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Belatacept was developed to replace calcineurin inhibitors in kidney transplantation. Its use is associated with better kidney transplant function, a lower incidence of anti-donor antibodies and higher graft survival. However, it is also associated with a higher risk of cellular rejection. We studied the activation and proliferation mechanisms of belatacept-resistant T lymphocytes (TLs), to identify new pathways for control. We performed a transcriptomic analysis on CD4+ CD57+ PD1- memory TLs, which are responsible for a higher incidence of graft rejection, after allogeneic stimulation with activated dendritic cells (aDCs) in the presence or absence of belatacept. After six hours of contact with aDCs, the (CD4+ CD57+ PD1- ) (CD4+ CD57+ PD1+ ) and (CD4+ CD57- ) lymphocytes had different transcriptional profiles with or without belatacept. In the CD4+ CD57+ PD1- population, the IFNα-dependent activation pathway was positively overrepresented, and IRF7 transcript levels were high. IRF7 was associated with IFNα/β and IL-6 regulation. The inhibition of both these cytokines in a context of belatacept treatment inhibited the proliferation of CD4+ CD57+ PD1- T cells. Our results show that IRF7 is rapidly upregulated in belatacept-resistant CD4+ CD57+ PD1- TLs. The inhibition of type I IFN or IL-6 in association with belatacept treatment reduces the proliferation of belatacept-resistant TLs, paving the way for new treatments for use in organ transplantation.

BK-virus-associated nephropathy (BKvAN) is a major complication in kidney transplant recipients, associated with a higher level of BK-virus (BKv) replication and leading to poor graft survival. In a large cohort of kidney transplant recipients with various BKv reactivation levels, we found that BKvAN was associated with a low BKv-specific memory CD8 T-cell functionality and an exhausted-like phenotype. This severe lymphocyte impairment was associated with a low level of class II HLA mismatches. In vitro experiments showed that allogeneic CD4 T cells partly restored BKv-specific memory CD8 T-cell responses. Our results suggest that in kidney transplant recipient, allogeneic CD4 T cells may provide a heterospecific help that maintain an effective BKv-specific memory CD8 T-cell response, and allows a better control of BKv replication in the kidney graft.

Background The coronavirus disease 2019 (COVID-19) may be associated with kidney injury, which may impact patient's prognosis. Methods We report a multicentric retrospective case series of patients with COVID-19 who developed acute kidney injury (AKI) and/or proteinuria and underwent a kidney biopsy in Paris and its metropolitan area. Results Forty-seven patients (80.9% men) with COVID-19 who underwent a kidney biopsy between 8 March and 19 May 2020 were included. The median age was 63 years (interquartile range 52–69). Comorbidities included hypertension (66.0%), diabetes mellitus (27.7%), obesity (27.7%), history of chronic kidney disease (25.5%), cardiac diseases (38.6%) and respiratory diseases (27.3%). Initial symptoms were fever (85.1%), cough (63.8%), shortness of breath (55.3%) and diarrhoea (23.4%). Almost all patients developed AKI (97.9%) and 63.8% required renal replacement therapy. Kidney biopsy showed two main histopathological patterns, including acute tubular injury in 20 (42.6%) patients, and glomerular injury consisting of collapsing glomerulopathy (CG) and focal segmental glomerulosclerosis in 17 (36.2%) patients. Two (4.3%) patients had acute vascular nephropathy, while 8 (17%) had an alternative diagnosis most likely unrelated to COVID-19. Acute tubular injury occurred almost invariably in the setting of severe forms of COVID-19, whereas patients with glomerular injury had various profiles of COVID-19 severity and CG was only observed in patients harbouring a combination of APOL1 risk variants. At the last follow-up, 16 of the 30 patients who initially required dialysis were still on dialysis, and 9 had died. Conclusions This study describes the spectrum of kidney lesions in patients with COVID-19. While acute tubular injury is correlated with COVID-19 severity, the pattern of glomerular injury is intimately associated with the expression of APOL1 risk variants.

Kidney transplantation has become the preferred treatment option in end-stage chronic renal failure as it provides significant improvements over dialysis in terms of both quality and duration of life. Even after several randomized studies conducted in the last 20 years, the combination of CNI, MMF, and steroids continues to be considered the gold standard for kidney transplantation. However, novel molecules aimed at minimizing renal and cardiovascular toxicity, particularly with CNI sparing, are being identified. The present review assesses various such molecules available currently and briefly discusses the existing combination strategies and novel perspectives for the redesigning of protocols based on our novel therapeutic arsenal.

