BRAF / MEK inhibitors (vemurafenib · dabrafenib · trametinib)
BRAF/MEK inhibitor
Tubulointerstitial AKI; vemurafenib strongest.
ATNAINLYTE
Mild71% phenotype match
BRAF inhibitor
Dabrafenib
Tafinlar · DAB
BRAF inhibitor · approved 2013 · 8 citations
Aging evidence· through 2022
Emerging evidence4/9 · 5 signals▾
- 8 citations
- Deep literature (12+ refs)
- Accrued over 8+ years
- Beyond single case reports
- High-impact journal
- Landmark reference
- Registrational / key trials
- Current through 2022
- Real-world FAERS signal
Grades the strength of the evidence base (volume, journal quality, landmark trials, recency, real-world corroboration) — not the drug's severity. A rule-based summary, not a formal certainty appraisal.
The gentler BRAF inhibitor — mostly pyrexia-driven, reversible AKI, with granulomatous interstitial nephritis as its rare histologic signature.
MildTargeted therapy (2010s BRAF/MEK)
BRAF V600E/K-mutant unresectable or metastatic melanoma (with trametinib)Adjuvant treatment of resected stage III BRAF V600E/K-mutant melanoma (with trametinib)BRAF V600E-mutant metastatic non-small cell lung cancer (with trametinib)BRAF V600E anaplastic thyroid cancer (with trametinib)BRAF V600E-mutant unresectable/metastatic solid tumors, tumor-agnostic (with trametinib)Pediatric BRAF V600E low-grade glioma (with trametinib)
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Signature kidney injury
Signature lesion
Representative incidence21%
AKI is relatively common on dabrafenib-based therapy but usually mild and reversible. In the largest cohort, 42/199 (21%) of patients on dabrafenib/trametinib developed AKI within 12 months, and roughly 24% of those episodes occurred during the drug-induced febrile (pyrexia) syndrome (Seethapathy 2022). Pharmacovigilance places dabrafenib well below vemurafenib: FAERS acute-kidney-injury reporting-odds-ratio approximately 1.35 (95% CI 1.15–1.60) for dabrafenib versus approximately 3.28 for vemurafenib (Sanagawa 2021). Biopsy-proven granulomatous/acute interstitial nephritis and clinically significant electrolyte disorders (hyponatremia, hypokalemia, hypophosphatemia) are each individually rare — documented mainly in case reports and small FAERS counts. Registrational trials did not flag renal toxicity; the signal emerged post-marketing.Source: Seethapathy et al., Nephrol Dial Transplant 2022 (PMID 33355659): 42/199 (21%) of dabrafenib/trametinib patients developed AKI within 12 months in a single-center retrospective cohort, with ~24% of AKI episodes occurring during the drug-induced pyrexia/febrile syndrome. This is all-cause AKI on combination therapy and largely mild/reversible; drug-specific granulomatous interstitial nephritis is far rarer.
Onset & rechallenge
Time to injuryVariable / unpredictable
Biphasic: pyrexia-associated AKI clusters in the first weeks to months, while granulomatous/acute interstitial nephritis has appeared from a few weeks to as late as ~5 years.
Distilled from: “Variable and biphasic. Pyrexia-associated AKI clusters early, in the first weeks to months of therapy and coincides with febrile episodes. Biopsy-proven granulomatous/acute interstitial nephritis has appeared anywhere from a few weeks to as late as ~5 years into treatment.” · PMID 33355659
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Renal toxicities, ranked
This agent's kidney lesions ordered by prominence — the #1 signature lesion first, then secondary and rare patterns. Cited incidence is shown where a citable figure exists; otherwise the tier stands qualitatively.
Immune-mediated inflammation of the renal interstitium — the signature kidney injury of checkpoint inhibitors.
Renal hypoperfusion from capillary leak and cytokine storm — IL-2 and CAR-T cytokine release syndrome.
