Analyse descriptive et étude de la réponse à la plasmathérapie de la microangiopathie thrombotique de l adulte à ADAMTS13 détectable (étude rétrospective multicentrique)

PARIS7-Xavier Bichat (751182101) / SudocSudocFranceF

Critères d’indications de la biopsie rénale chez les patients diabétiques de type 2 protéinuriques : enquête auprès des néphrologues français

National audienceDiabetic 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

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

Survival studies.

<p><b>A</b>. Specific limitation of calpain activity in melanoma cells only by calpastatin overexpression in vivo. C57BL/6 WT mice were injected with one million melanoma B16-F10 cells either transgenic for calpastatin (Calpast-Mel) or transfected with a control plasmid (Ctrl-Mel), n = 10/group. Limitation of calpain activity in melanoma cells only did not modify survival at day 30. <b>B</b>. Specific limitation of calpain activity in mice transgenic for calpastatin. C57BL/6 control (WT mice) or transgenic mice (CalpTG mice) were injected with one million control melanoma B16F10 cells, n = 10/group. Limitation of calpain activity in host did not modify survival at day 30.</p

Inhibition of calpains in host mice only.

<p>C57BL/6 control (WT mice) or transgenic mice (CalpTG mice) were injected with one million melanoma B16F10 cells and sacrificed at day 16 for tissue analysis.<b>A</b>. Tumor growth was measured from day 11 to day 16. Calpastatin overexpression in host did not modify tumor growth. N = 10/group. <b>B</b>. Tumor weight at day 16. Calpastatin overexpression in hosts did not modify tumor weight. N = 10/group, p = NS. <b>C</b>. Proportion of metastatic regional lymph nodes at day 16. CalpTG mice had a trend to have more metastatic lymph nodes than WT mice (9/10 vs 4/10 respectively, N = 10/group, p = NS). <b>D,E,F</b>. Angiogenesis as assessed by vessel count at 200×magnification after CD-31 staining. Neo-angiogenesis was significantly decreased in CalpTG mice when compared to WT mice. N = 10/group, * p<0.05. <b>G,H,I,J</b>: CD3, CD4, CD8 and NK cell number/HPF (200×magnification). Immune cell infiltrate was significantly lower in CalpTG mice than in WT mice. N = 10/group, * p<0.05.</p

Inhibition of calpains in melanoma cells only: an in vivo approach.

<p>C57BL/6 WT mice were injected with one million melanoma B16-F10 cells either transgenic for calpastatin (Calpast-Mel) or transfected with a control plasmid (Ctrl-Mel) and sacrificed at day 16 for tissues analysis. <b>A</b>. Tumor growth was measured from day 9 to day 16. Calpastatin overexpression in melanoma decreased significantly tumor growth. N = 10/group, * p< 0.05. <b>B</b>. Tumor weight at day 16. Calpastatin overexpression reduced significantly melanoma weight. N = 10/group, * p<0.05. <b>C</b>. Proportion of metastatic regional (axillary) lymph nodes at day 16. Mice injected with melanoma cells with reduced calpain activity (Calpast-Mel) had significantly more metastatic lymph nodes than controls (Ctrl-Mel) (10/10 vs 5/10 respectively, * p<0.05). <b>D</b>. Angiogenesis assessed by vessel count at 200×magnification after CD-31 (PECAM) staining. Neo-angiogenesis was similar in transgenic and control melanomas. N = 10/group, p = NS. <b>E,F,G,H</b>: CD3, CD4, CD8 and NK cell number/HPF (200×magnification). Immune cell infiltrate was similar in transgenic and control tumors. N = 10/group, p = NS.</p

Inhibition of calpains in both host and melanoma cells (global inhibition).

<p>C57BL/6 control (WT mice) and transgenic mice (CalpTG mice) were injected with one million melanoma B16-F10 cells transfected with control plasmid (WT/Ctrl-Mel) and calpastatin plasmid (TG/Calpast-Mel) respectively. Mice were sacrificed at day 16 for tissue analysis. <b>A</b>. Tumor growth was measured from day 9 to day 16. Calpastatin overexpression in both hosts and melanoma decreased significantly tumor growth. N = 10/group, * p<0.05. <b>B</b>. Tumor weight at day 16. Calpastatin overexpression in both hosts and melanoma decreased non-significantly tumor weight. N = 10/group, p = NS. <b>C</b>. Angiogenesis assessed by vessel count at 200×magnification after CD-31 staining. TG/Calpast-Mel mice had a trend to have less neo-angiogenesis than WT mice. N = 10/group, p = NS. <b>D,E,F,G.</b> CD3, CD4, CD8 and NK cell number/HPF (200×magnification). Immune cell infiltrate was significantly lower in TG/calpast Mel mice than in WT/Ctrl mice. N = 10/group, * p<0.05. <b>H.</b> Proportion of metastatic regional lymph nodes at day 16. TG/Calpast-Mel mice had a trend to have more metastatic lymph nodes than WT mice (9/10 vs 4/10 respectively, p = NS).</p

Predictive features of chronic kidney disease in atypical haemolytic uremic syndrome

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

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

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

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