Clinical features of acute kidney injury in patients receiving dabrafenib and trametinib

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.

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.

KEY LEARNING POINTS

What is already known about this subject?

• Proto-oncogene B-Raf (BRAF) and mitogen-activated protein kinase (MEK) inhibitors such as dabrafenib and trametinib drastically improved the prognosis of BRAFV600E/K-mutant metastatic melanoma.

• Recent reports have suggested that other BRAF/MEK inhibitors may be nephrotoxic in certain patients, causing acute and chronic tubular injury and interstitial fibrosis.

• The prescribing information for dabrafenib and trametinib list acute interstitial nephritis (AIN) as a side effect occurring in <10% of recipients; to date, there is only one case of AIN reported in the literature.

What this study adds?

• In 5% of the cohort, acute kidney injury (AKI) occurred in patients experiencing a severe febrile syndrome attributed to dabrafenib and trametinib toxicity.

• The rate of dabrafenib and trametinib-associated AKI in our study is higher than suggested in prior trials and the prescribing information.

• We identified another case of biopsy-proven AIN occurring in a patient receiving dabrafenib and trametinib; however, our results suggest that the incidence of AIN is <1%.

What impact this may have on practice or policy?

• Clinicians should be aware that AKI is common in patients receiving dabrafenib and trametinib. Monitoring of kidney function (serum creatinine and urinalysis) should be part of standard assessment in patients receiving these drugs.

• In patients whose AKI does not quickly resolve with cessation of therapy and supportive care, clinicians should consider a kidney biopsy to evaluate if AIN is present.

INTRODUCTION

Proto-oncogene B-Raf (BRAF) and mitogen-activated protein kinase (MEK) inhibitors have significantly improved the prognosis of BRAF^V600E/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 BRAF^V600E/K-mutant melanoma and in locally advanced or metastatic BRAF^V600E/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 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 oncologists note just prior to beginning dabrafenib and trametinib. Baseline chronic obstructive pulmonary disease (COPD) and chronic liver disease were defined by 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 proteinuria 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 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.

RESULTS

We identified 266 patients who received dabrafenib between 2010 and 2019 within the Mass General Brigham healthcare network, which includes patients seen at two major centers (Massachusetts General Hospital Cancer Center and Dana Farber Cancer Institute) in Boston, MA, USA. After applying our exclusion criteria, 199 patients were included in the analysis. Reasons for exclusion were insufficient records to establish the start date of dabrafenib and trametinib (n = 33), lack of baseline creatinine (n = 26), lack of repeat creatinine after starting dabrafenib and trametinib (n = 7) or receiving dialysis at treatment initiation (n = 1). Patients were followed for an average of 680 days (SD 692) and the 6- and 12-month survival was 81 and 54%, respectively.

Baseline characteristics

The mean age was 59 years (SD 16), 56% were male, 94% were white, 10% had diabetes mellitus, 57% had hypertension and 30% had liver disease at baseline (Table 1). The majority (75%) received dabrafenib and trametinib to treat melanoma. Most (95%) initiated standard dosing of dabrafenib 150 mg twice daily and trametinib 2 mg daily. A total of 29% had recent or concurrent ICI. The mean baseline creatinine was 0.9 mg/dL (SD 0.2) and 20 patients (10%) had chronic kidney disease (eGFR <60 mL/min/1.73 m²) at baseline. Overall, 42 patients (21%) experienced AKI at a mean of 141 days (SD 116) after starting dabrafenib. AKI Stage 1 (creatinine >1.5–2 times baseline) was seen in 21 patients (50%), AKI Stage 2 (creatinine >2–3 times baseline) in 13 patients (31%) and AKI Stage 3 (creatinine >3 times baseline or need for dialysis) in 8 patients (19%).

Table 1.

