Cisplatin
Platinol · Platinum agent
Proximal tubular ATN + magnesium wasting; the archetype.
ATNLYTEPRE
SevereOpen →
Marine alkylating agent
Trabectedin
Yondelis · TRAB
A marine minor-groove binder whose kidney injury is indirect — rhabdomyolysis driving pigment nephropathy.
ModerateMarine alkylating agent (ecteinascidin) · approved 2015
Unresectable or metastatic liposarcoma and leiomyosarcoma after an anthracycline-containing regimenRelapsed platinum-sensitive ovarian cancer (in combination, outside the US)
Signature kidney injury
Acute Tubular Necrosis
The drug is not directly nephrotoxic and shows no cumulative renal toxicity; clinically important AKI is rare and driven by rhabdomyolysis. The per-cycle rhabdomyolysis rate is not quantified (case-level). For context, the dominant organ toxicity is hepatic — grade 3-4 transaminitis fell from ~34% to ~2% with dexamethasone premedication.
Source: Demetri et al., J Clin Oncol 2015
Mechanism of kidney injury
Indirect pigment (myoglobinuric) nephropathy: drug-induced rhabdomyolysis releases myoglobin that causes proximal tubular oxidative injury, intratubular heme-pigment cast obstruction, and renal vasoconstriction, producing ATN. The drug itself is not a direct tubular toxin; CYP3A4 inhibitors/herbals and hepatic dysfunction potentiate the muscle injury.
Clinical presentation
Myalgia/weakness with a markedly elevated CK (often >1000 or >5x ULN), myoglobinuria (heme-positive dipstick without red cells), and a rising creatinine; concurrent transaminase elevation, hyperkalemia, hyperphosphatemia, hyperuricemia and hypocalcemia. Rhabdomyolysis often emerges around cycle 4.
Onset
Rhabdomyolysis often around the 4th cycle; hepatotoxicity/myelosuppression nadir ~days 5-15.
Reversibility
Reversible
Anticancer mechanism
Marine-derived tetrahydroisoquinoline alkaloid that binds the DNA minor groove and alkylates guanine N2, bending DNA toward the major groove and poisoning transcription-coupled nucleotide-excision repair; it also disrupts activated transcription and tumor-associated macrophages. Myxoid liposarcoma (FUS-DDIT3 fusion) is especially sensitive.
Management
Hold the drug; treat rhabdomyolysis with early aggressive IV crystalloid (the cornerstone), correct electrolytes, and use renal replacement therapy if needed. Mannitol/bicarbonate have no proven benefit. Dosing is liver-driven (bilirubin), not kidney-driven.
Risk factors
- Hepatic impairment (gates dosing; potentiates toxicity)
- Concurrent CYP3A4 inhibitors and herbal supplements (e.g. bioflavonoid-rich products)
- Concurrent statins
- Cumulative dosing and volume depletion
Prevention
- Mandatory dexamethasone premedication (20 mg IV before infusion) — reduces hepatic and marrow toxicity
- Avoid strong CYP3A4 inhibitors and herbal supplements; review medications each cycle
- Correct hepatic dysfunction before dosing and maintain hydration
- Check CK and renal function with any muscle symptoms
Note · Established renal mechanism (pigment nephropathy from rhabdomyolysis) supported by case series; no direct tubular toxin and no cumulative renal toxicity.
Clinical depth
Renal dose adjustment
Standard 1.5 mg/m2 IV over 24 h every 3 weeks. Dose modification is gated by bilirubin/hepatic function, not CrCl; avoid in severe hepatic impairment. No established CrCl-based reduction; it has not been studied in CrCl <30 mL/min, so use caution.
Dialyzability & ESKD dosing
Not dialyzable — ~94-98% protein-bound with a large volume of distribution and predominantly biliary elimination (<10% urinary). Dialysis is used to support AKI, not to remove the drug.
Differential diagnosis
Pigment (rhabdomyolysis) ATN — heme-positive dipstick without red cells plus high CK — versus prerenal/sepsis AKI, tumor lysis, contrast nephropathy and hepatorenal physiology. The CK and myoglobinuria pattern identify the mechanism.
Monitoring
- LFTs/bilirubin/alkaline phosphatase and CBC before each cycle
- CK/CPK with any myalgia or weakness
- Creatinine and electrolytes with muscle symptoms or rising CK
- Medication/supplement review for CYP3A4 interactions each visit
Key trials & series
- Demetri phase III vs dacarbazine (J Clin Oncol 2015) — registrational LPS/LMS trial
- Grosso EJC 2006 — dexamethasone premedication markedly reduces hepatic/marrow toxicity
Clinical pearls
- Renal injury is indirect — an unexplained creatinine rise with myalgia or dark urine should prompt a CK.
- Dexamethasone premedication is mandatory and the most protective single measure.
- Screen for CYP3A4 inhibitors and herbal supplements every cycle — they precipitate rhabdomyolysis.
- Dosing is liver-driven (bilirubin), not kidney-driven.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Tubular Lumen
The urine flow path
Injury signatures
Acute Tubular NecrosisElectrolyte Wasting
Beyond the kidney
Class-level context for the major non-renal toxicities of marine alkylating agents.
Ophthalmic
Keratopathy, uveitis, retinopathy
- Visual disturbance (crizotinib)
Hepatic / Liver
Transaminitis, hepatitis, VOD/SOS
- Transaminitis
Neurologic
Neuropathy, encephalopathy, ICANS, PRES
- CNS effects (lorlatinib)
Evidence
8 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkEfficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial.Demetri GD et al. · J Clin Oncol 2015 · PMID 26371143Pivotal phase III vs dacarbazine supporting the 2015 FDA approval for liposarcoma/leiomyosarcoma.PMIDOverall survival and histology-specific subgroup analyses from a phase 3, randomized controlled study of trabectedin or dacarbazine in patients with advanced liposarcoma or leiomyosarcoma.Patel S et al. · Cancer 2019 · PMID 31173362Final OS/histology subgroup analysis of the registrational trial.PMIDET-743: more than an innovative mechanism of action.Scotto KW · Anticancer Drugs 2002 · PMID 12173491Seminal mechanism paper (minor-groove binding and transcription-coupled NER interference).PMIDTrabectedin-related rhabdomyolysis: an uncommon but fatal toxicity.Stoyianni A et al. · Tumori 2011 · PMID 21617727Key case report and review of rhabdomyolysis leading to renal failure.PMIDHerbal-drug interaction induced rhabdomyolysis in a liposarcoma patient receiving trabectedin.Strippoli S et al. · BMC Complement Altern Med 2013 · PMID 23899130CK/myoglobin-confirmed rhabdomyolysis after cycle 4 with a CYP3A4 herbal trigger.PMIDSevere Rhabdomyolysis during Treatment with Trabectedin in Combination with a Herbal Drug in a Patient with Metastatic Synovial Sarcoma: A Case Report.Damato A et al. · Case Rep Oncol 2017 · PMID 28512407Reversible severe rhabdomyolysis after 4 cycles with a herbal/CYP3A4 trigger.PMIDSteroid premedication markedly reduces liver and bone marrow toxicity of trabectedin in advanced sarcoma.Grosso F et al. · Eur J Cancer 2006 · PMID 16737808Practice-defining: dexamethasone cut grade 3-4 transaminitis from ~34% to ~2%.PMIDA comprehensive safety evaluation of trabectedin and drug-drug interactions of trabectedin-based combinations.Leporini C et al. · BioDrugs 2014 · PMID 25209722Safety/PK review documenting no cumulative renal toxicity and the CYP3A4 interaction profile.