The role of donor hypertension and angiotensin II in the occurrence of early pancreas allograft thrombosis.

Background: About 10-20% of pancreas allografts are still lost in the early postoperative period despite the identification of numerous detrimental risk factors that correlate with graft thrombosis. Methods: We conducted a multicenter study including 899 pancreas transplant recipients between 2000 and 2018. Early pancreas failure due to complete thrombosis, long-term pancreas, kidney and patient survivals were analyzed and adjusted to donor, recipient and perioperative variables using a multivariate cause-specific Cox model stratified to transplant centers. Results: Pancreas from donors with history of hypertension (6.7%), as well as with high body mass index (BMI), were independently associated with an increased risk of pancreas failure within the first 30 post-operative days (respectively, HR= 2.57, 95% CI from 1.35 to 4.89 and HR= 1.11, 95% CI from 1.04 to 1.19). Interaction term between hypertension and BMI was negative. Donor hypertension also impacted long-term pancreas survival (HR= 1.88, 95% CI from 1.13 to 3.12). However, when pancreas survival was calculated after the postoperative day 30, donor hypertension was no longer a significant risk factor (HR= 1.22, 95% CI from 0.47 to 3.15). A lower pancreas survival was observed in patients receiving a pancreas from a hypertensive donor without RAAS (Renin Angiotensin Aldosterone System) blockers compared to others (50% vs 14%, p < 0.001). Pancreas survival was similar among non-hypertensive donors and hypertensive ones under RAAS blockers. Conclusion: Donor hypertension was a significant and independent risk factor of pancreas failure. The well-known pathogenic role of renin-angiotensin-aldosterone system seems to be involved in the genesis of this immediate graft failure.

Risk Factors for Adverse Outcomes in Kidney Transplants From Donors After Circulatory Death With Normothermic Regional Perfusion: A Systematic Analysis.

BACKGROUND: This study examined 1071 adult primary kidney transplants from the French-controlled donation after the circulatory determination of death (cDCD) program, which uses normothermic regional perfusion (NRP), and involves short cold ischemia times (CIT) and constrained asystole times differing by donor age. METHODS: Logistic regression identified risk factors for primary nonfunction (PNF), delayed graft function (DGF), and graft failure. RESULTS: Risk factors for PNF included donor hypertension, admission for ischemic vascular stroke, and HLA DR mismatches. Risk factors for DGF included functional warm ischemia time >40 min, dialysis >2 y, recipient body mass index of 30 kg/m2 or higher, recipient diabetes, and CIT >10 h. Risk factors for 1-y graft failure included donor hypertension, donor lung recovery, ostial calcification, recipient cardiovascular comorbidities, and HLA DR mismatches. A high donor estimated glomerular filtration rate protected against DGF and graft failure at 1-y. After adjustment restricted to recipient and graft factors and donor age, the risks of PNF, DGF, and graft failure increased with donor age up to 65 y and then remained stable. CONCLUSIONS: The study suggests that cDCD kidney transplants are highly successful, but also that its outcomes are influenced by lung recovery, poor HLA DR matching, and warm ischemia times differing with donor age. Our study identified several risk factors for kidney transplantation failure after cDCD with systematic use of NRP and some of them seem as modifiable variables associated with cDCD transplant outcome.

Solid Organ Transplant Litigation at One of Europe's Largest University Hospitals.

Due to its intrinsic complexity and the principle of collective solidarity that governs it, solid organ transplantation (SOT) seems to have been spared from the increase in litigation related to medical activity. Litigation relating to solid organ transplantation that took place in the 29 units of the Assistance Publique-Hôpitaux de Paris and was the subject of a judicial decision between 2015 and 2022 was studied. A total of 52 cases of SOT were recorded, all in adults, representing 1.1% of all cases and increasing from 0.71% to 1.5% over 7 years. The organs transplanted were 25 kidneys (48%), 19 livers (37%), 5 hearts (9%) and 3 lungs (6%). For kidney transplants, 11 complaints (44%) were related to living donor procedures and 6 to donors. The main causes of complaints were early post-operative complications in 31 cases (60%) and late complications in 13 cases (25%). The verdicts were in favour of the institution in 41 cases (79%). Solid organ transplants are increasingly the subject of litigation. Although the medical institution was not held liable in almost 80% of cases, this study makes a strong case for patients, living donors and their relatives to be better informed about SOT.

