Mechanisms of beta-lactam antibiotic nephrotoxicity.
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Animals↗
Biomedical subjects
B M Tune
Publications and source records attributed to B M Tune.
Mechanisms of nephrotoxicity of beta-lactam antibiotics.
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Animals↗
The renal mitochondrial toxicity of beta-lactam antibiotics: in vitro effects of cephaloglycin and imipenem.
The nephrotoxic beta-lactam antibiotics cephaloridine, cephaloglycin, and imipenem produce irreversible injury to renal mitochondrial anionic substrate uptake and respiration after 1 to 2 h of in vivo exposure. Toxicity during in vitro exposure is nearly identical but is immediate in onset and is reversed by the mitochondria being washed or the substrate concentrations being increased. A model of injury that accounts for these findings proposes that the beta-lactams fit carriers for mitochondrial substrate uptake, causing inhibition that is initially reversible and becomes irreversible as the antibiotics acylate the transporters. These studies were designed to create an environment of prolonged in vitro exposure, first, to determine whether toxicity becomes irreversible with time and, second, to study the molecular properties of toxicity. Respiration with and the uptake of succinate and ADP were measured in rabbit renal cortical mitochondria exposed for 2 to 6 h to 300 to 3,000 micrograms of cephalexin (nontoxic) or cephaloglycin or imipenem (nephrotoxic) per mL and then washed to remove the antibiotic. In vitro cephalexin reduced respiration only slightly and was therefore not studied further. Cephaloglycin and imipenem irreversibly reduced both respiration and succinate uptake. ADP uptake was unaffected by cephaloglycin and was slightly reduced by imipenem. Finally, cilastatin, which prevents the tubular necrosis produced by imipenem in vivo, reduced its mitochondrial toxicity in vitro. It is concluded that the pattern of in vitro injury of the nephrotoxic beta-lactams to mitochondrial substrate uptake and respiration evolves in a time-dependent and concentration-dependent manner, consistent with the proposed model of acylation and inactivation of substrate transporters, and that the protective action of cilastatin against imipenem occurs at least partly at a subcellular level.
Adenosine Diphosphate↗
The renal mitochondrial toxicity of cephalosporins: specificity of the effect on anionic substrate uptake.
Previous work in this laboratory has demonstrated a reduction by the nephrotoxic beta-lactam antibiotics cephaloridine, cephaloglycin and imipenem of renal mitochondrial uptake of and respiration with the anionic substrate succinate. The present studies were done to test further the hypothesis that reduced substrate uptake and decreased respiration are causally related. Using cephaloridine in the rabbit, we examined the specificity of this association in regard to the toxic cephalosporin insult, the involvement of renal mitochondria and the reduction of carrier-mediated anionic substrate transport. 1) Specificity of insult in renal cortical mitochondria: cephaloridine (300 mg/kg bwt. i.v., 1 hr before sacrifice) reduces both the uptake of and respiration with succinate, whereas the same dose of cephalexin, which is not nephrotoxic, has neither effect; 25 min of acute unilateral renal artery occlusion reduces both the uptake of and respiration with succinate, but, unlike cephaloridine, ischemia causes a large increase of substrate efflux; and the respiratory toxins cyanide (1 mM) and oligomycin (2 micrograms/g of protein) reduce respiration by a direct effect on the mitochondrial respiratory chain and therefore have no effect on substrate uptake. 2) Specificity of target organ: cephaloridine has no significant effect on either the uptake of or respiration with succinate in hepatic mitochondria.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine Diphosphate↗
Thienamycin nephrotoxicity. Mitochondrial injury and oxidative effects of imipenem in the rabbit kidney.
