title: Drug-induced reduction in estimated glomerular filtration rate in patients with ALK-positive non-small cell lung cancer treated with the ALK inhibitor crizotinib.
abstract: BACKGROUND
  To the best of the authors' knowledge, the renal side effects of crizotinib have not been investigated previously.
  
  
  METHODS
  The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration creatinine-based prediction equation during the first 12 weeks of crizotinib therapy and after crizotinib but before the introduction of any further systemic therapy.
  
  
  RESULTS
  A total of 38 patients with stage IV anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer who were treated with crizotinib were identified. The mean eGFR decreased by 23.9% compared with baseline (P < .0001; 95% confidence interval, 21.3%-26.6%), with the majority of the decrease occurring within the first 2 weeks of therapy. Clinical history and blood urea nitrogen/creatinine ratios did not suggest prerenal causes. The objective response rate among evaluable patients (n = 27) was 41%. Tumor shrinkage was not correlated with changes in eGFR (correlation coefficient, -0.052; P = .798). Among the 16 patients for whom data after treatment with crizotinib were available, recovery to within 84% of the baseline eGFR occurred in all patients. After adjusting for the number of scans with intravenous contrast and the use of known nephrotoxic drugs, the issue of whether a patient was on or off crizotinib treatment was found to be significantly associated with changes in eGFR (P < .0001).
  
  
  CONCLUSIONS
  As assessed by the Chronic Kidney Disease Epidemiology Collaboration prediction equation, eGFR is reduced by treatment with crizotinib, but the majority of patients will recover their eGFR after the cessation of therapy. The early onset, size of the change, minimal cumulative effect, and rapid reversibility raise the possibility that this may be a pharmacological and/or tubular creatinine secretion effect rather than a direct nephrotoxic effect. Increased vigilance with regard to the concomitant use of renally cleared medications or nephrotoxic agents should be considered for patients receiving crizotinib and, when eGFR is reduced, additional renal investigations should be undertaken.
authors.affiliation: Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Evelyn M
authors.initials: EM
authors.lastname: Brosnan
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Weickhardt
authors.forename: Xian
authors.initials: X
authors.lastname: Lu
authors.forename: Delee A
authors.initials: DA
authors.lastname: Maxon
authors.forename: Anna E
authors.initials: AE
authors.lastname: Barón
authors.forename: Michel
authors.initials: M
authors.lastname: Chonchol
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
mesh_terms: D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D014408:Biomarkers, Tumor / Q000032:analysis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D000077547:Crizotinib; D057286:Electronic Health Records; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects*; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis*; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: anaplastic lymphoma kinase (ALK) gene rearrangements; crizotinib; glomerular filtration rate (GFR); kidney injury; non-small cell lung cancer; renal function