Strong Association of the HLA-DR/DQ Locus with Childhood Steroid-Sensitive Nephrotic Syndrome in the Japanese Population

Background Nephrotic syndrome is the most common cause of chronic glomerular disease in children. Most of these patients develop steroid-sensitive nephrotic syndrome (SSNS), but the loci conferring susceptibility to childhood SSNS are mainly unknown.Methods We conducted a genome-wide association study (GWAS) in the Japanese population; 224 patients with childhood SSNS and 419 adult healthy controls were genotyped using the Affymetrix Japonica Array in the discovery stage. Imputation for six HLA genes (HLA-A, -C, -B, -DRB1, -DQB1, and -DPB1) was conducted on the basis of Japanese-specific references. We performed genotyping for HLA-DRB1/-DQB1 using a sequence-specific oligonucleotide-probing method on a Luminex platform. Whole-genome imputation was conducted using a phased reference panel of 2049 healthy Japanese individuals. Replication was performed in an independent Japanese sample set including 216 patients and 719 healthy controls. We genotyped candidate single-nucleotide polymorphisms using the DigiTag2 assay.Results The most significant association was detected in the HLA-DR/DQ region and replicated (rs4642516 [minor allele G], combined Pallelic=7.84×10−23; odds ratio [OR], 0.33; 95% confidence interval [95% CI], 0.26 to 0.41; rs3134996 [minor allele A], combined Pallelic=1.72×10−25; OR, 0.29; 95% CI, 0.23 to 0.37). HLA-DRB1*08:02 (Pc=1.82×10−9; OR, 2.62; 95% CI, 1.94 to 3.54) and HLA-DQB1*06:04 (Pc=2.09×10−12; OR, 0.10; 95% CI, 0.05 to 0.21) were considered primary HLA alleles associated with childhood SSNS. HLA-DRB1*08:02-DQB1*03:02 (Pc=7.01×10−11; OR, 3.60; 95% CI, 2.46 to 5.29) was identified as the most significant genetic susceptibility factor.Conclusions The most significant association with childhood SSNS was detected in the HLA-DR/DQ region. Further HLA allele/haplotype analyses should enhance our understanding of molecular mechanisms underlying SSNS.

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An updated view of the pathogenesis of steroid-sensitive nephrotic syndrome

Pediatric Nephrology ◽

10.1007/s00467-021-05401-4 ◽

2022 ◽

Author(s):

Tomoko Horinouchi ◽

Kandai Nozu ◽

Kazumoto Iijima

Keyword(s):

Nephrotic Syndrome ◽

Genome Wide Association Study ◽

Human Leukocyte ◽

Leukocyte Antigen ◽

Genome Wide ◽

A Genome ◽

Immunological Mechanisms ◽

Steroid Sensitive Nephrotic Syndrome ◽

Steroid Sensitive ◽

Genetic Techniques

Abstract Idiopathic nephrotic syndrome is the most common childhood glomerular disease. Most forms of this syndrome respond to corticosteroids at standard doses and are, therefore, defined as steroid-sensitive nephrotic syndrome (SSNS). Immunological mechanisms and subsequent podocyte disorders play a pivotal role in SSNS and have been studied for years; however, the precise pathogenesis remains unclear. With recent advances in genetic techniques, an exhaustive hypothesis-free approach called a genome-wide association study (GWAS) has been conducted in various populations. GWASs in pediatric SSNS peaked in the human leukocyte antigen class II region in various populations. Additionally, an association of immune-related CALHM6/FAM26F, PARM1, BTNL2, and TNFSF15 genes, as well as NPHS1, which encodes nephrin expressed in podocytes, has been identified as a locus that achieves genome-wide significance in pediatric SSNS. However, the specific mechanism of SSNS development requires elucidation. This review describes an updated view of SSNS pathogenesis from immunological and genetic aspects, including interactions with infections or allergies, production of circulating factors, and an autoantibody hypothesis.

