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Among sensitized patients awaiting a transplant, females are disproportionately represented, partly because of pregnancy-induced sensitization. Using female NHPs sensitized by pregnancy alone, we examined the efficacy of costimulation blockade and proteasome inhibition for desensitization. Three animals received no desensitization (control), and seven animals received weekly carfilzomib (27 mg/m 2 ) and belatacept (20 mg/kg) before kidney transplantation. All animals received renal allografts from crossmatch-positive/maximally MHC-mismatched donors. Controls and three desensitized animals received tacrolimus-based immunosuppression. Four desensitized animals received additional belatacept with tacrolimus-based immunosuppression. Multiparous females had less circulating donor-specific antibody when compared to skin-sensitized males before transplantation. While females receiving desensitization showed only a marginal survival benefit over control females (MST = 11 days versus 63 days), additional belatacept to posttransplant maintenance significantly prolonged graft survival (MST > 164 days) and suppressed posttransplant DSA and circulating follicular helper T-like cells. This combination of therapies demonstrates great potential to reduce antibody-mediated rejection in sensitized recipients.

Sensitized patients, those who had prior exposure to foreign human leukocyte antigens, are transplanted at lower rates due to challenges in finding suitable organs. Desensitization strategies have permitted highly sensitized patients to undergo kidney transplantation, albeit with higher rates of rejection. This study assesses targeting plasma cell and interleukin (IL)-6 receptor for desensitization in a sensitized nonhuman primate kidney transplantation model. All animals were sensitized using two sequential skin transplants from maximally major histocompatibility complex-mismatched donors. Carfilzomib (CFZ)/tocilizumab (TCZ) desensitization (N = 6) successfully decreased donor-specific antibody (DSA) titers and prevented the expansion of B cells compared to CFZ monotherapy (N = 3). Dual desensitization further delayed, but did not prevent humoral rebound, as evidenced by a delayed increase in post-kidney transplant DSA titers. Accordingly, CFZ/TCZ desensitization conferred a significant survival advantage over CFZ monotherapy. A trend toward increased T follicular helper cells was also observed in the dual therapy group along the same timeline as an increase in DSA and subsequent graft loss. Cytomegalovirus reactivation also occurred in the CFZ/TCZ group but was prevented with ganciclovir prophylaxis. In accordance with prior studies of CFZ-based dual desensitization strategies, the addition of IL-6 receptor blockade resulted in desensitization with further suppression of posttransplant humoral response compared to CFZ monotherapy.

Sensitized kidney transplant recipients experience high rates of antibody-mediated rejection due to the presence of donor-specific antibodies and immunologic memory. Here we show that transient peri-transplant treatment with the central complement component C3 inhibitor Cp40 significantly prolongs median allograft survival in a sensitized nonhuman primate model. Despite donor-specific antibody levels remaining high, fifty percent of Cp40-treated primates maintain normal kidney function beyond the last day of treatment. Interestingly, presence of antibodies of the IgM class associates with reduced median graft survival (8 vs. 40 days; p = 0.02). Cp40 does not alter lymphocyte depletion by rhesus-specific anti-thymocyte globulin, but inhibits lymphocyte activation and proliferation, resulting in reduced antibody-mediated injury and complement deposition. In summary, Cp40 prevents acute antibody-mediated rejection and prolongs graft survival in primates, and inhibits T and B cell activation and proliferation, suggesting an immunomodulatory effect beyond its direct impact on antibody-mediated injury. Donor-specific antibodies in sensitized recipients may cause kidney transplant rejection. Here the authors show that complement component C3 inhibition prolongs graft survival by inhibiting T and B cell proliferation/activation and hence tissue injury, despite antibody levels remaining unaffected.

International audience; BACKGROUND: The first wave of the Covid-19 pandemic resulted in a drastic reduction in kidney transplantation and a profound change in transplant care in France. It is critical for kidney transplant centers to understand the behaviors, concerns and wishes of transplant recipients and waiting list candidates. METHODS: French kidney patients were contacted to answer an online electronic survey at the end of the lockdown. RESULTS: At the end of the first wave of the pandemic in France (11 May 2020), 2112 kidney transplant recipients and 487 candidates answered the survey. More candidates than recipients left their home during the lockdown, mainly for health care (80.1% vs. 69.4%; P\textless0.001). More candidates than recipients reported being exposed to Covid-19 patients (2.7% vs. 1.2%; P=0.006). Many recipients and even more candidates felt inadequately informed by their transplant center during the pandemic (19.6% vs. 54%; P\textless0.001). Among candidates, 71.1% preferred to undergo transplant as soon as possible, 19.5% preferred to wait until Covid-19 had left their community, and 9.4% were not sure what to do. CONCLUSIONS: During the Covid-19 pandemic in France, the majority of candidates wished to receive a transplant as soon as possible without waiting until Covid-19 had left their community. Communication between kidney transplant centers and patients must be improved to better understand and serve patients' needs.

