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ObjectiveTo identify characteristics of granulomatosis with polyangiitis (GPA) associated with induction failure, describe salvage therapies and their efficacy.MethodsWe conducted a nationwide retrospective case-control study of GPA with induction failure between 2006 and 2021. Each patient with induction failure was randomly paired to three controls matched for age, sex and induction treatment.ResultsWe included 51 patients with GPA and induction failure (29 men and 22 women). At induction therapy, median age was 49 years. Twenty-seven patients received intravenous cyclophosphamide (ivCYC) and 24 rituximab (RTX) as induction therapy. Patients with ivCYC induction failure more frequently had PR3-ANCA (93% vs 70%, P = 0.02), relapsing disease (41% vs 7%, P 100 µmol/l in 42% vs 8%, P = 0.02) compared with controls. After salvage therapy, remission was achieved at 6 months in 35 (69%) patients. The most frequent salvage therapy was switching from ivCYC to RTX (or vice versa), showing an efficacy in 21/29 (72%). Remission was achieved in nine (50%) patients with inappropriate response to ivCYC, while in patients with progression after RTX induction, remission was achieved in four (100%) who received ivCYC (with or without immunomodulatory therapy), but only in three (50%) after adding immunomodulatory therapy alone.ConclusionIn patients with induction failure, characteristics of GPA, salvage therapies and their efficacy vary according to induction therapy and failure modality.

Background Calcineurin inhibitors (CNIs) remain the cornerstone of maintenance immunosuppression (IS) after lung transplantation (LTx), although CNI-related life-threatening toxic effects may occur. Belatacept, a novel immunosuppressant that blocks a T-cell co-stimulation pathway, is a non-nephrotoxic drug indicated as an alternative to CNIs in kidney Tx. In LTx, there are only a few reports of belatacept conversion as a CNI-free or CNI-sparing IS treatment. Methods We reviewed a series of 10 LTx recipients with conversion to a CNI-free belatacept IS regimen within the first year post-LTx (n = 7) or a belatacept/low-dose CNI combination after the first year (n = 3). Results Use of belatacept was triggered by severe renal failure in 9 patients and under-IS with previous other IS-related toxicities in 1 patient. Mean estimated glomerular filtration rate after starting belatacept significantly improved at 6 months after initiation and at the last-follow-up (p = 0.006, and p = 0.002 respectively). The incidence of recurrent and/or severe acute cellular rejection (ACR) episodes was high in patients with CNI-free belatacept-based IS (n = 4/7). Chronic graft allograft dysfunction developed in 2 of 9 recipients under belatacept IS. Belatacept was stopped in 6 patients because of recurrent/severe ACR (n = 3), recurrent opportunistic infections (n = 1), center modified policy (n = 1), or other cause (n = 1). Conclusion Early conversion to CNI-free belatacept-based IS improved renal function in this series but was counterbalanced by a high incidence of recurrent ACR, including life-threatening episodes. Other studies are needed to better determine the indications for its use after LTx, possibly with lower immunological risk IS regimens, such as CNI-sparing belatacept.

The optimal duration of eculizumab treatment in patients with atypical hemolytic uremic syndrome (aHUS) remains poorly defined. We conducted a prospective national multicenter open-label study to assess eculizumab discontinuation in children and adults with aHUS. Fifty-five patients (including 19 children) discontinued eculizumab (mean treatment duration, 16.5 months). Twenty-eight patients (51%) had rare variants in complement genes, mostly in MCP (n = 12; 22%), CFH (n = 6; 11%), and CFI (n = 6; 10%). At eculizumab discontinuation, 17 (30%) and 4 patients (7%) had stage 3 and 4 chronic kidney disease, respectively. During follow-up, 13 patients (23%; 6 children and 7 adults) experienced aHUS relapse. In multivariable analysis, female sex and presence of a rare variant in a complement gene were associated with an increased risk of aHUS relapse, whereas requirement for dialysis during a previous episode of acute aHUS was not. In addition, increased sC5b-9 plasma level at eculizumab discontinuation was associated with a higher risk of aHUS relapse in all patients and in the subset of carriers with a complement gene rare variant, both by log-rank test and in multivariable analysis. Of the 13 relapsing patients, all of whom restarted eculizumab, 11 regained their baseline renal function and 2 had a worsening of their preexisting chronic kidney disease, including 1 patient who progressed to end-stage renal disease. A strategy of eculizumab discontinuation in aHUS patients based on complement genetics is reasonable and safe. It improves the management and quality of life of a sizeable proportion of aHUS patients while reducing the cost of treatment. This trial was registered at www.clinicaltrials.gov as #NCT02574403.

