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Sicard A.,Hospices Civils de Lyon | Sicard A.,French Institute of Health and Medical Research | Sicard A.,University of Lyon | Ducreux S.,Laboratoire dHistocompatibilite | And 22 more authors.
Journal of the American Society of Nephrology | Year: 2015

Antibody-mediated rejection (AMR) is a major cause of kidney graft loss, yet assessment of individual risk at diagnosis is impeded by the lack of a reliable prognosis assay. Here, we tested whether the capacity of anti-HLA antibodies to bind complement components allows accurate risk stratification at the time of AMR diagnosis. Among 938 kidney transplant recipients for whom a graft biopsy was performed between 2004 and 2012 at the Lyon University Hospitals, 69 fulfilled the diagnosis criteria for AMR and were enrolled. Sera banked at the time of the biopsy were screened for the presence of donor-specific anti-HLAantibodies (DSAs) and their ability to bind C1q and C3d using flow bead assays. In contrast with C4d graft deposition, the presence of C3d-binding DSA was associated with a higher risk of graft loss (P<0.001). Despite similar trend, the difference did not reach significance with a C1q-binding assay (P=0.06). The prognostic value of a C3d-binding assay was further confirmed in an independent cohort of 39 patients with AMR (P=0.04). Patients with C3d-binding antibodies had worse eGFR and higher DSA mean fluorescence intensity. In a multivariate analysis, only eGFR<30 ml/min per 1.73 m2 (hazard ratio [HR], 3.56; 95% confidence interval [CI], 1.46 to 8.70; P=0.005) and the presence of circulating C3d-binding DSA (HR, 2.80; 95% CI, 1.12 to 6.95; P=0.03) were independent predictors for allograft loss at AMR diagnosis. We conclude that assessment of the C3d-binding capacity of DSA at the time of AMR diagnosis allows for identification of patients at risk for allograft loss. © 2015 by the American Society of Nephrology.


PubMed | Groupe Hospitalier Pitie Salpetriere 47 83 Boulevard Of Lhopital, Hopital Cardiologique, University of Versailles, AP HP and 12 more.
Type: | Journal: Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | Year: 2016

Mutations in PRKAG2, the gene encoding for the 2 subunit of 5-AMP-activated protein kinase (AMPK), are responsible for an autosomal dominant glycogenosis with a cardiac presentation, associating hypertrophic cardiomyopathy (HCM), ventricular pre-excitation (VPE), and progressive heart block. The aim of this study was to perform a retrospective time-to-event study of the clinical manifestations associated with PRKAG2 mutations.A cohort of 34 patients from 9 families was recruited between 2001 and 2010. DNA were sequenced on all exons and flanking sequences of the PRKAG2 gene using Sanger sequencing. Overall, four families carried the recurrent p.Arg302Gln mutation, and the five others carried private mutations among which three had never been reported. In the total cohort, at 40 years of age, the risk of developing HCM was 61%, VPE 70%, conduction block 22%, and sudden cardiac death (SCD) 20%. The global survival at 60 years of age was 66%. Thirty-two per cent of patients (N = 10) required a device implantation (5 pacemakers and 5 defibrillators) at a median age of 66 years, and two patients required heart transplant. Only one patient presented with significant skeletal muscle symptoms. No significant differences regarding the occurrence of VPE, ablation complications, or death incidence were observed between different mutations.This study of patients with PRKAG2 mutations provides a more comprehensive view of the natural history of this disease and demonstrates a high risk of cardiac complications. Early recognition of this disease appears important to allow an appropriate management.