Graft-versus-host recognition by passenger donor lymphocytes within organ transplants can trigger host alloantibody production (Charmetant et al .) .

The incidence of incisional hernia after kidney transplantation varies between 1.1% and 3.8%. These are usually repaired electively using polypropylene mesh. We present here a case where a patient presented as an emergency, with a large painful incisional hernia over his kidney transplant, and evidence of local erythema and systemic inflammation. As this could have represented either infection or rejection, the patient was started on antibiotics and subsequently underwent graft nephrectomy and hernia repair using a biological (porcine-derived) acellular dermal matrix, Strattice™, with a satisfactory outcome. In addition, histology showed evidence of allograft rejection. This is the first reported case of an incisional hernia containing a rejecting kidney allograft, managed with nephrectomy and biological mesh repair.

Preexisting donor-specific antibodies (DSA) to MHC antigens increase the risk of antibody-mediated rejection (AMR) in sensitized transplant recipients and reduces graft survival. Pretransplant desensitization with costimulation blockade and proteasome inhibition has facilitated transplantation in our preclinical nonhuman primate (NHP) model. However, long-term graft survival is limited by rebound of DSA after transplantation. In this study, we performed kidney transplants between highly sensitized, maximally MHC-mismatched NHPs (n=14). At kidney transplantation, primates received T cell depletion with rhesus-specific anti-thymocyte globulin (rhATG; n=10) or monoclonal anti-CD4 and anti-CD8 antibodies (n=4). Maintenance immunosuppression consisted of belatacept and tacrolimus (n=5) or belatacept and rapamycin (n=9) with steroids. Rebound of DSA post–kidney transplantation was significantly reduced compared with maintenance immunosuppression with tacrolimus, mycophenolate, and steroids. Protocol lymph node biopsy specimens showed a decrease in germinal center activity, with low frequencies of T follicular helper cells and class-switched B cells after kidney transplantation. Combined belatacept and rapamycin was superior in controlling viral reactivation, enabling weaning of ganciclovir prophylaxis. Tacrolimus was associated with increased morbidity that included cytomegalovirus and parvovirus viremia and post-transplant lymphoproliferative disorder. All primates in the tacrolimus/belatacept group failed discontinuation of antiviral therapy. Overall, belatacept-based immunosuppression increased AMR-free graft survival by controlling post-transplant humoral responses in highly sensitized NHP recipients and should be further investigated in a human clinical trial.

BACKGROUND: Donor-specific antibodies are associated with increased risk of antibody-mediated rejection and decreased allograft survival. Therefore, reducing the risk of these antibodies remains a clinical need in transplantation. Plasma cells are a logical target of therapy given their critical role in antibody production. METHODS: To target plasma cells, we treated sensitized rhesus macaques with daratumumab (anti-CD38 mAb). Before transplant, we sensitized eight macaques with two sequential skin grafts from MHC-mismatched donors; four of them were also desensitized with daratumumab and plerixafor (anti-CXCR4). We also treated two patients with daratumumab in the context of transplant. RESULTS: The animals treated with daratumumab had significantly reduced donor-specific antibody levels compared with untreated controls (57.9% versus 13% reduction; P

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.

BackgroundIn transplantation, plasmapheresis and IVIg provide the mainstay of treatment directed at reducing or removing circulating donor-specific antibody (DSA), yet both have limitations. We sought to test the efficacy of targeting the IgG recycling mechanism of the neonatal Fc receptor (FcRn) using anti-FcRn mAb therapy in a sensitized non-human primate (NHP) model, as a pharmacological means of lowering DSA.MethodsSix (6) rhesus macaque monkeys, previously sensitized by skin transplantation, received a single dose of 30mg/kg anti-RhFcRn IV, and effects on total IgG, as well as DSA IgG, were measured, in addition to IgM and protective immunity. Subsequently, 60mg/kg IV was given in the setting of kidney transplantation from skin graft donors. Kidney transplant recipients received RhATG, and tacrolimus, MMF, and steroid for maintenance immunosuppression.ResultsCirculating total IgG was reduced from a baseline 100% on D0 to 32.0% (mean, SD ± 10.6) on d4 post infusion (pConclusionTargeting the FcRn-mediated recycling of IgG is an effective means of lowering circulating donor-specific IgG in the sensitized recipient, although in the setting of organ transplantation mechanisms of rapid antibody rise post-transplant remains unaffected.

