Publications by authors named "David Buob"

102 Publications

AA amyloidosis complicating monoclonal gammopathies, an unusual feature validating the concept of "monoclonal gammopathy of inflammatory significance"?

Int J Clin Pract 2021 Sep 7:e14817. Epub 2021 Sep 7.

Sorbonne University, AP-HP, Tenon hospital, Department of Internal Medicine, Centre de référence des maladies auto-inflammatoires et des amyloses d'origine inflammatoire (CEREMAIA), GRC -28, Paris, France.

Introduction: AL amyloidosis is caused by the proliferation of an immunoglobulin-secreting B cell clone. AA amyloidosis is a rare complication of chronic inflammation. However, some patients present with diseases combining monoclonal immunoglobulin production and chronic inflammation. The aim of this work was to describe cases of AA amyloidosis associated with monoclonal gammopathies.

Patients And Methods: We reviewed all patients reported in French national amyloid centers presenting with AA amyloidosis and monoclonal gammopathy and performed a literature review. The quality of AA amyloidosis diagnosis and the causal relationship with monoclonal gammopathy were assessed.

Results: In total, 4 patients from our centers and 8 from the literature fulfilled the inclusion criteria. The hematological disorders presenting with monoclonal gammopathy were as follows: Waldenström macroglobulinemia (n=8), Schnitzler syndrome (n=2), multiple myeloma (n=1), and monoclonal gammopathy of undetermined significance (n=1). Treatment strategies varied among the cases, with treatment of the hematological disorder in 4 and anti-inflammatory treatment in 2.

Conclusion: Monoclonal gammopathies might be a rare and poorly known cause of AA amyloidosis. Such monoclonal gammopathies could be named "monoclonal gammopathies of inflammatory significance".
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http://dx.doi.org/10.1111/ijcp.14817DOI Listing
September 2021

The Exostosin Immunohistochemical Status Differentiates Lupus Membranous Nephropathy Subsets With Different Outcomes.

Kidney Int Rep 2021 Jul 5;6(7):1977-1980. Epub 2021 May 5.

Service d'Anatomie et Cytologie Pathologiques, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France.

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http://dx.doi.org/10.1016/j.ekir.2021.04.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258496PMC
July 2021

AA Amyloidosis in the Course of HIV Infection: A Report of 19 Cases Including 4 New French Cases and a Comprehensive Review of Literature.

Nephron 2021 Jul 15:1-9. Epub 2021 Jul 15.

Department of Internal Medicine, Sorbonne University, AP-HP, Tenon Hospital, Centre De Référence Des Maladies Auto-Inflammatoires Et Des Amyloses D'origine Inflammatoire (CEREMAIA), Paris, France.

Introduction: HIV infection has been recently retained as an unclear cause of AA amyloidosis. Our aim was to investigate cases of AA amyloidosis associated with HIV infection to understand if it could be considered as a cause of AA amyloidosis.

Methods: A comprehensive literature review was conducted as well as retrospective study from French cases collected from our national reference center for AA amyloidosis.

Results: Altogether, 19 patients with AA amyloidosis and HIV infection were found with 68% of men and median age at amyloidosis diagnosis of 38 years (range 28-75 years). Clinical presentation was nephrotic syndrome in 94% (n = 17/18). Among patients with renal involvement and assessable outcome (n = 17), 11 (64.7%) progressed to chronic kidney disease, with 6 (35%) end-stage renal disease. Seventy-five percent of patients had uncontrolled HIV infection and 71.4% CD4 counts <400/mm3 at amyloidosis diagnosis. Repeated or chronic bacterial or fungal infection was found in 47% of cases and a history of parenteral drug use in 55% of patients. Three patients had no classical or at least no suspected AA amyloidosis cause found or reported.

Conclusions: AA Amyloidosis is a rare condition in HIV patients with common renal involvement and significant risk of progression to chronic renal insufficiency. Because of the frequency related to other inflammatory conditions in this population, HIV is probably not an independent risk factor for AA amyloidosis.
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http://dx.doi.org/10.1159/000516982DOI Listing
July 2021

The Case | Membranous nephropathy after alemtuzumab treatment.

Kidney Int 2021 07;100(1):249-250

Department of Nephrology-Dialysis-Transplantation, Bicêtre Hospital, APHP, Le Kremlin-Bicêtre, France; Paris Saclay University, Le Kremlin-Bicêtre, France. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2021.02.030DOI Listing
July 2021

Amyloid Goiter in Familial Mediterranean Fever: Description of 42 Cases from a French Cohort and from Literature Review.

J Clin Med 2021 May 5;10(9). Epub 2021 May 5.

Internal Medicine Department and National Reference Center for Autoinflammatory Diseases and Inflammatory Amyloidosis (CEREMAIA), APHP, Tenon Hospital, Sorbonne University, 4 rue de la Chine, 75020 Paris, France.