Baseline characteristics of patients receiving dabrafenib/trametinib

Characteristics	Overall cohort	AKI	No AKI	P-value
Patients, n (%)	199	42 (21)	157(79)
Age (years), n (%)				0.62
≤65	111 (56)	22 (52)	89 (57)
≥66	88 (44)	20 (48)	68 (43)
Gender, n (%)				0.40
Male	111 (56)	21 (50)	90 (57)
Race, n (%)				1.00
White	188 (94)	40 (96)	148 (94)
Other	11 (6)	2 (4)	9 (6)
Concurrent ICI, n (%)	57 (29)	13 (31)	44 (28)	0.95
Melanoma, n (%)	150 (75)	33 (79)	117 (75)	0.59
Baseline kidney function, n (%)				0.36
eGFR >90 mL/min/ 1.73 m2	90 (45)	23 (55)	67 (43)
eGFR 60–89 mL/min/ 1.73 m2	89 (45)	15 (35)	74 (47)
eGFR 30–59 mL/min/ 1.73 m2	20 (10)	4 (10)	16 (10)
eGFR <30 mL/min/ 1.73 m2	0 (0)	0 (0)	0 (0)
Medical comorbidities, n (%)
Diabetes	24 (10)	6 (14)	18 (11)	0.62
Hypertension	114 (57)	23 (55)	91 (58)	0.71
COPD	10 (5)	0 (0)	10 (6)	0.98
Liver disease	59 (30)	21 (50)	38 (24)	<0.01
Daily trametinib dose, n (%)				0.93
2 mg	190 (95)	40 (95)	150 (96)
<2 mg	9 (5)	2 (5)	7 (4)
Daily dabrafenib dose, n (%)
300 mg	194 (97)	39 (93)	155 (99)	0.06
<300 mg	5 (3)	3 (7)	2 (1)
Baseline medication use, n (%)
PPI	65 (33)	19 (45)	46 (29)	0.05
ACEi/ARB	36 (18)	6 (14)	30 (19)	0.47
NSAIDS	36 (18)	8 (19)	28 (18)	0.89
Diuretics	20 (10)	5 (12)	15 (10)	0.65
Antibiotics	22 (11)	4 (10)	18 (11)	0.72
Allopurinol	3 (2)	0 (0)	3 (2)	0.99
AIN-related medications	101 (51)	24 (57)	77 (49)	0.35

ACEi/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker.

Etiology and predictors of AKI

Through detailed chart review of the 42 patients with AKI, we discovered clear alternative causes for AKI in 32 patients (Figure 1). However, 10 patients (5% of the total cohort, 24% of AKI patients) experienced AKI in the context of dabrafenib and trametinib–induced febrile syndromes characterized by an acute febrile illness; all experienced a combination of fever, chills and gastrointestinal distress (nausea/vomiting/diarrhea). Supplementary data, Table S1 summarizes the clinical finding in these cases. Eight patients (80%) had elevated liver enzymes, two (20%) had a new-onset rash and none had eosinophilia. Urinalysis was performed in eight patients; only two had leukocyturia and one had hematuria (Supplementary data, Table S1). The majority improved quickly with the withdrawal of dabrafenib and trametinib. Four patients (40%) received corticosteroid (prednisone ≥10 mg daily or equivalent) due to persistent symptoms. The severity of AKI in these 10 patients was as follows: five patients had Stage 1 AKI, three had Stage 2 AKI and two had Stage 3 AKI. Half were hospitalized at the time of AKI and half were outpatients. Six of 10 patients were rechallenged with dabrafenib and trametinib at lower doses; 2 of 6 (33%) had recurrent AKI (Supplementary data, Table S1).

FIGURE 1.

Etiology and severity of AKI. Chart review of each case of AKI uncovered the following etiologies, adjudicated by two nephrologists. Dabrafenib and trametinib–associated AKI [n = 10 (24%)] occurred in patients manifesting systemic symptoms of fever, rash and liver function test abnormalities attributed to dabrafenib–trametinib toxicity by their primary oncologist. Prerenal azotemia [n = 17 (40%)] occurred due to dehydration (poor oral intake, diarrhea and vomiting) that resolved within 48 h of supportive care. Infection-associated ATN [n = 4 (10%)] lasted >48 h despite supportive care and in all cases was associated with a documented infection/sepsis. AKI due to other nephrotoxic anticancer agents [n = 3 (7%)] was attributed to either vemurafenib (n = 1) or pembrolizumab use (n = 2). AKI associated with terminal illness [n = 8 (19%)] occurred at the time of hospice enrollment or death.

Other etiologies of AKI included prerenal azotemia (40% of AKI), sepsis-related ATN (10%), nephrotoxicity due to other anticancer agents in 7% (attributed to pembrolizumab in 2 or vemurafenib in 1) and AKI that occurred as a part of terminal decline (19%). The breakdown of AKI etiologies and severity stages is shown in Figure 3.

FIGURE 3.

