A randomized prospective trial of amphotericin B lipid emulsion versus dextrose colloidal solution in critically ill patients.

BACKGROUND: Amphotericin B is the agent of choice for most invasive fungal infections in critically ill patients. It is associated with at least a 50% incidence of nephrotoxicity, despite prophylactic measures such as sodium loading. Newer formulations of amphotericin B are available but are costly and have unknown bioavailability in critically ill patients. Previous trials in neutropenic and critically ill patients have demonstrated that mixing amphotericin B with 20% lipid solution (Intralipid; Clintec Nutrition, Deerfield, III) may decrease nephrotoxicity. METHODS: In this randomized, prospective clinical trial, patients with positive fungal blood cultures, tracheal/sputum cultures or peritoneal cavity cultures were randomized to receive either 0.5 mg/kg per day of amphotericin B dextrose or 1.0 mg/kg per day of amphotericin B lipid emulsion. Duration of therapy was determined by the primary care team. Weekly 24-hour creatinine clearance was measured until 2 weeks after amphotericin B therapy was completed. RESULTS: The two groups were similar based on age, white blood cell count, serum creatinine, and creatinine clearance at the beginning of therapy. The group receiving amphotericin B lipid emulsion had significantly less decrease in creatinine clearance compared with controls, despite receiving significantly more amphotericin B. CONCLUSION: Amphotericin B lipid emulsion can be given at a higher total cumulative dose than amphotericin B dextrose with less nephrotoxicity.     

Invasive fungal infections. Epidemiology and new therapies

RISING INCIDENCE: In the past two decades, systemic fungal infections, essentially invasive candidiasis, but also invasive aspergillosis, has increased substantially. Despite the currently available antifungal drugs, amphotericin B (AmB), azole compounds (fluconazole or FLU, itraconazole or ITR), these infections are associated with significant morbidity and mortality. AmB remains the drug of choice for treatment of most fungal diseases because of its broad spectrum and potent fungicidal activity, but significant side effects limit its clinical utility. The azole antifungal agents are easier to take, less toxic than AmB, but their use is limited by multiazole-resistant strains. NEW ANTIFUNGAL AGENTS: Lipid formulations have recently attracted much attention due to a significantly lower toxicity: this concerns lipid formulations of AmB and perhaps nystatin in the future. New triazoles (voriconazole, ravuconazole, posaconazole) have shown a wide spectrum of action including against azole-resistant isolates. A new class of antifungal agents, lipopeptides (MK-0991, LY303366, FK463), with an original mechanism of action are being developed. These new compounds are reported to possess a large fungicidal activity against most isolates including AmB and azole-resistant strains.     

The aminoglycosides

Aminoglycoside antibiotics continue to be indispensable in the management of complex aerobic gram-negative infections. In the United States approximately 4,000,000 patients receive this antibiotic class each year. Although the clinical efficacy of aminoglycosides is unsurpassed, these antibiotics nonetheless have an inherent tendency to produce undesirable side effects. In particular, nephrotoxicity and ototoxicity continue to be the toxicologic side effects that merit special concern in patient management. If careful attention is paid to the dose of an aminoglycoside, the duration of its use, and other clinical issues, such as the state of hydration of the patient, toxic side effects can be reduced to the minimum. Aminoglycosides are chemically and microbiologically ideally suited for inclusion in polymethylmethacrylate bone cements as a delivery system for prevention or treatment of orthopedic surgical infections.     

Rehabilitating role of glutathione ester on cisplatin induced nephrotoxicity

Cisplatin caused differential toxic effects on blood glucose and plasma urea, uric acid and creatinine levels. Cisplatin also showed an inhibitory effect on kidney marker enzymes like alkaline phosphatase, acid phosphatase, aspartate aminotransferase and alanine aminotransferase. However, administration of glutathione ester modulates the toxic side effect of cisplatin observed in kidney enzymes, and in blood parameters. It seems that glutathione ester plays an important role in protecting against the cisplatin induced nephrotoxicity by inhibiting the accumulation of platinum in kidneys.     