BACKGROUND: “Textbook outcome” (TO) is a novel composite quality measure that encompasses multiple postoperative endpoints, representing the ideal “textbook” hospitalization for complex surgical procedures. We defined TO for kidney transplantation using a cohort from a high-volume institution. METHODS: Adult patients who underwent isolated kidney transplantation at our institution between 2016 and 2019 were included. TO was defined by clinician consensus at our institution to include freedom from intraoperative complication, postoperative reintervention, 30-day intensive care unit or hospital readmission, length of stay >75(th) percentile of kidney transplant patients, 90-day mortality, 30-day acute rejection, delayed graft function, and discharge with a Foley catheter. Recipient, operative, financial characteristics, and post-transplant patient, graft, and rejection-free survival were compared between patients who achieved and failed to achieve TO. RESULTS: A total of 557 kidney transplant patients were included. Of those, 245 (44%) achieved TO. The most common reasons for TO failure were delayed graft function (N=157, 50%) and hospital readmission within 30 days (N=155, 50%); the least common was mortality within 90 days (N=6, 2%). Patient, graft, and rejection-free survival were significantly improved among patients who achieved TO. On average, patients who achieved TO incurred approximately $50,000 less in total inpatient charges compared to those who failed TO. CONCLUSIONS: TO in kidney transplantation was associated with favorable post-transplant outcomes and significant cost-savings. TO may offer transplant centers a detailed performance breakdown to identify aspects of perioperative care in need of process improvement.

Antibody incompatibility is a barrier to living kidney transplantation; antibody incompatible transplantation (AIT) is an accepted treatment modality, albeit higher risk. This study aims to determine changes to clinical decision making and access to AIT in the UK. An electronic survey was sent to all UK renal transplant centres (n = 24), in 2014, and again in 2018. Questions focused on entry & duration in the UKLKSS for HLA and ABO-incompatible pairs, Can and provision of direct AIT transplantation within those centres. Between 2014 & 2018, the duration recommended for patients in the UKLKSS increased. In 2014, 34.8% of centres reported leaving HLA-i pairs in the UKLKSS indefinitely, or reviewing on a case by case basis, by 2018 this increased to 61%. Centres offering direct HLA-i transplantation reduced from 58% to 37%. For low titre (1:8) ABO-i recipients, 66% of centres recommended at least 9 months (3 matching runs) in the UKLKSS scheme in 2018, compared to 47% in 2014, 50% fewer units consider direct ABO-i transplantation for unsuccessful pairs with high ABO titres (>1:512). Over time, clinicians appear to be facilitating more conservative management of AIT patients, potentially limiting access to living donor transplantation.

Sensitized patients are difficult to transplant due to pre-formed anti-donor immunity. We have previously reported successful desensitization using carfilzomib and belatacept in a non-human primate (NHP) model. Here we evaluated selective blockade of the co-stimulatory signal (CD28-B7) with Lulizumab, which preserves the co-inhibitory signal (CTLA4-B7). Five maximally MHC-mismatched pairs of NHPs were sensitized to each other with two sequential skin transplants. Individuals from each pair were randomized to either desensitization with once-weekly Carfilzomib (27mg/m(2) IV) and Lulizumab (12.5mg/kg SC) over four weeks, or no desensitization (Control). NHPs then underwent life-sustaining kidney transplantation from their previous skin donor. Rhesus-specific anti-thymocyte globulin was used as induction therapy and immunosuppression maintained with tacrolimus, mycophenolate, and methylprednisolone. Desensitized subjects demonstrated a significant reduction in donor-specific antibody, follicular helper T cells (CD4(+)PD-1(+)ICOS(+)), and proliferating B cells (CD20(+)Ki67(+)) in the lymph nodes. Interestingly, regulatory T cell (CD4(+)CD25(+)CD127(lo)) frequency was maintained after desensitization in addition to increased frequency of naïve CD4 T cells (CCR7(+)CD45RA(+)) and naïve B cells (IgD(+)CD27(−)CD20(+)) in circulation. This was associated with significant prolongation in graft survival (MST = 5.8 ± 4.0 vs. 64.8 ± 36.3; p

