Publications by authors named "Magali Colombat"

53 Publications

Administration of the High-Density Lipoprotein Mimetic CER-001 for Inherited Lecithin-Cholesterol Acyltransferase Deficiency.

Ann Intern Med 2021 Mar 2. Epub 2021 Mar 2.

Institut National de la Science et de la Recherche Médicale, INSERM U1297-Institut des Maladies Métaboliques et Cardiovasculaires, and Université Paul Sabatier-Toulouse III, Toulouse, France.

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http://dx.doi.org/10.7326/L20-1300DOI Listing
March 2021

Mass spectrometry-based proteomic analysis of parathyroid adenomas reveals PTH as a new human hormone-derived amyloid fibril protein.

Amyloid 2021 Feb 13:1-5. Epub 2021 Feb 13.

Laboratoire de Génétique Moléculaire, Fédération de Génétique, Hôpital Necker-Enfants Malades, APHP.CUP, Université de Paris, Paris, France.

Background: Congo red-positive material was described in normal and diseased parathyroids (adenoma and hyperplasia) 50 years ago. However, the incidence and the clinical significance of such observation are unknown, and the causal fibril protein has never been convincingly demonstrated.

Methods: We conducted the present study including an exceptional case report accompanied with a retrospective study of 105 parathyroid adenomas. We used histopathological, immunohistochemical, ultrastructural, mass spectrometry-based proteomic analysis of parathyroid adenoma tissue samples, and genetic analysis.

Results: We describe a 57-year-old man with mild hypercalcemia and elevated parathyroid hormone (PTH) level for whom histopathological analysis revealed a parathyroid adenoma associated with nodular typical amyloid deposits. Tandem mass spectrometry after laser microdissection (LMD-MS) of amyloid adenoma identified PTH as the fibril protein, and no germline mutation in the gene was detected. Congo red-positive PTH-deposits were further observed in 6.6% of the parathyroid adenomas analyzed, and were associated with complete/incomplete or absent universal amyloid signature, but with fibrillar morphology at ultrastructural level.

Conclusions: Inappropriate PTH production leads to progressive disease-amyloid aggregation of PTH in a subset of parathyroid adenomas, providing new insights into the pathophysiology of this condition and adding PTH to the list of amyloid protein derived from hormones.
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http://dx.doi.org/10.1080/13506129.2021.1885023DOI Listing
February 2021

Do anti-IL-6R blockers have a beneficial effect in the treatment of antibody-mediated rejection resistant to standard therapy after kidney transplantation?

Am J Transplant 2020 Nov 3. Epub 2020 Nov 3.

Department of Nephrology and Organ Transplant, CHU Toulouse Rangueil, Toulouse, France.

Antibody-mediated rejection (AMR) that resists to standard of care (SOC) therapy remains a major challenge after kidney transplantation and leads to graft failure in a majority of cases. The use of anti-IL6 receptor antibodies was suggested to treat chronic antibody-mediated rejection (cAMR) after failure of classical treatments. We treated nine patients with AMR resistant to apheresis, rituximab, and intravenous immunoglobulins, with a monthly infusion of tocilizumab and compared them with a historical cohort of 37 patients with similar clinical, immunological, and histological characteristics. The 1-year graft survival and the decline in renal function did not differ between patients who received tocilizumab and those who did not. Histological follow-up showed that despite a decrease in inflammation and tubulitis scores after tocilizumab, the course of antibody-mediated lesions and chronic glomerulopathy were similar in both groups. In our study, the addition of monthly infusions of tocilizumab did not alter the course of AMR that resist to SOC therapy. Large randomized studies are urgently needed to assess the effect of tocilizumab in this context.
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http://dx.doi.org/10.1111/ajt.16391DOI Listing
November 2020

Confocal LASER endomicroscopy in Niemann-Pick disease type B.

Eur Respir J 2021 Feb 4;57(2). Epub 2021 Feb 4.

Service de Pneumologie, Hôpital Larrey, Université Paul Sabatier, CHU Toulouse, Toulouse, France.

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http://dx.doi.org/10.1183/13993003.02306-2020DOI Listing
February 2021

Gateway and journey of patients with cardiac amyloidosis.

ESC Heart Fail 2020 10 26;7(5):2418-2430. Epub 2020 Jun 26.

Department of Cardiology, Rangueil University Hospital, Toulouse, France.

Aims: Advances have been made over the last decade in the management of cardiac amyloidosis (CA), but a delayed diagnosis is still common. The aim of this study was to describe the journey to CA diagnosis from initial clinical and to analyse time to diagnosis.

Methods And Results: Between January 2001 and May 2019, 270 consecutive patients with CA diagnosed at Toulouse University Hospital were retrospectively included in this cross-sectional study: 111 (41%) light chain amyloidosis, 122 (45%) wild-type transthyretin amyloidosis, and 37 (14%) hereditary transthyretin amyloidosis. CA onset occurred mostly with dyspnoea (50%) or systematic follow-up (10%). The cardiologist was the first line specialist in 68% of patients, followed by the nephrologist (9%) and neurologist (8%). Patients encountered a median (minimum-maximum) number of two (1-7) physician specialists and performed a median (minimum-maximum) number of three (1-8) tests before diagnosis. Median delay between symptom onset and CA diagnosis was 8 [IQR 5-14], 10 [IQR 3-34], and 18 [IQR 4-49] months, respectively, in light chain amyloidosis, wild-type transthyretin amyloidosis, and hereditary transthyretin amyloidosis subgroups (P = .060). Having performed electromyography or spirometry was associated with a longer delay in diagnosis in the overall population: odds ratio = 1.13; 95% confidence interval 1.02 to 1.24; and odds ratio = 1.13; 1.03 to 1.24, respectively, probably due to non-specific initial symptoms.

