Reparative and Regenerative Effects of Mesenchymal Stromal Cells-Promising Potential for Kidney Transplantation?

Mesenchymal stromal cells (MSCs) possess reparative, regenerative and immunomodulatory properties. The current literature suggests that MSCs could improve kidney transplant outcome via immunomodulation. In many clinical domains, research has also focussed on the regenerative and reparative effects of therapies with MSCs. However, in the field of transplantation, data on this subject remain scarce. This review provides an overview of what is known about the regenerative and reparative effects of MSCs in various fields ranging from wound care to fracture healing and also examines the potential of these promising MSC properties to improve the outcome of kidney transplantations

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

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

Molecular Aspects of Volatile Anesthetic-Induced Organ Protection and Its Potential in Kidney Transplantation

Ischemia reperfusion injury (IRI) is inevitable in kidney transplantation and negatively impacts graft and patient outcome. Reperfusion takes place in the recipient and most of the injury following ischemia and reperfusion occurs during this reperfusion phase; therefore, the intra-operative period seems an attractive window of opportunity to modulate IRI and improve short- and potentially long-term graft outcome. Commonly used volatile anesthetics such as sevoflurane and isoflurane have been shown to interfere with many of the pathophysiological processes involved in the injurious cascade of IRI. Therefore, volatile anesthetic (VA) agents might be the preferred anesthetics used during the transplantation procedure. This review highlights the molecular and cellular protective points of engagement of VA shown in in vitro studies and in vivo animal experiments, and the potential translation of these results to the clinical setting of kidney transplantation

The First ITS Meeting

The first International Transplant Science (ITS) meeting jointly organized by AST, ESOT and TTS was held on November 10-13, 2019 in Clearwater, Florida, to focus on issues related to the basic and translational science of immunology and transplantation. The 148 participants included international experts in transplantation, immunology, cell biology and organ engineering, as well as young investigators and trainees in these areas. The objectives of the meeting were to (1) introduce and discuss the latest discoveries, technologies and concepts in basic science of relevance to transplantation; (2) provide opportunities for every trainee and young investigators to present their work in mini-oral and mentored poster sessions; (3) have programmed networking opportunities to allow for the free exchange of ideas and developing new collaborations. Participants came away from the meeting inspired by the quality of science presented, excited by the opportunities to discuss science with fellow attendees, and enthusiasm for the next ITS meeting in 2020 in Europe

Normothermic machine perfusion of ischaemically damaged porcine kidneys with autologous, allogeneic porcine and human red blood cells

In porcine kidney auto-transplant models, red blood cells (RBCs) are required for ex-vivo normothermic machine perfusion (NMP). As large quantities of RBCs are needed for NMP, utilising autologous RBCs would imply lethal exsanguination of the pig that is donor and recipient-to-be in the same experiment. The purpose of this study was to determine if an isolated porcine kidney can also be perfused with allogeneic porcine or human RBCs instead. Porcine kidneys, autologous and allogeneic blood were obtained from a local slaughterhouse. Human RBCs (O-pos), were provided by our transfusion laboratory. Warm ischaemia time was standardised at 20 minutes and subsequent hypothermic machine perfusion lasted 1.5–2.5 hours. Next, kidneys underwent NMP at 37°C during 7 hours with Williams’ Medium E and washed, leukocyte depleted RBCs of either autologous, allogeneic, or human origin (n = 5 per group). During perfusion all kidneys were functional and produced urine. No macroscopic adverse reactions were observed. Creatinine clearance during NMP was significantly higher in the human RBC group in comparison with the allogeneic group (P = 0.049) but not compared to the autologous group. The concentration of albumin in the urine was significantly higher in the human RBC group (P <0.001) compared to the autologous and allogeneic RBC group. Injury marker aspartate aminotransferase was significantly higher in the human RBC group in comparison with the allogeneic group (P = 0.040) but not in comparison with the autologous group. Renal histology revealed glomerular and tubular damage in all groups. Signs of pathological hyperfiltration and microvascular injury were only observed in the human RBC group. In conclusion, perfusion of porcine kidneys with RBCs of different origin proved technically feasible. However, laboratory analysis and histology revealed more damage in the human RBC group compared to the other two groups. These results indicate that the use of allogeneic RBCs is preferable to human RBCs in a situation where autologous RBCs cannot be used for NMP

