Characteristics of Early Antibody Mediated Rejection in Antibody Incompatible Living Donor Kidney Transplantation.

Antibody incompatible transplantation (AIT) may be an only option for highly sensitized patients. Severe form of early antibody mediated rejection (AMR) adversely affects graft survival after AIT. The aim of this study was to identify individuals at risk of AMR. We analyzed 213 living donor AITs performed at our center. Among 120 ABOi, 58 HLAi and 35 DSA + FCXM-negative cases, the rates of early AMR were 6%, 31%, and 9%, respectively (p < 0.001). On multivariate analysis for graft loss, early AMR had a HR of 3.28 (p < 0.001). The HLAi group had worse death-censored graft survival (p = 0.003). In the HLAi group, Patients with aggressive variant AMR (AAMR) had greater percentage of C3d complement fixing DSA, higher baseline class I and total DSA MFI levels and B-cell FCXM RMF. C1q and C3d complement fixing DSA and strong positivity of baseline B- or T-cell FXCM as predictors of AAMR had 100% sensitivity. Early AMR is of significant clinical concern in AIT as it results in poor graft survival and is not well described in literature. An aggressive variant is characterized by massive rise in DSA levels at rejection. Baseline DSA, C1q, and C3d and baseline FCXM values can be used to risk-stratify candidates for AIT.

British Transplantation Society guidelines on abdominal organ transplantation from deceased donors after circulatory death.

The British Transplantation Society (BTS) 'Guideline on transplantation from deceased donors after circulatory death' has recently been updated and this manuscript summarises the relevant recommendations in abdominal organ transplantation from Donation after Circulatory Death (DCD) donors, encompassing the chapters on liver, kidney, pancreas and islet cell transplantation.

Normothermic machine perfusion versus static cold storage in donation after circulatory death kidney transplantation: a randomized controlled trial.

Kidney transplantation is the optimal treatment for end-stage renal disease, but it is still severely limited by a lack of suitable organ donors. Kidneys from donation after circulatory death (DCD) donors have been used to increase transplant rates, but these organs are susceptible to cold ischemic injury in the storage period before transplantation, the clinical consequence of which is high rates of delayed graft function (DGF). Normothermic machine perfusion (NMP) is an emerging technique that circulates a warmed, oxygenated red-cell-based perfusate through the kidney to maintain near-physiological conditions. We conducted a randomized controlled trial to compare the outcome of DCD kidney transplants after conventional static cold storage (SCS) alone or SCS plus 1-h NMP. A total of 338 kidneys were randomly allocated to SCS (n = 168) or NMP (n = 170), and 277 kidneys were included in the final intention-to-treat analysis. The primary endpoint was DGF, defined as the requirement for dialysis in the first 7 d after transplant. The rate of DGF was 82 of 135 (60.7%) in NMP kidneys versus 83 of 142 (58.5%) in SCS kidneys (adjusted odds ratio (95% confidence interval) 1.13 (0.69-1.84); P = 0.624). NMP was not associated with any increase in transplant thrombosis, infectious complications or any other adverse events. A 1-h period of NMP at the end of SCS did not reduce the rate of DGF in DCD kidneys. NMP was demonstrated to be feasible, safe and suitable for clinical application. Trial registration number: ISRCTN15821205 .

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.

Outcomes of pregnancy in simultaneous pancreas and kidney transplant recipients: A single-center retrospective study.

Simultaneous pancreas and kidney (SPK) transplantation, in uremic women with insulin-dependent diabetes, increases the chance of a successful pregnancy and minimizes the risk to infants. The aim of this study was to document pregnancy and explore the challenges in this cohort of women. Retrospective analysis of women who underwent pancreas transplantation between January 1, 1998 and 8 January, 2019 was conducted. Seventeen pregnancies were identified in 13 women. Mean transplant-to-pregnancy interval was 4.6 years (range, 1.1-10.2 years). Eleven pregnancies resulted in live birth (65%), and six (35%) ended in miscarriage/fetal loss at a median gestational age of 8.5 weeks. Mean gestational age at delivery was 34.9 weeks (SD ±3 weeks). Preeclampsia and C-section rates were 77% and 67%, respectively. Adverse fetal and graft outcomes were observed in 100% of unplanned pregnancies, compared to 10% of planned pregnancies (P < .001). One kidney allograft was lost during pregnancy; one pancreas and two kidney allografts were lost within 3 years of pregnancy. This is a high-risk group for grafts and offspring. Pre-pregnancy planning is vital. A multidisciplinary approach by obstetric and transplant teams is important pre-pregnancy, antenatally, and peripartum. This is the largest published series of pregnancies in SPK recipients from a single center.

