• Tatjana Vujić Agency for Drugs and Medical Devices of Bosnia and Herzegovina, Veljka Mlađenovića bb, Banja Luka
  • Biljana Davidović Plavšić Banja Luka University, Faculty of Science, Mladena Stojanovića 2, 78000 Banja Luka, Republic of Srpska
  • Snežana Uletilović Banja Luka University, Faculty of Medicine, Save Mrkalja 14, 78000 Banja Luka, Republic of Srpska
  • Svjetlana Stoisavljević Šatara Banja Luka University, Faculty of Medicine, Save Mrkalja 14, 78000 Banja Luka, Republic of Srpska
  • Jelica Predojević Samardžić University-Clinical Center Banja Luka
  • Živko Saničanin Banja Luka University, Faculty of Medicine, Save Mrkalja 14, 78000 Banja Luka, Republic of Srpska



In order to study methotrexate nephrotoxicity, the activities of proximal tubule epithelial cell membrane enzymes: alanine aminopeptidase (AAP) and gamma-glutamyltransferase (GGT), as well as of lysosomal N-acetyl-beta-D-glucosaminidase (NAG) and urinary albumin concentrations were determined in 12-h-urine samples of 30 patients with lymphoblastomous leukemia. The patients were i.v. receiving 4 individual methotrexate doses of 2000 mg/m2 every 15 days followed by leucovorin as a protector. Control and methotrexate-treated group, each consisting of 30 examinees, included 4–10 years old children of both sexes.

Statistically significant increase of AAP and GGT activities, expressed as U/mmol creatinine was observed after the first two (p < 0.05), as well as after the remaining two therapies (p < 0.01) in relation to the control. Enzymatic activities of these two enzymes decreased to control value before the second and the third methotrexate application, but they increased again after the third application and remained elevated up to the end of experiments. Significant increase of NAG activity expressed as U/mmol creatinine
(p < 0.01), as well as urinary albumin levels (mg/mmol creatinine; p < 0.01) were registered after the third methotrexate therapy and this elevation of the same statistical significance of the differences remained stable till the end of the therapy. Based on these results it can be concluded that during the time period of two first applications nephrotoxic methotrexate action is reversible and at the level of proximal tubule epithelial cell membranes. During the last two applications impairment is irreversible and at the level of cell organelles and glomerular filtration.


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