Introduction:The inhibitory Fc receptor, FcγRIIb, regulates innate and adaptive immunity by inhibiting activation of myeloid and B cells.The role of FcγRIIb in transplantation has not yet been studied.Methods: Acute and chronic cardiac allograft rejection were investigated using the BALB/c (H-2 d ) to Bl/6 (H-2 b ) and bm12 to Bl/6 (MHC class II-mismatched) mouse models and survival compared to FcγRIIb -/-Bl/6, and transgenic Bl/6 recipients bearing increased FcγRIIb on their macrophages (MPTG) or B cells (BTG).We have previously shown that bm12 heart graft rejection is characterised by chronic allograft vasculopathy with the development of antinuclear autoantibody (quantified by staining HEp-2 cells).In the acute model, alloantibody was assayed using ELISA and cytotoxic CD8 T cell responses by IFNγ ELISPOT.Results: WT Bl/6 mice rejected bm12 hearts slowly (MST = 95d, n = 13), while rejection in FcγRIIb -/-recipients occurred rapidly (MST = 28d, n = 8) and was associated with augmented graft vasculopathy and autoantibody responses.In contrast, BTG and MPTG mice had delayed bm12 heart graft rejection, suggesting that accelerated rejection in FcγRIIb -/-mice is due to loss of inhibitory signalling on both B cells and macrophages.In the acute model, FcγRIIb -/-recipient mice rejected BALB/c heart grafts at the same tempo (MST = 7d, n = 6), and with similar alloantibody and cytotoxic CD8 T cell responses, as WT recipients.Conclusions: FcγRIIb plays a role in chronic but not acute allograft rejection.Polymorphisms in FcγRIIb gene expression exist in humans and are thus likely to influence allograft survival.FcγRIIb is a potential target for immunomodulation in clinical transplantation.Take-home message: The inhibitory Fc receptor, FcγRIIb, regulates innate and adaptive immunity by inhibiting activation of myeloid and B cells.My work has demonstrated that FcγRIIb appears to play a role in chronic but not acute allograft rejection.FcγRIIb is therefore a potential target for immunomodulation in clinical transplantation.
To determine the utility of pre-implantation renal biopsy (PIB) to predict renal allograft outcomes.This is a retrospective review of all patients that underwent PIB from January 2003 to December 2011 at the Great Ormond Street Hospital for Children in London, United Kingdom. Thirty-two male patients (56%) aged 1.5-16 years (median: 10.2) at the time of transplantation were included in the study and followed-up for 33 (6-78) months. The results were compared with 33 controls.The PIB showed normal histopathological findings in 13 patients (41%), mild chronic vascular changes in 8 (25%), focal tubular atrophy in one, moderate to severe chronic vascular change in 3, mild to moderate acute tubular damage in 6, and tissue was inadequate in one subject. Delayed graft function (DGF) was observed in 3 patients; 2 with vascular changes in PIB, and one with normal histopathological findings. Two subjects with PIB changes lost their grafts. The estimated glomerular filtration rate at 3-, and 6-months post-transplantation was lower in children with abnormal PIB changes compared with those with normal PIB. There was one case of DGF in the control group, and 4 children lost their grafts including the one with DGF.Pre-implantation renal biopsy can provide important baseline information of the graft with implications on subsequent medical treatment for pediatric renal transplant recipients.