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Increased ischemia-modified albumin levels in children with steroid-sensitive nephrotic syndrome

Pakistan Journal of Medical Sciences ◽

10.12669/pjms.36.7.2924 ◽

2020 ◽

Vol 36 (7) ◽

Author(s):

Gokhan Cakirca ◽

Ahmet Guzelcicek ◽

Kenan Yilmaz ◽

Cemal Nas

Keyword(s):

Oxidative Stress ◽

Nephrotic Syndrome ◽

Pediatric Nephrology ◽

Cross Sectional Study ◽

Healthy Controls ◽

Cross Sectional ◽

Ischemia Modified Albumin ◽

Creative Commons ◽

Steroid Sensitive Nephrotic Syndrome ◽

Steroid Sensitive

Objective: Growing evidence shows that oxidative stress plays an important role in the development and progression of nephrotic syndrome (NS). In this study, we aimed to examine serum IMA levels as an indicator of oxidative stress in children with steroid-sensitive NS (SSNS) in remission and relapse. Methods: This cross-sectional study was carried out at the Pediatric Nephrology Unit of Sanliurfa Training and Research Hospital, Sanliurfa, Turkey, from April 2019 to December 2019. In this study Serum IMA and albumin levels were determined in 70 children with SSNS and 45 healthy controls. Among the children with SSNS, 50 were in remission and 20 were in relapse. Then, adjusted IMA levels were calculated from the IMA/albumin ratio. Results: IMA and adjusted IMA levels significantly increased and albumin significantly decreased in children with SSNS in relapse and remission compared with those of the healthy controls. Moreover, these alterations were more prominent in the relapse group than in the remission group. IMA was inversely correlated with albumin in children with SSNS (r= −0.881, p= <0.001). Conclusions: Our findings demonstrated that elevated IMA and adjusted IMA levels observed in patients with SSNS were associated with increased oxidative stress and could indirectly reflect the degree of oxidative damage in glomerular structures. doi: https://doi.org/10.12669/pjms.36.7.2924 How to cite this:Cakirca G, Guzelcicek A, Yilmaz K, Nas C. Increased ischemia-modified albumin levels in children with steroid-sensitive nephrotic syndrome. Pak J Med Sci. 2020;36(7):---------. doi: https://doi.org/10.12669/pjms.36.7.2924 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Free vitamin D levels in steroid-sensitive nephrotic syndrome and healthy controls

Pediatric Nephrology ◽

10.1007/s00467-019-04433-1 ◽

2019 ◽

Vol 35 (3) ◽

pp. 447-454

Author(s):

Sushmita Banerjee ◽

Surupa Basu ◽

Shakil Akhtar ◽

Rajiv Sinha ◽

Ananda Sen ◽

...

Keyword(s):

Vitamin D ◽

Nephrotic Syndrome ◽

Healthy Controls ◽

Vitamin D Levels ◽

Free Vitamin D ◽

Steroid Sensitive Nephrotic Syndrome ◽

Steroid Sensitive

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Biochemical bone markers in children with steroid sensitive nephrotic syndrome in remission

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20182570 ◽

2018 ◽

Vol 5 (4) ◽

pp. 1588

Author(s):

Neha Sinha ◽

Poonam Wade ◽

Radha Gulati Ghildiyal ◽

Hemil Maniar

Keyword(s):

Vitamin D ◽

Nephrotic Syndrome ◽

Hypovitaminosis D ◽

Vitamin D Supplementation ◽

Study Cohort ◽

Healthy Controls ◽

Cross Sectional ◽

Vitamin D Levels ◽

Steroid Sensitive Nephrotic Syndrome ◽

Steroid Sensitive

Background: Glucocorticoids, the recommended first line treatment of steroid sensitive nephrotic syndrome (SSNS), are notorious for causing osteoporosis. There are very few studies from tropical countries looking at the lasting effects of a short course of glucocorticoids in SSNS. The objective is to study the effect of glucocorticoids and its dose on Vitamin D levels and biochemical markers of calcium metabolism in children with SSNS and to formulate a criterion to administer prophylactic calcium and vitamin D supplementation to such patients.Methods: A cross-sectional case-control study was conducted on 30 children with SSNS in remission and 30 healthy controls. Serum levels of 25 hydroxycholecalciferol [25(OH)D], calcium, phosphorous, albumin, alkaline phosphatase (ALP) and intact parathyroid (PTH) were measured. Total glucocorticoid exposure during the illness was summarized.Results: Children with SSNS had significantly lower height [median-100.00 (interquartile range {IQR}- 14.5) vs. controls [115.50 (17.5)] cm; P= 0.0003. Serum ALP levels was significantly higher in the cases [median 264 (IQR-80.7)] IU/L vs. controls [median 234 (IQR- 132)] IU/L; P= 0.028. Though hypovitaminosis D was universal in the study cohort; children with SSNS had worse Vitamin D status (76.7%) than healthy controls (50%). Levels of serum calcium, phosphorous, vitamin D and PTH were not significantly different between the two groups, nor were they related to total cumulative dose of steroid. Vitamin D levels showed no significant co-relation with number of relapses, age, calcium, phosphate, ALP, or PTH levels.Conclusions: Children with SSNS may benefit from routine measurement of 25 (OH) D and prophylactic supplementation with calcium and Vitamin D.

