Effects of Sevoflurane and Isoflurane on Renal Function and on Possible Markers of Nephrotoxicity

Background: Low-flow sevoflurane anesthesia is associated with increasing circuit concentrations of compound A, which is nephrotoxic in rats, but the effect of compound A and low-flow sevoflurane anesthesia on renal function in humans is unclear. The authors compared the effects of high- and low-flow sevoflurane and isoflurane anesthesia on renal function and on several possible markers of nephrotoxicity in humans.

Methods: Forty-two patients without preexisting renal disease underwent either low-flow isoflurane (1 l/min, n = 14), low-flow sevoflurane (1 l/min, n = 14), or high-flow sevoflurane (6 l/min, n = 14) anesthesia for body-surface-area surgery scheduled to last at least 4 h. Twenty-four-hour urinary excretion of N-acetyl-[small beta, Greek]-glucosaminidase (NAG), [small beta, Greek]2-microglobulin, protein, glucose, blood urea nitrogen (BUN), and serum creatinine concentrations were measured before and after anesthesia.

Results: There were no differences in blood urea nitrogen, creatinine, and creatinine clearance among the three groups after anesthesia. Increased urinary N-acetyl-[small beta, Greek]-glucosaminidase excretions were seen in the low-flow and high-flow sevoflurane groups, but not in the low-flow isoflurane group (P < 0.01). Ten patients in the low-flow sevoflurane group had 24-h urinary excretion of protein that exceeded the normal ranges after anesthesia, but only one patient in the isoflurane and none in the high-flow sevoflurane groups had this.     

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.     

Clinical Sevoflurane Metabolism and Disposition: I. Sevoflurane and Metabolite Pharmacokinetics

Background: Sevoflurane has low blood and tissue solubility and is metabolized to free fluoride and hexafluoroisopropanol (HFIP). Although sevoflurane uptake and distribution and fluoride formation have been described, the pharmacokinetics of HFIP formation and elimination are incompletely understood. This investigation comprehensively characterized the simultaneous disposition of sevoflurane, fluoride, and HFIP.

Methods: Ten patients within 30% of ideal body weight who provided institutional review board-approved informed consent received sevoflurane (2.7% end-tidal, 1.3 MAC) in oxygen for 3 h after propofol induction, after which anesthesia was maintained with propofol, fentanyl, and nitrous oxide. Sevoflurane and unconjugated and total HFIP concentrations in blood were determined during anesthesia and for 8 h thereafter. Plasma and urine fluoride and total HFIP concentrations were measured during and through 96 h after anesthetic administration. Fluoride and HFIP were quantitated using an ion-selective electrode and by gas chromatography, respectively.

Results: The total sevoflurane dose, calculated from the pulmonary uptake rate, was 88.8 plus/minus 9.1 mmol. Sevoflurane was rapidly metabolized to the primary metabolites fluoride and HFIP, which were eliminated in urine. HFIP circulated in blood primarily as a glucuronide conjugate, with unconjugated HFIP less or equal to 15% of total HFIP concentrations. In blood, peak unconjugated HFIP concentrations were less than 1% of peak seroflurane concentrations. Apparent renal fluoride and HFIP clearances (mean plus/minus SE) were 51.8 plus/minus 4.5 and 52.6 plus/minus 6.1 ml/min, and apparent elimination half-lives were 21.4 plus/minus 2.8 and 20.1 plus/minus 2.6 h, respectively. Renal HFIP and net fluoride excretion were 4,300 plus/minus 540 and 3,300 plus/minus 540 micro mol. Compared with the estimated sevoflurane uptake, 4.9 plus/minus 0.5% of the dose taken up was eliminated in the urine as HFIP. For fluoride, 3.7 plus/minus 0.4% of the sevoflurane dose taken up was eliminated in the urine, which, because a portion of fluoride is sequestered in bone, corresponded to approximately 5.6% of the sevoflurane dose metabolized to fluoride.     

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.     

Clinical Sevoflurane Metabolism and Disposition: II. The Role of Cytochrome P450 2E1 in Fluoride and Hexafluoroisopropanol Formation

Background: Sevoflurane is metabolized to free fluoride and hexafluoroisopropanol (HFIP). Cytochrome P450 2E1 is the major isoform responsible for sevoflurane metabolism by human liver microsomes in vitro. This investigation tested the hypothesis that P450 2E1 is predominantly responsible for sevoflurane metabolism in vivo. Disulfiram, which is converted in vivo to a selective inhibitor of P450 2E1, was used as a metabolic probe for P450 2E1.

