Prevention of endothelial aggression in a model of antibody-mediated rejection in allogeneic kidney transplantation

La survenue de rejets diminue la survie des transplants rénaux, en particulier les rejets aigus ou chroniques médiés par des anticorps dirigés contre le complexe majeur d’histocompatibilité (CMH) du donneur (Donor specific antibodies, DSA). Les traitements des rejets médiés par les anticorps et la transplantation des patients présentant des DSA avant transplantation restent peu efficients à ce jour. Nous avons étudié différentes stratégies de protection de l’endothélium du transplant contre la toxicité des DSA dans un modèle porcin de transplantation rénale allogénique chez un receveur allo-immunisé. Nous avons testé l’effet d’un anticorps monoclonal dirigé contre le CMH de classe I porcin. In vitro, cet anticorps protége partiellement les cellules endothéliales de la toxicité des DSA. La perfusion de cet anticorps lors de la préservation du rein sur machine de perfusion hypothermique entraîne sa fixation à l’endothélium mais n’est pas suffisante pour retarder la survenue d’un rejet aigu. Nous avons étudié l’intérêt du resveratrol, un polyphénol naturel, dans la protection de l’endothélium. Le resveratrol induit in vitro l’expression de molécules cytoprotectrices et de molécules régulatrices du complément par les cellules endothéliales. De plus, l’incubation des cellules endothéliales avec le resveratrol diminue l’activation de ces cellules en réponse au TNF. Ainsi, différentes stratégies de protection de l’endothélium peuvent être envisagées pendant la période de préservation de l’organe avant transplantation.Kidney allograft survival is limited by the occurrence of rejection, particularly acute or chronic antibody-mediated rejection (ABMR) mediated by antibodies against donor major histocompatibility complex (MHC) (so-called donor specific antibodies, DSA). Finding means of transplanting patients with preformed DSA and treatment of antibody-mediated rejections are major issues in kidney transplantation. We study strategies to protect the endothelium against DSA toxicity in a porcine model of allogeneic kidney transplantation to an alloimmunised recipient. First we tested the protective potential of a monoclonal anti-porcine MHC class I antibody. In vitro, this antibody partially protected endothelial cells against DSA complement-dependent cytotoxicity. We perfused the kidney with this antibody during hypothermic machine preservation, resulting in its binding to transplant endothelium. However, this was not sufficient to delay the occurence of ABMR. Then, we studied the impact of resveratrol, a natural polyphenol, on endothelial protection. Incubation of endothelial cells with resveratrol induces the expresion of genes for cytoprotective molecules and complement regulatory proteins. Furthermore, incubation of endothelial cells with resveratrol protects them from activation induced by TNF-alpha. Thus, different therapeutic intervention could be implemented ex vivo during organ preservation for transplant endothelium protection

Baseline proteinuria level and adverse outcomes in pregnant women with chronic kidney disease: new evidence and a note of caution

International audienceAbout 3% of all pregnancies occur in patients with some degree of chronic kidney disease (CKD) and, in turn, CKD is a risk factor for developing hypertensive disorders of pregnancies (HDP) and unfavorable pregnancy outcomes, at both the maternal and fetal level. CKD is often characterized by proteinuria and proteinuria is a risk factor for HDP. However, even if the positive correlation between proteinuria and unfavorable pregnancy outcomes is well acknowledged, the degree of proteinuria associated with adverse outcomes is still a matter of debate. In this issue of the Journal, Li et al. present a retrospective study that shows that >1 g of proteinuria/day is associated with worse maternal outcomes while >2 g/day with worse fetal ones. This study gives proteinuria thresholds for unfavorable outcomes in pregnant CKD patients, but it should be kept in mind that there is a linear correlation between proteinuria and worse pregnancy outcomes, thus a strict surveillance during the entire gestation should be advised independently of the proteinuria level

New immunosuppressive agents in transplantation

International audienceImmunosuppressive agents have enabled the development of allogenic transplantation during the last 40 years, allowing considerable improvement in graft survival. However, several issues remain such as the nephrotoxicity of calcineurin inhibitors, the cornerstone of immunosuppressive regimens and/or the higher risk of opportunistic infections and cancers. Most immunosuppressive agents target T cell activation and may not be efficient enough to prevent allo-immunization in the long term. Finally, antibody mediated rejection due to donor specific antibodies strongly affects allograft survival. Many drugs have been tested in the last decades, but very few have come to clinical use. The most recent one is CTLA4-Ig (belatacept), a costimulation blockade molecule that targets the second signal of T cell activation and is associated with a better long term kidney function than calcineurin inhibitors, despite an increased risk of acute cellular rejection. The research of new maintenance long-term immunosuppressive agents focuses on costimulation blockade. Agents inhibiting CD40-CD40 ligand interaction may enable a good control of both T cells and B cells responses. Anti-CD28 antibodies may promote regulatory T cells. Agents targeting this costimulation pathways are currently evaluated in clinical trials. Immunosuppressive agents for ABMR treatment are scarce since anti-CD20 agent rituximab and proteasome inhibitor bortezomib have failed to demonstrate an interest in ABMR. New drugs focusing on antibodies removal (imlifidase), B cell and plasmablasts (anti-IL-6/IL-6R, anti-CD38.. .) and complement inhibition are in the pipeline, with the challenge of their evaluation in such a heterogeneous pathology

