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Allosensitization represents a major barrier to heart transplantation (HTx). We assessed the efficacy and safety of complement inhibition at transplant in highly sensitized heart transplant recipients. We performed a single-center, single-arm, open-label trial (NCT02013037). Patients with panel reactive antibodies (PRA) ≥70% and pre-formed donor-specific antibodies (DSA) were eligible. In addition to standard of care, patients received nine infusions of eculizumab during the first 2 months posttransplant. The primary composite endpoint was antibody-mediated rejection (AMR) ≥pAMR2 and/or left ventricular dysfunction during the first year. Secondary endpoints included hemodynamic compromise, allograft rejection, and patient survival. Twenty patients were included. Median cPRA and mean fluorescence intensity of immunodominant DSA were 95% (90%-97%) and 6250 (5000-10 000), respectively. Retrospective B cell and T cell flow crossmatches were positive in 14 and 11 patients, respectively. The primary endpoint occurred in four patients (20%). Survival at 1 year was 90% with no deaths resulting from AMR. In a prespecified analysis comparing treated patients to matched control patients, we observed a dramatic reduction in the risk of biopsy-proven AMR in patients treated with eculizumab (HR = 0.36, 95% CI = 0.14-0.95, p = .032). Our findings support the prophylactic use of complement inhibition for heart transplantation at high immunological risk. ClinincalTrials.gov, NCT02013037.

The transplantation field requires the identification of specific risk factors associated with the level of immunosuppression. Here, our aim was to analyze the association between the number of circulating lymphocytes, monitored routinely by complete blood cell counts during outpatient visits, and patient and graft survival. In total, 2,999 kidney or combined kidney-pancreas recipients transplanted between 2000 and 2016, from two University hospitals, were enrolled. We investigated the etiological relationship between time-dependent lymphocyte count beyond one year after transplantation and patient and graft survival, viral infection and cancer risk using time-dependent multivariate Cox models. Model 1 considered kidney function at one year and model 2 as time-dependent variable. At the time of inclusion (one year after transplantation), 584 patients (19.4%) had deep lymphopenia (under 750 /mm3) and 1,072 (35.7%) had a normal count (over 1,500 /mm3). A patient with deep lymphopenia at a given follow-up time had significantly higher risks of graft failure, death and viral infection than comparable patients with a normal lymphocyte count at the same time point. Thus, after the first year of transplantation, the occurrence of deep lymphopenia within a patient's follow-up is a risk factor for long-term graft failure, death and viral infection.

Background Over the past decades, an international group of experts iteratively developed a consensus classification of kidney transplant rejection phenotypes, known as the Banff classification. Data-driven clustering of kidney transplant histologic data could simplify the complex and discretionary rules of the Banff classification, while improving the association with graft failure. Methods The data consisted of a training set of 3510 kidney-transplant biopsies from an observational cohort of 936 recipients. Independent validation of the results was performed on an external set of 3835 biopsies from 1989 patients. On the basis of acute histologic lesion scores and the presence of donor-specific HLA antibodies, stable clustering was achieved on the basis of a consensus of 400 different clustering partitions. Additional information on kidney-transplant failure was introduced with a weighted Euclidean distance. Results Based on the proportion of ambiguous clustering, six clinically meaningful cluster phenotypes were identified. There was significant overlap with the existing Banff classification (adjusted rand index, 0.48). However, the data-driven approach eliminated intermediate and mixed phenotypes and created acute rejection clusters that are each significantly associated with graft failure. Finally, a novel visualization tool presents disease phenotypes and severity in a continuous manner, as a complement to the discrete clusters. Conclusions A semisupervised clustering approach for the identification of clinically meaningful novel phenotypes of kidney transplant rejection has been developed and validated. The approach has the potential to offer a more quantitative evaluation of rejection subtypes and severity, especially in situations in which the current histologic categorization is ambiguous.

The European Society for Organ Transplantation (ESOT) submitted a Broad Scientific Advice request to the European Medicines Agency (EMA) in 2018, to explore whether updating guidelines on clinical trial endpoints would encourage innovations in kidney transplantation research, thereby improving long-term outcomes for allograft recipients. The request was refined collaboratively by the EMA and ESOT, with the EMA issuing a final response in December 2020. This Transplant International special issue explores the topics that were the focus of these interactions between the EMA and ESOT. Articles explore the current issues and dilemmas in kidney transplantation, primarily relating to unclear or outdated risk stratification and markers of transplantation success, although several potential improvements for outcomes assessment are also suggested. Discussions between the EMA and ESOT and recommendations are summarized, in the hope that this project will generate further discussion eventually generating a consensus on clinical trial endpoints and risk stratification, increase the quality of research in transplantation medicine, and improve long-term outcomes for kidney transplant recipients. ispartof: TRANSPLANT INTERNATIONAL vol:35 ispartof: location:Switzerland status: published

