Modelling acute antibody-mediated rejection of human kidney transplants using ex-vivo warm machine perfusion.

BACKGROUND: Transplant rejection is a major cause of graft loss and morbidity. Currently, no human models of antibody-mediated rejection (AMR) exist, limiting mechanistic investigation and organ-specific targeted therapy. Here, using 12 human kidneys and ex-vivo normothermic machine perfusion, we demonstrate phenotypes of AMR after addition of antibodies against either human HLA class I or blood group antigens (A, B), thus modelling clinical AMR that can follow HLA incompatible (HLAi) or blood group incompatible (ABOi) transplantation. METHODS: Discarded human kidneys with wide ranging demographics and cold ischaemia times (11-54 h) were perfused with red blood cells and fresh frozen plasma (FFP) as a source of complement/coagulation factors. For the HLAi model, 600 µg of W6/32 anti-class 1 HLA antibody was added to the circuit (time '0'). For the ABOi model, high titre FFP of the relevant blood group antibody was added. Renal blood flow index (RBFi, mL/min/100 g), C3 desArg, prothrombin fragments 1 + 2 and histology were determined. Our endpoints included haemodynamic changes, thrombosis, and biopsy proven complement deposition. FINDINGS: Compared to control kidneys perfused without anti-donor antibodies, both models demonstrated haemodynamic collapse after antibody perfusion with only the HLAi model showing glomerular C4d deposition. INTERPRETATION: We show that a clinically relevant human kidney model of AMR is feasible, and anticipate that these models, with refinements, could provide a basis to test different strategies to prevent AMR. FUNDING: The Rosetrees and Stonygate Trust, The Royal College of Surgeons of England Fellowship Grant, NIHR Biomedical Research Centre/KCL Early Career Grant, Kidney Research U.K.

Blood component use in critical care in patients with COVID-19 infection: a single-centre experience.

There has been a significant surge in admissions to critical care during the coronavirus disease 2019 (COVID-19) pandemic. At present, the demands on blood components have not been described. We reviewed their use during the first 6 weeks of the outbreak from 3 March 2020 in a tertiary-level critical care department providing venovenous extracorporeal membrane oxygenation (vv-ECMO). A total of 265 patients were reviewed, with 235 not requiring ECMO and 30 requiring vv-ECMO. In total, 50 patients required blood components during their critical care admission. Red cell concentrates were the most frequently transfused component in COVID-19-infected patients with higher rates of use during vv-ECMO. The use of fresh frozen plasma, cryoprecipitate and platelet transfusions was low in a period prior to the use of convalescent plasma.

A Late Holocene community burial area: Evidence of diverse mortuary practices in the Western Cape, South Africa.

Over several decades, human skeletal remains from at least twelve individuals (males, females, children and infants) were recovered from a small area (ca. 10 x 10 m) on the eastern shore of Table Bay, Cape Town, near the mouth of the Diep River where it empties into the sea. Two groups, each comprising four individuals, appear to have been buried in single graves. Unusually for this region, several skeletons were interred with large numbers of ostrich eggshell (OES) beads. In some cases, careful excavation enabled recovery of segments of beadwork. One collective burial held items including an ostrich egg-shell flask, a tortoise carapace bowl, a fragmentary bone point or linkshaft and various lithic artefacts. This group appears to have died together and been buried expediently. A mid-adult woman from this group sustained perimortem blunt-force trauma to her skull, very likely the cause of her death. This case adds to the developing picture of interpersonal violence associated with a period of subsistence intensification among late Holocene foragers. Radiocarbon dates obtained for nine skeletons may overlap but given the uncertainties associated with marine carbon input, we cannot constrain the date range more tightly than 1900-1340 calBP (at 2 sigma). The locale appears to have been used by a community as a burial ground, perhaps regularly for several generations, or on a single catastrophic occasion, or some combination thereof. The evidence documents regional and temporal variation in burial practices among late Holocene foragers of the south-western Cape.

For the many: permitting deceased donor kidney transplantation across low-titre blood group antibodies can reduce wait times for blood group B recipients, and improve the overall number of 000MM transplants - a multicentre observational cohort study.

Blood group O or B recipients wait longer for a kidney transplant. We studied the distribution of anti-ABO blood group antibody titres in patients awaiting a kidney transplant, and modelled the effect of altering the UK National Kidney Allocation Scheme to allow for patients with 'LOW' titres (≤1:8, ≤3 dilutions) to receive a deceased donor ABOi (ddABOi) transplant. In a prospective study of 239 adult patients on the waiting list for a transplant in 2 UK centres, ABO-antibody titres (anti-A and anti-B) were measured. Based on the proportions of 'LOW' anti-A or anti-B antibodies, four simulations were performed to model the current allocation rules compared with variations allowing ddABOi allocation under various conditions of blood group, HLA matching, and waiting time. The simulations permitting ddABOi resulted in more blood group B recipients being transplanted, with median waiting time reduced for this group of recipients, and more equitable waiting times across blood groups. Additionally, permitting ddABOi resulted in greater numbers of 000MM allocations overall in compatible transplants under modelled conditions. Changing allocation in the UK to permit ddABOi in patients with 'LOW' titres would not change the total number of transplants, but redistributes allocation more equitably amongst blood groups, altering waiting times accordingly.

Distribution of ABO blood group antibody titers in pediatric patients awaiting renal transplantation: implications for organ allocation policy.

BACKGROUND: Blood group-incompatible transplantation is one strategy used when a potential recipient does not have a compatible living donor. Current practice includes desensitization strategies to reduce antibody titers. However, when antibodies are low, in cardiac transplantation in neonates for example, no desensitization is required. This study is the first to examine the distribution of ABO blood group antibody titers in a population of pediatric patients on the deceased-donor renal transplantation waiting list. METHODS: All patients from two pediatric nephrology centers active on the national deceased-donor waiting list had antibody titers (total immunoglobulin load) measured. A simulation modeling the effect of allocating blood group-incompatible deceased-donor kidneys to those patients with titers of 16 or lower was developed. RESULTS: Twenty-four children were screened; eight (33.3%) had titers of either anti-A or anti-B antibodies of 8 or lower. A further three (12.5%) had either an anti-A or anti-B antibody titer of 16. Blood group A or B patients had lower antibody levels than blood group O patients. In blood group O patients, levels of anti-A antibodies were higher than anti-B antibodies (Wilcoxon signed rank test, P=0.028). The simulation model showed that a change in organ allocation policy would increase pediatric transplant activity by 2.2% and reduce the median waiting time for a transplant. CONCLUSION: This allocation strategy may be of particular benefit to those pediatric patients who have been on the deceased-donor waiting list for a long time or those with a high calculated reaction frequency.

High anti-A titres may not preclude ABO-incompatible renal transplantation: an autoantibody could be the culprit.

ABO-incompatible live donor renal transplantation is a growing field. To avoid hyperacute rejection, pre-operative ABO antibody titres should be < 8. There are a number of therapeutic measures used to reduce these titres if they are high. This case report describes a patient initially found to have an extremely high anti-A IgG titre (512). The high titre results were concomitant with a positive atypical antibody screen, which showed no specificity on identification. A strategy to assess true titre levels and remove sub-clinical autoantibodies was devised, leading to successful transplantation.