Conclusions: CA is a protean disease with various first line specialists causing a diagnostic wandering despite increasing medical community awareness. It requires a multidisciplinary specialist care networks to educate and manage symptoms and therapies.
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http://dx.doi.org/10.1002/ehf2.12793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524246PMC
October 2020

New clinical forms of hereditary apoA-I amyloidosis entail both glomerular and retinal amyloidosis.

Kidney Int 2020 07 23;98(1):195-208. Epub 2020 Apr 23.

Laboratoire de Génétique Moléculaire, Fédération de Génétique, Hôpital Necker-Enfants Malades, Université de Paris, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address:

Apolipoprotein A1 amyloidosis (ApoAI) results from specific mutations in the APOA1 gene causing abnormal accumulation of amyloid fibrils in diverse tissues. The kidney is a prominent target tissue in ApoAI amyloidosis with a remarkable selectivity for the renal medulla. Here, we investigated six French families with ApoAI Glu34Lys, p.His179Profs∗47, and a novel p.Thr185Alafs∗41 variant revealing unprecedented clinical association of a glomerular with a retinal disease. Comprehensive clinicopathological, molecular and proteomics studies of numerous affected tissues ensured the correlation between clinical manifestations, including novel unrecognized phenotypes, and apoA-I amyloid deposition. These ophthalmic manifestations stemmed from apoA-I amyloid deposition, highlighting that the retina is a previously unrecognized tissue affected by ApoAI amyloidosis. Our study provides the first molecular evidence that a significant fraction of ApoAI amyloidosis cases with no family history result from spontaneous neomutations rather than variable disease penetrance. Finally, successful hepatorenal transplantation resulted in a life- and vision-saving measure for a 32-year-old man with a hitherto unreported severe ApoAI amyloidosis caused by the very rare Glu34Lys variant. Our findings reveal new modes of occurrence and expand the clinical spectrum of ApoAI amyloidosis. The awareness of glomerular and ocular manifestations in ApoAI amyloidosis should enable earlier diagnosis and avoid misdiagnosis with other forms of renal amyloidosis. Thus, documented apoA-I amyloid deposition in the retina offers new biological information about this disease and may change organ transplantation practice to reduce retinal damage in patients with ApoAI amyloidosis.
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http://dx.doi.org/10.1016/j.kint.2020.03.033DOI Listing
July 2020

Paraffin Immunofluorescence Increases Light-Chain Detection in Extra-Renal Light Chain Amyloidosis and Other Light-Chain-Associated Diseases.

Arch Pathol Lab Med 2021 Mar;145(3):352-358

From the Université de Lille, CNRS, Inserm, CHU Lille, Pathology Department, Centre de Biologie Pathologie, UMR9020 - UMR-S 1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France (Gibier, Gnemmi).

Context.—: Distinguishing the different types of amyloid is clinically important because treatments and outcomes are different. Mass spectrometry is the new gold standard for amyloid typing, but it is costly and not widely available. Therefore, immunolabeling remains the first step in identifying the most common types of amyloidosis. In amyloid subtyping, direct immunofluorescence works well when applied to frozen sections, but immunohistochemistry on formalin-fixed, paraffin-embedded material often yields poor results, particularly for light chain amyloidosis. Recently, paraffin immunofluorescence has been described as a valuable salvage technique in renal pathology when frozen sections are not available but it has not been evaluated for extra-renal diseases.

Objectives.—: To evaluate the use of paraffin immunofluorescence for light-chain detection in extra-renal amyloidosis and other light-chain-associated diseases.

Design.—: First, we compared the staining intensity of both light chains between paraffin immunofluorescence and immunohistochemistry on a retrospective cohort of 28 cases of amyloidosis that have been previously typed. Then, we studied the role of paraffin immunofluorescence as an addition to our classical immunohistochemistry panel for amyloidosis typing.

Results.—: In the retrospective cohort, we found that paraffin immunofluorescence outperformed immunohistochemistry for light-chain detection. Then, in the prospective part of the study, we showed that the proportion of correctly classified cases increased from 50% to 71.9% with the adjunction of second-intention paraffin immunofluorescence to the immunohistochemistry procedure.

Conclusions.—: We therefore view paraffin immunofluorescence as a significant addition to the routine workflow for detection of light-chain-related diseases.
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http://dx.doi.org/10.5858/arpa.2020-0018-OADOI Listing
March 2021

Diffuse alveolar haemorrhage secondary to e-cigarette "vaping" associated lung injury (EVALI) in a young European consumer.

Eur Respir J 2020 07 16;56(1). Epub 2020 Jul 16.

Service de Pneumologie, Hôpital Larrey, Université Paul Sabatier, CHU Toulouse, Toulouse, France.

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http://dx.doi.org/10.1183/13993003.00143-2020DOI Listing
July 2020

An 80-Year-Old Woman With a Solitary Pulmonary Nodule.

Chest 2020 03;157(3):e85-e89

Pathology Department, Centre de Biologie Pathologie, University of Lille, CHU Lille, Lille, France.

