Journal of Clinical Oncology, Vol 1, 208-216, Copyright © 1983 by American Society of Clinical Oncology
Methotrexate-induced renal impairment: clinical studies and rescue from systemic toxicity with high-dose leucovorin and thymidine
HT Abelson, MT Fosburg, GP Beardsley, AM Goorin, C Gorka, M Link and D Link
Four separate groups of patients have been studied: (1) The effect of
high-dose methotrexate (MTX) administration on glomerular filtration rate
was determined by pre- and posttreatment inulin and creatinine clearances
in nine patients. Measurements were made prior to and 24-40 hr after drug
administration. Inulin and creatinine clearances both decreased a mean of
43%. No signs of systemic toxicity occurred. (2) Three other patients given
high-dose courses of MTX developed MTX toxicity. Their creatinine clearance
decreased an average of 61%. (3) In a separate group of five patients
undergoing weekly MTX treatment, comparison of serum MTX pharmacokinetics
with and without alkalinization of the urine demonstrated no significant
difference in peak serum MTX levels or serum MTX decay. (4) Eight
additional patients with severe renal dysfunction secondary to MTX were
treated with increased doses of leucovorin and a continuous infusion of
thymidine (8 g/m2/day) once renal failure was recognized. When high-dose
leucovorin and thymidine were begun 48-72 hr after the MTX infusion, severe
toxicity in the form of leukopenia, thrombocytopenia, diffuse mucositis,
stomatitis, or skin rash was averted. We concluded the following: (1)
high-dose MTX causes a subclinical decrease in glomerular filtration rate
with each administration, even in nontoxic courses; (2) alkalinization of
the urine with sodium bicarbonate does not alter plasma MTX decay, while
volume expansion (hydration) is maintained constant; and (3) rigorous
monitoring of serum creatinine and serum MTX levels 24-48 hr after MTX
administration allows for the institution of rescue measures, including
leucovorin and thymidine, which will abort the systemic toxicity that
accompanies MTX-induced renal failure.
