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International audience; Background: Long-term psychosocial outcomes and health-related quality of life (HRQOL) in adults with pediatric onset of frequently relapsing or steroid-dependent idiopathic nephrotic syndrome (FRNS or SDNS) remain to be determined.Methods: In this prospective cohort study, 59 adults with pediatric onset of FRNS/SDNS and persistent active glomerular disease in adulthood completed the GEDEPAC-2 questionnaire exploring 11 well-being domains. Data were compared to the French general population (FGP) with standardized incidence ratio ([SIR]; adjusted for period, age, gender). Regression models were performed to identify predictive factors of psychosocial well-being.Results: In 82% of cases, the questionnaire was completed while the participants (n = 59; 47 men; median age = 32 years; median number of relapses = 13) were in complete remission (under specific therapy in 76% of cases). Participants had higher educational degree than in the FGP (SIR = 6.3; p < 0.01) and more frequently a managerial occupation (SIR = 3.1; p < 0.01). Social integration was acceptable with regard to marital status and experience of sexual intercourse, but experiences of discrimination were far more frequent (SIR = 12.5; p < 0.01). The SF-12 mental component summary (MCS) score was altered (Z-score = - 0.6; p < 0.01) and mean multidimensional fatigue inventory (MFI-20) global fatigue score appeared high (12). Transfer from pediatric to adult healthcare was followed by a period of discontinued care for 33% of participants. Multivariate analysis revealed a close relationship between MFI-20, physical health, and MCS.Conclusions: This study shows that pediatric onset FRNS and SDNS may have a long-term negative impact on mental HRQOL and highlights the impact of fatigue, which is often not adequately considered in routine care.

The long-term consequences of pre-eclampsia (PrE) for renal function have never been determined in patients with sickle cell disease (SCD). Between 2008 and 2015, we screened 306 pregnancies in women with SCD and identified 40 with PrE (13%). The control group consisted of 65 pregnant SCD patients without PrE. In multivariable analysis, PrE events were associated with an increase of 1 log of lactate dehydrogenase level (adjusted odds ratio, aOR = 3·83, P = 0·05), a decrease of 10 g/l of haemoglobin levels (aOR = 2·48, P = 0·006) and one or more vaso-occlusive crisis during pregnancy (aOR = 16·68, P = 0·002). Estimated glomerular filtration rate (eGFR) was similar in the two groups at steady state but was significantly lower in the PrE group after one year of follow-up and at last follow-up (130 vs 148 ml/min/1·73 m2 , P < 0·001 and 120 vs 130 ml/min/1·73 m2 , P < 0·001, respectively). In multivariable analysis, eGFR had returned to steady-state levels one year after pregnancy in patients without PrE but continued to decrease in patients with PrE (β = -18·15 ml/min/1·73 m2 , P < 0·001). This decline was more marked at the end of follow-up (β = -31·15 ml/min, P < 0·001). In conclusion, PrE episodes are associated with a significant risk of subsequent renal function decline in SCD patients.

BACKGROUND AND AIMS Tumor angiogenesis is one of the therapeutic targets used in oncology, to limit cancer growth and spreading. The main angiogenesis signalling pathway is mediated by the vascular endothelial growth factor (VEGF) that binds to its tyrosine kinase receptor (VEGFR), mainly expressed on endothelial cells. The antiangiogenic therapy could target the VEGF ligand (anti-VEGF), or its receptors by inhibition of kinase activity (tyrosine kinase inhibitor, TKI) such as sorafenib. The toxicity of antiangiogenic therapies is a growing concern in clinical use. Indeed, nephrotoxicity is a critical side-effect that leads to discontinuation of therapy. Renal histological illustration of this toxicity is minimal change nephropathy/focal segmental glomerulosclerosis (MCNS/FSGS) and thrombotic micro-angiopathy (TMA), involving two distinct cell types, podocytes and endothelial cells respectively. Podocytes are the main source of VEGF and express VEGFR in the glomerulus. Mechanisms linking TKI therapy to podocyte dysfunction and nephrotic level proteinuria are still poorly understood. The working hypothesis is that nephrotoxicity of sorafenib is primarily through its effect on glomerular podocytes. METHOD Based on LC-MS/MS proteomic analysis, we have identified dysregulated cellular pathways on sorafenib-exposed podocytes. We validated these results by western blotting and immunofluorescence staining, on a cultured podocyte line exposed to sorafenib (2.5 µmol/L, 24-h). RESULTS Our results showed that sorafenib inhibits the downstream signalling pathways of VEGFR on podocytes, which induce injury by decreasing the expression of podocyte-specific markers (WT1, podocin). This is associated with podocyte morphology changes with podocyte cytoskeleton damages (actin and microtubules) and focal adhesions loss. We identified a novel podocyte target of sorafenib: the GSK3β. Indeed, sorafenib reduces significantly GSK3β inhibitory phosphorylation. Moreover, GSK3β regulates Tau, microtubule-associated proteins (MAP) and key regulator of microtubules remodelling. We show that tau phosphorylation increases significantly in sorafenib-treated cells. Furthermore, we found that sorafenib impairs the autophagic flux in podocytes, as indicated by an increase in LC3-II/LC3-I ratio in western blot, reflect of autophagosomes accumulation in podocytes. These results indicate that GSK3β overactivity induced by sorafenib participates in the disruption of the microtubules through tau phosphorylation, which interferes with cellular vesicle trafficking and blocks autophagic flux in podocytes. In addition, sorafenib leads to podocyte apoptosis through induction of endoplasmic reticulum (ER) stress (GADD153 protein induction and its nuclear translocation) and mitochondrial dysfunction. ER stress induced a decrease in podocyte protein synthesis with increased eIF2α phosphorylation. Sorafenib also causes mitochondrial membrane potential loss and mitochondrial depolarization. CONCLUSION Thus, in the current study, we show that sorafenib has a direct effect on podocytes, modulating specific signalling pathways to induce podocyte damage and ultimately glomerular lesions. However, we have to confirm the clinical relevance of our results on kidney biopsies from patients diagnosed with nephrotic syndrome following sorafenib treatment.