PubMed | Laboratoire dEpidemiologie, Laboratoire dAnatomopathologie and Service de Nephrologie
Type: | Journal: The Pan African medical journal | Year: 2016

The contribution of renal needle biopsy (RNB) to make a diagnosis, a treatment selection and a prognostic evaluation of nephropathies is significant. No Moroccan study has evaluated the practice and the contribution of RNB. Our aim was to study RNB indications, to determine the frequency of kidney diseases identified by RNB in our region and make a comparison between clinical and biological data and histological diagnosis. This is a retrospective study conducted between January 2009 and December 2012. We included all patients in the Department of Nephrology, CHU Hassan II, Fez, who underwent biopsy of native kidneys. 522 RNB were performed. We excluded 8 biopsies due to lack of informations and 514 were retained. The average age of the patients at the time of RNB was 3917 years (3-82 years). Sex ratio was 0.9. Nephrotic syndrome was the most common clinical diagnosis to all ages (58.2%). Glomerular nephropathies represent 94,2% of diagnosed renal diseases, their distribution varies according to patients age. RNB confirmed the first clinically suspected diagnosis in 40.65% of cases, whereas it revealed an unexpected diagnosis in 22.5% of them. Syndromic diagnosis can orient the clinician toward the most probable kidney disease and guide any emergency treatment while awaiting RNB results. But it can never replace RNB which remains the gold standard.


Thomas P.A.,Service de chirurgie thoracique | Payan-Defais M.J.,Laboratoire danatomopathologie
Revue de Pneumologie Clinique | Year: 2010

Epithelial tumours of the thymus include thymomas, thymic carcinomas and neuro-endocrine tumours. Rare, they nevertheless represent 20% of all mediastinal tumours and 50% of those located in the anterior mediastinum. Thymomas, in particular, can be associated to auto-immune disorders, among which predominates myasthenia gravis. Their clinical behaviour varies widely, from a relative indolence to the potential of lymph node and/or systematic metastases. However, even patients with an invasive disease may have a long clinical history, explaining that a 10-year or 20-year survival from diagnosis does not imply a definitive cure. In daily practice, both the clinical Masaoka's staging system and the WHO histological classification condition the treatment strategies and allow to anticipate the prognosis. The initial treatment, as well as that of the recurrence, is based mainly on a complete resection. Postoperative radiotherapy is systematically added to the treatment of invasive tumours and/or to those with an aggressive histological subtype. Inoperable or metastatic tumours require a cisplatine and anthracyclin-based chemotherapy, followed by radical surgery and/or radiotherapy. © 2009 Elsevier Masson SAS. All rights reserved.


Nambotin S.B.,French Institute of Health and Medical Research | Lefrancois L.,French Institute of Health and Medical Research | Sainsily X.,French Institute of Health and Medical Research | Berthillon P.,French Institute of Health and Medical Research | And 8 more authors.
Journal of Hepatology | Year: 2011

Background & Aims: We previously reported the frequent overexpression of the FZD7 membrane receptor in hepatocellular carcinoma (HCC) and its role for controlling cancer phenotype. Herein, this study aimed at assessing the anticancer properties of compounds inhibiting FZD7 activity by disrupting its binding with the cytosolic Dishevelled (DVL) adaptator. Methods: We have designed small interfering peptides (RHPDs) that are able to enter within cells and to competitively antagonize the binding of FZD7 to the PDZ domain of DVL. Their anti-neoplastic properties were assessed in vitro on a panel of human HCC cell lines and in vivo on the SV40-TAg transgenic mouse model of HCC. Results: We have shown that RHPDs decrease cell viability via apoptosis depending on their affinity for PDZ, with a therapeutic index between cancerous and non-cancerous cells. RHPD properties were linked to β-catenin degradation and PKCδ activation. In transgenic mice, intra-tumor injection of RHPDs inhibited HCC progression. Conclusions: We have completed a proof-of-concept showing that in vitro and in vivo the pharmacological inhibition of FZD7 displays anti-cancerous properties against HCC. The mechanisms can involve β-catenin and PKCδ modulations. Further studies are warranted to design protocols showing the compatibility with systemic in vivo applications. © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Sberro-Soussan R.,University of Paris Descartes | Zuber J.,University of Paris Descartes | Suberbielle-Boissel C.,Laboratoire dHistocompatibilite | Candon S.,University of Paris Descartes | And 13 more authors.
American Journal of Transplantation | Year: 2010