To the Editor: Vaccine-induced thrombosis and thrombocytopenia (VITT) may follow immunization with the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2.1, 2 Autoantibodies to platelet factor 4 (PF4) may mediate VITT through antibody-dependent platelet activation, though the underlying etiology is uncertain.3 Anti-PF4 antibodies are also seen in heparin-induced thrombocytopenia, though most cases of VITT do not have prior heparin exposure. More than 20 million people in the United Kingdom (UK) have received the ChAdOx1 nCoV-19 vaccine. We carried out an early analysis of organ donation and transplantation from UK donors with VITT, to understand the implications of this emerging syndrome. Articles 6(1)(e) and 9(2)(h) and (i) of the General Data Protection Regulations provide the basis for NHSBT to use patient identifiable data without prior consent, for the purposes of monitoring the safety of the national transplant program. We identified 13 consented deceased organ donors, who presented with thrombosis and/or hemorrhage and laboratory features consistent with VITT,4 between 28 January and 9 April 2021. All had received their first dose of ChAdOx1 nCoV-19 vaccine before admission (see Table 1). Ten donors proceeded to donate 27 allografts to 26 recipients. After a median follow-up of 19 days, 21 of 27 (78%) allografts have satisfactory function. Three recipients developed early allograft failure requiring explantation (two livers and one kidney); two transplanted kidneys have impaired allograft function, currently requiring hemodialysis; and one recipient died within a day of transplantation from a presumed cardiac event. There were seven major thrombotic or hemorrhagic postoperative complications (three bleeds and four venous or arterial allograft thromboses) in six recipients, resulting in the loss of three transplants as described above; these events occurred within 9 days of transplantation. Of the six recipients with bleeding or thrombotic events, two had received their second dose of ChAdOx1 nCoV-19 vaccine within 30 days before transplantation; neither patient had features suggestive of VITT at the time of transplantation. Two of the three patients with bleeding had preexisting risk factors for hemorrhage (dual antiplatelet agent therapy, anticoagulation for metallic cardiac valve); none of the patients with thromboses had significant preexisting procoagulant tendencies. So far, three liver recipients had detectable anti-PF4 antibodies between 3 and 22 days posttransplant; one of these recipients experienced a thrombotic complication without allograft loss and the other two had uncomplicated postoperative courses. Ten recipients (six kidneys and four livers) tested negative for anti-PF4 antibodies. The UK experience to date suggests that the potential risks of transplanting organs from donors with VITT are twofold. First, early major thrombosis or clinically significant bleeding, which may result from preexisting hemostatic and endothelial dysfunction in the allograft. Second, possible transmission of pathogenic lymphocytes producing anti-PF4. The clinical significance of this is unclear; further follow-up will determine whether this portends development of VITT in the recipient. UK guidance has been drawn up for the selection, recovery, and transplantation of organs from donors with VITT, as well as recipient monitoring.5 We suggest that liver, lung, pancreas, and small bowel transplants from donors with VITT should only proceed in urgent situations, as these organs contain high numbers of "passenger" donor lymphocytes. Since anti-PF4 antibodies can provoke platelet activation and thromboses, platelet transfusion should be avoided during organ recovery and transplantation processes where possible. The contribution of systemic heparinization during organ recovery to thrombosis within the allograft is uncertain, and argatroban is an alternative anticoagulant.5 Current UK guidance recommends that heparin can be used as per standard practice in the recipient unless features of VITT develop.5 For recipients of organs from VITT donors, monitoring of the platelet count, fibrinogen, D-dimers, and anti-PF4 antibodies is essential.5 Further experience of organ transplantation from donors with VITT and longer term recipient follow-up will help guide clinical decision-making. In the meantime, transplantation of organs from these donors should only proceed after careful consideration of the methods for organ recovery and of the risks and benefits for a potential recipient, and an appropriate consent discussion. The authors are grateful to the organ donation teams, specialist nurses in organ donation, National Organ Retrieval Service teams, and the staff of the platelet immunology laboratory at NHSBT Filton who assisted with aspects of donor characterization. They also thank the recipient transplant coordinators, and other members of the transplant teams caring for the transplant recipients, who supplied follow-up information required for this study. Lastly, and most of all, they thank all deceased donors and their families. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
Abstract Aim Coronary artery stenosis is a key risk factor for major adverse cardiovascular events (MACE). Left anterior descending (LAD) artery stenosis is regarded to be the most severe vessel-specific coronary artery stenosis as depicted by its appellation widow-maker. We hypothesised that right coronary artery (RCA) stenoses may present poorer or similar outcomes to LAD. This study sought to investigate the association of vessel-specific coronary artery stenosis using computed tomography coronary angiogram (CTCA) with MACE in a renal transplant cohort. Method This was a single-centre retrospective study of all end-stage renal disease (ESRD) patients eligible for kidney transplantation who underwent CTCA between 2012 to 2014. MACE occurrences (heart failure, AMI, unstable angina, CVA, PVD, and TIA) were recorded within a 10-year follow-up period. CTCA datasets were assessed by 2 independent specialists, visually grading stenosis severity into 2 classifications (<50% or >50% coronary diameter reduction). Results Of 106 patients in our study, a total of 419 coronary arteries (106 RCA, 104 LAD, 104 circumflex (CX), 104 left mainstem (LM)) were graded by CTCA. 43 patients (40.6%) experienced at least one MACE within the timeframe. Statistical significance in MACE was observed when stratified by RCA stenosis severity (p = 0.022) while no statistical significance in MACE observed when stratified by LAD (p = 0.904), CX (p = 0.472) & LM (p = 0.222). Conclusions This challenges the conventional wisdom on individual vessel-specific coronary artery stenosis and suggests that RCA stenoses are associated with MACE in the transplant cohort. This also offers the possibility of RCA stenosis as a prognostic tool in predicting MACE in ESRD patients.
