Clinical Features Of Acute Kidney Injury in Patients Receiving Dabrafenib And Trametinib
Dec 01, 2023
ABSTRACT
Background. Our objective was to characterize the incidence, risk factors and clinical features of acute kidney injury (AKI) in patients receiving dabrafenib and trametinib. Methods. We performed a retrospective cohort study examining the kidney outcomes of patients in a large healthcare system who received dabrafenib/trametinib between 2010 and 2019. The primary outcome was AKI, defined as a 1.5-fold increase in serum creatinine from baseline within a 12-month study period. AKI severity and etiology was determined for each case by chart review. Logistic regression was used to evaluate baseline predictors of AKI.
CISTANCHE EXTRACT WITH 25% ECHINACOSIDE AND 9% ACTEOSIDE FOR KIDNEY
Results. A total of 199 patients who received dabrafenib in our healthcare system from 2010 to 2019 were included in the analysis. Forty-two patients (21%) experienced AKI within 12 months; 10 patients (5% of the total cohort, 24% of AKI patients) experienced AKI occurring during a dabrafenib/ trametinib-induced febrile syndrome characterized by fever, chills, gastrointestinal symptoms and elevated liver enzymes. Preexisting liver disease was the only significant predictor of AKI in the cohort. One patient had biopsy-proven granulomatous acute interstitial nephritis that resolved with corticosteroids.
Conclusions. Oncologists and nephrologists should be aware that AKI is common after dabrafenib/trametinib and a substantial number of cases occur in the setting of treatment-induced pyrexia.
Keywords: acute kidney injury, BRAF, MEK, nephrotoxicity
INTRODUCTION
Proto-oncogene B-Raf (BRAF) and mitogen-activated protein kinase (MEK) inhibitors have significantly improved the prognosis of BRAFV600E/K-mutant metastatic melanoma by synergistically targeting the MEK pathway [1, 2]. Data from clinical trials have revealed that the most common adverse events related to BRAF inhibitors include fever, chills, fatigue, nausea/vomiting, arthralgia, and rash. Each BRAF inhibitor has a distinct adverse event profile, and while it was not immediately evident from the clinical trials, recent reports have suggested that BRAF inhibitors may be nephrotoxic in a subset of patients, with tubular injury as the dominant finding on kidney biopsies [3, 4].
Dabrafenib, paired with trametinib (a MEK inhibitor), was first approved in 2013 to treat metastatic melanoma and is now also approved for non–small cell lung cancer, as adjuvant therapy for earlier stage BRAFV600E/K-mutant melanoma and in locally advanced or metastatic BRAFV600E/K mutant anaplastic thyroid cancer [5–8]. The US Food and Drug Administration (FDA) prescribing information states that serious febrile reactions may rarely be accompanied by acute kidney injury (AKI) and also lists acute interstitial nephritis (AIN) as a potential side effect [9, 10]. However, to date, there has been only one case of biopsy-proven AIN after dabrafenib–trametinib reported in the literature [11, 12]. We aimed to define the overall incidence and clinical features of AKI in a real-world cohort of patients receiving dabrafenib and trametinib within our healthcare network.
MATERIALS AND METHODS
Participants and setting
Using the Research Patient Data Registry, we identified all patients who received a prescription for dabrafenib and trametinib between January 2010 and November 2019 at the Mass General Brigham healthcare system in Boston, MA, USA. We excluded patients who were on dialysis, did not have a baseline or follow-up creatinine or did not have a clear start date of dabrafenib and trametinib. Patients had to have a minimum of 3 months follow-up to be included and were followed until death or until the end of the 12-month study period. Death was determined by chart review and defined by notice of death or final encounter date if enrolled in hospice.
Data acquisition and primary outcome
Clinical details such as demographics, comorbidities, medications, malignancy type, laboratory values and patient survival were determined through a review of the electronic health record. Baseline creatinine was determined by chart review as the value just prior to starting dabrafenib and trametinib. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation [13]. Baseline comorbidities including hypertension and diabetes were recorded by either a diagnosis code or by virtue of an antihypertensive or diabetic medication prescription noted in the oncologist's note just prior to beginning dabrafenib and trametinib. Baseline chronic obstructive pulmonary disease (COPD) and chronic liver disease were defined by the International Classification of Diseases, 9th Revision (ICD-9) and 10 Revision (ICD-10) codes. Chronic liver disease was defined by at least one diagnosis code for liver disease, including alcoholic liver disease, liver disease with cholestasis, acute hepatitis, chronic hepatitis, fatty liver and toxic liver disease not otherwise specified.
Concomitant medications were determined by the active medication list on the date of starting dabrafenib–trametinib. Concurrent immune checkpoint inhibitor (ICI) use was defined as receiving a dose within 6 months of the start date of dabrafenib and trametinib or any time within the 1-year study period. The primary outcome was AKI, defined by at least a 1.5-fold increase in serum creatinine from baseline creatinine within 1 year after starting dabrafenib and trametinib. The Kidney Diseases: Improving Global Outcomes criteria were used to stage AKI severity [14]. All urinalyses obtained within 1 week of meeting the criteria for AKI were reviewed and pro-teinuria and erythrocyte and leukocyte counts were recorded. All cases of AKI were chart reviewed by two nephrologists (H.S. and M.E.S.) to determine the etiology. A third nephrologist (O.E.) was available to resolve disagreements. The etiology of AKI was divided into five categories: (i) prerenal azotemia due to dehydration (poor oral intake, diarrhea, and vomiting) that resolved within 48 h of supportive care; (ii) acute tubular necrosis (ATN) lasting >48 h despite supportive care and in all cases was associated with a documented infection/sepsis; (iii) nephrotoxic AKI attributed to other concurrent medications; (iv) AKI associated with a terminal illness in the immediate lead up to hospice enrollment or death and (v) dabrafenib and trametinib– induced AKI, occurring in patients manifesting systemic symptoms of fever, rash, liver function test abnormalities and attributed to dabrafenib–trametinib toxicity by their primary oncologist after having excluded other potential causes.
Statistical analysis
Baseline characteristics were described using means [standard deviations (SDs)] for continuous variables and counts and percentages for categorical variables. Univariable logistic regression was performed to evaluate for predictors of AKI. Multivariable logistic regression was performed using variables that were statistically significant, with a P-value <0.10 in the univariable model. All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). The Institutional Review Board at Partners Healthcare System approved this study and waived the need for informed consent.
Methods for FDA Adverse Event Reporting System (FAERS) analysis
The FAERS contains adverse events reported by drug manufacturers, healthcare professionals and consumers. The legacy file from FAERS was queried for adverse renal events related to dabrafenib from 2013 to 2020 [15]. In the FAERS database, events noted as 'renal failure', 'renal impairment', 'renal failure acute', 'renal injury' and 'nephritis' are presented as one under 'Renal Injury'.
Statement of ethics This study was approved by our institute's Committee on Human Research. This research was conducted in accordance with the World Medical Association Declaration of Helsinki.
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