Our aim was to describe the main features of amyloid goiter in adults with amyloidosis secondary to familial Mediterranean fever. Therefore, we analyzed cases from a French cohort of familial Mediterranean fever patients with amyloidosis and from literature review. Forty-two cases were identified: 9 from the French cohort and 33 from literature review. Ninety percent of patients were on hemodialysis for renal amyloidosis before the development of goiter. The goiter grew up rapidly in 88% of cases; 75.6% of patients were euthyroid, 58% displayed dyspnea, and 44.8% dysphagia. Various features were seen on ultrasound, from diffuse to multinodular goiter. When it was performed, fine-needle aspiration biopsy almost always revealed amyloidosis. Thirty-one patients underwent thyroidectomy: to manage compressive symptoms (72%) or rule out malignancy (27%). Histology showed mature adipose tissue in 64% of cases and lymphocytic infiltration in 21.4%. In conclusion, amyloid goiter in familial Mediterranean fever preferentially occurs in patients with end stage renal failure. Fine-needle aspiration biopsy seems to be a sensitive exam for diagnosis, but thyroidectomy remains sometimes necessary to rule out malignancy or release compressive symptoms.
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http://dx.doi.org/10.3390/jcm10091983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125620PMC
May 2021

Protocadherin 7-Associated Membranous Nephropathy.

J Am Soc Nephrol 2021 05 8;32(5):1249-1261. Epub 2021 Apr 8.

Unité Mixte de Recherche S 1155, Sorbonne Université, Université Pierre et Marie Curie Paris 06 and Institut National de la Santé et de la Recherche Médicale, Paris, France.

Background: Membranous nephropathy (MN) results from deposition of antigen-antibody complexes along the glomerular basement membrane (GBM). PLA2R, THSD7A, NELL1, and SEMA3B account for 80%-90% of target antigens in MN.

Methods: We performed laser microdissection and mass spectrometry (MS/MS) in kidney biopsies from 135 individuals with PLA2R-negative MN, and used immunohistochemistry/immunofluorescence and confocal microscopy to confirm the MS/MS finding, detect additional cases, and localize the novel protein. We also performed MS/MS and immunohistochemistry on 116 controls and used immunofluorescence microscopy to screen biopsy samples from two validation cohorts. Western blot and elution studies were performed to detect antibodies in serum and biopsy tissue.

Results: MS/MS studies detected a unique protein, protocadherin 7 (PCDH7), in glomeruli of ten (5.7%) PLA2R-negative MN cases, which also were negative for PLA2R, THSD7A, EXT1/EXT2, NELL1, and SEMA3B. Spectral counts ranged from six to 24 (average 13.2 [SD 6.6]). MS/MS did not detect PCDH7 in controls (which included 28 PLA2R-positive cases). In all ten PCDH7-positive cases, immunohistochemistry showed bright granular staining along the GBM, which was absent in the remaining cases of PLA2R-negative MN and control cases. Four of 69 (5.8%) cases in the validation cohorts (all of which were negative for PLA2R, THSD7A, EXT1, NELL1, and SEMA3B) were PCDH7-positive MN. Kidney biopsy showed minimal complement deposition in 12 of the 14 PCDH7-associated cases. Confocal microscopy showed colocalization of PCDH7 and IgG along the GBM. Western blot analysis using sera from six patients showed antibodies to nonreduced PCDH7. Elution of IgG from frozen tissue of PCDH7-associated MN showed reactivity against PCDH7.

Conclusions: MN associated with the protocadherin PCDH7 appears to be a distinct, previously unidentified type of MN.
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http://dx.doi.org/10.1681/ASN.2020081165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259689PMC
May 2021

The spectrum of kidney biopsies in hospitalized patients with COVID-19, acute kidney injury, and/or proteinuria.

Nephrol Dial Transplant 2021 Feb 12. Epub 2021 Feb 12.

INSERM U1018, Equipe 5, CESP (Centre de Recherche en Épidémiologie et Santé des Populations), Université Paris Saclay et Université Versailles Saint Quentin en Yvelines), Villejuif, France.

We report a multicentric retrospective case series of patients with COVID-19 who developed acute kidney injury and/or proteinuria and underwent a kidney biopsy in the Paris and its metropolitan area. Forty-seven patients (80.9% men) with COVID-19 who underwent a kidney biopsy between March 08 and May 19, 2020 were included. Median age was 63 years IQR [52-69]. Comorbidities included hypertension (66.0%), diabetes mellitus (27.7%), obesity (27.7%), history of chronic kidney (25.5%), cardiac (38.6%) and respiratory (27.3%) diseases. Initial symptoms were fever (85.1%), cough (63.8%), shortness of breath (55.3%), and diarrhea (23.4%). Almost all patients developed acute kidney injury (97.9%) and 63.8% required renal replacement therapy. Kidney biopsy showed two main histopathological patterns, including acute tubular injury in 20 (42.6%) patients, and glomerular injury consisting of collapsing glomerulopathy and focal segmental glomerulosclerosis in 17 (36.2%) patients. Two (4.3%) patients had acute vascular nephropathy, while eight (17%) had alternative diagnosis most likely unrelated to COVID-19. Acute tubular injury occurred almost invariably in the setting of severe forms of COVID-19, whereas patients with glomerular injury had various profiles of COVID-19 severity and collapsing glomerulopathy was only observed in patients harboring a combination of APOL1 risk variants. At last follow-up, 16 of the 30 patients who initially required dialysis were still on dialysis, and 9 died. The present study describes the spectrum of kidney lesions in patients with COVID-19. While acute tubular injury is correlated with COVID-19 severity, the pattern of glomerular injury is intimately associated with the expression of APOL1 risk variants.
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http://dx.doi.org/10.1093/ndt/gfab042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928708PMC
February 2021

The Case | Acute kidney injury associated with chronic myelomonocytic leukemia.