Evaluation of a delayed liver transplantation strategy for patients with HCC receiving bridging therapy: the DELTA-HCC study.

BACKGROUND & AIMS: To maximize utility and prevent premature liver transplantation (LT), a delayed LT strategy (DS) was adopted in France in 2015 in patients listed for any single HCC treated with resection or thermal ablation during the waiting phase. The DS involves postponing LT until recurrence. The purpose of this study was to evaluate the DS to make sure that it did not hamper pre- and post-LT outcomes. METHODS: Patients listed for HCC in France between 2015 and 2018 were studied. After data extraction from the national LT database, 2,025 patients were identified and classified according to six groups: single tumor entering DS, single tumor not entering DS, multiple tumors, no curative treatment, untreatable HCC or T1 tumors. Kaplan-Meier estimates of the 18-month risk of dropout for death, too sick to be transplanted or tumor progression before LT, 5-year post-LT HCC recurrence and post-LT survival rates were compared. RESULTS: Median waiting-time in the DS group was 910 days. Pre-LT dropout probability was significantly lower in the DS group compared to other groups (13% vs. 19%, p = 0.0043) and significantly higher in the T1 group (25.4%, p = 0.05). Post-LT HCC recurrence rate in the multiple nodules group was significantly higher (19.6%, p = 0.019), while 5-year post-LT survival did not differ among groups and was 74% in the DS group (p = 0.22). CONCLUSION: The DELTA-HCC study shows that DS does not negatively impact either pre- nor post-LT patient outcomes, and has the potential to allow for redistribution of organs to patients in more urgent need of LT. It can reasonably be proposed and pursued. The unexpectedly high risk of dropout in T1 patients seems related to the MELD-based offering rules underserving this subgroup. IMPACTS AND IMPLICATIONS: To maximize utility and prevent premature liver transplantation (LT), a delayed LT strategy was adopted in France in 2015. It involves postponing LT until recurrence in patients listed for any single HCC curatively treated by surgical resection or thermal ablation. The DELTA-HCC study was conducted to evaluate this nationwide strategy. It shows in a European LT program that delayed strategy does not negatively impact pre- nor post-LT patient outcomes and is relevant to up to 20% of LT candidates; thus, it could potentially enable the redistribution of organs to patients in more urgent need of LT. Such a delayed strategy can reasonably be pursued and extended to other LT programs. Of note, an unexpectedly high risk of dropout in T1 patients, seemingly related to MELD-based offering rules which underserve these patients, calls for further scrutinization and revision of allocation rules in this subgroup.

Recipient age influences survival after liver transplant: Results of the French national cohort 2007-2017.

BACKGROUND: In recent years, age at liver transplantation (LT) has markedly increased. In the context of organ shortage, we investigated the impact of recipient age on post-transplantation mortality. METHODS: All adult patients who received a first LT between 2007 and 2017 were included in this cross-sectional study. Recipients' characteristics at the time of listing, donor and surgery data, post-operative complications and follow-up of vital status were retrieved from the national transplantation database. The impact of age on 5-year overall mortality post-LT was estimated using a flexible multivariable parametric model which was also used to estimate the association between age and 10-year net survival, accounting for expected age- and sex-related mortality. RESULTS: Among the 7610 patients, 21.4% were aged 60-65 years, and 15.7% over 65. With increasing age, comorbidities increased but severity of liver disease decreased. Older recipient age was associated with decreased observed survival at 5 years after LT (p < .001), with a significant effect particularly during the first 2 years. The linear increase in the risk of death associated with age does not allow any definition of an age's threshold for LT (p = .832). Other covariates associated with an increased risk of 5-year death were dialysis and mechanical ventilation at transplant, transfusion during LT, hepatocellular carcinoma and donor age. Ten-year flexible net survival analysis confirmed these results. CONCLUSION: Although there was a selection process for older recipients, increasing age at LT was associated with an increased risk of death, particularly in the first years after LT.

