in specific questioning regarding analgesic intake. A history of analgesic abuse, coupled with associated laboratory and radiologic abnormalities, usually suffices to make the diagnosis. A favorable prognosis is dependent on early diagnosis and discontinuation of all analgesic use.

Analgesics↗
PubMed1985

Total parathyroidectomy for posttransplantation hyperparathyroidism.

The acute and short-term clinical course of 19 subjects who underwent total parathyroidectomy and forearm implantation for persistent hyperparathyroidism following successful kidney transplantation (mean [+/- SD] time after transplant 43.7 +/- 29.5 months) is described. Their mean preoperative serum calcium level of 10.8 +/- 0.5 mg% decreased to a nadir of 7.9 +/- 0.9 mg%, 62.5 +/- 27.7 hr after the operation. The lowest serum ionized calcium (1.80 +/- 0.2 mEq/L) was recorded 57 +/- 49 hr postoperatively. After an average of five hospital days, the patients were discharged with a mean serum total calcium concentration of 8.3 +/- 1.0 mg%. Three months following the operation, the mean serum total calcium concentration was 9.5 +/- 0.6 mg%. With an average follow-up of 19 months (range 3-36 months) serum total calcium was 9.6 +/- 0.6 mg%, with only one subject requiring calcium supplementation. Total parathyroidectomy with forearm implantation was associated with normalization of serum-immunoreactive parathyroid hormone concentrations and maintenance of stable allograft function. Our experience suggest that this procedure is an effective modality with a predictable postoperative recovery of parathyroid function when used to treat persistent hyperparathyroidism in the long-term survivor of renal transplantation.

Adolescent↗
PubMed1985

Attenuation of experimental tobramycin nephrotoxicity by ticarcillin.

It is well known that in vitro the combination of carbenicillin, ticarcillin, or other antipseudomonal penicillins with gentamicin, tobramycin, or other aminoglycoside antibiotics results in the inactivation of the antibacterial activity of the aminoglycoside. To assess the influence of the in vivo interaction of tobramycin and ticarcillin on experimental nephrotoxicity, male Fischer 344 rats were given either tobramycin alone (120 mg/kg per day), tobramycin (120 mg/kg per day) and ticarcillin (250 mg/kg per day) concomitantly, or the combination of these drugs at the same doses that had been preincubated for 24 h and at the time of delivery contained but 63 and 25%, respectively, of the initial concentrations of tobramycin and ticarcillin as measured by conventional analytical procedures. Initial experiments were conducted to determine the concentrations of the antibiotics in serum achieved after administration of each test solution. After a single dose of the test solution, ticarcillin concentrations in serum were higher and more prolonged in rats given tobramycin plus ticarcillin than in rats given ticarcillin alone. After 7 days of exposure to the test solutions, inulin clearance in animals given tobramycin alone was 0.15 +/- 0.1 (mean +/- 2 standard errors) ml/min per 100 g of body weight as compared with 0.53 +/- 0.1 in rats given tobramycin and ticarcillin concomitantly, 0.59 +/- 0.1 in animals given the partially inactivated tobramycin-ticarcillin mixture, and 0.79 +/- 0.1 in control rats. Although there was some improvement in inulin clearance in the group containing tobramycin alone, the three treatment groups maintained the same rank relationship in inulin clearance through 14 days of treatment. Real histology confirmed the attenuation of tubular injury in animals given tobramycin and ticarcillin concomitantly. There was no evidence of toxicity from the presumed inactivation complexes of tobramycin-ticarcillin. These results document an in vivo protective effect of ticarcillin on experimental tobramycin nephrotoxicity.

Animals↗
PubMed1985

Modification of experimental gentamicin nephrotoxicity by selective parathyroidectomy.

