title: Evaluation of incidence and risk factors for high-dose methotrexate-induced nephrotoxicity.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Pharmacy, The James Cancer Hospital and Solove Research Institute at The Ohio State University, Columbus, OH, USA Tracy.Wiczer@osumc.edu.
authors.forename: Tracy
authors.initials: T
authors.lastname: Wiczer
authors.affiliation: Department of Pharmacy, The James Cancer Hospital and Solove Research Institute at The Ohio State University, Columbus, OH, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Dotson
authors.affiliation: Department of Pharmacy, The James Cancer Hospital and Solove Research Institute at The Ohio State University, Columbus, OH, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Tuten
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, OH, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Phillips
authors.affiliation: Department of Hematology, The James Cancer Hospital and Solove Research Institute at The Ohio State University, Columbus, OH, USA.
authors.forename: Kami
authors.initials: K
authors.lastname: Maddocks
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology*; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D015994:Incidence; D007938:Leukemia / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology; D008223:Lymphoma / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000009:adverse effects*; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate
keywords: High-dose methotrexate; drug interactions; methotrexate toxicity; nephrotoxicity; renal toxicity; risk factors