Literature search and review of mechanism of renal toxicity for methotrexate.

Fråga: Literature search and review of mechanism of renal toxicity for methotrexate.

Sammanfattning: MTX nephrotoxicity is rare with non-toxic plasma levels, but is the most important side effect in patients treated with high doses of methotrexate. NSAIDs - especially ketoprofen and indomethacin - can increase plasma levels and toxicity of MTX.

Svar: Methotrexate (MTX) is a well-known antineoplastic drug which competes with folic acid. As with other antineoplastics, hematopoietic toxicity, including anemia, leucopenia, granulocytopenia and thrombocytopenia are frequent (between 2 and 25 per cent) (1,2,3). Hepatic toxicity (around 5 per cent) and gastrointestinal symptoms, as well as skin reactions or alopecia have been described.

With low doses, nephrotoxicity is occasionally seen, but is rare. Nevertheless, at high doses this toxicity becomes the principal side effect. Nephrotoxicity is seen as an extensive tubular necrosis, possibly due to a local antifolic effect. Crystalluria with tubular obstruction may occur when plasma concentrations are very high (4,5).

Recently (6-9) a life-threatening interaction between high doses of MTX and NSAIDs has been reported. Nephrotoxicity was found in 9 of 118 patients treated with high dose methotrexate (HDMTX) (6). In 5 of these patients ketoprofen and diclofenac were also used. Two other cases had other possible explanations for the renal impairment. Moreover, in two cases, readministration of ketoprofen after HDMTX did not result in any kidney damage. These patients had higher plasma MTX concentrations than controls suggesting a drug interaction for the elimination of MTX. Ketoprofen and HDMTX were not given together in patients without renal toxicity. Later reports (7-10) confirmed these findings.

MTX undergoes biotransformation in the liver to 7-OH-MTX but renal excretion of unchanged drug is the main route of excretion (11). While impaired hepatic MTX biotransformation by NSAIDs cannot be excluded, the kidney is the most probable site of interaction. In fact, the known side-effects of ketoprofen do not include specific renal complications, but HDMTX is a recognised cause of acute renal toxicity (1-5).

The increase in MTX levels could be due to a inhibition of renal prostaglandin synthesis by ketoprofen which would decrease renal perfusion and thus inhibit MTX clearance (6,9). A second alternative could be a competitive renal secretion of these two drugs, which are both eliminated to a large extent by the kidney (6,7,10,11). Furthermore the inhibition of renal renin release is also dependent on PGE2 (9). These together decrease the renal elimination of MTX, and increase the plasma concentrations over the toxic threshold.

Careful monitoring of plasma levels, leucovorin rescue, effective diuresis with urine alkalinization as well as allopurinol treatment (9) allow the use of HDMTX with very low toxicity. Concomitant treatment with NSAIDs and other nephrotoxic compounds should be avoided. 1 Goodman and Gilman, The pharmacological basis of therapeutics. 1985; 7th ed: 1266-1267 2 Meyler´s, Side effects of drugs. Ed by MNG Dukes. Elsevier, Amsterdam. 1984; 10th ed: 844-845 3 Hilgers RD, Alberts DS, Standefer JC, Skipper BE, Miles NJ, Borst J: Phase II and pharmacokinetic study of high-dose methotrexate in the treatment of advanced gynecologic malignancy. Gynecol Oncol 1984; 18: 62-70 4 Cordonnier D, Alix JL, Schaerer R, Swiercz P, Vialtel P, Bayle F: Nephrotoxicity of antitumoral chemotherapeutic agents. Presse Med 1984; 13: 1141-1145 5 Guelpa G: Nephrotoxicity of antitumoral chemotherapeutic agents. Schweiz Rundschau Med 1985; 74: 581-582 6 Thyss A, Kubar J, Milano G, Namer M, Schneider M: Clinical and pharmacokinetic evidence of a life-threatening interaction between methotrexate and ketoprofen. Lancet 1986; I: 256-258 7 Daly H, Boyle J, Roberts C, Scott G: Interaction between methotrexate and non-steroidal anti-inflammatory drugs. Lancet 1986; I: 557 8 Twelves CJ: Folinic acid rescue and methotrexate toxicity. Lancet 1986; I: 737 9 Maiche AG: Acute renal failure due to concomitant action of methotrexate and indomethacin. Lancet 1986; I: 1390 10 Singh RR, Malaviya AN, Pandey JN, Guleria JS: Fatal interaction between methotrexate and naproxen. Lancet 1986; I: 1390 11 Shen DD, Azarnoff DL: Clinical pharmacokinetics of methotrexate. Clin Pharmacokinet 1978; 3: 1-13