Kidney Int 2021 02;99(2):495-496

Assistance Publique des Hôpitaux de Paris - Sorbonne Université, Paris, France.

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http://dx.doi.org/10.1016/j.kint.2020.06.028DOI Listing
February 2021

Nephronophthisis in Young Adults Phenocopying Thrombotic Microangiopathy and Severe Nephrosclerosis.

Clin J Am Soc Nephrol 2021 04 2;16(4):615-617. Epub 2020 Dec 2.

Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, 4 Rue de la Chine, Assistance Publique-Hôpitaux de Paris, Paris, France

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http://dx.doi.org/10.2215/CJN.11890720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092057PMC
April 2021

AA Amyloidosis Secondary to Primary Immune Deficiency: About 40 Cases Including 2 New French Cases and a Systematic Literature Review.

J Allergy Clin Immunol Pract 2021 02 30;9(2):745-752.e1. Epub 2020 Sep 30.

Sorbonne Université, AP-HP, Hôpital Tenon, Service de médecine interne, Centre de référence des maladies auto-inflammatoires et des amyloses d'origine inflammatoire (CEREMAIA), GRC-28 (Groupe de recherche clinique amylose AA Sorbonne univeristé), Paris, France. Electronic address:

Background: Primary immune deficiencies (PIDs) are a heterogeneous group of disorders resulting from defects in immune system. They lead to increased susceptibility to infections and immune dysregulation. The resulting chronic inflammation can induce long-term complications, including AA amyloidosis (AAA).

Objectives: To present the French cases of PID-related AAA and perform a systematic literature review to determine its main features and predisposing factors.

Methods: A systematic literature review was performed by searching MEDLINE up until 2019. New French cases were identified with the help of the Reference Center for Auto-Inflammatory Diseases and AA Amyloidosis and the Reference Center for Hereditary Immune Deficiencies.

Results: Forty patients were identified including 2 new French cases. PIDs were varied: immunoglobulin deficits (n = 30), chronic granulomatous disease (n = 3), hyper-IgM syndrome (n = 3), hereditary complete C4 deficiency (n = 1), leucocyte adhesion deficiency type 1 (n = 1), hyper-IgE syndrome (n = 1), and Chediak-Higashi syndrome (n = 1). The mean age at PID diagnosis was 22.2 ± 16.02 years. Renal involvement was the most common manifestation of AAA (80%). Infections were extremely heterogeneous; bacterial infection with pulmonary involvement was the most frequent. Bronchiectasis was particularly common (52.5%). The delay between the first symptoms of PID and AAA diagnosis was 16.18 ± 7 years. Thirteen concomitant diagnoses were made. Twenty patients died during follow-up.

Conclusion: AAA is a rare life-threatening complication of PID, especially in cases of long diagnostic and therapeutic delays. Bronchiectasis should be considered as a warning sign of chronic inflammation and increased risk of AAA.
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http://dx.doi.org/10.1016/j.jaip.2020.09.023DOI Listing
February 2021

De Novo Focal and Segmental Glomerulosclerosis After COVID-19 in a Patient With a Transplanted Kidney From a Donor With a High-risk APOL1 Variant.

Transplantation 2021 01;105(1):206-211

Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Henri-Mondor, Service de Néphrologie et Transplantation, Centre de Référence Maladie Rare "Syndrome Néphrotique Idiopathique", Fédération Hospitalo-Universitaire, Innovative Therapy for Immune Disorders, Créteil, France.

Background: 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.

Methods: We report the case of a renal transplant recipient with non-severe COVID-19, who subsequently developed nephrotic syndrome associated with acute renal injury.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1097/TP.0000000000003432DOI Listing
January 2021

Retinal Arteriolar Occlusions and Exudative Retinal Detachments in Malignant Hypertension: More Than Meets the Eye.

Am J Hypertens 2021 02;34(1):30-33

Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, Assistance Publique Hôpitaux de Paris, Sorbonne Université, Paris, France.

Background: Malignant hypertension is macrovascular and microvascular endothelial injury responsible for multiple organ damage. Considering the anatomical and functional homologies between the posterior pole of the eye and the kidney, ophthalmological explorations may inform clinicians on the mechanisms underpinning concurrent kidney injury in this condition. More specifically, we investigated whether the wall-to-lumen ratio (WLR) of retinal arterioles measured by adaptive optics ophthalmoscopy could be correlated to WLR of kidney arterioles as determined by pathology. We sought to estimate the incidence of retinal arteriole occlusion a supposedly uncommon complication of malignant hypertension.

Methods: All patients hospitalized in our renal Intensive Care Unit for malignant hypertension between 2016 and 2019 were referred to ophthalmological examinations.

Results: Twenty-seven patients were included. Median retinal WLR was 0.39 [0.31-0.47] and was correlated with initial systolic (r = 0.56, P = 0.003) and mean blood pressure (r = 0.46, P = 0.02) upon admission. The retinal WLR was not correlated to renal pathological findings, as assessed by juxtaglomerular WLR (r = 0.38, P = 0.2), ratio of glomerulosclerosis (r = -0.39, P = 0.2), or tubulointerstitial fibrosis (r = -0.45, P = 0.08). Retinal WLR was not associated with neurological or cardiovascular end-organ damage. Branch retinal artery occlusion was detected in 18.5% of patients and exudative retinal detachment (ERD) in 29.6% of patients, without any significant correlation with canonical signs of retinal hypertension including optic disc swelling.

