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

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.

Association between HLA alleles and sub-phenotype of childhood steroid-sensitive nephrotic syndrome

Background Few studies have addressed the effects of human leukocyte antigen (HLA) alleles on different clinical sub-phenotypes in childhood steroid-sensitive nephrotic syndrome (SSNS), including SSNS without recurrence (SSNSWR) and steroid-dependent nephrotic syndrome/frequently relapse nephrotic syndrome (SDNS/FRNS). In this study, we investigated the relationship between HLA system and children with SSNSWR and SDNS/FRNS and clarified the value of HLA allele detection for precise typing of childhood SSNS. Methods A total of 241 Chinese Han individuals with SSNS were genotyped using GenCap-WES Capture Kit, and four-digit resolution HLA alleles were imputed from available Genome Wide Association data. The distribution and carrying frequency of HLA alleles in SSNSWR and SDNS/FRNS were investigated. Additionally, logistic regression and mediating effects were used to examine the relationship between risk factors for disease process and HLA system. Results Compared with SSNSWR, significantly decreased serum levels of complement 3 (C3) and complement 4 (C4) at onset were detected in SDNS/FRNS (C3, P < 0.001; C4, P = 0.018). The average time to remission after sufficient initial steroid treatment in SDNS/FRNS was significantly longer than that in SSNSWR (P = 0.0001). Low level of C4 was further identified as an independent risk factor for SDNS/FRNS (P = 0.008, odds ratio = 0.174, 95% confidence interval 0.048–0.630). The HLA-A*11:01 allele was independently associated with SSNSWR and SDNS/FRNS (P = 0.0012 and P = 0.0006, respectively). No significant HLA alleles were detected between SSNSWR and SDNS/FRNS. In addition, a mediating effect among HLA-I alleles (HLA-B*15:11, HLA-B*44:03 and HLA-C*07:06), C4 level and SDNS/FRNS was identified. Conclusions HLA-I alleles provide novel genetic markers for SSNSWR and SDNS/FRNS. HLA-I antigens may be involved in steroid dependent or frequent relapse in children with SSNS as mediators of immunoregulation.

Role of Zinc Supplementation in Reducing Relapses in Steroid Sensitive Nephrotic Syndrome

Objective: To evaluate and compare the effectiveness of zinc and B-Complex supplementation to prevent the recurrence of nephrotic syndrome in the cases priory responsive to corticosteroid therapy. Methodology It is a randomized controlled trial conducted at OPD Pediatric medicine, Shaheed Zulfiqar Ali Bhutto University, PIMS Children Hospital Islamabad from October 3, 2016 to April 2, 2017. 192 patients (96 in each group) were included in the study after obtaining informed consent from parents or guardians taken before determining the population. Patients were randomly assigned to two groups (Group 1: Zinc and Group 2: B-Complex) to receive oral zinc sulphate (10 mg / day) or B-Complex using a random number table. The patients were followed up after 4 months. All data were collected by the researchers themselves in a structured form. Results: The age of 192 participants of the trial averaged 6.38±3.42 years of age ranging from 1-12 years. There were 88 (45.8%) men and 104 (54.2%) women cases. In group 1, there were 22 (22.9%) and in group 2, there were 47 (49%) cases that had been pardoned. The recurrence of nephrotic syndrome was significantly higher in group 1 than group 2 (p = <0.001). Conclusion: The findings of this study suggest that Zinc supplementation is more preferrable to B-Complex supplementation as the rate of continuous remission was higher in the zinc group, so in the future may be added to the treatment regimen to treat steroid-sensitive nephrotic syndrome.

