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The first report of nephrotoxicity appeared in 1964, when Paddock and colleagues reported three cases of acute renal insufficiency, two of whom were found to have calcium oxalate crystals in the renal tubules at autopsy.  In 1966, Crandell and colleagues reported a series in which 17/95 (18%) of patients developed an unusual type of nephropathy after operations in which methoxyflurane was used as a general anesthetic. This particular type of renal insufficiency was characterized by vasopressin -resistant high-output renal failure (production of large volumes of poorly concentrated urine) with a negative fluid balance, pronounced weight loss, elevation of serum sodium, chloride, osmolality and blood urea nitrogen. The urine of these patients was of a relatively fixed specific gravity and an osmolality very similar to that of the serum. Furthermore, the high urine output persisted a challenge test of fluid deprivation. Most cases resolved within 2–3 weeks, but evidence of renal dysfunction persisted for more than one year in 3 of these 17 cases (18%), and more than two years in one case (6%).