Effect of delayed graft function on longer-term outcomes after kidney transplantation from donation after circulatory death donors in the United Kingdom: A national cohort study.

Kidneys from donation after circulatory death (DCD) donors are utilized variably worldwide, in part due to high rates of delayed graft function (DGF) and putative associations with adverse longer-term outcomes. We aimed to determine whether the presence of DGF and its duration were associated with poor longer-term outcomes after kidney transplantation from DCD donors. Using the UK transplant registry, we identified 4714 kidney-only transplants from controlled DCD donors to adult recipients between 2006 and 2016; 2832 recipients (60·1%) had immediate graft function and 1882 (39·9%) had DGF. Of the 1847 recipients with DGF duration recorded, 926 (50·1%) had DGF < 7 days, 576 (31·2%) had DGF 7-14 days, and 345 (18·7%) had DGF >14 days. After risk adjustment, the presence of DGF was not associated with inferior long-term graft or patient survivals. However, DGF duration of >14 days was associated with an increased risk of death-censored graft failure (hazard ratio 1·7, p = ·001) and recipient death (hazard ratio 1·8, p < ·001) compared to grafts with immediate function. This study suggests that shorter periods of DGF have no adverse influence on graft or patient survival after DCD donor kidney transplantation and that DGF >14 days is a novel early biomarker for significantly worse longer-term outcomes.

The use of third-party packed red blood cells during ex situ normothermic machine perfusion of organs for transplantation: Underappreciated complexities?

Ex situ normothermic machine perfusion (NMP) is being used increasingly in the assessment of higher risk deceased donor organs and to facilitate prolonged organ storage. Third-party packed red blood cells (pRBCs) are often used as an oxygen carrier in the perfusate of ex situ NMP. Despite the increasing interest in NMP, comparatively little attention has been paid to the appropriate selection of pRBCs. This includes the choice of ABO blood group and Rhesus D status, the need for special requirements for selected recipients, and the necessity for traceability of blood components. Flushing organs with cold preservation solution after NMP removes the overwhelming majority of third-party allogeneic pRBCs, but residual pRBCs within the organ may have biologically relevant effects following implantation as they enter the recipient's circulation. This review considers these issues, and suggests that national transplant and blood transfusion agencies work together to develop a co-ordinated approach within each country. This is especially important given the possibility of organ re-allocation between centers after ex situ NMP, and the ongoing development of organ perfusion hubs.

Spinal Cord Ischemia in Pancreas Transplantation: The UK Experience.

BACKGROUND: Spinal cord ischemia (SCI) is a rare but devastating condition that can occur in the perioperative period resulting in paraplegia. Although diabetes mellitus is a risk factor for SCI in other types of major surgery, SCI is not widely recognized in transplantation. The aim of this study was to quantify the risk of SCI in pancreatic transplantation. METHODS: All UK pancreas transplant units were surveyed between 2017 and 2018. The risk of SCI in pancreas transplantation was estimated using the number of radiologically confirmed cases relative to the number of pancreatic transplants from UK registry data during the same time period. RESULTS: There have been 6 cases of SCI during pancreas transplantation since 2002. No aortic clamping occurred in any recipient. During or after surgery, all patients experienced episodes of hypotension (systolic blood pressure ≤ 90 mm Hg) before the onset of neurological symptoms. Epoprostenol, epidural anesthesia, and postoperative hemodialysis may have contributed to systemic hypotension. The mainstay of early treatment for SCI for all cases was blood pressure control. CONCLUSIONS: Based on these findings, there is approximately a 1:440 risk of SCI in pancreas transplantation. Hypotension appears to be a prominent risk factor. Strategies for mitigating the risk of SCI are discussed, drawing on evidence from thoraco-abdominal aortic aneurysm surgery. The risk of long-term neurological deficit should be discussed with prospective pancreas recipients given the potential impact on posttransplant quality of life.

