Shifting Paradigms for Suppressing Fibrosis in Kidney Transplants: Supplementing Perfusion Solutions With Anti-fibrotic Drugs

Abstract

Great efforts have been made toward addressing the demand for donor kidneys. One of the most promising approaches is to use kidneys from donation after circulatory death donors. These kidneys, however, suffer from more severe ischemia and reperfusion injury than those obtained via donation after brain death and are thus more prone to develop interstitial fibrosis and tubular atrophy. Even though machine perfusion is increasingly used to reduce ischemia and reperfusion injury, there are no effective treatments available to ameliorate interstitial fibrosis and tubular atrophy, forcing patients to resume dialysis, undergo re-transplantation, or suffer from premature death. Safe and effective anti-fibrotic therapies are therefore greatly desired. We propose a new therapeutic approach in which machine perfusion solutions are supplemented with anti-fibrotic compounds. This allows the use of higher concentrations than those used in humans whilst eliminating side effects in other organs. To the authors' knowledge, no one has reviewed whether such an approach could reduce interstitial fibrosis and tubular atrophy; we therefore set out to explore its merit. In this review, we first provide background information on ischemia and reperfusion injury as well as interstitial fibrosis and tubular atrophy, after which we describe currently available approaches for preserving donor kidneys. We then present an evaluation of selected compounds. To identify promising compounds, we analyzed publications describing the effects of anti-fibrotic molecules in precision-cut kidneys slices, which are viable explants that can be cultured ex vivo for up to a few days whilst retaining functional and structural features. LY2109761, galunisertib, imatinib, nintedanib, and butaprost were shown to exert anti-fibrotic effects in slices within a relatively short timeframe (<48 h) and are therefore considered to be excellent candidates for follow-up ex vivo machine perfusion studies.

Doxycycline Alters the Porcine Renal Proteome and Degradome during Hypothermic Machine Perfusion

“…Although further studies are needed to confirm whether the addition of doxycycline is beneficial during machine perfusion, the emergence of machine perfusion itself provides opportunities for marginal graft repair by means of ex vivo targeted drug delivery [69]. We have identified multiple pathways such as metabolic pathways and complement and coagulation pathways that show upregulated degradation during NMP.…”

Exploring Porcine Precision-Cut Kidney Slices as a Model for Transplant-Related Ischemia-Reperfusion Injury

“…PCKS have been widely implemented for kidney research as a model to study the metabolism, toxicity, and efficacy of drugs [42][43][44][45][46]. The advantage is that multiple compounds or conditions using the same kidney can be studied, therefore keeping biological differences minimal [47]. PCKS could provide a platform to investigate biopharmaceuticals that target IRI, inflammation, and fibrosis-related injury.…”

Cold but not too cold: advances in hypothermic and normothermic organ perfusion

“…HMP opens the possibility of evaluating kidney function with the intention to increase the number of available organs from ECD and DCD. NMP could be effective for the repair of kidneys either alone or by administration of various drugs [ 61 ]. Even immune modulation and other methods to reduce organ damage, such as the use of anti-inflammatory drugs, can be introduced.…”