European Society for Organ Transplantation (ESOT)-TLJ 3.0 Consensus on Histopathological Analysis of Pre-Implantation Donor Kidney Biopsy: Redefining the Role in the Process of Graft Assessment.

The ESOT TLJ 3.0. consensus conference brought together leading experts in transplantation to develop evidence-based guidance on the standardization and clinical utility of pre-implantation kidney biopsy in the assessment of grafts from Expanded Criteria Donors (ECD). Seven themes were selected and underwent in-depth analysis after formulation of PICO (patient/population, intervention, comparison, outcomes) questions. After literature search, the statements for each key question were produced, rated according the GRADE approach [Quality of evidence: High (A), Moderate (B), Low (C); Strength of Recommendation: Strong (1), Weak (2)]. The statements were subsequently presented in-person at the Prague kick-off meeting, discussed and voted. After two rounds of discussion and voting, all 7 statements reached an overall agreement of 100% on the following issues: needle core/wedge/punch technique representatively [B,1], frozen/paraffin embedded section reliability [B,2], experienced/non-experienced on-call renal pathologist reproducibility/accuracy of the histological report [A,1], glomerulosclerosis/other parameters reproducibility [C,2], digital pathology/light microscopy in the measurement of histological variables [A,1], special stainings/Haematoxylin and Eosin alone comparison [A,1], glomerulosclerosis reliability versus other histological parameters to predict the graft survival, graft function, primary non-function [B,1]. This methodology has allowed to reach a full consensus among European experts on important technical topics regarding pre-implantation biopsy in the ECD graft assessment.

Proposed Definitions of T Cell-Mediated Rejection and Tubulointerstitial Inflammation as Clinical Trial Endpoints in Kidney Transplantation.

The diagnosis of acute T cell-mediated rejection (aTCMR) after kidney transplantation has considerable relevance for research purposes. Its definition is primarily based on tubulointerstitial inflammation and has changed little over time; aTCMR is therefore a suitable parameter for longitudinal data comparisons. In addition, because aTCMR is managed with antirejection therapies that carry additional risks, anxieties, and costs, it is a clinically meaningful endpoint for studies. This paper reviews the history and classifications of TCMR and characterizes its potential role in clinical trials: a role that largely depends on the nature of the biopsy taken (indication vs protocol), the level of inflammation observed (e.g., borderline changes vs full TCMR), concomitant chronic lesions (chronic active TCMR), and the therapeutic intervention planned. There is ongoing variability-and ambiguity-in clinical monitoring and management of TCMR. More research, to investigate the clinical relevance of borderline changes (especially in protocol biopsies) and effective therapeutic strategies that improve graft survival rates with minimal patient morbidity, is urgently required. The present paper was developed from documentation produced by the European Society for Organ Transplantation (ESOT) as part of a Broad Scientific Advice request that ESOT submitted to the European Medicines Agency for discussion in 2020. This paper proposes to move toward refined definitions of aTCMR and borderline changes to be included as primary endpoints in clinical trials of kidney transplantation.

Proposed Definitions of Antibody-Mediated Rejection for Use as a Clinical Trial Endpoint in Kidney Transplantation.

Antibody-mediated rejection (AMR) is caused by antibodies that recognize donor human leukocyte antigen (HLA) or other targets. As knowledge of AMR pathophysiology has increased, a combination of factors is necessary to confirm the diagnosis and phenotype. However, frequent modifications to the AMR definition have made it difficult to compare data and evaluate associations between AMR and graft outcome. The present paper was developed following a Broad Scientific Advice request from the European Society for Organ Transplantation (ESOT) to the European Medicines Agency (EMA), which explored whether updating guidelines on clinical trial endpoints would encourage innovations in kidney transplantation research. ESOT considers that an AMR diagnosis must be based on a combination of histopathological factors and presence of donor-specific HLA antibodies in the recipient. Evidence for associations between individual features of AMR and impaired graft outcome is noted for microvascular inflammation scores ≥2 and glomerular basement membrane splitting of >10% of the entire tuft in the most severely affected glomerulus. Together, these should form the basis for AMR-related endpoints in clinical trials of kidney transplantation, although modifications and restrictions to the Banff diagnostic definition of AMR are proposed for this purpose. The EMA provided recommendations based on this Broad Scientific Advice request in December 2020; further discussion, and consensus on the restricted definition of the AMR endpoint, is required.

Risks for donors associated with living kidney donation: meta-analysis.

BACKGROUND: Living kidney donation risk is likely to differ according to donor's demographics. We aimed to analyse the effects of age, sex, body mass index (BMI) and ethnicity. METHODS: A systematic review and meta-analysis was undertaken of the effects of preoperative patient characteristics on donor kidney function outcomes, surgical complications, and hypertension. RESULTS: 5129 studies were identified, of which 31 met the inclusion criteria, mainly from the USA and Europe. The estimated glomerular filtration rate (eGFR) in donors aged over 60 years was a mean of 9.54 ml per min per 1.73 m2 lower than that of younger donors (P < 0.001). Female donors had higher relative short- and long-term survival. BMI of over 30 kg/m2 was found to significantly lower the donor's eGFR 1 year after donation: the eGFR of obese donors was lower than that of non-obese patients by a mean of -2.70 (95 per cent c.i. -3.24 to -2.15) ml per min per 1.73 m2 (P < 0.001). Obesity was also associated with higher blood pressure both before and 1 year after donation, and a higher level of proteinuria, but had no impact on operative complications. In the long term, African donors were more likely to develop end-stage renal disease than Caucasians. CONCLUSION: Obesity and male sex were associated with inferior outcomes. Older donors (aged over 60 years) have a larger eGFR decline than younger donors, and African donors have a higher incidence of ESRD than Caucasians.

