Combined Liver-Kidney Transplantation With Preformed Anti-human Leukocyte Antigen Donor-Specific Antibodies

Introduction: the impact of preformed donor-specific anti-human leukocyte antigen (HLA) antibodies (pDSAs) after combined liver-kidney transplantation (CLKT) is still uncertain. Methods: we conducted a retrospective study in 8 European high-volume transplant centers and investigated the outcome of 166 consecutive CLKTs, including 46 patients with pDSAs. Results: patient survival was lower in those with pDSAs (5-year patient survival rate of 63% and 78% with or without pDSA, respectively; P = 0.04). The presence of pDSAs with a mean fluorescence intensity (MFI) ≥ 5000 (hazard ratio 4.96; 95% confidence interval: 2.3-10.9; P < 0.001) and the presence of 3 or more pDSAs (hazard ratio 6.5; 95% confidence interval: 2.5-18.8; P = 0.05) were independently associated with death. The death-censored liver graft survival was similar in patients with or without pDSAs. Kidney graft survival was comparable in both groups. (The 1- and 5-year death-censored graft survival rates were 91.6% and 79.5%, respectively, in patients with pDSAs and 93% and 88%, respectively, in the donor-specific antibody [DSA]-negative group, P = not significant). Despite a higher rate of kidney graft rejection in patients with pDSAs (5-year kidney graft survival rate without rejection of 87% and 97% with or without pDSAs, respectively; P = 0.04), kidney function did not statistically differ between both groups at 5 years post-transplantation (estimated glomerular filtration rate 45 ± 17 vs. 57 ± 29 ml/min per 1.73 m2, respectively, in patients with and without pDSAs). Five recipients with pDSAs (11.0%) experienced an antibody-mediated kidney rejection that led to graft loss in 1 patient. Conclusion: our results suggest that CLKT with pDSAs is associated with a lower patients' survival despite good recipients', liver and kidney grafts' outcome

Impact of hypoxia and reoxygenation on the extra/intracellular metabolome and on transporter expression in a human kidney proximal tubular cell line

Introduction Ischemia-reperfusion injury (IRI) induces several perturbations that alter immediate kidney graft function after transplantation and may affect long-term graft outcomes. Given the IRI-dependent metabolic disturbances previously reported, we hypothesized that proximal transporters handling endo/exogenous substrates may be victims of such lesions. Objectives This study aimed to determine the impact of hypoxia/reoxygenation on the human proximal transport system through two semi-targeted omics analyses. Methods Human proximal tubular cells were cultured in hypoxia (6 or 24 h), each followed by 2, 24 or 48-h reoxygenation. We investigated the transcriptomic modulation of transporters. Using semi-targeted LC–MS/MS profiling, we characterized the extra/intracellular metabolome. Statistical modelling was used to identify significant metabolic variations. Results The expression profile of transporters was impacted during hypoxia (y + LAT1 and OCTN2), reoxygenation (MRP2, PEPT1/2, rBAT, and OATP4C1), or in both conditions (P-gp and GLUT1). The P-gp and GLUT1 transcripts increased (FC (fold change) = 2.93 and 4.11, respectively) after 2-h reoxygenation preceded by 24-h hypoxia. We observed a downregulation (FC = 0.42) of y+LAT1 after 24-h hypoxia, and of PEPT2 after 24-h hypoxia followed by 2-h reoxygenation (FC = 0.40). Metabolomics showed that hypoxia altered the energetic pathways. However, intracellular metabolic homeostasis and cellular exchanges were promptly restored after reoxygenation. Conclusion This study provides insight into the transcriptomic response of the tubular transporters to hypoxia/reoxygenation. No correlation was found between the expression of transporters and the metabolic variations observed. Given the complexity of studying the global tubular transport systems, we propose that further studies focus on targeted transporters

A Universal Bleeding Risk Score in Native and Allograft Kidney Biopsies: A French Nationwide Cohort Study

BackgroundThe risk of bleeding after percutaneous biopsy in kidney transplant recipients is usually low but may vary. A pre-procedure bleeding risk score in this population is lacking.MethodsWe assessed the major bleeding rate (transfusion, angiographic intervention, nephrectomy, hemorrhage/hematoma) at 8 days in 28,034 kidney transplant recipients with a kidney biopsy during the 2010-2019 period in France and compared them to 55,026 patients with a native kidney biopsy as controls.ResultsThe rate of major bleeding was low (angiographic intervention: 0.2%, hemorrhage/hematoma: 0.4%, nephrectomy: 0.02%, blood transfusion: 4.0%). A new bleeding risk score was developed (anemia = 1, female gender = 1, heart failure = 1, acute kidney failure = 2 points). The rate of bleeding varied: 1.6%, 2.9%, 3.7%, 6.0%, 8.0%, and 9.2% for scores 0 to 5, respectively, in kidney transplant recipients. The ROC AUC was 0.649 (0.634-0.664) in kidney transplant recipients and 0.755 (0.746-0.763) in patients who had a native kidney biopsy (rate of bleeding: from 1.2% for score = 0 to 19.2% for score = 5).ConclusionsThe risk of major bleeding is low in most patients but indeed variable. A new universal risk score can be helpful to guide the decision concerning kidney biopsy and the choice of inpatient vs. outpatient procedure both in native and allograft kidney recipients