(A–C) Kidney biopsy findings in the patient with AIN. (A) The kidney biopsy showed extensive interstitial inflammation with focal granuloma formation (arrow; hematoxylin and eosin, 100×). (B) The interstitial infiltrate was composed of lymphocytes, eosinophils and histiocytes (hematoxylin and eosin, 400×). (C) Interstitial noncaseating granuloma (arrows) was associated with interstitial inflammation and tubulitis (periodic acid–Schiff, 400×).

The univariable logistic regression model shown in Table 1 demonstrated that preexisting liver disease was the only characteristic that was significantly higher in patients who developed AKI compared with those who did not. In a multivariable model that also included age and gender, preexisting liver disease remained predictive of AKI, with an adjusted odds ratio of 3.13 (95% confidence interval 1.55–6.35; P < 0.01) (Supplementary data, Table S2). Proton pump inhibitor (PPI) use was higher in the group that developed AKI, but this was not statistically significant. Baseline kidney function and concurrent intake of other medications associated with AIN were not associated with AKI. We note that our definition of baseline medication use, which captured prescription data and not over-the-counter use, is likely to have underestimated the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Review of the 10 cases of dabrafenib and trametinib–induced AKI revealed that half reported taking NSAIDs to treat fever at the time AKI was diagnosed (Supplementary data, Table S1).

We identified one patient with biopsy-proven AIN. He was a 70-year-old man with a history of Stage IIIA malignant melanoma who presented to the hospital with fever, elevated creatinine and liver function test abnormalities. He had been started on dabrafenib and trametinib 5 months prior to presentation after undergoing a wide excision and axillary lymph node removal. His treatment was complicated by recurrent fevers that worsened despite dose adjustments and treatment holidays (Figure 2). His last dose of dabrafenib and trametinib was 10 days prior to presentation and his baseline creatinine was 1.1 mg/dL at that time. He endorsed rare ibuprofen use, with the last dose taken >1 week prior to admission. In his oncologist’s office, laboratory testing revealed an elevated serum creatinine of 2.2 mg/dL and abnormal liver function tests (alanine aminotransferase 151 U/L, aspartate transferase 127 U/L, alkaline phosphatase 652 U/L, total bilirubin 0.5 mg/dL and albumin 3.5 g/dL). His urine sodium was 99 mg/dL and the spot urine protein:creatinine ratio was 0.25 g/g creatinine (normal range <0.15 g/g). Urine sediment microscopy showed rare leukocyte casts. Complete blood count (CBC) with differential was only remarkable for mild lymphopenia and normocytic anemia with hemoglobin of 10.4 g/dL; eosinophilia was not present. When his creatinine did not improve with intravenous normal saline administration, he was admitted to the hospital and underwent kidney biopsy. The biopsy showed diffuse interstitial inflammation involving up to 70% of the cortex, associated with edema, granuloma formation, focal tubular rupture and severe tubulitis (Figure 3). He was treated with intravenous methylprednisolone 500 mg for 2 days, then started on prednisone 60 mg daily, which was tapered by 10 mg every 3 days for an 18-day total course of corticosteroids. Serum creatinine improved to 1.3 mg/dL within the first week of treatment and remained at 1.2 mg/dL at his last follow-up, >6 weeks after completing steroids (Figure 2). His liver function tests also normalized with corticosteroids. His adjuvant therapy was permanently discontinued but he remains in complete remission.

FIGURE 2.

Clinical course of the patient with AIN. The patient began standard doses of dabrafenib–trametinib. He began to experience recurrent episodes of fever and chills starting 1 week after initiation of dabrafenib–trametinib that resulted in dose interruptions and reductions. His creatinine continued to rise despite 10 days of withholding therapy. He was admitted to the hospital, given intravenous hydration and underwent kidney biopsy that showed granulomatous interstitial nephritis. He received two doses of intravenous methylprednisolone 500 mg and was discharged with a rapid prednisone taper (started with 60 mg and tapered by 10 mg every 3 days).

Analysis of the FAERS database revealed a total of 250 kidney-related adverse events reported in patients on dabrafenib (Supplementary data, Table S3). Forty percent of the adverse events were noted in males while 32% were noted in females (28% unknown). The mean age of adverse events was 67 years (SD 11) for males and 64 years (SD 23) for females. ‘Renal injury’ was the most common adverse renal event, noted in 115 patients. Other kidney-related adverse events included hyponatremia (26%) and hypokalemia (16%).