Conclusions: In the setting of malignant hypertension, we failed to demonstrate a significant relationship between WLR and other meaningful end-organ injuries. However, branch retinal artery occlusion and ERD may have been hitherto underestimated.
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http://dx.doi.org/10.1093/ajh/hpaa138DOI Listing
February 2021

Ockham's razor defeated: about two atypical cases of hemolytic uremic syndrome.

BMC Nephrol 2020 07 11;21(1):269. Epub 2020 Jul 11.

Service d'urgences néphrologiques et transplantation rénale, hôpital Tenon, Paris, France.

Background: Medical investigation is a favorite application of Ockham's razor, in virtue of which when presented with competing hypotheses, the solution with the fewest assumptions should be privileged. Hemolytic uremic syndrome (HUS) encompasses diseases with distinct pathological mechanisms, such as HUS due to shiga-like toxin-producing bacteria (STEC-HUS) and atypical HUS, linked to defects in the alternate complement pathway. Other etiologies such as Parvovirus B19 infection are exceptional. All these causes are rare to such extent that we usually consider them mutually exclusive. We report here two cases of HUS that could be traced to multiple causes.

Cases Presentation: Case 1 presented as vomiting and diarrhea. All biological characteristics of HUS were present. STEC was found in stool (by PCR and culture). After initial remission, a recurrence occurred and patient was started on Eculizumab. Genetic analysis revealed the heterozygous presence of a CFHR1/CFH hybrid gene. The issue was favorable under treatment. In case 2, HUS presented as fever, vomiting and purpura of the lower limbs. Skin lesions and erythroblastopenia led to suspect Parvovirus B19 primo-infection, which was confirmed by peripheral blood and medullar PCR. Concurrently, stool culture and PCR revealed the presence of STEC. Evolution showed spontaneous recovery.

Conclusions: Both cases defy Ockham's razor in the sense that multiple causes could be traced to a single outcome; furthermore, they invite us to reflect on the physiopathology of HUS as they question the classical distinction between STEC-HUS and atypical HUS. We propose a two-hit mechanism model leading to HUS. Indeed, in case 1, HUS unfolded as a result of the synergistic interaction between an infectious trigger and a genetic predisposition. In case 2 however, it is the simultaneous occurrence of two infectious triggers that led to HUS. In dissent from Ockham's razor, an exceptional disease such as HUS may stem from the sequential occurrence or co-occurrence of several rare conditions.
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http://dx.doi.org/10.1186/s12882-020-01926-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353709PMC
July 2020

Semaphorin 3B-associated membranous nephropathy is a distinct type of disease predominantly present in pediatric patients.

Kidney Int 2020 11 11;98(5):1253-1264. Epub 2020 Jun 11.

Sorbonne Université, Université Pierre et Marie Curie Paris 06, and Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S 1155, Paris, France; Department of Nephrology, Day Hospital, Tenon Hospital, AP-HP 6, Paris, France.

Membranous nephropathy results from subepithelial antigen-antibody complex deposition along the glomerular basement membrane. Although PLA2R, THSD7A, and NELL-1 account for a majority (about 80%) of the target antigens, the target antigen in the remaining cases is not known. Using laser microdissection of PLA2R-negative glomeruli of patients with membranous nephropathy followed by mass spectrometry we identified a unique protein, Semaphorin 3B, in three cases. Mass spectrometry failed to detect Semaphorin-3B in 23 PLA2R-associated cases of membranous nephropathy and 88 controls. Semaphorin 3B in all three cases was localized to granular deposits along the glomerular basement membrane by immunohistochemistry. Next, an additional eight cases of Semaphorin 3B-associated membranous nephropathy were identified in three validation cohorts by immunofluorescence microscopy. In four of 11 cases, kidney biopsy also showed tubular basement membrane deposits of IgG on frozen sections. Confocal microscopy showed that both IgG and Semaphorin 3B co-localized to the glomerular basement membrane. Western blot analysis of five available sera showed reactivity to reduced Semaphorin 3B in four of four patients with active disease and no reactivity in one patient in clinical remission; there was also no reactivity in control sera. Eight of the 11 cases of Semaphorin 3B-associated membranous nephropathy were pediatric cases. Furthermore, in five cases, the disease started at or below the age of two. Thus, Semaphorin 3B-associated membranous nephropathy appears to be a distinct type of disease; more likely to be present in pediatric patients.
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http://dx.doi.org/10.1016/j.kint.2020.05.030DOI Listing
November 2020

AA amyloidosis associated with Fabry disease.

Int J Clin Pract 2020 Oct 27;74(10):e13577. Epub 2020 Aug 27.

Service de médecine interne, Centre de référence des maladies auto-inflammatoires et des amyloses d'origine inflammatoire (CEREMAIA), AP-HP, Hôpital Tenon, Sorbonne Université, Paris, France.

Background: Fabry disease (FD) is the second most common lysosomal storage disorder, carrying a large morbidity and mortality. It has been recently reported that lysosomal storage disorders could cause inflammation and, subsequently, AA amyloidosis (AAA). Our aim was to describe AAA cases occurring in the course of FD.

Patients And Methods: We described two patients displaying both AAA and FD and an additional case from the literature.

