Influence of high-dose methotrexate therapy (HD-MTX) on glomerular and tubular kidney function.
BACKGROUND
The present investigation was intended to further clarify the mechanisms involved in renal dysfunction following high-dose methotrexate (HD-MTX) treatment.


METHODS
Fifty eight predominately pediatric patients [39 male, 19 female; mean age 12.3 years (range 2.2-34.1)] suffering from acute lymphoblastic leukemia (ALL, n = 28), Non Hodgkins lymphoma (NHL, n = 13), osteosarcoma (n = 8), malignant brain tumor (n = 6), or an ALL relapse (n = 3), were prospectively examined. In the course of 220 infusions of HD-MTX, glomerular and tubular renal function was determined by measuring proteinuria and glomerular filtration rate (GFR), as well as renal excretion of alpha-1-microglobulin (AMG) and N-acetyl-beta-D-glucosaminidase (NAG). It was investigated whether there were differences in MTX toxicity in dependence on the administered dose (1, 5, or 12 g/m(2) BSA), on the combination with other cytostatic agents (ifosfamide or cyclophosphamide), on the metabolism of MTX into 7-OH-MTX, and on pre-treatment with MTX.


RESULTS
The administration of HD-MTX has no direct tubulotoxic effect. The disturbance in glomerular function was dose dependently and indicated by an increase in proteinuria as well as by a decrease in GFR; all changes were completely reversible and did not correlate to the metabolism of MTX to 7-OH-MTX. Increasing the number of MTX therapeutic cycles did not increase the nephrotoxicity of MTX.


CONCLUSIONS
MTX is not directly tubulotoxic. Its side effects on glomeruli are usually without clinical relevance.
Hempel
Lutz
L
Department of Pediatric Hematology and Oncology, Friedrich Schiller University, Jena, Germany.
Misselwitz
Joachim
J
Fleck
Christian
C
Kentouche
Karim
K
Leder
Christiane
C
Appenroth
Dorothea
D
Rost
Michael
M
Zintl
Felix
F
D000293:Adolescent; D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006801:Humans; D007262:Infusions, Intravenous; D007674:Kidney Diseases / Q000139:chemically induced* / Q000503:physiopathology; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D011446:Prospective Studies; D011507:Proteinuria / Q000209:etiology
D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate