Nephrotoxic Properties Research Articles

Southwestern Internal Medicine Conference: Plasma Cell Dyscrasias and the Kidney

ABSTRACT Renal manifestations of plasma cell dyscrasias (PCD) are common. Most patients with multiple myeloma, for example, develop abnormal levels of proteinuria, and nearly one-half develop renal failure, a major cause of morbidity and mortality in these patients. The manifestations, causes, and treatment of renal disease associated with PCD are reviewed. Abnormal light chain production appears to be an especially important factor causing renal involvement in the setting of PCD, although not all light chains have demonstrable nephrotoxic properties. Renal failure, the most serious form of renal involvement in patients with PCD, should be managed aggressively, because even severe renal failure is reversible in some cases and need not preclude prolonged survival.

A COMPARATIVE TOXICOLOGICAL STUDY OF CYCLOSPORINE AND Nva2-CYCLOSPORINE IN SPRAGUE-DAWLEY RATS

Adult, male Sprague-Dawley rats were given 50 mg/kg cyclosporine (CsA), cyclosporine G (nor-valine2-cyclosporine [CsG], or drug vehicle by orogastric intubation every 24 hr for 14 days. Both drugs profoundly suppressed humoral immune responses. Similar trough whole-blood cyclosporine levels were recorded in each group at days 7 and 14. In CsA-treated animals, significant lymphopenia was evident on day 14, together with monocytosis and neutrophilia. Only the monocytosis was seen in the CsG group. CsA and CsG both caused significant impairment of renal function by day 7, although at this time the effect was less marked with CsG. In both drug-treated groups, there was evidence of further deterioration in glomerular filtration rate (GFR) by day 14. A significant rise in enzymuria was also recorded in each group. Typical cyclosporine-induced proximal straight tubular cell vacuolation was evident in four of the eight rats given CsG and in three of seven CsA-treated animals. Liver function was also significantly impaired in both CsA and CsG groups. These data show that, at the selected dose, CsG shares the nephrotoxic and hepatotoxic properties of CsA. The extent to which these effects of CsG are dose-related and the true clinical potential of this cyclosporine analogue have yet to be evaluated.

The predictive value of enzymuria in cyclosporin ainduced renal toxicity in the rat

The acute nephrotoxic properties of cyclosporin A (CsA) were investigated in normotensive, adult male Sprague-Dawley rats. Animals received either 50 or 100 mg CsA/kg by gastric intubation for 7 days. Within 24 h, significant increases in urinary N- acetyl-β- d- glucosaminidase (NAG) and γ-glutamyl transpeptidase (γGT) activity were observed at both doses of CsA. Renal function abnormalities, however, were not apparent until 2 days (100 mg/kg) or 7 days (50 mg/kg). Progressive increases in enzymuria were evident in both groups between 1 and 4 days, at which later time proximal straight tubular cell damage was first observed. The data obtained using this model clearly demonstrate that enzymuria provides a sensitive index of acute CsA-induced renal cell damage and that enzymuria precedes detectable renal functional and structural abnormalities.

Amelioration of cyclosporin-induced nephrotoxicity in rats by induction of hepatic drug metabolism

The aim of this study was to determine the effect of altered hepatic drug metabolism on the nephrotoxic and immunosuppressive properties of cyclosporin A (CsA) in the rat. From a consideration of the structures of those CsA metabolites identified so far, it seemed probable that the metabolism of CsA would occur at the hepatic cytochrome P-450 (cyt P-450) enzyme system. CsA (50 mg/kg/24 hr) administered orally for 14 days resulted in significant increases in both serum urea concentration and urinary N-acetyl-β- d-glucosaminidase activity, accompanied by renal proximal tubular vacuolation. The concomitant administration of either Aroclor 1254 (25 mg/kg/24 hr, i.p.) or phenobarbitone (PB) (40 mg/kg/24 hr, i.p.) but not 3-methylcholanthrene (3-MC) (15 mg/kg/72 hr, i.p.) resulted in abolition of the nephrotoxicity, assessed both biochemically and histologically, whilst the suppressive effect on the humoral response to SRBC was unaltered. Phenobarbitone also significantly decreased serum CsA concentrations. These results suggest that the PB-inducible set of cyt P-450 isoenzymes may be responsible or partly responsible for hepatic CsA metabolism.

