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MEK inhibitor

Trametinib

Mekinist · TRA

MEK inhibitor · approved 2013 · 7 references

A MEK1/2 inhibitor with only a modest direct renal footprint — its main kidney story is hemodynamic AKI during the dabrafenib-trametinib pyrexia syndrome, with rare biopsy-proven interstitial nephritis and glomerular injury.

Signature injury
Prerenal / Hemodynamic AKI
Severity
Moderate
Reversibility
Variable
Onset
Variable. Pyrexia-associated AKI tends to appear early, tracking the febrile syndrome that often begins within the first weeks to few months of dabrafenib/trametinib. The rare biopsy-proven interstitial nephritis and glomerulonephritis cases have presented later — generally around 2 to 6 months into therapy.

Signature kidney injury & incidence

Prerenal / Hemodynamic AKI — representative incidence ~21%.

The renal signal from trametinib itself is modest. In an FDA Adverse Event Reporting System (FAERS) disproportionality analysis, trametinib carried a statistically significant but low acute-kidney-injury reporting odds ratio of 1.32 (95% CI 1.11-1.56) — well below vemurafenib's — and at mean steady-state plasma concentrations trametinib produced no measurable cytotoxicity in cultured proximal-tubular, glomerular endothelial or glomerular epithelial cells (Sanagawa, Anticancer Drugs 2021). Most of the quantified AKI burden comes from combination use: in a single-center retrospective cohort of 199 patients receiving dabrafenib/trametinib, 42 (21%) met an AKI definition (1.5x creatinine rise) within 12 months, and roughly a quarter of those episodes (about 5% of the whole cohort) occurred during a treatment-induced pyrexia syndrome (Seethapathy, Nephrol Dial Transplant 2022). Biopsy-proven interstitial nephritis and glomerular lesions are rare and reported only as individual cases; kidney impairment was rarely reported in the pivotal monotherapy trial.

Source: Seethapathy, Nephrol Dial Transplant 2022 (n=199 dabrafenib/trametinib cohort; 21% AKI at 12 months — combination therapy, not monotherapy)

Reported injury signatures: Prerenal / Hemodynamic AKI, Acute Interstitial Nephritis, Glomerular Injury / Proteinuria, Hypertension.

Renal toxicity profile

  1. Prerenal / Hemodynamic AKIPrimary
  2. Acute Interstitial NephritisSecondary
  3. Glomerular Injury / ProteinuriaSecondary
  4. HypertensionSecondary

Onset timing & rechallenge

Variable / unpredictable — Pyrexia-associated AKI appears early (first weeks to few months); the rare biopsy-proven interstitial nephritis/glomerulonephritis presents later, around 2 to 6 months.

Mechanism of kidney injury

Trametinib is not a classic direct nephrotoxin. Blocking MEK1/2-ERK signaling in the kidney is, if anything, protective in models — in a mouse cisplatin-AKI study trametinib reduced tubular MEK/ERK phosphorylation, macrophage infiltration, oxidative stress, apoptosis and necroptosis and improved renal function (Lee, Molecules 2024) — and at therapeutic plasma levels it caused no cytotoxicity in human proximal-tubular or glomerular cells (Sanagawa, Anticancer Drugs 2021). The clinically observed AKI is therefore mostly indirect: (1) hemodynamic/prerenal injury during the dabrafenib/trametinib pyrexia syndrome, in which recurrent fever, vasodilation and gastrointestinal fluid losses reduce renal perfusion; and (2) uncommon immune-mediated lesions — acute (sometimes granulomatous) interstitial nephritis and, more rarely, crescentic/anti-GBM-pattern glomerulonephritis or renal granulomatous vasculitis — proposed to arise from MAPK-pathway inhibition enhancing autoimmunity and from BRAF-inhibitor-related podocyte injury, frequently in patients co-exposed to immune checkpoint inhibitors. As a MEK-pathway class effect, an effect on the vasculature (hypertension, peripheral edema) can also raise blood pressure.

