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.

Keywords: IF/TA; IRI; donation after circulatory death (DCD); machine perfusion; personalized medicine; precision cut tissue slices; renal transplantation.

Figure 1

(A) Total number of organs transplanted worldwide. (B) Number of donors per donor type within Eurotransplant over the past 10 years. (C) Number of kidney transplants and active waiting list for a kidney transplant within Eurotransplant over the past 10 years. Data obtained from Global observatory on donation and transplantation in the year 2019 (6) and Eurotransplant (7). DBD, donation after brain death; DCD, donation after circulatory death; LD, living donor.

Figure 2

The process of donation after circulatory death, organ procurement, and transplantation. Created with BioRender.com.

Figure 3

Ischemia and reperfusion injury as a result of donation after circulatory death. ATP, adenosine triphosphate; ROS, reactive oxygen species. Created with BioRender.com.

Figure 4

Kidney repair after ischemia and reperfusion injury by means of fibrogenesis and tubular dedifferentiation. TNF-α, tumor necrosis factor; IL-6, Interleukin; IL-β1, interleukin 1β; TGF-ß, transforming growth factor. Created with BioRender.com.

Figure 5

Chronic injury and development of interstitial fibrosis and tubular atrophy (IF/TA). Continuous activation of myofibroblasts cause excessive deposition of extracellular matrix (ECM). Given enough time, the dense, fibrotic ECM perpetuates myofibroblast activation. Tubular dedifferentiation is impeded by cell senescence and apoptosis. Pathways such as the platelet-derived growth factor (PDGF) and the transforming growth factor (TGF-ß) SMAD2/3 pathway play a key role in myofibroblast activation and therefore represent promising drug targets. TNF-α, tumor necrosis factor; IL-6, Interleukin 6; IL-1β, interleukin 1β. Created with BioRender.com.

Figure 6

Current strategies for preserving donor kidneys. Created with BioRender.com.

Figure 7

Workflow for preparing precision-cut kidney slices (PCKS). First, cores are drilled from the renal cortex and sliced using a Krumdieck tissue slicer. Next, PCKS are transferred to culture plates with fresh culture medium containing nutrients and antibiotics, as well as compounds of choice. Finally PCKS can be incubated for up to 72 h (82). Created with BioRender.com.

Figure 8

Potential compounds to limit the development of post-transplant fibrosis and their mechanism of action. PDGF: platelet-derived growth factor, TGF-β, transforming growth factor beta; PGE₂, Prostaglandin E₂. Created with BioRender.com.