The complement system is an essential component of innate immunity and plays a major role in the pathogenesis of ischemia-reperfusion injury (IRI). In this study, we investigated the impact of human C1-inhibitor (C1INH) on the early inflammatory response to IRI and the subsequent progression to fibrosis in mice. We evaluated structural damage, renal function, acute inflammatory response, progression to fibrosis and overall survival at 90-days post-injury. Animals receiving C1INH prior to reperfusion had a significant improvement in survival rate along with superior renal function when compared to vehicle (PBS) treated counterparts. Pre-treatment with C1INH also prevented acute IL-6, CXCL1 and MCP-1 up-regulation, C5a release, C3b deposition and infiltration by neutrophils and macrophages into renal tissue. This anti-inflammatory effect correlated with a significant reduction in the expression of markers of fibrosis alpha smooth muscle actin, desmin and picrosirius red at 30 and 90 days post-IRI and reduced renal levels of TGF-β1 when compared to untreated controls. Our findings indicate that intravenous delivery of C1INH prior to ischemic injury protects kidneys from inflammatory injury and subsequent progression to fibrosis. We conclude that early complement blockade in the context of IRI constitutes an effective strategy in the prevention of fibrosis after ischemic acute kidney injury.

Organ transplantation is characterized by a sequence of steps that involve operative trauma, organ preservation, and ischemia-reperfusion injury in the transplant recipient. During this process, the release of damage-associated molecular patterns (DAMPs) promotes the activation of innate immune cells via engagement of the toll-like receptor (TLR) system, the complement system, and coagulation cascade. Different classes of effector responses are then carried out by specialized populations of macrophages, dendritic cells, and T and B lymphocytes; these play a central role in the orchestration and regulation of the inflammatory response and modulation of the ensuing adaptive immune response to transplant allografts. Organ function and rejection of human allografts have traditionally been studied through the lens of adaptive immunity; however, an increasing body of work has provided a more comprehensive picture of the pivotal role of innate regulation of adaptive immune responses in transplant and the potential therapeutic implications. Herein we review literature that examines the repercussions of inflammatory injury to transplantable organs. We highlight novel concepts in the pathophysiology and mechanisms involved in innate control of adaptive immunity and rejection. Furthermore, we discuss existing evidence on novel therapies aimed at innate immunomodulation and how this could be harnessed in the transplant setting.

Background. Kidney transplant recipients (KTRs) are a vulnerable immunocompromised population at risk of severe COVID-19 disease and mortality after SARS-CoV-2 infection. We sought to characterize the post-infection sequelae in KTRs at our center. Methods. We studied all adult KTRs (with a functioning allograft) who had their first episode of SARS-CoV-2 infection between 04/2020 and 04/2022. Outcomes of interest included risk factors for hospitalization, all-cause mortality, COVID-19-related mortality, and allograft failure. Results. Of 979 KTRs with SARS-CoV-2 infection, 381 (39) were hospitalized. In the multivariate analysis, risk factors for hospitalization included advanced age/year (HR: 1.03, 95 CI: 1.021.04), male sex (HR: 1.29, 95 CI: 1.041.60), non-white race (HR: 1.48, 95 CI: 1.171.88), and diabetes as a cause of ESKD (HR: 1.77, 95 CI: 1.412.21). SARS-CoV-2 Vaccination was associated with decreased risk of hospitalization (HR: 0.73, 95 CI: 0.590.90), all-cause mortality (HR: 0.52, 95 CI: 0.370.74), and COVID-19-related mortality (HR: 0.47, 95 CI: 0.310.71) in the univariate and multivariate analyses. Risk factors for both all-cause and COVID-19-related mortality in the multivariate analyses included advanced age, hospitalization, and respiratory symptoms for hospital admission. Furthermore, additional risk factors for all-cause mortality in the multivariate analysis included being a non-white recipient and diabetes as a cause of ESKD, with being a recipient of a living donor as protective. Conclusions. Hospitalization due to COVID-19-associated symptoms is associated with increased mortality. Vaccination is a protective factor against hospitalization and mortality.