BACKGROUND AND AIMS Idiopathic nephrotic syndrome (INS) comprises a group of rare glomerulopathies attributed to direct or indirect interaction of putative circulating factors with podocytes. One of the pathological manifestations of INS is the rapid recurrence of focal and segmental glomerulosclerosis (rFSGS) after renal transplant, which occurs in 30–50% of cases. To date, the nature and identity of circulating factors have not been confirmed, while the pathogenic mechanisms in the podocyte are partially understood. Direct analysis of patient plasma proteome has been scarcely addressed, mainly due to methodological difficulties associated with plasma complexity and dynamic range. To better understand the mechanisms involved in FSGS recurrence, the present study had two main objectives: (i) to perform a differential proteomic analysis of soluble plasma proteins and of extracellular vesicles (EV) from rFSGS patients and from controls; and (ii) to study the early proximal signaling events in podocytes in response to plasma from post-transplant rFSGS patients as compared to plasma from controls, by a combination of phosphoproteomics and lipid raft proteomics (raftomics). METHOD We obtained first post-transplant plasma exchange fluid from either rFSGS or non-INS patients (n = 4), the latter used as controls, as well as blood plasma from healthy individuals (n = 4). In a first study, by a combination of immunodepletion and high pH fractionation, we performed in parallel a differential proteomic analysis of soluble plasma proteins and of extracellular vesicles (EV) from the three groups. In a second study, we incubated differentiated human podocytes for 30 min with 10% of plasma exchange fluid from either rFSGS or non-INS patients. Then, we isolated lipid rafts from podocytes by a detergent-free method and performed differential proteomics. In addition, we performed differential phosphoproteomics after phosphopeptide enrichment in a TiO2 column. Proteomics by LC-MS/MS analysis was performed in a TimsTOF Pro mass spectrometer on plasma samples, and in a nanoRSLC-Q Exactive PLUS instrument on podocyte samples. RESULTS The approximate number of proteins identified was 500 in immunodepleted plasma, 1400 in EV, 2500 in podocyte rafts and 4900 podocyte phosphosites. In both soluble and EV protein sets from rFSGS patients, we found a statistically significant increase in a cluster of proteins involved in neutrophil degranulation. A group of lipid binding proteins, generally associated with lipoproteins, was found decreased in the soluble set from rFSGS patients. In addition, several aminoacid transporters involved in mTORC1 activation were found significantly increased in EV from rFSGS individuals. As regards podocyte proteome analyses, the differences found in protein expression and phosphorylation associated with rFSGS plasma incubation suggested alterations in the mTOR pathway, in autophagy, in mitochondrial metabolism and in cytoskeleton organization. In particular, validation experiments indicated an altered phosphorylation pattern of Hsp27. CONCLUSION The technological approaches used in the plasma study show the feasibility of direct proteomic analysis of this material, as well as the potential of some of the identified differential proteins as FSGS biomarkers. The observed changes in podocyte proteome associated with rFSGS plasma incubation highlight some of the potential mechanisms involved in FSGS recurrence and could be used as specific early markers of circulating factor activity on podocytes. Further research will be necessary to confirm and validate these findings.

BACKGROUND AND AIMS Gemcitabine (GEM) is an anticancer drug, indicated in the treatment of several types of solid cancers such as pancreatic, breast, bladder cancer, etc. This molecule is effective in tumor processes but causes adverse effects on other organs, including the haematopoietic system and the kidney. The renal toxicity of gemcitabine is illustrated by thrombotic microangiopathy (TMA), whose onset is dramatic and associated in more than 97% of cases with acute renal failure. This adverse effect induces discontinuation of treatment with negative consequences on tumor control. It is, therefore, essential to understand the pathophysiological mechanisms of gemcitabine nephrotoxicity. TMA at the glomerular level reflects damage to the endothelial cell (ECs). However, previously, data of our team show that other glomerular cells, parietal epithelial cells (PECs), could be involved in these lesions. Thus, in this project, we want: i) to describe the modifications of the PEC and EC proteome exposed to gemcitabine and ii) to analyse PEC and EC secretome exposed to gemcitabine and to study the cell communication between PECs and ECs. METHOD In our in vitro experiments, we used a murine PEC cell line and a murine EC cell line. The PECs are exposed to 100 μM GEM for 24-h and the culture supernatants are recovered. These PEC supernatants are used in conditioned media experiments to expose ECs for 24-h. On the other hand, ECs were directly exposed to 1 μM GEM for 24-h and culture supernatants were also recovered. Analyses of protein expression are carried out by western blot and immunofluorescence staining. RESULTS When PECs are exposed to GEM (100 µM, 24-h), we observe an increase in apoptosis (caspase 3 cleavage) as well as DNA damage (γH2AX). However, PECs specific markers, such as PAX2 and Claudin-1, do not appear to be affected. Our results also show an increase in the expression of the transcription factor CHOP and the chaperone protein BIP, suggesting the presence of endoplasmic reticulum (ER) stress in PECs exposed to gemcitabine. In order to study cell communication between PECs and ECs, we set up conditioned media experiments. We first studied the expression of different endothelial markers on ECs exposed to PEC supernatants. The expression of the endothelial markers such as E-cadherin, CD31 and PDGFRβ decreases compared with control cells when ECs are exposed to PEC supernatants. Actin cytoskeleton reorganization is also observed with an increase in cortical actin. Moreover, the microtubule network seems to be also affected with a tendency to decrease tubulin expression. Finally, there is an increase in γH2AX suggesting the presence of DNA damage in ECs exposed to PEC supernatant. The next experiments aim at identifying the factors responsible for this cell communication (proteins, lipid mediators, non-coding RNA, extracellular vesicles). CONCLUSION Our results show GEM has a direct effect on PECs (apoptosis, DNA damage, ER stress). In addition, we show the effect of PEC supernatants exposed to GEM on ECs (decrease in endothelial markers, cytoskeleton modifications, DNA damage).

Background The Wilms tumor 1 suppressor gene, WT1, is expressed throughout life in podocytes and is essential for their function. Downregulation of WT1 has been reported in podocyte diseases but the underlying mechanisms remain unclear. Podocyte injury is the hallmark of idiopathic nephrotic syndrome (INS), the most frequent glomerular disease in children and young adults. An increase in the abundance of Cmaf‐inducing protein (CMIP) has been found to alter podocyte function, but it is not known whether CMIP affects WT1 expression. Methods Transcriptional and post‐transcriptional regulation of WT1in the presence of CMIP was studied using transient transfection, mouse models, and siRNA handling. Results We showed that overproduction of CMIP in the podocyte was consistently associated with a downregulation of WT1 according to two mechanisms. We found that CMIP prevented the NF‐kB‐mediated transcriptional activation of WT1. We demonstrated that CMIP interacts directly with WT1 through its leucine‐rich repeat domain. Overexpression of CMIP in the M15 cell line induced a downregulation of WT1, which was prevented by lactacystin, a potent proteasome inhibitor. We showed that CMIP exhibits an E3 ligase activity and targets WT1 to proteasome degradation. Intravenous injection of Cmip‐siRNA specifically prevented the repression of Wt1 in lipopolysaccharides‐induced proteinuria in mice. Conclusions These data suggest that CMIP is a repressor of WT1 and might be a critical player in the pathophysiology of some podocyte diseases. Because WT1 is required for podocyte integrity, CMIP could be considered a therapeutic target in podocyte diseases., INS patients show increased CMIP and decreased WT1 expression in podocytes.CMIP inhibits NF‐κB‐driven WT1 transcription in M15 cells.CMIP targets WT1 to proteasome degradation via ubiquitin ligase activity in M15 cells.RNAi against Cmip restores Wt1 expression in a mouse model of proteinuria.

"Targeted therapies and pathophysiological mechanisms of proteinuria Targeted therapy represents a promising therapeutic approach for patients with diverse cancers and has enabled significant development in medical oncology. This new class of anticancer drugs includes antibodies, fusion-proteins and receptor tyrosine kinase inhibitors among others. Depending on their molecular targeting, side effects can affect multiple organs, especially the kidney. Antiangiogenic agents inhibit the VEGF/VEGFR pathway resulting in reduction of nitric oxide production and alteration of podocytes function, which causes hypertension and proteinuria. EGFR inhibitors are responsible of electrolytic disorders. Hereby, we synthetized the current knowledge on renal toxicities on main molecular targeted therapies. Toxicities management is mainly based on clinical and biological monitoring, which can lead to drug withdrawing or dose adaptation.""Thérapies ciblées et mécanismes physiopathologiques de la protéinurie Les thérapies ciblées occupent désormais une place majeure en oncologie médicale. Elles existent sous plusieurs formes d’administration, parentérale ou per os, et comportent entre autres des anticorps, des protéines de fusion et des inhibiteurs de récepteur des tyrosine kinases. Les effets indésirables liés à ces thérapies dépendent généralement de leur classe thérapeutique. Les antiangiogéniques, qui altèrent les podocytes et la production de monoxyde d’azote via l’inhibition de la voie VEGF/VEGFR, entraînent hypertension artérielle et protéinurie et sont parfois à l’origine de microangiopathies thrombotiques. Les inhibiteurs de l’EGFR entraînent principalement des troubles hydroélectrolytiques par inhibition de transporteurs rénaux. D’autres toxicités sont plus rares, comme les inhibiteurs de BRAF, parfois à l’origine d’insuffisances rénales aiguës immuno-allergiques. La prise en charge de ces toxicités repose généralement sur la surveillance clinique et biologique et peut conduire à la suspension des traitements ou à leur adaptation posologique."