Cisplatin metabolites in plasma, a study of their pharmacokinetics and importance in the nephrotoxic and antitumour activity of cisplatin

For rats dosed with cisplatin the rate of appearance in plasma of ultrafilterable metabolites containing platinum has been investigated using HPLC. At least seven species containing platinum in addition to cisplatin are present 15 min following injection i.p. of 15 mg kg −1. Unchanged cisplatin has been almost completely eliminated from the plasma within 3 hr of dosing; however, metabolite species are still present. The same metabolite species form when cisplatin is incubated in vitro with plasma although in different proportions. After incubation for 24 hr at 37% a mixture of metabolites is produced which contains less than 4% cisplatin. This mixture, when injected i.p. into rats, is nephrotoxic at doses of platinum at which cisplatin is not. The mixture of metabolites has considerably less antitumour activity than cisplatin when tested against the mouse L1210 leukemia assay. Although no metabolite species has been unequivocally identified we present evidence which suggests that amongst the principle metabolite species are an hydrolysis product and methionine substitution products of cisplatin. A mixture of cisplatin methionine substitution complexes showed neither antitumour nor nephrotoxic properties. However, an hydrolysis product was shown to be nephrotoxic at a dose of platinum at which cisplatin is not. The work reported here is the first direct experimental demonstration that cisplatin metabolites are more nephrotoxic but less effective antitumour agents than the parent compound.

Cyclosporine: immunology, toxicity and pharmacology in experimental animals.

Cyclosporine (CsA) is the first of a new order of pharmacological immune suppressants and represents a significant advance in the clinical control of graft rejection. In laboratory animals, its capacity to prolong allograft survival has been well documented, including reports of indefinite donor-specific immunological tolerance after shortterm CsA treatment. There is also evidence that CsA can inhibit the onset or progress of a variety of experimental autoimmune diseases. Underlying these properties of the drug is its capacity to selectively interfere with T helper cell activation and lymphokine production, although some direct effects on B cells have also been reported. In addition, sparing of suppressor cells may in part explain the mode of action of CsA which, at the molecular level, is not understood. CsA-induced nephrotoxicity in the rat has been extensively studied and is characterized by reversible proximal tubular cell damage. This problem may be aggravated by concomitant administration of other potentially nephrotoxic drugs, such as gentamicin, or by therapeutic agents which interfere with the metabolism of CsA. CsA is metabolized in the liver and excreted in the bile. Although the pathway of hepatic metabolism of CsA has not been precisely elucidated, animal studies suggest that agents capable of inducing metabolism of the drug CsA could be used to alleviate its nephrotoxic properties.

Renal handling and acute urinary electrolyte effects of aminoglycoside antibiotics: Use of a solitary renal autotransplant in the conscious sheep

Renal handling of the aminoglycoside antibiotics gentamicin and tobramycin were studied before and after one hour of constant intravenous infusions adjusted to maintain a concentration of 15 μg/mL. A solitary renal autotransplant model in four conscious volume replete 40 Kg sheep was used. This unique surgical preparation allows sampling of renal arterial and renal venous blood as well as urine drained through an exteriorized parotid-ureteral fistula. This surgical preparation has considerable potential in renal pharmacology since it uses a conscious, large animal. Baseline studies in this preparation demonstrated normal, 51CrEDTA and 125I PAH, clearances which were unaffected by the drugs. Aminoglycoside binding to pooled sheep sera was 11% at physiologic PH. calcium and magnesium concentrations. A–V difference was 1.3 ± .3 μg/mL and extraction by the kidney was 9 ± 3.2% with no differences between gentamicin and tobramycin. Clearance of gentamicin was 84% and tobramycin 86% of GFR. There was no evidence of tubular injury as evidenced by unchanged urinary beta-2 microglobulin excretion. Serum Na, K, Ca and Mg did not change over the course of the study. Both drugs caused a prompt decrease in absolute and fractional sodium excretion while only gentamicin produced a kaliuresis. Early aminoglycoside effects on electrolyte balance may be an eventual determinant of nephrotoxic potential rather than differences in renal drug handling. Nephrotoxicity is a major side effect of aminoglycoside antibiotic therapy. Although gentamicin and tobramycin have similar pharmacokinetics, including renal cortical accumulation, both double blind clinical studies (1) and experimental data (2) have shown that gentamicin is more frequently associated with renal dysfunction. Recent studies in the dog have suggested that hypokalemia due to renal potassium wasting is a risk factor predisposing to nephrotoxicity (3). In clinical usage aminoglycosides may induce hypokalemia and hypocalcemia, perhaps resulting from drug-induced magnesium depletion (4). Previous studies reporting data concerning the acute effects of aminoglycosides on renal function and electrolyte excretion have used anesthetized animals (5) or isolated perfused kidney preparations (6). The present experiments utilize a unique surgical preparation in which a solitary kidney is autotransplanted to the neck of a sheep followed by a contral ateral nephrectomy. Urine flow is exteriorized through a uretero-parotid-cutaneous fistula thus providing a conscious animal with ready access to renal arterial and renal venous blood. Our results show that renal handling of gentamicin and tobramycin do not differ during short-term constant infusions. Both drugs caused a decrease in sodium excretion while gentamicin caused a larger increase in fractional and absolute potassium excretion. This raises the possibility that nephrotoxic properties of aminoglycosides may be secondary to their effects on electrolytes.