Managing immunosuppressive therapy in potentially cured post-kidney transplant cancer (excluding non-melanoma skin cancer): an overview of the available evidence and guidance for shared decision-making.

Kidney transplant recipients (KTRs) have increased incidence of de novo cancers. After having undergone treatment for cancer with curative intent, reducing the overall immunosuppressive load and/or switching to an alternative drug regimen may potentially be of great benefit to avoid cancer recurrence, but should be balanced against the risks of rejection and/or severe adverse events. The TLJ (Transplant Learning Journey) project is an initiative from the European Society for Organ Transplantation (ESOT). This article reports a systematic literature search undertaken by TLJ Workstream 3 to answer the questions: (1) Should we decrease the overall anti-rejection therapy in potentially cured post-kidney transplant cancer (excluding non-melanoma skin cancer)? (2) Should we switch to mammalian target of rapamycin inhibitors (mTORi) in potentially cured post-kidney transplant cancer (excluding non-melanoma skin cancer)? The literature search revealed insufficient solid data on which to base recommendations, so this review additionally presents an extensive overview of the indirect evidence on the benefits versus risks of alterations in immunosuppressive medication. We hope this summary will help transplant physicians advise KTRs on how best to continue with anti-rejection therapy after receiving cancer treatment with curative intent, and aid shared decision-making, ensuring that patient preferences are taken into account.

Systematic Review and Meta-Analysis of Posttransplant Hepatic Artery and Biliary Complications in Patients Treated With Transarterial Chemoembolization Before Liver Transplantation.

BACKGROUND: Hepatic artery complications are feared complications after liver transplantation and may compromise the biliary tract, graft, and patient survival. The objective of this systematic review and meta-analysis was to compare risk of hepatic artery and biliary complications after liver transplantation in patients who underwent neoadjuvant transarterial chemoembolization (TACE) versus no TACE. METHODS: Comprehensive searches were performed in Embase, MEDLINE OvidSP, Web of Science, Google Scholar, and Cochrane databases to identify studies concerning hepatocellular cancer patients undergoing preliver transplantation TACE. Quality assessment of studies was done by the validated checklist of Downs and Black. Meta-analyses were performed to evaluate the incidence of all hepatic artery complications, hepatic artery thrombosis, and biliary tract complications, using binary random-effect models. RESULTS: Fourteen retrospective studies, representing 1122 TACE patients, met the inclusion criteria. Postoperative hepatic artery complications consisted of hepatic artery thrombosis, stenosis, and (pseudo)-aneurysms. Preliver transplantation TACE was significantly associated with occurrence of posttransplant hepatic artery complications (odds ratio, 1.57; 95% confidence interval, 1.09-2.26; P = 0.02). No significant association between neoadjuvant TACE and hepatic artery thrombosis alone or biliary tract complications was found. CONCLUSIONS: Patients treated with TACE before liver transplantation may be at increased risk for development of hepatic artery complications after liver transplantation.

Does belatacept improve outcomes for kidney transplant recipients? A systematic review.

BACKGROUND: Belatacept was intended to provide better outcomes for kidney transplant (KT) recipients by allowing minimization/withdrawal of calcineurin inhibitors (CNI) and steroids. METHODS: We searched for randomized controlled trials (RCTs) in adult KT comparing belatacept with CNIs. Methodological quality was assessed. Meta-analyses were performed to calculate odds ratios (OR) and mean differences (MD). RESULTS: Six RCTs were included. Pooled analyses found no differences for acute rejection at any time point. Renal function [Calculated glomerular filtration rate (cGFR)] was better with belatacept at 12 and 24 months (MD = 11.7 and 13.7 ml/min/1.73 m(2) ). New onset diabetes after transplantation was lower with belatacept at 12 months (OR = 0.43). Systolic and diastolic blood pressures were lower at 12 months (MD -7.2 and -3.1 mmHg) as were triglycerides at 12 and 24 months (MD = -32.9 and -41.7 mg/dl). Total and low-density lipoprotein cholesterol were lower with belatacept at 24 months (MD = -19.8 and -10.6 mg/dl). There were no differences for other outcomes. CONCLUSION: Limited available data suggest a potential benefit for belatacept by reducing the risk of CNI toxicity, especially renal function, without evidence of increased acute rejection. There were no safety issues apart from a possible risk of post-transplant lymphoproliferative disorder in Epstein-barr virus-seronegative recipients. Further studies are required to confirm this benefit.

Evidence-based medicine in daily surgical decision making: a survey-based comparison between the UK and Germany.

