SPECTRUM AND SUBCELLULAR DETERMINANTS OF FLUORINATED ANESTHETIC-MEDIATED PROXIMAL TUBULAR INJURY

Currently used fluorinated anesthetics are chemically related to metho xyflurane (MF), a drug that caused many cases of clinical acute renal failure during previous widespread use. To determine whether newer flu orinated anesthetics might also have nephrotoxic effects, three curren tly used agents (isoflurane (IF), sevoflurane (SF), and desflurane) or MF were added to rat proximal tubular segments, followed by assessmen ts of cell integrity (ATP levels and percent lactic dehydrogenase rele ase). Ether served as a negative control. MF, IF, and SF each induced lethal proximal tubular segment injury (up to 92, 71, and 30% lactic d ehydrogenase release, respectively) and massive ATP depletion. ATP los ses were observed at or near clinically relevant drug levels, they pre ceded lethal injury, and they correlated with similar to 50% and simil ar to 100% reductions in total and Na,K-ATPase-driven respiration, res pectively, Clinically relevant inorganic fluorine levels simulated flu orinated anesthetic toxicity. However, fluoride release from the anest hetics (a cytochrome p450 process) did not appear to be required for t oxicity (no protection with P450 inhibitors and no detectable inorgani c fluoride release). As IF was judged to be one-third as toxic as MF, subclinical tubular injury (increased urine N-acetyl-beta-D-glucosamin idase (NAG) levels) after its use was sought in 19 surgical patients. Fifteen patients undergoing comparable operations with SF (approximate ly one-half as toxic as IF in vitro) and nine patients undergoing regi onal/ local anesthesia were controls. The IF group doubled its urinary NAG levels by the end of surgery (P < 0.005). Conversely, NAG levels remained stable in both control groups. The conclusions are that 1) cu rrently used fluorinated anesthetics, particularly IF, share (but to a lesser degree) MF's tubulotoxic effects, 2) ATP depletion (probably d ue to decreased production) and Na,K-ATPase inhibition are likely cont ributing mechanisms, 3) fluoride is a prime determinant of this toxici ty, and 4) tubular injury can be expressed at or near clinically relev ant anesthetic/inorganic fluoride levels. That increased enzymuria can develop in patients after IF anesthesia suggests that the above in vi tro data could have potential clinical relevance in selected patients.