Design, cohort profile and comparison of the KTD-Innov study: a prospective multidimensional biomarker validation study in kidney allograft rejection.

There is an unmet need for robust and clinically validated biomarkers of kidney allograft rejection. Here we present the KTD-Innov study (ClinicalTrials.gov, NCT03582436), an unselected deeply phenotyped cohort of kidney transplant recipients with a holistic approach to validate the clinical utility of precision diagnostic biomarkers. In 2018-2019, we prospectively enrolled consecutive adult patients who received a kidney allograft at seven French centers and followed them for a year. We performed multimodal phenotyping at follow-up visits, by collecting clinical, biological, immunological, and histological parameters, and analyzing a panel of 147 blood, urinary and kidney tissue biomarkers. The primary outcome was allograft rejection, assessed at each visit according to the international Banff 2019 classification. We evaluated the representativeness of participants by comparing them with patients from French, European, and American transplant programs transplanted during the same period. A total of 733 kidney transplant recipients (64.1% male and 35.9% female) were included during the study. The median follow-up after transplantation was 12.3 months (interquartile range, 11.9-13.1 months). The cumulative incidence of rejection was 9.7% at one year post-transplant. We developed a distributed and secured data repository in compliance with the general data protection regulation. We established a multimodal biomarker biobank of 16,736 samples, including 9331 blood, 4425 urinary and 2980 kidney tissue samples, managed and secured in a collaborative network involving 7 clinical centers, 4 analytical platforms and 2 industrial partners. Patients' characteristics, immune profiles and treatments closely resembled those of 41,238 French, European and American kidney transplant recipients. The KTD-Innov study is a unique holistic and multidimensional biomarker validation cohort of kidney transplant recipients representative of the real-world transplant population. Future findings from this cohort are likely to be robust and generalizable.

Evolution of HLA-sensitization according to immunosuppressive therapy management among kidney transplant patients returning to dialysis between 2008 and 2019: A French retrospective study.

BACKGROUND: The optimal management of immunosuppressive therapy (IT) after kidney allograft failure (KAF) remains controversial. Although maintaining IT may reduce HLA-sensitization and improve access to retransplantation, it may also increase the rate of immunosuppression-related complications. The overall impact on patient mortality is unknown. The main objective of this study was to compare the evolution of HLA-sensitization 6 months after KAF according to IT management. METHODS: Individual clinical and health care data were extracted from the French national end-stage kidney disease registry (Renal Epidemiology and Information Network [REIN]) and the French National Health Data system (SNDS), respectively. Patients aged > 18 years returning to dialysis after KAF between January 2008 and December 2019 in Lorraine were included. Patients were classified into two groups, IT continuation or IT discontinuation. HLA-sensitization was defined as an increase in incompatible graft rate (IGR) between KAF and 6 months post-KAF (change to a higher predefined category (0%-5%), (5%-20%), (20%-50%), (50%-85%), (85%-95%), (95%-98%), (98%-100%)). Secondary outcome was patient survival according to IT management. RESULTS: A total of 121 patients were included, 35 (29%) of whom continued IT. HLA-sensitization after KAF tended to be higher in the "IT discontinuation" group (57% vs. 38% in the "IT continuation" group, p = .07). In multivariate analysis, IT continuation was associated with a lower increase in IGR (OR .37, 95% CI [.14; .93]). IT management was not associated with patient mortality. CONCLUSIONS: Continuation of IT after KAF was associated with less change in IGR and was not associated with excess mortality.

Improving equity in kidney transplant allocation policies through a novel genetic metric: The Matched Donor Potential.

The demand for donors' kidneys continues to increase amid a shortage of available donors. Managing policies to thoughtfully allocate this scarce resource is a complex process. Although human leukocyte antigen (HLA) matching has been shown to prolong graft survival, its relative contribution to allocation schemes is empirically compromised owing to competing priorities. We explored using a new metric, Matched Donor Potential (MDP), to facilitate improved HLA matching while promoting equity. We interrogated all active kidney waitlist patients (N = 164 427), their corresponding unacceptable antigen files, and all effective donors in the Scientific Registry of Transplant Recipients (January 1, 2016-December 31, 2017). Cause-specific hazard functions were evaluated to assess the potential impact of the MDP metric on deceased donor transplant access rates for all candidates. Access was affected by ethnicity, blood group type, and calculated Panel Reactive Antibody (cPRA). Importantly, we show that access to transplantation is influenced by the patient's own HLA makeup regardless of their ethnicity and by the HLA makeup of effective donors. The MDP metric demonstrates a high association with access to transplantation. Adjusting Cox models to include this new metric resulted in improved access to kidney transplantation for waitlist candidates of minority heritage while significantly promoting HLA matching. Thus, the MDP metric accounts for balanced, equitable organ allocation algorithms.

