Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
Alkylator
Dacarbazine
DTIC · DTIC
A melanoma alkylator that menaces the hepatic endothelium far more than the nephron.
MildAlkylator · approved 1975
Metastatic melanomaHodgkin lymphoma (ABVD)Soft-tissue sarcoma
Signature kidney injury
Prerenal / Hemodynamic AKI
Direct nephrotoxicity is minimal and not well quantified; the notable vascular toxicity is hepatic veno-occlusive disease / sinusoidal obstruction (now recognized as not rare), with renal effects largely secondary to severe systemic illness, hepatic injury or volume loss.
Source: Marsh JC, Hepatology 1989
Mechanism of kidney injury
Dacarbazine and its reactive metabolites are selectively toxic to hepatic sinusoidal endothelial cells through a glutathione-dependent mechanism (depletion of endothelial GSH precedes toxicity), the basis of hepatic veno-occlusive disease and, occasionally, fatal hepatic vein thrombotic occlusion. The kidney is not a primary target; any AKI is typically prerenal from vomiting/volume depletion or hepatorenal-type hypoperfusion accompanying severe hepatic injury.
Clinical presentation
When present, prerenal azotemia (elevated BUN:creatinine ratio, low urine sodium) in the setting of nausea/vomiting and volume depletion; in VOD, hepatomegaly, right-upper-quadrant pain, weight gain and hyperbilirubinemia with secondary renal hypoperfusion.
Onset
Variable; hepatic VOD typically days to weeks after exposure.
Reversibility
Reversible
Anticancer mechanism
Imidazole-carboxamide prodrug activated in the liver (CYP-mediated N-demethylation) to a methylating diazonium species that alkylates DNA at O6-guanine. Used for metastatic melanoma, Hodgkin lymphoma (ABVD) and soft-tissue sarcoma.
Management
Supportive: rehydration and antiemetics for prerenal AKI; supportive care for VOD. Prerenal injury reverses with restoration of perfusion; severe hepatic vascular toxicity can be fatal.
Risk factors
- Volume depletion from severe emesis
- Hepatic veno-occlusive disease / eosinophilia (reported association)
- Concurrent hepatotoxins/nephrotoxins
Prevention
- Robust antiemesis and hydration
- Monitor liver function/clinical exam for VOD
- Maintain renal perfusion
Note · The listed signature is prerenal/vascular because intrinsic dacarbazine nephrotoxicity is minimal; the characteristic vascular toxicity is hepatic VOD rather than renal TMA.
Clinical depth
Renal dose adjustment
No established renal CrCl dose modification; dacarbazine is partly renally excreted but dose adjustment is driven mainly by hematologic toxicity and hepatic function. Use general caution and maintain hydration in renal impairment.
Dialyzability & ESKD dosing
Short-lived parent prodrug undergoing hepatic activation; not a drug managed by dialysis. ESKD data are minimal.
Differential diagnosis
Renal injury here is almost always prerenal (low FeNa, volume-responsive) or hepatorenal in the setting of VOD - not intrinsic tubular or microangiopathic injury. Recognizing VOD (tender hepatomegaly, weight gain, hyperbilirubinemia) reframes the AKI as a hepatic, not renal, problem.
Monitoring
- Volume status and antiemetic adequacy each cycle
- Liver function tests and clinical exam for veno-occlusive disease
- Serum creatinine if volume-depleted or hepatically ill
Key trials & series
- ABVD lymphoma and dacarbazine-based melanoma regimens as the principal exposure context
- Marsh Hepatology 1989 / Ceci Cancer 1988 - hepatic vascular (VOD/Budd-Chiari) toxicity series
Clinical pearls
- Dacarbazine's dangerous vascular toxicity is hepatic (VOD), not renal - the kidney suffers only secondarily.
- Most dacarbazine-associated AKI is simple prerenal azotemia from emesis - hydrate and the creatinine follows.
- New hepatomegaly, weight gain and jaundice after dacarbazine should trigger a VOD work-up, not a renal biopsy.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Injury signatures
Prerenal / Hemodynamic AKI
Beyond the kidney
Class-level context for the major non-renal toxicities of alkylators.
Hematologic
Cytopenias, thrombosis, TMA
- Myelosuppression; secondary malignancy risk
Neurologic
Neuropathy, encephalopathy, ICANS, PRES
- Ifosfamide encephalopathy (chloroacetaldehyde)
Cardiac
Cardiomyopathy, QT, ischemia, myocarditis
- High-dose cyclophosphamide cardiotoxicity
Evidence
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkDacarbazine toxicity in murine liver cells: a model of hepatic endothelial injury and glutathione defense.DeLeve LD · J Pharmacol Exp Ther 1994 · PMID 8138939Mechanistic basis: sinusoidal endothelial cell as the initial target of dacarbazine veno-occlusive injury.PMIDHepatic vascular toxicity of dacarbazine (DTIC): not a rare complication.Marsh JC · Hepatology 1989 · PMID 2707742Clinical series reframing hepatic vascular toxicity of dacarbazine as not rare.PMIDFatal hepatic vascular toxicity of DTIC. Is it really a rare event?Ceci G et al. · Cancer 1988 · PMID 3359400Fatal hepatic vein thrombotic occlusion case series in melanoma patients.PMIDToxicity of azathioprine and monocrotaline in murine sinusoidal endothelial cells and hepatocytes: the role of glutathione and relevance to hepatic venoocclusive disease.DeLeve LD et al. · Hepatology 1996 · PMID 8617441Mechanistic series situating dacarbazine sinusoidal endothelial toxicity within VOD pathogenesis.PMIDCellular target of cyclophosphamide toxicity in the murine liver: role of glutathione and site of metabolic activation.DeLeve LD · Hepatology 1996 · PMID 8855185Companion VOD-mechanism study on glutathione-dependent endothelial injury relevant to alkylators.PMIDAnticancer drug-induced kidney disorders.Kintzel PE · Drug Saf 2001 · PMID 11219485Onconephrology review framing prerenal and secondary renal injury mechanisms.
Related agents
Other agents sharing the same signature kidney injury.