Evidence Of Nephrotoxicity Research Articles

The nephrotoxic potential of gentamicin in the cat: enzymuria and alterations in urine concentrating capability.

This study investigated the potential for nephrotoxicity of gentamicin in cats by measuring marker enzyme concentrations, [Na], [K], osmolality, and pH of the urine, and blood urea nitrogen (BUN) levels. Gentamicin was administered i.m. at 4.4 mg/kg once daily (s.i.d.) or twice daily (b.i.d.) for 7 days. Concentrations of lactic dehydrogenase (LDH), lysozyme (LZM), alkaline phosphatase (AP), and glutamate dehydrogenase (GD) were measured as total 24-h excretions. The s.i.d. regimen produced only a slight increase in LDH excretion after 5 days, whereas the b.i.d. regimen caused an increase in the excretion of all enzymes. The greatest elevations were observed for LZM and LDH. Of the enzymes studied, these appeared to be the most appropriate to monitor for potential nephrotoxicity, except that urinary concentrations did not correlate well with duration of gentamicin administration. Only slight elevations in BUN were observed for either regimen. Single daily administration increased urine osmolality slightly, but b.i.d. treatment caused a marked and immediate decrease in urine osmolality, [Na], and total Na excretion. Urinary [K] was also depressed, as was total K excretion after 6 days. Urine pH was not substantially affected. This study showed that the recommended daily dose of 4.4 mg/kg produced little if any evidence of nephrotoxicity as indicated by the parameters measured. Twice daily dosing, however, produced elevations in urine enzyme concentrations, and markedly decreased urine osmolality and Na and K excretion. Compared to other species studied, the cat appears particularly sensitive to urine concentrating alterations resulting from repeated gentamicin administration.

Long-term Use of Cyclosporin in Liver Grafting

The clinical course of 29 liver graft recipients in the Cambridge/King's College Hospital series who have received cyclosporin A (CyA) for up to five years (median 40 months) was analysed with particular reference to the immunosuppressive effectiveness and adverse effects of the drug. Eight patients had been maintained on prednisolone and azathioprine for two to six years before treatment was changed to cyclosporin A and the remainder were started on cyclosporin A after operation. Results in both groups over a one to five year study period are similar, and showed that cyclosporin A was effective in maintaining adequate immunosuppression, allowing complete withdrawal of prednisolone in 16 patients. Episodes of rejection were observed in only three patients and in two of these it was of the chronic 'vanishing bile duct' variety. Some evidence of nephrotoxicity (serum creatinine greater than 150 mumol/l) occurred in 72 per cent (21 of 29 patients) but it was necessary to discontinue treatment in only two. Hypertension, occasionally of sudden onset, was found in nine patients and led to the withdrawal of the drug in two. Additional hypotensive drug treatment was required in five. In one other patient cyclosporin A was discontinued on account of severe headaches. Cyclosporin A was withdrawn in two further patients. Withdrawal led to considerable risk of acute rejection and increased doses of corticosteroids as well as substitution of azathioprine were required at that time.

GENERAL ANAESTHESIA FOR CAESAREAN SECTION IN SEVERE PRE-ECLAMPSIA: Comparison of the renal and hepatic effects of enflurane and halothane

In a randomized study of patients undergoing Caesarean section, either enflurane (mean 0.24 MAC-h) or halothane (mean 0.23 MAC-h) and 50% nitrous oxide in oxygen were administered to women (n = 12) with severe pre-eclampsia-eclampsia and to 16 healthy pregnant patients with normal renal and hepatic function. No evidence of nephrotoxicity was found in any pre-eclamptic or normal patient. Metabolism of enflurane resulted in plasma inorganic fluoride concentrations (max 15 mumol litre -1) which were well below the toxic value. Postoperative liver function tests showed no important changes from preoperative values, although reductive metabolites of halothane were not measured. In patients with severe pre-eclampsia there appears no contraindication to enflurane or, probably, halothane as volatile supplements during general anaesthesia.

Effect of 'high-dose' amikacin in children.

