Childhood Steroid-sensitive Nephrotic Syndrome Research Articles

Genetic risk variants for childhood nephrotic syndrome and corticosteroid response.

The etiology of most cases of nephrotic syndrome (NS) remains unknown, therefore patients are phenotypically categorized based on response to corticosteroid therapy as steroid sensitive NS (SSNS), or steroid resistant NS (SRNS). Genetic risk factors have been identified for SSNS from unbiased genome-wide association studies (GWAS), however it is unclear if these loci are disease risk loci in other forms of NS such as SRNS. Additionally, it remains unknown if these risk loci are associated with response to therapy. Thus, we investigated the association between SSNS risk loci and therapy response in a large, multi-race cohort of children along the entire spectrum of childhood-onset NS. We enrolled 1,000 patients with childhood-onset NS comprised of SSNS and SRNS. Genotyping was done using TaqMan and Direct Sanger Sequencing for 9 previously reported childhood SSNS risk loci. We compared the allele frequencies (AF) and variant burden between NS vs. controls and SRNS vs. SSNS. All 9 risk loci were associated with NS compared with healthy controls (p = 3.5 × 10-3-<2.2 × 10-16). Variant burden greater than 7 was associated with risk of SRNS (OR 7.4, 95% CI 4.6-12.0, p = 8.2 × 10-16). Our study showed that genetic risk loci for childhood SSNS are associated with pattern of therapy response, may help predict disease outcome, and set the stage for individualized treatment of NS.

A genomic association study revealing subphenotypes of childhood steroid-sensitive nephrotic syndrome in a larger genomic sequencing cohort

Dissecting the genetic components that contribute to the two main subphenotypes of steroid-sensitive nephrotic syndrome (SSNS) using genome-wide association studies (GWAS) strategy is important for understanding the disease. We conducted a multicenter cohort study (360 patients and 1835 controls) combined with a GWAS strategy to identify susceptibility variants associated with the following two subphenotypes of SSNS: steroid-sensitive nephrotic syndrome without relapse (SSNSWR, 181 patients) and steroid-dependent/frequent relapse nephrotic syndrome (SDNS/FRNS, 179 patients). The distribution of two single-nucleotide polymorphisms (SNPs) in ANKRD36 and ALPG was significant between SSNSWR and healthy controls, and that of two SNPs in GAD1 and HLA-DQA1 was significant between SDNS/FRNS and healthy controls. Interestingly, rs1047989 in HLA-DQA1 was a candidate locus for SDNS/FRNS but not for SSNSWR. No significant SNPs were observed between SSNSWR and SDNS/FRNS. Meanwhile, chromosome 2:171713702 in GAD1 was associated with a greater steroid dose (>0.75 mg/kg/d) upon relapse to first remission in patients with SDNS/FRNS (odds ratio = 3.14; 95% confidence interval, 0.97–9.87; P = 0.034). rs117014418 in APOL4 was significantly associated with a decrease in eGFR of greater than 20% compared with the baseline in SDNS/FRNS patients (P = 0.0001). Protein–protein intersection network construction suggested that HLA-DQA1 and HLA-DQB1 function together through GSDMA. Thus, SSNSWR belongs to non-HLA region-dependent nephropathy, and the HLA-DQA/DQB region is likely strongly associated with disease relapse, especially in SDNS/FRNS. The study provides a novel approach for the GWAS strategy of SSNS and contributes to our understanding of the pathological mechanisms of SSNSWR and SDNS/FRNS.

