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Hazzan M.,Service de Nephrologie | Hertig A.,Urgences Nephrologiques et Transplantation Renale | Hertig A.,French Institute of Health and Medical Research | Noel C.,Service de Nephrologie | And 4 more authors.
Journal of the American Society of Nephrology | Year: 2011

Maintenance immunosuppression with cyclosporine A (CsA) can cause nephrotoxicity in renal transplant recipients. Identifying patients at increased risk for CsA nephrotoxicity may allow interventions to prolong graft survival. Here, we studied the effect of early CsA withdrawal or maintenance among 96 kidney recipients at risk for interstitial fibrosis and tubular atrophy (IF/TA) on the basis of tubular expression of vimentin and β-catenin in a protocol biopsy performed 3 months after transplant. In this retrospective analysis of biopsies collected during a randomized trial of early withdrawal of CsA or mycophenolate mofetil, the semiquantitative score of early phenotypic changes suggestive of epithelial-to-mesenchymal transition (EMT) progressed with time among those maintained on a CsA-containing regimen. EMT-positive grafts displayed a significantly higher IF/TA score and greater progression of the IF/TA score at 12 months (P = 0.001 and 0.008, respectively). EMT-positive grafts exposed to CsA also had a greater decrease in estimated GFR compared with EMT-negative grafts exposed to CsA and EMT-positive grafts withdrawn from CsA exposure. Multivariable analysis revealed that the presence of EMT was an independent risk factor for a 10% decline in graft function up to 4 years posttransplant (odds ratio 4.49; 95% confidence interval 1.02 to 19.9). Collectively, these data demonstrate that changes consistent with EMT are strong prognostic biomarkers in renal transplant recipients exposed to CsA. Copyright © 2011 by the American Society of Nephrology.


PubMed | University Of Lille Umr 995, Urgences Nephrologiques et Transplantation Renale and Lille University Hospital Center
Type: Journal Article | Journal: Clinical transplantation | Year: 2016

Despite long-term side effects, calcineurin inhibitors (CNI) remain a cornerstone of immunosuppression in renal transplantation. Few trials assessed the long-term outcome after early CNI withdrawal.This intention-to-treat study assessed the 10-year outcome of 108 patients randomly converted from a cyclosporine (CsA)-mycophenolate mofetil (MMF)-prednisone regimen to a dual therapy (CsA-prednisone or MMF-prednisone) at 3months postgraft.At 10years, 3.7% in the CsA group and 35.2% in the MMF group remained on the protocol regimen (P<.001). eGFR was higher in the MMF group (64.421 vs 49.714.7 mL/min/1.73 m, P<.001), although acute rejection (12 vs 4 in the CsA group, P=.03) and Class II DSA incidences were increased. CNI-related toxicity (P=.019) and moderate-to-severe IF/TA (P=.004) were higher in the CsA group. Ten-year graft and patient survivals were not different. In multivariate analysis, acute rejection remained the strongest predictor of graft loss (HR=11.64, 95% CI [5.05-26.79], P<.0001).MMF withdrawal largely failed due to CNI toxicity, while CsA withdrawal led to increased graft failure due to uncontrolled acute rejection without increasing graft survival. From this study, it remains unclear which patients could benefit from limiting CNI exposure.


PubMed | Service de Nephrologie et Transplantation Adulte, Laboratoire danatomie pathologique, French Institute of Health and Medical Research, Service de Nephrologie et Dialyses and Urgences Nephrologiques et Transplantation Renale
Type: | Journal: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons | Year: 2016

Urinary messenger RNA (mRNA) quantification is a promising method for noninvasive diagnosis of renal allograft rejection (AR), but the quantification of mRNAs in urine remains challenging due to degradation. RNA normalization may be warranted to overcome these issues, but the strategies of gene normalization have been poorly evaluated. Herein, we address this issue in a case-control study of 108 urine samples collected at time of allograft biopsy in kidney recipients with (n = 52) or without (n = 56) AR by comparing the diagnostic value of IP-10 and CD3 mRNAs-two biomarkers of AR-after normalization by the total amount of RNA, normalization by one of the three widely used reference RNAs-18S, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Hypoxanthine-guanine phosphoribosyltransferase (HPRT)-or normalization using uroplakin 1A (UPK) mRNA as a possible urine-specific reference mRNA. Our results show that normalization based on the total quantity of RNA is not substantially improved by additional normalization and may even be worsened with some classical reference genes that are overexpressed during rejection. However, considering that normalization by a reference gene is necessary to ensure polymerase chain reaction (PCR) quality and reproducibility and to suppress the effect of RNA degradation, we suggest that GAPDH and UPK1A are preferable to 18S or HPRT RNA.


