The effects of diltiazem on methotrexate-induced nephrotoxicity

Summary We have tested the effects of calcium channel blockade with diltiazem on methotrexate-induced nephrotoxicity in patients with biopsy-proven malignant disease. The patients were randomized in a cross-over fashion to receive MTX (4 g · m^–2 body surface area) with or without Diltiazem (360 mg per day orally) during two consecutive periods separated by a 3-week interval.Methotrexate caused reversible acute renal failure, with an increase in serum creatinine from 89 (7)µmol·1^–1 on day 0 to 150 (6)µmol.·1^–1 on Day 6. The patterns of ₂-microglobulin and N-acetyl glucosaminidase urinary excretion were similar, with a sharp increase from Day 0 to Day 3. Urinary ₂-microglobulin excretion increased from 161 (57) µg·1^–1 on Day 0 to 1160 (840) µg·l^–1 on Day 3 and fell to 918 (530) µg·l^–1 on Day 10. Urinary Nacetyl glucosaminidase excretion increased from 250 (100) mmol·h^–1 per mg of creatinine on Day 0 up to 655 (261) on Day 3 and fell to 285 (82) on Day 10.The evolution of renal function was not influenced by diltiazem. In patients receiving diltiazem, serum creatinine increased from 93 (0) µmol·l^–1 on Day 0 to 151 (68) µmol·l^–1 on Day 6 (p = NS when compared with control values). Urinary enzyme excretion also markedly increased from Day 0 to Day 3 to the same extent as in the group not receiving diltiazem.Our data indicate that acute deterioration in renal function caused by methotrexate is accompanied by tubular damage. Diltiazem was ineffective in preventing the acute renal failure induced by methotrexate. An inadequate dosage of diltiazem or multifactorial toxic effects of methotrexate may account for this negative result.