Le diagnostic de nephropathie diabetique est generalement clinique. Une biopsie renale peut etre realisee en cas d’atypie afin d’eliminer une maladie renale non diabetique. Nous avons evalue l’opinion des nephrologues francophones par un questionnaire anonyme portant sur les criteres cliniques et biologiques — en particulier l’absence de retinopathie diabetique, la presence d’une hematurie, la diminution du debit de filtration glomerulaire ou l’elevation de la proteinurie — les amenant a retenir l’indication de biopsie renale chez des patients diabetiques de type 2 avec albuminurie>0,5g/jour ou equivalent. Cent quatre-vingt-huit personnes ont repondu au questionnaire, reparties entre internes (12 %), assistants (13 %), praticiens en hopital universitaire (26 %), en hopital general (24 %), en secteur associatif (10 %), en secteur prive (10 %), en exercice mixte (3 %) ou sans pratique clinique (2 %). L’elevation de la proteinurie etait un critere d’indication de biopsie renale pour 51 % des participants, le syndrome nephrotique pour 56 % des participants, l’absence de retinopathie diabetique pour 57 % des participants, la courte duree du diabete pour 65 % des participants, la progression rapide de l’insuffisance renale chronique pour 75 % des participants et l’hematurie pour 78 % des participants. Notre enquete revele donc une incertitude de la communaute nephrologique quant aux criteres d’indication de biopsie renale chez les patients diabetiques de type 2 ayant une proteinurie et la discordance des opinions vis-a-vis des recommandations et de la litterature, en particulier au regard de l’absence de retinopathie diabetique. Ces resultats soulignent la necessite d’une etude analysant les resultats de ces biopsies au regard de leurs indications.

Resume Le lupus est l’archetype de la maladie auto-immune impliquant des mecanismes d’auto-reactivite a l’origine de lesions tissulaires. L’atteinte renale y est frequente et concerne de 10 a 40 % des patients. Le diagnostic est histologique et la biopsie doit etre realisee des lors qu’existe une proteinurie superieure a 0,5 g/g. Dans plus de la moitie des cas, il s’agit d’une forme severe (glomerulonephrite proliferative avec activite : classes III et IV A ou A/C de la classification ISN/RPS 2003), qui met en jeu le pronostic fonctionnel renal. Le traitement doit permettre la remission de la glomerulonephrite et la prevention des rechutes dans le but de preserver la fonction renale et le pronostic vital, avec le moins d’effets indesirables possible. Le traitement d’attaque le plus eprouve de la glomerulonephrite lupique active est le cyclophosphamide associe aux corticoides a fortes doses. Si l’utilisation du cyclophosphamide n’est pas possible ou non souhaitee (dose cumulee trop importante, contre-indication, souhait de preserver la fertilite), un traitement par mycophenolate mofetil est propose. Pour le traitement d’entretien, le mycophenolate mofetil est le traitement de choix, l’azathioprine etant une alternative possible. La duree minimale communement admise du traitement d’entretien est de 3 ans. Les indications et les strategies de traitement des glomerulonephrites extramembraneuses (classe V) doivent etre precisees par de futures etudes. Pour les patientes en remission d’une atteinte renale du lupus, les grossesses sont possibles mais doivent etre encadrees par une adaptation therapeutique, une preparation et un suivi multidisciplinaire etroit. Si elle devait survenir, la prise en charge de l’insuffisance renale terminale est peu specifique et la transplantation renale est le traitement de suppleance offrant la meilleure survie.

