scholarly journals Identification of a Novel ACTN4 Gene Mutation Which Is Resistant to Primary Nephrotic Syndrome Therapy

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Lingzhang Meng ◽  
Shan Cao ◽  
Na Lin ◽  
Jingjie Zhao ◽  
Xulong Cai ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Target Gene ◽  
Minimal Change ◽  
Cleavage Sites ◽  
Primary Nephrotic Syndrome ◽  
Minimal Change Nephropathy ◽  
Filtration Barrier ◽  
Capture Method ◽  
Generation Sequencing ◽  
Target Gene Capture

ACTN4, a gene which codes for the protein α-actinin-4, is critical for the maintenance of the renal filtration barrier. It is well known that ACTN4 mutations can lead to kidney dysfunction, such as familial focal segmental glomerulosclerosis (FSGS), a common cause of primary nephrotic syndrome (PNS). To elucidate whether other mutations of ACTN4 exist in PNS patients, we sequenced the ACTN4 gene in biopsies collected from 155 young PNS patients (≤16 years old). The patients were classified into five groups: FSGS, minimal change nephropathy, IgA nephropathy, membranous nephropathy, and those without renal puncture. Ninety-eight healthy people served as controls. Samples were subjected to Illumina’s next generation sequencing protocols using FastTarget target gene capture method. We identified 5 ACTN4 mutations which occurred only in PNS patients: c.1516G > A (p.G506S) on exon 13 identified in two PNS patients, one with minimal change nephropathy and another without renal puncture; c.1442 + 10G > A at the splice site in a minimal change nephropathy patient; c.2191-4G > A at the cleavage site, identified from two FSGS patients; and c.1649A > G (p.D550G) on exon 14 together with c.2191-4G > A at the cleavage sites, identified from two FSGS patients. Among these, c.1649A > G (p.D550G) is a novel ACTN4 mutation. Patients bearing the last two mutations exhibited resistance to clinical therapies.

Minimal change nephropathy

2009 ◽  
pp. 179-214 ◽  
Author(s):  
Rosanna Coppo ◽  
Claudio Ponticelli
Keyword(s):  
Nephrotic Syndrome ◽  
Light Microscopy ◽  
Renal Biopsy ◽  
Minimal Change Disease ◽  
Minimal Change ◽  
Minimal Change Nephropathy ◽  
The Usa

Minimal change nephropathy (MCN), also called ‘minimal change disease’ in the USA, is chiefly characterized by episodes of nephrotic syndrome—presenting with massive proteinuria, hypoalbuminemia, generalized edema, hyperlipidemia—and no lesions or only minimal glomerular abnormalities in the renal biopsy examined by light microscopy.

scholarly journals Terapia della sindrome nefrosica idiopatica: ruolo delle tecniche aferetiche

2013 ◽  
Vol 25 (4_suppl) ◽  
pp. S41-S45
Author(s):  
Luigi Moriconi
Keyword(s):  
Nephrotic Syndrome ◽  
Idiopathic Nephrotic Syndrome ◽  
Sono State ◽  
Minimal Change ◽  
Glomerular Sclerosis ◽  
Minimal Change Nephropathy ◽  
Focal Segmental Glomerular Sclerosis ◽  
Segmental Glomerular Sclerosis ◽  
State Identificate

La Sindrome Nefrosica Idiopatica (Idiopathic Nephrotic Syndrome, INS) ricorre essenzialmente in presenza di due glomerulopatie: la MCN (Minimal Change Nephropathy) e la FSGS (Focal Segmental Glomerular Sclerosis). La prima ha un decorso più benigno ed è più frequente nei bambini, mentre la seconda ha un decorso più severo, può portare a Insufficienza Renale Cronica Terminale e può re-cidivare nel trapianto. Soprattutto per la FSGS sono state identificate possibili eziologie virali o genetiche, oltre a forme secondarie in corso di altre malattie, per cui non è semplice classificare queste glomerulopatie. Le forme ricorrenti nel rene trapiantato costituiscono un gruppo più omogeneo. I fattori che sembrano essere comuni alla MCN e alla FSGS, anche se maggiormente espressi e studiati nella seconda, sono la lesione glomerulare caratterizzante a carico dei podociti, e il frequente riscontro di sostanze circolanti, definite fattori di permeabilità (PFs), capaci di indurre proteinuria. Corticosteroidi e Immunosoppressori sono la terapia standard della INS. Tuttavia, la presenza di casi farmaco-resistenti e l'identificazione di alcuni PFs circolanti hanno consentito di utilizzare nuove terapie dirette a bloccare la sintesi o l'azione di queste molecole e hanno fornito un ulteriore razionale alla loro rimozione mediante plasmaferesi convenzionale (PEX) o aferesi selettiva.

