Fotemustine
Muphoran · Nitrosourea (alkylating)
Class delayed cumulative tubulointerstitial/ATN; usually mild; acute signal often really cisplatin.
CINATNLYTE
Moderate75% phenotype match
BRAF inhibitor
Vemurafenib
Zelboraf · VEM
BRAF inhibitor · approved 2011 · 6 citations
Aging evidence· through 2021
Emerging evidence6/9 · 6 signals▾
- 6 citations
- Deep literature (12+ refs)
- Accrued over 10+ years
- Beyond single case reports
- High-impact journal
- Landmark reference
- Registrational / key trials
- Current through 2021
- 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 first-in-class BRAF inhibitor that transformed melanoma — and, nearly alone in its class, injures the proximal tubule.
ModerateFirst-in-class BRAF inhibitor (2011)
BRAF V600E mutation-positive unresectable or metastatic melanomaErdheim-Chester disease with BRAF V600 mutationOften combined with a MEK inhibitor (cobimetinib) to improve efficacy and reduce paradoxical/off-target toxicity
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Signature kidney injury
Signature lesion
Clinically meaningful AKI is a recognized but variably quantified effect, and vemurafenib is the strongest renal offender of the BRAF/MEK class. Small serum-creatinine rises are common and usually low-grade; overt AKI produced the first case series of 8 patients with significant-to-severe renal insufficiency (Launay-Vacher, Cancer 2014) and 132 vemurafenib AKI reports to FDA FAERS over 3 years, far exceeding dabrafenib's 13 (Jhaveri, JAMA Oncol 2015). In a single-center cohort treated with vemurafenib plus cobimetinib, 24% developed AKI, all within the first three months and mostly KDIGO stage 1-2, and adding the MEK inhibitor reduced AKI incidence roughly 60% versus vemurafenib monotherapy (Teuma 2017). A clean denominator-based monotherapy incidence is not established, so a single headline percentage is deliberately left unquantified.Source: Teuma et al., Cancer Chemother Pharmacol 2017; Jhaveri et al., JAMA Oncol 2015
Onset & rechallenge
Time to injurySubacute (~1–6 weeks)
Most AKI arises within the first weeks to three months of therapy; later onset is uncommon.
Distilled from: “Early — most cases arise within the first weeks to three months of therapy (all AKI events in the Teuma cohort occurred in the first trimester of treatment); later onset is uncommon.” · PMID 28396940
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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.
Direct death of tubular epithelial cells — the dose-limiting lesion of the platinums and zoledronate.
Global failure of proximal tubule reabsorption — glucosuria, phosphaturia and acidosis, classically from ifosfamide.
Renal electrolyte derangement — magnesium/potassium/calcium wasting (cisplatin, anti-EGFR antibodies) or retention (FGFR-inhibitor hyperphosphatemia, tumor-lysis hyperkalemia/hyperphosphatemia).
Slow, cumulative tubulointerstitial scarring — fibrosis, tubular atrophy and glomerulosclerosis with no discrete acute phase. The nitrosourea (carmustine/lomustine) lesion and delayed radioligand (radiation) nephropathy; often irreversible and detected only as a creeping creatinine months to years later.
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
Incidence not quantified
SeverityModerate
ReversibilityPartially reversible
Evidence0 refs
Nephron map
Proximal TubuleBulk reabsorption + drug uptake (OCT2, OATs)
Distal Tubule / Collecting DuctFine-tuning of Na, K, Mg, acid & water
Interstitium
Acute Tubular Necrosis
Direct death of tubular epithelial cells — the dose-limiting lesion of the platinums and zoledronate.
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Kidney injury
Mechanism of kidney injury
Predominantly direct, off-target (MAPK-independent) proximal tubular epithelial toxicity. In human cell work, vemurafenib reduced viability and increased cell death in proximal renal tubular epithelial cells (RPTEC) and glomerular epithelial cells (podocytes) at 10 microM — below its steady-state blood Cmax (~115 microM) — while sparing glomerular endothelial cells, and its intrinsic cytotoxicity exceeded that of dabrafenib, cobimetinib, and trametinib (Sanagawa 2021). This tubular injury manifests histologically as acute tubular injury/necrosis, with proximal tubular dysfunction (Fanconi-type glycosuria, phosphaturia, low-molecular-weight proteinuria) and electrolyte wasting in some cases; a tubulointerstitial/interstitial-nephritis component has also been described on the limited biopsy literature (Jhaveri 2015). Concurrent volume depletion from drug-related fever, diarrhea, and reduced intake frequently adds a prerenal/ischemic hit on top of the intrinsic tubular toxicity.
Clinical presentation
Usually an asymptomatic rise in serum creatinine detected on routine labs, often accompanied by electrolyte abnormalities — hypokalemia, hyponatremia, and hypophosphatemia are reported. Proximal tubulopathy (glycosuria with normal glucose, phosphaturia, aminoaciduria, LMW proteinuria) points to Fanconi-type injury. Most episodes are low-grade (CTCAE/KDIGO stage 1-2), but severe AKI requiring drug interruption and, rarely, dialysis has occurred, and some patients are left with persistent CKD. A striking, unexplained male predominance was seen in FAERS (85 men vs 47 women; p<.001).