Resume Le syndrome des antiphospholipides est une thrombophilie caracterisee par l’association d’un evenement clinique thrombotique (arteriel et/ou veineux) ou obstetrical, associe a la presence durable d’anticorps antiphospholipides. L’atteinte pouvant toucher l’ensemble de l’arbre vasculaire, une atteinte renale est frequemment associee avec la description maintenant bien codifiee de la nephropathie associee au syndrome des antiphospholipides. Nous proposons dans cette revue des recommandations actualisees sur la prise en charge du syndrome des antiphospholipides en nephrologie. La therapeutique se base sur une anticoagulation plus ou moins une antiagregation a long terme en fonction des evenements cliniques sans oublier le recours a une nephroprotection classique (controle strict de la pression arterielle avec notamment des therapeutiques bloquant le systeme renine–angiotensine–aldosterone). Le syndrome catastrophique des antiphospholipides est une complication extremement grave pouvant mettre en jeu le pronostic vital du patient. Celui-ci justifie une attention toute particuliere, ainsi qu’une prevention dans les situations a risque. Nous illustrons egalement les difficultes de prise en charge au long cours de ces patients, tant en dialyse qu’en transplantation renale.

Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease due to central nervous system replication of the human polyomavirus JC virus (JCV) in immunosuppressed patients. The only effective therapeutic approach is to restore anti-JCV T-cell responses. In this study, we describe a case of rapidly fatal PML with JCV T-cell anergy in a renal transplant patient treated with CTLA4-Ig (belatacept, a CD28-B7 costimulation blocker and T-cell anergy inducer). T-cell anergy could not be reversed despite several therapeutic approaches. Progressive multifocal leukoencephalopathy secondary to biotherapy-induced T-cell anergy may thus represent a subset of PML with major resistance to anti-JCV immune recovery.

Introduction La leuco-encephalopathie multifocale progressive (LEMP) est une affection demyelinisante du systeme nerveux central, secondaire a la replication intracerebrale du Polyomavirus virus humain JC-virus (JCV) et caracterisee par son extreme gravite chez les patients immunodeprimes. La seule approche therapeutique actuellement demontree de la LEMP est la restauration de la reponse cellulaire T specifique du JCV. Observation Nous decrivons ici un cas de LEMP d’evolution fatale chez un patient transplante renal sous belatacept. Nous avons mis en evidence chez ce patient une alteration profonde de la fonctionnalite des lymphocytes T specifiques du JCV (secretions cytokiniques, proliferation et cytotoxicite) tout au long de l’evolution de la LEMP, associee a une sur-expression du recepteur inhibiteur PD-1. L’ajout in vitro d’un anticorps bloquant PD-1 n’a pas permis de lever cette inhibition lymphocytaire, suggerant un etat d’anergie lymphocytaire. Discussion Cet etat anergique des lymphocytes T specifiques du JCV pourrait avoir ete induit par l’administration de belatacept (CTLA4-Ig, inhibiteur selectif du deuxieme signal d’activation lymphocytaire induisant un etat d’anergie lymphocytaire [1] ). Conclusion Ainsi, les biotherapies induisant une anergie lymphocytaire pourraient favoriser l’emergence de LEMP resistantes a la restauration de l’immunite cellulaire specifique du JCV et donc a la seule approche therapeutique actuellement efficace.

In renal transplantation, BK-virus-associated nephropathy has emerged as a major complication, with a prevalence of 5–10% and graft loss in >50% of cases. BK-virus is a member of the Polyomavirus family and rarely induces apparent clinical disease in the general population. However, replication of polyomaviruses, associated with significant organ disease, is observed in patients with acquired immunosuppression, which suggests a critical role for virus-specific cellular immunity to control virus replication and prevent chronic disease. Monitoring of specific immunity combined with viral load could be used to individually assess the risk of viral reactivation and virus control. We review the current knowledge on BK-virus specific cellular immunity and, more specifically, in immunocompromised patients. In the future, immune-based therapies could allow us to treat and prevent BK-virus-associated nephropathy.

