Efficacy of cilastatin sodium in a translational large animal crush syndrome model

Background: Crush syndrome (consisting of hyperkalemia, acidosis, hypocalcemia, and acute kidney injury), is the second-most common cause of death in earthquakes, and a frequent cause of critical illness after burn, blast, and prolonged immobility. No specific treatment exists; supportive treatment is burdensome, contributing to deaths in austere environments, especially disasters and conflicts. There is urgent need for specific treatment which reduces burden of care. Crush syndrome is dependent on the renal megalin-dependent endocytic system. We investigated whether cilastatin sodium, a megalin inhibitor which is US Food and Drug Administration-approved for another purpose, has efficacy as a crush syndrome treatment in a highly translational large animal trauma model. Methods: Anesthetized 40 kg female pigs received blunt muscle injury and 48 h protocolized critical care management. Cilastatin sodium or vehicle was administered 30 minutes after injury in randomized, blinded fashion. Renal function and injury were assessed by repeated quantification of iohexol clearance, serial plasma assessment, and histopathologic analysis. Linear mixed models and Kaplan-Meier analysis were used to assess differences. A power estimate for a clinical trial was performed. Results: Here we show that cilastatin has efficacy to reduce kidney impairment from crush syndrome, resulting in increased measured glomerular filtration rate and reduced creatinine, histopathologic kidney damage, and need for treatment of hyperkalemia. Animals receiving cilastatin excrete more myoglobin in the urine and are more likely to recover from acute kidney injury. The effect size suggests feasibility of future clinical trials. Conclusions: Cilastatin sodium has efficacy to ameliorate crush syndrome in a translational large animal model These results support further efforts to translate this potential therapy.