Attenuation of chloroquine-induced renal damage by alpha-lipoic acid: possible antioxidant mechanism

The toxic effect of chloroquine (CQ) has been attributed to oxidative stress with the consequences of lipid peroxidation. This study investigates the effects of alpha-lipoic acid (LA) on CQ-induced nephrotoxicity in rats. A single oral administration of CQ (970 mg/kg)-induced nephrotoxicity, manifested biochemically by a significant increase in serum creatinine and blood urea nitrogen concentrations. In addition, renal tissue from CQ-treated rats showed a significant increase in lipid peroxides measured as thiobarbituric acid reactive substances and hydroperoxides, along with significant decrease in nonenzymic antioxidants (vitamin C, vitamin E, and reduced glutathione) and enzymic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase) levels. Oral administration of LA (10, 30, or 100 mg/kg) in different doses for 10 days produced a significant protection against nephrotoxicity induced by CQ. Treatment with LA markedly reduced the elevated lipid peroxidation, restored the depleted renal antioxidant defense system. LA at 100 mg/kg was effective when compared with other doses (10 and 30 mg/kg). This was accompanied by the histopathological observations in kidney tissue. The results suggest that LA ameliorate the lipid peroxidation and the loss of cellular antioxidants, thereby protecting the CQ-induced oxidative damage in kidney.     

Attenuation of Chloroquine‐Induced Renal Damage by α‐Lipoic Acid: Possible Antioxidant Mechanism

The toxic effect of chloroquine (CQ) has been attributed to oxidative stress with the consequences of lipid peroxidation. This study investigates the effects of α‐lipoic acid (LA) on CQ‐induced nephrotoxicity in rats. A single oral administration of CQ (970 mg/kg)‐induced nephrotoxicity, manifested biochemically by a significant increase in serum creatinine and blood urea nitrogen concentrations. In addition, renal tissue from CQ‐treated rats showed a significant increase in lipid peroxides measured as thiobarbituric acid reactive substances and hydroperoxides, along with significant decrease in nonenzymic antioxidants (vitamin C, vitamin E, and reduced glutathione) and enzymic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, and glutathione‐S‐transferase) levels. Oral administration of LA (10, 30, or 100 mg/kg) in different doses for 10 days produced a significant protection against nephrotoxicity induced by CQ. Treatment with LA markedly reduced the elevated lipid peroxidation, restored the depleted renal antioxidant defense system. LA at 100 mg /kg was effective when compared with other doses (10 and 30 mg/kg). This was accompanied by the histopathological observations in kidney tissue. The results suggest that LA ameliorate the lipid peroxidation and the loss of cellular antioxidants, thereby protecting the CQ‐induced oxidative damage in kidney.     

New insights into the mechanism of methoxyflurane nephrotoxicity and implications for anesthetic development (part 1): Identification of the nephrotoxic metabolic pathway