Methods: Twenty-one patients within 30% of ideal body weight, who provided institutional review board-approved informed consent and were randomized to receive disulfiram (500 mg oral, n = 11) or nothing (control, n = 10) the night before surgery, were evaluated. All patients received sevoflurane (2.7% end-tidal, 1.3 MAC) in oxygen for 3 h after propofol induction. Thereafter, sevoflurane was discontinued, and anesthesia was maintained with propofol, fentanyl, and nitrous oxide. Blood sevoflurane concentrations during anesthesia and for 8 h thereafter were measured by gas chromatography. Plasma and urine fluoride and total (unconjugated plus glucuronidated) HFIP concentrations were measured by an ion-selective electrode and by gas chromatography, respectively, during anesthesia and for 96 h postoperatively.

Results: Patient groups were similar with respect to age, weight, sex, case duration, and intraoperative blood loss. The total sevoflurane dose, measured by cumulative end-tidal sevoflurane concentrations (3.7 plus/minus 0.1 MAC-h; mean plus/minus SE), total pulmonary uptake, and blood sevoflurane concentrations, was similar in both groups. In control patients, plasma fluoride and HFIP concentrations were increased compared to baseline values intraoperatively and postoperatively for the first 48 and 60 h, respectively. Disulfiram treatment significantly diminished this increase. Plasma fluoride concentrations increased from 2.1 plus/minus 0.3 micro Meter (baseline) to 36.2 plus/minus 3.9 micro Meter (peak) in control patients, but only from 1.7 plus/minus 0.2 to 17.0 plus/minus 1.6 micro Meter in disulfiram-treated patients (P < 0.05 compared with control patients). Peak plasma HFIP concentrations were 39.8 plus/minus 2.6 and 14.4 plus/minus 1.1 micro Meter in control and disulfiram-treated patients (P < 0.05), respectively. Areas under the plasma fluoride- and HFIP-time curves also were diminished significantly to 22% and 20% of control patients, respectively, by disulfiram treatment. Urinary excretion of fluoride and HFIP was similarly significantly diminished in disulfiram-treated patients. Cumulative 96-h fluoride and HFIP excretion in disulfiram-treated patients was 1,080 plus/minus 210 and 960 plus/minus 240 micro mol, respectively, compared to 3,950 plus/minus 560 and 4,300 plus/minus 540 micro mol in control patients (P < 0.05).     

Protective Effect of Docosahexaenoic Acid Against Cyclosporine A-Induced Nephrotoxicity in Rats: A Possible Mechanism of Action

The aim of this experimental study was to investigate whether, and how then, docosahexaenoic acid (DHA) could alleviate the cyclosporine A (CsA)-induced nephrotoxicity. Three main groups of Sprague–Dawley rats were treated orally with CsA (25 mg/kg), DHA (100 mg/kg), and CsA along with DHA. A corresponding control group was also used. DHA administration significantly reduced CsA-induced nephrotoxicity and associated hyperlipidemia and proteinuria as assessed by estimating serum triacylglycerol, serum total cholesterol, serum total protein, serum urea, and creatinine clearance. Furthermore, urinary excretions of protein and N-acetyl-β-d-glucosaminidase were significantly inhibited following DHA administration. DHA supplementation slightly attenuated the oxidative damage in kidney tissues as evaluated by the levels of thiobarbituric acid-reacting substances and protein carbonyl content in the kidney homogenate, although there were no significant differences between CsA-intoxicated and DHA-treated animals. Moreover, DHA treatment significantly restored total nitric oxide (NO) levels in both renal tissues and urine. This study demonstrates the ability of DHA to ameliorate CsA-induced renal dysfunction, which might be beneficial to enhance the therapeutic index of CsA. The data suggest that the protective potential of DHA in the prevention of CsA nephrotoxicity in rats was mainly associated with the increase of total NO bioavailability in renal tissues. Nevertheless, the exact independent mechanism in which DHA exerts its beneficial effect is yet to be fully elucidated.     