The new French kidney allocation system for donations after brain death: Rationale, implementation, and evaluation.

In recent decades, the allocation policies of many countries have moved from center-based to patient-based approaches. The new French kidney allocation system (KAS) of donations after brain death for adult recipients, implemented in 2015, was principally designed to introduce a unified allocation score (UAS) to be applied locally for one kidney and nationally for the other and to replace regional borders by a new geographical model. The new KAS balances dialysis duration and waiting time to compensate for listing delays and provides more effective longevity matching between donors and recipients with better HLA and age matching. We report these changes, with their rationale and main results. Results show improved HLA matching for young recipients and more rapid access to transplant for older recipients. Young recipients also had better access to transplantation. Transplant access decreased for recipients aged 60-69 and required tuning of KAS parameters. In conclusion, our results strongly indicate that national or adequately broad geographic allocation areas, combined with multiplicative interactions between allocation criteria, permit multivariate optimization of organ allocation and thus improve national kidney sharing and balance HLA matching and age matching, at the price of longer cold ischemic times and more logistical constraints than with local allocation.

[Perspectives for future development of the kidney paired donation programme in France]. / Perspectives pour une évolution du programme de don croisé de reins en France.

Almost one third of kidney donation candidates are incompatible (HLA and/or ABO) with their directed recipient. Kidney paired donation allows potential donors to be exchanged and gives access to a compatible kidney transplant. The Bioethics Law of 2011 authorised kidney paired donation in France with reciprocity between 2 incompatible "donor-recipient" pairs. A limited number of transplants have been performed due to a too restricted authorization compared to other European practices. This study presents the perspectives of the new Bioethics Law, enacted in 2021, which increases the authorised practices for kidney paired donation in France. The two simulated evolutions are the increase of the number of pairs involved in a kidney paired donation to 6 (against 2 currently) and the use of a deceased donor as a substitution to one of living donor. Different scenarios are simulated using data from the Agence de la Biomedecine; incompatible pairs registered in the kidney paired donation programme in France between December 2013 and February 2018 (78 incompatible pairs), incompatible transplants performed during the same period (476 incompatible pairs) and characteristics of deceased donors as well as proposals made over this period. Increasing the number of pairs has a limited effect on the number of transplants, which increases from 18 (23% of recipients) in the current system to 25 (32% of recipients) when 6 pairs can be involved. The use of a deceased donor significantly increases the number of transplants to 41 (52% of recipients). This study makes it possible to evaluate the increase in possibilities of kidney transplants by kidney paired donation following the new bioethics law. A working group and an information campaign for professionals and patients will be necessary for its implementation.

Removing administrative boundaries using a gravity model for a national liver allocation system.

Geographic disparities emerged as an increasing issue in organ allocation policies. Because of the sequential and discrete geographical models used for allocation scores, artificial regional boundaries may impede the access of candidates with the greatest medical urgency to vital organs. This article describes a continuous geographical allocation model that provides accurate organ access by introducing a multiplicative interaction between the patient's condition and the distance to the graft by using a gravity model. Patients with the most urgent need will thus have access to organs from farther away, while those in less urgent need may only have access to organs geographically closer. Compared to the previous French liver allocation scheme, the gravity model precluded transplantations for candidates with a Model for End-Stage Liver Disease (MELD) ≤ 14 for decompensated cirrhosis from 10.3% to 0.6%. Death and delisting while on the waiting list at 1 year also decreased from 30.1% to 22.4% for MELD ≥ 35. Waiting list (cumulative hazard ratio (CHR)  0.84 after adjustment) and posttransplant survival improved significantly (hazard ratio = 0.83 after adjustment). This new liver allocation system provides more equitable access to liver transplants and an efficient and safe alternative to administrative boundaries for geographical models in organ allocation.

New French heart allocation system: Comparison with Eurotransplant and US allocation systems.

