Non-myeloma light chain cast nephropathy: a multicenter retrospective study on clinicopathological characteristics

Not available

Physiopathology of Idiopathic Nephrotic Syndrome and therapeutic approach with targeted nanointerference

Le syndrome néphrotique idiopathique (SNI) est une maladie du glomérule rénal caractérisée par une protéinurie massive et une hypoalbuminémie pouvant évoluer vers l´insuffisance rénale chronique terminale et qui est due à des anomalies ultrastructurales du glomérule rénal pouvant évoluer vers l´insuffisance rénale chronique terminale. Le SNI est lié à des anomalies immunologiques aboutissant à la synthèse d’un facteur toxique circulant impliquant les lymphocytes T(LT) ou B (LB). Notre laboratoire a identifié une nouvelle molécule (c-mip) fortement induite dans les LT, podocytes et LB de patients atteints de SNI. De précédents résultats montrent que dans une lignée de LB surexprimant c-mip, l’activation B pouvait être modifiée et qu’un facteur B circulant pourrait être sécrété. Les objectifs de ce travail sont de comprendre le rôle de c-mip dans la signalisation B sur des LB de patients isolés en poussée et en rémission et d'élucider le rôle du LB dans la pathogénie du SNI en testant le surnageant de LB sur des podocytes pour rechercher des altérations fonctionnelles podocytaires et identifier un facteur relevant par analyse protéomique différentielle et enfin de développer une technique de nanointerférence ciblée permettant d'éteindre l'activité de c-mip et récupérer un phénotype normal au sein des lymphocytes B des patients en poussée.Idiopathic nephrotic syndrome (INS) is caused by ultrastructural abnormalities of the renal glomerulus caracterised by a heavy proteinuria and hypoalbuminemia and may progress to end stage renal disease. Immunologic abnormalities in INS lead to the synthesis of a toxic factor involving circulating T lymphocytes (TL) or B lymphocytes (LB). Our lab has identified a new molecule (c-mip) strongly induced in LT, podocytes and LB of patients suffering from SNI. Earlier results show that in a line of LB overexpressing c-mip, activating B could be modified and that a circulating factor B may be secreted. The goals of this work are the understanding of the role of c-mip in signaling B on LB isolated patients in thrust and in remission and to elucidate the role of LB in the pathogenesis of SNI by testing the LB supernatant on podocytes to search for functional alterations on podocytes and identify a relevant factor by differential proteomic analysis and finally to develop a technique of targeted nanointerference in order to extinguish the activity of c- mip and recover a regular phenotype in B cells of ill patients

Glucose- and H2O2-dual responsives drug delivery particle based on the boronic acid chemistry

International audienceHerein, we report on responsive systems presenting dual response to two different stimuli, namely glucose and hydrogen peroxide which are interesting for biological applications. New chemical stimulus-responsive multilayer assemblies have been designed through the layer-by-layer deposition of oppositely charged biopolymer on either flat or spherical surfaces. (diethylaminoethyl-dextran hydrochloride/alginate derivative) polyelectrolytes pair was selected for hydrogen peroxide-response and (polylysine/alginate derivative) polyelectrolyte pair for glucose-response. Concentration-dependent glucose and hydrogen peroxide responsiveness were reached via the incorporation of phenylboronic acid moieties inside the alginate chain. Wettability and quartz crystal microbalance measurements showed that the alginate derivate self-assembles though electrostatically-driven interactions with the polycation. These techniques also evidenced that the multilayer assemblies present tuneable behaviour according to the addition of glucose- and/or- hydrogen. This approach was further extended to the preparation of smart microparticles using calcium carbonate as initial substrate. The porosity of these microparticles has been advantageously used to entrap a probe. Its release could then be triggered via glucose or hydrogen peroxide. The present system may be used to targeted drug delivery to diseased tissue or as sugar-sensing device for diabetic treatmen

Glucose- and H2O2-dual responsives drug delivery particle based on the boronic acid chemistry

International audienc

Cationic poly(cyclodextrin)/alginate nanocapsules: From design to application as efficient delivery vehicle of 4-hydroxy tamoxifen to podocyte in vitro