Case Presentation: An 80-year-old-woman was referred for evaluation of chest pain that appeared after providing care at home for her sick husband, which included helping him to get up and move about. The pain was initially triggered by lifting heavy objects but then became constant, without exacerbating or relieving factors. The pain was located in the left hemithorax and was not associated with shortness of breath or cough. Because the patient did not feel any better after a month, her general practitioner ordered a radiograph, which revealed a suspicious pulmonary nodule in the left upper lobe. She was a lifelong nonsmoker and denied any drug abuse. She had not been professionally exposed to lung carcinogens. She had a medical history of type 2 diabetes, ischemic cardiomyopathy, and renal artery stenosis. Her father died of lung cancer. She resided in Lille, France, and did not report any recent travel.
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http://dx.doi.org/10.1016/j.chest.2019.10.056DOI Listing
March 2020

Anti-IL-2R blockers comparing with polyclonal antibodies: Higher risk of rejection without negative mid-term outcomes after ABO-incompatible kidney transplantation.

Clin Transplant 2019 10 8;33(10):e13681. Epub 2019 Sep 8.

Department of Nephrology and Organ Transplant, CHU Rangueil, Toulouse, France.

There is no recommendation regarding the type of induction therapy to use in ABO-incompatible (ABOi) kidney transplantation. The aim of this retrospective study was to compare the outcome of ABOi living donor kidney transplant (LDKT) recipients who received either polyclonal antibodies or anti-interleukin-2 receptor (IL-2R) blockers as an induction agent. All ABOi HLA-compatible patients that received a LDKT between 03/11 and 03/18 in three French transplantation center (Paris Saint-Louis, Paris Necker, and Toulouse) were included in the study. Fifty-eight patients were given polyclonal antibodies and 39 patients received anti-IL-2R blockers. We identified by a Cox proportional hazard model the use of polyclonal antibodies as a protective factor against acute rejection (HR = 0.4, 95%CI [0-0.9], P < .05). However, pathological findings on protocol biopsies at 1 year were similar in both groups, as were patient and graft survivals, renal function, and complications. We conclude that the acute rejection rate was significantly higher in patients given anti-IL-2R blockers compared to polyclonal antibodies. However, in our series, there was no negative impact on mid-term outcome.
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http://dx.doi.org/10.1111/ctr.13681DOI Listing
October 2019

A transgenic mouse model reproduces human hereditary systemic amyloidosis.

Kidney Int 2019 09 28;96(3):628-641. Epub 2019 Mar 28.

Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France. Electronic address:

Amyloidoses are rare life-threatening diseases caused by protein misfolding of normally soluble proteins. The fatal outcome is predominantly due to renal failure and/or cardiac dysfunction. Because amyloid fibrils formed by all amyloidogenic proteins share structural similarity, amyloidoses may be studied in transgenic models expressing any amyloidogenic protein. Here we generated transgenic mice expressing an amyloidogenic variant of human apolipoprotein AII, a major protein of high density lipoprotein. According to amyloid nomenclature this variant was termed STOP78SERApoAII. STOP78SER-APOA2 expression at the physiological level spontaneously induced systemic amyloidosis in all mice with full-length mature STOP78SER-ApoAII identified as the amyloidogenic protein. Amyloid deposits stained with Congo red were extracellular, and consisted of fibrils of approximately 10 nm diameter. Renal glomerular amyloidosis was a major feature with onset of renal insufficiency occurring in mice older than six months of age. The liver, heart and spleen were also greatly affected. Expression of STOP78SER-APOA2 in the liver and intestine in mice of the K line but not in other amyloid-laden organs showed they present systemic amyloidosis. The amyloid burden was a function of STOP78SER-APOA2 expression and age of the mice with amyloid deposition starting in two-month-old high-expressing mice that died from six months onwards. Because STOP78SER-ApoAII conserved adequate lipid binding capacity as shown by high STOP78SER-ApoAII amounts in high density lipoprotein of young mice, its decrease in circulation with age suggests preferential deposition into preformed fibrils. Thus, our mouse model faithfully reproduces early-onset hereditary systemic amyloidosis and is ideally suited to devise and test novel therapies.
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http://dx.doi.org/10.1016/j.kint.2019.03.013DOI Listing
September 2019

Atrial fibrillation and subtype of atrial fibrillation in cardiac amyloidosis: clinical and echocardiographic features, impact on mortality.

Amyloid 2019 Sep 7;26(3):128-138. Epub 2019 Jun 7.

a Department of Cardiology, Rangueil University Hospital , Toulouse , France.

Atrial fibrillation (AF) commonly affects patients with cardiac amyloidosis (CA). Amyloid deposition within the left atrium may be responsible for the subtype of AF in either permanent or non-permanent form. The prognostic implications of AF and its clinical subtype according to the type of CA are still controversial in this population. This study sought to investigate the prevalence, incidence and prognostic implications of AF and the clinical subtype of AF (permanent or non-permanent) in patients with CA. Two hundred and thirty-eight patients with CA and full medical records were retrospectively enrolled in the study: About 115 (48%) with light chain (AL) amyloidosis and 123 (52%) with transthyretin amyloidosis (ATTR). Patient's medical records were reviewed to establish baseline prevalence, incidence and impact on all-cause and cardiovascular mortality during follow-up of AF. One hundred and four (44%) patients had history of AF at the time of diagnosis: 62 (60%) permanent and 42 (40%) non-permanent. There were 30 (26%) and 74 (60%) patients with history of AF among patients with AL and ATTR (including 5 hereditary and 69 wild-type), respectively (<.0001). During the follow-up, 48 new patients developed AF (29, 12 and 7 among patients with AL, wild-type ATTR and hereditary ATTR). After adjustment for age, survival was similar in patients with or without history of AF (HR 0.87 (95% CI, 0.60 to 1.27;  = .467). AF had no impact on cardiovascular mortality. Among the 152 patients with history of AF included in the whole study, there were 75 (49%) patients with permanent AF. After adjustment for age, survival was similar in patients with permanent and non-permanent AF: HR 1.29 (95% CI, 0.84 to 1.99;  = .251). The results were the same among patients with AL or wild-type amyloidosis. Subtype of AF had no impact on cardiovascular mortality. AF is common in patients with CA. However, AF and clinical subtype of AF have no impact on all-cause mortality, whatever the type of amyloidosis.
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http://dx.doi.org/10.1080/13506129.2019.1620724DOI Listing
September 2019