The Two layer method (TLM) has been extremely successful in the preservation of the pancreas. However, this has not been thoroughly investigated in other organs or in clinically relevant large animal models. The aim of this study was to assess the effects of TLM in a large animal model of kidney preservation.Porcine kidneys were retrieved after 10 minutes of warm ischaemic injury and flushed with 300 ml UW solution at 4°C. Kidneys were then either placed in University of Wisconsin solution (UW) or TLM using pre-oxygenated perfluorodecalin and UW. Kidneys were stored for 18 hours at 4°C then reperfused with oxygenated autologous blood to assess renal function.Renal blood flow (RBF) was significantly lower and intra-renal resistance (IRR) higher in TLM compared to UW group [Area under the curve (AUC) RBF, UW; 427±168 vs TLM; 247±55 ml/min/100g.h; P=0.041, AUC IRR, UW; 7.7±2.2 vs TLM; 10.5±1.9 ml/min/mmHg; P=0.041]. Levels of creatinine clearance (CrCl) were significantly lower in TLM group [AUC CrCl, UW; 1.8±1.0 vs TLM; 0.6±0.4 ml/min/100 g.h; P=0.034]. Levels of lipid peroxidation were significantly lower in TLM group [8-isoprostane/Cr ratio 3h; UW 3338±896 vs TLM 2072±886 pg/ml/mmol/L; P=0.04]. Levels of total nitric oxide were significantly higher in TLM group (P=0.009).TLM did not improve the preservation condition of porcine kidneys. Furthermore, there appeared to be increased inflammation, endothelial injury and reduced renal function compared to preservation with UW. Further experimental work is needed to determine the role of PFC in kidney preservation.
Introduction: Optimal access for haemodialysis is in the form of Arteriovenous Fistula (AVF) for majority of patients. Failure of AVF not only leads to a major burden on the NHS but more importantly is a significant morbidity for the patients. Haemodialysis (HD) machines record a considerable amount of data automatically that in theory can be used by Artificial Intelligence (AI) algorithms to predict fistula failure and thus preempting the treatment. We worked on an AI-enabled machine learning model to create a proof of concept for AI to predict fistula failure using common clinical measurements. Methods: Data was collected for 100 patients undergoing dialysis through an AVF between April 2013 to August 2019. Half of these patients had a working fistula since the first use and others had failed during the follow-up. Demographic information and comorbidities (diabetes mellitus, hypertension, heart failure, thrombophilia, peripheral arterial disease, anticoagulant, central stenosis) were taken into consideration. A wide range of other data including flow on the dialysis machine, litres of blood processed, needle size, type of fistula, anticoagulation, arterial and venous pressure, blood pressure and weight pre & post dialysis session were also assessed. We originally looked at all 14 variables accumulated from the HD machine, however, a further analysis during the feature selection process assisted us to include only three variables- litres of blood processed, arterial and venous pressures. A wide range of supervised machine learning algorithms such as Decision Trees, Support Vector Machines (SVM), k-Nearest Neighbours (KNN) and ensemble algorithms were explored to construct a predictive model and evaluate the impact of variables on the functionality of the fistula. Results: The 10-fold cross-validated discriminant subspace-based ensemble algorithms attained 85% classification accuracy to predict the functionality of the fistula. Using the 95% confidence interval, the sensitivity and specificity found to be within 71.41% to 92.98% and 72.76% to 94.06%, respectively. The training accuracy of discriminant subspace-based ensemble algorithms was 87%, whereas some other ensemble algorithms such as Random Forest (RF) and ensemble of a subset of kNN classifiers showed 100% training accuracy. RF and kNN subspace-based ensemble attained around 77% accuracy during 10-fold cross-validation. The large difference in accuracy between training and testing by RF and kNN subspace-based ensemble reveals the models to be overfitted, and their inability to provide correct prediction when new data is presented. Therefore, discriminant subspace-based ensemble algorithms was used as the preferred classifier for our problem.Conclusion: These results show the potential of artificial intelligence to predict fistula failure in real world example from retrospect data. There is significant room to improve the accuracy of the classification algorithms.