Novel TBC1D8B Variant in a 6-Month-Old Boy With Steroid-Sensitive Nephrotic Syndrome: A Case Report

A structural abnormality or dysfunction of podocytes is the major cause of nephrotic syndrome (NS). The TBC1D8B protein interacts with nephrin, a podocyte slit diaphragm protein, regulates vesicle transport, and functions in the pathogenesis of NS. We report a novel potentially pathogenic variant in the TBC1D8B gene in a 6-month-old boy with NS. A 6-month-old boy was admitted to the hospital because of edema and fever. Our systematic examination led to a diagnosis of NS. Because of the early age of onset, we performed trio whole-exome sequencing of him and his parents. The results showed a new potentially pathogenic variant in the TBC1D8B gene on the X chromosome, c.2717A&gt;G (p.His906Arg). After routine glucocorticoid therapy, his urine protein turned negative, indicating steroid-sensitive NS. The new TBC1D8B variant identified here, c.2717A&gt;G (p.His906Arg), may be associated with early-onset NS in children. Although NS due to pathogenic variants in this gene is more commonly steroid-resistant, our patient had steroid-sensitive NS.

B Lymphocyte Subsets in Children With Steroid-Sensitive Nephrotic Syndrome: A Longitudinal Study

Background: B-cell subsets may be involved in the pathogenesis of childhood steroid-sensitive nephrotic syndrome (SSNS). Horizontal control studies have shown that homeostasis of B-cell subsets changes at different stages of the SSNS. However, there is a lack of longitudinal studies that have investigated dynamic changes in B cell subpopulations.Methods: Blood samples were collected at the following time points from 15 children with SSNS treated at our hospital: before administration of steroid and after 3 days, 1 week, and 3, 6, 9, and 12 months. The proportions of circulating total B cells (CD19+), transitional B cells (CD19+CD24highCD38high), mature B cells (CD19+CD24lowCD38intermediate), and memory B cells (CD19+CD24highCD38−) were monitored by flow cytometry.Results: The proportion of CD19+ B cells before steroid administration was significantly higher than that observed at any other time point or in the healthy control (HC) group (p &lt; 0.001). However, this proportion was significantly lower than that in the HC group at 12 months (p = 0.031). Transitional B cells before (%BL 9.5 ± 4.4) and 3 days after steroid administration (%BL 10.6 ± 5.1) were significantly higher than at any other time point or in the HC group (p &lt; 0.001). Although these cells declined after the 3rd day the percentage was still significantly lower than that of the HC group at 12 months (p = 0.029). Memory B cells increased gradually after steroid administration and decreased to the normal range after 9 months.Conclusions: B cell subpopulations show dynamic changes in children with SSNS, suggesting that they are involved in the pathogenesis of the disorder. Further studies are required to determine whether this change can guide individualized treatment.

Circulating extracellular vesicles of steroid sensitive nephrotic syndrome patients have higher RAC1 and induce recapitulation of nephrotic syndrome phenotype in podocytes

Since previous research suggests a role of a circulating factor in the pathogenesis of steroid-sensitive nephrotic syndrome (SSNS), we speculated that circulating plasma extracellular vesicles (EVs) are a candidate source of such a soluble mediator. Here, we aimed to characterize and try to delineate the effects of these EVs in vitro. Plasma EVs from 20 children with SSNS in relapse and remission, 10 healthy controls and 6 disease controls were obtained by serial ultracentrifugation. Characterization of these EVs was performed by electron microscopy, flow cytometry and western blotting. The major proteins from the plasma EVs were identified via mass spectrometry. A Gene Ontology classification analysis and integuinity pathway analysis were performed on selectively expressed EV proteins during relapse. Immortalized human podocyte culture was used to detect the effects of EVs on podocytes. The protein content and the particle number of plasma EVs were significantly increased during NS relapse. Relapse NS EVs selectively express proteins which involved actin cytoskeleton rearrangement. Among these, the level of RAC-GTP was significantly increased in relapse EVs compared to remission and disease control EVs. Relapse EVs were efficiently internalized by podocytes and induced significantly enhanced motility and albumin permeability. Moreover, relapse EVs induced significantly higher levels of RAC-GTP and phospho p38 (p-p38) and decreased levels of synaptopodin in podocytes. Circulating relapse EVs are biologically active molecules that carry active RAC1 as cargo and induce recapitulation of the nephrotic syndrome phenotype in podocytes in vitro.