DISCUSSION

In a cohort of nearly 200 patients receiving dabrafenib and trametinib, we found that, like other BRAF–MEK combination therapies, AKI is common, occurring in 21% within the first year. However, we found that in 10 patients (5% of the overall cohort), AKI occurred in the setting of severe febrile syndromes attributed to dabrafeninb and trametinib; this is unique when compared with reports of AKI after vemurafenib–cobimetinib and encorafenib–binimitinib. Patients presented with gastrointestinal symptoms and liver function test abnormalities and a minority also had rash or mental status changes. The rate of dabrafenib and trametinib–associated AKI in this real-world study is higher than suggested in prior trials and the prescribing information [9, 10]. Although the majority of cases resolved with cessation of therapy, several patients required corticosteroids to reduce fevers and resolve AKI. Most patients were rechallenged with dabrafenib and trametinib, and although some had recurrence of febrile syndrome and AKI, several were able to tolerate a dose reduction without recurrent AKI. We also identified the second reported case of severe biopsy-proven AIN occurring after dabrafenib–trametinib. Despite the fact that AIN is listed as a common adverse event in the prescribing information for dabrafenib, the true incidence is unclear, as only one prior case is reported in the literature [11]. This series suggests that the incidence of AIN is <1%, although no other patients with dabrafenib and trametinib–induced AKI in this series underwent kidney biopsy, thus AIN may have been underdiagnosed.

Other BRAF inhibitors and BRAF–MEK combinations have been associated with AKI [3, 4, 16–19]. Cases of biopsy-proven interstitial fibrosis and acute focal tubular damage have been reported with vemurafenib [3, 19, 20]. The incidence of AKI after vemurafenib use (defined as a 1.5-fold increase in creatinine from baseline) was 60% in a 74-patient series [19]. The incidence of AKI in patients receiving BRAF–MEK combination therapy is lower, ranging from 24 to 26% in patients treated with vemurafenib and cobimitinib or encorafenib and binimetinib [4, 21]. One study found that the mechanism of elevated creatinine in patients receiving vemurafenib may relate to inhibited tubular secretion of creatinine as well as kidney function impairment; two patients in this series underwent biopsies showing direct kidney tubular epithelial cell injury [22]. In a recent series of AKI after encorafenib and binimetinib, patients demonstrated signs of renal tubular injury. None of the patients with AKI had fever, rash or clinical features of AIN, but none were biopsied [4]. Other case reports have suggested that glomerular lesions may occur after BRAF–MEK inhibition, but this appears to be rare [16, 23]. Perisco et al. [23] tested the effect of dabrafenib and trametinib on cultured human podocytes, showing dabrafenib interacted with and downregulates PLCe1, a slit diaphragm-associated protein, and also downregulated nephrin and increased permeability of podocyte monolayers. However, in our study, patients with dabrafenib and trametinib–associated AKI did not have significant proteinuria; only one case had ≥2+ proteinuria on dipstick.

Febrile syndromes that share overlapping features with cytokine release syndrome are being recognized more commonly after targeted cancer therapies, particularly when given after ICIs [24, 25]. It is important to note that 7 of 10 of our cases of dabrafenib and trametinib–associated AKI did not have concurrent exposure to ICIs (Supplementary data, Table S1). The FDA prescribing information recommends withholding dabrafenib and trametinib for fever >104°F or for serious febrile reactions or fever accompanied by hypotension, rigors or chills, dehydration or AKI [9, 10]. Careful monitoring of serum creatinine during episodes of severe pyrexia is also recommended.

The mechanism of AIN after dabrafenib and trametinib is unclear. There is considerable debate about whether corticosteroids should be used in AIN versus simply withholding the offending agent [26–28]. We note that in this case, the patient’s serum creatinine continued to rise for >10 days of not receiving dabrafenib and trametinib despite supportive care with intravenous hydration. The kidney biopsy showed severe, active tubulitis with granuloma formation, thus corticosteroids were administered. His creatinine rapidly improved once he received methylprednisolone and he did not have recurrent AKI after completing an 18-day course of prednisone. This is in contrast to the previous report of biopsy-proven AIN after dabrafenib and trametinib in the literature, where the patient had recurrent AKI after corticosteroids were discontinued [11]. Because of prominent fevers and chills that may be caused by dabrafenib and trametinib, patients are often advised to treat fever with alternating acetaminophen and NSAIDs. NSAIDs can potentiate prerenal azotemia and are associated with AIN and half of the patients with AKI had recently reported NSAID use [29, 30]. The complex relationship between AIN-provoking concomitant medications as a risk factor for kidney immune-related adverse events in patients treated with ICIs has also been reported [31]. In case reports, dabrafenib has been described as a potential trigger for reactivation of preexisting autoimmune diseases, such as dermatomyositis and antineutrophil cytoplasmic antibody (ANCA)-associated granulomatosis with polyangiitis [32, 33]. The mechanisms behind such dabrafenib-related immune enhancement are not established. It is not known if dabrafenib-mediated AIN and the aforementioned autoimmune disease reactivation follow the same pathway and further research is required in this area. ANCA was not measured in any of our cases of dabrafenib-associated AKI.