Proteomic evidence of specific IGKV1-8 association with cystic lung light chain deposition disease.

Blood 2019 06 9;133(26):2741-2744. Epub 2019 Apr 9.

Département d'Anatomie Pathologique, Institut Universitaire du Cancer, Toulouse, France.

We previously reported a new form of light chain deposition disease (LCDD) presenting as diffuse cystic lung disorder that differs from the usual systemic form with respect to patient age, the male/female ratio, the involved organs, and the hematologic characteristics. We also demonstrated that the light chains were produced by an intrapulmonary B-cell clone and that this clone shared a stereotyped antigen receptor IGHV4-34/IGKV1. However, we only analyzed 3 patients. We conducted a retrospective study including lung tissue samples from 24 patients with pulmonary LCDD (LCDD) matched with samples from 13 patients with pulmonary κ light chain amyloidosis (AL amyloidosis) used as controls. Mass spectrometry-based proteomics identified immunoglobulin κ peptides as the main protein component of the tissue deposits in all patients. Interestingly, in LCDD, IGKV1 was the most common κ family detected (86.4%), and IGKV1-8 was overrepresented compared with AL amyloidosis (75% vs 11.1%, = .0033). Furthermore, IGKV1-8 was predominantly associated with a diffuse cystic pattern (94%) in LCDD. In conclusion, the high frequency of IGKV1-8 usage in cystic LCDD constitutes an additional feature arguing for a specific entity distinct from the systemic form that preferentially uses IGKV4-1.
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http://dx.doi.org/10.1182/blood.2019898577DOI Listing
June 2019

Proteomics in Kidney Allograft Transplantation-Application of Molecular Pathway Analysis for Kidney Allograft Disease Phenotypic Biomarker Selection.

Proteomics Clin Appl 2019 03 4;13(2):e1800091. Epub 2019 Feb 4.

Nephrology - Transplantation Department, UMR_S. INSERM UMR_S 1109, ImmunoRhumatologie Moléculaire, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg, Institut d'Immunologie et d'Hématologie, 67085, Strasbourg, France.

There is a need for accurate, robust, non-invasive methods to provide early diagnosis of graft lesions after kidney transplantation. A multitude of proteomic biomarkers for the major kidney allograft disease phenotypes defined by the BANFF classification criteria have been described in literature. None of these biomarkers have been established in the clinic. A key reason for this is the lack of clinical validation which is difficult, as even the gold standard of diagnosis, kidney biopsy, is often ambiguous. The semantic clustering by ReviGO on top of transcriptomic pathway analysis is evaluated to connect histological and transcriptomic kidney allograft disease characteristics with proteomic biomarker qualification. By using public data generated in microarray studies of kidney allograft tissue, biological processes and key molecules specifically associated with the different kidney allograft disease phenotypes are identified. Semantic clustering holds the promise to guide adaptation of proteomic marker panels to molecular pathology. This can support the development of noninvasive tests (e.g. in urine, by capillary electrophoresis mass spectrometry) that simultaneously detect diverse kidney allograft phenotypes with high accuracy and sensitivity.
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http://dx.doi.org/10.1002/prca.201800091DOI Listing
March 2019

Vitreous amyloidosis with autonomic neuropathy of the digestive tract associated with a novel transthyretin p.Gly87Arg variant in a Bangladeshi patient: a case report.

J Med Case Rep 2017 Aug 13;11(1):222. Epub 2017 Aug 13.

Department of Ophthalmology, Hôpital Cochin, AP-HP, Université Paris-Descartes, 75014, Paris, France.

Background: Hereditary transthyretin amyloidosis is an autosomal dominant inherited disorder, first described in families with sensorimotor and autonomic neuropathy. Since its first description, more than 120 amyloidogenic transthyretin mutations have been reported with various geographic distributions and associated with a wide range of phenotypes involving the peripheral nerve, the heart, the gastrointestinal tract, the eyes, the central nervous system, or the kidneys. In some cases of transthyretin amyloidosis, the first clinical manifestation is vitreous opacity.

Case Presentation: A 46-year-old Bangladeshi woman presented with vitreous amyloidosis and progressive autonomic neuropathy of the digestive tract as initial clinical manifestations, with no clinical evidence of cardiac, renal, central nervous system, or peripheral nerve dysfunction. A novel transthyretin mutation, p.Gly87Arg, was identified in the heterozygous state in this proband of Bangladeshi origin. Histological examination of accessory salivary glands and gastric biopsies revealed Congo-red-positive deposits. Laser microdissection of salivary gland Congo-red deposits and tandem mass spectrometry-based proteomic analysis identified the mutated transthyretin peptide containing the arginine residue at position 87 of the mature protein.