Background The aim of this study was to evaluate the prognostic value of persistent retroperitoneal fibrosis FDG uptake using FDG/PET CT in patients with idiopathic retroperitoneal fibrosis (IRF). Methods In this monocentric retrospective cohort study, all patients admitted for IRF from January 2009 to December 2017 underwent a FDG/PET CT at diagnosis and during follow up. Metabolic activity of IRF was assessed by retroperitoneal fibrosis FDG uptake measured as maximal standardized uptake value (SUVmax). The primary outcome was IRF relapse rate during follow-up. Results 23 consecutive patients (54.7 [36.9–89] years, 73.9% of men) diagnosed with IRF had FDG/PET CT imaging performed at diagnosis, 3.1 [1–8.7] months (i.e 1st evaluation) and 10.4 [4.9–17.5] months (i.e 2nd evaluation) after diagnosis. High FDG retroperitoneal fibrosis uptake was present in all patients at diagnosis (SUVmax 6.5 [3.8–11.9]) and persisted in 16 (69.6%; SUVmax 3.65 [2.1–5.4]) and 12 (52.2%; SUVmax 3.75 [2.7–7.8]) patients, at 1st and 2nd evaluation respectively. All but one patient had received steroids at IRF diagnosis and 21 (91.3%) were in complete remission at both 1st and 2nd evaluation. During a median follow-up period of 38.7 [3–106.9] months, 6 (26.1%) patients suffered IRF relapse that occurred 15.7 [9.2–42.8] months after diagnosis. Multivariate analysis showed that only persistent retroperitoneal fibrosis FDG uptake at 2nd evaluation was associated with IRF relapse (p = .046). Conclusions In IRF, persistent retroperitoneal fibrosis FDG uptake during follow up is associated with clinical outcome. FDG/PET CT may help to better stratify the risk of relapse and target therapy in IRF.

Systemic lupus erythematosus is the most characteristic of auto-immune disorders that can lead to tissue damage in many organs, including kidney. Lupus nephritis occurs in 10 to 40% of lupus patients. Its clinical hallmark is the appearance of a proteinuria as soon as a 0.5 g/g or 0.5 g/d threshold, which calls for a renal histological evaluation in order to determine the lupus nephritis severity and the need for specific therapy. More than half of renal biopsies lead to the diagnosis of active lupus nephritis-class III or class IV A according to the ISN/RPS classification-that are the most severe in regards to renal prognosis and mortality. Their treatment aims to their clinical remission and to the prevention of relapse with minimal adverse effects for eventually the preservation of renal function, the prevention of other irreversible damage, and the reduction of risk of death. The remission is obtained through induction therapies of which the association of high dose steroids and cyclophosphamide is the most experienced. When this association must be challenged by the prevention of side-effect, in particular infertility, mycophenolate can be given instead of cyclophosphamide. Maintenance therapy, for the prevention of relapse, consists in mycophenolate or in azathioprine, mycophenolate being the most efficient however associated with a high risk of teratogenicity. Withdrawal of maintenance therapy is possible after two to three years in absence of high risk factors of relapse of lupus nephritis, however a reliable assessment of the risk of relapse is still lacking. Only pure membranous lupus nephritis (pure class V) associated with high level proteinuria requires specific therapies that usually associates steroids and an immunosuppressive drug. However, their choice hierarchy and even the use of less immunosuppressive strategies remain to be determined in terms of benefice over risk ratios. In spite of its trigger effect on lupus activity, pregnancy can be safe and successful if scheduled in the lowest risk periods with close multidisciplinary monitoring before, during and after. When necessary, renal replacement therapy does not require specific adaptation, renal transplantation is the best option when possible, as early as possible.

International audience; BACKGROUND: Human immunodeficiency virus (HIV) is associated with diverse glomerular diseases. Characteristics of minimal change nephrotic syndrome (MCNS) in this setting have been little studied, and the specific features of this uncommon association remain to be determined. METHODS: We conduct a retrospective study. Clinical, biological and pathological characteristics of patients with MCNS and HIV infection were assessed. We evaluated HIV infection by in situ hybridization and CMIP expression by immunochemistry on kidney biopsies and compared it to HIV-associated nephropathy (HIVAN) and idiopathic MCNS. RESULTS: Eight patients were identifies. In all but one of these cases, MCNS occurred after HIV diagnosis (mean of 9.5 years). Acute kidney injury was detected in three cases. Mean CD4(+) lymphocyte count was 733/mm(3) and three patients had a detectable HIV viral load. In situ hybridization for HIV-1 RNA detection yielded a positive signal in a few tubular cells in the renal parenchyma in two of four patients with HIV infection associated with MCNS. Podocytes of these patients presented strong positive immunostaining for CMIP (4/4). Three patients suffered steroid-dependent nephrotic syndrome, and another two patients had at least one relapse. Rituximab treatment was initiated in four cases. After a median follow-up of 20 months, all patients were in remission (complete in 5 cases). CONCLUSIONS: In patients with MCNS occurring in a context of HIV infection, podocyte injury seems to be associated with CMIP induction rather than renal HIV infection but further studies are needed to determine the molecular link between these two conditions.