Persistence of donor-specific anti-HLA antibodies (DSA) associated with antibody-mediated graft injuries following kidney transplantation predicts evolution toward chronic humoral rejection and reduced graft survival. Targeting plasma cells, the main antibody-producing cells, with the proteasome inhibitor bortezomib may be a promising desensitization strategy. We evaluated the in vivo efficacy of one cycle of bortezomib (1.3 mg/m2 × 4 doses), used as the sole desensitization therapy, in four renal transplant recipients experiencing subacute antibody-mediated rejection with persisting DSA (>2000 [Mean Fluorescence Intensity] MFI). Bortezomib treatment did not significantly decrease DSA MFI within the 150-day posttreatment period in any patient. In addition, antivirus (HBV, VZV and HSV) antibody levels remained stable following treatment suggesting a lack of efficacy on long-lived plasma cells. In conclusion, one cycle of bortezomib alone does not decrease DSA levels in sensitized kidney transplant recipients in the time period studied. These results underscore the need to evaluate this new desensitization agent properly in prospective, randomized and well-controlled studies. © 2010 The American Society of Transplantation and the American Society of Transplant Surgeons.


Thervet E.,University of Paris Descartes | Aouizerate J.,Service de Transplantation | Noel L.H.,Laboratoire dAnatomopathologie | Brocheriou I.,Service dAnatomopathologie | And 3 more authors.
Transplantation | Year: 2011

Background. Henoch-Schonlein Purpura nephropathy (HSPN) recurrence in renal transplant recipients (RTRs) has been reported in 35% of patients, leading in 11% of these patients to graft loss at 5 years. However, its true incidence is unknown. The aim of this study was to investigate this recurrence incidence using routine allograft biopsies (RBs). Methods. All RTRs with biopsy-proven HSP initial nephropathy were included (13 RTRs and 18 renal transplantations). At transplantation, the median age was 34 years, and 85% of RTRs were men. Overall, we analyzed 66 RBs that were routinely performed at 3 and 12 months after RT and when clinically indicated. Histologic recurrence was defined as the presence of IgA deposits within the mesangium and along the glomerular capillary walls. Results. After a median follow-up of 83 months (range, 13-232 months; interquartile range, 26-235 months), histologic recurrence was detected in 69% of patients and in 61% of grafts after a mean period of 24 months (range, 1-156 months). Clinical or biological signs were absent in all but one. Patient survival was 92.8%. Graft loss occurred in five cases, never were related to recurrence. At the last follow-up, the mean glomerular filtration rate was 48±14.2 mL/min/1.73 m; in patients with and without recurrence, the mean rates were 52.1±17.5 and 42.4±5.3 mL/min/1.73 m, respectively (P=0.27). Conclusion. Histologic recurrence of HSPN after RT is frequently observed on routine RBs but is not associated with clinical consequences. The short-term prognosis of recurrence is good, but its long-term prognosis remains to be determined. © 2011 by Lippincott Williams & Wilkins.


Lerolle N.,University of Angers | Lerolle N.,University of Paris Descartes | Nochy D.,University of Paris Descartes | Nochy D.,Laboratoire dAnatomopathologie | And 6 more authors.
Intensive Care Medicine | Year: 2010