Dietary calcium loading reduces gentamicin nephrotoxicity in rats. Since parathyroid hormone increases renal brush border membrane anionic phospholipids, the putative gentamicin receptors, the effects of selective parathyroidectomy on gentamicin nephrotoxicity were examined. Male Fisher 344 rats underwent parathyroidectomy or sham surgery. All animals were fed a diet containing 0.5% calcium for 2 wk prior to gentamicin, 20 mg/kg twice daily for 6 and 10 days. Other parathyroidectomized rats were fed a 4% calcium diet for 2 wk and treated similarly with gentamicin On day 6, serum creatinine (mg/100 ml) was 2.0 +/- 0.9 in the sham-operated animals, 1.7 +/- 1.6 in the parathyroidectomized animals on the 0.5% diet, and 0.8 +/- 0.1 in the parathyroidectomized animals on the 4% diet. By 10 days, the sham-operated animals had creatinine values of 6.3 +/- 1.6 (mg/100 ml) compared with 1.7 +/- .9 in the parathyroidectomized animals on the same diet and 0.8 +/- 0.2 in the 4% diet animals. More severe tubular necrosis was present in the sham-operated compared with the parathyroidectomized animals. High calcium diet in the parathyroidectomized animals produced structural and functional protection from gentamicin nephrotoxicity. Human parathyroid hormone (1-34) 20 IU twice daily given subcutaneously to a separate group of parathyroidectomized rats, eliminated the protective effect of parathyroidectomy on renal structure and function. Parathyroidectomy modifies experimental gentamicin nephrotoxicity. The additional protective effect of dietary calcium loading may be independent of parathyroid ablation.

Animals↗
PubMed1985

Effect of amiloride on experimental gentamicin nephrotoxicity.

Potassium and magnesium deficiency have been reported as risk factors for experimental gentamicin nephrotoxicity. Amiloride, a potassium-sparing diuretic, also leads to increased renal magnesium reabsorption. Amiloride, 2 mg/kg/day, was given to groups of 8-12 Fischer 344 rats receiving gentamicin, 20 mg/kg b.i.d., for 3, 7, 10 and 14 days. Control animals received the vehicle for gentamicin, amiloride alone or gentamicin alone. The degree of renal failure and weight loss were similar in gentamicin and gentamicin + amiloride groups at all time points despite increases in serum potassium and magnesium in the amiloride-treated animals. Tubular dysfunction as assessed by depression of renal cortical slice uptake of p-aminohippurate and N-methylnicotinamide was not improved by the addition of amiloride. In addition, a comparable degree of tubular necrosis and regeneration was observed in all gentamicin-treated groups. Maximum gentamicin concentrations in the renal cortex did not differ. Thus, despite reduction of urinary losses of potassium and magnesium with resultant increased serum values, amiloride did not protect against experimental gentamicin nephrotoxicity. The tubular electrolyte wasting noted clinically is likely to be a result, rather than a cause of proximal tubular cell damage.

Amiloride↗
PubMed1985

Experimental gentamicin nephrotoxicity: effect of streptozotocin-induced diabetes.

To determine the effect of diabetes mellitus on gentamicin nephrotoxicity we treated male F344 rats with streptozotocin 22 mg/kg (DM rats). DM rats were compared to controls (C) and nondiabetic rats ingesting the osmotic diuretic isosorbide administered to simulate glycosuric diuresis (C/I). Base-line C/I renal function and histology did not differ from C. However, in DM rats base-line inulin clearance (CIN) was 20% lower, and renal cortical slice uptake of p-aminohippurate was reduced compared to C and C/I. DM rats also had foci of renal tubular epithelial dysplasia not seen in C or C/I. Gentamicin was administered at 40 mg/kg-day to C and C/I and 32 mg/kg-day to DM rats to adjust for base-line CIN. Acute tubular necrosis, associated with depression of CIN and renal cortical p-aminohippurate and N-methylnicotinamide uptake, developed in all three groups. There were no differences between C and C/I. However, the degree of acute tubular necrosis and dysfunction was less in DM rats than C and C/I. Renal cortical gentamicin accumulation was also slower in DM than either C or C/I, and changes in renal cortical gentamicin over time followed a different pattern in DM rats. These results indicate that 1) attenuation of gentamicin injury in DM rats may be related to reduced accumulation of gentamicin by the renal cortex, 2) this reduced accumulation may be due to subtle baseline tubular injury mediated by streptozotocin or the diabetic state, and 3) osmotic diuresis does not account for attenuation of renal injury in DM.

Animals↗