Early acute microvascular kidney transplant rejection in the absence of anti-HLA antibodies is associated with preformed IgG antibodies against diverse glomerular endothelial cell antigens

International audienceBACKGROUND: Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allografts, non-anti-HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed.METHODS: We conducted a nationwide study to identify kidney transplant recipients without anti-HLA donor-specific Abs who experienced acute graft dysfunction within 3 months after transplantation and showed evidence of microvascular injury, called acute microvascular rejection (AMVR). We developed a crossmatch assay to assess serum reactivity to human microvascular endothelial cells, and used a combination of transcriptomic and proteomic approaches to identify non-HLA Abs.RESULTS: We identified a highly selected cohort of 38 patients with early acute AMVR. Biopsy specimens revealed intense microvascular inflammation and the presence of vasculitis (in 60.5%), interstitial hemorrhages (31.6%), or thrombotic microangiopathy (15.8%). Serum samples collected at the time of transplant showed that previously proposed anti-endothelial cell Abs-angiotensin type 1 receptor (AT1R), endothelin-1 type A and natural polyreactive Abs-did not increase significantly among patients with AMVR compared with a control group of stable kidney transplant recipients. However, 26% of the tested AMVR samples were positive for AT1R Abs when a threshold of 10 IU/ml was used. The crossmatch assay identified a common IgG response that was specifically directed against constitutively expressed antigens of microvascular glomerular cells in patients with AMVR. Transcriptomic and proteomic analyses identified new targets of non-HLA Abs, with little redundancy among individuals.CONCLUSIONS: Our findings indicate that preformed IgG Abs targeting non-HLA antigens expressed on glomerular endothelial cells are associated with early AMVR, and that cell-based assays are needed to improve risk assessments before transplant

Donor CMV infection and solid organ transplantation : impact on CMV specific immune response and graft survival

Introduction : l’infection par le cytomégalovirus (CMV) humain est la plus fréquente des infections après greffe d'organe. Des effets indirects à long terme sont fortement suspectés mais restent encore largement incompris. Notre travail de thèse s’est intéressé à mieux comprendre les conséquences de l’infection du donneur par le CMV sur la réponse immunitaire du receveur et sur le devenir de son greffon. Résultat : nous avons initialement rapporté que l'infection du donneur (D+) par le CMV est un facteur de risque indépendant de perte de fonction du greffon rénal particulièrement si le receveur est également séropositif avant la greffe (D+R+ comparé aux D+R-). Le risque est fortement majoré en cas de mésappariement complet en HLA de classe I entre le receveur et son donneur. Puis nous avons analysé le rôle du greffon infecté dans le développement de la réponse lymphocytaire anti-CMV. Nous avons rapporté pour la première fois que la superinfection CMV entraine une augmentation du nombre de LT CD8 répondeurs spécifiques du CMV à distance de la transplantation, à condition que le donneur et le receveur partagent des identités HLA-I. De plus nous avons montré chez le sujet D+R- que l'expansion des lymphocytes T CD8 anti CMV restreints par le HLA-A2 nécessite l'expression de ce HLA par le donneur. Ces résultats ensemble indiquent le rôle des cellules du donneur dans l’inflation des LT CD8 anti-CMV à distance de la greffe. Dans un troisième travail, nous avons montré qu’un polymorphisme du gène de Programmed Cell Death 1 (PD-1.3) influe sur la survie des greffons rénaux et pulmonaires D+, les patients porteurs de l’allèle variant A ayant un meilleur pronostic que les patients homozygotes GG. Nos données indiquent aussi que les patients homozygotes AA ont un plus grand nombre de lymphocytes anti-CMV producteurs d'IFN-ɣ, suggérant que ce polymorphisme pourrait être associé à une dysfonction de la réponse immunitaire spécifique anti-CMV. Conclusion : ensemble ces données suggèrent pour la première fois que la qualité de la réponse lymphocytaire cytotoxique anti-CMV pourrait être importante pour contrôler la réplication virale dans le greffon et les lésions induites par cette dernière. Ainsi nous proposons deux mécanismes à l’origine du développement des lésions liées à l'infection à CMV dans le rein: défaut de reconnaissance des cellules allogéniques infectées en cas de mésappariement complet en HLA de classe I et une dysfonction LT CD8 anti-CMV.Background: cytomegalovirus (CMV) is the leading cause of viral infection after solid organ transplantation. Despite a large body of literature, the effects of chronic cytomegalovirus (CMV) infection on graft outcome remain controversial.Results: we first reported that donor CMV infection (D+) was an independent risk factor of kidney graft loss, especially in pretransplant infected recipients (R+). In addition, we observed that full HLA-I mismatching was an important determinant of this risk. In a second study, we focused on effect of donor CMV infection on anti-CMV specific immune response. We reported that CMV superinfection greatly increased the number of anti-CMV IFN-ɣ-producing T cells, provided that donor and recipient shared at least one HLA-I identity. Then in D+R- HLA-A2-expressing recipients, we compared the number of anti-CMVpp65 CD8+T cells restricted by HLA-A2 depending on whether the donor expressed or not HLA-A2. Patients who received non-HLA-A2 kidneys developed very few anti-CMVpp65 T-cells restricted by HLA-A2 as compared to those who received an HLA-A2-expressing kidney. This result indicated that presentation of CMV peptides by donor cells was crucial to stimulate the expansion of pp65-specific memory CD8 T cells. Finally, we established that a SNP in the Programmed Cell Death 1 gene (PD-1.3) influenced D+ kidney and lung transplants survival, while it was also associated with the level of anti-CMV specific T-cell response. Conclusion: taken together, these data suggest that anti-CMV specific immune response is pivotal to control infection within the graft and prevent subsequent organ damages. We propose two mechanisms to explain effect of donor CMV infection on graft outcome: (1) inability of anti-CMV CD8 T cells to recognize donor-infected cells in case of full HLA-I mismatching, (2) dysfunction of anti-CMV CD8 T cells after transplantation in some patients, highlighted by our genetic study