INHIBITION OF LYSINOALANINE FORMATION IN FOOD PROTEINS

ABSTRACTLysinoalanine (LAL), an amino acid derivative which exhibits nephrotoxic properties when fed to rats, is currently of considerable interest to the food industry. LAL has been shown to be present in a number of alkaline and/or heat treated food products. Rate studies were carried out to measure the formation of LAL in the presence and absence of mercaptoamino acids such as cysteine and glutathione. Addition of the mercapto amino acids to casein and soy protein during alkaline processing nearly eliminated the formation of LAL.

Presented in part at the 35th Annual Meeting of the Institute of Food Technologists, Chicago, June 1975.

To find out whether alkali-treated proteins posses nephrotoxic properties, feeding studies were conducted with drastically treated soybean protein and casein, and also with lysinoalanine (LAL), the amino acid known to be formed in protein subjected to high pH at elevated temperature. The feeding of synthesized LAL to rats at dietary levels of 100 ppm and above induced typical renal changes, called nephrocytomegalia. No such changes or any other indications of toxicity were observed, however, upon feeding much higher levels of LAL (up to 6,000 ppm) when provided as the protein-bound compound in alkali-treated casein or soybean protein. When set free by complete acid hydrolysis, LAL induced considerable renal activity, comparable to that of the synthetic compound. These results indicate that alkali treatment of proteins does not induce nephrotoxic properties provided that the compound remains protein-bound. Some nephrotoxic activity was observed, however, with peptide-boound LAL in break-down products (molecular weight less than 5,000) of alkali-treated casein, but considerably less than that of the free compound. LAL-analyses in blood, urine, and feces of rats fed free or protein-bound LAL indicated a positive correlation between intestinal absorption and nephrotoxic potential. No renal changes were encountered upon feeding diets with 1,000 ppm synthetic LAL to mice, hamsters, rabbits, quail, dogs or monkeys, which suggest a species specificity of LAL-induced renal changes in rats.

Lower respiratory infections treated with cephacetrile

The study is concerned with the pharmacological and clinical evaluation of cephacetrile as given by the results obtained in 23 patients with lower respiratory infections. The criteria employed comprised not only pharmacokinetic parameters such as serum and urine concentrations and the serum half-life, but also bacteriological and clinical data obtained in the course of careful examinations carried out before, during, and after treatment. The studies conducted for this purpose included various laboratory tests, as well as differential blood counts, tests of respiratory function, sputum investigations, and tests of hepatic and renal function. In the patients under review, most of whom were old (average age 62 years) and in moderate or poor condition, treatment with cephacetrile (1 g twice daily i. m.) enabled a complete clinical success to be achieved in 69 % of cases, a partial success being obtained in a further 13 %. The bacteriological and laboratory findings (e.g. improvement in the sputum characteristics) correlated well with the clinical response. Cephacetrile was well tolerated; in particular, it appeared to have no nephrotoxic properties.

Antileukaemic and nephrotoxic properties of platinum compounds.

THE antitumour properties of certain inorganic platinum compounds in mice were first reported by Rosenberg et al.1. Of thirty-four compounds tested the cis-platinum (ii) diamminodichloride and the cis-platinum (iv) diamminotetrachloride had the highest activity, producing marked regression of large solid sarcoma 180 tumours in 63–100% of mice.