Tracking Circulating HLA-Specific IgG-Producing Memory B Cells with the B-Cell ImmunoSpot Assay

Donor-specific antibodies (DSA) against human leukocyte antigen (HLA) molecules are a major risk factor for rejection of transplanted organs (in antibody-mediated rejection [ABMR]), particularly in patients who have prior sensitization or receive insufficient immunosuppression through minimization or noncompliance. These DSA are measured routinely in the serum of patients prior to transplantation mainly using bead-based technologies or cell-based assays. However, the absence of detectable serum DSA does not always reflect the absence of sensitization or histologically defined ABMR, and so it has been proposed that the detection and measurement of memory B cells capable of secreting antibodies against donor HLA antigens could be carried out using B-cell ImmunoSpot, to better inform the degree of immune sensitization of transplant patients prior to as well as after transplantation. Such an assay is described here.</p

Protection of transplants against antibody-mediated injuries: from xenotransplantation to allogeneic transplantation, mechanisms and therapeutic insights

International audienceLong-term allograft survival in allotransplantation, especially in kidney and heart transplantation, is mainly limited by the occurrence of antibodymediated rejection due to anti-Human Leukocyte Antigen antibodies. These types of rejection are difficult to handle and chronic endothelial damages are often irreversible. In the settings of ABO-incompatible transplantation and xenotransplantation, the presence of antibodies targeting graft antigens is not always associated with rejection. This resistance to antibodies toxicity seems to associate changes in endothelial cells phenotype and modification of the immune response. We describe here these mechanisms with a special focus on endothelial cells resistance to antibodies. Endothelial protection against anti-HLA antibodies has been described in vitro and in animal models, but do not seem to be a common feature in immunized allograft recipients. Complement regulation and anti-apoptotic molecules expression appear to be common features in all these settings. Lastly, pharmacological interventions that may promote endothelial cell protection against donor specific antibodies will be described

Minimal change disease relapse following SARS-CoV-2 mRNA vaccine

International audienceNo abstract availabl

Collapsing glomerulopathy in a patient with APOL1 intermediate-risk genotype triggered by lupus nephritis and SARS-CoV-2 infection: lessons for the clinical nephrologist

International audienceNo abstract availabl

Relapse of IgG4-related nephritis following mRNA COVID-19 vaccine

International audienceNo abstract availabl

Complex Management of Nephrotic Syndrome and Kidney Failure during Pregnancy in a Type 1 Diabetes Patient: A Challenging Case

International audiencePregnancy with chronic kidney disease is challenging, and patients with diabetic nephropathy are at particular risk of a rapid kidney function decline during pregnancy. While indications for the management of pregnant patients with initial diabetic nephropathy are widely available in the literature, data on patients with severe nephrotic syndrome and kidney function impairment are lacking, and the decision on whether and when dialysis should be initiated is not univocal. We report a type 1 diabetes patient who started pregnancy with a severe nephrotic syndrome and shifted from CKD stage 3b to stage 5 during pregnancy. The management was complicated by a fetal heart malformation and by poorly controlled diabetes. The evidence for and against starting dialysis was carefully evaluated, and the choice of strict nephrological and obstetrical monitoring, nutritional management, and diuretic treatment made it possible to avoid dialysis in pregnancy, after ruling out pre-eclampsia. This experience enables examination of some open issues and contributes to the discussion of when to start dialysis in pregnancy

Hypothermic pulsatile perfusion of human pancreas: Preliminary technical feasibility study based on histology

International audienceBackground: There are currently two approaches to hypothermic preservation for most solid organs: static or dynamic. Cold storage is the main method used for static storage (SS), while hypothermic pulsatile perfusion (HPP) and other machine perfusion-based methods, such as normothermic machine perfusion and oxygen persufflation, are the methods used for dynamic preservation. HPP is currently approved for kidney trans-plantation.Methods: We evaluated, for the first time, the feasibility of HPP on 11 human pancreases contraindicated for clinical transplantation because of advanced age and/or history of severe alcoholism and/or abnormal laboratory tests. Two pancreases were used as SS controls, pancreas splitting was performed on 2 other pancreases for SS and HPP and 7 pancreases were tested for HPP. HPP preservation lasted 24 h at 25 mmHg. Resistance index was continuously monitored and pancreas and duodenum histology was evaluated every 6 h.Results: The main finding was the complete absence of edema of the pancreas and duodenum at all time-points during HPP. Insulin, glucagon and somatostatin staining was normal. Resistance index decreased during the first 12 h and remained stable thereafter.Conclusion: 24 h hypothermic pulsatile perfusion of marginal human pancreas-duodenum organs was feasible with no deleterious parenchymal effect. These observations encourage us to further develop this technique and evaluate the safety of HPP after clinical transplantation