Pharmacological optimization of ex vivo lung and kidney perfusion
Pharmacological optimization of ex vivo lung and kidney perfusion
Organ transplantation remains the gold standard for end-stage organ failure, yet a persistent global donor shortage forces transplant teams to rely increasingly on marginal organs. These organs are particularly vulnerable to ischemia-reperfusion injury (IRI), a pathophysiological process involving mitochondrial dysfunction, endothelial damage, reactive oxygen species (ROS) production, mitochondrial permeability transition pore (mPTP) opening, and downstream inflammatory cascades. Static cold storage (SCS), the current standard preservation method, fails to actively limit IRI, driving interest in normothermic machine perfusion (NMP) as a dynamic preservation platform that maintains physiological conditions, enables real-time organ assessment, and allows targeted therapeutic delivery.
This thesis of Shuqi Yang investigates the hypothesis that pharmacological interventions targeting core IRI mechanisms can improve organ quality during NMP. Two complementary strategies were studied: sevoflurane, a volatile anesthetic with pleiotropic protective effects on endothelial integrity, inflammation, and cellular homeostasis; and MitoQ, a mitochondria-targeted antioxidant designed to reduce oxidative stress and preserve mitochondrial function.
Studies examined technical feasibility, dose-response relationships, and organ-specific effects of sevoflurane during lung and kidney perfusion, alongside safety and efficacy of MitoQ during normothermic kidney perfusion. Results demonstrated clear organ-specific differences: sevoflurane showed concentration-dependent effects in EVLP, with low doses exerting anti-inflammatory and endothelial-protective effects, while higher doses optimized mechanical lung function. In kidney perfusion, both agents showed more limited and complex responses, highlighting that therapeutic windows cannot be extrapolated across organs. Validated outcome measures and organ-specific dosing strategies remain essential prerequisites for successful clinical translation.