Management
Confirm the creatinine rise and screen for reversible contributors — volume depletion (very common with vemurafenib fever/diarrhea), other nephrotoxins, obstruction, and contrast. For drug-attributable AKI, hold vemurafenib, restore volume, and replete electrolytes (potassium, phosphate, sodium, magnesium). Most low-grade injury recovers with interruption; on recovery, resume at a reduced dose with close monitoring, and permanently discontinue for recurrent or severe injury. Adding a MEK inhibitor (cobimetinib) both improves outcomes and reduces AKI frequency/severity roughly 60% versus monotherapy (Teuma 2017). If biopsy shows acute interstitial nephritis, a corticosteroid course may be considered (limited evidence). Persistent, severe, or diagnostically unclear injury warrants nephrology referral and consideration of kidney biopsy.Lesion-level management framework
Risk factors
- Male sex (marked predominance in pharmacovigilance data)
- Volume depletion from drug-related fever, diarrhea, nausea, or reduced oral intake
- Concomitant nephrotoxins (NSAIDs, RAAS inhibitors, diuretics, iodinated contrast)
- Higher drug exposure / prolonged therapy
- Pre-existing CKD (worsens tolerance of any AKI, though the Teuma cohort paradoxically found better baseline GFR in those who developed AKI — pre-existing impairment is not a prerequisite)
Prevention
- Check baseline serum creatinine/eGFR and electrolytes, then monitor at least monthly on therapy
- Maintain euvolemia; counsel on hydration and prompt reporting of fever, diarrhea, or poor intake
- Avoid stacking nephrotoxins (NSAIDs, contrast, high-dose diuretics/RAAS blockade) where possible
- Consider combination with a MEK inhibitor (cobimetinib), which lowers AKI incidence and severity while improving efficacy
- Hold or bridge dosing around intercurrent volume-depleting illness
Anticancer mechanism· how it treats cancer
Oral small-molecule, ATP-competitive inhibitor of mutated BRAF kinase (V600E/V600K). By shutting down constitutively active RAF-MEK-ERK (MAPK) signaling in BRAF V600-mutant melanoma cells, it drives cell-cycle arrest and apoptosis. In BRAF wild-type cells it paradoxically activates ERK through CRAF, the mechanistic basis for its cutaneous squamous proliferations (and part of the rationale for co-administering a downstream MEK inhibitor).
Note · Nephrotoxicity was not recognized in the pivotal registrational program and emerged only through post-marketing case series and FAERS pharmacovigilance. Much of the incidence evidence is combination (vemurafenib+cobimetinib) or spontaneous-report data, so quantitative estimates should be read as directional rather than precise.
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Clinical depth
Renal dose adjustment
No renal-based dose adjustment is specified for mild-to-moderate impairment. Because vemurafenib is hepatically metabolized (CYP3A4) and eliminated almost entirely in feces, with only ~1% renal excretion, exposure is not expected to change materially with reduced GFR, though data in severe impairment and ESKD are lacking. Dose modification is therefore driven by toxicity, not clearance: for drug-attributable AKI or intolerable toxicity, interrupt and, on recovery, resume at reduced dose (label steps 960 -> 720 -> 480 mg twice daily); permanently discontinue for recurrent severe events. Do not reduce below 480 mg twice daily.
Dialyzability & ESKD dosing
Not meaningfully dialyzable. Vemurafenib is >99% protein-bound, highly lipophilic, and eliminated predominantly in feces (~94%) with renal excretion near 1%; hemodialysis is not expected to remove appreciable drug and no post-dialysis supplemental dose is indicated. Dedicated dialysis pharmacokinetic data are lacking.
Differential diagnosis
Separate direct vemurafenib tubular toxicity/ATN from (1) prerenal azotemia due to the drug's fever, diarrhea, and anorexia (low FeNa, responds to volume — often coexists); (2) acute interstitial nephritis (sterile pyuria, eosinophiluria, rash/fever/eosinophilia, sometimes from a concomitant drug); (3) other nephrotoxins and iodinated contrast; and (4) melanoma-related obstruction or renal infiltration. Early onset (first trimester), proximal tubular electrolyte wasting (hypokalemia, hypophosphatemia, glycosuria), and the characteristic male predominance favor vemurafenib tubular toxicity; a lower renal signal with dabrafenib supports an agent-specific effect rather than a pure MAPK-pathway class effect.