International audience; Most 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.

International audience; The C-Maf-Inducing protein (CMIP) was first described as overexpressed in T cell subpopulations of idiopathic nephrotic syndrome (INS) patients. Later, it was found concomitantly upregulated in podocytes. CMIP expression has also been reported in several types of cancer, including blood malignancies and solid tumors, in many cases accompanied by nephrotic syndrome. In addition to these observations, the duality of CMIP overexpression in the kidney and INS lesions, has been extensively reported as one of the adverse effects of anticancer therapy based on anti-receptor tyrosine kinase drugs. As a consequence, a growing body of evidence points at CMIP as playing a role in cancer. This includes its reciprocal regulatory ties with NF-κB and WT1, and the more recent reports showing an involvement in regulatory circuits in cancer cells. The ensemble of the current information justifies to propose CMIP as an important piece of the puzzle of biological systems involved in cancer and other diseases and its potential as a target.

International audience; The use of inhibitors of vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR2) signaling for the treatment of cancer has increased over the last decade. This signaling pathway plays a fundamental role in angiogenesis and also in kidney physiology. The emergence of anti-angiogenic therapies has led to adverse nephrotoxic effects, despite improving the outcomes of patients. In this review, we will present the different anti-angiogenic therapies targeting the VEGFR pathway in association with the incidence of renal manifestations during their use. In addition, we will discuss, in detail, the pathophysiological mechanisms of frequent renal diseases such as hypertension, proteinuria, renal dysfunction, and electrolyte disorders. Finally, we will outline the cellular damage described following these therapies.

There is compelling evidence that renal complications in a native kidney are a major concern in patients infected with severe acute respiratory syndrome coronavirus 2, the causal agent of coronavirus disease 2019 (COVID-19). The spectrum of renal lesions observed on renal grafts in this context remains to be determined.We report the case of a renal transplant recipient with non-severe COVID-19, who subsequently developed nephrotic syndrome associated with acute renal injury.Renal biopsy demonstrated focal and segmental glomerulosclerosis lesions classified as not otherwise specified histological variant. Genotyping for 2 risk alleles of the apolipoprotein L1 gene demonstrated that the donor was homozygous for the G2/G2 genotype.In renal transplant patients receiving kidneys from donors with high-risk apolipoprotein L1 variants, COVID-19 may promote acute glomerular injury in the form of focal and segmental glomerulosclerosis.

International audience; Gangliosides constitute a subgroup of glycosphingolipids characterized by the presence of sialic acid residues in their structure. As constituents of cellular membranes, in particular of raft microdomains, they exert multiple functions, some of them capital in cell homeostasis. Their presence in cells is tightly regulated by a balanced expression and function of the enzymes responsible for their biosynthesis-ganglioside synthases-and their degradation-glycosidases-. Dysregulation of their abundance results in rare and common diseases. In this review we make a point on the relevance of gangliosides and some of their metabolic precursors, such as ceramides, in the function of podocytes, the main cellular component of the glomerular filtration barrier, as well as their implications in podocytopathies. The results presented in this review suggest the pertinence of clinical lipidomic studies targeting these metabolites.

Upon their interaction with cognate antigen, T cells integrate different extracellular and intracellular signals involving basal and induced protein-protein interactions, as well as the binding of proteins to lipids, which can lead to either cell activation or inhibition. Here, we show that the selective T cell expression of CMIP, a new adapter protein, by targeted transgenesis drives T cells toward a naïve phenotype. We found that CMIP inhibits activation of the Src kinases Fyn and Lck after CD3/CD28 costimulation and the subsequent localization of Fyn and Lck to LRs. Video microscopy analysis showed that CMIP blocks the recruitment of LAT and the lipid raft marker cholera toxin B at the site of TCR engagement. Proteomic analysis identified several protein clusters differentially modulated by CMIP and, notably, Cofilin-1, which is inactivated in CMIP-expressing T cells. Moreover, transgenic T cells exhibited the downregulation of GM3 synthase, a key enzyme involved in the biosynthesis of gangliosides. These results suggest that CMIP negatively impacts proximal signaling and cytoskeletal rearrangement and defines a new mechanism for the negative regulation of T cells that could be a therapeutic target.

Background and objectives Malaria, a potentially life-threatening disease, is the most prevalent endemic infectious disease worldwide. In the modern era, the spectrum of glomerular involvement observed in patients after malarial infections remains poorly described. Design, setting, participants, & measurements We therefore performed a retrospective multicenter study to assess the clinical, biologic, pathologic, and therapeutic characteristics of patients with glomerular disease demonstrated by kidney biopsy in France within 3 months of an acute malaria episode. Results We identified 23 patients (12 men), all but 1 of African ancestry and including 10 patients with concomitant HIV infection. All of the imported cases were in French citizens living in France who had recently traveled back to France from an endemic area and developed malaria after their return to France. Eleven patients had to be admitted to an intensive care unit at presentation. Plasmodium falciparum was detected in 22 patients, and Plasmodium malariae was detected in 1 patient. Kidney biopsy was performed after the successful treatment of malaria, a mean of 24 days after initial presentation. At this time, all patients displayed AKI, requiring KRT in 12 patients. Nephrotic syndrome was diagnosed in 17 patients. Pathologic findings included FSGS in 21 patients and minimal change nephrotic syndrome in 2 patients. Among patients with FSGS, 18 had collapsing glomerulopathy (including 9 patients with HIV-associated nephropathy). In four patients, immunohistochemistry with an antibody targeting P. falciparum histidine-rich protein-2 demonstrated the presence of the malaria antigen in tubular cells but not in podocytes or parietal epithelial cells. An analysis of the apoL1 risk genotype showed that high-risk variants were present in all seven patients tested. After a mean follow-up of 23 months, eight patients required KRT (kidney transplantation in two patients), and mean eGFR for the other patients was 51 ml/min per 1.73 m2. Conclusions In patients of African ancestry, imported Plasmodium infection may be a new causal factor for secondary FSGS, particularly for collapsing glomerulopathy variants in an APOL1 high-risk variant background.

Background The recent success achieved with the use of B cell-depleting agents in some patients with minimal change nephrotic syndrome (MCNS) suggests an unexpected role for B lymphocytes in the pathogenesis of this immune-mediated glomerular disease. Nevertheless, no extensive B-cell phenotyping analysis has ever been performed in untreated adult patients soon after MCNS diagnosis. Methods We investigated the distribution of the different B-cell subpopulations in 22 untreated adult patients with biopsy-proven MCNS [MCNS relapse (MCNS-Rel)]. We compared these data with those for 24 healthy controls, 13 MCNS patients in remission (with no specific treatment) and 19 patients with idiopathic membranous nephropathy (IMN). Results Patients with MCNS-Rel or IMN had higher proteinuria and lower serum albumin and gammaglobulin levels (P Conclusions An increase in the proportion of circulating plasmablasts seems to be a hallmark of untreated MCNS in adult patients. Further studies are required to more precisely determine the phenotype and functions of these cells.