Rejet humoral chronique actif associé à des lésions inflammatoires de la microcirculation du greffon rénal (caractéristiques et évolution)

TOURS-BU Médecine (372612103) / SudocSudocFranceF

Transplant center characteristics associated with living‐donor kidney transplantation: a cohort study with a hierarchical modeling approach

International audienceTransplant center organization, that is a modifiable factor, may affect the access to living-donor kidney transplantation (LDKT). The objective of this study was to identify the center characteristics associated with LDKT using a hierarchical analysis. This was a retrospective multicenter observational study of 8701 patients who received a first renal graft between 2010 and 2014 in 32 transplantation centers of France. Hierarchical modeling was used to estimate the center effect and organization associated with LDKT. Among 8507 patients, 1225 (12%) were transplanted with a LD kidney. There was a transplant center effect on the proportion of LDKT. After adjustment for patient and center characteristics, the random effect variance decreased by 47%. Patients transplanted at a center with more than four nephrologists [1.81 (95% CI: 1.10-2.95)] and more than 1.5 nurse transplant coordinators [1.98 (95% CI: 1.26-3.13)] were more likely to be transplanted with a LD kidney. ABO-incompatible program was associated with LDKT [2.23 (95% CI: 1.22-4.06)]. There was a transplant center effect on the proportion of LDKT that could be decreased by modifiable center characteristics. Our study suggests the importance of the transplant team organization on the LDKT utilization

A Prognostic Tool for Individualized Prediction of Graft Failure Risk within Ten Years after Kidney Transplantation

Identification of patients at risk of kidney graft loss relies on early individual prediction of graft failure. Data from 616 kidney transplant recipients with a follow-up of at least one year were retrospectively studied. A joint latent class model investigating the impact of serum creatinine (Scr) time-trajectories and onset of de novo donor-specific anti-HLA antibody (dnDSA) on graft survival was developed. The capacity of the model to calculate individual predicted probabilities of graft failure over time was evaluated in 80 independent patients. The model classified the patients in three latent classes with significantly different Scr time profiles and different graft survivals. Donor age contributed to explaining latent class membership. In addition to the SCr classes, the other variables retained in the survival model were proteinuria measured one-year after transplantation (HR=2.4, p=0.01), pretransplant non-donor-specific antibodies (HR=3.3, p<0.001), and dnDSA in patient who experienced acute rejection (HR=15.9, p=0.02). In the validation dataset, individual predictions of graft failure risk provided good predictive performances (sensitivity, specificity, and overall accuracy of graft failure prediction at ten years were 77.7%, 95.8%, and 85%, resp.) for the 60 patients who had not developed dnDSA. For patients with dnDSA individual risk of graft failure was not predicted with a so good performance

Relationship Between Antithymocyte Globulin Concentrations and Lymphocyte Sub-Populations in Kidney Transplant Patients

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