Contains fulltext : 252103.pdf (Publisher’s version ) (Open Access) Conditional marketing authorization (CMA) facilitates timely access to new drugs for illnesses with unmet clinical needs, such as late graft failure after kidney transplantation. Late graft failure remains a serious, burdensome, and life-threatening condition for recipients. This article has been developed from content prepared by members of a working group within the European Society for Organ Transplantation (ESOT) for a Broad Scientific Advice request, submitted by ESOT to the European Medicines Agency (EMA), and reviewed by the EMA in 2020. The article presents the rationale for using surrogate endpoints in clinical trials aiming at improving late graft failure rates, to enable novel kidney transplantation therapies to be considered for CMA and improve access to medicines. The paper also provides background data to illustrate the relationship between primary and surrogate endpoints. Developing surrogate endpoints and a CMA strategy could be particularly beneficial for studies where the use of primary endpoints would yield insufficient statistical power or insufficient indication of long-term benefit following transplantation.

Contains fulltext : 252052.pdf (Publisher’s version ) (Open Access) Clinical study endpoints that assess the efficacy of interventions in patients with chronic renal insufficiency can be adopted for use in kidney transplantation trials, given the pathophysiological similarities between both conditions. Kidney dysfunction is reflected in the glomerular filtration rate (GFR), and although a predefined (e.g., 50%) reduction in GFR was recommended as an endpoint by the European Medicines Agency (EMA) in 2016, many other endpoints are also included in clinical trials. End-stage renal disease is strongly associated with a change in estimated (e)GFR, and eGFR trajectories or slopes are increasingly used as endpoints in clinical intervention trials in chronic kidney disease (CKD). Similar approaches could be considered for clinical trials in kidney transplantation, although several factors should be taken into account. The present Consensus Report 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 EMA in 2020. This paper provides a contemporary discussion of primary endpoints used in clinical trials involving CKD, including proteinuria and albuminuria, and evaluates the validity of these concepts as endpoints for clinical trials in kidney transplantation.

BACKGROUND AND AIMS Graphical Abstract In kidney transplantation, day-zero biopsies are used to assess organ quality and discriminate lesions inherited from the donor or acquired after transplantation. However, many centres worldwide do not perform those biopsies which remain invasive, costly and may delay the transplant procedure. We aimed to develop and validate a noninvasive virtual biopsy system. METHOD A total of 17 centres were included from Europe, North America and Australia from 2000 to 2019. Candidate predictors were assessed following a prespecified protocol. Outcome measures were the day-zero biopsy lesions (Banff classification) including CV, AH, IFTA scores and % of sclerotic glomeruli. Six machine learning models were developed and their performances were assessed. RESULTS A total of 12 992 day-zero biopsies were included. Eleven parameters were used to build the classifiers, including donor age, kidney function, hypertension, BMI, proteinuria, diabetes, sex, donor type, cause of death and Hep-C status. The ensemble models (random forests, neural networks, gradient boosting, extreme gradient boosting tree, linear discriminant analysis, and naive Bayes) showed multi-AUC of 0.738, 0.817 and 0.788 for prediction of CV, AH and IFTA scores, and a good performance for predicting glomerulosclerosis (mean absolute error, MAE = 4.766). We confirmed the robustness and generalizability in multiple clinical scenarios and subpopulations and built an online interface for clinicians: https://transplant-pred/Virtual_Biopsy. CONCLUSION We developed and validated the first virtual biopsy system that enables the prediction of day-zero biopsy, based on routinely collected parameters. This can assist clinicians in assessing allograft quality, discrimination of donor derived versus acquired lesions after transplantation and prevent overdiagnosis of calcineurin inhibitor (CNI) toxicity.

BACKGROUND AND AIMS Predicting kidney transplant patient mortality has been hampered by registry-based studies and low-level phenotyped cohorts without specific design towards mortality prediction. This represents a limitation for decision making and ultimately patient care. We aimed to build a robust patient mortality prognostication system. METHOD We enrolled 1446 patients transplanted in France between 2004 and 2014 in whom a protocol-based collection including more than 160 parameters from the recipient (past medical history, risk factors) donor and graft, biological and imaging data, was performed on the day of transplantation (TX) and during the first year of transplantation. Multivariable Cox model was used to develop an individual predictive score of mortality, further improved by a Lasso regression in order to retain the strongest predictors of mortality. RESULTS Among the 1446 kidney transplant recipients included, 309 patients died after a median post-TX follow-up time of 7.6 years (IQR 5.40–10.78). Among the 120 parameters, 19 predictors were selected using lasso regression. The strongest predictors of patient survival were (1) baseline recipient factors (age, history of cancer, diabetes mellitus, chronic obstructive pulmonary disease, cardiovascular events: myocardial infarction, stroke or arteritis, supraventricular cardiac rhythm disorder, psychiatric history and VHC status); (2) post-TX parameters (need for dialysis, cardiovascular complications and cancer in the first year of TX); and (3) seven biological variables (HbA1c, C-reactive protein, albumin, gamma-glutamyl transferase, uric acid, neutrophils and urinary protein). The mortality score showed accurate calibration and discrimination at 10 years [C-statistic = 0.81; 95% confidence interval (95% CI) 0.78–0.83]. CONCLUSION We generate the first integrative patient survival score that shows a superior prediction performance when compared to previous prognostic systems, reaching 81% prediction accuracy at 10 years. A reliable survival prediction tool will enable improved patient monitoring and therapeutic decision making to alter the course of an unfavorable patient survival outcome and may provide a surrogate endpoint in clinical trials.