The nephrotoxic cephalosoprins cephaloridine and cephaloglycin both produce mitochondrial respiratory toxicity in renal cortex. Recent work has provided evidence that this respiratory toxicity is caused by acylation and inactivation of mitochondrial anionic substrate transporters. While cephaloridine also causes significant lipid peroxidative injury in cortical mitochondria and microsomes, cephaloglycin causes little or no oxidative damage under identical conditions. The recently released thienamycin antibiotic, imipenem, like the toxic cephalosporins, produces acute proximal tubular necrosis which can be prevented completely by prior administration of probenecid. The ability of imipenem to block mitochondrial substrate uptake and respiration and produce oxidative changes has not been examined. We therefore evaluated the effects of imipenem in rabbit renal cortex on the following: (1) mitochondrial function [respiration with and uptake of succinate, and uptake of ADP]; and (2) evidence of oxidative change [depletion of reduced glutathione (GSH), production of oxidized glutathione (GSSG), and production of lipid peroxidative injury, as reflected in microsomal conjugated dienes (CDs)]. The mitochondrial effects of 300 mg/kg body wt of imipenem, given i.v. 1 and 2 hr before killing the animals, were comparable to those of the nephrotoxic cephalosporins. There was significant reduction of respiration with, and unidirectional uptake of, succinate at both times, while mitochondrial ADP transport was comparatively unaffected. Imipenem also depleted GSH and increased GSSG and CDs at 1 hr. These effects, however, were considerably smaller than those of a comparably nephrotoxic dose of cephaloridine, and this evidence of oxidative stress had resolved by 2 hr. We conclude that imipenem and the nephrotoxic cephalosporins have similar effects on mitochondrial substrate uptake and respiration, but differ significantly in their production of oxidative injury.
Adenosine Diphosphate↗
Oxidative and mitochondrial toxic effects of cephalosporin antibiotics in the kidney. A comparative study of cephaloridine and cephaloglycin.
Cephaloridine and cephaloglycin are the two most nephrotoxic cephalosporins released for human use. Cephaloridine has been shown to produce both oxidative and mitochondrial respiratory injury in renal cortex in patterns of dose (or concentration) and time that are consistent with pathogenicity. Cephaloglycin also produces respiratory toxicity, and recent studies have provided evidence that this injury results from an inactivation of mitochondrial anionic substrate transporters. The abilities of cephaloglycin to produce oxidative changes and cephaloridine to block mitochondrial substrate uptake have not been examined yet. We therefore compared these two cephalosporins with one another and with cephalexin, which is not nephrotoxic, in the production of the following: (1) several components of oxidative stress or damage [depletion of reduced glutathione (GSH) and production of oxidized glutathione (GSSG) in renal cortex, inhibition of glutathione reductase in vitro, and production of the lipid peroxidation products malondialdehyde (MDA) and conjugated dienes (CDs) in renal cortex]; and (2) renal cortical mitochondrial toxicity [to both respiration with, and the transport of, succinate]. Cephaloridine depleted GSH and elevated GSSG in renal cortex, inhibited glutathione reductase, and increased both MDA in whole cortex and CDs in cortical microsomes and mitochondria. While cephaloglycin depleted GSH at least as much as did cephaloridine, it produced one-fifth as much GSSG and had little or no effect on glutathione reductase activity or on cortical MDA or microsomal CDs; cephaloglycin caused a transient small increase of mitochondrial CDs. Cephalexin produced no oxidative changes except for a slight increase of mitochondrial CDs comparable to that produced by cephaloglycin. Both cephaloridine and cephaloglycin, but not cephalexin, decreased the unidirectional uptake of, and respiration with, succinate in cortical mitochondria. We conclude that cephaloridine and cephaloglycin are both toxic to mitochondrial substrate uptake and respiration, but differ significantly in their generation of products of oxidation.
Animals↗
Mechanism of the mitochondrial respiratory toxicity of cephalosporin antibiotics.
In summary, cephaloglycin, a nephrotoxic cephalosporin, produces a specific pattern of mitochondrial toxicity, decreasing both respiration with and the net uptake of succinate in renal cortical mitochondria after either in vivo or in vitro exposure, with no effect on succinate efflux. There is little or no reduction of ADP uptake by the same toxic exposures. Cephalexin, which is not toxic in vivo, inhibits respiration and uptake only with in vitro exposure. Fragmentation of mitochondria, which allows access of succinate to intramitochondrial enzymes without the need for carrier-mediated uptake, partially corrects the respiratory toxicity of cephaloglycin. We conclude that cephalosporin toxicity to succinate transport parallels the pattern of injury to mitochondrial respiration and may be pathogenic in this respiratory toxicity. These observations are consistent with the hypothesis that a) both nephrotoxic and nontoxic cephalosporins can fit the carriers for mitochondrial anionic substrate transport, and b) in situ nephrotoxicity develops as inhibition of transport becomes irreversible through acylation of these carriers.
Adenosine Diphosphate↗
Effects of anti-lipid A human monoclonal antibody on lipopolysaccharide-induced toxicity to the kidney.
