Autosomal-dominant familial hematuria with retinal arteriolar tortuosity and contractures: A novel syndrome

Autosomal-dominant familial hematuria with retinal arteriolar tortuosity and contractures: A novel syndrome.BackgroundAutosomal-dominant forms of hematuria have been mostly related to mutations in the COL4A3/COL4A4 genes. Patients with thin basement membrane (BM) disease do not have extrarenal manifestations, while those with Alport syndrome often present with hearing loss, anterior lenticonus, and dot-and-fleck retinopathy.MethodsWe performed a phenotypic study and a candidate gene approach in a four-generation family presenting with autosomal-dominant hematuria associated with extrarenal manifestations. Renal biopsy was analyzed for determination of BM thickness and expression of chains of type IV collagen. Linkage to 18 candidate genes/loci was investigated using polymorphic microsatellite markers.ResultsIn all affected patients, hematuria without proteinuria was associated with muscular contractures and retinal arterial tortuosities responsible for retinal hemorrhages. Cardiac arrythmia, Raynaud phenomena, and brain MRI abnormalities were also observed. Despite the presence of red cells in tubule sections, no glomerular abnormalities were found by electron microscopy. Expression of type IV collagen chains and glomerular BM thickness was normal. We searched for a molecular defect affecting either BM or angiogenesis. Linkage analyses of genes encoding BM components (COL4A3/COL4A4, COL6A1, COL6A2, COL6A3, FBLN1), and angiogenic factors or their receptors (VHL, ANPT1, ANPT2, TIE, TEK, NOTCH2, NOTCH3, NOTCH4, DLL4, JAG1, JAG2) and of the facio-sapulo-humeral dystrophy and 3q21 loci failed to show segregation of the disease with those gene loci.ConclusionWe have identified a new inherited hematuria syndrome associated with retinal vessel tortuosities and contractures. We recommend performing a fundus examination in patients with familial hematuria and episodes of visual impairment, as well as a urinary analysis in patients with retinal arterial tortuosity or congenital muscular contractures

Acute metabolic acidosis in a GLUT2-deficient patient with Fanconi-Bickel syndrome: new pathophysiology insights

Fanconi-Bickel syndrome is a rare autosomal-recessive disorder caused by mutations in the SLC2A2 gene coding for the glucose transporter protein 2 (GLUT2). Major manifestations include hepatomegaly, glucose intolerance, post-prandial hypoglycaemia and renal disease that usually presents as proximal tubular acidosis associated with proximal tubule dysfunction (renal Fanconi syndrome). We report a patient harbouring a homozygous mutation of SLC2A2 who presented a dramatic exacerbation of metabolic acidosis in the context of a viral infection, owing to both ketosis and major urinary bicarbonate loss. The kidney biopsy revealed nuclear and cytoplasmic accumulation of glycogen in proximal tubule cells, a lack of expression of GLUT2, and major defects of key proteins of the proximal tubule such as megalin, cubilin and the B2 subunit of H+-ATPase. These profound alterations of the transport systems most likely contributed to proximal tubule alterations and profound bicarbonate los

Serum Protein Signatures Using Aptamer-Based Proteomics for Minimal Change Disease and Membranous Nephropathy

Introduction: Minimal change disease (MCD) and membranous nephropathy (MN) are glomerular diseases (glomerulonephritis [GN]) that present with the nephrotic syndrome. Although circulating PLA2R antibodies have been validated as a biomarker for MN, the diagnosis of MCD and PLA2R-negative MN still relies on the results of kidney biopsy or empirical corticosteroids in children. We aimed to identify serum protein biomarker signatures associated with MCD and MN pathogenesis using aptamer-based proteomics. Methods: Quantitative SOMAscan proteomics was applied to the serum of adult patients with MCD (n = 15) and MN(n = 37) and healthy controls (n = 20). Associations between the 1305proteins detected with SOMAscan were assessed using multiple statistical tests, expression pattern analysis, and systems biology analysis. Results: A total of 208 and 244 proteins were identified that differentiated MCD and MN, respectively, with high statistical significance from the healthy controls (Benjamin-Hochberg [BH] P \u3c 0.0001). There were 157 proteins that discriminated MN from MCD (BH P \u3c 0.05). In MCD, 65 proteins were differentially expressed as compared with MN and healthy controls. When compared with MCD and healthy controls, 44 discriminatory proteins were specifically linked to MN. Systems biology analysis of these signatures identified cell death and inflammation as key pathways differentiating MN from MCD and healthy controls. Dysregulation of fatty acid metabolism pathways was confirmed in both MN and MCD as compared with the healthy subjects. Conclusion: SOMAscan represents a promising proteomic platform for biomarker development in GN. Validation of a greater number of discovery biomarkers in larger patient cohorts is needed before these data can be translated for clinical care

Screening for Cancer in Patients with Glomerular Diseases

International audienc

Atteinte rénale au cours des vascularites cryoglobulinémiques mixtes d origine non infectieuse