Results: Three female patients originating from Europe (n = 2) and Algeria (n = 1) harboured heterozygous GLA mutations. The median age at AAA diagnosis was 61 years old. The diagnosis of Fabry was made before the diagnosis of AAA (n = 1) or concomitantly (n = 2). At AAA diagnosis, two patients displayed a nephrotic syndrome; all had inflammation.

Conclusion: Fabry disease can be associated with AAA, suggesting that an inflammatory component could exist in this genetic disease.
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http://dx.doi.org/10.1111/ijcp.13577DOI Listing
October 2020

Tubuloreticular inclusions in COVID-19-related collapsing glomerulopathy.

Kidney Int 2020 07 27;98(1):241. Epub 2020 Apr 27.

Department of Nephrology, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Université de Paris, Centre de recherche sur l'inflammation, INSERM UMR1149, CNRS EL8252, Laboratoire d'Excellence Inflamex, Université de Paris, Paris, France.

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http://dx.doi.org/10.1016/j.kint.2020.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185005PMC
July 2020

Clinicopathologic features of infection-related glomerulonephritis with IgA deposits: a French Nationwide study.

Diagn Pathol 2020 May 27;15(1):62. Epub 2020 May 27.

Université de Tours, PRES Centre-Val de Loire, Tours, France.

Background: Infection-related glomerulonephritis with IgA deposits (IRGN-IgA) is a rare disease but it is increasingly reported in the literature. Data regarding epidemiology and outcome are lacking, especially in Europe. We aimed to assess the clinical, pathologic and outcome data of IRGN-IgA.

Methods: Clinical and outcome data from patients from 11 French centers over the 2007-2017 period were collected retrospectively. We reviewed pathologic patterns and immunofluorescence of renal biopsies and evaluated C4d expression in IRGN-IgA. We analyzed the correlation between histological presentation and outcome.

Results: Twenty-seven patients (23 men, mean age: 62 ± 15 years) were included. Twenty-one (78%) had Staphylococcus aureus infection and twelve (44%) were diabetic. At the time of biopsy, 95.2% had haematuria, 48.1% had a serum creatinine level of > 4 mg/dL, and 16% had hypocomplementemia. The most common pathologic presentation included mesangial (88.9%) and endocapillary proliferative glomerulonephritis (88.9%) with interstitial fibrosis and tubular atrophy (IF/TA) (85.1%). Diffuse and global glomerular C4d expression was found in 17.8%, mostly in biopsies with acute or subacute patterns, and was associated with a short delay between infection and renal biopsy compared to segmental and focal staining. After median follow-up of 13.2 months, 23.1% died, 46.2% had persistent renal dysfunction and 15.4% reached end-stage renal disease. Renal outcome was correlated to IF/TA severity.

Conclusions: Infection-related glomerulonephritis with IgA deposits is usually associated with Staphylococcus infections and mainly affects adult men. This entity has a poor prognosis which is correlated to interstitial fibrosis and tubular atrophy severity.
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http://dx.doi.org/10.1186/s13000-020-00980-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254713PMC
May 2020

Renal involvement in IgG4-related disease.

Presse Med 2020 Apr 29;49(1):104017. Epub 2020 Mar 29.

Inserm UMRS 1155, department of pathology, Sorbonne université, hôpital Tenon, AP-HP, 75020 Paris, France.

IgG4-RD may affect several organs including kidneys. The kidney is involved in approximately 20% of patient with IgG4-RD. The most common intrinsic kidney disease is tubulointerstitial nephritis (IgG4-TIN). Retroperitoneal fibrosis (IgG4-RPF) may induce obstructive acute renal failure. More rarely, IgG4-RKD can manifest as a glomerular disease, in particular as a membranous nephropathy (MN). It mostly affects middle-aged to elderly men and causes acute or chronic renal dysfunction, multiple hypodense lesions on CT-Scan and various extra-renal lesions. Increased serum IgG4 and hypocomplementemia are the most important serological findings for the diagnosis of IgG4-RD and thus should be systematically assessed when IgG4-RKD is suspected. Specific diagnosis criteria for IgG4-TIN including interstitial infiltration of IgG4-positive plasma cells, storiform fibrosis and tubular basement membrane immune complex deposits have been proposed. Corticosteroids are effective and remain the first-line therapy but relapses or severe forms could respond to immunosuppressive therapy.
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http://dx.doi.org/10.1016/j.lpm.2020.104017DOI Listing
April 2020

Microvasculature partial endothelial mesenchymal transition in early posttransplant biopsy with acute tubular necrosis identifies poor recovery renal allografts.

Am J Transplant 2020 09 12;20(9):2400-2412. Epub 2020 Apr 12.

Sorbonne Université, Institut national de la santé et de la recherche médicale (INSERM), Unité mixte de recherche (UMR), Paris, France.

Acute tubular necrosis (ATN), a frequent histopathological feature in the early post-renal transplant biopsy, affects long-term graft function. Appropriate markers to identify patients at risk of no or incomplete recovery after delayed graft function are lacking. In this study, we first included 41 renal transplant patients whose biopsy for cause during the first month after transplantation showed ATN lesions. Using partial microvasculature endothelial (fascin, vimentin) and tubular epithelial (vimentin) to mesenchymal transition markers, detected by immunohistochemistry, we found a significant association between partial endothelial to mesenchymal transition and poor graft function recovery (Spearman's rho = -0.55, P = .0005). Transforming growth factor-β1 was strongly expressed in these phenotypic changed endothelial cells. Extent of ATN was also correlated with short- and long-term graft dysfunction. However, the association of extensive ATN with long-term graft dysfunction (24 months posttransplant) was observed only in patients with partial endothelial to mesenchymal transition marker expression in their grafts (Spearman's rho = -0.64, P = .003), but not in those without. The association of partial endothelial to mesenchymal transition with worse renal graft outcome was confirmed on 34 other early biopsies with ATN from a second transplant center. Our results suggest that endothelial cell activation at the early phase of renal transplantation plays a detrimental role.
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http://dx.doi.org/10.1111/ajt.15847DOI Listing
September 2020

Light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits is associated with a high detection rate of the pathogenic plasma cell clone.

