What is the mechanism by which cisplatin causes renal toxicity?

Mechanism of Cisplatin-Induced Renal Toxicity

Cisplatin causes renal toxicity primarily through direct tubular injury and acute tubular necrosis, resulting from DNA damage, oxidative stress, and activation of apoptotic pathways in renal tubular cells. 1, 2

Cellular Uptake and Accumulation

Cisplatin nephrotoxicity begins with its preferential accumulation in renal tubular cells through specific transporters:

• Cellular transporters: Human copper transport protein 1 (Ctr1) and organic cation transporter 2 (OCT2) facilitate cisplatin entry into renal tubular cells 2
• Renal cortex accumulation: Cisplatin concentrates in the renal cortex at levels higher than other tissues, explaining its selective nephrotoxicity 3
• Proximal tubule targeting: The S3 segment of proximal tubules is particularly vulnerable to cisplatin damage 4

Pathophysiological Mechanisms

Once inside renal cells, cisplatin causes damage through multiple pathways:

1. DNA damage:

   • Cross-linking with DNA, interfering with DNA replication 1
   • Formation of DNA adducts that trigger cell cycle arrest and apoptosis 2

2. Oxidative stress:

   • Depletion of glutathione and other cellular antioxidants 2
   • Generation of reactive oxygen species (ROS) 5
   • Reduction in sulfhydryl groups in kidney tissue 3

3. Mitochondrial dysfunction:

   • Disruption of mitochondrial membrane potential
   • Release of cytochrome c and activation of intrinsic apoptotic pathway 2

4. Inflammatory response:

   • Activation of pro-inflammatory cytokines and chemokines
   • Infiltration of inflammatory cells into renal tissue 6

5. Endoplasmic reticulum stress:

   • Disruption of protein folding
   • Activation of unfolded protein response 2

Histopathological and Clinical Manifestations

The nephrotoxic effects of cisplatin manifest as:

• Acute tubular injury and necrosis: Primary histopathological finding 1
• Proximal tubulopathy: Including cytoplasmic vacuolization, tubular dilatation, and pyknotic degeneration 3
• Electrolyte disturbances:
  • Hypomagnesemia (most common)
  • Hypocalcemia
  • Hypokalemia 7, 3
• Fanconi syndrome: Generalized proximal tubular dysfunction 1
• Nephrogenic diabetes insipidus: Impaired water reabsorption 1
• Sodium and magnesium wasting: Due to tubular transport defects 1

Time Course and Dose Relationship

• Onset: Renal dysfunction typically begins during the second week after cisplatin administration 8
• Manifestation: Elevations in BUN and creatinine, increased serum uric acid, and decreased creatinine clearance 8
• Dose-dependence: Nephrotoxicity is dose-related and cumulative, becoming more severe with repeated courses 8
• Incidence: Occurs in approximately 28-36% of patients receiving a single dose of 50 mg/m² 8
• Long-term effects: May cause up to 30% reduction in GFR, which can persist for years 7

Risk Factors

Several factors increase susceptibility to cisplatin nephrotoxicity:

• Advanced age: Elderly patients are more vulnerable 8
• Pre-existing renal impairment: Increases risk and severity 5
• Concomitant nephrotoxic medications: Particularly aminoglycosides 8
• Dehydration: Exacerbates renal injury 7
• Higher doses and rapid infusion rates: Increase risk (>50 mg/m² or >1 mg/kg per hour) 8, 3

Understanding these mechanisms is crucial for developing effective preventative strategies, including adequate hydration, magnesium supplementation, and appropriate dosing to minimize cisplatin-induced nephrotoxicity while maintaining its anticancer efficacy.