Clinical presentation

Two distinct pictures. (1) The common, dominant one is a rise in serum creatinine during the dabrafenib/trametinib pyrexia syndrome — fever, chills, rigors, gastrointestinal upset (nausea, vomiting, diarrhea) and elevated liver enzymes — i.e., a largely hemodynamic/prerenal AKI from fever-driven vasodilation and volume depletion, typically with a bland urine and little proteinuria. (2) Rarely, an intrinsic lesion: biopsy-proven (sometimes granulomatous) acute interstitial nephritis presenting with a subacute creatinine rise, or a glomerular process (crescentic/anti-GBM-pattern glomerulonephritis, granulomatous vasculitis) with proteinuria, hematuria and dysmorphic red cells / RBC casts — the glomerular cases cluster in patients also exposed to immune checkpoint inhibitors or the BRAF-inhibitor partner. As a MEK class effect, peripheral edema and hypertension can occur and should prompt blood-pressure monitoring.

Management

Most episodes are hemodynamic and reverse with supportive care: treat the pyrexia, restore volume, hold dabrafenib/trametinib during the febrile syndrome (per label) and resume once fever and creatinine settle; look for and remove other nephrotoxins. If creatinine does not recover promptly, or there is proteinuria/hematuria/an active sediment, pursue a kidney biopsy — the answer changes management. Biopsy-proven acute interstitial nephritis is treated with corticosteroids (e.g., methylprednisolone/prednisone) and drug discontinuation, with renal recovery reported; crescentic/anti-GBM-pattern or granulomatous glomerulonephritis has been managed with corticosteroids with or without cyclophosphamide. After biopsy-proven AIN, rechallenge with a different BRAF/MEK pair (e.g., encorafenib/binimetinib) has been done successfully in a patient with full renal recovery and limited options, but should be a considered, closely monitored decision. Treat MEK-associated hypertension with standard antihypertensives. Trametinib dose modifications are otherwise driven by cardiomyopathy/LVEF, ocular, skin, pyrexia and hepatic toxicity — not by creatinine.

Risk factors

  • Combination with dabrafenib — most quantified AKI comes from the combination, not trametinib monotherapy
  • The dabrafenib/trametinib-induced pyrexia syndrome (fever, chills, GI losses causing volume depletion)
  • Pre-existing liver disease — the only significant baseline predictor of AKI in the 199-patient cohort (Seethapathy 2022)
  • Prior or concurrent immune checkpoint inhibitor exposure (linked to the glomerular/AIN case reports)
  • Volume depletion, diuretics or other nephrotoxins during febrile episodes
  • Older age and baseline CKD (general AKI susceptibility)

Prevention

  • Check baseline creatinine/eGFR, blood pressure and urinalysis before starting, and recheck each cycle
  • Counsel on the pyrexia syndrome — treat fever early, hold the drugs per label for recurrent/severe pyrexia, and maintain hydration to prevent prerenal AKI
  • Monitor blood pressure (MEK class effect) and treat new or worsening hypertension
  • Minimize concurrent nephrotoxins (NSAIDs, iodinated contrast, aminoglycosides) during febrile episodes
  • Keep a low threshold for urine protein/sediment testing if creatinine rises, especially with prior checkpoint-inhibitor exposure

Renal dose adjustment

No renal dose adjustment is specified. Trametinib undergoes predominantly hepatic metabolism (deacetylation and oxidation) with mainly fecal excretion and only minor (roughly under 20%) urinary elimination, so kidney function has little effect on exposure; mild-to-moderate renal impairment does not require a change, and no formal recommendation exists for severe impairment or dialysis (not studied). Management of AKI is drug interruption plus supportive/immunosuppressive treatment as above, not a renal-clearance-based dose reduction.

Dialyzability & ESKD dosing

Not meaningfully dialyzable. Trametinib is highly plasma-protein bound (~97%) with a large volume of distribution and is cleared hepatically/fecally rather than renally, so hemodialysis is not expected to remove appreciable drug or serve as a route of elimination in overdose. There is no renal dosing benefit from dialysis, and no formal dialysis pharmacokinetic data exist.