Introduction L’expression de la proteine CMIP a ete mise en evidence dans une sous-population de lymphocytes T et dans les podocytes des patients de syndrome nephrotique idiopathique (SNI). Son expression est liee a une alteration de la signalisation proximale (associee aux radeaux lipidiques ou « rafts »). L’invalidation de Cmip chez la souris previent le developpement de proteinurie en reponse aux traitements par LPS et adriamycine. CMIP presente un domaine « pleckstrin homology » dans son extremite N-terminale, qui suggere une interaction avec des lipides membranaires. Description Nous avons voulu verifier cette interaction et evaluer l’impact de la surexpression de CMIP sur le lipidome podocytaire. Methodes L’interaction de CMIP avec des differentes classes de lipides membranaires a ete evaluee par protein-lipid overlay a partir d’extraits de cellules HEK transfectees avec la sequence codante de CMIP humain. L’analyse du lipidome a ete effectuee a partir de podocytes de souris transfectes de facon transitoire avec la sequence CMIP humaine en utilisant un vecteur vide comme temoin. Les extraits lipidiques ont ete obtenus a 48 h post transfection et soumis a LC-MS/MS. Resultats CMIP interagit selectivement avec les phosphatidylinositol bis-phosphate (PIP2), et non avec les autres familles de phospholipides. L’analyse lipidomique non ciblee a mis en evidence une diminution significative des gangliosides GM3 et GM2 dans les podocytes surexprimant CMIP, ainsi qu’une accumulation des ceramides (precurseurs des gangliosides). L’analyse lipidomique ciblee sur les phosphoinositides n’a pas montre de difference significative. Ces resultats suggerent que l’interaction de CMIP avec les PIP2 serait associe a sa localisation transitoire au niveau de la membrane. La diminution en gangliosides GM3 et GM2, majoritaires dans les microdomaines raft des podocytes, suggerent un effet specifique sur la voie de biosynthese des glycosphingolipides. Conclusion L’expression de CMIP aurait un double impact sur l’homeostasie lipidique qui pourrait etre a l’origine de l’inhibition des voies de signalisation proximale.

Introduction We show here, overproduction of C-mip was consistenly associated with a downregulation of WT1. C-mip interacts physically with WT1, and exhibits an E3 ligase activity, which targets WT1 to proteasome degradation. Description Overexpression of C-mip in M15 cell line induced a downregulation of WT1, which was prevented by lactacystin. We showed that C-mip exhibits an E3 ligase activity, which targets WT1 to proteasome degradation. Intravenous injection of c-mip-siRNA specifically prevented the repression of WT1 in LPS-induced proteinuria in mice. Methods (1) Transfected C-mip plasmid to M15 cell line, which expresses a high level of WT1, to see whether C-mip down-regulates the expression of WT1. (2) Cotransfected WT1 and C-mip expression plasmids into HEK cells, then the cells were incubated with lactacystin. (3) E3 ubiquitin ligase kit was used to determine whether C-mip could have an E3 ligase activity that drives ubiquitylation of WT1. (4) Knockdown of c-mip in vivo by RNA interference in LPS-treated mice. Results (1) WT1 abundance fell by 50% at 12 hours after transfection of C-mip plasmid to M15 cell line, shows C-mip destabilizes the WT1. (2) The abundance of WT1 protein was significantly reduced in the presence of C-mip, but coincubation with lactacystin inhibited WT1 decay, suggesting that C-mip targets WT1 to proteasome mediated degradation. (3) E3 ligase activity assay showed, C-mip stimulated the formation of polyubiquitin chains in a dose dependent manner, suggesting that C-mip exhibits an intrinsic ubiquitin E3 ligase activity. (4) In vivo c-mip siRNA treatment indicated knockdown of c-mip restores the expression of WT1 in LPS-treated mice. Conclusion (i) In vivo, in vitro overproduction of C-mip is associated with a downregulation of WT1; (ii) C-mip interacts directly with WT1 and displays E3 ligase activity, which promotes WT1 to proteasome-mediated degradation; (iii) Silencing endogenous c-mip expression with RNAi prevents the downregulation of WT1 in LPS-treated mice.

We performed a retrospective study to assess the changes in clinical, biological and heart echocardiographic parameters in 32 sickle cell disease (SCD) patients beginning haemodialysis. Acute SCD-related complications were similar at 6 months before and 6 months after the initiation of haemodialysis. Median haemoglobin level did not change significantly, but the need for blood transfusions increased (P

Introduction Les therapies anti-angiogeniques ciblant le vascular endothelial growth factor (VEGF) ou ses recepteurs (receptor tyrosine kinase inhibitor [RTKI]) sont de plus en plus utilisees en oncologie. Le sorafenib est un RTKI indique notamment en premiere intention dans le carcinome hepatocellulaire metastatique. Or, une nephrotoxicite est rapportee chez environ 20 % des patients, se manifestant histologiquement par une hyalinose segmentaire et focale caracterisee par une atteinte du podocyte. Le podocyte, principale source de VEGF du glomerule, semble etre la cible directe de differents RTKI, en particulier du sorafenib. Description Ce travail a cherche a identifier les voies de signalisation podocytaire affectees par le sorafenib. Methodes A partir d’une analyse proteomique, nous avons etudie l’expression de certaines proteines cibles, sur des podocytes humains en culture exposes au sorafenib (2,5 μmol/L, 24 heures), par western blot et immunofluorescence. Resultats Nos resultats montrent que le sorafenib inhibe les voies de signalisation MAPK/ERK et PI3 K/AKT en aval du VEGFR, impliquees dans la survie cellulaire. Il induit une profonde desorganisation du cytosquelette podocytaire, a la fois des microtubules associes a une accumulation des autophagosomes, mais aussi des microfilaments d’actine. Nous observons egalement une dedifferenciation podocytaire, avec diminution de marqueurs specifiques comme la podocine et WT1. Face a une baisse significative de plusieurs formes totales des proteines, dont NFκB, notre etude revele une diminution du profil d’ubiquitination des proteines, suggerant une augmentation d’activite du proteasome sous sorafenib. Conclusion Ce travail met en evidence un role direct du sorafenib sur les podocytes, en modulant les voies de signalisation en aval du VEGFR. Cela ayant pour consequences un remaniement du cytosquelette et une dedifferenciation podocytaire. Ces resultats preliminaires in vitro ouvrent de multiples pistes potentielles a explorer afin d’elucider les mecanismes impliques dans la podotoxicite du sorafenib chez les patients.