Graft allocation rules for heart transplantation are necessary because of the shortage of heart donors, resulting in high waitlist mortality. The Agence de la biomédecine is the agency in charge of the organ allocation system in France. Assessment of the 2004 urgency-based allocation system identified challenging limitations. A new system based on a score ranking all candidates was implemented in January 2018. In the revised system, medical urgency is defined according to candidate characteristics rather than the treatment modalities, and an interplay between urgency, donor-recipient matching, and geographic sharing was introduced. In this article, we describe in detail the new allocation system and compare these allocation rules to Eurotransplant and US allocation policies.

Disparities in Acceptance of Deceased Donor Kidneys Between the United States and France and Estimated Effects of Increased US Acceptance.

IMPORTANCE: Approximately 3500 donated kidneys are discarded in the United States each year, drawing concern from Medicare and advocacy groups. OBJECTIVE: To estimate the effects of more aggressive allograft acceptance practices on the donor pool and allograft survival for the population of US wait-listed kidney transplant candidates. DESIGN, SETTING, AND PARTICIPANTS: A nationwide study using validated registries from the United States and France comprising comprehensive cohorts of deceased donors with organs offered to kidney transplant centers between January 1, 2004, and December 31, 2014. Data were analyzed between September 1, 2018, and April 5, 2019. MAIN OUTCOMES AND MEASURES: The primary outcome was kidney allograft discard. The secondary outcome was allograft failure after transplantation. We used logistic regression to model organ acceptance and discard practices in both countries. We then quantified using computer simulation models the number of kidneys discarded in the United States that a more aggressive system would have instead used for transplantation. Finally, based on actual survival data, we quantified the additional years of allograft life that a redesigned US system would have saved. FINDINGS: In the United States, 156 089 kidneys were recovered from deceased donors between 2004 and 2014, of which 128 102 were transplanted, and 27 987 (17.9%) were discarded. In France, among the 29 984 kidneys recovered between 2004 and 2014, 27 252 were transplanted, and 2732 (9.1%, P < .001 vs United States) were discarded. The mean (SD) age of kidneys transplanted in the United States was 36.51 (17.02) years vs 50.91 (17.34) years in France (P < .001). Kidney quality showed little change in the United States over time (mean [SD] kidney donor risk index [KDRI], 1.30 [0.48] in 2004 vs 1.32 [0.46] in 2014), whereas a steadily rising KDRI in France reflected a temporal trend of more aggressive organ use (mean [SD] KDRI, 1.37 [0.47] in 2004 vs 1.74 [0.72] in 2014; P < .001). We applied the French-based allocation model to the population of US deceased donor kidneys and found that 17 435 (62%) of kidneys discarded in the United States would have instead been transplanted under the French system. We further determined that a redesigned system with more aggressive organ acceptance practices would generate an additional 132 445 allograft life-years in the United States over the 10-year observation period. CONCLUSIONS AND RELEVANCE: Greater acceptance of kidneys from deceased donors who are older and have more comorbidities could provide major survival benefits to the population of US wait-listed patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03723668.

Optimization of heart allocation: The transplant risk score.

The new French heart allocation system is designed to minimize waitlist mortality and extend the donor pool without a detrimental effect on posttransplant survival. This study was designed to construct a 1-year posttransplant graft-loss risk score incorporating recipient and donor characteristics. The study included all adult first single-organ recipients transplanted between 2010 and 2014 (N = 1776). This population was randomly divided in a 2:1 ratio into derivation and validation cohorts. The association of variables with 1-year graft loss was determined with a mixed Cox model with center as random effect. The predictors were used to generate a transplant-risk score (TRS). Donor-recipient matching was assessed using 2 separate recipient- and donor-risk scores. Factors associated with 1-year graft loss were recipient age >50 years, valvular cardiomyopathy and congenital heart disease, previous cardiac surgery, diabetes, mechanical ventilation, glomerular filtration rate and bilirubin, donor age >55 years, and donor sex: female. The C-index of the final model was 0.70. Correlation between observed and predicted graft loss rate was excellent for the overall cohort (r = 0.90). Hearts from high-risk donors transplanted to low-risk recipients had similar survival as those from low-risk donors. The TRS provides an accurate prediction of 1-year graft-loss risk and allows optimal donor-recipient matching.

Impact of transplant accessibility for sensitized patients by avoiding unacceptable antigens.

