Carboxypeptidase-G2 rescue in a patient with high dose methotrexate-induced nephrotoxicity.

Abstract

High dose methotrexate (HDMTX) induced renal failure is a medical emergency, as methotrexate (MTX) is primarily eliminated by renal excretion. High doses of leucovorin (LV) do not necessarily prevent toxicity in the presence of sustained elevated plasma MTX concentrations. The bacterial enzyme carboxypeptidase-G2 (CPDG2) hydrolyzes MTX into inactive metabolites and has been demonstrated to lower plasma MTX concentrations to nontoxic levels rapidly in the nonhuman primate after HDMTX infusion. Therefore, CPDG2 was evaluated as a rescue agent in a patient with acute renal dysfunction secondary to HDMTX: A 16 year old patient with osteosarcoma experienced acute renal dysfunction after HDMTX administration, which resulted in markedly elevated and sustained plasma MTX concentrations. She received three doses of CPDG2 on the fifth day after HDMTX: Plasma MTX concentrations were determined before and after CPDG2 administration. The plasma MTX concentrations decreased from 60 to 1.2 microM within 15 minutes after the first dose of CPDG2. No rebound increase in plasma MTX concentrations or adverse reactions to the enzyme were observed. The patient developed only mild mucositis. Serum creatinine at the time of CPDG2 administration was 5 mg/dl and returned to normal within 7 weeks of enzyme administration. Carboxypeptidase-G2 rapidly, markedly, and persistently lowered plasma MTX concentrations to a level that could be rescued safely with LV. Based on the experience with this patient and on preclinical studies in nonhuman primates, CPDG2 appears to be more effective than hemodialysis or hemoperfusion, and may prove beneficial for patients at risk for life-threatening toxicity secondary to delayed excretion of MTX.