Introduction Le syndrome nephrotique idiopathique cortico-dependant (SNICD) apparu dans l’enfance constitue une maladie chronique faite de phases de poussees et de remissions. Toutefois, son impact global (insertion socio-professionnelle, qualite de vie, transition) a long terme est mal connu. Methodes Les donnees de 59 adultes (20 services de nephrologie) suivis pour un SNICD avec 1ere poussee avant 16 ans ont ete recueillies sur dossier medical et par auto-questionnaire entre decembre 2016 et avril 2017. L’auto-questionnaire GEDEPAC2 comporte 109 items, explorant 11 domaines du bien-etre (education, emploi, logement, securite materielle, liens sociaux, engagement civique, loisirs, environnement, sante physique/conduites risque, qualite de vie, vie sexuelle) et inclue 3 questionnaires (qualite de vie SF-12 ; Treatment Burden questionnaire ; fatigue MFI-20). Analyse descriptive et comparative a la population generale (INSEE) par ratios standardises d’incidence (RSI) ajustes sur âge, sexe et periode. Resultats obtenus ou attendus Parmi les 59 participants (âge median = 32 ans [Q1 = 26 ;Q3 = 37] ; hommes = 80 %), 34 % avaient eu moins de 10 rechutes, 26 % plus de 20 rechutes ; 84 % etaient en remission complete au remplissage du questionnaire. La vie en couple etait aussi frequente qu’attendue (RSI = 1,48 ; IC95 % = [0,89 ;2,07]). 56,9 % avaient un diplome superieur contre 16 % attendu (RSI = 3,52 ; IC95 % = [2,24 ;4,81]), traduisant un possible surinvestissement scolaire chez ces enfants. Le chomage etait plus frequent (21 % ; RSI = 2,78 ; IC95 % = [1,21 ;4,36]). Du fait de la maladie, 50 % avait renonce au sport et 76 % disaient avoir subi des discriminations, particulierement a l’ecole. La qualite de vie etait alteree au niveau des scores composites SF-12 physique (moyenne = 50 ± 10) et mental (moyenne = 41 ± 10). La transition pediatrie/services d’adultes etait souvent bien vecue (sentiment de continuite pour 74 %). Mais la majorite des patients deplorent une preparation insuffisante(65 %) ( Fig. 1 ). Conclusion Cette etude apporte un nouvel eclairage sur le bien-etre des adultes avec SNICD a debut pediatrique. Si leur insertion sociale parait satisfaisante d’apres certains indicateurs, ces personnes rencontrent au quotidien des difficultes professionnelles, des discriminations ou encore une fatigue intense.

Introduction La recidive de la hyalinose segmentaire et focale (HSF) sur le greffon concerne 30 a 50 % des patients, pouvant conduire a une impasse therapeutique et condamner les patients a une dialyse a vie. La recherche du facteur causal requiert la realisation de tests in vitro souvent bases sur l’evaluation de l’integrite du cytosquelette (phalloidine, synaptopodine) ou de l’expression des proteines du diaphragme de fente (nephrine, podocine). L’activation de deux voies de signalisation impliquees dans la regulation du cytosquelette a ete recemment mise en evidence dans des podocytes cultives en presence de plasma de patients de recidive de HSF (rHSF) : celle initiee par l’activation de la GTPase Rac-1 et celle de la vasodilator stimulated phosphoprotein (VASP). Patients/Materiels et methodes Notre objectif a ete d’identifier des marqueurs specifiques d’alteration podocytaire en reponse au plasma de patients rHSF. Pour cela nous avons incube des lignees de podocytes de souris et humains avec 10 % de plasma rHSF pendant 4 h ou 24 h, en utilisant comme controle le plasma d’un patient traite pour un rejet de greffe et beneficiant d’un traitement equivalent (immunosuppresseur plus echanges plasmatiques et a distance des bolus de solumedrol). Par microscopie de fluorescence, nous avons evalue l’etat du cytosquelette d’actine par marquage a la phalloidine, ainsi que l’expression de la nephrine. Par western blot, nous avons etudie l’etat de phosphorylation de PAK-1 (proteine effectrice de l’activation de Rac-1) et de VASP (Ser157 et Ser239). Observation/Resultats Nos resultats preliminaires montrent, par immunofluorescence, que le plasma rHSF induit une legere diminution de l’expression de la nephrine, ainsi qu’une rarefaction des fibres de stress apres 4 h d’incubation, avec un retrecissement du cytoplasme dans une proportion importante des cellules a 24 h. Ces modifications, bien que moindres, sont aussi observees apres incubation avec le plasma controle. Par western blot nous avons observe une augmentation de la phosphorylation de PAK-1 apres 4 h et une augmentation de sa forme totale apres 24 h d’incubation avec rHSF. La phosphorylation de VASP (Ser239) diminue a 24 h d’incubation avec rHSF, alors que l’abondance de sa forme totale ne varie pas. En presence de plasma controle, nous n’avons pas observe de modification sauf une legere augmentation de la phosphorylation de PAK-1 a 4 h. Discussion/Conclusion En conclusion, la dynamique d’expression et phosphorylation de PAK-1 et VASP pourrait etre ciblee dans l’evaluation in vitro de l’activite des facteurs de permeabilite glomerulaire. Ces resultats suggerent l’implication de ces deux voies dans les mecanismes de toxicite podocytaire associes a la rHSF.

Introduction La physiopathologie du syndrome nephrotique a lesions glomerulaires minimes (SNLGM) reste incompletement elucidee, mais des arguments cliniques et experimentaux, suggerent que les lymphocytes B (LB) puissent jouer un role majeur dans la pathogenie de cette glomerulopathie. Methodes L’objectif de ce travail est de decrire les sous-populations de LB chez des patients atteints de SNLGM naifs de tout traitement corticoide ou immunosuppresseur. Cette etude prospective, multicentrique, porte sur 21 malades atteints de SNLGM en premiere poussee ou en rechute a plus de 6 mois de toute prise d’immunosuppresseurs (P), compares a 16 patients en remission (R) sans immunosuppresseurs depuis plus de 6 mois, 20 patients atteints de glomerulonephrite extra-membraneuse idiopathique (G) et 25 temoins sains (TS). Le phenotype B a ete analyse en cytometrie en flux avant traitement par differents marqueurs de surface : CD45, CD3, CD19, CD21, IgD, IgM, CD38, CD24, CD27. BAFF a ete mesure dans le plasma par ELISA. Resultats obtenus ou attendus Les patients des groupes P et G presentent une intensite de maladie identique (proteinurie, hypoalbuminemie et hypogammaglobulinemie). Parmi les populations analysees, nous observons uniquement une augmentation significative du pourcentage de plasmablastes (CD38+ CD24−) chez les patients P par rapport aux patients R (p = 0,01), aux patients G (p = 0,03) et aux TS (p Fig. 1 ). Conclusion Les plasmablastes et BAFF sont significativement augmentes chez les patients en pousssee de SNLGM suggerant une anomalie intrinseque des LB chez les patients P naifs de tout traitement.

International audience; Lipid disorders have been associated with glomerulopathies, a distinct type of renal pathologies, such as nephrotic syndrome. Global analyses targeting kidney lipids in this pathophysiologic context have been extensively performed, but most often regardless of the architectural and functional complexity of the kidney. The new developments in mass spectrometry imaging technologies have opened a promising field in localized lipidomic studies focused on this organ. In this article, we revisit the main works having employed the Matrix Assisted Laser Desorption Ionization Time of Flight (MALDI-TOF) technology, and the few reports on the use of TOF-Secondary Ion Mass Spectrometry (TOF-SIMS). We also present a first analysis of mouse kidney cortex sections by cluster TOF-SIMS. The latter represents a good option for high resolution lipid imaging when frozen unfixed histological samples are available. The advantages and drawbacks of this developing field are discussed.