Background Despite widespread uptake, the utility of Workplace Based Assessments (WBAs) is disputed and evidence underpinning their use is largely based upon their completion in ideal conditions, rather than the real-world setting. Aim To ascertain the real-world usage of WBAs, as perceived by UK surgical trainees. Materials and methods An anonymous online questionnaire conducted nationally via the Association of Surgeons in Training (ASiT). Evaluation of 906 completed trainee responses, across all surgical specialties and training levels, employed mixed methods to interpret quantitative and qualitative data. Results The sample permitted a 3.0% confidence level with acceptable internal consistency (Cronbach's alpha 0.755). Formative use was supported by 72.5% and summative use was rejected by almost as many (66.3%). WBA use was perceived to deviate markedly from that recommended by the Joint Committee on Surgical Training (JCST). Significant misuse was identified and elements perceived as inaccurate appear commonplace across the breadth of surgical specialties. Inaccurate completion was acknowledged by 89.6% of respondents and some trainers appear complicit, 147 individuals (16.2%) having reported this to trainers, 40.9% aware of ‘unobserved sign-off’, and 33.6% aware of ‘password disclosure’ by trainers. Furthermore, a majority of trainees felt the Annual Review of Competency Progression (ARCP) respected WBA quantity above quality (55.4%), and a third felt pressure to overstate the number completed (32.0%). Reasons for misuse appeared largely centred upon time restraints, lack of engagement and a will to achieve the required targets for career progression. 1.5 Conclusions This study demonstrates that UK surgical trainees perceive that most trainees deviate from guidance in their use of WBAs. This is worrying in both the apparent frequency and nature of misuse and somewhat undermines existing evidence for their role in surgical training. Trainees perceive that required numbers of WBAs are too high, that training programmes fail to encourage their use as formative assessments, and that there is a lack of engagement by many trainees and trainers. We present consensus recommendations from ASiT for the improvement of WBA use in UK surgical training.

Introduction Accurate recording of operative cases is essential during training to demonstrate experience. However, indicative numbers delineating minimum desirable experience may incentivise exaggeration or misrepresentation of experience. This study aimed to determine perceptions of real-world eLogbook use among UK surgeons in training. Material and methods An anonymous online questionnaire was disseminated electronically using a pre-planned yield-maximisation strategy, incorporating regional champions, email and social media. Evaluation employed mixed methods in a combined interpretation of quantitative and qualitative data from the questionnaire. Recommendations for development of the eLogbook were itemised from respondents’ free text items and a modified Delphi process, conducted within the Council of the UK national trainee representative body, the Association of Surgeons in Training, determined the strength of each recommendation. Results Analysis included 906 complete responses from training-grade surgeons (34.8% female) from all UK recognised specialties and all grades of training. More than two-thirds (68.5%) believed that overstatement or misrepresentation of case involvement occurs. A fifth (20.8%) reported witnessing trainees logging cases they had not actually participated in and almost a third (32.7%) had witnessed overstatement, yet few (15.1%) had raised such an issue with a supervisor. Most (85.2%) respondents had few or no eLogbook entries validated. More than a quarter of respondents felt pressure to overstate their involvement in cases (28.6%) and the number recorded (28.1%). Almost a third (31.5%) felt the required case number for completion of training was not achievable. Female trainees were less likely to feel well supervised (p = 0.022) and to perceive targets for completion of training were achievable (p = 0.005). Thematic analysis identified four key themes to explain logbook misuse: Pressure to achieve training milestones; eLogbook functionality issues; training deficiencies and probity. Conclusions Inaccurate operative recording was widely reported, primarily in response to perceived pressure to achieve targets for career progression. Operative logbooks may not be as accurate as intended. Consensus recommendations are made for improvement in the eLogbook and its use.

Thrombotic microangiopathy (TMA) is a histological feature of antibody-mediated rejection and has the potential to cause problematic graft dysfunction, particularly for highly sensitized cross-match positive kidney transplant recipients. Prompt recognition of pertinent histopathological and systemic features of TMA in kidney transplantation is necessary. Underlying mechanisms of this process involve the activation of both complement and coagulation systems as a response to HLA antibody. As serine proteases, coagulation and complement cascades exhibit similar characteristics with respect to homeostatic function. Increasing evidence now exists for the interaction between these innate defenses in both activation and regulation, lending scope for intervention. Understanding the complexities of these interactions remains a challenge. This review provides an overview of the current understanding, particularly with respect to the activation of coagulation and complement by HLA antibody in the setting of highly sensitized kidney transplantation.

