Accuracy of intra-operative PTH measurement during subtotal parathyroidectomy for tertiary hyperparathyroidism after renal transplantation

Background and aims: Intra-operative parathyroid hormone (IOPTH) results are not known in the setting of tertiary hyperparathyroidism (HPT) after renal transplantation. Materials and methods: A retrospective analysis of 35 tertiary HPT patients who all underwent subtotal parathyroidectomy and IOPTH monitoring was conducted. Results: The mean follow-up time was 2.2±1.4years. Thirty-four patients were cured; one patient (2.8%) had a persistent disease and was cured after reoperation. Median parathyroid hormone (PTH) (median percent decrease from highest) at baseline and at 5, 10, 20, and 30min were 244, 78 (69%), 63 (75%), 53 (79%), and 49pg/ml (83%), respectively. Four patients who were cured had a decrease of 50% at 10min. The sensitivity of the test was 94% at 10min using the Miami criteria. Conclusion: This study shows that IOPTH in tertiary hyperparathyroidism has a high sensitivity. However, because of the low risk of persistent hyperparathyroidism when a subtotal parathyroidectomy is performed, its potential impact on the overall success rate is very small. We therefore do not recommend the routine use of IOPTH in tertiary hyperparathyroidis

Heme Drives Susceptibility of Glomerular Endothelium to Complement Overactivation Due to Inefficient Upregulation of Heme Oxygenase-1

Atypical hemolytic uremic syndrome (aHUS) is a severe disease characterized by microvascular endothelial cell (EC) lesions leading to thrombi formation, mechanical hemolysis and organ failure, predominantly renal. Complement system overactivation is a hallmark of aHUS. To investigate this selective susceptibility of the microvascular renal endothelium to complement attack and thrombotic microangiopathic lesions, we compared complement and cyto-protection markers on EC, from different vascular beds, in in vitro and in vivo models as well as in patients. No difference was observed for complement deposits or expression of complement and coagulation regulators between macrovascular and microvascular EC, either at resting state or after inflammatory challenge. After prolonged exposure to hemolysis-derived heme, higher C3 deposits were found on glomerular EC, in vitro and in vivo, compared with other EC in culture and in mice organs (liver, skin, brain, lungs and heart). This could be explained by a reduced complement regulation capacity due to weaker binding of Factor H and inefficient upregulation of thrombomodulin (TM). Microvascular EC also failed to upregulate the cytoprotective heme-degrading enzyme heme-oxygenase 1 (HO-1), normally induced by hemolysis products. Only HUVEC (Human Umbilical Vein EC) developed adaptation to heme, which was lost after inhibition of HO-1 activity. Interestingly, the expression of KLF2 and KLF4—known transcription factors of TM, also described as possible transcription modulators of HO-1- was weaker in micro than macrovascular EC under hemolytic conditions. Our results show that the microvascular EC, and especially glomerular EC, fail to adapt to the stress imposed by hemolysis and acquire a pro-coagulant and complement-activating phenotype. Together, these findings indicate that the vulnerability of glomerular EC to hemolysis is a key factor in aHUS, amplifying complement overactivation and thrombotic microangiopathic lesions

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

Dysfonction chronique du greffon en transplantation rénale (stratégies immunosuppressives et approche anti-inflammatoire expérimentale)