Differential diagnosis

Distinguish the common hemodynamic/pyrexia AKI (temporal link to fever and GI losses, bland sediment, recovers with hydration and a drug hold) from intrinsic lesions that need a biopsy. Consider: acute interstitial nephritis (subacute rise, sometimes sterile pyuria/eosinophiluria — remember concurrent PPIs, NSAIDs, and especially prior/concurrent immune checkpoint inhibitors, which cause AIN in their own right and confound attribution); checkpoint-inhibitor-associated AKI when ICIs were used before or with the BRAF/MEK combo; glomerulonephritis (proteinuria, hematuria, RBC casts — anti-GBM-pattern and granulomatous/crescentic GN reported); dabrafenib or vemurafenib as the more nephrotoxic partner (vemurafenib has the strongest tubular cytotoxicity of the class); and simple prerenal azotemia from vomiting/diarrhea or diuretics. MEK-associated hypertension and peripheral edema should not be mistaken for a primary renal lesion.

Monitoring

  • Serum creatinine/eGFR at baseline and with each cycle, and promptly during any pyrexia episode
  • Blood pressure at baseline and periodically (MEK class effect)
  • Urinalysis / urine protein-to-creatinine ratio with microscopy if creatinine rises or edema/proteinuria appears
  • Volume status, temperature and liver enzymes during febrile syndromes (pyrexia AKI clusters with transaminitis)
  • If AIN or glomerulonephritis is suspected, nephrology referral and consideration of kidney biopsy before empiric steroids

Key trials & series

  • METRIC (Flaherty, N Engl J Med 2012) — phase 3 registrational trial of single-agent trametinib vs chemotherapy in BRAF V600E/K metastatic melanoma; established efficacy (improved PFS and OS) and the toxicity profile (rash, diarrhea, peripheral edema; infrequent reversible LVEF drop and ocular effects) with no signal of major direct nephrotoxicity.
  • Seethapathy dabrafenib/trametinib AKI cohort (Nephrol Dial Transplant 2022) — retrospective 199-patient study defining AKI incidence (21% at 12 months), the pyrexia-associated pattern, pre-existing liver disease as the only baseline predictor, and one biopsy-proven granulomatous interstitial nephritis.
  • Sanagawa FAERS / in-vitro study (Anticancer Drugs 2021) — real-world disproportionality plus human kidney-cell cytotoxicity showing trametinib's AKI reporting odds ratio is low (1.32; 95% CI 1.11-1.56) with no direct tubular/glomerular cytotoxicity at therapeutic concentrations.

Clinical pearls

  • Trametinib's own kidney signal is modest — the AKI seen on dabrafenib/trametinib is usually hemodynamic, occurring during the drug-induced pyrexia syndrome rather than from a direct tubular toxin; treat the fever and volume and it typically reverses.
  • Pre-existing liver disease was the only baseline predictor of AKI in the largest cohort — flag those patients for closer creatinine watching.
  • A rising creatinine with proteinuria, hematuria or an active sediment is a red flag to biopsy: rare but real AIN (sometimes granulomatous) and crescentic/anti-GBM-pattern GN have been documented and change management to steroids with or without cyclophosphamide.
  • Many glomerular/AIN cases occurred in patients also exposed to immune checkpoint inhibitors, so attribution is genuinely shared — review the full immuno-oncology timeline before blaming the MEK inhibitor.
  • After biopsy-proven AIN, switching to a different BRAF/MEK pair (encorafenib/binimetinib) has been tolerated with preserved renal function in a reported case — a reasonable option when disease control is needed and alternatives are limited.
  • Watch blood pressure and edema as a MEK class effect, and don't reflexively dose-reduce for creatinine: trametinib is hepatically cleared, so its dose modifications are driven by heart/eye/skin/liver toxicity, not renal function.