Renal electrolyte derangement — magnesium/potassium/calcium wasting (cisplatin, anti-EGFR antibodies) or retention (FGFR-inhibitor hyperphosphatemia, tumor-lysis hyperkalemia/hyperphosphatemia).
Inappropriate water retention at the collecting duct — high-dose cyclophosphamide.
Direct death of tubular epithelial cells — the dose-limiting lesion of the platinums and zoledronate.
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
0%incidence
SeverityMild
ReversibilityReversible
Evidence0 refs
Nephron map
Proximal Tubule
Distal Tubule / Collecting Duct
InterstitiumSupporting tissue around the tubules
Acute Interstitial Nephritis
Immune-mediated inflammation of the renal interstitium — the signature kidney injury of checkpoint inhibitors.
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Kidney injury
Mechanism of kidney injury
Two dominant routes, both indirect. (1) Pre-renal/hemodynamic: dabrafenib — especially combined with trametinib — provokes a systemic pyrexia/febrile syndrome (fever, chills, rigors, GI losses, transaminitis) that causes volume depletion and hemodynamic AKI, sometimes progressing to ischemic tubular injury; about one in four AKI episodes in the largest cohort occurred during this febrile syndrome. (2) Immunoallergic tubulointerstitial: biopsy-proven acute — often granulomatous — interstitial nephritis, at times with concurrent granulomatous dermatitis, implying a T-cell/hypersensitivity mechanism rather than direct nephrotoxicity. Unlike vemurafenib, dabrafenib shows little direct proximal-tubular or glomerular-epithelial cytotoxicity in vitro, consistent with its lower FAERS AKI signal. Electrolyte wasting (hyponatremia including an SIADH-like pattern, hypokalemia, hypophosphatemia) reflects disturbed tubular handling. Rare glomerular lesions have been reported but are confounded by concomitant immune-checkpoint-inhibitor exposure.
Clinical presentation
Most often an asymptomatic serum creatinine rise found on surveillance labs. When tied to the pyrexia syndrome, patients have fever, chills, rigors, GI symptoms, and transaminitis accompanying the creatinine rise. Interstitial nephritis cases may show sterile pyuria, low-grade proteinuria/microalbuminuria, peripheral edema, and sometimes a concurrent granulomatous skin rash; the classic AIN triad (fever/rash/eosinophilia) is usually incomplete. Electrolyte abnormalities — low sodium, potassium, or phosphate — can be the presenting clue.
Management
Pyrexia-associated AKI: hold dabrafenib (and usually trametinib), give IV/oral fluids and antipyretics, and resume at the same or a reduced dose once fever and creatinine recover; corticosteroids are used for recurrent/refractory pyrexia. Suspected interstitial nephritis: discontinue the drug, refer to nephrology, and consider kidney biopsy if AKI is persistent or unexplained — biopsy-proven granulomatous/acute interstitial nephritis is treated with corticosteroids (e.g., prednisone ~1 mg/kg with a slow taper) and is generally steroid-responsive, though relapse on premature taper is described. Electrolytes: replete potassium, phosphate, and magnesium; evaluate hyponatremia for SIADH versus volume depletion and treat by cause. Rechallenge is often feasible after pyrexia-driven AKI resolves, but should be avoided after biopsy-proven granulomatous interstitial nephritis.Lesion-level management framework
Risk factors
- Pre-existing liver disease (the only significant baseline predictor of AKI in the largest cohort)
- Drug-induced pyrexia/febrile syndrome (fever, chills, GI losses, transaminitis) with volume depletion
- Combination with trametinib (pyrexia and febrile-syndrome AKI are more frequent with the doublet)
- Prior or concurrent immune-checkpoint-inhibitor therapy (adds interstitial and glomerular injury risk; confounds attribution)
- Volume depletion from GI toxicity, diuretics, RAAS blockade, or intercurrent nephrotoxins/NSAIDs
- Male sex (FAERS reports skew male, though this likely reflects melanoma epidemiology)
Prevention
- Baseline and periodic serum creatinine, eGFR, and electrolytes (sodium, potassium, phosphate, magnesium)
- Recognize the pyrexia syndrome early — interrupt dabrafenib (per label at temperature >=38.5 C), hydrate, and give antipyretics before AKI develops
- Maintain volume during febrile episodes and GI losses; avoid unnecessary nephrotoxins/NSAIDs and iodinated contrast when febrile
- Correct volume depletion promptly and review concomitant nephrotoxic or ADH-active medications
- Surveillance urinalysis when creatinine rises to screen for interstitial nephritis
Anticancer mechanism· how it treats cancer
Selective ATP-competitive inhibitor of mutant BRAF V600E/K kinase that shuts down constitutive RAF–MEK–ERK (MAPK) signaling driving BRAF-mutant tumor proliferation. Almost always paired with the MEK inhibitor trametinib to deepen and prolong response and blunt paradoxical MAPK reactivation (fewer cutaneous squamous lesions than single-agent BRAF inhibition).