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Polymorphic variants of MIF gene and prognosis in steroid therapy in children with idiopathic nephrotic syndrome.

Acta Biochimica Polonica ◽

10.18388/abp.2014_1925 ◽

2014 ◽

Vol 61 (1) ◽

Cited By ~ 5

Author(s):

Monika Świerczewska ◽

Danuta Ostalska-Nowicka ◽

Bartosz Kempisty ◽

Aleksandra Szczepankiewicz ◽

Michał Nowicki

Keyword(s):

Nephrotic Syndrome ◽

Linkage Disequilibrium ◽

Steroid Therapy ◽

Molecular Mechanisms ◽

Statistical Significance ◽

Steroid Resistance ◽

Steroid Sensitive Nephrotic Syndrome ◽

Steroid Sensitive ◽

Polymorphic Variants

Nephrotic syndrome (NS) is the most common reason of proteinuria in children and can be caused by the pathology of renal glomeruli. Steroid therapy is typically used in this disorder. It has been shown that MIF is a cytokine which counteracts the immunosuppressive properties of glucocorticoids. The aim of this study was looking for a correlation between MIF polymorphisms and genetic susceptibility to steroid resistance in children with INS (Idiopathic NS). The study was performed in 71 patients with INS including SRNS (steroid resistance nephrotic syndrome) (41) and SSNS (steroid sensitive nephrotic syndrome) (30) and in 30 control subjects. We employed Sanger sequencing and capillary electrophoresis. Linkage disequilibrium was made using Haploview and PHASE. We didn't observe a statistical significance between SNPs detected in patients with INS and controls. Our studies revealed statistical significance for two polymorphisms: rs2070767C > T and rs2000466T > G between patients with SRNS and SSNS. The results for rs34383331T > A are close to being statistically significant. Statistical significance was revealed for CATT5/CATT6 genotype in SRNS group vs SSNS group (OR=4.604, 95%CI=1.356-15.632, p=0.0168). We found that the frequency of 5/X-CATT genotype compared with X/X-CATT genotype was significantly higher in SRNS patients vs SSNS (OR=3.167, 95%CI=1.046-9.585, p=0.0426). In linkage disequilibrium analysis we didn't show involvement in susceptibility to INS and steroid sensitive phenotype. Our results suggest that the role of MIF polymorphisms in the susceptibility to positive response to steroid therapy is still unresolved. It indicates that MIF may be involved in indirect and complex molecular mechanisms of steroid activity in hormone-dependent metabolic pathways in children with INS. Because of ambiguous findings, pleiotropic features of this cytokine require that more research should be undertaken.

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Steroid treatment for the first episode of childhood nephrotic syndrome: comparison of the 8 and 12 weeks regimen using an individual patient data meta-analysis

European Journal of Pediatrics ◽

10.1007/s00431-021-04035-w ◽

2021 ◽

Author(s):

Anne M. Schijvens ◽

Nynke Teeninga ◽

Eiske M. Dorresteijn ◽

Steven Teerenstra ◽

Nicholas J. Webb ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Individual Patient Data ◽