PubMed | Service de Medecine interne, Service de Medecine Interne, Urgences nephrologiques et transplantation renale, CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory and Paris-Sorbonne University
Type: Journal Article | Journal: American journal of hematology | Year: 2016

The standard four-rituximab infusions treatment in acquired thrombotic thrombocytopenic purpura (TTP) remains empirical. Peripheral B cell depletion is correlated with the decrease in serum concentrations of anti-ADAMTS13 and associated with clinical response. To assess the efficacy of a rituximab regimen based on B cell depletion, 24 TTP patients were enrolled in this prospective multicentre single arm phase II study and then compared to patients from a previous study. Patients with a suboptimal response to a plasma exchange-based regimen received two infusions of rituximab 375 mgm


PubMed | Matrix, University Pierre and Marie Curie, Urgences Nephrologiques et Transplantation renale, Anatomie pathologique and 2 more.
Type: | Journal: Journal of the American Society of Nephrology : JASN | Year: 2017

Vancomycin is a widely prescribed antibiotic, but the exact nature of vancomycin-associated nephrotoxicity is unclear, in particular when considering the frequent coadministration of aminoglycosides. We describe here the initial case of a 56-year-old woman with normal renal function developing unexplained ARF without hypovolemia after administration of vancomycin without coadministration of aminoglycosides. Studying the patients renal biopsy specimen, we ascertained that obstructive tubular casts composed of noncrystal nanospheric vancomycin aggregates entangled with uromodulin explained the vancomycin-associated ARF. We developed in parallel a new immunohistologic staining technique to detect vancomycin in renal tissue and confirmed retrospectively that deleterious vancomycin-associated casts existed in eight additional patients with acute tubular necrosis in the absence of hypovolemia. Concomitant high vancomycin trough plasma levels had been observed in each patient. We also reproduced experimentally the toxic and obstructive nature of vancomycin-associated cast nephropathy in mice, which we detected using different in vivo imaging techniques. In conclusion, the interaction of uromodulin with nanospheric vancomycin aggregates represents a new mode of tubular cast formation, revealing the hitherto unsuspected mechanism of vancomycin-associated renal injury.


Rafat C.,Urgences Nephrologiques et Transplantation Renale | Burbach M.,Urgences Nephrologiques et Transplantation Renale | Brocheriou I.,Anatomo Pathologie | Brocheriou I.,University Pierre and Marie Curie | And 7 more authors.
American Journal of Kidney Diseases | Year: 2013

Unlike hemoglobin or myoglobin, bilirubin, a breakdown product of the catabolism of heme molecules, usually is not seen as a nephrotoxic protein. We report the case of an adult kidney recipient who developed jaundice 4 years after transplantation because of a malignant cholangiocarcinoma. He progressively lost transplant function, accompanied by a continuous increase in bilirubinemia. Kidney biopsy showed bile granules in the cytoplasm of tubular epithelial cells and bile thrombi in dilated tubules, but no interstitial inflammation. The tumor was unresectable and the patient died 2 months later. Because the patient had no jaundice-associated confounding factor that could explain his kidney failure, such as sepsis, heart failure, or liver failure with hepatorenal syndrome, this exceptional case suggests that bilirubin per se should be seen as a potential cause of acute tubular necrosis. © 2013 National Kidney Foundation, Inc.