Kidney Int 2020 03 9;97(3):589-601. Epub 2019 Nov 9.

Department of Immunology, Joint Research Unit CNRS 7276, INSERM 1262, University of Limoges, French Reference Center for AL Amyloidosis, University Hospital Dupuytren, Limoges, France; Department of Nephrology, Dialysis and Renal Transplantation, University Hospital of Poitiers, French Reference Center for AL Amyloidosis, Poitiers, France.

IgG (mainly IgG3) is the most commonly involved isotype in proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID). Here we describe the first series of PGNMID with deposition of monoclonal immunoglobulin light chain only (PGNMID-light chain). This multicenter cohort of 17 patients presented with nephritic or nephrotic syndrome with underlying hematologic conditions of monoclonal gammopathy of renal significance (71%) or multiple myeloma (29%). Monoclonal immunoglobulin was identified by serum and urine immunofixation in 65% and 73%, respectively, with abnormal serum free light chain in 83%, and a detectable bone marrow plasma cell clone in 88% of patients. Renal biopsy showed a membranoproliferative pattern in most patients. By immunofluorescence, deposits were restricted to glomeruli and composed of restricted light chain (kappa in 71%) and C3, with granular appearance and subendothelial, mesangial and subepithelial distribution by electron microscopy. Proteomic analysis in four cases of kappa PGNMID-light chain revealed spectra for kappa constant and variable domains, without evidence of Ig heavy chains; spectra for proteins of the alternative pathway of complement and terminal complex were detected in three. The classical pathway was not detected in three cases. After median follow up of 70 months, the renal response was dependent on a hematologic response and occurred in six of ten patients treated with plasma cell-directed chemotherapy but none of five patients receiving other therapies. Thus, PGNMID-light chain differs from PGNMID-IgG by higher frequency of a detectable pathogenic plasma cell clone. Hence, proper recognition is crucial as anti-myeloma agents may improve renal prognosis. Activation of an alternative pathway of complement by monoclonal immunoglobulin light chain likely plays a role in its pathogenesis.
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http://dx.doi.org/10.1016/j.kint.2019.10.025DOI Listing
March 2020

Acute interstitial nephritis: aetiology and management.

Nephrol Dial Transplant 2020 Jan 25. Epub 2020 Jan 25.

Department of Renal Transplantation, Hôpital de La Pitié Salpêtrière, AP-HP, Sorbonne Université, Paris, France.

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http://dx.doi.org/10.1093/ndt/gfz262DOI Listing
January 2020

Tubulointerstitial damage and interstitial immune cell phenotypes are useful predictors for renal survival and relapse in antineutrophil cytoplasmic antibody-associated vasculitis.

J Nephrol 2020 Aug 8;33(4):771-781. Epub 2020 Jan 8.

Pathology Department, Lille University Hospital (CHU), Pathology Institute, Inserm UMR-S1172 Lille, JPARC-Jean-Pierre Aubert Research Center, Team 'Mucins, Epithelial Differentiation and Carcinogenesis", Lille University, CHU Lille, Avenue Oscar Lambret, 59000, Lille, France.

The aims of this study were to determine whether tubulointerstitial damage in the form of interstitial fibrosis/tubular atrophy and total interstitial inflammation predicted progression to end stage renal disease (ESRD) and/or renal relapse (RR) in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). One hundred thirteen patients with AAV from six French centers with an index biopsy performed between 2003 and 2013 were included. Histological assessments using the AAV glomerular classification and the kidney allograft Banff classification were performed on pathological review. Biopsy tissues were also investigated by CD3, CD20, CD68, CD163, FOXP3 and RORγt immunohistochemical staining. Competing risks models were calculated. Of the 113 patients, 26 (23.0%) died during follow-up and 29 (25.6%) developed ESRD. Among the 94 patients who achieved remission by the end of induction therapy without developing ESRD, 26 (27.6%) experienced RR. The two independent prognostic factors for ESRD were the estimated glomerular filtration rate at presentation (HR 0.35; 95% CI 0.23-0.51; P < 0.0001) and IF/TA > 25% (HR 2.27; 95% CI 1.18-4.37; P = 0.014). When the distribution of interstitial immune cell phenotypes was included in a second multivariable model, the organization of lymphocytic infiltrates was also an independent predictor of ESRD (HR 2.86; 95% CI 1.35-6.1, P = 0.006). The independent risk factors for RR were a higher CD3/CD20 ratio (HR 1.39; 95% CI 1.05-1.85; P = 0.02) and the presence of RORγt positive cells (HR 2.70; 95% CI 1.11-6.54; P = 0.02). Our results highlight the prognostic value of initial histological evaluations in AAV. Measurements of tubulointerstitial damage and interstitial immune cell phenotype distributions should be considered to improve risk assessments for ESRD and RR.
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http://dx.doi.org/10.1007/s40620-019-00695-yDOI Listing
August 2020

Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy.

