Pretransplant Screening for Prevention of Hyperacute Graft Loss in Pig-to-primate Kidney Xenotransplantation.

BACKGROUND: Xenotransplantation using pig organs is now a clinical reality. However, the process for xenograft recipient screening lacks clarity and scientific rigor: no established thresholds exist to determine which levels of preformed antipig natural antibodies (Nabs) will be safe for clinical xenograft transplantation, and hyperacute rejection (HAR) or acute humoral xenograft rejection (AHXR), which still impacts pig-to-primate kidney xenograft survivals, may impede broader application of pig-to-human clinical xenograft transplantation. METHODS: We retrospectively examined 28 cases of pig-to-baboon kidney xenotransplantation using GalTKO±human complement regulatory protein (hCRP)-transgenic (Tg) pig donors, as well as 6 cases of triple-KO multi-Tg (10GE) pig donors, and developed screening algorithms to predict risk of HAR/AHXR based on recipient antipig Nab levels. Preformed Nabs were evaluated using both complement-dependent cytotoxicity and antibody (IgM and IgG) binding flow-cytometry assays. RESULTS: High complement-dependent cytotoxicity was associated with HAR/AHXR as expected. However, we also found that high levels of IgG were independently associated with HAR/AHXR, and we developed 2 indices to interpret and predict the risk of IgG-mediated HAR/AHXR. CONCLUSIONS: Based on the data in this study, we have established a new 2-step screening, which will be used for future clinical kidney xenotransplantation trials.

Combined islet and kidney xenotransplantation for diabetic nephropathy: an update in ongoing research for a clinically relevant application of porcine islet transplantation.

Combined islet and kidney xenotransplantation for the treatment of diabetic nephropathy represents a compelling and increasingly relevant therapeutic possibility for an ever-growing number of patients who would benefit from both durable renal replacement and cure of the underlying cause of their renal insufficiency: diabetes. Here we briefly review immune barriers to islet transplantation, highlight preclinical progress in the field, and summarize our experience with combined islet and kidney xenotransplantation, including both challenges with islet-kidney composite grafts as well as our recent success with sequential kidney followed by islet xenotransplantation in a pig-to-baboon model.

Vascularized Islet Transplantation as Composite Islet-Kidney Grafts with Nanoparticle-Labeled Islets in Large Animal Preclinical Transplant Models.

Although there are many patients with diabetes and end-stage renal failure (DM/ESRD) who would benefit from a transplantation strategy that addresses both their ESRD and its underlying cause, current methods of islet and kidney transplantation using live donors have had only limited success. The first major obstacle is that the number of islets obtained from a live donor partial pancreatectomy is generally insufficient to cure diabetes in recipients, as large numbers of intraportally administered islets are lost due to ischemia before they are engrafted and vascularized in the recipient liver. To overcome this hurdle, we have developed a strategy to transplant islets as a vascularized graft. Autologous prevascularization of donor islets under the donor's own renal capsule prior to transplantation preserves islets and thus achieves normal glycemic control in diabetic recipients in our preclinical transplant models with a limited donor pancreas resection. In addition, from an immunological perspective, the innate tolerogenic qualities of the kidney provide immunoprotection for the engrafted, vascularized islets when they are transplanted as part of the composite islet-kidney (I-K) grafts. This "Trojan Horse" approach of transplanting a composite I-K eliminates the lengthy time which is otherwise required for vascularization of intraportally administered free islets, minimizing loss of islets to ischemic damage and facilitating the induction of tolerance. We have also recently developed a strategy to further minimize the required size of resected donor pancreas to prepare composite I-K graft using a novel, synthesized, small interfering RNA (siRNA)-nanoparticle probe. In this chapter, we introduce our living donor transplantation strategy to cure diabetic nephropathy using composite I-K graft.

Progress in Xenotransplantation: Immunologic Barriers, Advances in Gene Editing, and Successful Tolerance Induction Strategies in Pig-To-Primate Transplantation.

Organ transplantation is the most effective treatment for end stage organ failure, but there are not enough organs to meet burgeoning demand. One potential solution to this organ shortage is xenotransplantation using pig tissues. Decades of progress in xenotransplantation, accelerated by the development of rapid genome editing tools, particularly the advent of CRISPR-Cas9 gene editing technologies, have enabled remarkable advances in kidney and heart xenotransplantation in pig-to-nonhuman primates. These breakthroughs in large animal preclinical models laid the foundation for three recent pig-to-human transplants by three different groups: two kidney xenografts in brain dead recipients deemed ineligible for transplant, and one heart xenograft in the first clinical grade study of pig-to-human transplantation. However, despite tremendous progress, recent data including the first clinical case suggest that gene-modification alone will not overcome all xenogeneic immunologic barriers, and thus an active and innovative immunologic strategy is required for successful xenotransplantation. This review highlights xenogeneic immunologic barriers, advances in gene editing, and tolerance-inducing strategies in pig-to-human xenotransplantation.