Meta Analysis ◽

Steroid Treatment ◽

First Episode ◽

Childhood Nephrotic Syndrome ◽

Steroid Sensitive Nephrotic Syndrome ◽

Steroid Sensitive ◽

First Relapse ◽

Steroid Regimen

AbstractSteroids are the cornerstone of the treatment of childhood nephrotic syndrome. The optimal duration for the first episode remains a matter of debate. The aim of this study is to determine whether the 8 weeks International Study of Kidney Disease in Children (ISKDC) regimen is equally effective as the 12 weeks steroid regimen from the German society of pediatric nephrology (Arbeitsgemeinschaft für Pädiatrische Nephrologie [APN]). An individual patient data (IPD) meta-analysis of randomized controlled trials reporting on prednisolone treatment for a first episode of childhood nephrotic syndrome was conducted. European trials aimed at investigating the ISKDC and/or APN steroid regimen were selected. The lead investigators of the selected trials were requested to provide the IPD of the specific treatment groups. Four trials included European cohorts using dosing schedules according to the regimens studied. IPD of two trials were available. A significant difference was found in time to first relapse after cessation of steroid treatment between the 8 and 12 weeks treatment group with a median time to relapse of 29 and 63 days, respectively. Moreover, relapse rate ratios during total follow-up were 51% higher for the 8 weeks regimen. Finally, younger children have a significantly lower time to first relapse and frequently relapsing nephrotic syndrome.Conclusions: The results of this IPD meta-analysis suggest that the 8 weeks steroid regimen for a first episode of steroid-sensitive nephrotic syndrome may not be equally effective as the 12 weeks steroid regimen. Moreover, this study highlights the importance of using uniform definitions to enable accurate comparison and interpretation of trial results.Trial registration: Registration number: CRD42020199244, date of registration 16-08-2020 What is Known:• Steroids are the cornerstone of the treatment of childhood nephrotic syndrome, however the optimal duration for the first episode remains a matter of debate.• Currently, the 8 weeks ISKDC protocol and 12 weeks APN protocol are among the most frequently used protocols in Europe. What is New:• The 8 weeks steroid regimen for a first episode of steroid-sensitive nephrotic syndrome may not be equally effective as the 12 weeks steroid regimen for the treatment of a first episode of nephrotic syndrome.• Younger children have a significantly shorter time to first relapse and time to frequent relapsing nephrotic syndrome.

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Distribution of serum adiponectin isoforms in pediatric patients with steroid-sensitive nephrotic syndrome

Clinical and Experimental Nephrology ◽

10.1007/s10157-021-02085-w ◽

2021 ◽

Author(s):

Tetsuro Tamai ◽

Kaori Kamijo ◽

Yoshifusa Abe ◽

Satoshi Hibino ◽

Shunsuke Sakurai ◽

...

Keyword(s):

Molecular Weight ◽

Nephrotic Syndrome ◽

Pediatric Patients ◽

Serum Adiponectin ◽

Total Serum ◽

Control Subjects ◽

Remission Period ◽

Total Adiponectin ◽

Steroid Sensitive Nephrotic Syndrome ◽

Steroid Sensitive

Abstract Background Serum adiponectin circulates in three multimeric isoforms: high-molecular-weight (HMW), middle-molecular-weight (MMW), and low-molecular-weight (LMW) isoforms. Potential change in the circulating adiponectin levels in patients with nephrotic syndrome (NS) remain unknown. This study aimed to assess the levels of total adiponectin and the distribution of its isoforms in pediatric patients with NS. Methods We sequentially measured total adiponectin and each adiponectin isoform levels at the onset of NS, initial remission, and during the remission period of the disease in 31 NS patients. We also calculated the ratios of HMW (%HMW), MMW (%MMW), and LMW (%LMW) to total adiponectin incuding 51 control subjects. Results The median of total serum adiponectin levels in patients were 36.7, 36.7, and 20.2 μg/mL at the onset, at initial remission, and during the remission period of NS, respectively. These values were significantly higher than those in control subjects. The median values of %HMW, %MMW, and %LMW values were 56.9/27.0/14.1 at the onset, 62.0/21.8/13.4 at the initial remission, and 58.1/21.7/17.5 at during the remission period of NS, respectively. Compared with control subjects, %HMW at initial remission and %MMW at the onset were high, and the %LMW values at the onset and at initial remission were low. Conclusions In patients with NS, total serum adiponectin levels increase at the onset of the disease, and the ratio of adiponectin isoforms changes during the course of the disease. Further studies are needed to delineate the mechanisms between proteinuria and adiponectin isoforms change.

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