Background Henoch-Schonlein purpura, more recently renamed immunoglobulin A vasculitis (IgAV), is a systemic vasculitis characterized by IgA deposits. The current markers used to assess IgAV inaccurately evaluate the risk of nephritis occurrence and its long-term outcomes. The current study assessed biomarkers of nephritis outcomes. Methods This French multicentre prospective study enrolled 85 adult patients at the time of disease onset. Patients were assessed for clinical and biological parameters and re-examined after 1 year. Immunoglobulins, cytokines, IgA glycosylation, IgA complexes and neutrophil gelatinase-associated lipocalin (NGAL) concentrations were assessed in blood and urine. Results We identified 60 patients with IgAV-related nephritis (IgAV-N) and 25 patients without nephritis (IgAV-woN). At the time of inclusion (Day 1), the serum levels of galactose-deficient IgA1 (Gd-IgA1) and urinary concentrations of IgA, IgG, IgM, NGAL, interleukin (IL)-1β, IL-6, IL-8, IL-10, IgA-IgG and IgA-sCD89 complexes were higher in the IgAV-N patients than in the IgAV-woN patients (P

Few studies have examined the occurrence of minimal change nephrotic syndrome (MCNS) in patients with non-Hodgkin lymphoma (NHL). We report here a series of 18 patients with MCNS occurring among 13,992 new cases of NHL. We analyzed the clinical and pathologic characteristics of this association, along with the response of patients to treatment, to determine if this association relies on a particular disorder. The most frequent NHLs associated with MCNS were Waldenstrom macroglobulinemia (33.3%), marginal zone B-cell lymphoma (27.8%), and chronic lymphocytic leukemia (22.2%). Other lymphoproliferative disorders included multiple myeloma, mantle cell lymphoma, and peripheral T-cell lymphoma. In 4 patients MCNS occurred before NHL (mean delay, 15 mo), in 10 patients the disorders occurred simultaneously, and in 4 patients MCNS was diagnosed after NHL (mean delay, 25 mo). Circulating monoclonal immunoglobulins were present in 11 patients. A nontumoral interstitial infiltrate was present in renal biopsy specimens from 3 patients without significant renal impairment. Acute kidney injury resulting from tubular lesions or renal hypoperfusion was present in 6 patients. MCNS relapse occurred more frequently in patients treated exclusively by steroid therapy (77.8%) than in those receiving steroids associated with chemotherapy (25%). In conclusion, MCNS occurs preferentially in NHL originating from B cells and requires an aggressive therapeutic approach to reduce the risk of MCNS relapse.

Early acute renal failure (ARF) is a common complication after lung transplantation (LTx), and is associated with higher long-term mortality. Calcineurins inhibitors (CNIs) toxicity play a major role in ARF in the early phase post-LTx, and alternate nonnephrotoxic immunosuppressive (IS) regimen are needed in LTx. Belatacept, a novel immunosuppressant that blocks a T-cell costimulation pathway, is a nonnephrotoxic drug indicated as an alternative to CNIs in kidney Tx. In LTx, a few cases of CNI-belatacept conversion have been reported so far, only in the late long-term follow-up (>3 years post-LTx). We here report a single-center series of 4 LTx recipients converted to a belatacept primary IS-regimen in the early-postoperative period after LTx (month [M] 2, M2, M2, M5). Causes of conversion were persistent severe renal failure, due to: [1] thrombotic microangiopathy; [2] CNI toxicity/acute tubular necrosis (ATN); [3] ATN/FSglomerulosclerosis; [4] CNI toxicity. Following belatacept-conversion, acute rejection (AR) episodes occurred in 2 high immunologic risk recipients, with detection of donor-specific antibodies (asymptomatic AR both in patient 1 [graded A2B0] and patient 2 [A2Bx], which were both resolved with pulsed steroids). All 4 recipients remained with stable pulmonary function and significant renal function improvement at last available follow-up postbelatacept (M2, M3, M3, and M4). Outcome at 9 months postbelatacept, including incidence of AR and chronic lung allograft dysfunction, graft survival, and renal function outcome will be presented at the ERS 2017 congress.