BACKGROUND: Methoxyflurane nephrotoxicity results from biotransformation; inorganic fluoride is a toxic metabolite. Concern exists about potential renal toxicity from volatile anesthetic defluorination, but many anesthetics increase fluoride concentrations without consequence. Methoxyflurane is metabolized by both dechlorination to methoxydifluoroacetic acid (MDFA, which may degrade to fluoride) and O-demethylation to fluoride and dichloroacetatic acid. The metabolic pathway responsible for methoxyflurane nephrotoxicity has not, however, been identified, which was the aim of this investigation. METHODS: Experiments evaluated methoxyflurane metabolite formation and effects of enzyme induction or inhibition on methoxyflurane metabolism and toxicity. Rats pretreated with phenobarbital, barium sulfate, or nothing were anesthetized with methoxyflurane, and renal function and urine methoxyflurane metabolite excretion were assessed. Phenobarbital effects on MDFA metabolism and toxicity in vivo were also assessed. Metabolism of methoxyflurane and MDFA in microsomes from livers of pretreated rats was determined in vitro. RESULTS: Phenobarbital pretreatment increased methoxyflurane nephrotoxicity in vivo (increased diuresis and blood urea nitrogen and decreased urine osmolality) and induced in vitro hepatic microsomal methoxyflurane metabolism to inorganic fluoride (2-fold), dichloroacetatic acid (1.5-fold), and MDFA (5-fold). In contrast, phenobarbital had no influence on MDFA renal effects in vivo or MDFA metabolism in vitro or in vivo. MDFA was neither metabolized to fluoride nor nephrotoxic. Barium sulfate diminished methoxyflurane metabolism and nephrotoxicity in vivo. CONCLUSIONS: Fluoride from methoxyflurane anesthesia derives from O-demethylation. Phenobarbital increases in methoxyflurane toxicity do not seem attributable to methoxyflurane dechlorination, MDFA toxicity, or MDFA metabolism to another toxic metabolite, suggesting that nephrotoxicity is attributable to methoxyflurane O-demethylation. Fluoride, one of many metabolites from O-demethylation, may be toxic and/or reflect formation of a different toxic metabolite. These results may have implications for interpreting anesthetic defluorination, volatile anesthetic use, and methods to evaluate anesthetic toxicity.     

Propofol: the challenges of formulation

Propofol is a potent lipophilic anesthetic that was initially formulated in Cremophor El for human use. Because of the occurrence of Cremophor EL anaphylaxis and improvements in the quality of lipid emulsions, it was ultimately brought to market as 1% propofol formulated in 10% soybean oil emulsion. Emulsions represent complex formulation compositions whose suitability for intravenous administration is dependent on a number of factors. Despite the success of propofol emulsions, drawbacks to such formulations include inherent emulsion instability, injection pain, a need for antimicrobial agents to prevent sepsis, and a concern of hyperlipidemia-related side effects. Efforts to overcome such drawbacks have involved the development of propofol emulsions with altered propofol and lipid contents, the addition of different excipients to emulsions for antimicrobial activity, and study of nonemulsion formulations including propofol-cyclodextrin and propofol-polymeric micelle formulations. In addition, a number of propofol prodrugs have been made and evaluated.     

Effects of cyclosporine on the isolated perfused rat kidney

Although cyclosporine (CsA) has been shown to cause decreased renal function in humans, the mechanisms important in cyclosporine nephrotoxicity are not well understood. Investigations of cyclosporine nephrotoxicity in animal models have been complicated by systemic toxic effects not seen in humans. In the present study, the direct renal effects of cyclosporine were investigated in the isolated perfused rat kidney (IPRK) model. Cyclosporine delivered by nontoxic liposomes had no effect on IPRK resistance, perfusate flow, inulin clearance, or fractional reabsorption of sodium, despite marked tissue accumulation of CsA (55.1 +/- 7.2 micrograms/g kidney tissue). In contrast, a 63% decrease in inulin clearance was observed following the administration of intravenous cyclosporine (0.1 ml). However, similar changes in IPRK function were seen after the administration of 0.1 ml of the intravenous cyclosporine vehicle, cremophor, suggesting that the alterations in function were secondary to the vehicle. All together, these findings suggest that cyclosporine nephrotoxicity may be secondary to renal innervation, toxic metabolites, or other systemic effects of cyclosporine not present in the IPRK.     

Liposomal Formulation Increases Local Delivery of Amphotericin from Bone Cement: A Pilot Study

Background  

Amphotericin is a highly toxic hydrophobic antifungal. Delivery of amphotericin from antifungal-loaded bone cement (ALBC) is much lower than would be expected for an equivalent load of water-soluble antibacterials. Lipid formulations have been developed to decrease amphotericin toxicity. It is unknown how lipid formulations affect amphotericin release and compressive strength of amphotericin ALBC.     

