Renal Delivery of Pharmacologic Agents During Machine Perfusion to Prevent Ischaemia-Reperfusion Injury: From Murine Model to Clinical Trials

Abstract

Donor organ shortage still remains a serious obstacle for the access of wait-list patients to kidney transplantation, the best treatment for End-Stage Kidney Disease (ESKD). To expand the number of transplants, the use of lower quality organs from older ECD or DCD donors has become an established routine but at the price of increased incidence of Primary Non-Function, Delay Graft Function and lower-long term graft survival. In the last years, several improvements have been made in the field of renal transplantation from surgical procedure to preservation strategies. To improve renal outcomes, research has focused on development of innovative and dynamic preservation techniques, in order to assess graft function and promote regeneration by pharmacological intervention before transplantation. This review provides an overview of the current knowledge of these new preservation strategies by machine perfusions and pharmacological interventions at different timing possibilities: in the organ donor, ex-vivo during perfusion machine reconditioning or after implementation in the recipient. We will report therapies as anti-oxidant and anti-inflammatory agents, senolytics agents, complement inhibitors, HDL, siRNA and H2S supplementation. Renal delivery of pharmacologic agents during preservation state provides a window of opportunity to treat the organ in an isolated manner and a crucial route of administration. Even if few studies have been reported of transplantation after ex-vivo drugs administration, targeting the biological pathway associated to kidney failure (i.e. oxidative stress, complement system, fibrosis) might be a promising therapeutic strategy to improve the quality of various donor organs and expand organ availability.

Balancing the View of C1q in Transplantation: Consideration of the Beneficial and Detrimental Aspects

“…This could be accomplished by eliminating CCR2 + C1q lo resident macrophages, while preserving CCR2 - C1q hi resident macrophages ( 31 ). Alternatively or additionally, biologically modified C1q could be added to the perfusate ( 65 ). Various mutant C1q molecules have been described that retain PRR function but lack binding sites for C1r or C1s ( 66 ).…”

Perfusate metabolomics content and tubular transporters expression during kidney graft preservation by hypothermic machine perfusion

“…However, our negative result is in line with a recent systematic review that highlighted the lack of accuracy and hindsight of metabolomics in human kidney graft perfusates 16 . The evaluation of perfusate metabolomics variations might still be relevant 25 , since it recently suggested a higher de novo metabolic activity of kidneys preserved on machine versus SCS 26 , or it could highlight the metabolic variations occurring with oxygen supplementation 27,28 or pharmacological agents 29,30 .…”

The Role of Ferroptosis in Acute Kidney Injury

“…IRI is also an important factor in contributing to AKI. The main pathophysiological mechanisms of renal IRI include inflammation, oxidative stress and lipid peroxidation, mitochondrial dysfunction, and activation of the renin-angiotensin system ( Franzin et al, 2021 ). A recent study suggests that ferroptosis may be one of the main drivers of renal IRI ( Tonnus and Linkermann, 2017 ).…”