Trametinib

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.

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.

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.Lesion-level management framework

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.

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.

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.