Studies were done to evaluate the effects of the human monoclonal anti-lipid A IgM antibody A6(H4C5) on several components of the hemodynamic and renal toxicity of the cell wall lipopolysaccharide of E. coli 0111:B4. Antibody (0.25 to four mg./kg. BW) was administered 0.5 hour before, or premixed for one hour with, lipopolysaccharide (0.05 mg./kg., a 14 to 18% lethal dose), and the following measurements made over 0.5 to 3.5 hours of study: systemic arterial blood pressure, renal plasma flow, and glomerular filtration. The proximal tubular cell cytotoxicity of 90 mg./kg. of the cephalosporin cephaloridine was also quantified in similarly treated animals sacrificed 48 hours later. While one mg./kg. of antibody prevented the reduction by the lipopolysaccharide of renal plasma flow, it did not prevent the nephrotoxic synergy with cephaloridine, and four times the antibody dose did not prevent lipopolysaccharide-induced hypotension or reduced glomerular filtration. These amounts of this antibody protect leukopenic rabbits against the lethality of the slow onset bacteremic model of Pseudomonas conjunctivitis. It is suggested that the incompleteness of protection in this study may be the result of the sensitivity of the assay methods used and/or the acute endotoxemia produced in these animals.
Animals↗
Vitamin A intoxication presenting with ascites and a normal vitamin A level.
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Ascites↗
Mechanisms of the bacterial endotoxin-cephaloridine toxic synergy and the protective effects of saline infusion in the rabbit kidney.
To examine the mechanisms of the nephrotoxic synergy of bacterial cell wall lipopolysaccharide (LPS) (or endotoxin) and the cephalosporin antibiotics, we have studied: 1) the effects on mean arterial blood pressure and the clearances of inulin, p-aminohippurate and cephaloridine (Cld) of a 12%-lethal dose of Escherichia coli 0111-B4 LPS (0.05 mg/kg b.wt.i.v.), with both low and high rates of saline infusion (0.1 ml/min vs. a 7.5-ml/kg load followed by 0.4 ml/min, respectively, in approximately 2-kg rabbits); 2) the separate and combined effects of LPS and saline infusion on the concentrations of Cld in renal cortex and serum; and 3) the separate and combined effects of LPS and saline infusion on the nephrotoxicity of Cld, quantified by acute tubular necrosis scoring and serum creatinine concentrations 48 hr after treatment with 90 mg/kg of Cld i.v. and by mitochondrial respiratory toxicity, depletion of reduced glutathione and production of lipid peroxidation products in renal cortex 1 hr after treatment with 90 to 360 mg/kg of Cld i.v. The following was found: 1) the increased saline infusion (saline) largely prevented an LPS-induced fall of inulin clearance and partially prevented a fall of blood pressure and p-aminohippurate and Cld clearance; 2) as a result, saline prevented slightly elevated late serum and cortical Cld concentrations in LPS-treated animals; 3) the tubular necrosis and elevation of serum creatinine caused by Cld alone was reduced slightly and that produced by the combination of LPS plus Cld was reduced greatly by saline; 4) the comparable mitochondrial respiratory toxicity found after Cld and LPS-plus-Cld was prevented by saline infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The mitochondrial respiratory toxicity of cephalosporin antibiotics. An inhibitory effect on substrate uptake.
Cephalosporin antibiotics can produce renal cortical mitochondrial respiratory toxicity after either in vitro or in vivo exposure. In vitro toxicity is immediate, nonselective among toxic and nontoxic cephalosporins and reversed by substrate excess. In vivo toxicity is delayed, specific to the nephrotoxic cephalosporins and not reversible. Both routes of exposure affect respiration with succinate (S) more than with glutamate plus malate as substrates. Because glutamate and malate gain access to the intramitochondrial electron transport chain proximal to S, this pattern suggests that the cephalosporins affect a mitochondrial function outside the respiratory chain. A model of respiratory toxicity incorporating all of these features proposes that all cephalosporins can fit the affected transporters for mitochondrial substrate uptake, but, in the intact kidney, this causes limited or transient respiratory inhibition with nontoxic cephalosporins; in vivo toxicity, which is seen after later isolation and washing of mitochondria exposed in situ, develops with the more sequestered and reactive (nephrotoxic) cephalosporins that acylate these transporters. As a test of this hypothesis, studies were done, using the method of sieve filtration, to evaluate the effects of in vivo and in vitro exposure to cephaloglycin (toxic) and cephalexin (nontoxic) on the uptake of S and ADP by rabbit renal cortical mitochondria. In vivo and in vitro exposure to cephaloglycin reduced the net uptake of S by 70% and had a considerably smaller and less consistent effect on ADP uptake; cephalexin inhibited S uptake only with in vitro exposure. The rate of S washout from cephaloglycin-intoxicated mitochondria was no greater than from controls, ruling out increased efflux as a cause of decreased net uptake.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine Diphosphate↗
Treatment of childhood prednisone-resistant nephrotic syndrome and focal segmental glomerulosclerosis with intravenous methylprednisolone and oral alkylating agents.