Patients on organ transplant waiting lists are evaluated for preexisting alloimmunity to minimize episodes of acute and chronic rejection by regularly monitoring for changes in alloimmune status. There are few studies on how alloimmunity changes over time in patients on kidney allograft waiting lists, and an apparent lack of research-based evidence supporting currently used monitoring intervals.To investigate the dynamics of alloimmune responses directed at HLA antigens, we retrospectively evaluated data on anti-HLA antibodies measured by the single-antigen bead assay from 627 waitlisted patients who subsequently received a kidney transplant at University Hospital Zurich, Switzerland, between 2008 and 2017. Our analysis focused on a filtered dataset comprising 467 patients who had at least two assay measurements.Within the filtered dataset, we analyzed potential changes in mean fluorescence intensity values (reflecting bound anti-HLA antibodies) between consecutive measurements for individual patients in relation to the time interval between measurements. Using multiple approaches, we found no correlation between these two factors. However, when we stratified the dataset on the basis of documented previous immunizing events (transplant, pregnancy, or transfusion), we found significant differences in the magnitude of change in alloimmune status, especially among patients with a previous transplant versus patients without such a history. Further efforts to cluster patients according to statistical properties related to alloimmune status kinetics were unsuccessful, indicating considerable complexity in individual variability.Alloimmune kinetics in patients on a kidney transplant waiting list do not appear to be related to the interval between measurements, but are instead associated with alloimmunization history. This suggests that an individualized strategy for alloimmune status monitoring may be preferable to currently used intervals.

Crosstalk between B and T cells in transplantation is increasingly recognized as being important in the alloimmune response. T cell activation of B cells occurs by a 3-stage pathway, culminating with costimulation signals. We review the distinct T cell subtypes required for B-cell activation and discuss the formation of the germinal center (GC) after transplantation, with particular reference to the repopulation of the GC after depletional induction, and the subsequent effect of immunosuppressive manipulation of T cell-B cell interactions. In addition, ectopic GCs are seen in transplantation, but their role is not fully understood. Therapeutic options to target T cell-B cell interactions are of considerable interest, both as immunosuppressive tools, and to aid in the further understanding of these important alloimmune mechanisms.

Background: More than 40% of patients awaiting a kidney transplant in the UK are sensitised with human leucocyte antigen (HLA) antibodies. Median time to transplantation for such patients is double that of unsensitised patients at about 74 months. Removing antibody to perform an HLA-incompatible (HLAi) living donor transplantation is perceived to be high risk, although patient survival data are limited. We compared survival of patients opting for an HLAi kidney transplant with that of similarly sensitised patients awaiting a compatible organ. Methods: From the UK adult kidney transplant waiting list, we selected crossmatch positive living donor HLAi kidney transplant recipients who received their transplant between Jan 1, 2007, and Dec 31, 2013, and were followed up to Dec 31, 2014 (end of study). These patients were matched in a 1:4 ratio with similarly sensitised patients cases listed for a deceased-donor transplant during that period. Data were censored both at the time of transplantation (listed only), and at the end of the study period (listed or transplant). We used Kaplan-Meier curves to compare patient survival between HLAi and the matched cohort. Findings: Of 25 518 patient listings, 213 (1%) underwent HLAi transplantation during the study period. 852 matched controls were identified, of whom 41% (95% CI 32-50) remained without a transplant at 58 months after matching. We noted no difference in survival between patients who were in the HLAi group compared with the listed only group (log rank p=0·446), or listed or transplant group (log rank p=0·984). Interpretation: Survival of sensitised patients undergoing HLAi in the UK is comparable with those on dialysis awaiting a compatible organ, many of whom are unlikely to be have a transplant. Choosing a direct HLAi transplant has no detrimental effect on survival, but offers no survival benefit, by contrast with similar patients studied in a North American multicentre cohort. Funding: UK National Health Service Blood & Transplant and Guy's & St Thomas' National Institute for Health Research Biomedical Research Centre.

Introduction Colonic stenting in obstructing left sided colorectal cancer (CRC) using self-expanding metallic stents has been utilised as a conservative management intervention, as well as a bridge to definitive surgery. Despite high reported success rates technically and clinically of stent deployment, as well as improved rates of primary anastomosis, controversy remains about the use of this procedure as a bridge to surgery. We report on a decade of single centre experience. Methods Retrospective analysis of patients requiring urgent colorectal cancer stenting as a bridge to surgery between 2006 and 2017. Primary outcomes measured were clinical and technical success. Secondary outcomes recorded were survival, complications, primary anastomosis and stoma formation Results 36 patients underwent CRC stenting with the intention of being a bridge to elective surgery, of whom 44% were female. Mean age was 65.7 years. The majority of cases (84%) were undertaken by one of the 3 main operators. At staging, 9 patients (25%) were T3; 17 (47.3%) T4. 25% of patients were ASA 3. Technical success was reported in 89% of cases and clinical success 86%. At elective surgery primary anastomosis was achieved in 61%. 5 reported early complications, including 2 clinical perforations and 2 radiological perforations. Mean survival post stenting procedure was 24 months (range 3–55 months), with death due to metastatic CRC. There were no deaths within 30 days. Conclusions We demonstrate excellent technical success with this treatment modality. By temporising patients using endoscopic stenting, patients are optimised for elective surgery by colorectal surgeons with good primary anastomosis rates, and excellent post procedure mortality.