Note · Dabrafenib is almost always given with trametinib, so much of the renal data reflects the combination and all-cause AKI in melanoma patients rather than a pure single-agent, drug-attributable effect. Reported incidence should be read as combination, real-world, largely mild and reversible AKI.
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Clinical depth
Renal dose adjustment
No dedicated renal dose adjustment is specified in the FDA label. Dabrafenib is cleared predominantly by hepatobiliary metabolism (CYP2C8/CYP3A4) and fecal excretion with a minority renal route, so no adjustment is recommended for mild-to-moderate renal impairment. It has not been formally studied in severe renal impairment or ESRD — use with caution and monitor. In practice, dose interruptions/reductions are driven by pyrexia, transaminitis, and other toxicities rather than by eGFR.
Dialyzability & ESKD dosing
Not expected to be removed by dialysis and not established as dialyzable. Dabrafenib is highly protein-bound (~99.7%) with a large volume of distribution and hepatic metabolism, so hemodialysis is unlikely to clear meaningful drug; no data support supplemental dosing around dialysis.
Differential diagnosis
Distinguish pyrexia/febrile-syndrome pre-renal azotemia and volume depletion (most common, fully reversible with fluids and drug hold) from intrinsic drug-induced granulomatous/acute interstitial nephritis (biopsy-confirmed, steroid-responsive). Consider concomitant or sequenced immune-checkpoint-inhibitor nephritis or glomerulonephritis — a rare atypical anti-GBM glomerulonephritis has been reported in a patient on MAPK plus checkpoint inhibitors (Kyriazis 2021), so glomerular presentations are confounded. Exclude other nephrotoxins (NSAIDs, contrast, PPIs), sepsis, and tumor-related causes (obstruction, hypercalcemia). If therapy was switched from vemurafenib, note vemurafenib carries a higher intrinsic tubular-toxicity signal.
Monitoring
- Serum creatinine and eGFR at baseline and periodically, and during any febrile episode
- Electrolytes — sodium, potassium, phosphate, and magnesium
- Temperature/pyrexia surveillance (the febrile syndrome is the leading trigger for AKI)
- Urinalysis when creatinine rises — sterile pyuria, WBC casts, and low-grade proteinuria suggest interstitial nephritis
- Liver enzymes (transaminitis accompanies the febrile syndrome and pre-existing liver disease predicts AKI)
Key trials & series
- COMBI-v (Robert et al., N Engl J Med 2014; PMID 25399551): dabrafenib plus trametinib improved overall survival versus vemurafenib in BRAF V600 metastatic melanoma; renal toxicity was not flagged in the pivotal data.
- 5-year outcomes of dabrafenib plus trametinib in metastatic melanoma (Robert et al., N Engl J Med 2019; PMID 31166680): durable long-term benefit of the doublet.