La dysfonction chronique du greffon (DCG) résulte d'un processus inflammatoire chronique induit par des facteurs lésionnels immunologiques et non immunologiques. Malgré les progrès sensibles des protocoles d'immunosuppression qui ont permis d'améliorer les résultats à court terme, la DCG reste l'une des premières causes de perte tardive du greffon.Notre travail clinique a consisté à évaluer l'apport du mycophénolate mofétil (MMF) dans le cadre d'une stratégie d'élimination de la ciclosporine (CsA), en terme de prévention du rejet aigu et de la néphrotoxicité des inhibiteurs de la calcineurine, qui sont 2 facteurs de risque majeurs de DCG.Rétrospectivement, nous avons comparé l'azathioprine au mycophénolate mofétil en association à la CsA. L'association MMF et CsA a permis non seulement de réduire l'incidence mais également d'atténuer les conséquences délétère du rejet aigu, ce qui s'est traduit par une amélioration significative de la survie du greffon à 3 ans chez les patients ayant présenté un ou plusieurs épisodes de rejet aigu durant les 6 premiers mois de greffe.Dans une étude randomisée ouverte évaluant l'arrêt précoce (3 mois) de la CsA sous MMF et prednisone chez des patients à faible risque immunologique, nous avons observé une amélioration significative de la fonction rénale à 1 et 2 ans au décours du sevrage de la CsA. La pharmacocinétique du MMF et les modifications " borderline " sur la biopsie à 3 mois étaient les 2 facteurs indépendants prédictifs de rejet aigu à l'arrêt de la CsA, identifiés dans cette étude. La biopsie systématique à 1 an a mis en évidence l'apparition de dépôts de C4d pour une proportion importante de patients sevrés de la CsA, indépendamment de la survenue d'un rejet aigu précoce. Cependant, ni le bilan histologique à 1 an (Chronic Allograft Damage Index), ni la fonction rénale à 2 ans ne suggéraient l'installation d'un rejet chronique chez ces patients.Un suivi prolongé et des examens spécifiques (par exemple la recherche d'anticorps anti-HLA) seront nécessaires pour interpréter cette donnée, qui pose la question de la valeur pronostique des dépôts de C4d découverts sur des biopsies protocolaires effectués chez des patients stables.Dans la mesure où les agressions immunologiques et non immunologiques entretiennent un processus inflammatoire chronique, nous avons voulu évaluer l'impact de différentes molécules anti-inflammatoire et/ou immunomodulatrices sur la progression de la DCG. La pentoxifylline, les statines et les agonistes PPAR (Peroxisome Proliferator-Activated Receptors), dont on connaît les effets pléiotropes et la sécurité d'utilisation en pratique clinique, ont été testés dans un modèle murin d'allogreffe cutanée. Ni la pentoxifylline ni les statines n'ont influencé l'évolutivité du rejet chronique dans ce modèle. Paradoxalement, l'administration précoce de fénofibrate, agoniste PPAR , a provoqué une aggravation de la fibrose, tant au sein des greffons cutanés allogéniques que syngéniques. Ces données suggèrent que l'activation de PPAR , qui est exprimé transtoirement après une lésion cutanée, peut moduler la cicatrisation dans ce modèle.La prévention de la DCG repose en partie sur des modifications précoces de l'immunosuppression destinées à éviter à long terme la néphrotoxicité des inhibiteurs de la calcineurine. Cependant cette stratégie comporte un risque élevé de rejet aigu et ne peut être proposée à tous les patients. Ce risque peut être minimisé par une sélection rigoureuse des receveurs tenant compte à la fois des événements survenus pendant les 3 premiers mois de greffe, de la pharmacocinétique des immunosuppresseurs et des données histologiques à 3 mois. Néanmoins, la nephrotoxicité des inhibiteurs de la calcineurine n'est qu'un seul des multiples facteurs responsables du processus inflammatoire chronique conduisant à la DCG. Des médications anti-inflammatoires non spécifiques, en association au traitement immunosuppresseur, pourraient contribuer à contrôler la progression de la DCG. Une approche expérimentale peut être utile à la sélection de molécules potentiellement actives, avant la mise en place d'essais cliniques qui nécessiteront le suivi prolongé d'importantes cohortes de patients.Chronic allograft dysfunction (CAD) is a chronic inflammatory state inside the graft, causally related to immunological and non immunological injuries. Despite significant improvements in immunosuppressive regimens that led to better results in the short term, CAD remains a major cause of late graft lost in renal transplantation.The clinical part of this work was to evaluate the efficiency and safety of mycophenolate mofetil (MMF) in a strategy of cyclosporine (CsA) withdrawal, for the prevention of acute rejection and nephrotoxicity of calcineurin inhibitors, two of the strongest risk factors for CAD. In a retrospective study we compared azathioprine to