While most of the patients (75%) in our series had melanoma, dabrafenib and trametinib are also approved by the FDA for the treatment of BRAF^V600E-mutated non–small cell lung carcinoma and anaplastic thyroid carcinoma. These agents are also under clinical study in >80 clinical trials [34]. Due to the limited number of other cancers included in our population, it is difficult to draw any conclusions about whether dabrafenib and trametinib–related AKI may depend on the underlying type of cancer or stage of disease. Future clinical trials of BRAF–MEK inhibition should include descriptions of the cancers and longitudinal assessment of kidney function to identify differences in AKI across cancers and with different targeted therapies.

Our study has several limitations. First, this was a predominantly white population sourced from a single healthcare network, which limits generalizability. Additionally, it is possible that patients had laboratory studies performed at hospitals outside our healthcare network, resulting in an underestimation of the frequency of AKI. We only included patients who had at least one creatinine measured in the 12-month follow-up period to ensure that patients getting the majority of their care outside our healthcare system were not included in the analysis. Retrospective data collection led to limited clinical phenotyping of some cases of AKI and therefore we had to rely on the available laboratory data and clinical evaluation at the time of the event. However, a review of each case by two nephrologists was a strength. The fact that only one patient underwent kidney biopsy limits our ability to definitively define the incidence of AIN with dabrafenib and trametinib.

Knowledge of AKI risk and clinical features of AKI is important in patients undergoing anticancer therapy, since AKI negatively impacts cancer survival [35, 36]. In addition, AKI can lead to treatment interruptions and limit access to alternative cancer therapies or clinical trials, many of which are restricted or unstudied in patients with reduced kidney function [37, 38]. Clinicians should be aware that AKI is common in patients receiving dabrafenib and trametinib. Monitoring of kidney function (serum creatinine and urinalysis) should be part of the standard assessment in patients receiving these drugs. AKI may be a direct or indirect side effect of dabrafenib and trametinib use. In patients whose AKI does not quickly resolve with cessation of therapy and supportive care, clinicians should consider a kidney biopsy to evaluate if AIN is present.

SUPPLEMENTARY DATA

Supplementary data are available at ndt online.

FUNDING

M.E.S. is supported by National Institutes of Health (NIH; K23 DK 117014) and the Claflin Distinguished Scholars Award. The NIH had no role in study design; collection, analysis and interpretation of data; writing the report; or the decision to submit the report for publication.

AUTHORS’ CONTRIBUTIONS

M.E.S. and H.S. formulated the research proposals, drafted the results and conclusions and critically reviewed the final draft. I.A.S., D.F.C., N.R. and M.D.L. compiled the data, drafted the introduction and methods and critically reviewed the final draft. R.B.C. and I.A.R. provided renal pathology interpretation. O.E., R.B.C., I.A.R., R.M.F., K.L.R., R.J.S., H.L.K. and K.D.J. contributed insight into research methods and critically reviewed the final draft.

CONFLICT OF INTEREST STATEMENT

R.J.S. received research funding from Merck and Amgen and has served on scientific advisory boards for and/or engaged in consulting with Merck, Array BioPharma, Asana Biosciences, Iovance, Bristol Myers Squibb, Novartis, Replimune and Compugen. H.L.K. is an employee of Immuneering, is a consultant to Replimune and serves on the scientific advisory board of SapVax. K.D.J. servers as a consultant for Astex Pharmaceuticals and Natera. K.D.J. writes for Uptodate.com on targeted therapy–related nephrotoxicities and receives honorarium. M.E.S. has served as a scientific consultant to Merck, AbbVie, Gilead and Bioporto and received research funding from Gilead, EMD-Serono, Merck and AbbVie. R.M.F. serves as a consultant to Apricity Health. R.B.C. and I.A.R. serve as consultants for eGenesis. The remaining authors declare they have no relevant financial interests.