Diabetes mellitus remains a leading cause of morbidity worldwide, driven in type 1 diabetes by autoimmune destruction of pancreatic β-cells and in advanced type 2 diabetes by progressive β-cell dysfunction and failure. Diabetes affects around 830 million people globally, with the vast majority residing within low- and middle-income nations. Over the last few decades, the numbers of people who have diabetes and those with untreated diabetes have consistently increased. Although current pharmacologic therapies improve glycemic control, they do not restore functional β-cell mass. Consequently, strategies aimed at protecting, regenerating, or replacing insulin-producing cells have emerged as a major focus of regenerative medicine. Stem cell-based approaches offer the potential to generate renewable sources of glucose-responsive β-like cells, but challenges remain in achieving full functional maturation, immune protection, scalable manufacturing, and durable clinical engraftment. This review examines advances in engineering stem cell-derived insulin-producing cells for islet replacement therapy, with an emphasis on differentiation strategies, immunoprotective approaches, and the translational barriers that must be addressed for durable β-cell replacement.

Background.: Normothermic regional perfusion (NRP) is an organ procurement technique developed for donation after circulatory death (DCD). NRP is associated with better liver transplant outcomes and allows increased risk thresholds for medically complex DCD donors. DCD donors on extracorporeal membrane oxygenation (ECMO) are a category of medically complex donors lacking significant reported experience. Objectives.: This brief report describes the utilization of liver grafts from ECMO-DCD donors using an NRP procurement technique. Methods.: Retrospective analysis of donor and recipient outcomes in 3 cases following abdominal DCD-NRP with ECMO cannula exchange to an NRP circuit. Existing cannulas and tubing can be used for NRP inflow, outflow, or both depending on the configuration. Results.: All donors were older than the age of 50 y and had a functional warm ischemia time of <30 min. NRP duration ranged from 66 to 134 min. All 3 donors demonstrated lactate clearance while on NRP. Recipient age ranged from 52 to 68 and model for end-stage liver disease scores were 22, 26, and 7. All had a 1-d intensive care unit stay and 5- to 7-d total hospital length of stay. One of the 3 recipients had a biliary anastomotic stricture. Conclusions.: This report demonstrates the technical and clinical feasibility of liver transplantation from ECMO-DCD-NRP donors. Preoperative planning for the utilization of existing cannulas, the addition of needed inflow or outflow, and circuit exchange logistics is essential for a smooth transition to NRP in these cases.

Background.: Donation after circulatory death (DCD) is the major contributor to the growth in deceased organ donation in the United States. Normothermic regional perfusion (NRP) and ex situ machine perfusion (es-MP) have been vital for improving organ assessment and preservation in DCD donor organs. The procurement procedure and storage strategy for noncardiac donors were determined by liver transplant centers in the early era of machine perfusion in the United States. In this study, we analyzed the landscape of liver utilization from noncardiac DCD donors in the United States during the early era of machine perfusion. Methods.: All adult (18 y and older) DCD donors in the United States for which the heart was not used for transplantation from October 1, 2020, to December 31, 2023, were compared using procurement technique (NRP versus super rapid recovery [SRR]) and storage strategy (ex situ machine perfusion [es-MP] versus static cold storage). Results.: One hundred fifty-six livers were transplanted from 284 NRP donors (55% utilization) versus 2497 liver transplants from 9132 SRR donors (27% utilization). Es-MP was used in 19% (n = 30) of liver NRP cases versus 28% (n = 695) of liver SRR cases. Eight hundred fifty-one liver grafts (32%) were exposed to NRP, es-MP, or both. Conclusions.: Given the variation in liver graft management, further research needs to be conducted on the optimal strategies for using technologies such as NRP and es-MP in liver transplantation in the United States; better data collection is necessary to support this research and additional strategies are required to increase access to machine perfusion on a national level are needed.