Discovery of Autoantibodies Targeting Nephrin in Minimal Change Disease Supports a Novel Autoimmune Etiology

2021 ◽  
pp. ASN.2021060794
Author(s):  
Andrew Watts ◽  
Keith Keller ◽  
Gabriel Lerner ◽  
Ivy Rosales ◽  
A. Collins ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Animal Studies ◽  
Minimal Change Disease ◽  
Molecular Classification ◽  
Minimal Change ◽  
Filtration Barrier ◽  
Steroid Dependent ◽  
Renal Biopsies ◽  
End Stage ◽  
Autoimmune Etiology

Background Failure of the glomerular filtration barrier, primarily by loss of slit diaphragm architecture, underlies nephrotic syndrome in minimal change disease. The etiology remains unknown. The efficacy of B cell-targeted therapies in some patients, together with the known proteinuric effect of antinephrin antibodies in rodent models, prompted us to hypothesize that nephrin autoantibodies may be present in patients with minimal change disease. Methods We evaluated sera from patients with minimal change disease enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) cohort and from our own institutions for circulating nephrin autoantibodies by indirect ELISA and by immunoprecipitation of full-length nephrin from human glomerular extract or a recombinant purified extracellular domain of human nephrin. We also evaluated renal biopsies from our institutions for podocyte-associated punctate IgG colocalizing with nephrin by immunofluorescence Results In two independent patient cohorts, we identified in a subset of patients with minimal change disease circulating nephrin autoantibodies during active disease that were significantly reduced or absent during treatment response. We correlated the presence of these autoantibodies with podocyte-associated punctate IgG in renal biopsies from our institutions. We also identified a patient with steroid-dependent childhood minimal change disease that progressed to end-stage kidney disease; she developed a massive posttransplant recurrence of proteinuria that was associated with high pretransplant circulating nephrin autoantibodies. Conclusions Our discovery of nephrin autoantibodies in a subset of adults and children with minimal change disease aligns with published animal studies and provides further support for an autoimmune etiology. We propose a new molecular classification of nephrin autoantibody minimal change disease to serve as framework for instigation of precision therapeutics for these patients.

Minimal change disease

2018 ◽  
Author(s):  
Patrick Niaudet ◽  
Alain Meyrier
Keyword(s):  
Differential Diagnosis ◽  
Nephrotic Syndrome ◽  
Renal Biopsy ◽  
Minimal Change Disease ◽  
Minimal Change ◽  
Direct Effects ◽  
Glomerular Filtration Barrier ◽  
Common Cause ◽  
Filtration Barrier ◽  
Steroid Responsiveness

Minimal change disease is the most common cause of nephrotic syndrome in childhood but is not rare in adults. The factors altering permeability of the glomerular filtration barrier are not known, but podocyte structure is significantly altered in the condition and it seems certain that this cell is the target of whatever factors are responsible for the condition. It is still not clear that it is immunologically mediated and many of the agents used to treat it have direct effects on the podocyte. The differential diagnosis includes any other disease causing nephrotic syndrome, and a renal biopsy narrows this down. In children, steroid unresponsiveness is often used as a diagnostic test, and consideration of genetic or other pathologies reserved for patients who show no or poor steroid responsiveness.

scholarly journals Mechanism Underlying Selective Albuminuria in Minimal Change Nephrotic Syndrome

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Akihiro Tojo
Keyword(s):  
Nephrotic Syndrome ◽  
A Priori ◽  
Minimal Change Nephrotic Syndrome ◽  
Cytoplasmic Dynein ◽  
Minimal Change ◽  
Filtration Barrier ◽  
Urinary Protein Level ◽  
Foot Process ◽  
Albumin Receptor ◽  
Albumin Endocytosis

As water and solutes are filtered through the slit membrane, it is an a priori concept that a slit membrane is an essential filtration barrier for proteins, including albumin. However, in cases of minimal change nephrotic syndrome, the number of slit membranes is reduced by the foot process effacement and tight junction-like cell adhesion. Furthermore, albumin endocytosis is enhanced in the podocytes under condition of minimal change disease, and albumin is selectively transported by the albumin receptor FcRn. Suppressing the endocytosis of albumin with anti-FcRn antibody decreases the urinary protein level. The expression of motor molecules, such as cytoplasmic dynein 1 and myosin IX, is increased in the podocytes under conditions of minimal change nephrotic syndrome, suggesting the enhanced transport of vesicles containing albumin. Podocyte vesicle transport may play an important role in the pathology of selective albuminuria in cases of nephrotic syndrome.