L atteinte rénale au cours des vascularites cryoglobulinémiques mixtes (VCM) non liées au virus de l hépatite C n a été que peu étudiée. Elle en représente pourtant un facteur pronostique de survie. Grâce à une étude multicentrique et nationale (enquête CryoVas ), nous avons identifié 80 patients avec une atteinte rénale, prouvée histologiquement, liée à une VCM non infectieuse, ce qui représente la plus grande série rapportée à ce jour. Le syndrome de Gougerot-Sjögren primitif et les hémopathies malignes représentaient 22,5% et 28,7% des causes, les cas restants (48,8%) étant des VCM dites essentielles . L atteinte rénale était souvent présente au diagnostic (76,3%) en association avec des manifestations systémiques (86,2%) : cutanées, neurologiques et articulaires. Elle était typiquement associée à une cryoglobulinémie de type II (incluant un IgM kappa monoclonale) et une diminution des fractions C3 et C4 du complément. Elle était caractérisée par une hématurie (97,4%), une protéinurie >=1g/j (84,8%), une hypertension artérielle (85,3%) et une insuffisance rénale (82,3%). La glomérulonéphrite membranoproliférative était la principale forme histologique (90%), fréquemment associée à des lésions tubulo-interstitielles et vasculaires. Si le risque d évolution vers l insuffisance rénale terminale était modéré (9%), la mortalité élevée (24%) était principalement liée à la survenue d infections sévères. L évolution était aussi marquée par la survenue d hémopathie maligne de novo (8,9%). Des études contrôlées, incluant des stratégies de minimisation des corticoïdes, sont nécessaires pour mieux définir le traitement optimal de ces formes sévères de VCM.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

HEMATURIE, CRAMPES MUSCULAIRES, TORTUOSITES RETINIENNES A TRANSMISSION AUTOSOMIQUE DOMINANTE (ETUDE PHENOTYPIQUE ET APPROCHE GENETIQUE)

PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Étude de l'atteinte rénale au cours des cryoglobulinémies mixtes non induites par le virus de l'hépatite C

PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Advances in Membranous Nephropathy

International audienceMembranous nephropathy (MN) is a rare auto-immune disease where the glomerulus is targeted by circulating auto-antibodies mostly against podocyte antigens, which results in the formation of electron-dense immune complexes, activation of complement and massive proteinuria. MN is the most common cause of nephrotic syndrome in adults leading to severe thrombotic complications and kidney failure. This review is focused on the recent therapeutic and pathophysiological advances that occurred in the last two years. For a long time, we were lacking a head-to-head comparison between cyclophosphamide considered as the gold standard therapy and other medications, notably rituximab. Substantial progress has been achieved owing to three randomized controlled trials. MENTOR (Membranous Nephropathy Trial of Rituximab) and STARMEN (Sequential Therapy with Tacrolimus and Rituximab in Primary Membranous Nephropathy) conclusively established that calcineurin inhibitor-based regimens are slower to result in an immunologic response than rituximab or cyclophosphamide, achieve fewer complete clinical remissions, and are less likely to maintainremission. Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO) suggested that competition between cyclophosphamide and rituximab remains open. Given the technological leap combining laser microdissection of glomeruli and mass spectrometry of solubilized digested proteins, four "new antigens" were discovered including NELL-1 and Semaphorin 3B in so-called primary MN, and exostosins 1 and 2 and NCAM 1 in lupus MN. NELL-1 is associated with about 8% of primary MN and is characterized by segmental immune deposits and frequent association with cancer (30%). Semaphorin 3B-associated MN usually occurs in children, often below the age of two years, where it is the main antigen, representing about 16% of non-lupus MN in childhood. Exostosins 1/2 and NCAM 1 are associated with 30% and 6% of lupus MN, respectively. Exostosins 1/2 (EXT1/2) staining is associated with a low rate of end-stage kidney disease (ESKD) even in mixed classes III/IV+V. These findings already lead to revisiting the diagnostic and therapeutic algorithms toward more personalized medicine

[Kidney and HIV infection].

International audienceScreening of chronic kidney disease (CKD) that includes estimation of the glomerular filtration rate (GFR) and evaluation proteinuria should be performed in all HIV-infected patients and these parameters have to be monitored annually in patients at higher risk for CKD. Black patients have a genetic predisposition to develop HIV-associated nephropathy. Suppression of HIV viral replication with antiretroviral therapy prevents the development of HIV-associated nephropathy or halts its progression. Kidney biopsy remains the most informative diagnosis test to differentiate various forms of kidney diseases in HIV-infected patients. Dosing antiretroviral agents with kidney metabolism should be adjusted when eGFR is bellow 50 mL/min/1.73 m(2). eGFR and serum phosphorus at baseline and during treatment should be carefully assessed in patients receiving tenofovir. Proximal renal tubular toxicity must be further evaluated in the presence of eGFR decrease and/or hypophosphatemia under tenofovir therapy

Immunoglobulin light (heavy)-chain deposition disease: from molecular medicine to pathophysiology-driven therapy.: Light-chain deposition disease

8 pagesLight-, light- and heavy-, and heavy-chain deposition diseases belong to a family of diseases that include light-chain (AL)-amyloid, nonamyloid fibrillary and immunotactoid glomerulonephritis, and cryoglobulinemic glomerulonephritis, in which monoclonal Ig or their subunits become deposited in kidney. In clinical and pathologic terms, light-, light- and heavy-, and heavy-chain deposition diseases essentially are similar and are characterized by prominent renal involvement with severe renal failure; extrarenal manifestations; diabetes-like nodular glomerulosclerosis; marked thickening of tubular basement membranes; and monotypic deposits of light chain, mostly kappa, and/or heavy chain that feature a nonorganized granular, electron-dense appearance by electron microscopy. The most common cause is myeloma. Recent progress has been made in the understanding of the molecular pathomechanisms of Ig-chain deposition and extracellular matrix accumulation, which opens up new therapeutic avenues in addition to eradication of the Ig-secreting plasma cell clone. Because these diseases represent a model of glomerular and interstitial fibrosis that is induced by a single molecule species, a better understanding of their pathomechanisms may help to unravel the pathophysiology of kidney fibrosis and renal disease progression