Mycophenolate-Induced Hepatotoxicity Precipitates Tacrolimus Nephrotoxicity in a Kidney Transplant Recipient: A Case Report

Mycophenolate (mycophenolate mofetil [MMF]; mycophenolate sodium [MPS]) and tacrolimus (FK-506) are commonly and concomitantly used to prevent rejection in organ transplant. Mycophenolate-induced hepatotoxicity causing the reduced FK-506 metabolism with nephrotoxicity may be less appreciated, leading to inappropriate management. We describe a new living donor kidney recipient receiving pretransplant and post-transplant immunosuppressants including oral mycophenolate (MMF 1 g daily) and tacrolimus (FK-506 4-8 mg daily) who developed progressive liver dysfunction (up to 10-fold increase) despite the reduced FK-506 dosage (6 mg daily). A thorough investigation including infection, inflammation, and autoimmune hepatitis were unremarkable. With a withdrawal of MMF, his liver function improved, but persistently higher trough serum FK-506 level (12-15 ng/mL) and increased serum creatinine were notable. Moreover, the reintroduction of MPS with the reduced FK-506 dosage (4 mg daily) worsened liver function along with FK-506 nephrotoxicity (serum creatinine from 1.4-2.4 mg/dL). The replacement of MPS with mammalian target of rapamycin inhibitor not only resolved liver injury but also normalized serum FK-506 level and kidney function. Mycophenolate should be kept in mind as a cause of drug-induced hepatotoxicity that can reduce tacrolimus metabolism, leading to FK-506 nephrotoxicity and acute kidney injury in organ transplant.     

Effects of Halothane and Methoxyflurane Anesthesia on Lipid and Carbohydrate Metabolism in Man

In Hinblick auf unsere früheren Befunde, die Stimulation der Lipolyse durch Halothan und Methoxyfluran und deren Metaboliten in vivo und in vitro an Ratten betreffend, wurden die Wirkungen von Halothan- und Methoxyflurannarkosen auf die Plasmaspiegel der freien Fettsäuren, von Glyzerol und Glukose am Menschen untersucht.
Die Untersuchungsserie umfaßte 18 Patienten, die für kleine elektive Eingriffe vorgesehen waren. Die Patienten wurden mit drei Anaesthesie-Kombinationen narkotisiert. Als Kontrolle wurden Lachgas und Thiopental verwendet; bei den anderen beiden Gruppen wurden Halothan bzw. Methoxyfluran zusätzlich verabreicht.
Sowohl Halothan als auch Methoxyfluran verursachten ein Ansteigen der freien Fettsäuren und der Glyzerolwerte im Plasma verglichen mit der Kontroll-Anaesthesiegruppe. Diese Stimulation der Lipolyse war bei Methoxyfluran gegen Ende der Narkose besonders ausgeprägt. Der Blutzuckerspiegel war nur während der Halothannarkose erhöht.
Diese Ergebnisse unterstützten somit unsere frühere Annahme, daß Halothan- und Methoxyflurannarkosen die Lipolyse anregen.     

Intrarenal lipoma: report of a case

We recently had the opportunity to study a case of renal lipoma. Pure intrarenal lipomas are very infrequent among all of the renal tumors and computed tomography is the only means of showing the fatty nature of such masses with its contrast discrimination property.     

Methoxyflurane (penthrane): a laboratory and clinical study

Canadian Journal of Anesthesia/Journal canadien d'anesthésie - Methoxyflurane is a new fluorinated and chlorinated saturated asymmetrical ether whose outstanding physical properties are an...     

Kidney Graft Function in Long-term Cyclosporine and Tacrolimus Treatment: Comparative Study With Nephrotoxicity Markers

Calcineurin inhibitors improve kidney allograft survival in the posttransplantation period; however, they may cause nephrotoxicity. The objective of this study was to compare the effect of cyclosporine (CsA) and tacrolimus (Tac) treatment on the transplanted kidney. The study included 219 patients aged 21 to 65 years. Of these, 120 (39 women and 81 men) were treated with CsA and 99 (38 women and 61 men) were treated with Tac. Patients were divided into 4 groups depending on the time since kidney transplantation. We evaluated urine markers of nephrotoxicity: proximal tubular cells lysosomal enzymes (N-acetyl-β-d-glucosaminidase [NAG] and its isoform NAG-B, β-d-galactosidase, and β-glucouronidase) and brush border enzymes (alanyl aminopeptidase and γ-glutamyl transpeptidase). Urine activities of nephrotoxicity markers were compared in CsA- and Tac-treated patients groups depending on the duration of treatment and allograft function as measured by serum creatinine concentration. Correlation studies between CsA and Tac levels and enzyme activities were performed in both groups and in the entire patient cohort. NAG and its isoform NAG-B seemed to be the most reliable markers of nephrotoxicity. Despite the significant correlation between NAG urine activity and serum creatinine concentration in the CsA group, there were no significant differences in NAG or NAG-B activities between CsA- and Tac-treated graft recipients.     