Conclusions: Vitreous amyloidosis should be considered a differential diagnosis of uveitis, in particular transthyretin amyloidosis. Proteomics data from our case, consistent with the genetic findings, highly suggests that this new p.Gly87Arg variant is amyloidogenic. Here, we described the second case of transthyretin amyloidosis reported in a Bangladeshi patient.
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http://dx.doi.org/10.1186/s13256-017-1407-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554541PMC
August 2017

Sequential cyclophosphamide-bortezomib-dexamethasone unmasks the harmful cardiac effect of dexamethasone in primary light-chain cardiac amyloidosis.

Eur J Cancer 2017 05 20;76:183-187. Epub 2017 Mar 20.

Paris XII University, UPEC, Créteil, France; GRC Amyloid Research Institute, IMRB-INSERM U955, and Mondor Amyloidosis Network, Créteil, France; Department of Cardiology, AP-HP, Henri-Mondor Hospital, Créteil, France; DHU ATVB, Créteil, France; Inserm Clinical Investigation Center 1430, Créteil, F-94000, France. Electronic address:

Chemotherapy combining cyclophosphamide, bortezomib and dexamethasone is widely used in light-chain amyloidosis. The benefit is limited in patients with cardiac amyloidosis mainly because of adverse cardiac events. Retrospective analysis of our cohort showed that 39 patients died with 42% during the first month. A new escalation-sequential regimen was set to improve the outcomes. Nine newly-diagnosed patients were prospectively treated with close monitoring of serum N-terminal pro-brain natriuretic peptide, troponin-T and free light chains. The results show that corticoids may destabilise the heart through fluid retention. Thus, a sequential protocol may be a promising approach to treat these patients.
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http://dx.doi.org/10.1016/j.ejca.2017.02.004DOI Listing
May 2017

(99m)Tc-HMDP scintigraphy rectifies wrong diagnosis of AL amyloidosis.

J Nucl Cardiol 2015 Aug 22;22(4):853-7. Epub 2015 May 22.

UPEC, 94000, Créteil, France,

A 71-year-old African man without history of cardiac disease was referred to our center for dyspnea. Transthoracic echocardiogram and cardiac MRI were suggestive of cardiac amyloidosis (CA). The diagnosis of the light-chain cardiac amyloidosis (AL-CA) was made after a first endomyocardial biopsy. Accordingly chemotherapy was started. Systematic 99mTc-HMDP scintigraphy showed moderate cardiac uptake (visual score of 2), unusual for AL-CA, and permitted to rectify the diagnosis. Hereditary transthyretin cardiac amyloidosis was confirmed by a second endomyocardial biopsy with a positive Congo-red and anti-transthyretin antibody stainings, mass spectrometry and genetic analysis (Val122Ile mutation).
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http://dx.doi.org/10.1007/s12350-015-0176-6DOI Listing
August 2015

Eculizumab for treatment of rapidly progressive C3 glomerulopathy.

Am J Kidney Dis 2015 Mar 17;65(3):484-9. Epub 2014 Dec 17.

INSERM, UMR-S 1064, and Department of Nephrology and Immunology, CHU de Nantes, Nantes, France. Electronic address:

C3 glomerulopathy (C3G) is a prototypic complement-mediated kidney disease. Rapidly progressive forms of C3G usually respond poorly to conventional treatments. We report on the efficacy of the terminal complement inhibitor eculizumab in 3 adult patients with rapidly progressive C3G. In all 3 patients, serum creatinine levels had increased by >50% in the 2 months preceding initiation of eculizumab treatment despite the use of conventional immunosuppressive drugs and/or plasma exchanges in 2 of these individuals. Of note, 2 patients had long-standing nephrotic syndrome. Kidney biopsy performed prior to eculizumab treatment disclosed marked glomerular inflammatory changes and increased C5b-9 deposition in all patients. Eculizumab use was associated with significant improvement in kidney function, with estimated glomerular filtration rates of patients increasing 22 to 38 mL/min/1.73 m(2). Eculizumab use also was associated with remission of nephrotic syndrome in the 2 affected patients, an effect observed as early as one week after treatment initiation. Repeat kidney biopsy disclosed regression of glomerular inflammatory changes and decreases in glomerular staining for C5b-9 in all patients. These results warrant further assessment of eculizumab for treatment of rapidly progressive forms of C3G with markedly increased glomerular C5b-9 deposits.
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http://dx.doi.org/10.1053/j.ajkd.2014.09.025DOI Listing
March 2015

Recurrent RAS and PIK3CA mutations in Erdheim-Chester disease.

Blood 2014 Nov 22;124(19):3016-9. Epub 2014 Aug 22.

Department of Internal Medicine & French Reference Center for Rare Auto-immune & Systemic Diseases, Hôpital Pitié-Salpêtrière Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France; Pierre and Marie Curie University, Paris, France;

Erdheim-Chester disease (ECD) is a rare histiocytic disorder that is challenging to diagnose and treat. We performed molecular analysis of BRAF in the largest cohort of ECD patients studied to date followed by N/KRAS, PIK3CA, and AKT1 mutational analysis in BRAF wild-type patients. Forty-six of 80 (57.5%) of patients were BRAFV600E-mutant. NRAS mutations were detected in 3 of 17 ECD BRAFV600E wild-type patients. PIK3CA mutations (p.E542K, p.E545K, p.A1046T, and p.H1047R) were detected in 7 of 55 patients, 4 of whom also had BRAF mutations. Mutant NRAS was present in peripheral blood CD14(+) cells, but not lymphoid cells, from an NRASQ61R mutant patient. Our results underscore the central role of RAS-RAF-MEK-ERK activation in ECD and identify an important role of activation of RAS-PI3K-AKT signaling in ECD. These results provide a rationale for targeting mutant RAS or PI3K/AKT/mTOR signaling in the subset of ECD patients with NRAS or PIK3CA mutations.
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http://dx.doi.org/10.1182/blood-2014-04-570937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224196PMC
November 2014

Lung transplantation for advanced cystic lung disease due to nonamyloid kappa light chain deposits.