Calciphylaxis is a small vessel vasculopathy, characterized by medial wall calcification that develops in a few patients with chronic renal failure. The prognosis of skin calciphylaxis has improved considerably since the introduction of sodium thiosulfate (STS), but it remains unclear whether this therapy is effective against organ lesions related to calciphylaxis. Pulmonary calciphylaxis is a usually fatal medical condition that may occur in association with skin involvement in patients with end-stage renal disease. We report here the case of a 49-year-old woman homozygous sickle cell disease patient on chronic hemodialysis with biopsy-proven systemic calciphylaxis involving the lungs and skin. On admission, ulcerative skin lesions on the lower limbs and bilateral pulmonary infiltrates on chest computerized tomography scan were the main clinical and radiological findings. Skin and bronchial biopsies demonstrated calciphylaxis lesions. The intravenous administration of STS in association with cinacalcet for 8 consecutive months led to a clear improvement in skin lesions and thoracic lesions on chest computerized tomography scan. This case suggests for the first time that organ lesions related to calciphylaxis, and particularly lung injury, are potentially reversible. This improvement probably resulted from the combination of 3 interventions (more frequent dialysis, cinacalcet, and STS), rather than the administration of STS alone.

Although the molecular mechanisms underlying the pathophysiology of minimal change nephrotic syndrome (MCNS) remain unclear, clinical and experimental observations point to an immune origin. MCNS is currently considered as being caused by a putative circulating factor which increases glomerular permeability and leads to podocyte cytoskeleton disorganization and proteinuria. We recently identified c-mip (c-maf-inducing protein) as a key factor involved in lymphocyte and podocyte dysfunction observed in MCNS patients. The aim of this review is to describe recent findings about the potential role of c-mip into MCNS pathogenesis.

Idiopathic nephrotic syndrome is the most frequent glomerular disease in children and in young adults. While genetic analyses have provided new insights into disease pathogenesis through the discovery of several podocyte genes mutated in distinct forms of inherited nephrotic syndrome, the molecular bases of minimal change nephrotic syndrome and focal and segmental glomerulosclerosis with relapses remain unclear. Although immune cell disorders, which may involve both innate and adaptive immunity, appear to play a role in the pathogenesis of steroid sensitive minimal change nephrotic syndrome, the mechanisms by which they induce podocyte dysfunction remain unresolved. It was postulated that podocyte injury results from a circulating factor secreted by abnormal T cells, but the possibility that bipolarity of the disease results from a functional disorder shared by both immune cells and the podocytes is not excluded. Minimal change nephrotic syndrome relapses are associated with an expansion of T and B cell compartments and production of growth factors as well as many cytokines. Dysfunction of T cells is supported by several findings including, inhibition of a type IV hypersensitivity reaction and unclassical T helper polarization, resulting from transcriptional interference between Th1 and Th2 transcriptional factors. A low serum level of some IgG fractions is frequently observed suggesting a defect in T-B cell cooperation, which remains to be explored. In this review, we discuss recent advances in the pathogenesis and the therapy of idiopathic nephrotic syndrome.

Preventive treatment of focal and segmental glomerulosclerosis (FSGS) allograft recurrence in high risk recipients having a prior history of graft loss caused by FSGS recurrence is still a challenging question. We retrospectively identified four patients who underwent a second renal transplantation because of recurrent FSGS and who received Rituximab therapy as a prophylactic treatment. Loss of their first allograft was directly related to an early (

Introduction La prevalence du syndrome nephrotique a lesions glomerulaires minimes (SNLGM) au cours de l’infection par le VIH serait de 1 a 4 %, mais les caracteristiques de ces patients n’ont jamais ete decrites avec precision. Patients et methodes Nous avons mene une etude retrospective permettant de recueillir les donnees des patients au sein de 7 hopitaux, entre 2000 et 2016. Les donnees demographiques, cliniques, biologiques, histologiques et therapeutiques etaient recueillies au moment de la ponction-biopsie renale et au moment de chaque rechute. Resultats Huit patients ont ete identifies (3 hommes, 5 femmes) avec une duree mediane de suivi apres le diagnostic de SNLGM de 20 mois. Sept avaient une infection VIH connue avant le SNLGM, 1 patient a presente les deux entites simultanement. La proteinurie et l’albuminemie moyennes etaient respectivement de 7,9 g/j (3,33 a 14,8) et de 17,5 g/L (7,7 a 29,5). Trois patients ont presente une insuffisance renale aigue. Au moment du SNLGM, 7 patients avaient des lymphocytes T CD4 + > 450/mm 3 et 5 avaient une charge virale indetectable. L’apparition du SNLGM a amene a modifier le traitement antiretroviral chez 3 patients. Six patients ont recu comme traitement de premiere intention une corticotherapie permettant une remission complete (RC) dans 4 cas. De maniere spontanee, un patient a presente une remission partielle (RP) et un autre une RC. Deux patients avaient un SNLGM corticodependant, deux autres ont presente des rechutes multiples et un patient une seule rechute. Un traitement par rituximab a ete instaure avec succes chez 4 patients. On note 4 episodes infectieux sans infection opportuniste chez 2 patients traites par rituximab. Discussion Les resultats de cette etude suggerent que la presence d’un SNLGM dans un contexte d’infection par le VIH soit une association rare, sans qu’un profil typique ne soit mis en evidence. Une etude complementaire par hybridation in situ est en cours pour rechercher la presence du virus dans les podocytes de ces patients. Conclusion Cette etude permet de decrire precisement les caracteristiques des patients infectes par le VIH presentant un SNLGM. Le lien etiopathogenique potentiel entre ces deux entites reste a determiner.

Les medicaments anti-angiogeniques (medicaments anti-VEGF sur le marche: bevacizumab (Avastin®), sunitinib (Sutent®), sorafenib (Nexavar®) sont de plus en plus utilises dans le traitement de certains cancers (colon, sein, poumon, foie et rein). Leurs effets secondaires sont mal connus des medecins. L’hypertension arterielle (HTA) est l’effet indesirable le plus frequent. Son incidence depend de la definition de la molecule et de la dose. Elle est generalement controlable par les traitements antihypertenseurs et compromet rarement la poursuite du traitement. Plus rarement, elle peut avoir des consequences graves (HTA maligne, leucoencephalopathie posterieure reversible, accident vasculaire cerebral, etc.). Des atteintes renales sont moins frequentes: proteinurie moderee le plus souvent, reversible, et plus rarement, syndrome nephrotique, insuffisance renale aigue, glomerulopathie proliferative, nephrite interstitielle et microangiopathie thrombotique. Allongement de l’espace QT et insuffisance cardiaque ont ete observes avec des tinibs. Sur le plan therapeutique: 1) avant l’administration d’une premiere dose d’un traitement anti-angiogenique, il ne faut pas retarder l’administration d’une premiere dose ou administrer un traitement antihypertenseur en raison d’une pression arterielle (PA) elevee; 2) le bilan initial comporte unemesure de la PA realisee avec un appareil de mesure valide soit par le medecin traitant, soit au mieux en automesure tensionnelle (« regle des 3 », http://www.has-sante.fr), soit en mesure ambulatoire de la PA (appareil de mesure humeral valide (liste: http://afssaps.sante.fr); 3) la bandelette urinaire (et le cas echeant, quantification de la proteinurie), l’estimation de la fonction renale (formule de MDRD simplifiee plutot que Cockcroft et Gault) doivent etre faites avant traitement et au cours du suivi; 4) la prise en charge therapeutique se fait conformement aux recommandations (HAS HTA 2005: http://www.has-sante.fr); 5) la surveillance et la prise en charge therapeutique se feront au mieux dans le cadre d’un travail en reseau comprenant medecin generaliste, oncologue, cardiologue et nephrologue.

