A 48-year-old man with Hodgkin lymphoma (stage IIIB) is initiated on ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine). After the second cycle, he develops severe nausea, vomiting, and mucositis. Laboratory studies show a creatinine of 1.8 mg/dL (baseline 0.9) and uric acid of 12.2 mg/dL. He has not received adequate prophylaxis. Which component of the ABVD regimen is the alkylating agent, and what is the primary mechanism of its nephrotoxicity in this clinical context?

Explanation

## Dacarbazine: Alkylating Agent and Nephrotoxicity ### Dacarbazine Classification and Mechanism **Key Point:** Dacarbazine (DTIC) is a triazene prodrug and imidazole carboxamide that functions as an alkylating agent. It requires hepatic activation via cytochrome P450 to form the active alkylating metabolite monomethyl triazene (MMT). ### Nephrotoxicity Mechanism 1. **Hepatic activation**: Dacarbazine undergoes N-demethylation to form MMT, the active alkylating species. 2. **Renal accumulation**: Both parent drug and metabolites are excreted renally and concentrate in tubular fluid. 3. **Direct tubular injury**: The alkylating metabolites cause: - Direct DNA alkylation in proximal tubular epithelial cells - Acute tubular necrosis (ATN) - Elevation of serum creatinine and BUN 4. **Tumor lysis syndrome (TLS) contribution**: In this case, the elevated uric acid (12.2 mg/dL) and creatinine suggest concurrent TLS from rapid tumor cell death, which exacerbates renal dysfunction through: - Uric acid precipitation in renal tubules - Hyperkalemia and hyperphosphatemia - Acute kidney injury (AKI) ### Clinical Presentation of Dacarbazine Nephrotoxicity | Feature | Timing | Severity | | --- | --- | --- | | Elevated creatinine | 2–5 days post-infusion | Mild to moderate | | Elevated BUN | 2–5 days post-infusion | Mild to moderate | | Oliguria | Rare, only severe cases | Variable | | Hyperuricemia | Concurrent with TLS | Severe | | Electrolyte abnormalities | Concurrent with TLS | Variable | **High-Yield:** Dacarbazine is the alkylating agent in ABVD. Its nephrotoxicity is dose-dependent and can be mitigated by aggressive hydration, alkalinization of urine (to prevent uric acid precipitation), and allopurinol or rasburicase prophylaxis. **Clinical Pearl:** In lymphomas with high tumor burden (stage IIIB), TLS is a major risk. The combination of dacarbazine-induced direct tubular toxicity PLUS TLS-induced uric acid precipitation creates a "double hit" on renal function. This patient should have received allopurinol or rasburicase before chemotherapy initiation. **Mnemonic: DTIC = Dacarbazine Triazene Imidazole Carboxamide (alkylating agent)** ### Why Dacarbazine Over Other ABVD Components Dacarbazine is the only alkylating agent in ABVD: - **Doxorubicin**: Anthracycline; causes cardiotoxicity and oxidative stress, not direct tubular alkylation. - **Vinblastine**: Vinca alkaloid; microtubule inhibitor, not an alkylating agent. - **Bleomycin**: Glycopeptide antibiotic; causes pulmonary fibrosis and vascular injury, not alkylating-agent-type nephrotoxicity.