Ann Am Thorac Soc 2014 Sep;11(7):1025-31

1 Service de Pneumologie, Groupe de Transplantation Pulmonaire, Nouvel Hôpital Civil, and.

Rationale: Cystic lung light chain deposition disease (LCDD) is a severe and rare form of nonamyloid kappa light chain deposits localized in the lung, potentially leading to end-stage respiratory insufficiency.

Objectives: To assess the outcome after lung transplantation (LT) in this setting with particular attention to disease recurrence.

Methods: We conducted a retrospective multicenter study of seven patients who underwent LT for cystic lung LCDD in France between September 1992 and June 2012 in five centers.

Measurements And Main Results: In total, five females and two males (mean age, 39.1 ± 5.3 yr) underwent one single LT or seven double LT (one retransplantation). Before LT, the patients showed a constant obstructive ventilatory pattern with low carbon monoxide diffusing capacity and resting hypoxemia. Lung computed tomography revealed widespread cysts with occasional micronodulations. No extrapulmonary disease or plasma cell neoplasm was detected. The serum-free kappa/lambda light chain ratio was increased in three cases. The median follow-up after LT was 56 months (range, 1-110 mo). Kaplan-Meier survival was 85.7, 85.7, and 64.3% at 1, 3, and 5 years, respectively. Three patients died from multiorgan failure (n = 1), chronic rejection (n = 1), and breast cancer (n = 1) at 23 days, 56 months, and 96 months, respectively. At the end of follow-up, no patients showed recurrence on imaging or histopathology.

Conclusions: This small case series confirms that cystic lung LCDD is a severe disease limited to the lung, affecting mostly young females. LT appears to be a good therapeutic option allowing for satisfactory long-term survival. We found no evidence of recurrence of the disease after LT.
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http://dx.doi.org/10.1513/AnnalsATS.201404-137OCDOI Listing
September 2014

Cystic fibrosis and AA amyloidosis: a survey in the French cystic fibrosis network.

Amyloid 2014 Dec 23;21(4):231-7. Epub 2014 Jul 23.

Centre de Reference pour les Amyloses d'Origine Inflammatoire et de la Fièvre Mediterraneenne Familiale, Service de Medecine Interne, Assistance Publique - Hôpitaux de Paris, Hôpital Tenon , Paris France .

Introduction: To define the characteristics of CF patients developing AA amyloidosis.

Methods: A 30-year retrospective survey conducted within the national French CF network to identify cases of CF associated with AA amyloidosis.

Results: Nine cases of AA amyloidosis were identified (CF prevalence in France is approximately 6000 patients) and sufficient data were collected in six. The clinical presentation was renal disease in four cases, a compressive goiter in one case, and epigastric pain in one case. Organ involvement included kidney disease in all cases (proteinuria, with a median age at onset of 24 years, 4 cases with nephrotic syndrome, 5 with renal failure); gastrointestinal (4 cases with duodenal ulcer); thyroid (2 cases); and hepatobiliary system (3 cases). The median age at diagnosis of CF was 6.5 years. Five patients had pancreatic insufficiency. All patients had chronic respiratory infections requiring intravenous antibiotics several times a year. Five patients have died, at a median age of 29 years and a median duration of 6 years after the onset of proteinuria.

Conclusion: AA amyloidosis is a rare but morbid complication of CF. Renal involvement is predominant.
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http://dx.doi.org/10.3109/13506129.2014.943834DOI Listing
December 2014

Histologic reconstruction of bronchiolar lesions in lung transplant patients with bronchiolitis obliterans syndrome.

Am J Surg Pathol 2014 Aug;38(8):1157-8

*Service d'anatomie pathologique §Service de pneumologie, Hôpital Foch Suresnes †Hôpital Hautepierre, Service de pneumologie, Strasbourg ‡APHP, Hôpital Bichat, Service de pneumologie, Paris, France.

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http://dx.doi.org/10.1097/PAS.0000000000000181DOI Listing
August 2014

Epithelial phenotypic changes are associated with a tubular active fibrogenic process in human renal grafts.

Hum Pathol 2013 Jul 17;44(7):1251-61. Epub 2013 Jan 17.

AP-HP, Hôpital Tenon, Urgences Néphrologiques & Transplantation Rénale, F-75020, Paris, France; INSERM, UMR S 702, F-75020, Paris, France.