French Thrombotic Microangiopathies Reference Centre; International audience; Chronic kidney disease (CKD) is a frequent and serious complication of atypical haemolytic uremic syndrome (aHUS). We aimed to develop a simple accurate model to predict the risk of renal dysfunction in aHUS based on clinical and biological features available at hospital admission. Renal function at 1-year follow-up, based on an estimated glomerular filtration rate < 60mL/min/1.73m 2 as assessed by the Modification of Diet in Renal Disease equation, was used as an indicator of significant CKD. Prospectively collected data from a cohort of 156 aHUS patients who did not receive eculizumab were used to identify predictors of CKD. Covariates associated with renal impairment were identified by multivariate analysis. The model performance was assessed and a scoring system for clinical practice was constructed from the regression coefficient. Multivariate analyses identified three predictors of CKD: a high serum creatinine level, a high mean arterial pressure and a mildly decreased platelet count. The prognostic model had a good discriminative ability (area under the curve = .84). The scoring system ranged from 0 to 5, with corresponding risks of CKD ranging from 18% to 100%. This model accurately predicts development of 1-year CKD in patients with aHUS using clinical and biological features available on admission. After further validation , this model may assist in clinical decision making.

Introduction Le diagnostic de nephropathie diabetique (ND) est porte sur des arguments cliniques. Une biopsie renale (BR) n’est realisee qu’en cas d’atypie ou d’argument pour un autre diagnostic. Les donnees actuelles de la litterature sont discordantes. Nous avons evalue si cette discordance se traduisait egalement dans les pratiques des nephrologues, en particulier pour l’absence de retinopathie diabetique (RD), la presence d’une hematurie (HU), la diminution du DFG ou l’elevation de la proteinurie (PU). Patients/materiels et methodes Un questionnaire en ligne a ete diffuse aupres des nephrologues. Il etait anonyme et posait la question suivante : « Chez un patient diabetique de type 2, presentant une albuminurie superieure a 500 mg/24 h (ou equivalent), lesquels parmi les elements suivants vous semblent rendre necessaire la realisation d’une biopsie renale pour exclure une maladie renale non diabetique ? ». Elle etait suivie d’une serie de situations auxquelles il pouvait etre repondu « oui » ou « non ». Resultats Situations Non Oui. Absence de RD 43 % 57 %. Presence d’une HU 22 % 77 % dont 63 % apres elimination d’une cause urologique. Diminution « rapide » du DFG 24 % 76 %. Elevation « rapide » de la PU 47 % 53 % dont 36 % en l’absence de baisse des IEC/Sartan. Syndrome nephrotique 45 % 55 % dont 38 % en cas d’apparition brutale. Duree courte du diabete 34 % 66 %. Neoplasie connue 57 % 43 %. Maladie auto-immune 3 % 97 %. FAN sans specificites 70 % 30 %. ANCA sans specificite 56 % 44 %. Anticorps Anti-dsDNA 19 % 81 %. Anticorps Anti-MPO/Anti-PR3 13 % 87 %. MGUS 25 % 75 %. IRA 14 % 86 %. Seropositivite VIH, VHB ou VHC 26 % 74 % dont 40 % si la charge virale est positive. Proteinurie precedent le diabete 24 % 76 %. Presence d’un purpura cutane 11 % 89 %. Signe de maladie systemique 6 % 94 %. L’analyse des reponses par genre, tranche d’âge et type d’exercice sont superposables aux reponses globales. Discussion Si les reponses a certaines situations temoignent d’une pratique consensuelle en cas d’anti-dsDNA, d’anti-MPO/PR3 ou de maladie auto-immune, il n’en va pas de meme pour l’absence de retinopathie diabetique (57 % vs 43 %), la progression de la proteinurie (53 % vs 47 %) ou la presence d’un syndrome nephrotique (55 % vs 45 %). En effet, dans les 3 cas, les avis divergent fortement entre ceux qui ne retiennent jamais l’indication de BR et ceux qui la pratiquent systematiquement ou sous condition. Conclusion Les criteres d’indication d’une biopsie renale chez un patient diabetique varient selon les cliniciens. Cette heterogeneite des pratiques coincide avec l’absence de donnees de la litterature sur ce sujet, et, justifie la realisation d’enquete prospective multicentrique.

