Cisplatin
Platinol · Platinum agent
Proximal tubular ATN + magnesium wasting; the archetype.
ATNLYTEPRE
SevereOpen →
MEK inhibitor
Cobimetinib
Cotellic · Cobi
A MEK inhibitor partnered with vemurafenib — and, notably, it cut BRAF-inhibitor AKI in practice.
MildMEK inhibitor · approved 2015
BRAF V600-mutant melanoma (with vemurafenib)
Signature kidney injury
Acute Tubular Necrosis
AKI with BRAF/MEK therapy is uncommon and mostly mild; notably, a pharmacovigilance analysis found that adding a MEK inhibitor to vemurafenib was associated with a ~60% reduction in acute kidney injury versus vemurafenib alone.
Source: Teuma et al., Cancer Chemother Pharmacol 2017
Mechanism of kidney injury
MAPK-pathway inhibition can be associated with tubular injury or acute interstitial nephritis in case-level reports. Mechanistically the MEK component appears to mitigate the proximal-tubular injury attributed to the BRAF inhibitor vemurafenib (which itself can cause a Fanconi-like proximal tubulopathy and AIN), so the combination is renally protective relative to BRAF monotherapy.
Clinical presentation
Mild reversible creatinine elevation; occasional electrolyte disturbance. Severe AKI is unusual at standard combination dosing. CK elevation, photosensitivity, and serous retinopathy are other class/combination effects.
Onset
Weeks into therapy.
Reversibility
Reversible
Anticancer mechanism
Selective, reversible MEK1/2 inhibitor that blocks MAPK signaling downstream of BRAF. Used with vemurafenib in BRAF V600-mutant melanoma.
Management
Hold for significant AKI; supportive care and volume repletion; corticosteroids if interstitial nephritis is suspected/proven; resume per tolerance once renal function recovers.
Risk factors
- Volume depletion
- Concurrent nephrotoxins
- Pre-existing CKD
Prevention
- Monitor creatinine and electrolytes
- Maintain hydration
- Avoid concurrent nephrotoxins
Note · Real-world signal is favorable: the MEK partner reduced BRAF-inhibitor-associated AKI.
Clinical depth
Renal dose adjustment
No renal dose adjustment recommended for mild-moderate impairment; severe impairment and dialysis are not studied. Dose modification is driven mainly by CK elevation, retinopathy, LVEF, and photosensitivity.
Dialyzability & ESKD dosing
Highly protein-bound oral small molecule; not expected to be meaningfully dialyzed. No validated ESKD dosing.
Differential diagnosis
When AKI does occur, distinguish vemurafenib-driven proximal tubulopathy/AIN (often the dominant contributor) from prerenal causes and from MEK-related rhabdomyolysis (check CK). Remember the combination tends to lower, not raise, AKI risk versus BRAF monotherapy.
Monitoring
- Serum creatinine and electrolytes at baseline and periodically
- Creatine phosphokinase at baseline and periodically (rhabdomyolysis risk)
- LVEF and ophthalmologic assessment per label
Key trials & series
- coBRIM (cobimetinib + vemurafenib vs vemurafenib in BRAF-mutant melanoma)
- Teuma 2017 pharmacovigilance analysis (MEK addition reduces BRAF-inhibitor AKI)
Clinical pearls
- Counter-intuitively, adding the MEK inhibitor reduced BRAF-inhibitor AKI by ~60% in real-world data — the kidney signal here is favorable.
- If AKI appears, vemurafenib (not cobimetinib) is the more likely culprit; consider a Fanconi-pattern proximal tubulopathy.
- Check CK with any myalgia given MEK-inhibitor rhabdomyolysis risk.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Interstitium
Supporting tissue around the tubules
Injury signatures
Acute Tubular NecrosisAcute Interstitial Nephritis
Beyond the kidney
Class-level context for the major non-renal toxicities of mek 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
Evidence
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkAdjunction 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 28396940Pharmacovigilance analysis showing MEK inhibitor addition lowers BRAF-inhibitor AKI.PMIDBRAF/MEK inhibitor-associated nephrotoxicity in a real-world setting and human kidney cells.Sanagawa A et al. · Anticancer Drugs 2021 · PMID 34232935Characterizes BRAF/MEK-class renal injury in real-world data and kidney cell models.PMIDTruth or dare: switching BRAF/MEK inhibitors after acute interstitial nephritis in a patient with metastatic melanoma - A case report and review of the literature.De Ryck L et al. · Acta Clin Belg 2022 · PMID 35996969Case-based review of BRAF/MEK interstitial nephritis informing management and rechallenge.PMIDCombined vemurafenib and cobimetinib in BRAF-mutated melanoma.Larkin J et al. · N Engl J Med 2014 · PMID 25265494Pivotal coBRIM phase 3 registrational dataset establishing the vemurafenib + cobimetinib combination and its toxicity profile.PMIDTargeted Cancer Therapies Causing Elevations in Serum Creatinine Through Tubular Secretion Inhibition: A Case Report and Review of the Literature.Mach T et al. · Can J Kidney Health Dis 2022 · PMID 35756332Context for distinguishing transporter-mediated creatinine rise from true injury among kinase inhibitors.PMIDCurrent Trends in Anti-Cancer Molecular Targeted Therapies: Renal Complications and Their Histological Features.Tonooka A et al. · J Nippon Med Sch 2021 · PMID 34840210Onconephrology review including small-molecule targeted-therapy renal effects.