Kidney Int 2020 01 7;97(1):163-174. Epub 2019 Oct 7.

Sorbonne Université, Université Pierre et Marie Curie Paris 06, Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S 1155, Paris, France; Hôpital de Jour-Nephrology, Assistance Publique-Hôpitaux de Paris, Paris, France.

Membranous nephropathy is characterized by deposition of immune complexes along the glomerular basement membrane. PLA2R and THSD7A are target antigens in 70% and 1-5% of primary membranous nephropathy cases, respectively. In the remaining cases, the target antigen is unknown. Here, laser microdissection of glomeruli followed by mass spectrometry was used to identify novel antigen(s) in PLA2R-negative membranous nephropathy. An initial pilot mass spectrometry study in 35 cases of PLA2R-negative membranous nephropathy showed high spectral counts for neural tissue encoding protein with EGF-like repeats, NELL-1, in six cases. Mass spectrometry failed to detect NELL-1 in 23 PLA2R-associated membranous nephropathy and 88 controls. NELL-1 was localized by immunohistochemistry, which showed bright granular glomerular basement membrane staining for NELL-1 in all six cases. Next, an additional 23 NELL-1 positive cases of membranous nephropathy were identified by immunohistochemistry in a discovery cohort of 91 PLA2R-negative membranous nephropathy cases, 14 were confirmed by mass spectrometry. Thus, 29 of 126 PLA2R-negative cases were positive for NELL-1. PLA2R-associated membranous nephropathy and controls stained negative for NELL-1. We then identified five NELL-1 positive cases of membranous nephropathy out of 84 PLA2R and THSD7A-negative cases in two validation cohorts from France and Belgium. By confocal microscopy, both IgG and NELL-1 co-localized to the glomerular basement membrane. Western blot analysis showed reactivity to NELL-1 in five available sera, but no reactivity in control sera. Clinical and biopsy findings of NELL-1 positive membranous nephropathy showed features of primary membranous nephropathy. Thus, a subset of membranous nephropathy is associated with accumulation and co-localization of NELL-1 and IgG along the glomerular basement membrane, and with anti-NELL-1 antibodies in the serum. Hence, NELL-1 defines a distinct type of primary membranous nephropathy.
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http://dx.doi.org/10.1016/j.kint.2019.09.014DOI Listing
January 2020

[Kidney disease care for the elderly].

Nephrol Ther 2019 Dec 9;15(7):533-552. Epub 2019 Nov 9.

Service de néphrologie, hôpital Huriez, CHRU de Lille, 59037 Lille, France. Electronic address:

In our aging population, kidney disease management needs to take into account the frailty of the elderly. Standardized geriatric assessments can be proposed to help clinicians apprehend this dimension in their daily practice. These tools allow to better identify frail patients and offer them more personalized and harmless treatments. This article aims to focus on the kidney diseases commonly observed in elderly patients and analyze their specific nephrogeriatric care modalities. It should be noticed that all known kidney diseases can be also observed in the elderly, most often with a quite similar clinical presentation. This review is thus focused on the diseases most frequently and most specifically observed in elderly patients (except for monoclonal gammopathy associated nephropathies, out of the scope of this work), as well as the peculiarities of old age nephrological care.
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http://dx.doi.org/10.1016/j.nephro.2019.10.001DOI Listing
December 2019

Histological prognostic factors in children with Henoch-Schönlein purpura nephritis.

Pediatr Nephrol 2020 02 6;35(2):313-320. Epub 2019 Nov 6.

Pediatric Nephrology unit, Trousseau Hospital, APHP.6, DMU Origyne, 26 Avenue du Docteur Arnold Netter, 75012, Paris, France.

Background: The management of IgA vasculitis with nephritis (IgAVN) remains controversial because of the difficulty to identify prognostic factors. This study reports the prognosis of children with IgAVN in relation to histological parameters.

Methods: All children with IgAVN diagnosed between 2000 and 2015 in three pediatric nephrology centers were included. The following histological parameters were analyzed: mesangial proliferation (MP), endocapillary proliferation (EP), crescents, active, or chronic tubular and interstitial lesions (TIa lesions/TIc lesions), and segmental glomerulosclerosis (GS). Clinical and biological data were collected at the time of renal biopsy. The primary endpoint was IgAVN remission defined as a proteinuria < 200 mg/l without renal failure.

Results: One hundred fifty-nine children were included with a median age of 7.6 years. Acute glomerular or TI lesions including MP, EP, crescents, and TIa lesions were observed, respectively, in 81%, 86%, 49%, and 21% of patients. Chronic glomerular lesions including GS and TIc lesions were observed in 6 and 7% of patients. Median initial proteinuria was 330 mg/mmol, albuminemia 32 g/l, and eGFR 110 ml/min/1.73 m. One hundred twelve (70%) patients were in remission at the end of a median follow-up of 37.4 months. Chronic lesions were significantly associated with the absence of remission in multivariate analysis, whereas EP, crescents and TIa were not associated with a poor prognosis.

Conclusions: Of children with IgAVN, 30% present a persistent renal disease at the end of a 3-year follow-up. Chronic histological lesions, but not EP or crescents, are associated with a bad prognosis and must be evaluated in IgAVN histological classification.
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http://dx.doi.org/10.1007/s00467-019-04363-yDOI Listing
February 2020

Infrequent tacrolimus-induced nephrotoxicity in French patients with steroid-dependent nephrotic syndrome.

