Long-term outcome of idiopathic steroid-resistant nephrotic syndrome: a multicenter study

Mekahli, Djalila; Liutkus, Aurélia; Ranchin, Bruno; Yu, Anchalee; Bessenay, Lucie; Girardin, Éric; Damme‐Lombaerts, Rita Van; Palcoux, Jean-Bernard; Cachat, François; Lavocat, Marie-Pierre; Bourdat-Michel, Guylhène; Nobili, François; Cochat, Pierre

doi:10.1007/s00467-009-1138-5

Cited by 180 publications

(167 citation statements)

References 34 publications

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“…3 In early childhood, INS is two times more frequent in boys than in girls, but this balance is disrupted in adolescence affecting both girls and boys equally. Mekahli et al 4 found the ratio between boys and girls to be 1.4/1 and it was 1.5/1 in our study. The age of disease onset is usually towards two years; and the majority of the children are under the age of 6 years.…”

Section: Discussionsupporting

confidence: 61%

Long-term prognosis of idiopathic nephrotic syndrome in children

Özlü¹,

Demircin²,

Tökmeci³

et al. 2015

Renal Failure

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Background: To investigate the demographic, clinical and laboratory data of the children with idiopathic nephrotic syndrome (INS), and to determine prognostic factors that affect the clinical outcome of the patients. Methods: Medical charts of 372 patients diagnosed to have INS and followed up at least 5 years between January 1990 and December 2008 were evaluated, respectively. After initial demographic, clinical and laboratory findings of the patients were documented, therapeutic protocols, prognosis and prognostic factors were investigated. Results: 299 of the patients (80.4%) were steroid responsive and 73 (19.6%) were not. Focal segmental glomerulosclerosis (FSGS) was observed in 57%, minimal change disease (MCD) in 20.6% and diffuse mesengial proliferation in 21.9% renal biopsy materials. Steroid sensitivity was higher in patients with MCD and under the age of five years. Resistance to steroids was higher in children with FSGS. Complete remission was achieved in 96% of patients who were sensitive to steroids and in 46.6% who were resistant. 15% of patients who were steroid resistant developed chronic kidney disease (CKD). Conclusion: Intercurrent infections and response to steroid therapy are the most important factors affecting the prognosis of the disease.

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Section: Discussionsupporting

confidence: 61%

Long-term prognosis of idiopathic nephrotic syndrome in children

Özlü¹,

Demircin²,

Tökmeci³

et al. 2015

Renal Failure

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“…Steroid-resistant nephrotic syndrome (SRNS) is a challenging clinical condition with highly variable outcomes, and 50% of children progress to ESRD within 15 years (3,4). Although in some patients, temporary or persistent remission is achieved by intensified immunosuppressive therapies (IITs), others exhibit a multidrug-resistant phenotype.…”

Section: Introductionmentioning

confidence: 99%

Spectrum of Steroid-Resistant and Congenital Nephrotic Syndrome in Children

Trautmann¹,

Bodria²,

Özaltın³

et al. 2015

Clinical Journal of the American Society of Nephrology

249

229

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Background and objectives Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome.

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“…The prognosis of steroid-resistant nephrotic syndrome (SRNS) is poor, with a high proportion of patients rapidly developing end-stage renal disease, requiring dialysis or transplantation (1,2). The GFB is comprised principally of podocytes, specialised epithelial cells which interdigitate at junctions known as slit diaphragms (SDs).…”

mentioning

confidence: 99%

Endoplasmic reticulum–retained podocin mutants are massively degraded by the proteasome

Serrano-Pérez

Tilley

Névo

et al. 2018

Journal of Biological Chemistry

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Podocin is a key component of the slit diaphragm in the glomerular filtration barrier, and mutations in the podocin-encoding gene NPHS2 are a common cause of hereditary steroid-resistant nephrotic syndrome. A mutant allele encoding podocin with a p.R138Q amino acid substitution is the most frequent pathogenic variant in European and North American children, and the corresponding mutant protein is poorly expressed and retained in the endoplasmic reticulum (ER) both in vitro and in vivo. To better understand the defective trafficking and degradation of this mutant, we generated human podocyte cell lines stably expressing podocin wt or podocin R138Q . Although it has been proposed that podocin has a hairpin topology, we present evidence for podocin R138Q N-glycosylation, suggesting that most of the protein has a transmembrane topology. We find that N-glycosylated podocin R138Q has a longer half-life than non-glycosylated podocin R138Q , and that the latter is far more rapidly degraded than podocin wt . Consistent with its rapid degradation, podocin R138Q is exclusively degraded by the proteasome, whereas podocin wt is degraded by both the proteasomal and the lysosomal proteolytic machineries. In addition, we demonstrate an enhanced interaction of podocin R138Q with calnexin as the mechanism of ER retention. Calnexin knock-down enriches the podocin R138Q non-glycosylated fraction, whereas preventing exit from the calnexin cycle increases the glycosylated fraction. Altogether, we propose a model in which hairpin podocin R138Q is rapidly degraded by the proteasome, whereas transmembrane podocin R138Q degradation is delayed due to entry into the calnexin cycle.Nephrotic syndrome (NS) is clinically characterized by proteinuria, edema, hypoalbuminemia and hyperlipidemia, and is a consequence of glomerular filtration barrier (GFB) dysfunction. The prognosis of steroid-resistant nephrotic syndrome (SRNS) is poor, with a high proportion of patients rapidly developing end-stage renal disease, requiring dialysis or transplantation (1,2). The GFB is comprised principally of podocytes, specialised epithelial cells which interdigitate at junctions known as slit diaphragms (SDs). Mutations in the NPHS2 gene, encoding the slit diaphragm (SD) protein podocin, are the most frequent monogenic cause of SRNS in childhood (3,4 Podocin R138Q quality control and ERAD North America (4), and is associated with an earlyonset and rapidly progressing form of the disease (5). In accordance with the severe clinical phenotype, podocin p.R138Q (Pod R138Q ) is retained in the ER of podocytes and does not reach the SD, thus impairing correct functioning of the GFB (6,7).Podocin belongs to the stomatin and prohibitin homology domain (PHB) protein family and is specifically expressed in podocytes. It has been proposed that podocin acts as a molecular scaffold for other SD proteins in lipid raft membrane subdomains. For example, podocin interacts with both nephrin and CD2AP through its carboxy (C)-terminus, and participates in various signaling...

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Long-term outcome of idiopathic steroid-resistant nephrotic syndrome: a multicenter study

Cited by 180 publications

References 34 publications

Long-term prognosis of idiopathic nephrotic syndrome in children

Long-term prognosis of idiopathic nephrotic syndrome in children

Spectrum of Steroid-Resistant and Congenital Nephrotic Syndrome in Children

Endoplasmic reticulum–retained podocin mutants are massively degraded by the proteasome

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