1675. Toxicity undermines sex equality: Klaassen, C. D. & Plaa, G. L. (1967). Susceptibility of male and female mice to the nephrotoxic and hepatotoxic properties of chlorinated hydrocarbons. Proc. Soc. exp. Biol. Med.124, 1163. Klaassen, C. D. & Plaa, G. L. (1967). Relative effects of various chlorinated hydrocarbons on liver and kidney function in dogs. Toxic. appl. Pharmac.10, 119

1675. Toxicity undermines sex equality: Klaassen, C. D. & Plaa, G. L. (1967). Susceptibility of male and female mice to the nephrotoxic and hepatotoxic properties of chlorinated hydrocarbons. Proc. Soc. exp. Biol. Med.124, 1163. Klaassen, C. D. & Plaa, G. L. (1967). Relative effects of various chlorinated hydrocarbons on liver and kidney function in dogs. Toxic. appl. Pharmac.10, 119

Susceptibility of Male and Female Mice to the Nephrotoxic and Hepatotoxic Properties of Chlorinated Hydrocarbons.

SummaryMale and female mice were tested for their susceptibility to the nephro-toxic properties of chloroform and 1,1,2-trichloroe thane. Renal dysfunction, as determined by phenolsulfonephthalein excretion was demonstrated in male mice with chloroform at 0.078 ml/kg and 0.17 ml/kg for 1,112-trichloroethane. Renal dysfunction could not be produced in female mice with chloroform and 1,1,2-trichloroethane, even at lethal doses. Male and female mice were also tested for their susceptibility to the hepatotoxic properties of carbon tetrachloride. Liver dysfunction, as determined by elevated serum glu-tamic-pyruvic transaminase activity, could be demonstrated in both male and female mice at 0.009 ml/kg. No sex difference was observed in the 24-hour LD50 values for the three agents tested. This indicates that with these agents nephrotoxicity is not an important contributing factor in the deaths occurring during the first 24 hours.

943 Kidney toxicity of halogenated hydrocarbons: Plaa, G. L. & Larson, R. E. (1965). Relative nephrotoxic properties of chlorinated methane, ethane, and ethylene derivatives in mice. Toxic. appl. Pharmac.7, 37

943 Kidney toxicity of halogenated hydrocarbons: Plaa, G. L. & Larson, R. E. (1965). Relative nephrotoxic properties of chlorinated methane, ethane, and ethylene derivatives in mice. Toxic. appl. Pharmac.7, 37

815. Kidney damage from simple chlorinated hydrocarbons: Plaa, G. L. & Larson, R. E. (1965). Relative nephrotoxic properties of chlorinated methane, ethane and ethylene derivatives in mice. Toxic. appl. Pharmac.7, 37

815. Kidney damage from simple chlorinated hydrocarbons: Plaa, G. L. & Larson, R. E. (1965). Relative nephrotoxic properties of chlorinated methane, ethane and ethylene derivatives in mice. Toxic. appl. Pharmac.7, 37

Relative nephrotoxic properties of chlorinated methane, ethane, and ethylene derivatives in mice

The relative acute nephrotoxic properties of chlorinated methane, ethane, and ethylene derivatives has been studied in mice, using phenolsulfonephthalein (PSP) excretion, the presence of proteinuria and glucosuria (Combistix), and histopathology. Dose-response curves were obtained and all derivatives except trichloroethylene resulted in abnormalities in at least one of the parameters. However, most of the abnormalities occurred with doses within the acute lethal range. Only CHCl 3 and 1,1,2-trichloroethane produced renal dysfunction in a majority of the animals in nonlethal doses. Ethanol intoxication failed to enhance the susceptibility of mice to the nephrotoxic action of CHCl 3. Comparison of CHCl 3 to CCl 4 indicates that nephrotoxicity does not parallel hepatotoxicity.

Combined bacitracin-neomycin ointment in treatment of pyogenic infections of the skin.

Bacitracin is quite effective locally against a wide variety of Gram-positive micro-organisms, including Staphylococcus, beta hemolytic Streptococcus, Pneumococcus, Clostridium welchii, some of the actinomycetes, Treponema pallidum, and others. Its nephrotoxic properties and irritative local effects when injected intramuscularly have precluded its use except as a topical application, where it has been used with great success. Neomycin is very effective locally against Gram-negative and Gram-positive organisms. However, the hepatotoxic and ototoxic properties of neomycin preclude its systemic adminstration. Some patients with hemolytic Streptococcus and B. pyocyaneus (Pseudomonas aeruginosa) infections, in a series treated by Kile, did not respond satisfactorily to neomycin ointment. Since both bacitracin and neomycin are not used systemically and since the two together are effective against all Gram-negative and Gram-positive organisms, a combination of the two in a petrolatum ointment base containing 500 units of bacitracin and 5 mg. of neomycin sulfate per gram of base*was