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.

Impact of direct antiviral agents for hepatitis C virus -induced liver diseases on registration, waiting list and liver transplant activity in France.

Direct-acting antivirals (DAA) has dramatically improved the prognosis of liver transplantation (LT) candidates for HCV end-stage liver disease (ESLD). We aimed to evaluate the impact of DAA on waiting list (WL) registration and LT activity in France. We evaluated all patients registered to the French WL for HCV ESLD between 2000 and 2018. Timespan was divided into two periods according to DAA availability: 2010-2013 versus 2014-2018. Changes in the indications of LT, outcome on WL were evaluated. Then, we evaluated the activity of LT and outcome for HCV recipients in France. Among 3,173 HCV candidates, registration on WL decreased by 33% between 2013 and 2018. The 1-year waitlist survival increased from 76.9% (95%CI: 74.2%-79.4%) in 2010-2013 to 79.8% (95%CI: 77.2%-82.1%) in 2014-2018 (p < 0.01). Regarding LT activity, the part of HCV ESLD decreased from 26% in 2010 to 16% in 2018. The 1-year graft survival rate in HCV recipients increased from 76.9% (95%CI: 73.7%-79.7%) in 2010-2012 to 84.9% (95%CI: 82.9%-86.7%) in 2013-2018 (p < 0.01). The availability of DAA to treat HCV infection is associated with a significant decrease of registration for LT, death and drop out for worsening condition on the LT. In addition, it has decreased the number of HCV+ LT and improved the 1-year graft survival in France.

Impact of the COVID-19 pandemic on liver transplant waitlist outcome in France.

The objective of this study was to investigate the impact of the COVID-19 pandemic on the outcome of patients on the liver transplantation (LT) waitlist in 2020 in France, in particular, the incidence of deaths and delisting for worsening condition, depending on the allocation score component. The 2020 cohort of patients on the waiting list was compared with the 2018/2019 cohorts. 2020 saw fewer LTs than in either 2019 or 2018 (1128, 1356, and 1325, respectively), together with fewer actual brain dead donors (1355, 1729, and 1743). In 2020, deaths or delisting for worsening condition increased significantly versus 2018/2019 (subdistribution hazard ratio 1.4, 95% confidence interval [CI] 1.2-1.7), after adjustment for age, place of care, diabetes, blood type, and score component, although COVID-19-related mortality was low. This increased risk mainly concerned patients with hepatocellular carcinoma (1.52, 95% CI 1.22-1.90), with 650 MELD exception points (2.19, 95% CI 1.08-4.43), and especially those without HCC and MELD scores from 25 to 30 (3.36 [95% CI 1.82-6.18]). In conclusion, by significantly decreasing LT activity in 2020, the COVID-19 pandemic increased the number of waitlist deaths and delisting for worsening condition, and significantly more for particular components of the score, including intermediate severity cirrhosis.

[French legislation on organ transplantation]. / Épidémiologie de la transplantation d'organes en France.

EPIDEMIOLOGY OF ORGAN TRANSPLANTATION IN France. The number of transplants has been rising for ten years. Nevertheless, the stabilization of the number of brain-dead people identified as potential organ donors, and the persistently high rate of opposition to organ removal, accentuate the substantial gap between the number of candidates for transplantation and the number of transplants performed each year. Strategies are being used to reduce this imbalance, such as broadening the brain-dead donors selection criteria and increasing procurement from living donors and deceased donors after circulatory death. Unfortunately, the Covid-19 pandemic has further aggravated the difference between the supply of transplants and the need.