17 children with serious infections were treated for an average period of 9.5 days with 420 mg/m2/dose of amikacin every 8 h. The nephrotoxicity and ototoxicity of this 'high-dose' regimen was studied. None of the children had evidence of nephrotoxicity. Of 9 children who could be clearly evaluated, 1 child experienced a delayed transient auditory dysfunction. 1 child experienced delayed serious deafness, but was receiving other ototoxic drugs. Despite the fact that the doses averaged 54.1 mg/kg/day, 5 children in our series had peak concentrations lower than that recommended for adults with serious infection.

Pharmacokinetics and clinical effects of cefuroxime in patients with severe renal insufficiency.

The pharmacokinetics and clinical effects of cefuroxime were investigated in 5 patients with severe impairment of renal function (creatinine clearance less than or equal to 23 ml/min), suffering from an urinary tract infection. Bolus i.v. injections of cefuroxime 750 mg b.i.d. or 750 mg once daily were given to the patients depending on the degree of renal impairment. The concentration of drug in serum and urine was measured during treatment, and pharmacokinetic parameters were evaluated on the second and last days; the parameters obtained on the 2 days did not differ significantly. Drug elimination half-life increased from 4.2 h (creatinine clearance 23.0 ml/min) to 22.3 h (creatinine clearance 5.0 ml/min) with decreasing renal function. The apparent volume of distribution ranged from 11.6 to 17.9 l, and showed a substantial increase to 29.6 l in the patient with the poorest renal function. A linear correlation was found between the total and renal clearance of cefuroxime and the creatinine clearance; the extrarenal clearance was 8.24 ml/min. Concomitant treatment with furosemide did not impair renal function and no evidence of nephrotoxicity was found. The clinical efficacy of the drug was good. Symptoms of infection subsided after 3-4 days and the isolated pathogens were eradicated. No relapse or episodes of reinfection were observed in a following-up period of 3 months. The drug was well tolerated and no side effects or changes in haematological or biochemical values were seen.

Cefotaxime therapy of serious infections with multiresistant gram-negative bacilli.

33 patients with serious gram-negative bacillary infections were treated with cefotaxime. In patients with normal renal function the dose varied between 1.5 to 4 g/day. 17 patients had urinary tract infections, 5 respiratory tract infections, 1 combined urinary tract infection and respiratory tract infection, and 10 miscellaneous infections. 16 patients had septicemia. 25 infections were due to pathogens resistant in vitro to ampicillin, cephalothin, gentamicin and/or tobramycin. 15 infections had failed to respond to ampicillin, cefazolin, gentamicin or tobramycin therapy. 32/33 patients responded favourably to cefotaxime (cure or improvement) but 4 patients developed superinfection with cefotaxime-resistant bacteria. No evidence of nephrotoxicity was observed except for a transient moderate rise in creatinine in one patient.

Use of ceftazidime in severe Gram-negative infections -- a preliminary study

Ceftazidime was used to treat ten patients with serious Gram-negative bacillary infections. Seven patients had bronchopulmonary infections and three had urinary tract infections. In addition three patients were bacteraemic. Causative agents were: Pseudomonas aeruginosa 4, Escherichia coli 2, Proteus species 2, and Klebsiella pneumoniae 2. Doses ranged between 2 and 6 g/day. Nine out of ten patients responded favourably to ceftazidime (cure or improvement). Colonization with ceftazidime-resistant strains occurred in three cases. No evidence of nephrotoxicity was noted.

Evaluation of cefoxitin nephrotoxicity in experimentally induced renal failure.

The nephrotoxicity of cefoxitin was studied in a rat model of impaired renal function. Two levels of renal impairment were produced: "moderate," with blood urea concentrations of 100 to 150 mg/100 ml (16.7 to 25.1 mmol/liter) and glomerular filtration rates 25 to 35% of normal, and "severe," with blood urea concentrations greater than 150 mg/100 ml (greater than 25.1 mmol/liter) and glomerular filtration rates 10 to 20% of normal. Sham-operated animals were used as controls. Three dose schedules of cefoxitin were administered to these controls--500, 1,000, and 2,500 mg/kg per day administered as a divided dose for 5 days. Doses given to the moderately and severely uremic animals were adjusted so that serum levels of cefoxitin were similar to those attained in the sham-operated control animals. Concentrations of urea and creatinine in blood, glomerular filtration rates, and the urinary concentrating capacities of the experimental animals were monitored before and after cefoxitin treatment. There was no evidence of nephrotoxicity in even the most challenging experiment, in which blood serum levels of cefoxitin reached 2,000 microgram/ml in animals, with 15% renal function. These findings support available clinical data, suggesting that cefoxitin can be administered safely to patients with compromised renal function.