Introduction Le diagnostic de nephropathie diabetique (ND) est generalement porte sur des arguments cliniques. En effet, la frequence de la ND dans la population diabetique est telle que la biopsie renale (BR), geste invasif a risque de complications graves, n’est realisee qu’en cas d’atypie dans la presentation ou d’argument pour un autre diagnostic. Patients et methodes Nous avons separe les patients diabetiques ayant eu une BR pour syndrome glomerulaire entre 2006 et 2015 dans notre service selon l’indication de la BR. Le groupe 1 (G1) comprenait les BR motivees uniquement par la presence d’une ou plusieurs atypies (absence de retinopathie diabetique [RD], presence d’une hematurie [HU], evolution rapide de la maladie renale, augmentation rapide de la proteinurie, ou syndrome nephrotique brutal) et le groupe 2 (G2) par la presence d’un ou plusieurs arguments pour un maladie renale non diabetique (MRND). Nous avons ensuite compare les frequences de ND seule et de MRND seule ou en association avec la ND et des complications de la BR. Resultats Cent quarante-quatre patients ont ete identifies, 68 dans le groupe 1 et 76 dans le groupe 2. Il n’y avait pas de difference significative entre les 2 groupes pour le genre, l’âge, la presence d’une HTA, la creatininemie, le ratio proteine/creatinine urinaire, la presence d’une hematurie, la presence d’une retinopathie, le traitement par IEC/ARAII et la duree du diabete. Les HbA1c etaient differentes (7,8 ± 2,2 dans le G1 vs. 7,1 ± 1,4 dans le G2, p = 0,036). Une ND seule etait presente chez 90 % des patients du G1 et 50 % de ceux du G2 ( p p = 0,027). Discussion Il n’y a pas de consensus concernant l’indication de la BR chez les sujets diabetiques. L’association de certains elements cliniques et/ou biologique a la presence d’une ND a ete rapportee. A l’inverse, nous avons etudie la rentabilite diagnostique de la BR chez un patient diabetique pour le diagnostic d’une MRND selon l’indication. Il est particulierement notable qu’aucun des patients biopsies pour l’absence de RD ou la presence d’HU n’avait de MRND. De plus, le taux de complication etait plus eleve dans ce groupe. Conclusion L’absence de RD ou la presence d’HU ne constituent pas une indication pour la realisation d’une BR, ce d’autant plus qu’une complication est plus probable chez ces patients.

Conventional calpains are ubiquitous cysteine proteases whose activity is promoted by calcium signaling and specifically limited by calpastatin. Calpain expression has been shown to be increased in human malignant cells, but the contribution of the calpain/calpastatin system in tumorigenesis remains unclear. It may play an important role in tumor cells themselves (cell growth, migration, and a contrario cell death) and/or in tumor niche (tissue infiltration by immune cells, neo-angiogenesis). In this study, we have used a mouse model of melanoma as a tool to gain further understanding of the role of calpains in tumor progression. To determine the respective importance of each target, we overexpressed calpastatin in tumor and/or host in isolation. Our data demonstrate that calpain inhibition in both tumor and host blunts tumor growth, while paradoxically increasing metastatic dissemination to regional lymph nodes. Specifically, calpain inhibition in melanoma cells limits tumor growth in vitro and in vivo but increases dissemination by amplifying cell resistance to apoptosis and accelerating migration process. Meanwhile, calpain inhibition restricted to host cells blunts tumor infiltration by immune cells and angiogenesis required for antitumor immunity, allowing tumor cells to escape tumor niche and disseminate. The development of highly specific calpain inhibitors with potential medical applications in cancer should take into account the opposing roles of the calpain/calpastatin system in initial tumor growth and subsequent metastatic dissemination.