International audienceMost of the drug molecules are partially insoluble in aqueous solution and then may accumulate in fat tissues hampering efficient therapy. Innovative drug delivery strategies have emerged in industry or academia over the last decades, however preserving the activity of the encapsulated drug, having high drug loading capacity and controlling drug release kinetics, are still challenging. In this context, we explored the preparation of new nanocarriers, namely nanocapsules, via a templating method, and using polysaccharides exhibiting biological functions. Cationic poly(cyclodextrin) (P(CD+)) and alginate (alg−) were initially self-assembled layer-by-layer on colloidal gold nanoparticles. Removal of gold nanoparticles was then induced thorough cyanide-assisted hydrolysis, enabling the recovery of nanocapsules. A hydrophobic drug known to allow the mutation of genes inside cells, namely 4-hydroxy-tamoxifen, was loaded within the nanocapsules’ shell via inclusion with the cyclodextrin cavities. The so-designed nanomaterials were incubated with immortalized podocytes to investigate i) their incorporation inside cells and ii) their efficiency for in vitro 4-hydroxy-tamoxifen-induced CreERT2 recombination. This work undoubtedly highlights a proof-of-concept for drug delivery using polysaccharides-based capsules with host properties

Nephrotic Syndrome in Small Cell Lung Cancer and Induction of C-Mip in Podocytes

Paraneoplastic nephrotic syndrome is often a complication in patients with cancer, and various histologic lesions have been described in the kidney. We report the case of a 76-year-old woman who presented with a podocytopathy that was found to be associated with a small cell lung carcinoma (SCLC). One cycle of carboplatin-etoposide combination therapy led to resolution of nephrotic syndrome and remission of the lung carcinoma. C-Maf-inducing protein (C-Mip) was overexpressed in both podocytes and cancer cells, but was not found in control kidney and lung tissue samples. C-Mip also was absent in SCLC cells from 30 patients without nephrotic syndrome. Exposing cultured podocytes to a sample of our patient's serum that was collected prior to chemotherapy led to disorganization of the podocyte cytoskeleton and induction of C-Mip expression, which was not observed with control serum or our patient's serum sampled after chemotherapy. These observations suggest that C-Mip may play an important role in SCLC-related podocytopathy and that a circulating factor likely induces its expression in the kidney

Rituximab and Fibrillary Glomerulonephritis: Interest of B Cell Reconstitution Monitoring

Fibrillary glomerulonephritis (FGN) is a rare glomerular disease characterized by glomerular deposition of randomly arranged non-amyloid fibrils. FGN has a poor renal prognosis and its optimal treatment is a medical challenge. Rituximab therapy has recently emerged as a promising approach even though its mechanism of action remains hypothetical. We describe the case of a 55-year-old woman with FGN successfully treated by rituximab. During the 36-month follow-up, she had three relapses of FGN, occurring each time in the context of B cell recovery. Investigation of the distribution of B cell subpopulations at the time of the third relapse showed, as previously described for some immunological diseases, an increase in the proportion of switched memory B cells relative to healthy subjects, whereas global memory B cell pool was not yet recovered. This case suggests that B cell reconstitution should be carefully monitored in the management of FGN treated with rituximab

Kidney–Targeted drug delivery systems based on tailor-made nanocapsules

International audienc

Expression of CMIP in podocytes is restricted to specific classes of lupus nephritis.

Lupus glomerulopathies are classified into various histological patterns, which probably result from different pathophysiological origins. Podocyte injury can be demonstrated in lupus nephritis but its clinical relevance is far little appreciated and is often masked by proliferative lesions and inflammatory cell infiltrations. Two patterns of podocyte lesions may be considered, either occurring in the context of renal inflammation or reflecting podocyte dysfunction in non-proliferative and non-inflammatory glomerulopathies. This distinction remains elusive since no reliable biomarker discriminates between both entities. CMIP was recently found induced in some glomerular disease but its expression in different lupus nephritis classes has not been investigated. Twenty-four adult patients with lupus nephritis, including non-proliferative (n = 11) and proliferative (n = 13) glomerulopathies were analyzed. Clinical, biological and immunological data were compared with immunomorphological findings. We analyzed by quantitative and qualitative methods the expression of CMIP in different histological classes. We found CMIP abundance selectively increased in podocytes in class II and class V glomerulopathies, while in proliferative forms (class III and class IV), CMIP was rarely detected. CMIP was not expressed in cellular crescents, endothelial cells or mesangial cells. CMIP colocalized with some subsets of B and T cells within glomerular or interstitial mononuclear cell infiltrates but never with macrophages. Hematuria is rarely present in lupus glomerulopathies expressing CMIP. There was no correlation between classical immunological markers and CMIP expression. Thus, CMIP induction in lupus nephritis seems restricted to non-proliferative glomerulopathies and may define a specific pattern of podocyte injury

CMIP is a negative regulator of T cell signaling

International audienceUpon interaction with cognate antigen, T cells integrate different extra and intracellular signals, involving basal and induced protein-protein interactions as well as binding of proteins to lipids, which can lead to either cell activation or inhibition. Here we show that selective T-cell expression of CMIP, a new adaptor protein, by targeted transgenesis drive