Monitoring
- Baseline and at least monthly serum creatinine/eGFR
- Serum electrolytes each cycle — potassium, sodium, phosphate, magnesium (proximal tubular wasting)
- Urinalysis for glycosuria, phosphaturia, or proteinuria when tubulopathy/Fanconi is suspected
- Volume status and symptoms of fever/diarrhea that precipitate prerenal injury
- Reassess renal recovery after any dose hold before resuming
Key trials & series
- BRIM-3 (Chapman, NEJM 2011): phase 3 registrational trial vs dacarbazine establishing survival benefit; renal toxicity was not flagged in the pivotal safety profile, and the nephrotoxicity signal emerged post-marketing
- Jhaveri (JAMA Oncol 2015): FAERS pharmacovigilance analysis defining the class signal — 132 vemurafenib AKI reports vs 13 for dabrafenib, with male predominance
- Teuma (Cancer Chemother Pharmacol 2017): single-center cohort showing 24% AKI on vemurafenib+cobimetinib and ~60% AKI reduction from adding the MEK inhibitor
- Sanagawa (Anticancer Drugs 2021): real-world FAERS ROR plus human-cell work localizing direct cytotoxicity to proximal tubular and glomerular epithelial cells
Clinical pearls
- Vemurafenib is the outlier of the BRAF/MEK class for kidney injury — FAERS AKI ROR ~3.3 vs ~1.35 for dabrafenib (Sanagawa 2021; Jhaveri 2015). If a BRAF inhibitor is needed and kidney risk is a concern, dabrafenib carries a substantially lower renal signal.
- Adding a MEK inhibitor (cobimetinib) is not just about efficacy: it cut AKI incidence roughly 60% versus vemurafenib monotherapy (Teuma 2017).
- Injury is early and usually low-grade and reversible on hold, but severe episodes can leave persistent CKD — don't dismiss a creatinine bump in the first three months.
- Renal excretion is trivial (~1%), so there is no pharmacokinetic reason to renally dose-adjust — dose modification is driven by the toxicity itself.
- Electrolyte wasting (hypokalemia, hyponatremia, hypophosphatemia) and glycosuria are clues that the proximal tubule, not the glomerulus, is the target.
- The unexplained male predominance of vemurafenib AKI is a genuine, reproducible pharmacovigilance finding, not a sampling artifact.
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
6 peer-reviewed references. Citation metadata via PubMed / NLM.
Evidence accrual
6 references · 2011–2021 · 1 since 2019Citations 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.LandmarkNephrotoxicity of the BRAF Inhibitors Vemurafenib and Dabrafenib.Jhaveri KD et al. · JAMA Oncol · 2015 · PMID 26182194Seminal FAERS analysis defining the class signal: 132 vemurafenib AKI reports vs 13 for dabrafenib, marked male predominance, tubulointerstitial injury — the reference the research hint points to.
- 2.LandmarkAcute renal failure associated with the new BRAF inhibitor vemurafenib: a case series of 8 patients.Launay-Vacher V et al. · Cancer · 2014 · PMID 24737576First case series documenting significant-to-severe AKI with vemurafenib, including renal sequelae and persistent kidney disease.
- 3.LandmarkBRAF/MEK inhibitor-associated nephrotoxicity in a real-world setting and human kidney cells.Sanagawa A et al. · Anticancer Drugs · 2021 · PMID 34232935Mechanistic + pharmacovigilance anchor: FAERS AKI ROR 3.28 for vemurafenib vs 1.35 for dabrafenib, with direct proximal tubular (RPTEC) and podocyte cytotoxicity below steady-state Cmax, sparing glomerular endothelium.
- 4.Adjunction of a MEK inhibitor to Vemurafenib in the treatment of metastatic melanoma results in a 60% reduction of acute kidney injury.Teuma C et al. · Cancer Chemother Pharmacol · 2017 · PMID 28396940Cohort quantifying AKI incidence (24% on vemurafenib+cobimetinib, all in the first trimester, mostly stage 1-2) and showing ~60% AKI reduction from adding a MEK inhibitor.
- 5.BRAF inhibitors - do we need to worry about kidney injury?Wanchoo R et al. · Expert Opin Drug Saf · 2016 · PMID 26954036Focused nephrology review of BRAF-inhibitor renal safety, monitoring, and management framing.
- 6.LandmarkImproved survival with vemurafenib in melanoma with BRAF V600E mutation.Chapman PB et al. · N Engl J Med · 2011 · PMID 21639808BRIM-3 registrational phase 3 trial establishing efficacy; nephrotoxicity was absent from the pivotal safety profile and emerged only 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 Vemurafenib 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
Nimustine (ACNU)
Nidran · Nitrosourea (alkylating)
Water-soluble nitrosourea; renal risk inferred at class level; cumulative delayed tubulointerstitial injury; DLT is myelosuppression.
CINATNLYTE
Moderate74% phenotype match
BRAF / MEK inhibitors (vemurafenib · dabrafenib · trametinib)
BRAF/MEK inhibitor
Tubulointerstitial AKI; vemurafenib strongest.
ATNAINLYTE
Mild64% phenotype match
Trastuzumab deruxtecan
Enhertu · Antibody-drug conjugate (HER2/DXd)
Emerging AKI/proteinuria reports — under-published.
ATNFANCLYTE
Moderate64% phenotype match
Pemetrexed
Alimta · Antifolate
Cumulative tubular toxicity, RTA and nephrogenic DI.
ATNLYTE
Moderate63% phenotype match
Lenalidomide
Revlimid · Immunomodulatory drug (IMiD)
Renally cleared; AKI and rare Fanconi/TMA.
ATNFANCTMA
Moderate58% 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.