- COMBI-AD (Long et al., N Engl J Med 2017; PMID 28891408): adjuvant dabrafenib plus trametinib in resected stage III BRAF-mutant melanoma.
Clinical pearls
- Dabrafenib is the 'kinder-to-kidney' BRAF inhibitor: FAERS AKI reporting-odds-ratio is ~1.35 versus ~3.28 for vemurafenib, and in vitro it lacks vemurafenib's direct tubular cytotoxicity.
- Most AKI on dabrafenib/trametinib is pyrexia-driven and pre-renal — think fever plus volume depletion and hold/hydrate before reaching for a biopsy.
- The one true histologic signature is granulomatous/acute interstitial nephritis, sometimes paired with a granulomatous dermatitis; it is steroid-responsive but relapses if steroids are tapered too quickly.
- Check electrolytes — hyponatremia (including an SIADH-like pattern), hypokalemia, and hypophosphatemia are reported.
- Pre-existing liver disease was the only baseline predictor of AKI in the largest cohort — flag these patients for closer monitoring.
- Renal signals were essentially absent in the registrational trials and emerged from post-marketing case reports and FAERS, so incidence figures should be hedged accordingly.
Beyond the kidney — non-renal toxicities· 4 organ systems
Class-level context for the major non-renal toxicities of braf inhibitors.
Dermatologic
Rash, HFS, SJS/TEN, vitiligo
- Rash, photosensitivity, squamous-cell carcinomas (BRAF)
Cardiac
Cardiomyopathy, QT, ischemia, myocarditis
- Reduced LVEF (MEK)
Ophthalmic
Keratopathy, uveitis, retinopathy
- Retinopathy / retinal vein occlusion (MEK)
Vascular
Hypertension, VTE/ATE, bleeding, aneurysm
- Pyrexia syndrome, hypertension
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References
8 peer-reviewed references. Citation metadata via PubMed / NLM.
Evidence accrual
8 references · 2014–2022 · 4 since 2020Citations per year in this profile — a proxy for how actively the agent's renal literature is accruing. Recent years are highlighted. Reflects curation depth, not a systematic bibliometric count.
- 1.LandmarkClinical features of acute kidney injury in patients receiving dabrafenib and trametinib.Seethapathy H, et al. · Nephrol Dial Transplant · 2022 · PMID 33355659Largest cohort of dabrafenib/trametinib AKI: 21% (42/199) within 12 months, ~24% during the drug-induced pyrexia syndrome, one biopsy-proven granulomatous AIN, and pre-existing liver disease as the only baseline predictor. Anchors the headline incidence and the pyrexia mechanism.
- 2.LandmarkNephrotoxicity of the BRAF Inhibitors Vemurafenib and Dabrafenib.Jhaveri KD, et al. · JAMA Oncol · 2015 · PMID 26182194FAERS analysis establishing that vemurafenib is more nephrotoxic than dabrafenib (13 dabrafenib AKI cases), with hyponatremia and hypokalemia reported and tubulointerstitial injury as the apparent mode. Grounds the milder-than-vemurafenib framing and electrolyte disturbances.
- 3.LandmarkRenal effects of BRAF inhibitors: a systematic review by the Cancer and the Kidney International Network.Wanchoo R, et al. · Clin Kidney J · 2016 · PMID 26985376Systematic review concluding dabrafenib has lower rates of kidney disease than vemurafenib, with tubulointerstitial damage (acute and chronic components) on biopsy and electrolyte disorders (hypokalemia, hyponatremia, hypophosphatemia); recommends routine creatinine/electrolyte monitoring.
- 4.BRAF/MEK inhibitor-associated nephrotoxicity in a real-world setting and human kidney cells.Sanagawa A, et al. · Anticancer Drugs · 2021 · PMID 34232935FAERS reporting-odds-ratio for AKI of 1.35 (95% CI 1.15-1.60) for dabrafenib versus 3.28 for vemurafenib, plus in vitro data showing dabrafenib lacks vemurafenib's direct tubular/glomerular epithelial cytotoxicity. Supports the quantitative signal and mechanism.