BACKGROUND AND AIMS Conversion to a belatacept regimen after transplant seems to be safe. However, no studies have reported the long-term efficacy and safety outcomes after conversion to a belatacept regimen and compared it with patients treated with a CNI-based regimen in kidney transplantation. This study aims to investigate the long-term outcomes of patients converted to a belatacept regimen compared with matched patients under a CNI regimen. METHOD Kidney transplant recipients transplanted between 1998 and 2019 from two French academic transplant canters were recruited. We used a propensity score to match with a 1:1 ratio of patients at the time of the biopsy, which indicates the conversion to a belatacept regimen to control patients under a CNI regimen with a biopsy after transplant. We used 11 parameters associated with graft survival for the matching, 4 baseline transplant characteristics (recipient age, prior transplant status, donor type and dgf) and 7 at time of the biopsy (time after transplant, eGFR, proteinuria, DSA and Banff scores cv, ah, IFTA). Transplant outcomes defined by graft and patient survival, as well as safety outcomes, were compared between the matched patients. RESULTS From 3215 kidney transplant recipients transplanted during the study period with the inclusion criteria (311 patients under belatacept and 2904 patients under CNI). A total of 243 patients under belatacept were matched with 243 controls under CNI. All prognostic parameters were well-balanced before conversion between the two groups, with a mean age of 54.7 ± 15.1 years (P = .4543), a mean time of 2.2 ± 3.2 years after transplant (P = .586), a mean eGFR of 33.0 ± 13.3 mL/min/1.73 m2 (P = .976), a median proteinuria of 0.23 (0.12–0.50) g/g (P = .278) and 30.9% of positive anti-HLA DSA (P = 1.0) in the belatacept group. After a mean follow-up time after conversion of 4.4 ± 2.5 years, 36 (14.8%) patients lost their grafts and 39 (16.0%) patients died in the belatacept cohort. After conversion to a belatacept regimen, the graft survival was significantly improved when we compared with the matched patients’ under CNI P < .0001 (Fig. 1). Patients converted to Belatacept showed a lower death rate of 16.0% compared with 30.0% for the CNI treated patients (P < .001). The safety outcomes showed a similar rate of biopsy proven rejection (P = .08), major adverse cardiovascular events and cancer between the two groups, while a significant higher rate of CMV disease was observed among the belatacept treated patients P < .01). CONCLUSION This study confirms that conversion to belatacept post-transplant is associated with improved long-term graft outcome and acceptable safety. Conversion to belatacept after transplant should be considered as a valuable therapeutic option for kidney recipients.

BACKGROUND AND AIMS Kidney allograft loss is a common cause of end-stage renal disease but accurate prediction models of kidney allograft loss are lacking in children. The iBOX system has been broadly validated among adults. We aimed to validate the iBOX system in a large international cohort of pediatric kTx recipients. METHOD In this observational study, we used data from pediatric ( RESULTS A total of 573 kTx recipients were included. Median time from transplantation to evaluation was 1.0 (0.5–2.0) year with a mean age at evaluation at 12.1 (5.5) years and mean follow-up after transplantation 5.1 (2.8) years. Five-year death-censored graft survival from evaluation was 95%. At the time of evaluation, mean eGFR and uPCR were 65.5 (29.6) mL/min/1.73 m2 and 0.25 (1.2) g/g, respectively. A total of 118 (20.6%) of the patients had DSA. The iBOX system showed good discrimination with a c-statistic of 0.81 and good calibration (Figure 1). CONCLUSION The iBOX system demonstrated high accuracy in predicting kidney allograft loss in children with performances similar to those reported in adults.

