swine models of kidney transplant

One of the prerequisites for successful organ xenotransplantation is a reasonable size match between the porcine organ and the recipient's organ to be replaced. Therefore, the selection of a suitable genetic background of source pigs is important. In this study, we investigated body and organ growth, cardiac function, and genetic diversity of a colony of Auckland Island pigs established at the Center for Innovative Medical Models (CiMM), LMU Munich. Male and female Auckland Island pig kidney cells (selected to be free of porcine endogenous retrovirus C) were imported from New Zealand, and founder animals were established by somatic cell nuclear transfer (SCNT)...

BACKGROUND: Polyclonal rabbit antithymocyte globulins (ATGs) are commonly used in organ transplantation as induction. Anti-N-glycolylneuraminic acid carbohydrate antibodies which develop in response to rabbit carbohydrate antigens might lead to unwanted systemic inflammation. LIS1, the first new generation of antilymphocyte globulins (ALGs) derived from double knockout swine, lacking carbohydrate xenoantigens was already tested in nonhuman primates and rodent models. METHODS: This open-label, single-site, dose escalation, first-in-human, phase 1 study evaluated the safety, T cell depletion, pharmacokinetics, and pharmacodynamics of LIS1...

UNLABELLED: Presensitized patients awaiting a kidney transplant have a lower graft survival and a longer waiting time because of the limited number of potential donors and the higher risk of antibody-mediated rejection (AMR), particularly in the early posttransplant period, because of preformed donor-specific antibodies binding major histocompatibility complex (MHC) molecules expressed by the graft endothelium followed by the activation of the complement. Advances in kidney preservation techniques allow the development of ex vivo treatment of transplants...

Anti-thymocyte or anti-lymphocyte globulins (ATGs/ALGs) are immunosuppressive drugs used in induction therapies to prevent acute rejection in solid organ transplantation. Because animal-derived, ATGs/ALGs contain highly immunogenic carbohydrate xenoantigens eliciting antibodies that are associated with subclinical inflammatory events, possibly impacting long-term graft survival. Their strong and long-lasting lymphodepleting activity also increases the risk for infections. We investigated here the in vitro and in vivo activity of LIS1, a glyco-humanized ALG (GH-ALG) produced in pigs knocked out for the two major xeno-antigens αGal and Neu5Gc...

Organ transplantations have an increasing medical relevance. It is becoming a regular procedure with an increase in individuals waiting for organs.The increase in the number of discarded organs is mostly due to the donor bacterial and/or viral infection. In this article, we are demonstrating the feasibility of reduction of the bacterial load in kidney model by using Ultraviolet-C (UV-C) as a germicidal agent in circulating liquids. Using Staphylococcus aureus as a bacteria model, we were able to demonstrate that in less than 30 min of liquid circulation and associated to irradiation, the bacterial load of the perfusate Custodiol® HTK, histidine-tryptophan-ketoglutarate (solution with 5 log CFU mL-1 ), was fully eliminated...

Pigs, or Sus scrofa domestica, are commonly used animal models in translational transplantation research due to their anatomical, physiological, and immunological similarities to humans. In solid organ transplantation studies, immunosuppressive medications may be administered to pigs to prevent rejection. We provide an overview of the immunosuppressive regimens used in allogeneic solid organ transplantation in pigs, including heart, lung, kidney, bowel and cotransplanted organs and focus on the use of tacrolimus, mycophenolate mofetil, and corticosteroids...

Renal ischemia-reperfusion injury is an important contributor to the development of delayed graft function, which is associated with higher rejection rates and worse long-term outcomes of the allografts. One of the earliest impairments during ischemia is insufficient ATP supply-induced Na/K pump dysfunction, which results in subsequent cellular damage. Consequently, strategies that preserve ATP levels or Na/K pump function may limit the extent of renal injury during ischemia-reperfusion. In this study, we developed a novel technique that applies an oscillating electrical field to first synchronize the pump molecules, and then modulate their pumping rates...

Organ transplantations have an increasing medical relevance. It is becoming a regular procedure with an increase in individuals waiting for organs. The increase in the number of discarded organs is mostly due to the donor bacterial and/or viral infection. In this article, we are demonstrating the feasibility of reduction of the bacterial load in kidney model by using ultraviolet-C as a germicidal agent in circulating liquids. Using Staphylococcus aureus as a bacteria model, we were able to demonstrate that in less than 30 min of liquid circulation and associated to irradiation, the bacterial load of the perfusate Custodiol HTK, histidine-tryptophan-ketoglutarate (solution with 5 log CFU mL-1 ), was fully eliminated...

BACKGROUND: It is necessity to maintain donor kidneys at a low temperature for laparoscopic orthotopic kidney transplantation (LOKT). We recently designed a controllable double-cycle cryogenic device (DCD) with a safer and more effective cooling setting. This study aimed to evaluate the safety and efficacy of this device in a swine model. METHODS: A total of 20 pigs were procured for this study. We performed LOKT on 8 pigs using the controllable DCD for hypothermia, on another 8 pigs using the silicon tube cage (STC) for hypothermia, and on 4 pigs as the control group with no hypothermia measures (NH)...