- 5.Acute granulomatous interstitial nephritis in a patient with metastatic melanoma on targeted therapy with dabrafenib and trametinib-A case report.Krelle A, et al. · Cancer Rep (Hoboken) · 2021 · PMID 34350734Biopsy-proven granulomatous interstitial nephritis appearing 5 years into dabrafenib/trametinib, presenting as asymptomatic AKI, resolving with drug cessation and prednisolone 1 mg/kg. Documents the delayed-onset AIN signature.
- 6.Granulomatous nephritis and dermatitis in a patient with BRAF V600E mutant metastatic melanoma treated with dabrafenib and trametinib.Jansen YJ, et al. · Melanoma Res · 2015 · PMID 26512791Concurrent granulomatous nephritis and dermatitis, steroid-responsive with rapid relapse when corticosteroids were stopped and re-normalization on reintroduction — the basis for the 'don't taper too fast' management pearl.
- 7.Atypical anti-glomerular basement membrane glomerulonephritis in a patient with metastatic melanoma treated with mitogen-activated protein kinase and immune checkpoint inhibitors: a case report.Kyriazis P, et al. · J Med Case Rep · 2021 · PMID 33810799Rare crescentic/linear-IgG atypical anti-GBM glomerulonephritis during dabrafenib/trametinib after checkpoint-inhibitor therapy — illustrates that glomerular lesions are reported but confounded by prior immunotherapy, for the differential.
- 8.LandmarkImproved overall survival in melanoma with combined dabrafenib and trametinib.Robert C, et al. · N Engl J Med · 2014 · PMID 25399551COMBI-v registrational trial showing overall-survival benefit of dabrafenib plus trametinib over vemurafenib; renal toxicity was not a flagged adverse event, underscoring that nephrotoxicity emerged post-marketing.
Guidelines & consensus· 12
General onco-nephrology references
ADQIThe nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroupNat Rev Nephrol 2026 · PMID 41361704Provides expert-based statements (modified Delphi) on preventing and managing cisplatin/platinum-associated AKI, including isotonic IV hydration, attention to volume status and concomitant nephrotoxins, and incorporates evidence that IV magnesium supplementation may reduce cisplatin-associated AKI; emphasizes risk stratification and standardized AKI definitions.SIRMSIRM-SIN-AIOM: appropriateness criteria for evaluation and prevention of renal damage in the patient undergoing contrast medium examinations-consensus statements from Italian College of Radiology (SIRM), Italian College of Nephrology (SIN) and Italian Association of Medical Oncology (AIOM)Radiol Med 2022 · PMID 35303246Recommends eGFR-based renal risk assessment and pre/post-contrast isotonic saline or sodium bicarbonate hydration; advises maintaining a 5-7 day interval between iodinated contrast administration and cisplatin in cancer patients to reduce additive nephrotoxicity.KDIGOKDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancerKidney Int 2020 · PMID 33126977Identifies platinum compounds (especially cisplatin) as leading cytotoxic causes of acute tubular injury, AKI, and electrolyte/magnesium wasting; calls for interdisciplinary onco-nephrology care, accurate GFR estimation, and individualized drug dosing in patients with reduced kidney function.KDIGOKDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantationKidney Int 2020 · PMID 33276867Addresses chemotherapy-associated AKI/CKD in hematologic cancer, GFR estimation and chemotherapy dosing in patients with reduced kidney function, and management priorities and research gaps for onco-nephrology care.ADDIKDIntegrating International Consensus Guidelines for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) into everyday practiceEClinicalMedicine 2025 · PMID 40290844Provides GRADE-based, drug-specific dose-adjustment recommendations for anticancer agents in kidney dysfunction (illustrated for methotrexate, cisplatin, carboplatin and nivolumab); the recommendations