A peculiar vacuolization in the kidney transplant of a child treated with tacrolimus

Tacrolimus (TAC) is a useful immunosuppressive agent in the prevention of rejection. However, the blood level between its therapeutic and toxic levels is narrow such that its nephrotoxicity is a problem. Moreover, its bioavailability and pharmakokinetics are highly variable. We experienced a case of acute nephrotoxicity, in which the blood level rose about 10 times above the expected level. We found a peculiar vacuolization in the transplant biopsy specimen. This change showed a marked vacuolization of the tubular cells, suggestive of acute nephrotoxicity by TAC.     

New insights into the mechanism of methoxyflurane nephrotoxicity and implications for anesthetic development (part 2): Identification of nephrotoxic metabolites

BACKGROUND: Methoxyflurane nephrotoxicity results from its metabolism, which occurs by both dechlorination (to methoxydifluoroacetic acid [MDFA]) and O-demethylation (to fluoride and dichloroacetic acid [DCAA]). Inorganic fluoride can be toxic, but it remains unknown why other anesthetics, commensurately increasing systemic fluoride concentrations, are not toxic. Fluoride is one of many methoxyflurane metabolites and may itself cause toxicity and/or reflect formation of other toxic metabolite(s). This investigation evaluated the disposition and renal effects of known methoxyflurane metabolites. METHODS: Rats were given by intraperitoneal injection the methoxyflurane metabolites MDFA, DCAA, or sodium fluoride (0.22, 0.45, 0.9, or 1.8 mmol/kg followed by 0.11, 0.22, 0.45, or 0.9 mmol/kg on the next 3 days) at doses relevant to metabolite exposure after methoxyflurane anesthesia, or DCAA and fluoride in combination. Renal histology and function (blood urea nitrogen, urine volume, urine osmolality) and metabolite excretion in urine were assessed. RESULTS: Methoxyflurane metabolite excretion in urine after injection approximated that after methoxyflurane anesthesia, confirming the appropriateness of metabolite doses. Neither MDFA nor DCAA alone had any effects on renal function parameters or necrosis. Fluoride at low doses (0.22, then 0.11 mmol/kg) decreased osmolality, whereas higher doses (0.45, then 0.22 mmol/kg) also caused diuresis but not significant necrosis. Fluoride and DCAA together caused significantly greater tubular cell necrosis than fluoride alone. CONCLUSIONS: Methoxyflurane nephrotoxicity seems to result from O-demethylation, which forms both fluoride and DCAA. Because their co-formation is unique to methoxyflurane compared with other volatile anesthetics and they are more toxic than fluoride alone, this suggests a new hypothesis of methoxyflurane nephrotoxicity. This may explain why increased fluoride formation from methoxyflurane, but not other anesthetics, is associated with toxicity. These results may have implications for the interpretation of clinical anesthetic defluorination, use of volatile anesthetics, and the laboratory methods used to evaluate potential anesthetic toxicity.     

Dithio-bis-mercaptoethanesulphonate (DIMESNA) does not prevent cellular damage by metabolites of ifosfamide and cyclophosphamide in LLC-PK1 cells