Some recently published works contest the epithelial origin of myofibroblasts, which are the major extracellular matrix producers. However, our previous studies showed that, in tubular cells, some phenotypic changes reminiscent of epithelial-to-mesenchymal transition constitute an interesting early marker that predicts the progression of fibrosis in renal grafts. We hypothesized that activated epithelial cells could directly contribute to fibrogenesis, although they remain within the tubules. Using immunohistochemistry, we studied the association between epithelial phenotypic changes (de novo expression of vimentin and intracellular translocation of β-catenin) and the production of profibrotic molecules (connective tissue growth factor, HSP47, and laminin), in tubular epithelial cells from 93 renal grafts biopsied of 77 patients. We observed the de novo production of connective tissue growth factor, HSP47, and laminin in the tubular epithelial cells displaying epithelial phenotypic changes. The score of vimentin was significantly correlated with those of connective tissue growth factor (r = 0.785, P < .0001), HSP47 (r = 0.887, P < .0001), and laminin (r = 0.836, P < .0001). The level of tubular expression of mesenchymal cell markers and profibrogenic molecules, but not graft histologic lesions according to Banff acute or chronic scores, was correlated with graft dysfunction and proteinuria at the time of biopsy (r = -0.611, P < .0001 for vimentin with estimated glomerular filtration rate) (r = 0.42, P = .0006 for vimentin with proteinuria). Our results demonstrate that the epithelial phenotypic switch is associated with an active fibrogenic process in tubular epithelial cells and with graft injury indicators. Perpetuation of this tissue injury-repair response may drive fibrogenesis in renal grafts. This "repair response" represents an interesting marker for renal graft surveillance.
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http://dx.doi.org/10.1016/j.humpath.2012.10.010DOI Listing
July 2013

Dramatic beneficial effect of interleukin-1 inhibitor treatment in patients with familial Mediterranean fever complicated with amyloidosis and renal failure.

Nephrol Dial Transplant 2012 May 19;27(5):1898-901. Epub 2011 Sep 19.

Service de Médecine Interne, Hôpital Tenon, Assistance Publique Hôpitaux de Paris (AP-HP), Université Paris 6 Pierre et Marie Curie (UPMC), Paris, France.

Background: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder, for which systemic AA amyloidosis is the major complication revealed most of the time by renal abnormalities. Current treatment is daily colchicine that prevents both recurrent inflammatory attacks and amyloidosis deposition in most patients. However, some patients still develop amyloidosis and renal failure. Functional studies suggest that interleukin (IL)-1 is implicated in the inflammatory reaction in FMF and therefore, IL-1 inhibitors could be a new approach to treat FMF. The aim of this series study was to evaluate anakinra in patients with FMF complicated with amyloidosis and renal failure.

Methods: We studied a series of adult patients with FMF complicated with amyloidosis and treated with anakinra in one reference centre were reviewed. A search for published patients with FMF associated amyloidosis treated with anakinra was performed by screening PubMed.

Results: We report four cases of patients with FMF-associated amyloidosis treated with anakinra and discuss the clinical pertinence of its use in these particular clinical settings.

Conclusions: Anakinra has a strong effect on both inflammatory attacks and general status in patients with FMF-associated amyloidosis. It may contribute to changing the prognosis of these patients. Long-term studies are needed to appreciate the effect of anakinra or other IL-1 inhibitors on the natural history of amyloidosis in these patients.
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http://dx.doi.org/10.1093/ndt/gfr528DOI Listing
May 2012

Tubular nuclear accumulation of Snail and epithelial phenotypic changes in human myeloma cast nephropathy.

Hum Pathol 2011 Aug 11;42(8):1142-8. Epub 2011 Feb 11.

AP-HP, Hôpital Tenon, Urgences Néphrologiques & Transplantation Rénale, F-75020 Paris, France.

The transcription factor Snail is an important repressor of E-cadherin gene expression. It plays a key role in the induction of epithelial-mesenchymal transition, an essential process important not only in embryonic development and tumor progression but also in organ fibrogenesis. We studied the expression of Snail by immunohistochemistry, along with several epithelial phenotypic changes suggestive of epithelial-mesenchymal transition, in 14 patients with multiple myeloma cast nephropathy. This nephropathy is characterized by a rapid progression toward fibrosis. As controls, we used normal kidneys and kidneys from patients displaying an idiopathic nephrotic syndrome, a syndrome unassociated with renal fibrosis. We discovered that, in all patients with multiple myeloma nephropathy, a drastic accumulation of Snail is seen in the nuclei from tubular epithelial cells showing epithelial phenotypic changes. In contrast, normal and idiopathic nephrotic syndrome kidneys did not exhibit either of these markers. Snail, a major player in the process of epithelial-to-mesenchymal transition, is highly expressed by tubular epithelial cells during multiple myeloma nephropathy. It is, therefore, a potential target to prevent multiple myeloma kidneys from fibrosing. Intranuclear accumulation of Snail is a characteristic in phenotypically altered tubular cells from multiple myeloma kidneys. The epithelial-mesenchymal transition pathway could, therefore, be involved in the rapid renal fibrogenesis observed in this setting.
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http://dx.doi.org/10.1016/j.humpath.2010.11.006DOI Listing
August 2011

[Pretreatment molecular biology analysis on small size biopsies].

Ann Pathol 2010 Nov 15;30(5 Suppl 1):67-72. Epub 2010 Sep 15.

Département d'anatomie et cytologie pathologiques, plateforme d'oncologie, pathologie et biologie moléculaire, hôpital Tenon, 4 rue de la Chine, Paris, France.

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http://dx.doi.org/10.1016/j.annpat.2010.07.041DOI Listing
November 2010

Release of metal particles from needles used for transbronchial needle aspiration.

Chest 2011 Jan 10;139(1):138-43. Epub 2010 Jun 10.

Service de Pneumologie et Réanimation, Hôpital Tenon, AP-HP, Faculté de Médecine, Université Pierre et Marie Curie, Paris, France.

