Hypoxic/ischemic proximal tubular necrosis results in activation of cysteine protease pathways involving calpains and both caspase-1 (an inflammatory caspase) and caspase-3 (an executioner caspase involved in apoptosis). Calpain is activated both by increased free cytosolic Ca2+ and decreased calpastatin. Calpain then activates caspase-1, which stimulates the inflammatory cytokine IL-18. The executioner caspase-3 cleaves calpastatin (