Progress in islet xenotransplantation: Immunologic barriers, advances in gene editing, and tolerance induction strategies for xenogeneic islets in pig-to-primate transplantation.

Islet transplantation has emerged as a curative therapy for diabetes in select patients but remains rare due to shortage of suitable donor pancreases. Islet transplantation using porcine islets has long been proposed as a solution to this organ shortage. There have already been several small clinical trials using porcine islets in humans, but results have been mixed and further trials limited by calls for more rigorous pre-clinical data. Recent progress in heart and kidney xenograft transplant, including three studies of pig-to-human xenograft transplant, have recaptured popular imagination and renewed interest in clinical islet xenotransplantation. This review outlines immunologic barriers to islet transplantation, summarizes current strategies to overcome these barriers with a particular focus on approaches to induce tolerance, and describes an innovative strategy for treatment of diabetic nephropathy with composite islet-kidney transplantation.

The Impact of Increasing Surgical Capacity at a Tertiary Hospital in Southern Haiti.

BACKGROUND: St. Boniface Hospital (SBH) plays a critical role in providing safe, accessible surgery in rural southern Haiti. We examine the impact of SBH increasing surgical capacity on case volume, patient complexity, and inpatient mortality across three phases. MATERIALS AND METHODS: A retrospective review and geospatial analysis of all surgical cases performed at SBH between 2015 and 2017 were performed. Inpatient mortality was defined by in-hospital deaths divided by the number of procedures performed. RESULTS: Between February 2015 and August 2017, over 2000 procedures were performed. The average number of surgeries per week was 3.1 with visiting surgical teams in phase 1 (P1), 10.4 with a single general surgeon in phase 2 (P2), and 20.1 with two surgeons and a resident in phase 3 (P3). There was a six-fold increase in surgical volume between P1 and P3 and a significant increase in case complexity. The distribution of American Society of Anesthesiologists scores of 1, 2, 3, and 4 during P2 was 81.05%, 14.74%, 3.42%, and 0.79%, respectively, whereas in P3, the distribution was 68.91%, 22.55%, 7.70%, and 0.84%. Surgical mortality was 0%, 1.2%, and 1.67% across phases. CONCLUSIONS: Increasing resources and surgical staff at SBH allowed for greater delivery of safe surgical care. This study highlights that investing in surgery has a significant impact in regions of great surgical need.

Unusual Mechanism for Superior Mesenteric Artery Syndrome after Scoliosis Surgery.

t Superior Mesenteric Artery (SMA) syndrome is an uncommon condition caused by mechanical obstruction of the distal third of the duodenum between the superior mesenteric artery and the abdominal aorta. SMA syndrome is associated with both operative and non-operative corrections of scoliosis, as well as anorexia nervosa, severe weight loss, tumors, burns, and other traumas.[1-4] We report an unusual case of SMA syndrome following corrective surgery for scoliosis in which post-operative gastric distension caused duodenal compression that subsequently resolved with gastric decompression, as opposed to the conventional, reverse series of events in which SMA syndrome causes the gastric dilatation. [Full article available at http://rimed.org/rimedicaljournal-2017-08.asp].

Intraoperative Femur Fracture Risk During Primary Direct Anterior Approach Cementless Total Hip Arthroplasty With and Without a Fracture Table.

BACKGROUND: There is no study to date comparing intraoperative femur fractures (IFFs) in the direct anterior approach (DAA) with and without a fracture table. We hypothesize that there is no significant difference in the IFF with and without a fracture table when performed by experienced DAA hip surgeons. METHODS: This study is a 1-year retrospective review of patients who underwent DAA total hip arthroplasty by 2 surgeons: one surgeon uses a flat table and manually elevates the femur with a large bone hook, while the other surgeon uses a fracture table and a mechanical femoral elevator. Exclusion criteria included cemented femoral implants, femoral neck fractures, and lack of 6-month follow-up. RESULTS: We identified 487 patients for analysis (220 male and 267 female, average age 66.55 years). There were 12 total IFFs (2.46%): 8 female and 4 male patients. The average age of IFF patients was 70.67 years and in nonfracture patients was 66.00 years. There was no difference in gender (P = .2981) or age (P = .2099) between IFF and nonfracture patients. In the fracture table group, there were 6 IFFs (2.22%) in 271 patients; in the nonfracture table group, there were 6 IFFs (2.76%) in 216 patients. There was no statistical difference in IFF between the 2 groups (P = .6973). We observed just 2 patients (0.4%) in this series where the IFFs changed management requiring a revision femoral stem. CONCLUSION: There was no statistical difference in IFF with or without the use of fracture table. Both DAA surgical technique variations are felt to be equivalent regarding the risk for IFF during DAA cementless total hip arthroplasty.