Anticancer mechanism

Oral, reversible, allosteric small-molecule inhibitor of the dual-specificity kinases MEK1 and MEK2 (MAP2K1/2), the node immediately downstream of BRAF in the RAS-RAF-MEK-ERK (MAPK) proliferation cascade. By blocking MEK-mediated phosphorylation of ERK1/2 it shuts down the constitutive MAPK signaling driven by BRAF V600E/K mutations. It is given almost always in combination with the BRAF inhibitor dabrafenib to deepen pathway blockade, improve response and delay resistance.

Note

The quantified 21% AKI incidence and the pyrexia-associated pattern come from combination dabrafenib/trametinib data; isolated trametinib monotherapy carries only a low FAERS AKI signal (ROR 1.32) and no in-vitro renal cytotoxicity. Interstitial and glomerular lesions are individual case reports, frequently confounded by concurrent immune checkpoint inhibitors or the BRAF-inhibitor partner. Based on articles retrieved from PubMed. Educational content, not medical advice.

Guidelines & consensus

  • ADQI (2026) — The nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroupProvides 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.Nat Rev Nephrol · PMID 41361704
  • SIRM (2022) — SIRM-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)Recommends 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.Radiol Med · PMID 35303246
  • KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancerIdentifies 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.Kidney Int · PMID 33126977
  • KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantationAddresses 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.Kidney Int · PMID 33276867
  • ADDIKD (2025) — Integrating International Consensus Guidelines for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) into everyday practiceProvides 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.EClinicalMedicine · PMID 40290844
  • ADDIKD (2025) — Aligning kidney function assessment in patients with cancer to global practices in internal medicineThree 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.EClinicalMedicine · PMID 40290845
  • ADDIKD (2025) — A methodology for determining dosing recommendations for anticancer drugs in patients with reduced kidney functionEstablishes 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.EClinicalMedicine · PMID 40290846
  • KDIGO (2013) — Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)Defines/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.Crit Care · PMID 23394211
  • KDIGO (2021) — Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular DiseasesProvides 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.Kidney Int · PMID 34556300
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated VasculitisUpdates 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.Kidney Int · PMID 38388147
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus NephritisUpdates 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.Kidney Int · PMID 38182299
  • KDIGO (2025) — Executive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV)Encourages 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.Kidney Int · PMID 40975525

References

7 peer-reviewed references. Citation metadata via PubMed / NLM.

  1. 1.Improved survival with MEK inhibition in BRAF-mutated melanoma.Flaherty KT, Robert C, Hersey P, et al. · N Engl J Med · 2012 · PMID 22663011
  2. 2.Clinical features of acute kidney injury in patients receiving dabrafenib and trametinib.Seethapathy H, Lee MD, Strohbehn IA, et al. · Nephrol Dial Transplant · 2022 · PMID 33355659
  3. 3.BRAF/MEK inhibitor-associated nephrotoxicity in a real-world setting and human kidney cells.Sanagawa A, Hotta Y, Mori N, et al. · Anticancer Drugs · 2021 · PMID 34232935
  4. 4.Efficacy of Trametinib in Alleviating Cisplatin-Induced Acute Kidney Injury: Inhibition of Inflammation, Oxidative Stress, and Tubular Cell Death in a Mouse Model.Lee JE, Kim JY, Leem J. · Molecules · 2024 · PMID 38930946
  5. 5.Truth 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, Delanghe S, Jacobs C, et al. · Acta Clin Belg · 2022 · PMID 35996969
  6. 6.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, Tiwary A, Freeman J, et al. · J Med Case Rep · 2021 · PMID 33810799
  7. 7.Glomerulonephritis and granulomatous vasculitis in kidney as a complication of the use of BRAF and MEK inhibitors in the treatment of metastatic melanoma: A case report.Maanaoui M, Saint-Jacques C, Gnemmi V, et al. · Medicine (Baltimore) · 2017 · PMID 28640105
Educational monograph from NephTox (nephtox.com). Not medical advice — verify against current guidelines before any clinical decision.