build on Part 1's standardised CKD-EPI eGFR assessment rather than Cockcroft-Gault creatinine clearance.ADDIKDAligning kidney function assessment in patients with cancer to global practices in internal medicineEClinicalMedicine 2025 · PMID 40290845Three consensus recommendations: assess kidney function by GFR (measured GFR or CKD-EPI eGFR), classify it using KDIGO categories, and use this uniform approach to dose anticancer drugs — moving cancer medicine away from Cockcroft-Gault estimated creatinine clearance.ADDIKDA methodology for determining dosing recommendations for anticancer drugs in patients with reduced kidney functionEClinicalMedicine 2025 · PMID 40290846Establishes that, where RCT evidence is lacking, anticancer drug dosing recommendations in kidney dysfunction should be derived by critically appraising observational literature via GRADE combined with structured international multidisciplinary consensus voting.KDIGODiagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)Crit Care 2013 · PMID 23394211Defines/stages AKI by serum creatinine and urine output; emphasizes avoiding nephrotoxins, maintaining euvolemia/perfusion, dose-adjusting drugs to kidney function, and monitoring high-risk patients — the framework applied to nephrotoxic anti-cancer agents.KDIGOExecutive summary of the KDIGO 2021 Guideline for the Management of Glomerular DiseasesKidney Int 2021 · PMID 34556300Provides the staging/treatment framework for drug-associated glomerular lesions (e.g., bisphosphonate- and interferon-related collapsing FSGS, VEGF-inhibitor podocytopathy/proteinuria), including immunosuppression and supportive RAAS-blockade strategies.KDIGOExecutive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated VasculitisKidney Int 2024 · PMID 38388147Updates immunosuppressive induction (rituximab/cyclophosphamide), incorporates avacopan and lower-dose or glucocorticoid-sparing regimens — the management framework for drug- and checkpoint-inhibitor-associated ANCA/pauci-immune glomerulonephritis.KDIGOExecutive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus NephritisKidney Int 2024 · PMID 38182299Updates first-line lupus nephritis therapy to combination immunosuppression with the addition of belimumab or a calcineurin inhibitor (voclosporin) — informs management of immune-complex/lupus-like glomerulonephritis encountered with immunotherapy.KDIGOExecutive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV)Kidney Int 2025 · PMID 40975525Encourages liberal kidney biopsy and stricter proteinuria control (<0.5 g/d, ideally <0.3 g/d) with RAAS blockers, SGLT2 inhibitors, and targeted-release budesonide — the framework for IgA-dominant glomerular lesions, including those triggered by immune-modulating cancer therapy.
Where Dabrafenib sits in nephrotoxicity space — each dot is an anti-cancer agent, positioned so neighbors share a kidney-injury phenotype.
Phenotype-similar agents· nearest neighbors in nephrotoxicity space
Profile
Cobimetinib
Cotellic · MEK inhibitor
Real-world AKI signal with BRAF partners.
ATNAIN
Mild61% phenotype match
Encorafenib
Braftovi · BRAF inhibitor
Class tubular signal; usually mild.
ATNAIN
Mild61% phenotype match
Avutometinib
Avmapki (co-packaged with defactinib as Avmapki Fakzynja) · RAF/MEK inhibitor
RAF/MEK clamp; CK elevation/rhabdomyolysis and tubular electrolyte wasting.
LYTEATNPRE
Moderate60% phenotype match
Retifanlimab
Zynyz · PD-1 immune checkpoint inhibitor
PD-1 blockade — kidney injury is immune-mediated interstitial nephritis, not direct tubular toxicity.
AINLYTEPRE
Moderate56% phenotype match
Sunvozertinib
Zegfrovy · EGFR exon20 TKI
2025 EGFR exon20 TKI; electrolyte effects emerging.
SIADHLYTEPRE
Mild53% phenotype match
Nearest agents by kidney-injury phenotype (shared injuries, nephron target, severity, class) — a similarity approximation, not a claim of shared drug identity or mechanism.