Gottlieb LS, Trey C. 1974. The effects of fluorinated anesthetics on the liver and kidneys. Ann. Rev. Med. 25: 411-429.
Possible Mechanisms of Action (p. 424-426)
The possible mechanisms of action of methoxyflurane on the kidney have been studied by Mazze et al (93-95, 97, 105, 106, 115-117), Holaday et al (114), Taves et al (118), and others. Holaday et al (114) labeled methoxyflurane with 14C in the methoxyl position. They showed, in man, that the biodegradation of methoxyflurane began immediately after the onset of exposure and continued to 12 hr. The identified products of the biotransformation were carbon dioxide, inorganic fluoride ion, dichloroacetic acid, and methoxyfluoroacetic acid. They concluded that fluoride ion and oxalate were both nephrotoxic and thus the prime toxicologic suspects. Frascino et al (109, 112) studied the effects of inorganic fluoride on the renal concentration mechanisms in dogs. The high blood fluoride levels interfere with both the generation of maximally concentrated urine and tubular free water reabsorption. Mazze et al (117) showed similar metabolic pathways to that of Holaday. Mazze found greater concentration of inorganic fluoride in patients who received methoxyflurane and developed polyuria than in those who did not develop renal failure. Fluoride inhibits anaerobic metabolism in renal medulla and thus may block sodium reabsorption. Taves et al (118) studied the inorganic fluoride and nonvolatile organic fluoride concentration in patients who developed methoxyflurane-associated kidney disease, and like Mazze, felt that inorganic fluoride ion is probably one of the more important responsible agents. In 1930, Goldemberg (119) reported a polyuric syndrome following the administration of sodium fluoride which was then used in the treatment of thyrotoxicosis. Roholm (120) suggested that polyuria is a prominent part of acute fluoride intoxication. Pindborg (121), Bond & Murray (122), as well as Taves et al (118) have described interstitial fibrosis in patients with history of long-term ingestion of fluoride.
Kosek et al (116) and Mazze et al (123) have conclusively demonstrated a physiological and anatomical renal tubular lesion in the rat identical to that seen in man. The lesion is proportional to methoxyflurane dosage and is not an idiosyncratic reaction. Inorganic fluoride ion formed by metabolism of the anesthetic agent appears to be responsible for the damage. From the same laboratory, Barr et al showed that methoxyflurane nephrotoxicity in the rat can be markedly aggravated by gentamicin, an event previously described by them in man (106). They have also shown that the metabolism of methoxyflurane and the susceptibility to the nephrotoxic effects varies in different strains of rats (115), but that there is a dose relationship to the nephrotoxicity (123).
Although oxalic acid has been implicated as a mechanism of nephrotoxicity and calcium oxalate crystals are found in the renal interstitia of patients with methoxyflurane renal failure, this may not explain the severe tubular dysfunction. In 1945, Jeghers & Murphy (124) reported that acute oxalate poisoning in man does not cause acute oliguric renal failure. Nor do we see a similar lesion acutely in patients with familiar hyperoxaluria (125). The patients with this familial disease show scarring, which occurs 40 to 50 years after the onset of deposition of calcium oxalate in the kidneys. Hollenberg et al (110) speculate that the critical factor lies in the metabolism of methoxyflurane into inorganic fluoride ion. They suggest that tubular obstruction with calcium oxalate may prevent recovery. The cortical flow is also reduced to levels that may be inadequate for the maintenance of glomerular filtration.
Aggravating factors in the methoxyflurane nephrotoxicity such as obesity were reported by Panner et al (108) in 2 fatal cases. Methoxyflurane is highly soluble in fat. Kuzucu (107) thought that tetracycline aggravated the onset of methoxyflurane renal disease. Mazze et al (105) reported gentamicin as aggravating the renal nephrotoxicity and demonstrated similar lesions in the rat. In the early cases of Paddock et al (104), surgical shock was implicated. However, in the case reports we have reviewed, this type of renal failure can be distinguished from the usual acute renal failure from surgery complicated by hypotension or mismatched blood transfusions. The onset of the renal failure occurred later than that expected after surgical shock -- in most reported patients on the 10th or 12th postoperative day. Despite well-maintained urinary volumes, the characteristic and pathological lesion was the deposition of calcium oxalate crystals in the kidney. There also have been reports of inappropriate antidiuretic hormone syndrome following administration of methoxyflurane (100). This syndrome was also noted by Mazze et al (95) in their prospective study; they also reported this occurrence after halothane administration. However, there has been no report of halothane causing the syndrome of nephrogenic diabetes insipidus as described in methoxyflurane anesthesia. There have been no reports of cross-reactivity between these two agents producing renal failure. The explanation could be in the biotransformation of the two anesthetic agents in man. Methoxyflurane biotransformation has been shown (34) to result in the release of an inorganic fluoride ion, whereas this has not been shown to occur with halothane.
We conclude from these studies that there is a real risk to renal function in the administration of methoxyflurane, and that some fatal cases have been documented and well studied. This risk seems to be confined to methoxyflurane at the moment, although the newer fluorinated anesthetics have not yet been adequately studied. We also know that there was concomitant hepatocellular disease in some of the patients with renal disease (13, 80). In 1971, the Committee on Anesthesia of the National Academy of Sciences-- National Research Council issued a special report on the evidence for the association of methoxyflurane anesthesia and renal dysfunction (126). They urged that the anesthetic continue to be available in clinical practice. Since that report, prospective studies have documented the nephrotoxic syndrome. The lesion has been reproduced in experimental animals and is dose-related. Fatalities have continued to be reported and their incidence is low perhaps because of the opportunity of recovery offered by renal dialysis and renal transplants. Although overall mortality from various anesthetic agents may be similar (3, 34, 99), we feel that the renal lesion should act as a deterrant to the use of methoxyflurane for prolonged surgery. Reasonable guidelines in relation to the prevention of severe renal effects have been suggested by Cousins & Mazze (97). Methoxyflurane should not be used in patients with pre-existing renal disease or given concurrently with other potential nephrotoxic drugs. In healthy individuals, the dose should not exceed 2-2.5 minimum alveolar concentration hours. Care in the use of accurate vaporizers and the measurements of renal function is necessary.
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125. Wyngaarden, J.B., Elder, T.D. 1966. The Metabolic Basis of Inherited Disease, ed. J.B. Stanbury, J.B. Wyngaarden, D.S. Fredrickson, 189-212. New York: McGraw
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