Introduction La leucoencephalopathie multifocale progressive [LEMP] est une infection opportuniste rare redoutee chez les patients traites par natalizumab. Nous decrivons le cas d’une LEMP survenue chez un patient traite par belatacept. Observation Un patient de 68 ans, transplante renal en 2013 et traite par belatacept, mycophenolate mofetil (MM) et prednisone aux posologies habituelles, presenta en mai 2015 un changement progressif de comportement avec une apathie et des episodes confusionnels transitoires. Il presenta le mois suivant une faiblesse du membre superieur droit d’installation brutale et une amputation du champ visuel droit sans anomalie visible a priori sur un premier scanner cerebral. L’IRM cerebrale realisee quelques jours plus tard mis en evidence une lesion de substance blanche, fronto-parietale gauche sans systematisation vasculaire, en hypersignal diffusion et Flair et en hyposignal T1, non rehaussee par le gadolinium. Le diagnostic LEMP fut confirme par une PCR JC positive dans le LCR. Le belatacept fut immediatement arrete et deux echanges plasmatiques furent rapidement realises. Le patient presentait alors 275 CD4+ circulants. Le MM fut arrete le 22/06 et devant l’evolution progressivement defavorable, 3 injections d’interleukine-7 furent administrees. La fonction renale resta stable tout au long de l’hospitalisation mais le patient s’aggrava progressivement sur le plan neurologique et deceda 10 semaines apres le diagnostic. Discussion Le belatacept est un anticorps humanise anti-CTLA4 non nephrotoxique qui inhibe l’activation lymphocytaire T en inactivant la co-stimulation lymphocytes T/cellule presentatrice d’antigene. Sous ce traitement, seuls deux cas de LEMP ont ete decrits dans la base de donnees anglo-saxonnes de pharmacovigilance. Les patients recevaient des posologies superieures a celles actuellement recommandees contrairement a notre patient. Conclusion La survenue d’une LEMP reste rare sous belatacept mais sa gravite et l’absence de ressource therapeutique, doivent la faire rechercher en cas de survenue de signes neurologiques rapidement progressifs.

Introduction Les perfusions de fer IV sont utilisees largement en dialyse pour traiter l’anemie et limiter les couts lies aux ASE. Les recommandations actuelles ne fixent pas de limites superieures aux cibles de ferritinemie et de CST. Elles peuvent amener les nephrologues a prescrire du fer meme en cas de ferritinemie elevee. Or de recentes publications suggerent des effets secondaires a court et a long termes lies a la surcharge que peut entrainer le fer IV. Dans une approche benefice-risque, nous decrivons l’impact d’une strategie de reduction de la posologie de fer IV. Patients et methodes Nous avons mene une etude prospective monocentrique visant a evaluer sur 8 mois une strategie de reduction des prescriptions de fer IV dans le traitement de l’anemie en dialyse au sein d’un centre de dialyse hospitalier. Nous sommes passes d’une strategie de prescription visant a maintenir un CST entre 30 et 50 %, quel que soit le taux de ferritine, a une strategie de prescription de fer si et seulement si le CST est Resultats Les donnees au cours des 6 mois etaient disponibles pour 45 patients suivis dans le centre. La dose moyenne de fer prescrite passait de 77,7 ± 86,1 mg a 24,4 ± 42 mg par patient et par semaine (p = 0,0003). La ferritinemie diminuait de 947,7 ± 1056,4 μg/L a 572,7 ± 424,4 μg/L (p = 0,0001) et le CST de 41,5 % ± 22,4 a 32,6 % ± 13,7 (p = 0,01). L’hemoglobine restait stable (11,13 ± 1,05 vs 11,0 ± 1,16 g/dL) (p = 0,54) ainsi que la dose d’ASE (126,4 ± 91,93 vs 108,2 ± 112,7 μg/28 jours [p = 0,07]). Discussion Malgre une nette diminution des doses de fer nous n’avons pas constate d’augmentation de besoin en EPO ou d’aggravation de l’anemie. Bien que la taille de l’echantillon reste faible les resultats semblent significatifs. Ces donnees doivent servir de point de depart a des etudes de plus grande envergure avec la presence d’un groupe temoin. Conclusion Notre etude suggere qu’a posologie d’ASE constante, avec une adaptation des posologies de fer IV basee sur les seuils inferieurs de CST et de ferritinemie des recommandations, le taux d’hemoglobine reste constant preservant ainsi le patient de la surcharge ferrique.

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