Ifosfamide (IF) is an alkylating cytostatic with urotoxic (haemorrhagic cystitis) and nephrotoxic (Fanconi syndrome) side effects. Cyclophosphamide (CP), a structural isomer of IF, shows urotoxic but no nephrotoxic side effects. The development of haemorrhagic cystitis during therapy with IF or CP can be prevented by the uroprotective drug sodium-2-mercaptoethanesulphonate (MESNA). However, even in the presence of MESNA, Fanconi syndrome may still develop after therapy with IF. Using the renal tubular cell line LLC-PK₁, we investigated whether there is a protective effect of either MESNA or of its major metabolite DIMESNA, in combination with metabolites of IF or CP, on thymidine incorporation, uridine incorporation or total protein. DIMESNA, the dimer of MESNA, is the dominant form of the molecule in the circulation; the proximal tubular cell must convert this back to MESNA at the expense of glutathione, before it can exert its uroprotective action. We did not find a protective effect of DIMESNA under any of the experimental conditions tested. LLC-PK₁ cells exposed to 3 mmol/l DIMESNA did not convert DIMESNA to MESNA. The toxic effect of the CP metabolite 4-OOH-CP was more pronounced in the presence of DIMESNA than in its absence. MESNA completely prevented the toxic effects of acrolein and of 4-OOH-CP. The toxic effects of 4-OOH-IF and of chloracetaldehyde, two major metabolites of IF, were significantly reduced in the presence of MESNA. However, even at a 30-fold molar excess of MESNA over 4-OOH-IF, thymidine incorporation remained reduced by 40% compared with controls, indicating incomplete protection of tubular cells against metabolites of IF. Similarly, the effect of chloracetaldehyde was not completely reversed by MESNA. Our data indicate that DIMESNA is not metabolized sufficiently by LLC-PK₁ cells. Moreover, DIMESNA may deprive the cell of glutathione and thus enhance the toxicity of 4-OOH-CP. The finding that MESNA does not protect LLC-PK₁ cells completely against the toxic effects of IF metabolites may explain the difference in nephrotoxicity of IF and CP. It also explains the development of tubular damage in the presence of MESNA and in the absence of haemorrhagic cystitis.     

Nephrotoxic drugs

The nephrotoxic effects of cyclosporine, aminoglycoside antibiotics, cisplatin, amphotericin B, beta-lactam antibiotics and indomethacin are reviewed. These drugs were chosen because they are among the most frequent causes of renal injury in children. In addition, their nephrotoxicity is caused by different mechanisms. Several generalizations can be made, however. First, agents which cause tubular damage tend to be synergistic in their toxic effects. This synergism is seen when several nephrotoxic drugs are given simultaneously. In addition, the use of a nephrotoxic agent in a patient with pre-existing renal disease can result in severe tubular injury. Second, serum levels of the drug frequently fail to correlate with the degree of nephrotoxicity in individual patients. Third, early signs of renal injury can be subtle (e.g., minor changes in electrolyte excretion) or dramatic (e.g., acute renal failure). The sublte changes are particularly important, since they can be useful predictors of serious nephrotoxicity.     

Role of organic anion transporter 1 (OAT1) in cephaloridine (CER)-induced nephrotoxicity

Role of organic anion transporter 1 (OAT1) in cephaloridine (CER)-induced nephrotoxicity. BACKGROUND: Cephaloridine (CER) has been used to elucidate the mechanisms of cephalosporin antibiotic-induced nephrotoxicity. Organic anion transporters have been thought to mediate CER uptake by the proximal tubule. The purpose of this study was to elucidate the possible involvement of organic anion transporter 1 (OAT1) in CER-induced nephrotoxicity. METHODS: A mouse terminal proximal straight tubule (S3) cell line stably expressing rat OAT1 (S3 rOAT1) was established and used in this study. The cellular uptake of [14C]-para-aminohippuric acid (PAH), a prototype organic anion, and that of [14C]-CER were measured. The effects of CER on the viability of the cells and the amount of lipid peroxidation were estimated. RESULTS: S3 rOAT1 expressed a functional organic anion transporter in the cytoplasmic membrane, and exhibited CER uptake activity. CER treatment resulted in a more significant decrease in the viability and a more significant increase in the amount of lipid peroxidation in S3 rOAT1 than in S3 cells transfected with an expression vector lacking the rOAT1 insert. Probenecid, an inhibitor of organic anion transport, and probucol, an antioxidant, significantly suppressed the decrease in viability and increase in the amount of lipid peroxidation in S3 rOAT1 treated with CER. The effects of various cephalosporin antibiotics on the uptake of [14C]PAH were correlated significantly with the effects of these drugs on cell viability. CONCLUSIONS: These results suggest that rOAT1 is, at least in part, responsible for the cellular uptake of CER and therefore CER-induced nephrotoxicity.     