Les medicaments anti-angiogeniques (medicaments anti-VEGF sur le marche: bevacizumab [Avastin®], sunitinib [sutent®], sorafenib [Nexevar®]) sont de plus en plus utilises dans le fraitement de certains cancers (colon, sein, poumon, foie et rein). Leurs effets secondaires sont mal connus des medecins. L'hypertension arterielle (HTA) est l'effet indesirable le plus frequent. Son incidence depend de la definition de la molecule et de la dose. Elle est generalement controlable par les traitements anti-hypertenseurs et compromet rarement la poursuite du traitement. Plus rarement, elle peut avoir des consequences graves (HTA maligne, leucoencephalopathie posterieure reversible, accident vasculaire cerebral,...). Des atteintes renales sont moins frequentes: proteinurie moderee le plus souvent, reversible, et, plus rarement, syndrome nephrotique, insuffisance renale aigue, glomerulopathie proliferative, nephrite interstitielle et microangiopathie thrombotique. Allongement de l'espace QT et insuffisance cardiaque ont ete observes avec des tinibs. Sur le plan therapeutique: 1) avant l'administration d'une premiere dose d'un traitement anti-angiogenique, il ne faut pas retarder l'administration d'une premiere dose ou administrer un traitement antihypertenseur en raison d'une PA elevee; 2) le bilan initial comporte une mesure de la PA realisee avec un appareil de mesure valide soif par le medecin traitant, soit, au mieux, en automesure tensionnelle (« Regle des 3 », http://www.has-sante.fr), soit en mesure ambulatoire de la PA (appareil de mesure humeral valide [liste: http://afssaps.sante.fr/]); 3) la bandelette urinaire (et le cas echeant, quantification de la proteinurie), l'estimation de la fonction renale (formule de MDRD simplifiee plutot que Cockcroft et Gault) doivent etre faites avant traitement et au cours du suivi; 4) la prise en charge therapeutique se fait conformement aux recommandations (HAS HTA 2005: http://www.has-sante.fr/); 5) la surveillance et la prise en charge therapeutique se feront au mieux dans le cadre d'un travail en reseau comprenant medecin generaliste, oncologue, cardiologue et nephrologue.

Angiogenesis inhibitor drugs (bevacizumab, sunitinib, sorafenib...) are now widely used for treatment of cancers, including colorectal, advanced renal cell and hepatocellular carcinomas, breast cancer). Vascular and renal side-effects of these drugs are not well known. Hypertension is one of the most common side effects. Incidence of hypertension may be different among angiogenis inhibitors and seems dose-depend. Arterial pressure can usually be controlled with anti-hypertensive medications, and treatment with angiogenesis inhibitors can be continued in most cases; however, serious hypertension-induced side effects were reported included malignant hypertension, stroke and reversible posterior leucoencephalopathy. Renal damage is infrequently reported: usually reversible mild or moderate proteinuria and in some rare cases nephritic syndrome, acute renal dysfunction, proliferative or collapsing glomerulonephritis, interstitial nephritis and thrombotic microangiopathy. Prolongation of the QT interval, congestive heart failure and left ventricular dysfunction have been reported in patients using tinibs. In the present guidelines, we recommend: (1) before the first administration of angiogenesis inhibitors: acute IV or oral antihypertensive medications should not be administered in a patient regardless of arterial pressure levels with postponing the administration because of hypertension is not recommended; (2) initial work-up should include ambulatory measurement of arterial pressure (by the general practitioner or by the patient using home blood pressure (three times in the morning and in the evening during three consecutive days) with a validated (cf: http://afssaps.sante.fr/) upper arm device: ideally, this device should be financed and provided by the pharmaceutical companies marketing the angiogenesis inhibitor drugs. Using 24-hour ambulatory blood pressure measurement is optional; (3) urine dipstick (and quantification if positive) and estimated glomerular filtration rate (using abbreviated MDRD rather than Cockcroft-Gault formula) must be performed before treatment and regularly during follow-up; (4) therapeutic management must be done in accordance with national or international guidelines (in France: http://www.has-sante.fr/); (5) optimal care is best achieved within a network of professionals including general practitioners, oncologists, cardiologists and nephrologists.

Background. Recurrence of nephrotic syndrome (NS) after renal transplantation for primary focal segmental glomerulosclerosis (FSGS) is a frequent and still unpredictable complication. However, risk factors for recurrence have not yet been clearly identified. Methods. Data from 33 patients who underwent 35 renal transplantations for FSGS in two French centres are reported. Results. Recurrent NS occurred in 12 transplant recipients (34%). A significantly higher number of patients in the group with recurrence (R group) compared with the group without recurrence (NR group) received cyclosporine for FSGS treatment before transplantation (83.3% vs 43.4%, P

Introduction Des resultats preliminaires ont montre que c-mip est surexprimee dans les lymphocytes B (LB) des patients en phase de poussee de syndrome nephrotique a lesions glomerulaires minimes (SNLGM). Materiels et methodes La relevance fonctionnelle et les consequences biochimiques de l’expression de c-mip dans les LB ont ete approchees in vitro dans une lignee cellulaire de LB humains (DHL4) qui n’expriment pas a l’etat basal c-mip. L’effet du surnageant des DHL4 exprimant ou non c-mip a ete evalue sur des podocytes humains differencies. Resultats L’expression de c-mip dans les LB (DHL4) entraine une augmentation significative de CD20 mais la densite de ce recepteur a la surface, etudiee par cytometrie en flux, ne semble pas etre modifiee, suggerant une alteration du recyclage ou une modification post-transcriptionnelle empechant son ciblage a la membrane plasmique. La regulation de CD20 semble egalement dependre du degre d’activation de certaines Src kinases impliquees dans l’activation proximale des LB. L’expression de c-mip dans les LB est associee a une baisse significative de l’expression de BTK. En revanche, c-mip ne semble pas alterer l’expression de Lyn et Syk. L’expression de c-mip dans les LB est associee a une diminution du niveau d’expression des formes actives de Src kinases (phosphorylees en position 418). Des experiences d’immunoprecipitation combinees a des analyses en microscopie confocale suggerent que CD20 interagit avec c-mip. Par ailleurs, l’exposition des podocytes humains en culture au surnageant des LB exprimant c-mip entraine une rarefaction de fibres de stress et l’apparition de vesicules d’actine sous-membranaires. Discussion La relation entre c-mip et le niveau d’expression de CD20 et la baisse de BTK apporte de nouveaux elements concernant le role du LB dans la physiopathologie du SNLGM. Conclusion Ces resultats suggerent que l’induction de c-mip pourrait modifier l’activation proximale des LB et alterer l’expression de CD20 et/ou sa regulation. En cas de confirmation de l’effet pathologique du surnageant des LB surexprimant c-mip sur les podocytes, nous essaierons d’identifier le ou les facteur(s) impliques par proteomique differentielle.