Neurolept anaesthesia for the renal transplant operation.

Between October 1973 and December 1976, neurolept anesthesia was used in 176 consecutive renal transplantations carried out in 155 patients. For premedication, the combination either of droperidol, diazepam and atropine or of oxicon and scopolamine was used; the latter was found to be more effective. The induction agent was droperidol or thiomebumal sodium, the barbiturate being found to be preferable. For maintenance, nitrous oxide and fentanyl were employed. Pancuronium was given as a muscle relaxant. The fact that the patients belonged to a high-risk category as regards anesthesia was apparent from the frequent occurrence of abnormal features in the heart-lung radiographs (47%) and ECG (53%). As could be expected in uraemic patients, anaemia and hypertension were fairly common. Induction was followed by a marked fall in blood pressure in 30% of the patients. During anaesthesia, there was a drop in blood pressure of more than 30% of the initial value in 35% of the patients, usually associated with a blood loss. In the majority of cases the course the anaesthesia was uneventful. In four patients (2.3%), the onset of respiration was delayed and re-intubation was resorted to. One patient developed arrhythmia requiring treatment. There was no evidence of nephrotoxicity. The per- and postoperative mortality was nil. The findings in this series indicate that neurolept anaesthesia is suitable for renal transplant operation.

Serum inorganic fluoride levels in obese patients during and after enflurane anesthesia.

Serum ionic fluoride levels in 24 markedly obese patients (127.6 +/- 6.0 kg) and seven nonobese control subjects (67.3 +/- 1.2 kg) were compared during and following enflurane anesthesia (less than 2.0 MAC hr). Peak serum fluoride levels were higher (28.0 +/- 1.9 vs 17.3 +/- 1.3 micrometers/L, p less than 0.01) and the rate at which fluoride levels increased was more rapid (slope 5.6 vs 2.5 micrometers/L/hr) in obese patients than in control patients. No clinical evidence of nephrotoxicity was found in either group. Vasopressin resistance tests were not performed, and thus it is inknown whether subclinical nephrotoxicity occurred in either study group. Possible reasons for increased enflurane metabolism in obesity are discussed. These possibilities include differences in fluoride ion kinetics, hepatic delivery and penetration of volatile anesthetics, and altered hepatic microsomal enzyme activity. Obesity rather than weight is an important determinant of anesthetic biotransformation.

Administration of Tobramycin and Gentamicin by the Intravenous Route Every 6 Hr in Patients with Normal Renal Function

The feasibility and safety of administration of tobramycin and gentamicin in every 6 hr rather than every 8 hr was studied in 18 patients with normal renal function. Eleven patients received tobramycin in a dose of 1.0-3.2 mg/kg every 6 hr, and seven received gentamicin in a dose of 1.4-2.0 mg/kg every 6 hr. The mean peak serum concentrations, excluding the levels in the three children given tobramycin, were 5.5 and 5.8 mug/ml in each group, respectively, after maximal dosage; trough levels 2 hr before the next dose were less than or equal to 1.8 mug/ml in both groups of patients. Neither drug accumulated in the serum when the dosage regimen was maintained for three to 19 days. There was no evidence of nephrotoxicity or ototoxicity. Administration of tobramycin and gentamicin every 6 hr seems to be a reasonable program for patients with normal renal function, pending further studies on safety.

Evaluation of doxycycline administration in patients with renal failure and in normal subjects.