Previous evidence suggests that a homeostatic germinal center (GC) response may limit bortezomib desensitization therapy. We evaluated the combination of costimulation blockade with bortezomib in a sensitized non-human primate kidney transplant model. Sensitized animals were treated with bortezomib, belatacept, and anti-CD40 mAb twice weekly for a month (n = 6) and compared to control animals (n = 7). Desensitization therapy-mediated DSA reductions approached statistical significance (P = .07) and significantly diminished bone marrow PCs, lymph node follicular helper T cells, and memory B cell proliferation. Graft survival was prolonged in the desensitization group (P = .073). All control animals (n = 6) experienced graft loss due to antibody-mediated rejection (AMR) after kidney transplantation, compared to one desensitized animal (1/5). Overall, histological AMR scores were significantly lower in the treatment group (n = 5) compared to control (P = .020). However, CMV disease was common in the desensitized group (3/5). Desensitized animals were sacrificed after long-term follow-up with functioning grafts. Dual targeting of both plasma cells and upstream GC responses successfully prolongs graft survival in a sensitized NHP model despite significant infectious complications and drug toxicity. Further work is planned to dissect underlying mechanisms, and explore safety concerns.

The amount of irreversible injury on renal allograft biopsy predicts function, but little is known about the early evolution of this damage. In a single-center cohort, we examined the relationship between donor-, recipient-, and transplantation-associated factors and change in a morphometric index of chronic damage (ICD) between protocol biopsies performed at implantation and at 2–3 months. We then investigated whether early delta ICD predicted subsequent biochemical outcomes. We found little evidence to support differences between the study group, who had undergone serial biopsies, and a contemporaneous control group, who had not. In allografts with serial biopsies (n = 162), there was an increase in ICD between implantation (median: 2%, IQR:0–8) and 2–3 months post-transplant (median 8% IQR:4–15; p < 0.0001). Donation from younger or live donors was independently associated with smaller early post-transplant increases in ICD. There was no evidence for a difference in delta ICD between donation after cardiac death vs. donation after brain death, nor association with length of cold ischemia. After adjustment for GFR at the time of the second biopsy, delta ICD after three months did not predict allograft function at one yr. These findings suggest that graft damage develops shortly after transplantation and reflects donor factors, but does not predict future biochemical outcomes.

Trauma patients produce a host of danger signals and high levels of damage-associated molecular patterns (DAMPs) after cellular injury and tissue damage. These DAMPs are directly and indirectly involved in the pathogenesis of various inflammatory and thrombotic complications in patients with severe injuries. No effective therapeutic agents for the removal of DAMPs from blood or tissue fluid have been developed. Herein, we demonstrated that nucleic acid binding polymers, e.g., polyethylenimine (PEI) and polyamidoamine dendrimers, immobilized onto electrospun microfiber mesh can effectively capture various DAMPs, such as extracellular DNAs and high mobility group box 1 (HMGB1). Furthermore, treatment with PEI-immobilized microfiber mesh abrogated the ability of DAMPs, released from dead and dying cells in culture or found in patients following traumatic injury, to activate innate immune responses and coagulation in vitro and in vivo. Nucleic acid scavenging microfiber meshes represent an effective strategy to combat inflammation and thrombosis in trauma.

The efficacy of bortezomib monotherapy in desensitizing kidney transplant candidates with preformed donor-specific antibodies remains unclear. We evaluated the effect of bortezomib on preformed antibodies and upstream components of the B cell response in a primate model sensitized by fully mismatched allogeneic skin transplants to provide mechanistic insights regarding the use of bortezomib as a means of desensitization. Bortezomib treatment given intravenously twice weekly for 1 month (1.3 mg/m2 per dose) clearly reduced the numbers of antibody-producing cells and CD38+CD19+CD20- plasma cells in the bone marrow (P