Patients with prednisone-resistant nephrotic syndrome and biopsy-proven focal segmental glomerulosclerosis were treated with intravenous methylprednisone. After the first 2 weeks of therapy, the average urine protein excretion decreased from 247 to 96 mg/m2/h (p less than 0.04). Two of the 7 patients have had long-term, nearly complete remissions. The other patients relapsed. One relapsing patient was retreated with methylprednisolone and is now in remission. Four relapsing patients were treated with alkylating agents, in combination with methylprednisolone. All of these patients entered complete or partial remissions. Methylprednisolone causes a significant decrease in the proteinuria of children with focal segmental glomerulosclerosis. In addition, although the follow-up period is relatively short, it would appear that methylprednisolone, often in conjunction with an alkylating agent, has significantly improved the clinical status of these patients.
Administration, Oral↗
Augmentation of antibiotic nephrotoxicity by endotoxemia in the rabbit.
The acute renal failure complicating bacterial septicemia has multiple potential causes, prominent among which are endotoxemic and antibiotic nephrotoxic injury. Because the toxic interactions of endotoxin and antibiotics cannot be manipulated for study in human disease, we have developed a model of this interaction in the rabbit. Toxicity was assessed by quantification of tubular necrosis and serum creatinine concentrations 48 hr after single-dose i.v. endotoxin and/or antibiotic administration. A minimally nephrotoxic quantity of endotoxin (Escherichia coli lipopolysaccharide 0111:B4, 0.5 mg/kg b.w.) significantly increased the nephrotoxicity of the cephalosporins cephaloglycin (60 mg/kg) and cephaloridine (90 mg/kg) and the aminoglycoside neomycin (60 mg/kg), each of which was mildly-to-minimally damaging by itself. In studies of the acute functional effects of endotoxemia, the lipopolysaccharide had different effects on the renal handling of the two cephalosporins. Endotoxin increased the uptake of cephaloglycin, but decreased uptake of cephaloridine, in renal cortex in the first 0.5 hr after antibiotic administration. However, a prolonged elevation of serum levels of cephaloridine allowed later uptake of toxic amounts of this cephalosporin. Although these findings suggest a role of altered transport in the endotoxin-cephalosporin toxic synergy, the synergy was not reduced when cephaloglycin was given 1.5 hr before the endotoxin, a time which allows substantial elimination of antibiotic before the endotoxemic insult. Studies in another laboratory have demonstrated an endotoxin-induced increase of cortical concentrations of aminoglycosides, which could be a mechanism of the augmented toxicity seen in the present study. It is concluded that endotoxemia causes significant augmentation of the nephrotoxicity of cephalosporin and aminoglycoside antibiotics.(ABSTRACT TRUNCATED AT 250 WORDS)
Aminoglycosides↗
Hypertension caused by an aldosterone-secreting adenoma. Occurrence in a 7-year-old child.
A 7-year-old girl had hyperaldosteronism due to an adrenal cortical adenoma, a rare, surgically remediable cause of hypertension. Although the plasma potassium concentration was only slightly below normal, and the plasma aldosterone concentration was in a high normal range, the consistently suppressed plasma renin activity suggested primary aldosteronism. This diagnosis was confirmed by the failure of saline infusion to lower the plasma aldosterone concentration. Glucocorticoid-remediable hyperaldosteronism was excluded when dexamethasone did not reduce the high plasma aldosterone concentration. An enlarged left adrenal gland was observed in the computed tomographic scan, and blood from the left adrenal vein contained much more aldosterone than blood from the right adrenal vein. Surgical excision of the left adrenal gland, containing an adenoma, was followed by a return of BP and biochemical measurements to their normal ranges. This case demonstrated the importance of a rational systematic approach in the evaluation of children with sustained unexplained hypertension and the need to obtain plasma renin activity values when either hypokalemia is present or initial investigations fall to provide a diagnosis.
Adenoma↗
Interaction of ischemic and antibiotic-induced injury in the rabbit kidney.