EBV Kidney Allograft Infection: Possible Relationship with a Peri-Graft Localization of PTLD

Post-transplant lymphoproliferative disorder (PTLD) is a grave complication of transplantation and the result of uncontrolled proliferation of B lymphocytes infected with Epstein-Barr virus (EBV). Herein we assess whether EBV infects renal grafts and whether there is a relationship between EBV kidney infection and PTLD. Allograft biopsies from 23 patients with PTLD were studied for the presence of EBV DNA and RNA (EBER-1, -2) by in situ hybridization and for CD21 by immunohistochemistry. Results were compared to 43 transplants from people without PTLD. EBV DNA and RNA were detected in 11/43 patients without PTLD (26%), and in 15/23 (65%) patients with PTLD (p = 0.004). EBV DNA and RNA localized to proximal tubular cells and these cells showed up-regulation of the EBV receptor CD21. EBV-infected allografts were noted in 12/12 patients with PTLD located near the allograft and in 3/11 (27%) of patients with PTLD distant from the graft. Multiple biopsies in eight patients showed that graft EBV infection can precede the diagnosis of PTLD by as long as 42 months. It is concluded that EBV can infect kidney allografts, and there appears to be a relationship between this infection and the presence of PTLD near the graft.     

Kidney Function and Intrarenal Blood Flow Distribution After Bleeding and Infusions of Mannitol and Dextran

Es wurde die Wirkung blutungsbedingter Hypotension auf die intrarenale Durchblutungsverteilung, vermittels interner Bestimmung von markierten roten Zellen mit Betadetektor und der Nierenfunktion bezüglich Clearance und Konzentrationsfähig-keit, des Säure-Basen-Verhältnisses, der renalen Haemodynamik und Nierenfunktion während der Verabreichung von Mannitol und Dextran geprüft. Mäßige Entblutung von 20 ml/kg bewirkte nur leichte änderung der untersuchten Parameter; zusätzliche Blutung von 5-10 ml/kg, welche eine Anurie bewirkte, hatte eine vermehrte Resistance der Rindengefäße zur Folge, während diese im Zirkulationsgebiet des Markraumes im wesentlichen unverändert blieb. Dies spricht für eine verschiedene Wirkung auf die vasokonstriktorischen Mechanismen dieser beiden renalen Gefäßbette. Das Ausmaß des Schockes dokumentierte sich im Säure-Basen-Verhältnis, besonders im Base-Exzess. Mannitol-Verabreichung hatte auf die untersuchten Parameter fast keine Wirkung, ausgenommen ein Anstieg der Harnproduktion und ein Abfall der Harnosmolalität. Plasmaexpansion mit Dextran ließ aile Werte auf das Kontrollniveau zurückkeh-ren und das Säure-Basen-Verhältnis normalisierte sich, was für eine Wiederherstellung der Sauerstoffversorgung der Gewebe spricht.     

Intrarenal pheochromocytoma: report of a case.

To our knowledge the first case of an intrarenal pheochromocytoma is reported. It is important to realize that an intrarenal or apparent intrarenal mass in a hypertensive patient might be a pheochromocytoma so that appropriate precautions can be taken.     