BACKGROUND: Evidence-based medicine (EbM) is a vital part of reasonable and conclusive decision making for clinicians in daily clinical work. To analyze the knowledge and the attitude of surgeons towards EbM, a survey was performed in the UK and Germany. METHODS: A web-based questionnaire was distributed via mailing lists from the Royal College of Surgeons of England (RCSE) and the Berufsverband Deutscher Chirurgen (BDC). Our primary aim was to get information about knowledge of EbM amongst German and British surgeons. RESULTS: A total of 549 individuals opened the questionnaire, but only 198 questionnaires were complete and valid for analysis. In total, 40,000 recipients were approached via the mailing lists of the BDC and RCSE. The response rate was equally low in both countries. On a scale from 1 (unimportant) to 10 (very important), all participants rated EbM as very important for daily clinical decision making (7.3 ± 1.9) as well as for patients (7.8 ± 1.9) and the national health system (7.8 ± 1.9). On a scale from 1 (unimportant) to 5 (very important), systematic reviews (4.6 ± 0.6) and randomized controlled trials (4.6 ± 0.6) were identified as the highest levels of study designs to enhance evidence in medicine. British surgeons considered EbM to be more important in daily clinical work when compared to data from German surgeons (7.9 ± 1.6 vs. 6.7 ± 2.1, p < 0.001). Subgroup analysis showed different results in some categories; however, a pattern to explain the differences was not evident. Personal requirements expressed in a free text field emphasized the results and reflected concerns such as broad unwillingness and lack of interdisciplinary approaches for patients (n = 59: 25 in the UK and 34 in Germany). CONCLUSION: The overall results show that EbM is believed to be important by surgeons in the UK and Germany. However, perception of EbM in the respective health system (UK vs. Germany) may be different. Nonetheless, EbM is an important tool to navigate through daily clinical problems although a discrepancy between the knowledge of theoretical abstract terms and difficulties in implementing EbM in daily clinical work has been detected. The provision of infrastructure, courses and structured education as a permanent instrument will advance the knowledge, application and improvement of EbM in the future.

Do wound complications or lymphoceles occur more often in solid organ transplant recipients on mTOR inhibitors? A systematic review of randomized controlled trials.

mTOR inhibitors have been associated with wound complications and lymphoceles. We systematically reviewed randomized controlled trials (RCTs) to compare these outcomes for solid organ transplant recipients. Relevant medical databases were searched to identify RCTs in solid organ transplantation comparing mTOR inhibitors with an alternative therapy reporting on wound complications and/or lymphoceles. Methodological quality of RCTs was assessed. Pooled analyses were performed to calculate odds ratios (OR) and 95% confidence intervals (CI). Thirty-seven RCTs in kidney, heart, simultaneous pancreas-kidney and liver transplantation were included. Pooled analyses showed a higher incidence of wound complications (OR 1.77, CI 1.31-2.37) and lymphoceles (OR 2.07, CI 1.62-2.65) for kidney transplant recipients on mTOR inhibitors together with calcineurin inhibitors (CNIs). There was also a higher incidence of wound complications (OR 3.00, CI 1.61-5.59) and lymphoceles (OR 2.13, CI 1.57-2.90) for kidney transplant recipients on mTOR inhibitors together with antimetabolites. Heart transplant patients receiving mTOR inhibitors together with CNIs also reported more wound complications (OR 1.82, CI 1.15-2.87). We found a higher incidence of wound complications and lymphoceles after kidney transplantation and a higher incidence of wound complications after heart transplantation for immunosuppressive regimens that included mTOR inhibitors from the time of transplantation.

The effect of ankle taping on detection of inversion-eversion movements in participants with recurrent ankle sprain.

BACKGROUND: Taping is often used to counter the proprioceptive deficit after joint injury such as ankle sprain. However, the effect of taping on proprioceptive acuity at the ankle is unclear, with conflicting findings. HYPOTHESIS: Application of tape improves detection of inversion and eversion movements at the ankle. STUDY DESIGN: Controlled laboratory study. METHODS: The 70% threshold for movement detection was measured in 16 participants with recurrent ankle sprain under 2 conditions: with the ankle taped or untaped. The threshold for movement detection was examined at 3 velocities (0.1 deg/s, 0.5 deg/s, and 2.5 deg/s) and in 2 directions (inversion and eversion). RESULTS: Application of tape significantly decreased the ability to detect movements at the ankle (P < .023). For example, at 0.5 deg/s, the 70% detection threshold was 3.40 degrees +/- 1.05 degrees in inversion and 3.49 degrees +/- 1.15 degrees in eversion at the untaped ankle, and 4.02 degrees +/- 0.86 degrees in inversion and 4.04 degrees +/- 0.89 degrees in eversion at the taped ankle. CONCLUSION: Taping the ankle decreased the ability to detect movement in the inversion-eversion plane in participants with recurrent ankle sprain. CLINICAL RELEVANCE: The findings suggest that the efficacy of taping is unlikely to be explained by an enhanced ability to detect inversion or eversion movements. However, because it has been found effective in reducing the incidence of ankle sprain, clinicians should continue taping to reduce the likelihood of resprain.