Treatment of Genetic Forms of Nephrotic Syndrome

Kemper, Markus J.; Lemke, Anja

doi:10.3389/fped.2018.00072

Cited by 27 publications

(15 citation statements)

References 51 publications

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“…There is no convincing evidence of complete response to intensified immunosuppression in monogenic disease, albeit several reported cases. (22,30,34) Here, one monogenic patient (out of 26) demonstrated complete response. This patient has a WT1 mutation, with Denys-Drash Syndrome.…”

Section: Discussionmentioning

confidence: 86%

Response to First Course of Intensified Immunosuppression in Genetically Stratified Steroid Resistant Nephrotic Syndrome

Mason

Sen

Bierżyńska

et al. 2020

CJASN

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Background and objectivesIntensified immunosuppression in steroid-resistant nephrotic syndrome is broadly applied, with disparate outcomes. This review of patients from the United Kingdom National Study of Nephrotic Syndrome cohort aimed to improve disease stratification by determining, in comprehensively genetically screened patients with steroid-resistant nephrotic syndrome, if there is an association between response to initial intensified immunosuppression and disease progression and/or post-transplant recurrence.Design, setting, participants, & measurementsPediatric patients with steroid-resistant nephrotic syndrome were recruited via the UK National Registry of Rare Kidney Diseases. All patients were whole-genome sequenced, whole-exome sequenced, or steroid-resistant nephrotic syndrome gene-panel sequenced. Complete response or partial response within 6 months of starting intensified immunosuppression was ascertained using laboratory data. Response to intensified immunosuppression and outcomes were analyzed according to genetic testing results, pattern of steroid resistance, and first biopsy findings.ResultsOf 271 patients, 178 (92 males, median onset age 4.7 years) received intensified immunosuppression with response available. A total of 4% of patients with monogenic disease showed complete response, compared with 25% of genetic-testing-negative patients (P=0.02). None of the former recurred post-transplantation. In genetic-testing-negative patients, 97% with complete response to first intensified immunosuppression did not progress, whereas 44% of nonresponders developed kidney failure with 73% recurrence post-transplant. Secondary steroid resistance had a higher complete response rate than primary/presumed resistance (43% versus 23%; P=0.001). The highest complete response rate in secondary steroid resistance was to rituximab (64%). Biopsy results showed no correlation with intensified immunosuppression response or outcome.ConclusionsPatients with monogenic steroid-resistant nephrotic syndrome had a poor therapeutic response and no post-transplant recurrence. In genetic-testing-negative patients, there was an association between response to first intensified immunosuppression and long-term outcome. Patients with complete response rarely progressed to kidney failure, whereas nonresponders had poor kidney survival and a high post-transplant recurrence rate. Patients with secondary steroid resistance were more likely to respond, particularly to rituximab.

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Section: Discussionmentioning

confidence: 86%

Response to First Course of Intensified Immunosuppression in Genetically Stratified Steroid Resistant Nephrotic Syndrome

Mason

Sen

Bierżyńska

et al. 2020

CJASN

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“…The same study also reported decreased levels of urinary acylcarnitine (C12:0) in patients with FSGS, suggesting impaired fatty acid oxidation and possible mitochondrial dysfunction. Mutations in SGPL1 , the gene which encodes S1P lyase, have been reported to be associated with steroid-resistant nephrotic syndrome [ 8 , 9 , 83 ], which manifests histologically with FSGS and diffuse mesangial sclerosis [ 84 ]. Sgpl knockout mice were shown to recapitulate many features of human renal disease [ 9 ].…”

Section: Sphingolipid Signaling In Glomerular Diseasementioning

confidence: 99%

Role of Sphingolipid Signaling in Glomerular Diseases: Focus on DKD and FSGS

Mitrofanova

Drexler

Merscher

et al. 2020

Journal of Cellular Signaling

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Sphingolipids are well-recognized as major players in the pathogenesis of many human diseases, including chronic kidney disease. The kidney is a very sensitive organ to alterations in sphingolipid metabolism. The critical issues to be addressed in this review relate to the role of sphingolipids and enzymes involved in sphingolipid metabolism in the pathogenesis of glomerular diseases with a special focus on podocytes, a key cellular component of the glomerular filtration barrier. Among several sphingolipids, we will highlight the role of ceramide, sphingosine, sphingosine-1-phosphate and ceramide-1-phosphate. Additionally, we will summarize the current knowledge with regard to the use of sphingolipids as therapeutic agents for the treatment of podocyte injury in kidney disease.

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“…Kidney biopsy of SRNS shows minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS) in majority of cases ( 3 , 5 ). For ~30% of children with SRNS, the condition results from a genetic cause, and who will not achieve remission after treatment with steroids and/or immunosuppression ( 6 ); and identification of these causative genes has provided fundamental insights into the pathogenesis of SRNS ( 3 , 7 – 10 ).…”

Section: Introductionmentioning

confidence: 99%

The Clinical and Genetic Features in Chinese Children With Steroid-Resistant or Early-Onset Nephrotic Syndrome: A Multicenter Cohort Study

Zhu

Zhang

et al. 2022

Front. Med.

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Steroid-resistant nephrotic syndrome (SRNS) is one of the major causes of end-stage kidney disease (ESKD) in children and young adults. For approximately 30% of children with SRNS results from a genetic cause. In this study, genotype-phenotype correlations in a cohort of 283 pediatric patients with SRNS or early-onset NS (nephrotic syndrome presenting within the first year of life) from 23 major pediatric nephrology centers in China were analyzed. All patients were performed with next-generation sequencing and Sanger sequencing. The overall mutation detection rate was 37.5% (106 of 283 patients). WT1 was the most frequently detected mutation, followed by NPHS1, NPHS2, and ADCK4, and these four major causative genes (WT1, NPHS1, NPHS2, and ADCK4) account for 73.6% of patients with monogenic SRNS. Thirteen of 106 individuals (12.3%) carried mutations in ADCK4 that function within the coenzyme Q10 biosynthesis pathway. In the higher frequently ADCK4-related SRNS, two mutations, c.737G>A (p.S246N) and c.748G>C (p.D250H), were the most prevalent. Our study provides not only definitive diagnosis but also facilitate available targeted treatment for SRNS, and prediction of prognosis and renal outcome. Our indications for genetic testing are patients with FSGS, initial SRNS, cases of positive family history or those with extra-renal manifestations.

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Treatment of Genetic Forms of Nephrotic Syndrome

Cited by 27 publications

References 51 publications

Response to First Course of Intensified Immunosuppression in Genetically Stratified Steroid Resistant Nephrotic Syndrome

Response to First Course of Intensified Immunosuppression in Genetically Stratified Steroid Resistant Nephrotic Syndrome

Role of Sphingolipid Signaling in Glomerular Diseases: Focus on DKD and FSGS

The Clinical and Genetic Features in Chinese Children With Steroid-Resistant or Early-Onset Nephrotic Syndrome: A Multicenter Cohort Study

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