Pediatr Nephrol 2019 12 13;34(12):2605-2608. Epub 2019 Sep 13.

Department of Pediatric Nephrology, Armand Trousseau Hospital, APHP, 26 Avenue du Docteur Arnold Netter, 75012, Paris, France.

Background: Chronic nephrotoxicity with potentially irreversible lesions is a major concern regarding calcineurin inhibitor (CNI) treatment in children with severe forms of idiopathic nephrotic syndrome (INS).

Case-diagnosis/treatment: We retrospectively included all children on CNI for steroid-dependent INS with a duration of CNI treatment of more than 1 year. Only patients in whom CNI could not be replaced by mycophenolate mofetil were included. All included patients underwent a kidney biopsy. All results were expressed as median and range. Twenty-one children (6 girls) were included. Age at disease onset was 49 (29-66) months and treatment duration on CNI was 30 (20-45) months. Age at kidney biopsy was 108 (78-170) months. Number of relapses was 7 (3-9) since disease onset. Serum creatinine level was transiently and moderately increased in two patients. Kidney biopsy revealed minimal change disease in 20/21 patients and focal segmental glomerulosclerosis in 1/21. Evidence for chronic CNI nephrotoxicity was found in one patient revealed by arteriolar hyalinosis and fibrosis in 50% of glomeruli.

Conclusions: CNI-induced chronic nephrotoxicity was infrequent. In patients who require long-term and/or high-dose CNI treatment, kidney biopsies might be useful to exclude chronic CNI-induced lesions.
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http://dx.doi.org/10.1007/s00467-019-04343-2DOI Listing
December 2019

Specific changes in faecal microbiota are associated with familial Mediterranean fever.

Ann Rheum Dis 2019 10 3;78(10):1398-1404. Epub 2019 Aug 3.

Service de Médecine Interne, Centre de référence des maladies auto-inflammatoires et des amyloses inflammatoires (CEREMAIA), Sorbonne Université, Assistance Publique des Hôpitaux de Paris, Hôpital Tenon, Paris, France

Objectives: Familial Mediterranean fever (FMF) can be complicated by AA amyloidosis (AAA), though it remains unclear why only some patients develop amyloidosis. We examined the gut microbiota composition and inflammatory markers in patients with FMF complicated or not by AAA.

Methods: We analysed the gut microbiota of 34 patients with FMF without AAA, 7 patients with FMF with AAA, 19 patients with AAA of another origin, and 26 controls using 16S ribosomal RNA gene sequencing with the Illumina MiSeq platform. Associations between bacterial taxa and clinical phenotypes were evaluated using multivariate association with linear models statistical method. Blood levels of interleukin (IL)-1β, IL-6, tumour necrosis factor-α and adipokines were assessed by ELISA; indoleamine 2,3-dioxygenase (IDO) activity was determined by high-performance liquid chromatography.

Results: Compared with healthy subjects, specific changes in faecal microbiota were observed in FMF and AAA groups. Several operational taxonomic units (OTUs) were associated with FMF. Moreover, two OTUs were over-represented in FMF-related AAA compared with FMF without AAA. Additionally, higher adiponectin levels and IDO activity were observed in FMF-related AAA compared with FMF without AAA (p<0.05).

Conclusion: The presence of specific changes in faecal microbiota in FMF and in FMF-related AAA suggests that intestinal microorganisms may play a role in the pathogenesis of these diseases. These findings may offer an opportunity to use techniques for gut microbiota manipulation.
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http://dx.doi.org/10.1136/annrheumdis-2019-215258DOI Listing
October 2019

Epidemiology of Castleman disease associated with AA amyloidosis: description of 2 new cases and literature review.

Amyloid 2019 Dec 31;26(4):197-202. Epub 2019 Jul 31.

Sorbonne Université, AP-HP, Hôpital Tenon, Service de médecine interne, Centre de référence des maladies auto-inflammatoires et des amyloses d'origine inflammatoire (CEREMAIA) , Paris , France.

HHV8-negative Castleman disease (CD) is classified as hyaline vascular (HV) type, or mixed or plasma cell (PC) types. It may present as multicentric CD (MCD) or unicentric CD (UCD). CD is a rare cause of AA amyloidosis (AAA). We aimed to report the main features of CD with secondary AAA through a description of new cases and a systematic literature review. New cases were identified from the French National Reference Center for AAA. A systematic literature review was performed to identify HHV8-negative CD cases associated with AAA. Thirty-seven patients were analysed, consisting of two new cases and 35 from literature. Twenty-three had UCD and 14 had MCD. PC was the main histologic subtype ( = 25; 68%) in both UCD and MCD patients. Surgical excision of UCD was performed in 21 patients (91%) with a favourable outcome, except for four patients (19%). Clinical and biologic remission was achieved in six patients with MCD (43%), all of whom were treated with anti-interleukin-6 (IL-6) therapy. AAA is a rare complication of CD, namely idiopathic MCD and UCD presenting with the PC histologic subtype. Surgical excision of UCD should be the first-line treatment whenever possible, while anti-IL-6 therapies seem effective for MCD.
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http://dx.doi.org/10.1080/13506129.2019.1641078DOI Listing
December 2019
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