Evaluation of incidence and risk factors for high-dose methotrexate-induced nephrotoxicity

J Oncol Pharm Pract. 2016 Jun;22(3):430-6. doi: 10.1177/1078155215594417. Epub 2015 Jul 6.


Introduction: High-dose methotrexate (doses ≥1 g/m(2)) is a key component of several chemotherapy regimens used to treat patients with leukemia or lymphoma. Despite appropriate precautions with hydration, urine alkalinization, and leucovorin, nephrotoxicity remains a risk which can lead to significant morbidity and mortality. Current reports of risk factors for nephrotoxicity focus on patients with nephrotoxicity with a lack of comparison to those without toxicity. This study aimed to describe the incidence of high-dose methotrexate-induced nephrotoxicity at our institution and determined risk factors for high-dose methotrexate-induced nephrotoxicity by examining characteristics of patients with and without nephrotoxicity.

Methods: This was a retrospective, single-center, chart review. Adult patients with a diagnosis of leukemia or lymphoma who received high-dose methotrexate were included. Serum creatinine values were used to evaluate nephrotoxicity according to Common Terminology Criteria for Adverse Events criteria v4.03. Data related to the following proposed risk factors were collected: age, sex, body mass index, methotrexate dose, number of high-dose methotrexate exposures, leucovorin administration route, baseline renal function, albumin, hydration status, Clostridium difficile infection, urine pH, and concomitant interacting and nephrotoxic medications. The primary endpoint was evaluated with exact binomial methods and risk factors were identified using multivariable random-effects logistic regression.

Results: Final analyses included 140 patients with 432 high-dose methotrexate exposures. There were no differences in baseline demographical characteristics. Fifty-four patients (38.6%) experienced nephrotoxicity of any grade: 27.9% with grade 1, 5.7% with grade 2, 3.6% grade 3, 0% with grade 4, and 1.4% with grade 5 toxicity. More patients in the toxicity group received doses of methotrexate ≥3 g/m(2) (58.3% versus 57.2%, p < 0.001), had an albumin level <3 g/dL (31.9% versus 15.9%, p = 0.04), and received an interacting medication during high-dose methotrexate clearance (44.4% versus 24.7%, p = 0.003). Male gender (OR 2.3, 95% CI: 1.27-4.18, p = 0.006), albumin (OR 0.44, 95% CI: 0.26-0.75, p = 0.002), number of drug interactions (OR 1.60, 95% CI: 1.15-2.21, p = 0.005), and use of furosemide (OR 2.56, 95% CI 1.46-4.48, p = 0.001) were all independent risk factors for the development of nephrotoxicity.

Conclusions: Nephrotoxicity is a possible complication of therapy with high-dose methotrexate with most instances comprising grade 1-2 toxicity. Male gender, low albumin, and administration of interacting drugs or furosemide during high-dose methotrexate clearance may predispose patients to nephrotoxicity.

Keywords: High-dose methotrexate; drug interactions; methotrexate toxicity; nephrotoxicity; renal toxicity; risk factors.

Publication types

  • Observational Study

MeSH terms

  • Acute Kidney Injury / chemically induced*
  • Acute Kidney Injury / diagnosis
  • Acute Kidney Injury / epidemiology*
  • Adult
  • Aged
  • Antimetabolites, Antineoplastic / administration & dosage*
  • Antimetabolites, Antineoplastic / adverse effects*
  • Drug Interactions
  • Female
  • Humans
  • Incidence
  • Leukemia / diagnosis
  • Leukemia / drug therapy
  • Leukemia / epidemiology
  • Lymphoma / diagnosis
  • Lymphoma / drug therapy
  • Lymphoma / epidemiology
  • Male
  • Methotrexate / administration & dosage*
  • Methotrexate / adverse effects*
  • Middle Aged
  • Retrospective Studies
  • Risk Factors
  • Young Adult


  • Antimetabolites, Antineoplastic
  • Methotrexate