Recent data have confirmed the negative impact of preformed donor-specific antibodies (pDSAs) after liver transplantation (LT). In order to reduce the risk of developing lesions associated with acute and chronic antibody-mediated rejection in LT recipients, we evaluated the consequences in terms of transplant accessibility, associated with avoiding pDSAs according to several mean fluorescence intensity (MFI) titer thresholds that have been previously reported to be relevant in LT. Among the 484 included LT candidates, 99 (20.5%) presented with anti-human leukocyte antibodies (HLAs). The predictive factors for anti-HLA sensitization were a history of previous kidney transplantation (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.30-1.9; P = 0.05), a history of previous LT (OR, 1.9; 95% CI, 1.6-2.1; P = 0.01), a history of blood transfusion (OR, 2.5; 95% CI, 2.2-4.1; P = 0.01), and a history of pregnancy (OR, 2.9; 95% CI, 2.4-3.3; P = 0.04). By applying a strategy of unacceptable mismatches for recipients with an antibody (Ab) MFI of > 5000, only 35 patients were affected (7% of the cohort), but 22 of these (63%) would have been considered incompatible with >50% of the donors. Using a MFI threshold of >10,000, only 16 patients were affected (1.4% of the cohort), but half of these would have been considered incompatible with >50% of the proposed donors. Considering only those with anti-class II Ab and a MFI >5000 and >10,000, respectively, 10/14 and 4/8 patients were considered incompatible with >50% of the donors. In conclusion, avoiding pDSAs affects a small but not negligible proportion of LT candidates. However, in these sensitive patients, avoiding pDSAs has the potential to significantly reduce the donor pool and, consequently, transplant accessibility. Liver Transplantation 23 880-886 2017 AASLD.

Prediction of Waitlist Mortality in Adult Heart Transplant Candidates: The Candidate Risk Score.

BACKGROUND: The cardiac allocation system in France is currently based on urgency and geography. Medical urgency is defined by therapies without considering objective patient mortality risk factors. This study aimed to develop a waitlist mortality risk score from commonly available candidate variables. METHODS: The study included all patients, aged 16 years or older, registered on the national registry CRISTAL for first single-organ heart transplantation between January 2010 and December 2014. This population was randomly divided in a 2:1 ratio into derivation and validation cohorts. The association of variables at listing with 1-year waitlist death or delisting for worsening medical condition was assessed within the derivation cohort. The predictors were used to generate a candidate risk score (CRS). Validation of the CRS was performed in the validation cohort. Concordance probability estimation (CPE) was used to evaluate the discriminative capacity of the models. RESULTS: During the study period, 2333 patients were newly listed. The derivation (n =1 555) and the validation cohorts (n = 778) were similar. Short-term mechanical circulatory support, natriuretic peptide decile, glomerular filtration rate, and total bilirubin level were included in a simplified model and incorporated into the score. The Concordance probability estimation of the CRS was 0.73 in the derivation cohort and 0.71 in the validation cohort. The correlation between observed and expected 1-year waitlist mortality in the validation cohort was 0.87. CONCLUSIONS: The candidate risk score provides an accurate objective prediction of waitlist mortality. It is currently being used to develop a modified cardiac allocation system in France.

Anti-HLA sensitization in extensively burned patients: extent, associated factors, and reduction in potential access to vascularized composite allotransplantation.

Extensively burned patients receive iterative blood transfusions and skin allografts that often lead to HLA sensitization, and potentially impede access to vascularized composite allotransplantation (VCA). In this retrospective, single-center study, anti-HLA sensitization was measured by single-antigen-flow bead analysis in patients with deep, second- and third-degree burns over ≥40% total body surface area (TBSA). Association of HLA sensitization with blood transfusions, skin allografts, and pregnancies was analyzed by bivariate analysis. The eligibility for transplantation was assessed using calculated panel reactive antibodies (cPRA). Twenty-nine patients aged 32 ± 14 years, including 11 women, presented with a mean burned TBSA of 54 ± 11%. Fifteen patients received skin allografts, comprising those who received cryopreserved (n = 3) or glycerol-preserved (n = 7) allografts, or both (n = 5). An average 36 ± 13 packed red blood cell (PRBC) units were transfused per patient. In sera samples collected 38 ± 13 months after the burns, all patients except one presented with anti-HLA antibodies, of which 13 patients (45%) had complement-fixing antibodies. Eighteen patients (62%) were considered highly sensitized (cPRA≥85%). Cryopreserved, but not glycerol-preserved skin allografts, history of pregnancy, and number of PRBC units were associated with HLA sensitization. Extensively burned patients may become highly HLA sensitized during acute care and hence not qualify for VCA. Alternatives to skin allografts might help preserve their later access to VCA.