Early activation of coagulation is an important factor in the initiation of innate immunity, as characterized by thrombotic microangiopathy (TMA). In transplantation, systemic anti-coagulation is difficult due to bleeding. A novel 'cytotopic' agent, 'Thrombalexin', (TLN) combines a cell-membrane bound (mirystoyl tail) anti-thrombin (HLL peptide) which can be perfused directly to the donor organ or cells.. Thromboelastography (TEG) was used to measure time to clot formation (r-time) in both rhesus and human blood, comparing TLN vs. HLL (without cytotopic tail) vs. negative-control. Both TLN and HLL treated rhesus or human whole blood result in significantly prolonged r-time compared to kaolin controls. Only TLN-treated human endothelial cells (EC) and neonatal porcine islets (NPI) prolonged time to clot formation. Detection of membrane-bound TLN was confirmed by immunohistochemistry and FACS. In vivo, perfusion of a NHP kidney TLN-supplemented preservation solution in a sensitized model of transplantation demonstrated no evidence of TLN systemically. Histologically, TLN was shown to be present up to four days after transplantation. There was no platelet deposition and TMA severity, as well as microvascular injury scores (glomerulitis + peritubular capillaritis) were less in the TLN treated animals. Despite promising evidence of localized efficacy, no survival benefit was demonstrated. This article is protected by copyright. All rights reserved.

The principle of "Fistula First" for hemodialysis has been widely adopted among adults with end-stage renal failure (ESRF). UK national targets aim to have 85 % of prevalent patients using permanent access (arteriovenous fistula or graft). Currently, hemodialysis in children relies heavily on central venous catheters (CVC). However, there is significant evidence that arteriovenous fistulae (AVF) are preferable for long-term dialysis in the pediatric population. We describe the principles of fistula formation including pre-operative work-up, surgical techniques for AVF creation, and post-operative monitoring.

BACKGROUND: The last Banff 2013 report recognizes acute/active antibody-mediated rejection (ABMR) and C4d staining without evidence of rejection. The goal of our study was to analyze the incidence of C4d deposition after ABO-incompatible transplantation and assess outcomes in patients with ABMR, C4d staining without evidence of rejection (all acute Banff scores = 0), and C4d staining with tubulointerstitial inflammation (i > 0 with or without tubulitis). METHODS: Three-months 'For cause' or protocol biopsies in 50 ABO-incompatible patients were rescored and were correlated with clinical outcomes and antibody titres. RESULTS: Active/acute ABMR was found in 23 patients (46%), C4d staining without evidence of rejection in 7 patients (14%), C4d staining with tubulointerstitial inflammation in 6 patients (12%), tubulointerstitial inflammation in 6 patients (12%), and no evidence of rejection in 8 patients (16%). Patients with active/acute ABMR had a 3-month estimated glomerular filtration rate (median,: 43 mL/min) lower than patients with no evidence of rejection (median, 61 mL/min; P = 0.01). However, after 3 months, a progressively declining estimated glomerular filtration rate was observed more frequently in patients with C4d staining and tubulointerstitial inflammation when compared to patients with no evidence of rejection (100% vs 25%, P = 0.03). Finally, independently of C4d status, interstitial inflammation occurred more frequently in patients with a pretransplant ABO antibody titre higher than 16 and/or posttransplant ABO antibody increase. CONCLUSIONS: Whereas isolated C4d deposition and isolated interstitial inflammation appear to be benign lesions, C4d deposition in association with interstitial inflammation is the biopsy finding most strongly associated with the development of chronic graft dysfunction.

We have established a model of sensitization in nonhuman primates and tested two immunosuppressive regimens. Animals underwent fully mismatched skin transplantation, and donor-specific antibody (DSA) response was monitored by flow cross-match. Sensitized animals subsequently underwent kidney transplantation from their skin donor. Immunosuppression included tacrolimus, mycophenolate, and methylprednisolone. Three animals received basiliximab induction; compared with nonsensitized animals, they showed a shorter mean survival time (4.7 ± 3.1 vs. 187 ± 88 days). Six animals were treated with T cell depletion (anti-CD4/CD8 mAbs), which prolonged survival (mean survival time 21.6 ± 19.0 days). All presensitized animals showed antibody-mediated rejection (AMR). In two of three basiliximab-injected animals, cellular rejection (ACR) was prominent. After T cell depletion, three of six monkeys experienced early acute rejection within 8 days with histological evidence of thrombotic microangiopathy and AMR. The remaining three monkeys survived 27-44 days, with mixed AMR and ACR. Most T cell-depleted animals experienced a rebound of DSA that correlated with deteriorating kidney function. We also found an increase in proliferating memory B cells (CD20(+) CD27(+) IgD(-) Ki67(+) ), lymph node follicular helper T cells (ICOS(+) PD-1(hi) CXCR5(+) CD4(+) ), and germinal center (GC) response. Depletion controlled cell-mediated rejection in sensitized nonhuman primates better than basiliximab, yet grafts were rejected with concomitant DSA rise. This model provides an opportunity to test novel desensitization strategies.