Purpose: Septic shock is one of the leading causes of acute kidney injury. The mechanisms of this injury remain mostly unknown notably because of the lack of data on renal histological lesions in humans. Methods: Kidney biopsy was performed immediately post-mortem in consecutive patients who died of septic shock. Comparisons were made with specimens from eight patients who died of trauma on scene and nine ICU patients that died of non-septic causes. Results: Nineteen septic patients were included, 11 were male, and age was 72 ± 12 years. Anuria occurred in all patients 2.2 ± 1.4 days before death. Seven patients had disseminated intravascular coagulation. In all patients we observed (1) acute tubular lesions whose intensity correlated with blood lactate concentration; (2) intense infiltration by leukocytes, mainly monocytic, in glomeruli and interstitial capillaries as compared to controls; (3) presence of tubular cell apoptosis proved by the presence of apoptotic bodies (2.9% of tubular cells) significantly more frequently than in controls and confirmed by TUNEL and activated caspase-3 staining. Arteriolar/arterial thromboses were observed in only 4 of 19 patients, without any association with presence of disseminated intravascular coagulation. Conclusions: Kidney lesions in septic shock go beyond those associated with simple acute tubular injury, notably capillary leukocytic infiltration and apoptosis. Vascular thrombosis, however, did not appear to play a major role in the majority of patients. The extent to which these lesions are specific to sepsis or are common to all multi-organ failure independent of its cause is yet to be elucidated. © 2009 Copyright jointly hold by Springer and ESICM.


Clave A.,University of Western Brittany | Yahi H.,Service de Gynecologie Pr Cosson | Hammou J.-C.,Laboratoire dAnatomopathologie | Montanari S.,Covidien | And 2 more authors.
International Urogynecology Journal and Pelvic Floor Dysfunction | Year: 2010

Introduction and hypothesis: Currently, most implants used for reinforcement in surgical treatment of pelvic floor disorders are knitted monofilament polypropylene (PP). While previously recognized as inert, PP is associated with high complication rates. Some recent literature suggests polyester prosthetics based on poly(ethylene terephthalate) (PET), which may be more inert in vivo. Methods: A sample of 100 implants explanted from patients due to complications was examined to evaluate the relative degradation characteristics of PP and PET prosthetics. Histological, microscopic (scanning electron microscopy, SEM) and chemical analysis (Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC)) were conducted on these explants. Results: Poly(ethylene terephtahlate) explants appeared to sustain less degradation in vivo than the PP explants observed in this cohort. Conclusions: This is the first study to evaluate synthetic implants used in a vaginal approach for pelvic floor reinforcement. The study provides evidence contrary to published literature characterizing PP as inert in such applications. Additionally, the study suggests the need for clinical trials comparatively investigating the performance of new types of monofilament prosthetics, such as those comprising PET. © 2009 The International Urogynecological Association.


Snanoudj R.,Service de Transplantation Renale Adulte | Snanoudj R.,University of Paris Descartes | Royal V.,Laboratoire dAnatomopathologie | Elie C.,University of Paris Descartes | And 12 more authors.
American Journal of Transplantation | Year: 2011

The specificity of chronic histological lesions induced by calcineurin inhibitors (CNI) is often questioned, but few studies have directly compared long-term lesions in renal-transplant patients who received this treatment and those who did not. We therefore conducted a retrospective study of 141 kidney-transplant recipients treated with (n = 48) or without (n = 93) cyclosporine (CsA) to compare the histological lesions observed at 3-month, 24-month and 10-year protocol biopsies. All of the chronic elementary lesions (glomerulosclerosis, interstitial fibrosis, tubular atrophy, arteriolar hyalinosis, fibrointimal thickening) progressed in frequency and severity in both groups, although significantly more in the CsA group. Ten-year biopsy results showed that 92% of patients in the CsA-treated group and 65% in the control group had arteriolar hyalinosis lesions. When we focused on muscular arteriolar hyaline deposits more specific to CsA arteriolopathy, we observed these lesions in 68% of CsA patients and 28% of patients who had never received CsA. CsA was not the sole factor involved in the development of arteriolar hyalinosis and was independently associated with an increased risk of graft loss. In summary, we observed that histological lesions commonly attributed to CsA nephrotoxicity were not sufficiently specific to definitively diagnose CNI nephrotoxicity. © Copyright 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.

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