Kormann R.,Urgences Nephrologiques et Transplantation Renale | Languille E.,Urgences Nephrologiques et Transplantation Renale | Amiot H.-M.,Urgences Nephrologiques et Transplantation Renale | Hertig A.,Urgences Nephrologiques et Transplantation Renale | Hertig A.,University Pierre and Marie Curie
BMJ Case Reports | Year: 2012

We report the case of a 70-year-old woman who developed life-threatening arrhythmia as a result of acute and severe hypokalaemia, which she developed after consuming large quantities of a liquorice-rich herb tea. She had no previous heart condition. We also discuss the legislative discrepancy in both the USA and in Europe, whereby consumers are warned about the risk of chronic hypertension whenever they buy a product containing liquorice, yet the risk of hypokalaemia may not be mentioned at all. Copyright 2012 BMJ Publishing Group. All rights reserved.


PubMed | French Institute of Health and Medical Research, Urgences Nephrologiques et Transplantation Renale and University Pierre and Marie Curie
Type: Journal Article | Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | Year: 2014

The epithelial response to injury is stereotypical and reminiscent of epithelial-to-mesenchymal transitions (EMTs), such as those observed during embryogenesis and tumour metastasis. In the context of solid organ transplantation, EMT-like features are often acquired by epithelial cells and are predictive of graft fibrosis. Here, we studied the possible involvement of several major transcriptional regulators, including snail1, phospho-Smad 2/3 and zeb1, in EMT induction in human renal grafts.We used immunohistochemistry to detect the presence of these EMT transcriptional regulators along with that of two validated EMT markers (intra-cytoplasmic translocation of -catenin, de novo expression of vimentin), in 103 renal graft biopsy samples taken for routine surveillance or for a clinical indication.We observed the nuclear accumulation of snail1 and phospho-smad2/3 in tubular cells displaying EMT. The level of snail1 was significantly correlated with the scores of EMT markers (-catenin: = 0.94, P < 0.0001; vimentin: = 0.93, P < 0.0001) and with deteriorated graft function and proteinuria at the time of biopsy. Furthermore, intense staining for both snail1 and vimentin in tubular cells (10% of tubules) was predictive of graft dysfunction 21 months post-biopsy, independently of the other known risk factor for long-term graft dysfunction. In contrast, in both normal and diseased graft, zeb1 expression was detected exclusively in the endothelial cells of glomeruli and peritubular capillaries.This study suggests that snail1 is closely related to the fibrogenic, EMT-like response of the tubular epithelium in human renal grafts and predictive of graft function loss.


Dubert M.,Urgences Nephrologiques et Transplantation Renale
BMJ case reports | Year: 2012

Antibiotics reduce the commensal flora in the gut, thereby facilitating the overgrowth of undesirable microorganisms such as Candida albicans. Here, we report the case of a 48-year-old woman with a history of obstructive uropathy consecutive to a radiation therapy, in whom both indwelling ureteral stents were rapidly occluded by fungal mycelia, resulting in a rapidly progressive kidney failure. Ascendant infection by C albicans had occurred after a 2- week course of antibiotics, prescribed for a perforative peritonitis also due to radiation-induced colitis. As shown by iterative CT scans made before (at the time of the diagnosis of peritonitis) and after the antibiotic course, kidney failure was explained by a sudden and bilateral pyelocaliceal dilation, due to the obstruction of the ureteral stents. Fungal mycelia were objectivised during the replacement procedure. Intravenous fluconazole was started, and renal function recovered ad integrum with the relief of the obstruction.


Lemaignen A.,Urgences Nephrologiques et Transplantation Renale | Ridel C.,Urgences Nephrologiques et Transplantation Renale | Hertig A.,Urgences Nephrologiques et Transplantation Renale | Rondeau E.,Urgences Nephrologiques et Transplantation Renale
Nephrologie et Therapeutique | Year: 2013

Hemolytic and uremic syndrome (HUS) is the most feared complication of infections with enterohemorrhagic Escherichia coli. During summer 2011, Europe was the scene of a large outbreak of shiga-toxin producing E. coli gastroenteritis, occasioning more than 800 cases of HUS, highlighting this public health problem. Last years, many advances have occurred, on the physiopathology, microbiology or therapeutics. We review here these different aspects, from molecular identification of the German bacteria, to the use of targeted therapies as eculizumab in severe forms, or even the major role of complement activation in the physiopathology of HUS. © 2012 Published by Elsevier Masson SAS on behalf of the Association Société de néphrologie.

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