Conversion to belatacept after lung transplantation: Report of 10 cases.

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.

Induction failure in granulomatosis with polyangiitis: a nationwide case-control study of risk factors and outcomes.

OBJECTIVE: To identify characteristics of granulomatosis with polyangiitis (GPA) associated with induction failure, describe salvage therapies and their efficacy. METHODS: We 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. RESULTS: We 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 < 0.001) and orbital mass (15% vs 0%, P < 0.01) compared with controls. Patients with disease progression despite RTX induction therapy more frequently had renal involvement (67% vs 25%, P = 0.02) with renal failure (serum creatinine >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. CONCLUSION: In patients with induction failure, characteristics of GPA, salvage therapies and their efficacy vary according to induction therapy and failure modality.

Importance des réseaux sociaux dans l'origine des intoxications : à propos d'un cas d'empoisonnement par la paraphénylènediamine.

Une femme de 63 ans rapporte avoir acheté une « pierre noire ¼ pour se protéger de la Covid-19 à la suite de conseils trouvés sur des réseaux sociaux. Dans les 24 heures qui suivent l'absorption d'une cuillère à soupe d'un mélange de « pierre ¼ avec du miel, apparaissent des myalgies puis une altération de l'état général qui la conduit à consulter aux urgences après 5 jours. L'examen clinique est sans autre particularité alors que le bilan biologique rapporte une insuffisance rénale aiguë et une rhabdomyolyse. L'évolution est marquée par une aggravation de l'insuffisance rénale nécessitant plusieurs séances d'hémodialyse. Les circonstances d'apparition des symptômes associées à la consommation de la « pierre ¼ font suspecter une origine toxique. Un tube de sang et la « pierre ¼ sont adressés au Laboratoire de toxicologie biologique pour analyses. La « pierre ¼ friable, noire en surface, blanche en interne, est soluble dans les alcools et peu soluble dans l'eau. L'analyse par plasma à couplage inductif - spectrométrie de masse - ne retrouve ni éléments métalliques, ni métalloïdes. L'analyse par chromatographie gazeuse couplée à la spectrométrie de masse met en évidence un pic identifié comme de la paraphénylènediamine (PPD). Une analyse par spectroscopie UV permet d'estimer la pureté de la « pierre ¼ à plus de 99 %. La PPD utilisée comme teinture capillaire noire ou adjuvant du henné est responsable d'intoxications graves, majoritairement volontaires, caractérisées par une détresse respiratoire, une rhabdomyolyse associée à des douleurs musculaires et à une insuffisance rénale. À l'exception de la détresse respiratoire, notre patiente a présenté tous les signes cliniques de l'intoxication. L'absence de détection de la PPD dans le plasma s'explique tant par la mise en œuvre de méthodes non adaptées à la détection de ce type de composés chimiques, que par le délai écoulé depuis la consommation de la « pierre ¼.

Eculizumab discontinuation in children and adults with atypical hemolytic-uremic syndrome: a prospective multicenter study.

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.

[Criteria to indicate kidney biopsy in type 2 diabetic patients with proteinuria: Survey among French nephrologists]. / Critères d'indications de la biopsie rénale chez les patients diabétiques de type 2 protéinuriques : enquête auprès des néphrologues français.

Diabetic nephropathy is usually a presumptive diagnosis based on clinical and biological evidence. Renal biopsies are performed in diabetic patients with atypical findings evoking non-diabetic renal disease who could benefit from specific therapies. French speaking nephrologists were asked which criteria they retain to indicate renal biopsy in patients with type 2 diabetes and albuminuria>0.5g/day or equivalent through an online anonymous questionnaire. Among the suggested criteria were absence of diabetic retinopathy, hematuria, rapid decrease in GFR, short diabetes duration or rapid raise of proteinuria. 188 people answered the poll among whom interns (12%), fellows (13%), university hospital practitioners (26%), general hospital practitioners (24%), practitioners in a non-profit organization (13%), practitioners on private activity (10%), multi-modal practitioners (3%) and people without clinical activity (2%). Increasing proteinuria was retained as an indication criterion for renal biopsy by 51% of respondents, nephrotic syndrome by 56% of respondents, absence of diabetic retinopathy by 57% of respondents, short diabetes duration by 65% of respondents, rapid GFR decline by 75% of respondents and hematuria by 78% of respondents. These data highlight the high diversity of opinions on this topic and their discrepancies with guidelines and current literature regarding the association between non-diabetic renal disease and clinical and biological features. The lack of adhesion of nephrologists to guidelines was especially noteworthy regarding the absence of diabetic retinopathy. These results emphasize the need for studies focusing on biopsy indication criteria in patients with type 2 diabetes.

Persistent FDG/PET CT uptake in idiopathic retroperitoneal fibrosis helps identifying patients at a higher risk for relapse.

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.

[Lupus nephritis]. / Atteintes rénales du lupus.

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.

Minimal change nephrotic syndrome in patients infected with human immunodeficiency virus: a retrospective study of 8 cases.

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/mm3 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.

Predictive features of chronic kidney disease in atypical haemolytic uremic syndrome.

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/1.73m2 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.

Minimal change nephrotic syndrome associated with non-Hodgkin lymphoid disorders: a retrospective study of 18 cases.

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 Waldenström 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.

The calpain/calpastatin system has opposing roles in growth and metastatic dissemination of melanoma.

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.