Tacrolimus: 20 years of use in adult kidney transplantation. What we should know about its nephrotoxicity

Tacrolimus (or FK506), a calcineurin inhibitor (CNI) introduced in field of transplantation in the 1990s, is the cornerstone of most immunosuppressive regimens in solid organ transplantation. Its use has revolutionized the future of kidney transplantation (KT) and has been associated with better graft survival, a lower incidence of rejection, and improved drug tolerance with fewer side effects compared to cyclosporine. However, its monitoring remains complicated and underexposure increases the risk of rejection, whereas overexposure increases the risk of adverse effects, primarily nephrotoxicity, neurotoxicity, infections, malignancies, diabetes, and gastrointestinal complaints. Tacrolimus nephrotoxicity can be nonreversible and can lead to kidney graft loss, and its diagnosis is therefore best made with reference to the clinical context and after exclusion of other causes of graft dysfunction. Many factors contribute to its development including: systemic levels of tacrolimus; local renal exposure to tacrolimus; exposure to metabolites of tacrolimus; local susceptibility factors for CNI nephrotoxicity independent of systemic or local tacrolimus levels, such as the age of a kidney; local renal P-glycoprotein, local intestinal and hepatic cytochrome P450A3, and renin angiotensin system activation. The aim of this review is to describe the pharmacokinetics, pharmacodynamics, and mechanisms of acute and chronic tacrolimus nephrotoxicity in adult KT.     

A case of systemic lupus erythematosus associated with cryptococcal meningitis which was successfully cured by the administration of massive dose of amphotericin B

A case of SLE with moderately deteriorated renal function due to lupus nephritis developed cryptococcal meningitis. Long term administration of amphotericin B (cumulative dose 5 g) combined with 5-flucytosine eradicated this fungal infection. Throughout amphotericin B administration urinary excretions of Na and K, as well as plasma HCO3 concentration were monitored, and, Na, K and HCO3 were supplemented orally and intravenously so much as to replace their urinary losses. Neither prominent water-electrolyte disturbance nor severe azotemia, which are the most serious side effects of amphotericin B, did not ensue. This case study indicates that sufficient water.electrolytes supplementation is important to prevent the nephrotoxicity of amphotericin B.     

中药菟丝子防治骨质疏松症的研究进展

骨质疏松症(osteoporosis, OP)已经成为世界范围内的一大难题,而OP所造成的骨质疏松性骨折直接影响着社会经济的发展和个人生活质量的提高。目前针对OP的治疗主要是促进骨生成和减少骨流失,虽然其作用靶点明确,疗效肯定,但具有一定的毒副作用。中药菟丝子及其组方在临床上广泛应用于抗骨质疏松,疗效显著。对菟丝子及其活性成分抗骨质疏松的研究也越来越多,并且取得了一定的成果。本文通过检索文献,对菟丝子中主要起抗骨质疏松作用的成分如菟丝子黄酮、菟丝子多糖等以及组方的研究进行归纳整理,进一步揭示菟丝子防治OP的作用机制,以期拓宽临床防治OP的思路。     

Nephrotoxicity of recreational party drugs

N-benzylpiperazine (BZP) is the active ingredient in recreational 'party' pills with a stimulant, euphoric mechanism of action akin to that of 3,4-methylenedioxymethamphetamine (MDMA or ecstasy). Many people (ab)use BZP-based party pills usually without any significant toxic effects. However, nephrotoxicity secondary to hyperthermia and rhabdomyolysis has been reported. Another serious renal-related side-effect is hyponatraemia with acute cerebral oedema. There is also evidence that these agents may have a specific toxic effect producing acute kidney injury. Thus, acute kidney injury either direct or secondary to the effects of BZP or MDMA need to be considered when any individual presents with symptoms of a recreational party drug overdose.