Background The association between sarcoidosis and glomerular diseases has not been extensively investigated in a large series and the potential features of this uncommon association remain to be determined. Methods We retrospectively identified 26 patients with biopsy-proven glomerular lesions that occurred in a sarcoidosis context. Potential remission of glomerular disease and sarcoidosis under specific treatment (steroid and/or immunosuppressive agents) was recorded for all patients. Demographic, clinical and biological characteristics were assessed at the time of kidney biopsy for each patient. Therapeutic data were analyzed for all patients. Results Glomerular disease occurred after the diagnosis of sarcoidosis in 11 of 26 cases (42%) (mean delay of 9.7 years). In six patients (23%), the glomerulopathy preceded the sarcoidosis diagnosis (mean delay 8 years). In the last nine patients (35%), both conditions occurred simultaneously. The most frequent glomerular disease occurring in sarcoidosis patients was membranous nephropathy in eleven cases. Other glomerular lesions included IgA nephropathy in six cases, focal segmental glomerulosclerosis in four patients, minimal change nephrotic syndrome for three patients and proliferative lupus nephritis in two patients. Granulomatous interstitial nephritis was associated with glomerular disease in six patients and was exclusively found in patients in whom the both disease occurred simultaneously. In nine patients with simultaneous glomerular and sarcoidosis diseases, we observed a strong dissociation between glomerular disease and sarcoidosis in terms of steroid responsiveness. At the end of the follow-up (mean of 8.4 years), six patients had reached end-stage renal disease and three patients had died. Conclusions A wide spectrum of glomerular lesions is associated with sarcoidosis. The close temporal relationship observed in some patients suggests common causative molecular mechanisms of glomerular injury but complete remission of both diseases in response to exclusive steroid therapy is infrequent.

Idiopathic nephrotic syndrome is the most frequent glomerular disease in children and in young adults. While genetic analyses have provided new insights into disease pathogenesis through the discovery of several podocyte genes mutated in distinct forms of inherited nephrotic syndrome, the molecular bases of minimal change nephrotic syndrome and focal and segmental glomerulosclerosis with relapses remain unclear. Although immune cell disorders, which may involve both innate and adaptive immunity, appear to play a role in the pathogenesis of steroid sensitive minimal change nephrotic syndrome, the mechanisms by which they induce podocyte dysfunction remain unresolved. It was postulated that podocyte injury results from a circulating factor secreted by abnormal T cells, but the possibility that bipolarity of the disease results from a functional disorder shared by both immune cells and the podocytes is not excluded. Minimal change nephrotic syndrome relapses are associated with an expansion of T and B cell compartments and production of growth factors as well as many cytokines. Dysfunction of T cells is supported by several findings including, inhibition of a type IV hypersensitivity reaction and unclassical T helper polarization, resulting from transcriptional interference between Th1 and Th2 transcriptional factors. A low serum level of some IgG fractions is frequently observed suggesting a defect in T-B cell cooperation, which remains to be explored. In this review, we discuss recent advances in the pathogenesis and the therapy of idiopathic nephrotic syndrome.

Preventive treatment of focal and segmental glomerulosclerosis (FSGS) allograft recurrence in high risk recipients having a prior history of graft loss caused by FSGS recurrence is still a challenging question. We retrospectively identified four patients who underwent a second renal transplantation because of recurrent FSGS and who received Rituximab therapy as a prophylactic treatment. Loss of their first allograft was directly related to an early (3 months) recurrence of FSGS that was either resistant to plasmapheresis therapy in two cases or had escaped to this therapeutic management in the two others. After the second renal transplantation, all patients were free of FSGS recurrence during follow-ups that were between 12 and 54 months long. These preliminary results demonstrate for the first time that Rituximab therapy may constitute an attractive prophylactic option for patients being considered for a second renal transplantation because of recurrent FSGS in their first graft.

Simultaneous cardiac and renal involvement is associated with a particularly poor prognosis in patients with AL amyloidosis (AL-A). We report the first case of a successful long-term outcome of combined heart and kidney transplantation not followed by autologous stem cell transplantation in a patient with systemic AL-A. The recipient was a 46-year-old man with end-stage renal failure associated with serious cardiac involvement in the context of AL-A. Before transplantation, two courses of oral melphalan plus prednisone induced partial hematologic remission, as shown by the decrease in circulating free light chain with no improvement of renal or heart function. The patient underwent combined heart and kidney transplantation as a rescue treatment. Three years after organ transplantation, plasma cell dyscrasia remains in complete remission, with normal free lambda light chain levels and no recurrence of amyloid deposition on heart and kidney grafts. This case report demonstrates that successful long-term outcome of combined heart and kidney transplantation not systematically associated with stem cell transplantation may be considered an additional therapeutic option in AL-A patients with severe organ dysfunction and partial hematologic remission.

Idiopathic nephrotic syndrome is the most frequent glomerular disease in children. While genetic analyses have provided new insights into disease pathogenesis through the discovery of several podocyte genes mutated in distinct forms of inherited nephrotic syndrome, the molecular bases of minimal change nephrotic syndrome (MCNS) and focal and segmental glomerulosclerosis (FSGS) with relapse remain unclear. Although immune cell disorders, which may involve both innate and adaptive immunity, appear to play a role in the pathogenesis of steroid sensitive MCNS, the mechanisms by which they induce podocyte dysfunction remain unresolved. It was postulated that podocyte injury results from a circulating factor secreted by abnormal T cells, but the possibility that bipolarity of the disease results from a functional disorder shared by both cell systems is not excluded. MCNS relapses are associated with an activation of the immune system, including an expansion of T and B cell compartments and production of growth factors as well as many cytokines. Dysfunction of T cells is supported by three main findings: (1) inhibition of a type III hypersensitivity reaction ; (2) defects in immunoglobulin switch ; (3) unclassical T helper polarization resulting from transcriptional interference between Th1 and Th2 transcriptional factors.

Angiogenesis inhibitor drugs (bevacizumab, sunitinib, sorafénib...) are now widely used for treatment of cancers, including colorectal, advanced renal cell and hepatocellular carcinomas, breast cancer). Vascular and renal side-effects of these drugs are not well known. Hypertension is one of the most common side effects. Incidence of hypertension may be different among angiogenis inhibitors and seems dose-depend. Arterial pressure can usually be controlled with anti-hypertensive medications, and treatment with angiogenesis inhibitors can be continued in most cases; however, serious hypertension-induced side effects were reported included malignant hypertension, stroke and reversible posterior leucoencephalopathy. Renal damage is infrequently reported: usually reversible mild or moderate proteinuria and in some rare cases nephritic syndrome, acute renal dysfunction, proliferative or collapsing glomerulonephritis, interstitial nephritis and thrombotic microangiopathy. Prolongation of the QT interval, congestive heart failure and left ventricular dysfunction have been reported in patients using tinibs. In the present guidelines, we recommend: (1) before the first administration of angiogenesis inhibitors: acute IV or oral antihypertensive medications should not be administered in a patient regardless of arterial pressure levels with postponing the administration because of hypertension is not recommended; (2) initial work-up should include ambulatory measurement of arterial pressure (by the general practitioner or by the patient using home blood pressure (three times in the morning and in the evening during three consecutive days) with a validated (cf: http://afssaps.sante.fr/) upper arm device: ideally, this device should be financed and provided by the pharmaceutical companies marketing the angiogenesis inhibitor drugs. Using 24-hour ambulatory blood pressure measurement is optional; (3) urine dipstick (and quantification if positive) and estimated glomerular filtration rate (using abbreviated MDRD rather than Cockcroft-Gault formula) must be performed before treatment and regularly during follow-up; (4) therapeutic management must be done in accordance with national or international guidelines (in France: http://www.has-sante.fr/); (5) optimal care is best achieved within a network of professionals including general practitioners, oncologists, cardiologists and nephrologists.