Background: Although mediastinoscopy is still the gold standard for diagnosis of mediastinal lymphadenopathy, minimally invasive procedures have been developed: transbronchial needle aspiration (TBNA) using a flexible bronchoscope (conventional TBNA) or linear echoendoscope (endobronchial ultrasound [EBUS]) allowing real-time guided lymph node aspiration. The observation of contamination of samples by foreign particles led us to determine the frequency and the nature of this material and to identify its origin.

Methods: From June 2007 to November 2008, 141 consecutive patients underwent conventional TBNA (n = 84) or EBUS-guided TBNA (EBUS-TBNA) (n = 57). All cytologic samples were reviewed in blinded fashion, and contamination was assessed semiquantitatively. Mineral analysis using a transmission electron microscope equipped with an energy dispersive x-ray spectrometer was performed on the solution obtained after rinsing unused needles and on four samples of calf thymuses punctured with EBUS needles.

Results: Foreign material, different from anthracosis, was identified in samples obtained with five different batches of needles, only from EBUS-TBNA (P < .0001). The contamination score was correlated to the number of passes (P = .035). Mineral analyses of the rinsing solutions from conventional TBNA needles were negative, whereas metal alloys of iron, titanium, nickel, and chromium were released with EBUS needles. The same contamination was identified in three of the four punctured calf thymuses.

Conclusions: Dedicated EBUS-TBNA needles are able to release metal particles, probably by friction between the stylet and the needle, with a potential risk to inject particles into nodes. The long-term consequences are unknown, but the need for safety measures should be evaluated.
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http://dx.doi.org/10.1378/chest.10-0371DOI Listing
January 2011

Clinical and morphologic spectrum of renal involvement in patients with mixed cryoglobulinemia without evidence of hepatitis C virus infection.

Medicine (Baltimore) 2009 Nov;88(6):341-348

From Nephrology and Transplantation Department (MM, PG), Henri Mondor Hospital, AP-HP, Institut Francilien de Recherche en Néphrologie et Transplantation (IFRNT), and Paris XII University, Créteil; Internal Medicine Department (PC, DS), Pitié Salpêtrière Hospital, AP-HP, Paris, and CNRS UMR 7087, Université Pierre et Marie Curie, Paris VI; Pathology Department (MC, BM), Tenon Hospital, AP-HP, Paris; Pathology Department (IB), Pitié Salpêtrière Hospital, AP-HP, Paris; Public Health and Biostatistics Department (FRT), Henri Mondor Hospital, AP-HP and Paris XII University, Créteil; Nephrology Department (PV), Valenciennes Hospital, Valenciennes; Nephrology Unit (OM), Nice University Hospital, Nice; Internal Medicine Department (EH, PYH), CHRU, Lille; Hematology Department (JPF), Saint-Louis Hospital, AP-HP, Paris; Nephrology and Dialysis Department (FF), Necker Hospital, AP-HP, Paris; and Nephrology and Dialysis Department (PR, EP), Tenon Hospital, AP-HP, Paris, France.

Hepatitis C virus (HCV) infection represents, by far, the major cause of mixed cryoglobulinemia (MC). The renal disease associated with this pathological condition is now well described. By contrast, renal involvement in patients with MC not associated with HCV has been only poorly described, and few cases have been reported. We analyzed the demographic, clinical, and laboratory features and outcome in patients presenting with renal disease associated with MC not related to HCV infection. Records of 20 patients with MC and renal disease, with no evidence of HCV by serology and polymerase chain reaction analysis, were retrospectively analyzed. Renal biopsies and extensive searches for lymphoproliferative disorder were performed in all patients at presentation. MC was related to primary Sjögren Syndrome (pSS) in 9 patients, and to non-Hodgkin lymphoma in 1 patient, while MC was classified as essential in the remaining 10 cases. Renal involvement was characterized by microscopic hematuria in all patients, nephrotic range proteinuria in 75% of patients, hypertension in 80% of patients, and renal failure in 85% of patients (mean glomerular filtration rate, 46 mL/min per 1.73 m). Membranoproliferative glomerulonephritis with subendothelial deposits was observed in all kidney specimens. Skin vasculitis was the main extrarenal manifestation. In all patients, cryoglobulinemia was classified as type II MC, characterized by monoclonal IgMkappa and polyclonal IgG. Most patients (17/20) were treated with steroids or immunosuppressive agents, or both. Initial renal remission was observed in 94% of patients. However, renal relapse occurred in most patients, with 10% reaching end-stage renal disease. Three patients with essential MC developed B-cell lymphoma 36-48 months after the diagnosis of MC. Unexpectedly, B-cell lymphoma induced by Epstein-Barr virus infection occurred in only 1 of the 9 pSS patients. Forty percent of patients died as a result of extrarenal causes.Renal disease associated with MC unrelated to HCV is characterized by the high prevalence of pSS (45%), the finding of CD20+ B-lymphocyte nodular infiltrates in the kidney interstitium, and a high incidence of overt B-cell lymphoma during follow-up. These findings emphasize the need for repetitive clinical evaluation in those patients.
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http://dx.doi.org/10.1097/MD.0b013e3181c1750fDOI Listing
November 2009

Membranoproliferative glomerulonephritis, chronic lymphocytic leukemia, and cryoglobulinemia.

Am J Kidney Dis 2010 Feb 6;55(2):391-4. Epub 2009 Aug 6.

AP-HP, Service de Néphrologie et Dialyses, Hôpital Tenon, Université Pierre et Marie Curie, Paris, France.

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http://dx.doi.org/10.1053/j.ajkd.2009.06.021DOI Listing
February 2010