Influence of nephrotoxic drugs on the late renal toxicity associated with bone marrow transplant conditioning regimens.

ABSTRACT

The total body irradiation that is given as part of bone marrow transplant conditioning regimens is a factor in the renal toxicity that is observed after bone marrow transplant, but it may not be the only factor. We hypothesize that nephrotoxic drugs used in prior chemotherapy can precipitate renal radiation damage. Studies were designed to determine if nephrotoxic antineoplastic drugs could shorten the latent period for the development of radiation nephritis. Rats were given bilateral renal irradiation using a radiation schedule that produced moderate nephritis. Cisplatinum, BCNU, or mitomycin were given before, during, or after irradiation at doses that produced only mild nephrotoxicity. All cisplatinum-radiation sequences resulted in decreased renal function, with radiation prior to cisplatinum producing the greatest dysfunction. BCNU increased renal dysfunction equally in all schedules, but mitomycin had only minimal effects. Most drug schedules, including those with mitomycin, produced earlier development of morbidity after fractionated renal irradiation. In a second set of studies, rats were given single doses of the same nephrotoxic drugs, followed 3 months later by total body irradiation plus bone marrow transplant. The drugs had no effect on the marrow ablation dose, but BCNU and cisplatinum decreased gastrointestinal tolerance. Four months after total body irradiation, rats which received drugs alone or total body irradiation alone have essentially normal renal function, but rats which received cisplatinum plus total body irradiation or BCNU plus total body irradiation show a dose-dependent decrease in renal function. These studies show that radiation nephritis can be precipitated by low doses of nephrotoxic drugs, and may help to explain the incidence of early radiation nephritis in bone marrow transplant patients conditioned with total body irradiation.