ÉPIDÉMIOLOGIE DE LA TRANSPLANTATION D'ORGANES EN France. Le nombre de greffes augmente depuis dix ans. Néanmoins, la stabilisation du nombre de personnes en état de mort encéphalique identifiées comme donneurs d'organes potentiels et le taux d'opposition au prélèvement d'organes qui reste élevé accentuent l'écart conséquent existant entre les candidats à une greffe et le nombre de greffes réalisées chaque année. L'élargissement des critères de sélection des donneurs en état de mort encéphalique et l'augmentation du prélèvement chez des donneurs vivants, ou décédés après arrêt circulatoire, sont autant de stratégies mises en place pour réduire le déséquilibre entre l'offre de greffes et les besoins, déséquilibre encore majoré par la pandémie de Covid-19.

[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.

Critical pathways for controlled donation after circulatory death in France.

INTRODUCTION: In 2015, France authorised controlled donation after circulatory death (cDCD) according to a nationally approved protocol. The aim of this study is to provide an overview from the perspective of critical care specialists of cDCD. The primary objective is to assess how the organ donation procedure affects the withdrawal of life-sustaining therapies (WLST) process. The secondary objective is to assess the impact of cDCD donors' diagnoses on the whole process. MATERIAL AND METHODS: This 2015-2019 prospective observational multicentre study evaluated the WLST process in all potential cDCD donors identified nationwide, comparing 2 different sets of subgroups: 1- those whose WLST began after organ donation was ruled out vs. while it was still under consideration; 2- those with a main diagnosis of post-anoxic brain injury (PABI) vs. primary brain injury (PBI) at the time of the WLST decision. RESULTS: The study analysed 908 potential cDCD donors. Organ donation remained under consideration at WLST initiation for 54.5% of them with longer intervals between their WLST decision and its initiation (2 [1-4] vs. 1 [1-2] days, P < 0.01). Overall, 60% had post-anoxic brain injury. Time from ICU admission to WLST decision was longer for primary brain injury donors (10 [4-21] vs. 6 [4-9] days, P < 0.01). Median time to death (agonal phase) was 15 [15-20] min. CONCLUSIONS: French cDCD donors are mostly related to post-anoxic brain injury. The organ donation process does not accelerate WLST decision but increases the interval between the WLST decision and its initiation.

Liver transplantation for critically ill cirrhotic patients: Results from the French transplant registry.

This study describes the population of cirrhotic patients who were transplanted from the ICU in France, identifying pre-transplant risk factors of post-transplant mortality and describing geographic variations in ICU transplant activity. Cirrhotic patients transplanted between 2008 and 2018 were included through the national transplant registry. The demographic, clinical and biological characteristics of the patients transplanted from the ICU were compared to cirrhotic patients who were transplanted from home or from the hospital. Risk factors of post-transplant one-year mortality were identified in uni- and multivariable analysis within the population transplanted from the ICU. Funnel plots were used to illustrate center-specific differences in ICU transplant activity. 1,047 cirrhotic patients were transplanted from the ICU during the study period. While the national rate of transplants performed from the ICU was 14.3% the absolute number and the rate of cirrhotic patients transplanted from the ICU varied significantly from one center to another, ranging from 6.6% to 22.8% (p < 0.05). Three recipient-associated independent risk factors one-year post-LT mortality were identified in the population transplanted from the ICU: age > 50 years (HR 1.65, 95%CI 1.16-2.36), p = 0.005), diabetes (HR 1.46, 95%CI 1.07-1.98, p = 0.02) and intubation (HR2.12, 95%CI 1.62-2.78), p < 0.001). Donor age was also independently associated with mortality (HR 1.01, 95%CI 1.01-1.02, p < 0.001). Funnel plots showed significant differences in the proportion of patients transplanted from the ICU and the distribution of risk factors across French transplant centers, especially the inclination to transplant intubated patients. This study underlines the increased post-transplant mortality among cirrhotic patients transplanted from the ICU. It identifies four clinically pertinent independent risk factors associated with post-transplant mortality in this specific sub-group of transplant candidates. Finally, it illustrates how diverse the landscape of liver transplantation for critically ill cirrhotic patients is across a single country, despite a unified allocation algorithm.

