How does cisplatin cause AKI and proximal tubule injury?
Cisplatin is a platinum-based agent whose nephrotoxicity is thought related to the chloride in the cis position. Cisplatin gains entry into tubular cells via uptake by the OCT-2 system on the basolateral membrane of proximal tubular cells.
• Cellular apoptosis/necrosis develops due to endoplasmic reticulum-induced stress, mitochondrial injury pathways, and a death receptor pathway.
• Normal cell-cycle regulation is disrupted by cisplatin, leading to tubular apoptosis and kidney injury.
• Cisplatin-induced DNA damage activates p53, which through various intracellular signals promotes cell apoptosis.
• Cisplatin stimulates production of reactive oxygen species and oxidative stress by depleting and inactivating glutathione and other related antioxidants.
• Cisplatin induces both inflammation and vascular injury, which further promotes kidney injury.
In addition to AKI, cisplatin causes proximal tubulopathy, salt wasting, loss of urinary concentrating ability, and magnesium wasting.
