Remaining Physiological Barriers in Porcine Kidney Xenotransplantation: Potential Pathways behind Proteinuria as well as Factors Related to Growth Discrepancies following Pig-to-Kidney Xenotransplantation

Abstract

Considerable shortages in the supply of available organs continue to plague the field of solid organ transplantation. Despite changes in allocation, as well as the utilization of extended criteria and living donors, the number of patients waiting for organs continues to grow at an alarming pace. Xenotransplantation, cross-species solid organ transplantation, offers one potential solution to this dilemma. Previous extensive research dedicated to this field has allowed for resolution of xenograft failure due to acute rejection, leaving new areas of unresolved challenges as barriers to success in large animal models. Specific to kidney xenotransplantation, recent data seems to indicate that graft compromise can occur due to discrepancies in growth between breeds of donors and significant proteinuria leading to nephrotic syndrome in the recipient. Given these potential limitations, herein, we review potential pathways behind proteinuria, as well as potential causative factors related to growth discrepancies. Control of both of these has the potential to allow xenotransplantation to become clinically applicable in an effort to resolve this organ shortage crisis.

The potential role of 3D-bioprinting in xenotransplantation

“…It is unclear whether a specific genetically-engineered pig will be ideal as a source of several different organs (kidneys, heart, liver, lungs), or whether it will be necessary to have organ-specific genetically-engineered pigs (because of organ-specific heterogeneity and immunogenicity). New technology, such as 3D-bioprinting, and even computational calculations [54*], may help us to obtain information we require (rapidly and less expensive), and thus help us to understand the remaining pathobiological and physiological barriers to that need to be overcome [55*-56].…”

Immunogenetics of xenotransplantation

“…Kidney pre‐clinical xenotransplantation studies have shown a significant increase in survival rate of life‐supporting xenografts during this last decade, from a maximum of 90–260 days (Cooper et al., 2014; Iwase et al., 2017). However, there are still major issues that remain to be solved such as differences in xenograft growth rate between donor and recipient, proteinuria appearance and selection of an adequate immunosuppressive regimen (Shah et al., 2018).…”

Clinical impact of high-profile animal-based research reported in the UK national pressClinical impact of high-profile animal-based research reported in the UK national press

“…53 A 2018 review noted that, while survival had increased over the years (decades) 'from days to months', 'additional barriers due to antigenic and physiologic differences in cross-species transplantation continue to remain a challenge'. 55 Ongoing work towards human trials centres around increasing 'tolerance' via multiple genetic modifications Open access of pigs, targeting the many (and increasing) antigens involved in organ rejection. The current level of immunosuppression required to prolong survival post-XTP is still unacceptably high, and so even greater genetic modification of pig donors is necessary.…”

“…56 This is already high: multitransgenic pig kidneys containing five modified genes have been tested in baboons: one combination allowed survival of 6 months or more, while another still resulted in serious problems, leading to the conclusion that 'the exact responsible genes have yet to be identified'. 55 It therefore must be asked; how much genetic modification might permit an adequate level of survival? And, even if it were possible, could it ever be enough?…”