Which alkylating agent is contraindicated in patients with severe renal impairment due to its nephrotoxic metabolites and is also associated with ototoxicity?

Explanation

## Cisplatin: Nephrotoxicity and Ototoxicity **Key Point:** Cisplatin is a platinum-based alkylating agent with dose-limiting nephrotoxicity and ototoxicity, making it contraindicated or requiring careful monitoring in patients with pre-existing renal impairment. ### Mechanism of Cisplatin Toxicity #### Nephrotoxicity 1. **Site of injury:** Proximal tubule cells of the kidney 2. **Mechanism:** Cisplatin accumulates in renal tubular cells and undergoes aquation, forming reactive species that bind to cellular proteins and DNA 3. **Result:** Acute tubular necrosis, elevated creatinine, and electrolyte wasting 4. **Prevention:** Aggressive hydration, mannitol diuresis, and amifostine (free radical scavenger) #### Ototoxicity 1. **Mechanism:** Damage to cochlear hair cells (outer hair cells more affected than inner) 2. **Pattern:** High-frequency hearing loss (typically 4–8 kHz) progressing to lower frequencies 3. **Irreversibility:** Often permanent and cumulative with dose 4. **Risk factors:** High cumulative dose, renal impairment, concurrent ototoxic drugs (aminoglycosides, loop diuretics) **High-Yield:** Cisplatin is the only alkylating agent with significant ototoxicity—this is a unique and testable feature. ### Dose-Limiting Toxicities of Alkylating Agents | Agent | Primary Dose-Limiting Toxicity | Secondary Toxicity | Renal Impact | |-------|--------------------------------|-------------------|-------------| | Cisplatin | Nephrotoxicity | Ototoxicity, neuropathy | Severe; contraindicated in renal disease | | Cyclophosphamide | Myelosuppression | Hemorrhagic cystitis | Minimal | | Melphalan | Myelosuppression | Secondary malignancy | Minimal | | Ifosfamide | Myelosuppression | Encephalopathy, cystitis | Moderate; requires hydration | **Mnemonic:** **CINO** — **C**isplatin → **I**otoxicity, **N**ephrotoxicity, **O**ther (neuropathy) **Clinical Pearl:** Cisplatin-induced nephrotoxicity is largely preventable with aggressive hydration (normal saline 1–2 L before and after infusion) and can be partially mitigated by amifostine, a cytoprotective agent that selectively protects normal tissues.