BACKGROUND AND AIMS Post-transplantation patient care requires development and validation of noninvasive biomarkers to improve allograft monitoring and prevention from unnecessary biopsies. Preliminary reports have suggested the association of donor derived cell-free DNA (dd-cfDNA) with allograft rejection. However, there is no proof of its added value beyond standard of care patient management in large and deep phenotyped cohorts. METHOD A total of 1210 concomitant evaluations of allograft histology, anti-HLA DSA and functional parameters between 2013 and 2018 were included corresponding to 637 evaluations in the derivation cohort and 573 in the validation cohort. dd-cfDNA was measured in plasma at the time of the evaluation. Diagnoses were assessed using Banff 2019 criteria. Parameters associated with kidney allograft rejection were assessed using uni- and multivariable logistic regression. We developed a risk model using the variables that were independently associated with rejection. RESULTS Higher levels of dd-cfDNA were observed for AMR and TCMR or both compared to other diagnoses (Figure 1A). We found incremental dd-cfDNA levels with increasing Banff lesion scores for g, ptc, i, t, cg and C4d (Figure 1B). There was no association of dd-cfDNA levels with allograft inactive lesions. In multivariable analysis, dd-cfDNA (P CONCLUSION We demonstrate the independent and added value of dd-cfDNA in addition to conventional features to predict rejection. This first integrative system shows improved performance for patient monitoring and could help physicians in decision-making process.

Main problem The number of kidney transplant candidates with prosthetic heart valves (PHVs) is increasing. Yet, outcomes of kidney transplantation in these patients are still unclear. This is the first report of post-transplant outcomes in patients with PHVs at time of kidney transplantation. Methods We conducted a matched cohort study among recipients from the multicentric and prospective DIVAT cohort to compare outcomes in patients with left-sided PHVs at time of transplantation and a group of recipients without PHV matched according to age, dialysis time, initial disease, pre-transplant DSA, diabetes and cardiovascular events. Results Of 23018 patients, 92 patients with PHVs were included and compared to 276 patients without PHV. Delayed graft function and post-operative bleeding occurred more frequently in patients with PHVs. Kidney graft survival was similar between groups. 5-year overall survival was 68.5 % in patients with PHV versus 87.9 % in patients without PHV (HR, 2.72[1.57-4.70], p=0.0004). Deaths from infection, endocarditis and bleeding were more frequent in patients with PHV. Mechanical valves, but not bioprosthetic valves, were independent risk factors for mortality (HR, 2.89[1.68-4.97], p=0.0001). Conclusions Patients with PHV have high mortality rates after kidney transplantation. These data suggest that mechanical valves, but not biological valves, increase risks of post-transplant mortality.

Stress-related disorders, such as posttraumatic stress disorder (PTSD), are highly prevalent and often difficult to treat. In rodents, stress-related, anxiety-like defensive behavioral responses may be characterized by social avoidance, exacerbated inflammation, and altered metabolic states. We have previously shown that, in rodents, subcutaneous injections of a heat-killed preparation of the soil-derived bacterium Mycobacterium vaccae NCTC 11659 promotes stress resilience effects that are associated with immunoregulatory signaling in the periphery and the brain. In the current study, we sought to determine whether treatment with a heat-killed preparation of the closely related M. vaccae type strain, M. vaccae ATCC 15483, would also promote stress-resilience in adult male rats, likely due to biologically similar characteristics of the two strains. Here we show that immunization with either M. vaccae NCTC 11659 or M. vaccae ATCC 15483 prevents stress-induced increases in hippocampal interleukin 6 mRNA expression, consistent with previous studies showing that M. vaccae NCTC 11659 prevents stress-induced increases in peripheral IL-6 secretion, and prevents exaggeration of anxiety-like defensive behavioral responses assessed 24 h after exposure to inescapable tail shock stress (IS) in adult male rats. Analysis of mRNA expression, protein abundance, and flow cytometry data demonstrate overlapping but also unique effects of treatment with the two M. vaccae strains on immunological and metabolic signaling in the host. These data support the hypothesis that treatment with different M. vaccae strains may immunize the host against stress-induced dysregulation of physiology and behavior.

BACKGROUND: No validated system currently exists to realistically characterize the chronic pathology of kidney transplants that represents the dynamic disease process and spectrum of disease severity. We sought to develop and validate a tool to describe chronicity and severity of renal allograft disease and integrate it with the evaluation of disease activity. METHODS: The training cohort included 3549 kidney transplant biopsies from an observational cohort of 937 recipients. We reweighted the chronic histologic lesions according to their time-dependent association with graft failure, and performed consensus k-means clustering analysis. Total chronicity was calculated as the sum of the weighted chronic lesion scores, scaled to the unit interval. RESULTS: We identified four chronic clusters associated with graft outcome, based on the proportion of ambiguous clustering. The two clusters with the worst survival outcome were determined by interstitial fibrosis and tubular atrophy (IFTA) and by transplant glomerulopathy. The chronic clusters partially overlapped with the existing Banff IFTA classification (adjusted Rand index, 0.35) and were distributed independently of the acute lesions. Total chronicity strongly associated with graft failure (hazard ratio [HR], 8.33; 95% confidence interval [CI], 5.94 to 10.88; P