UK renal transplant outcomes in low and high BMI recipients: the need for a national policy.

INTRODUCTION: We assessed the effect of recipient body mass index (BMI) on the outcomes of renal transplantation and the management of obese patients with end-stage renal disease across the UK. METHODS: We analyzed data of 25539 adult renal transplants (2007-2016) from the UK Transplant Registry. Patients were divided in BMI groups [underweight: < 18.5, normal: 18.5-24.9 (reference group), overweight: 25-29.9, class I obese: 30-34.9, class II/III obese: ≥ 35]. We also conducted a national survey of all UK renal transplant centers on the influence of BMI on decisions regarding management of renal transplant candidates. RESULTS: BMI ≥ 25 was an independent risk factor for delayed graft function and primary non-function (p ≤ 0.001). Underweight (p = 0.001), class I obese (p = 0.017) and class II/III obese recipients (p < 0.001) had poorer graft survival, however, 5- and 10-year graft survival rates were good. Patient survival was shorter for underweight recipients (p < 0.001) and longer for overweight (p = 0.028) and class I obese recipients (p = 0.013). The national survey revealed significant variability among transplant centers in BMI threshold for listing patients on transplant waiting list and limited support with conservative or surgical procedures for weight control. CONCLUSIONS: Obesity alone should not be a barrier for renal transplantation. A national strategy is required to give all patients equal chances in transplantation.

Dissemination of a novel organ perfusion technique: ex vivo normothermic perfusion of deceased donor kidneys.

Ex vivo normothermic perfusion (EVNP) technology is a promising means of organ preservation, assessment, and preconditioning prior to kidney transplantation, which has been pioneered by a single group. We describe the challenges of setting up clinical EVNP programs in 2 new centers, as well as early patient outcomes. Governance, training, and logistical pathways are described. In order to demonstrate safety and proficiency in this new technique, early patient outcomes are also described. Patient outcomes included the incidence of primary nonfunction, delayed graft function, graft and patient survival at 1 year. Contralateral kidneys undergoing static cold storage alone were used as a comparator group. Between March 2016 and July 2017, EVNP was performed on 14 kidneys from 12 donors (11 kidneys in center 1, 3 kidneys in center 2). Of the 14 kidneys that underwent EVNP, 12 organs were implanted into 10 recipients. Two pairs of kidneys were implanted as dual grafts and 1 kidney was implanted simultaneously with a pancreas. The remaining 7 kidneys were transplanted as single allografts. Seven pairs of kidneys were available for paired analysis comparing EVNP versus static cold storage. Graft and patient outcomes were comparable between the 2 preservation techniques. The introduction of a clinical EVNP service requires a careful multimodal approach, drawing on the expertise of specialists in transplantation, hematology, and microbiology. Both new clinical EVNP programs demonstrated proficiency and safety when a structured dissemination process was followed.

Duration of delayed graft function and outcomes after kidney transplantation from controlled donation after circulatory death donors: a retrospective study.

The impact of the duration of delayed graft function (DGF) on graft survival is poorly characterized in controlled donation after circulatory death (DCD) donor kidney transplantation. A retrospective analysis was performed on 225 DCD donor kidney transplants between 2011 and 2016. When patients with primary nonfunction were excluded (n = 9), 141 recipients (65%) had DGF, with median (IQR) duration of dialysis dependency of 6 (2-11.75) days. Longer duration of dialysis dependency was associated with lower estimated glomerular filtration rate at 1 year, and a higher rate of acute rejection. On Kaplan-Meier analysis, the presence of DGF was associated with lower graft survival (log-rank test P = 0.034), though duration of DGF was not (P = 0.723). However, multivariable Cox regression analysis found that only acute rejection was independently associated with lower graft survival [HR (95% CI) 4.302 (1.617-11.450); P = 0.003], whereas the presence of DGF and DGF duration were not. In controlled DCD kidney transplantation, DGF duration itself may not be independently associated with graft survival; rather, it may be that acute rejection associated with prolonged DGF is the poor prognostic factor.