Are there good reasons for inequalities in access to renal transplantation in children?

BACKGROUND: Studies in the USA and Europe have demonstrated inequalities in adult access to renal transplants. We previously demonstrate that the centre of treatment was impacting the time to be registered on the renal waiting list. In this study, we sought to ascertain the influence of patient and centre characteristics on the probability of transplantation within 1 year after registration on the waiting list for children. METHODS: We included patients <18 years awaiting transplantation from the French ESRD National Registry. The effects of patient and centre characteristics were studied by hierarchical logistic regression. Centre effects were assessed by centre-level residual variance. A descriptive survey was performed to investigate differences in the centres' practices, and linear regression was used to confirm findings of different HLA compatibility requirements between centres. RESULTS: The study included 556 patients treated at 54 centres; 450 (80.9%) received transplants in the year after their listing. HLA group scarcity, time of inactive status during the year, pre-emptive listing and listing after age 18 were associated with lower probabilities of transplantation. Patient characteristics explained most of the variability among centres, but patients treated in paediatric centres had a lower probability of transplantation within 1 year because of higher HLA compatibility requirements for transplants. CONCLUSIONS: Although patient characteristics explained most of the inter-centre variability, harmonization of some practices might enable us to reduce some inequalities in access to renal transplantation while maintaining optimal transplant survival and chances to get a second transplant when needed.

Denatured class I human leukocyte antigen antibodies in sensitized kidney recipients: prevalence, relevance, and impact on organ allocation.

BACKGROUND: Single antigen flow beads assays may overestimate sensitization because of the detection of supposedly irrelevant antibodies recognizing denatured class I human leukocyte antigens (HLAs). METHODS: Sera of 323 HLA-sensitized kidney transplant candidates positive with a class I HLA single antigen flow beads assay were retested after acid treatment of the beads. Denatured HLA antibodies were identified according to ratio between the measured fluorescence intensity for treated and nontreated beads. T-lymphocyte flow cytometry crossmatches were performed to characterize the ability of these antibodies to recognize HLA on normal cells as a surrogate of their potential clinical relevance. Their impact on organ allocation was evaluated through a calculated panel reactive antibody. The utility of single antigen flow beads largely devoid of denatured HLA (iBeads) was also evaluated. RESULTS: Denatured HLA antibodies were detected in 39% of the patients. They provided much less positive flow cytometry crossmatches than anti-native HLA antibodies (16% vs. 83%, P<0.0001). Removing the HLA-A and HLA-B antigens targeted by denatured HLA antibodies from unacceptable antigens lowered the calculated panel reactive antibody for 90 patients, sometimes dramatically. The iBeads assay demonstrated nearly the same ability to predict crossmatch results than the acid treatment assay. CONCLUSION: Denatured class I HLA antibodies are common, but the antigens they target should not be considered as unacceptable in most cases, because they negatively impact access to a transplant while predominantly providing negative sensitive crossmatches. The iBeads assay seems to be a valuable alternative to better define unacceptable antigens.

[Rules for allocation of livers for transplantation]. / Règles d'attribution des greffons hépatiques.

Previous rules of allocation of livers for transplantation were based mainly on local priorities, with final management left to the local team. This created substantial regional disparities. A prospective survey of waiting list deaths and dropouts due to aggravation of liver disease (2003-2005) validated the MELD (Model for End-stage Liver Disease) score on French data. A new allocation score (Liver Score) for liver transplants, based on specific variables for each liver disease, was introduced in March 2007. An initial evaluation, based on the first 5 months of practice, clearly shows that the Liver Score reduces the rates of deaths, dropouts, and futile transplantations; it also accelerates access to transplantation for the sickest patients. Several points remain unresolved: both the MELD and Liver scores may be improved. The variability of the MELD score related to different laboratory assay methods requires harmonization between laboratories.

Changing kidney allocation policy in France: the value of simulation.

This paper advocates the value of simulation to promote changes in kidney allocation. Due to the scarcity of organs and to the competition between transplantation centers to obtain the best organs for their patients, any change in organ allocation policy remains a sensitive issue in public health decision-making. Organ allocation is not easily available for prospective experimental study. Observational stud-ies only support limited changes. A simulation tool in this context permits the comparison of observed results against simulated ones. In our experience in France, it has shown to be a helpful tool during the allocation design phase providing objective facts for the debates and increasing the potential for change.