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

Ischemia-reperfusion injury (IRI) is a hallmark for tissue injury in donation after circulatory death (DCD) kidneys. The implementation of hypothermic machine perfusion (HMP) provides a platform for improved preservation of DCD kidneys. Doxycycline administration has shown protective effects during IRI. Therefore, we explored the impact of doxycycline on proteolytic degradation mechanisms and the urinary proteome of perfused kidney grafts. Porcine kidneys underwent 30 min of warm ischemia, 24 h of oxygenated HMP (control/doxycycline) and 240 min of ex vivo reperfusion. A proteomic analysis revealed distinctive clustering profiles between urine samples collected at T15 min and T240 min. High-efficiency undecanal-based N-termini (HUNTER) kidney tissue degradomics revealed significantly more proteolytic activity in the control group at T-10. At T240, significantly more proteolytic activity was observed in the doxycycline group, indicating that doxycycline alters protein degradation during HMP. In conclusion, doxycycline administration during HMP led to significant proteomic and proteolytic differences and protective effects by attenuating urinary NGAL levels. Ultimately, we unraveled metabolic, and complement and coagulation pathways that undergo alterations during machine perfusion and that could be targeted to attenuate IRI induced injury

Ischemia and reperfusion injury in kidney transplantation : relevant mechanisms in injury and repair

Ischemia and reperfusion injury (IRI) is a complex pathophysiological phenomenon, inevitable in kidney transplantation and one of the most important mechanisms for non- or delayed function immediately after transplantation. Long term, it is associated with acute rejection and chronic graft dysfunction due to interstitial fibrosis and tubular atrophy. Recently, more insight has been gained in the underlying molecular pathways and signalling cascades involved, which opens the door to new therapeutic opportunities aiming to reduce IRI and improve graft survival. This review systemically discusses the specific molecular pathways involved in the pathophysiology of IRI and highlights new therapeutic strategies targeting these pathways

The impact of donor pancreas extraction time on graft survival and postoperative complications in pancreas transplant recipients

Background: Simultaneous pancreas kidney transplantation (SPK) is the best therapeutic option for patients with diabetes mellitus type 1 and end-stage renal disease. Recently, donor organ extraction time has been shown to affect kidney and liver graft survival. This study aimed to assess the effect of pancreas donor extraction time on graft survival and postoperative complications. Methods: We retrospectively analyzed all pancreas transplants performed in two Eurotransplant centers. The association of pancreas extraction time with pancreas graft survival was analyzed by a Cox proportional hazards regression analysis after 3 months, 1 and 5 year. Besides, the effect of pancreas extraction time on the incidence of severe postoperative complications was analyzed. Results: A total of 317 pancreas transplants were included in this study. Death-censored pancreas graft survival was 85.7% after one year and 76.7% after five years. Median pancreas donor extraction time was 64 min [IQR: 52-79 min]. After adjustment for potential confounders, death censored graft survival after 30 days (HR 1.01, 95% CI 0.9-1.03 (p = 0.23), 1 year (HR 1.01, 95% CI 0.99-1.03 (p = 0.22) and 5 years (HR 1.00, 95% CI 0.99-1.02 (p = 0.57) was not associated with pancreas donor extraction time. However, extraction time was significantly associated with a higher incidence of Clavien-Dindo >3 complications compared to Clavien-Dindo 1 + 2 complications: OR 1.012, 95% CI 1.00-1.02 (p = 0.039). Conclusions: Our findings suggest that although no effect on graft survival was found, limiting pancreas extraction time can have a significant impact on lowering postoperative complications