Patients with chronic kidney disease stage 5 and those on immunosuppression are particularly vulnerable and are shielded as per public health strategy. We present our experience of coronavirus disease 2019 (COVID-19) transplant patients in one of the most affected parts of the UK with direct comparison to waitlisted patients.A single-center prospective study of symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive waitlisted and transplant patients was undertaken to compare these groups and assess clinical outcomes.A total of 60 consecutive symptomatic SARS-CoV-2 positive patients were identified with 32 active waitlisted patients and 28 functioning renal transplants. Demographics were similar. The incidence of symptomatic COVID-19 in the waitlisted group was 9.9% compared to 1.9% in renal transplant patients (P < 0.001). Immunosuppression did not influence initial symptomology. Fifteen percent of patients in the waitlisted and 32% in the transplant groups died (P = 0.726). Mortality as proportion of total waitlisted (321 patients) and transplant population (1434 patients) of our centre was 1.5% and 0.6% (P < 0.001), respectively. C-reactive protein (CRP) at 48 h and peak CRP were associated with mortality in both groups while quick sequential organ failure assessment score at 48 h (P = 0.036) was associated with mortality for transplant patients.Incidence of COVID-19 is higher in the waitlisted population but transplant patients have more severe disease, reflected by higher mortality. CRP at 48 h can be used as a predictive tool. In the absence of effective treatments, the current strategy of shielding is arguably the most important factor in protecting patients while resuming transplantation.
Renal allograft compartment syndrome (RACS) has recently been coined to describe early allograft dysfunction secondary to raised pressure in the retroperitoneal space. This may be caused by direct compression of the renal vessels or by a diffuse renal parenchymal compression. Herein, we report a renal allograft compartment syndrome secondary to a needle core transplant biopsy and discuss the management strategies in line with an updated literature review. A retrospective case-note review was carried out where a 45-year-old male had a transplant renal biopsy at 4-weeks after transplant for raising creatinine. Following biopsy patient developed abdominal discomfort and had haematuria. Doppler ultrasound scanning of graft demonstrated good perfusion but a small haematoma (2 × 2 × 2 cm) in the upper pole of the kidney at the site of the biopsy. Patient was thereafter assessed conservatively with serial ultrasound monitoring. After 24 h, significant deterioration of graft function was observed. The third scan, demonstrated reversed flow in diastole in the upper pole of the kidney with a resistive index of 1.0 in the main renal vessel. With the above findings the kidney transplant was explored immediately and the transplant released from a 300 ml of liquefied haematoma, which was under considerable pressure. In the next 24-h, the patient showed an immediate return of graft function. We recommend sequential ultrasound Doppler scanning as an invaluable tool to help identify early RACS. The surgical exploration and adequate heamostasis with surgical glue should be sought out in all RACS.
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder characterised by a genetic dysfunction that causes cystic malformation of the kidneys alongside features such as postaxial polydactyly, central obesity and a spectrum of learning difficulties. A rare cause of renal failure in children that ultimately requires transplantation at a very young age. We report the first case of successful renal transplantation in a 3 and a half year old child with both BBS and situs inversus totalis .
Patient and Methods
The patient had commenced peritoneal dialysis 14 months prior to transplant due to end-stage renal failure. Following transplant workup her father was deemed a suitable donor and a right sided hand assisted laparoscopic donor nephrectomy was performed. The recipient then underwent the transplant with a midline incision to allow access to the aorta and inferior vena cava to which the anastomoses were made. Anatomical reversal of the usual techniques used in paediatric transplantation were needed due to situs inversus. The kidney was then placed in the left iliac fossa. Native kidneys not removed and the abdomen was closed with peritoneal dialysis catheter removed at time of transplant.
Results
The patient recovered in the paediatric intensive care unit as per standard transplantation at the unit. Ultrasound imaging was performed immediately post operatively and showed good global perfusion of the kidney with no hydronephrosis or perinephric collection. The patient developed immediate graft function and was discharged with standardised outpatient follow up.
Discussion
Six cases of BBS and renal transplantation have been reported in literature and this is the first case report of a successful renal transplantation in a child with both BBS and situs inversus totalis. We therefore conclude that such anatomical malformations should not be considered a contra-indication for renal transplantation in children.
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