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Alkylator

Dacarbazine

DTIC · DTIC

Alkylator · approved 1975 · 2 references

A melanoma alkylator that menaces the hepatic endothelium far more than the nephron.

Signature injury
Prerenal / Hemodynamic AKI
Severity
Mild
Reversibility
Reversible
Onset
Variable; hepatic VOD typically days to weeks after exposure.

Signature kidney injury & incidence

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: Kintzel, Drug Saf 2001

Reported injury signatures: Prerenal / Hemodynamic AKI.

Onset timing & rechallenge

Variable / unpredictable — Onset is variable, with hepatic veno-occlusive disease typically occurring days to weeks after exposure.

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.

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

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
  • Hepatic vascular toxicity (veno-occlusive disease / Budd-Chiari) is the characteristic severe event; renal involvement is secondary

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.

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.

Guidelines & consensus

Each recommendation below is this atlas's faithful summary of the source, not a quotation from it — follow the PubMed link for the wording the society published. Summaries may be superseded; consult the current full text and individualize to the patient.

  • ADQI (2026) — Conventional cytotoxic chemotherapy-associated nephrotoxicity: consensus report of the 34th Acute Disease Quality Initiative (ADQI) WorkgroupCisplatin is identified as a leading cytotoxic nephrotoxin; the workgroup details preventive measures (adequate isotonic hydration, correction of volume depletion, avoidance of concurrent nephrotoxins, attention to electrolyte/magnesium wasting) and management of cisplatin-associated AKI, with a research agenda for knowledge gaps.Kidney Int · PMID 41881107
  • 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 (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknownsEvaluate and risk-stratify CKD, manage to delay progression and its complications, and practise explicit medication management and drug stewardship — the framework the atlas's G1–G5 eGFR banding and every renal dose-adjustment recommendation sit inside. Because the guideline excludes dialysis and transplant recipients by its own statement of scope, its recommendations do not carry to those settings, where this atlas's dialyzability and post-transplant guidance rests on other sources.Kidney Int · PMID 38519239
  • 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

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

  1. 1.[Hepatic veno-occlusive disease caused by Deticene: a cause of acute hypovolemic shock].Leroy B et al · Ann Fr Anesth Reanim · 1990 · PMID 2278422
  2. 2.Anticancer drug-induced kidney disorders.Kintzel PE · Drug Saf · 2001 · PMID 11219485
Educational monograph from NephTox (nephtox.com). Not medical advice — verify against current guidelines before any clinical decision.