Interleukin-4 and interleukin-4 receptor polymorphisms in minimal change nephropathy

1999 ◽  
Vol 96 (6) ◽  
pp. 665-668 ◽  
Author(s):  
R. G. PARRY ◽  
K. M. GILLESPIE ◽  
A. PARNHAM ◽  
A. G. B. CLARK ◽  
P. W. MATHIESON
Keyword(s):  
Nephrotic Syndrome ◽  
Genetic Predisposition ◽  
Allelic Variation ◽  
Minimal Change ◽  
Interleukin 4 ◽  
Minimal Change Nephropathy ◽  
Significant Difference ◽  
Genes Encoding ◽  
Interleukin 4 Receptor ◽  
Increased Activity

Minimal change nephropathy (MCN) is an important cause of nephrotic syndrome, especially in children, that is strongly associated with atopy and IgE production. The immunogenetics of MCN are poorly understood. Interleukin-4 (IL-4) is the critical cytokine involved in the development of atopy. Polymorphic regions in the genes encoding IL-4 itself and the IL-4 receptor have been demonstrated that may predispose to increased activity. We have analysed these polymorphisms in 149 patients with MCN and 73 controls to test the hypothesis that these loci are involved in genetic predisposition to MCN. In our populations there were no polymorphisms in the IL-4 promoter. We did confirm allelic variation in a dinucleotide repeat in the second intron of the IL-4 gene, but there was no significant difference between allele distributions in MCN and controls. Similarly, allele frequencies for the IL-4 receptor α chain polymorphism were similar in patients and controls. Genetic loci which are believed to influence IL-4 responsiveness and to predispose to atopy do not appear to be associated with susceptibility to MCN.

scholarly journals Primary Nephrotic Syndrome and Risks of End-Stage Kidney Disease, Cardiovascular Events, and Death: The Kaiser Permanente Nephrotic Syndrome Study

2021 ◽  
pp. ASN.2020111583
Author(s):  
Alan Go ◽  
Thida Tan ◽  
Glenn Chertow ◽  
Juan Ordonez ◽  
Dongjie Fan ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Kidney Disease ◽  
Membranous Nephropathy ◽  
Minimal Change Disease ◽  
Cardiovascular Outcomes ◽  
Minimal Change ◽  
End Stage Kidney Disease ◽  
Kaiser Permanente ◽  
Primary Nephrotic Syndrome ◽  
End Stage

Background Few population-based data exist about adults with primary nephrotic syndrome. Methods To evaluate kidney, cardiovascular, and mortality outcomes in adults with primary nephrotic syndrome, we identified adults within an integrated health care delivery system (Kaiser Permanente Northern California) with nephrotic-range proteinuria or diagnosed nephrotic syndrome between 1996-2012. Nephrologists reviewed medical records for clinical presentation, laboratory findings, and biopsy results to confirm primary nephrotic syndrome and assigned etiology. We identified a 1:100 time-matched cohort of adults without diabetes, diagnosed nephrotic syndrome, or proteinuria as controls to compare rates of end-stage kidney disease (ESKD), cardiovascular outcomes, and death through 2014, using multivariable Cox regression. Results We confirmed 907 cases of primary nephrotic syndrome (655 definite and 252 presumed cases of focal segmental glomerulosclerosis [FSGS, 40%], membranous nephropathy [40%], and minimal change disease [20%]). Mean age was 49 years; 43% were women. Adults with primary nephrotic syndrome had higher adjusted rates of ESKD (adjusted hazard ratio [aHR], 19.63; 95% confidence interval [95% CI], 12.76 to 30.20), acute coronary syndrome (aHR 2.58; 95% CI, 1.89 to 3.52), heart failure (aHR 3.01; 95%CI, 2.16 to 4.19), ischemic stroke (aHR 1.80; 95%CI,1.06 to 3.05), venous thromboembolism (aHR 2.56; 95%CI, 1.35 to 4.85), and death (aHR 1.34; 95%CI, 1.09 to 1.64) versus controls. Excess ESKD risk was significantly higher for FSGS and membranous nephropathy than for presumed minimal change disease. The three etiologies of primary nephrotic syndrome did not differ significantly in terms of cardiovascular outcomes and death. Conclusions Adults with primary nephrotic syndrome experience higher adjusted rates of ESKD, cardiovascular outcomes, and death, with significant variation by underlying etiology in risk for developing ESKD.

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