Graft survival seems to be worse in positive cross-match (HLAi) than in ABO-incompatible (ABOi) transplantation. However, it is not entirely clear why these differences exist. Sixty-nine ABOi, 27 HLAi and 10 combined ABOi+HLAi patients were included in this retrospective study, to determine whether the frequency, severity and the outcome of active antibody-mediated rejection (AMR) were different. Five-year death-censored graft survival was better in ABOi than in HLAi and ABOi+HLAi patients (99%, 69% and 64%, respectively, P = 0.0002). Features of AMR were found in 38%, 95% and 100% of ABOi, HLAi and ABOi+HLAi patients that had a biopsy, respectively (P = 0.0001 and P = 0.001). After active AMR, a declining eGFR and graft loss were observed more frequently in HLAi and HLAi+ABOi than in ABOi patients. The poorer prognosis after AMR in HLAi and ABOi+HLAi transplantations was not explained by a higher severity of histological lesions or by a less aggressive treatment. In conclusion, ABOi transplantation offers better results than HLAi transplantation, partly because AMR occurs less frequently but also because outcome after AMR is distinctly better. HLAi and combined ABOi+HLAi transplantations appear to have the same outcome, suggesting there is no synergistic effect between anti-A/B and anti-HLA antibodies.

Introduction Post‐partum vaginal laxity is a problem encountered by many women. More uncommon is a resulting vaginal defect. In most cases of laxity, a period of extensive physiotherapy can strengthen the pelvic muscles enough for symptoms to be minimized. However, this is not the case once there is a tissue defect. Aim To present a new reconstructive method for patients with posterior vaginal wall defects. Methods We present a case of a 38‐year‐old female who, 12 years prior to presentation, had a vaginal delivery. Due to complications during the delivery, she sustained pelvic trauma and developed a posterior vaginal wall defect. She had a sizable soft tissue defect, causing sexual, urinary, and confidence problems. Fat was harvested from the patient's abdomen and injected into the defect after more conservative treatment options were exhausted. Results The defect was corrected successfully using the minimally invasive Coleman fat grafting technique. Discussion/Conclusion This is to our knowledge the first case in the literature where a posterior vaginal defect has been corrected using Coleman fat grafting, and we believe that this treatment method may be of benefit to more patients. Zetlitz E, Manook M, MacLeod A, and Hamilton S. A new reconstructive technique for posteriorvaginal wall defects, a case report. J Sex Med 2013;10:2579–2581.

ABO blood group incompatible renal transplantation, using desensitization procedures, is an effective strategy. Efforts have been made to reduce desensitization: these are usually applied to all patients indiscriminately. The Guy's Hospital ABO blood group incompatible desensitization regimen uses a tiered approach, tailoring strategy according to initial antibody titres. Sixty-two ABO blood group incompatible living donor transplant recipients were compared with 167 recipients of blood group compatible living donor renal transplants. There were no statistically significant differences in allograft survival rates at 1 or 3 years post-transplant, rejection in the first year post-transplant or renal function in the first 3 years post-transplant. There was a higher rate of death in ABO blood group incompatible transplant recipients - this could be associated with differences in age and HLA mismatch between the two groups. Four ABO blood group incompatible patients experienced antibody-mediated rejection (no episode was associated with a rise in ABO blood group antibodies). Of the patients who received no desensitization, or rituximab alone, none has experienced antibody mediated rejection or experienced allograft loss. Tailoring the use of desensitization in ABO blood group incompatible renal transplantation according to initial ABO blood group antibody titres led to comparable results to blood group compatible transplantation.

Dear Editor: Brainstem haematoma (BSH) with hydrocephalus is a rare fonn of BSH [I]. Following the publication of the largest documented series of spontaneous BSH [I], we would like to present a particular scenario that was managed differently. A previously fit and well 54-year-old female, with no previous history of hypertension, presented with sudden onset of headache and drowsiness. Her initial Glasgow Coma Scale (GCS) of II dropped further to 8, at which point she was intubated and ventilated. An initial computed tomography (CT) scan was consistent with BSH with radiological evidence of hydrocephalus. An external ventricular drain was inserted and the initial increased intracranial pressure (ICP) was 30 cm of H20. The drain was progressively raised in height and removed. However, she subsequently had four attacks of recurrent drop in GCS and respiratory depression. All these episodes necessitated reinsertion of external ventricular drainage (EVD) or a drop in its height to facilitate drainage of cerebrospinal fluid (CSF). On all four occasions, a raised ICP was noted and the GCS improved following CSF drainage.