Chronic histological changes in deceased donor kidneys at implantation do not predict graft survival: a single-centre retrospective analysis.

The use of preimplantation kidney biopsies (PIKBs) to aid deceased donor kidney utilization decisions is controversial. Outcomes of transplants that had been biopsied after the decision had been made to implant were analysed, in order to determine the association between chronic histological changes at implantation and graft outcomes. A retrospective analysis of transplants between the year range 2006-2015 was performed. Karpinski scores on biopsies were collected, and graft outcomes were analysed using univariate and multivariable techniques. Also, Karpinski scores from single and dual kidney transplants from older donors were examined to determine if knowledge of the score preoperatively would have altered utilization. Four hundred and eight single kidneys were transplanted. Although kidneys with scores >4 had lower 1- and 3-year median (IQR) estimated glomerular filtration rates (eGFRs) than those scoring 0-4 (51 (37-66) vs. 35 (26-52) ml/min/1.73 m2 , P < 0.001, and 52 (34-64) vs. 35 (24-52) ml/min/1.73 m2 , P < 0.001, respectively), there was no significant association between Karpinski score and death-censored graft survival on univariate or multivariable analyses. The utilization analysis (75 single and 25 dual kidney transplant recipients) suggested that systematic use of PIKBs would have resulted in 29% fewer patients being transplanted. This analysis does not support the systematic use of PIKBs to determine deceased donor kidney utilization.

Mobile learning in medicine: an evaluation of attitudes and behaviours of medical students.

BACKGROUND: Mobile learning (mLearning) devices (such as tablets and smartphones) are increasingly part of the clinical environment but there is a limited and somewhat conflicting literature regarding the impact of such devices in the clinical learning environment. This study aims to: assess the impact of mLearning devices in the clinical learning environment on medical students' studying habits, attitudes towards mobile device supported learning; and the perceived reaction of clinicians and patients to the use of these devices as part of learning in the clinical setting. METHODS: Over three consecutive academic years, 18 cohorts of medical students (total n = 275) on a six-week rotation at a large teaching hospital in London were supplied with mLearning devices (iPad mini) to support their placement-based learning. Feedback on their experiences and perceptions was collected via pre- and post-use questionnaires. RESULTS: The results suggest mLearning devices have a positive effect on the students' perceived efficiency of working, while experience of usage not only confirmed pre-existing positive opinions about devices but also disputed some expected limitations associated with mLearning devices in the clinical workplace. Students were more likely to use devices in 'down-time' than as part of their clinical learning. As anticipated, both by users and from the literature, universal internet access was a major limitation to device use. The results were inconclusive about the student preference for device provision versus supporting a pre-owned device. CONCLUSION: M-learning devices can have a positive impact on the learning experiences medical students during their clinical attachments. The results supported the feasibility of providing mLearning devices to support learning in the clinical environment. However, universal internet is a fundamental limitation to optimal device utilisation.

Graft nephrectomy in children.

Kidney transplantation is recognised as the gold standard treatment of end-stage renal disease in most children, with excellent graft survival rates. When graft failure occurs, renal transplant recipients (RTRs) have the option of removal of the transplant (graft nephrectomy [GN]), or leaving the failed transplant in situ. The aims of this review are to discuss the indications for GN, surgical techniques, outcomes after GN (including risks of allosensitisation and the impact on subsequent transplants), and the possible role of routine GN in the asymptomatic RTR with a failed renal allograft. Literature in both the pediatric and adult renal transplant fields is reviewed. We also discuss how future research in this area could advance our knowledge of which patients to select for GN, and the most appropriate surgical approach.