Successful Reuse of Kidney Graft After Early Recurrence of Primary Focal and Segmental Glomerulosclerosis.

Primary focal and segmental glomerulosclerosis (FSGS) frequently recurs after transplantation and is associated with a poor prognosis. We describe here the successful kidney graft reuse in an adult recipient, 8 months after early primary FSGS recurrence resistant to all available therapeutics. Patient 1, a 23-year-old man, followed for kidney failure secondary to primary FSGS, was first transplanted in 2018 with a deceased donor graft. Unfortunately, we observed an immediate recurrence of biopsy-proven primary FSGS. After 4 lines of treatment (intravenous cyclosporine+corticosteroids, plasma exchanges, immunoadsorption, and rituximab), the patient was still highly nephrotic and kidney function was slowly deteriorating. After approval from both the patient and the health authority (Biomedicine Agency), the graft was detransplanted 8 months after transplantation and reimplanted in patient 2, a 78-year-old nonimmunized and anephric recipient (bi-nephrectomy 2 years previously for bilateral renal carcinoma). We observed immediate kidney function and progressive resolution of proteinuria (serum creatinine of 1.2mg/dL and proteinuria of 0.1 g/d 1 year later). Biopsies performed after surgery showed persistent FSGS lesions with a decrease in overall foot-process effacement. To our knowledge, this is the first reported case showing that kidney graft transfer may still be a viable option for refractory primary FSGS several months after transplantation.

Regulations and Procurement Surgery in DCD Liver Transplantation: Expert Consensus Guidance From the International Liver Transplantation Society.

Donation after circulatory death (DCD) donors are an increasingly more common source of livers for transplantation in many parts of the world. Events that occur during DCD liver recovery have a significant impact on the success of subsequent transplantation. This working group of the International Liver Transplantation Society evaluated current evidence as well as combined experience and created this guidance on DCD liver procurement. Best practices for the recovery and transplantation of livers arising through DCD after euthanasia and organ procurement with super-rapid cold preservation and recovery as well as postmortem normothermic regional perfusion are described, as are the use of adjuncts during DCD liver procurement.

Optimal donation of kidney transplants after controlled circulatory death.

Controlled donation after circulatory death (cDCD) is used for "extended criteria" donors with poorer kidney transplant outcomes. The French cDCD program started in 2015 and is characterized by normothermic regional perfusion, hypothermic machine perfusion, and short cold ischemia time. We compared the outcomes of kidney transplantation from cDCD and brain-dead (DBD) donors, matching cDCD and DBD kidney transplants by propensity scoring for donor and recipient characteristics. The matching process retained 442 of 499 cDCD and 809 of 6185 DBD transplantations. The DGF rate was 20% in cDCD recipients compared with 28% in DBD recipients (adjusted relative risk [aRR], 1.43; 95% confidence interval [CI] 1.12-1.82). When DBD transplants were ranked by cold ischemia time and machine perfusion use and compared with cDCD transplants, the aRR of DGF was higher for DBD transplants without machine perfusion, regardless of the cold ischemia time (aRR with cold ischemia time <18 h, 1.57; 95% CI 1.20-2.03, vs aRR with cold ischemia time ≥18 h, 1.79; 95% CI 1.31-2.44). The 1-year graft survival rate was similar in both groups. Early outcome was better for kidney transplants from cDCD than from matched DBD transplants with this French protocol.

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.