Nephrotoxicity as a cause of acute kidney injury in children

Many different drugs and agents may cause nephrotoxic acute kidney injury (AKI) in children. Predisposing factors such as age, pharmacogenetics, underlying disease, the dosage of the toxin, and concomitant medication determine and influence the severity of nephrotoxic insult. In childhood AKI, incidence, prevalence, and etiology are not well defined. Pediatric retrospective studies have reported incidences of AKI in pediatric intensive care units (PICU) of between 8% and 30%. It is widely recognized that neonates have higher rates of AKI, especially following cardiac surgery, severe asphyxia, or premature birth. The only two prospective studies in children found incidence rates of 4.5% and 2.5% of AKI in children admitted to PICU, respectively. Nephrotoxic drugs account for about 16% of all AKIs most commonly associated with AKI in older children and adolescents. Nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, amphotericin B, antiviral agents, angiotensin-converting enzyme (ACE) inhibitors, calcineurin inhibitors, radiocontrast media, and cytostatics are the most important drugs to indicate AKI as significant risk factor in children. Direct pathophysiological mechanisms of nephrotoxicity include constriction of intrarenal vessels, acute tubular necrosis, acute interstitial nephritis, and-more infrequently-tubular obstruction. Furthermore, AKI may also be caused indirectly by rhabdomyolysis. Frequent therapeutic measures consist of avoiding dehydration and concomitant nephrotoxic medication, especially in children with preexisting impaired renal function.     

Neuroprotective Effects of Propofol in Models of Cerebral Ischemia: Inhibition of Mitochondrial Swelling as a Possible Mechanism

Background: Propofol (2,6-diisopropylphenol) has been shown to attenuate neuronal injury in a number of experimental conditions, but studies in models of cerebral ischemia have yielded conflicting results. Moreover, the mechanisms involved in its neuroprotective effects are yet unclear.

Methods: The authors evaluated the neuroprotective effects of propofol in rat organotypic hippocampal slices exposed to oxygen-glucose deprivation, an in vitro model of cerebral ischemia. To investigate its possible mechanism of action, the authors then examined whether propofol could reduce Ca2+-induced rat brain mitochondrial swelling, an index of mitochondrial membrane permeability, as well as the mitochondrial swelling evoked by oxygen-glucose deprivation in CA1 pyramidal cells by transmission electron microscopy. Finally, they evaluated whether propofol could attenuate the infarct size and improve the neurobehavioral outcome in rats subjected to permanent middle cerebral artery occlusion in vivo.

Results: When present in the incubation medium during oxygen-glucose deprivation and the subsequent 24 h recovery period, propofol (10-100 [mu]m) attenuated CA1 injury in hippocampal slices in vitro. Ca2+-induced brain mitochondrial swelling was prevented by 30-100 [mu]m propofol, and so were the ultrastructural mitochondrial changes in CA1 pyramidal cells exposed to oxygen-glucose deprivation. Twenty-four hours after permanent middle cerebral artery occlusion, propofol (100 mg/kg, intraperitoneal) reduced the infarct size by approximately 30% when administered immediately after and up to 30 min after the occlusion. Finally, propofol administered within 30 min after middle cerebral artery occlusion was unable to affect the global neurobehavioral score but significantly preserved spontaneous activity in ischemic rats.     

Sevoflurane as a single anesthetic and physostigmine failure to enhance arousal

AIM: Sevoflurane is recommended for inhalational induction of anesthesia. Physostigmine may antagonize general anesthetics. The study investigates sevoflurane as a single anesthetic and its possible antagonism by physostigmine. METHODS: In 60 women scheduled for breast lump excision, anesthesia was induced with 8% sevoflurane. After 3 min of sevoflurane inhalation, a laryngeal mask airway (LMA) was inserted. Anesthesia was maintained with spontaneous ventilation at end tidal sevoflurane 3%. Systolic and diastolic blood pressure, heart rate and end tidal CO(2) were recorded intraoperatively. After skin closure and at end tidal sevoflurane 0.9%, physostigmine 2 mg or normal saline was given. After 2 min systolic, diastolic blood pressure, heart rate and end tidal CO(2) were recorded and sevoflurane was discontinued. Time to eyes opening, LMA removal and verbal response was recorded. Patients were also assessed for orientation, sedation, sitting ability and the 'picking up matches' test at 0, 15 and 30 min after LMA removal. RESULTS: Systolic, diastolic blood pressure and heart rate increased after laryngeal mask placement (P=0.0001, P=0.0001 and P=0.0001, respectively). Orientation, sitting ability and 'picking up' matches were similar in the 2 groups. Sedation at 15 min was less in the control group (P=0.004). CONCLUSIONS: Sevoflurane can be used as a single anesthetic but its recovery is not enhanced by physostigmine.