mycophenolate mofetil associated with CsA: MMF+CsA reduced the incidence of acute rejection and weakened the deleterious consequences of acute rejection, resulting in significantly increased 3-year graft survival rates in patients who had experienced one or more acute rejection episodes during the first 6 months post graft. In a randomized, open-labelled study to evaluate early (3 months) withdrawal of CsA under MMF and prednisone in low immunological risk recipients, we demonstrated a significant improvement of the renal function at 1 and 2 years after CsA discontinuation. However, a higher proportion of the recipients withdrawn from CsA experienced acute rejection, as compared with patients withdrawn from MMF and maintained under CsA and prednisone. Pharmacokinetics of MMF and borderline histological changes in the 3-month graft biopsy were identified as 2 independent predictors of acute rejection after CsA withdrawal. The 1-year systematic graft biopsy revealed that a significant number of patients withdrawn from CsA developed peritubular C4d deposits, independently of the occurrence of early acute rejection episodes. However, neither 1-year Chronic Allograft Damage Index nor 2-year graft function were suggestive of a progression towards chronic rejection in these patients. Further follow-up as well as specific investigations (e.g. HLA antibodies) are needed to clarify this result, which questions the prognostic value of C4d deposits on protocol biopsies in stable patients.Because both immunological and non immunological injuries contribute to a chronic inflammatory process, we evaluated the impact of different anti-inflammatory and/or immunomudulatory drugs on the progression of CAD. Pentoxifylline, statins, and PPAR (Peroxisome Proliferator-Activated Receptors) agonists were tested because of their known pleiotropic effects and their safety in clinical practice. In a murine model of skin allograft, neither pentoxifylline nor statins modified the course of chronic rejection in this model. The PPAR ligand fenofibrate paradoxically exacerbated fibrosis in allogeneic and syngeneic skin grafts when administrated immediately after the graft. These data suggest that activation of PPAR , which is transiently expressed after a cutaneous lesion, may interfere with wound healing in this model.Prevention of CAD can partly rely on early modifications of the immunosuppressive regimen to avoid long term nephrotoxicity of calcineurin inhibitors, but this strategy carries a significant risk of acute rejection, and CsA elimination cannot be recommended for all patients. This risk can be minimized in carefully selected recipients according to the early events post graft, pharmacokinetics of the immunosuppressive drugs, and histological results at 3 months. However, the nephrotoxicity of calcineurin inhibitors is only one among multiple factors involved in the chronic inflammatory process leading to CAD. Non-specific anti-inflammatory treatment in association with immunosuppressive drugs could slow down progression of graft failure. An experimental approach can help to select active molecules before initiating clinical trials that will require high numbers of patients and a prolonged follow-up.LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Anti-TNF alpha et sarcoïdose (efficacité de l'infliximab (à propos d'un cas))

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Intérêt de la biopsie systématique du greffon à 3 mois en transplantation rénale

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Glomérulonéphrite extra-membraneuse et lymphome malin non hodgkinien compliquant un syndrome de Gougerot-Sjögren (à partir d'un cas)

LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Greffe avec donneur vivant (suivi après prélèvement)

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Donneurs très âgés en transplantation rénale : jusqu’où peut-on aller ?

International audienceIn order to increase the pool of organ donors, kidney transplantation from very old-donors, notably aged more than 70, is increasing. Compared to the United States, where the use of these grafts does not reach 5%, in France it reaches over 20%. Kidney aging is determined by a progressive glomerusclerosis, interstitial fibrosis, and nephrosclerosis, responsible of a linear decrease of glomerular filtration rate with time. Aging in kidney transplantation goes along also with an increased immunogenicity and risk of ischemia-reperfusion injuries. Hence, the prognosis of these transplantations is worse than those from younger donors, even though it remains better than dialysis. Data is lacking on risk factors of graft loss in this specific population. Hypothermic perfusion machine, pre-implantation kidney biopsy, dual kidney transplantation and immunosuppressive strategies have been evaluated to improve the long-term prognosis of these grafts