The tubular necrosis produced by transient unilateral ischemia, three toxic cephalosporins, and the aminoglycoside neomycin were studied separately and in different combinations in the rabbit kidney. It was found that (1) mildly damaging transient ischemia (25 min) and a minimally toxic dose of the rapidly secreted cephalosporin cephaloglycin (60 mg/kg of body weight) are synergistically damaging; (2) there is no synergy between ischemia and the nonsecreted cephalosporin cephaloridine (90 mg/kg); and (3) ischemia and neomycin (100 mg/kg per day for three days) are not additively damaging, but the aminoglycoside has an additive effect with the combined insults of ischemia and cefazolin (500 mg/kg). Studies of transport showed that ischemia potentiates cephalosporin toxicity probably because it increases postischemic antibiotic concentrations in proximal tubular cells and that this increased uptake is the result of transiently augmented tubular secretion. Although this ischemic protocol reduced inulin clearance by 40%, it increased cephaloglycin secretion by an amount more than sufficient to overcome the decrease in filtration.
Acute Kidney Injury↗
Effect of piperonyl butoxide on organic anion and cation transport in rabbit kidneys.
Piperonyl butoxide has been shown to reduce accumulation of cephaloridine in rabbit renal cortex; however, the mechanism responsible for this effect remains unclear. Cephaloridine is a zwitterion and its accumulation in renal cortex has been suggested to be regulated by both organic anion and cation transport systems. Thus, it was of interest to determine the effect of piperonyl butoxide on renal transport of p-aminohippurate (PAH, an organic anion) and tetraethylammonium (TEA, an organic cation). Although pretreatment with piperonyl butoxide markedly inhibited renal cortical uptake of cephaloridine, the same treatment had less inhibitory effect on either PAH or TEA uptake. Efflux of PAH from preloaded renal cortical slices was enhanced by pretreatment with piperonyl butoxide; however, TEA efflux was unaffected. Thus, piperonyl butoxide appears to have effects on renal membrane functions which result in differential effects on PAH, TEA, and cephaloridine transport.
Aminohippuric Acids↗
Effects of piperonyl butoxide on cephalosporin nephrotoxicity in the rabbit. An effect on cephaloridine transport.
To evaluate the hypothesis that cytochrome P-450 mixed-function oxidase (MFO) activity may have a causal role in the production of cephalosporin nephrotoxicity, the effects of the MFO inhibitors cobaltous chloride and piperonyl butoxide on the nephrotoxicity of cephaloridine in the rabbit were examined. Although cobaltous chloride had no effect on cephaloridine nephrotoxicity, piperonyl butoxide had a significant protective effect. However, in correlated studies of the effects on the renal cortical uptake and disappearance of cephaloridine, it was found that piperonyl butoxide significantly reduces (by 50%) the cortical concentrations of the cephalosporin, both decreasing its uptake by and increasing its disappearance from tubular cells. Finally, we evaluated the effect of piperonyl butoxide on the nephrotoxicity of cephaloglycin, a more toxic cephalosporin that lacks the thiophene side-ring proposed as the target of MFO activation in earlier studies with cephaloridine. No protection against cephaloglycin was found. It is concluded that these inhibitors of MFO activity do not reduce cephalosporin nephrotoxicity in general, and that the reduction of cephaloridine toxicity by piperonyl butoxide can be explained by an effect on the intracellular concentrations of that particular cephalosporin.
Acute Kidney Injury↗
Reactivity and binding of beta-lactam antibiotics in rabbit renal cortex.
In studies designed to evaluate the reactivity of the beta-lactam antibiotics in the rabbit kidney, the binding to cortical macromolecules of isotopically labeled cephaloglycin (highly toxic) was compared in vivo and in vitro with that of cephalothin (minimally toxic) and benzylpenicillin (nontoxic). Three hours after administration of equal doses, the amounts of firmly bound antibiotic in whole cortex and in nuclear, mitochondrial, microsomal and cytosolic fractions of cortex were greatest for cephaloglycin (cortical concentration 7% of that measured at 0.5 hr), intermediate for cephalothin (2%) and least for benzylpenicillin (1%); the amounts of firmly bound antibiotic were unrelated to the earlier, peak cortical concentrations. Binding to cortical microsomes in vitro showed a similar pattern (greatest for cephaloglycin, least for benzylpenicillin); in addition, the binding in vitro of cephaloglycin was decreased by the addition of an NADPH-generating system and was not decreased by piperonyl butoxide. These studies provide evidence that the spontaneous reactivity of the beta-lactam ring may be an important determinant of the nephrotoxicity of the cephalosporins and fail to support the existence of a role of the cytochrome P-450 mixed-function oxidases in this reactivity.
Animals↗