Summary The biological half-life of doxycycline in serum was determined in 6 normal subjects and in 8 patients on maintenance haemodialysis. There was no significant difference in the half-life in the 2 groups. In 6 patients on maintenance haemodialysis the half-life of doxycycline was determined both during and between haemodialysis. There was a tendency for the half-life to be shorter during haemodialysis, but the differences were not statistically significant. It is concluded that no adjustment of dosage is required when doxycycline is employed in patients with severe renal failure, whether they are undergoing haemodialysis or not. Renal function was studied in 2 normal subjects who were given doxycycline in normal doses for 1 month. During this period there was no change in blood urea concentration, endogenous creatinine clearance or renal concentrating ability. Doxycycline was administered in normal doses to 8 patients with varying degrees of chronic renal failure for periods varying from 10 to 15 days. There was no evidence that doxycycline had any anti-anabolic effect and there was no evidence of nephrotoxicity. No toxic effects were noted in any of the patients studied. Doxycycline is therefore of particular value when a broad spectrum antibiotic is required in patients with renal failure.

Cephacetrile: clinical evaluation in 27 patients.

Cephacetrile, a new derivative of 7-aminocephalosporanic acid, was evaluated in 27 patients. Soft tissue infections due primarily to gram-positive cocci were treated in 16 patients; 12 had bacteriological and clinical cure, and 4 improved but the lesions resolved incompletely or cultures remained positive. Seven of eight patients with respiratory tract infections were cured, including three with pneumococcal pneumonia; the eighth proved to have a noninfectious process and failed to respond. Two patients with acute urinary tract infections due to Escherichia coli had prompt clinical and bacteriological improvement, but follow-up was incomplete. One patient with sepsis due to Staphylococcus aureus expired. Laboratory abnormalities observed during cephacetrile therapy included mild eosinophilia in four patients, thrombocytosis in nine, direct Coombs' test positivity in four, and an elevated serum glutamic pyruvic transaminase in eight patients. No evidence of nephrotoxicity was detected. Severe superinfection due to Enterobacter species was observed in one patient. Mean peak serum concentrations of cephacetrile were 22, 69, and 104 mug/ml after 1 g intramuscularly, 1 g intravenously, and 1.5 g intravenously, respectively. Thus, in early studies cephacetrile was efficacious for selected bacterial infections, but determination of its comparative value within the cephalosporin group of antibiotics requires further clinical investigation.

Pyrimidine Derivatives VIII: 5-Arylazopyrimidines and Their Inhibitory Effects against Transplantable Mouse Tumors

Twenty-five substituted 5-arylazopyrimidine derivatives have been prepared as potential "small molecule" antagonists of folic acid <i>via</i> reaction of 5-unsubstituted pyrim-idines with appropriate diazotized aniline derivatives. The antineoplastic activity of 19 of these compounds has been examined <i>in vivo</i> by means of a primary screening program utilizing five transplantable mouse tumors. At nontoxic dosages, several of these agents showed effective tumor growth inhibition, as evidenced by reduction in mean tumor size. Histopathological examination of mice treated with 2,4-diamino-6-hydroxy-5-phenylazopyrimidine revealed intestinal irritation and evidence of nephrotoxicity, as well as incomplete absorption of the drug.

EXPERIMENTAL TREATMENT OF ETHYLENE GLYCOL POISONING.

ETHYLENE GLYCOL has been widely used as a solvent for dyes and drugs and as a constituent of antifreeze mixtures for the cooling systems of automobiles.¹Forty to 60 deaths are thought to occur annually from accidental ingestion or from its use as a substitute for beverage alcohol.²The fatal dose in human adults is believed to be about 100 gm.³ Initially, the toxic manifestations of ethylene glycol poisoning relate to central nervous disorder with confusion, convulsions, and coma occurring commonly. Other evidence of neuropathy such as incoordinate movement, ataxia, and ocular palsy may occur. The early symptoms are not unlike those of acute intoxication with ethanol. These symptoms are sometimes associated with signs of cardiopulmonary disease. Tachycardia, tachypnea, cyanosis, and pulmonary edema have been observed early in the course of illness.⁴Later, however, there is evidence of nephrotoxicity.^4,5Blood and protein are found in