BACKGROUND: Nephrotic syndrome is a common complication of pig-to-baboon kidney xenotransplantation (KXTx) that adversely affects outcomes. We have reported that upregulation of CD80 and down-regulation of SMPDL-3b in glomeruli have an important role in the development of proteinuria following pig-to-baboon KXTx. Recently we found induced expression of human CD47 (hCD47) on endothelial cells and podocytes isolated from hCD47 transgenic (Tg) swine markedly reduced phagocytosis by baboon and human macrophages...

Pentraxins are a family of evolutionarily conserved pattern recognition molecules with pivotal roles in innate immunity and inflammation, such as opsonization of pathogens during bacterial and viral infections. In particular, the long Pentraxin 3 (PTX3) has been shown to regulate several aspects of vascular and tissue inflammation during solid organ transplantation. Our study investigated the role of PTX3 as possible modulator of Complement activation in a swine model of renal ischemia/reperfusion (I/R) injury...

PURPOSE: Although transplanting two kidneys from a single donor to two recipients has some advantages, the right and left kidneys are not anatomically identical; thus, a surgical procedure considering the anatomical features of the donor kidneys is needed when transplanting them into the opposite renal fossae. Based on vast experience, the surgical details of pig orthotopic kidney transplantation from one donor to two recipients was reported. METHODS: When the right kidney was transplanted to the left renal fossa, the graft was inverted upside down, not backwards, thus ensuring that the anteroposterior relationship of the renal vessels was maintained and anatomically natural vascular anastomosis could be performed...

In swine and nonhuman primates, kidney allografts can induce tolerance of heart allografts, leading to their long-term, immunosuppression-free survival. We refer to this phenomenon as kidney-induced cardiac allograft tolerance (KICAT). In this study, we have developed a murine model for KICAT to determine the underlining cellular/molecular mechanisms. Here, we show that spontaneously accepted DBA/2J kidneys in C57BL/6 recipients induce systemic tolerance that results in the long-term acceptance of DBA/2J heart allografts but not third-party cardiac allografts...

Acute kidney injury is a common clinical disorder and one of the major causes of morbidity and mortality in the postoperative period. In this study, the safety and efficacy of autologous mitochondrial transplantation by intra-arterial injection for renal protection in a swine model of bilateral renal ischemia-reperfusion injury were investigated. Female Yorkshire pigs underwent percutaneous bilateral temporary occlusion of the renal arteries with balloon catheters. Following 60 min of ischemia, the balloon catheters were deflated and animals received either autologous mitochondria suspended in vehicle or vehicle alone, delivered as a single bolus to the renal arteries...

BACKGROUND: Our initial studies utilizing a galactosyl-α1-3-galactosyltransferase gene knockout (GalTKO) pig-to-baboon renal transplant model demonstrated that the early development of nephrotic syndrome has been a significant obstacle to the long-term survival of baboon recipients. We have recently documented that sphingomyelin phosphodiesterase-3 (SMPDL3b) and CD80 expressed on podocytes in porcine kidney grafts contribute to this complication. We have hypothesized that one regulator of immune function is CD47 and that incompatibilities in CD47 between pig and baboon could potentially affect macrophage function, increasing the susceptibility of the kidney grafts to immunologically induced injury...

Over 100,000 patients in the United States are currently waiting for a kidney transplant. With just over 10,000 cadaveric kidneys transplanted annually, it is of the utmost importance to optimize kidney viability upon transplantation. One exciting avenue may be xenotransplantation, which has rejuvenated interest after advanced gene editing techniques have been successfully used in swine. Simultaneously, acute kidney injury (AKI) is associated with high morbidity and mortality and currently lacks effective treatment...

Pericytes are one of the principal sources of scar-forming myofibroblasts in chronic kidneys disease. However, the modulation of pericyte-to-myofibroblast transdifferentiation (PMT) in the early phases of acute kidney injury is poorly understood. Here, we investigated the role of complement in inducing PMT after transplantation. Using a swine model of renal ischemia/reperfusion (I/R) injury, we found the occurrence of PMT after 24 h of I/R injury as demonstrated by reduction of PDGFRβ+ /NG2+ cells with increase in myofibroblasts marker αSMA...

In islet transplantation, in addition to immunologic and ischemic factors, the diabetic/hyperglycemic state of the recipient has been proposed, although not yet validated, as a possible cause of islet toxicity, contributing to islet loss during the engraftment period. Using a miniature swine model of islet transplantation, we have now assessed the effect of a persistent state of hyperglycemia on islet engraftment and subsequent function. An islet-kidney (IK) model previously described by our laboratory was utilized...

Renal transplantation has become the preferred treatment for end stage kidney failure. Although short-term graft survival has significantly improved as advances in immunosuppression have occurred, long-term patient and graft survival have not. Approximately only 50% of renal transplant recipients are alive at 10 years due to the toxicities of immunosuppression and alloimmunity. Emerging research on cell-based therapies is opening a new door for patients to receive the organs they need without sacrificing quality of life and longevity because of drug-based immunosuppression...

Pigs represent a desirable animal model for the study of rejection in kidney transplantation with inbred Yucatan miniature swine (YMS) the most commonly studied strain due to well defined swine leukocyte antigen (SLA) genotypes. However, limitations to YMS may include cost and availability. Outbred Yorkshire pigs are widely available and significantly cheaper than YMS. Recent advances in SLA genotyping have allowed its application to outbred strains. On this basis, we theorized that Yorkshire pigs would be a viable alternative to YMS for the study of rejection in kidney transplantation...