Long-term outcomes of childhood steroid-sensitive nephrotic syndrome

Objective: To investigate the long-term outcomes and risk factors in children with steroid-sensitive nephrotic syndrome (SSNS). Methods: A retrospective cohort study was conducted on newly onset SSNS admitted to the Department of Pediatrics of the First Affiliated Hospital of Sun Yat-sen University from January 2006 to December 2010 and 105 cases with follow-up for more than 10 years were included. Clinical data including general characteristics, clinical manifestation, laboratory tests, treatment and prognosis. The primary outcome was the clinical cure, and the secondary outcomes were relapse or ongoing immunosuppressive treatment within the last 1 year of follow-up and complications at the last follow-up. According to the primary outcome, the patients were divided into clinical cured group and uncured group. Categorical variables were compared between 2 groups using the χ2 or Fisher exact test, and continuous variables by t or Mann-Whitney U test. Multiple Logistic regression models were used for multivariate analysis. Results: Of the 105 children with SSNS, the age of onset was 3.0 (2.1, 5.0) years, and 82 (78.1%) were boys, 23(21.9%) were girls. The follow-up time was (13.1±1.4) years; 38 patients (36.2%) had frequently relapsing or steroid-dependent nephrotic syndrome (FRNS or SDNS) and no death or progression to end-stage kidney disease. Eighty-eight patients (83.8%) were clinically cured. Seventeen patients (16.2%) did not reach the clinical cure criteria, and 14 patients (13.3%) had relapsed or ongoing immunosuppressive treatment within the last year of follow-up. The proportion of FRNS or SDNS (12/17 vs. 29.5% (26/88), χ2=10.39), the proportion of treatment with second-line immunosuppressive therapy (13/17 vs. 18.2% (16/88), χ2=21.39), and the level of apolipoprotein A1 at onset ((2.0±0.5) vs. (1.7±0.6) g/L, t=2.02) in the uncured group were higher than those in the clinical cured group (all P<0.05). Multivariate Logistic regression analysis showed that patients treated with immunosuppressive therapy had an increased risk of not reaching clinical cure in the long term (OR=14.63, 95%CI 4.21-50.78, P<0.001). Of the 55 clinically cured patients who had relapsed, 48 patients (87.3%) did not relapse after 12 years of age. The age at last follow-up was 16.4 (14.6, 18.9) years, and 34 patients (32.4%) were ≥18 years of age. Among the 34 patients who had reached adulthood, 5 patients (14.7%) still relapsed or ongoing immunosuppressive treatment within the last year of follow-up. At the last follow-up, among the 105 patients, 13 still had long-term complications, and 8 patients were FRNS or SDNS. The proportion of FRNS or SDNS patients with short stature, obesity, cataracts, and osteoporotic bone fracture was 10.5% (4/38), 7.9% (3/38), 5.3% (2/38), and 2.6% (1/38), respectively. Conclusions: The majority of SSNS children were clinically cured, indicating a favorable long-term prognosis. History of treatment with second-line immunosuppressive therapy was the independent risk factor for patients not reaching the clinical cure criteria in the long term. While it is not uncommon for children with SSNS to persist into adulthood. The prevention and control of long-term complications of FRNS or SDNS patients should be strengthened.

Common Risk Variants in AHI1 Are Associated With Childhood Steroid Sensitive Nephrotic Syndrome

Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of kidney disease in children worldwide. Genome-wide association studies (GWAS) have demonstrated the association of SSNS with genetic variation at HLA-DQ/DR and have identified several non-HLA loci that aid in further understanding of disease pathophysiology. We sought to identify additional genetic loci associated with SSNS in children of Sri Lankan and European ancestry. We conducted a GWAS in a cohort of Sri Lankan individuals comprising 420 pediatric patients with SSNS and 2339 genetic ancestry matched controls obtained from the UK Biobank. We then performed a transethnic meta-analysis with a previously reported European cohort of 422 pediatric patients and 5642 controls. Our GWAS confirmed the previously reported association of SSNS with HLA-DR/DQ (rs9271602, P= 1.12× 10-27, odds ratio [OR]= 2.75). Transethnic meta-analysis replicated these findings and identified a novel association at AHI1 (rs2746432, P= 2.79× 10-8, OR= 1.37), which was also replicated in an independent South Asian cohort. AHI1 is implicated in ciliary protein transport and immune dysregulation, with rare variation in this gene contributing to Joubert syndrome type3. Common variation in AHI1 confers risk of the development of SSNS in both Sri Lankan and European populations. The association with common variation in AHI1 further supports the role of immune dysregulation in the pathogenesis of SSNS and demonstrates that variation across the allele frequency spectrum in a gene can contribute to disparate monogenic and polygenic diseases.

Can Oral Zinc Supplementation Reduce Relapses in Childhood Steroid-Sensitive Nephrotic Syndrome? A Systematic Review.

Frequent relapses and steroid dependence are common treatment challenges of steroid-sensitive nephrotic syndrome (SSNS) in children. Acute respiratory infection (ARI) is the most frequently reported trigger of relapse. Given the role of zinc supplementation in preventing ARI, some studies show that this targeted intervention may reduce relapses in childhood SSNS. This systematic review aimed to determine if oral zinc supplementation can significantly reduce relapses in this disease. We searched the PubMed and Google Scholar electronic databases for interventional and observational analytical studies without limiting their year or language of publication. We selected studies with primary data that met our inclusion criteria, screened their titles and abstracts, and removed duplicates. We used a preconceived structured form to extract data items from selected studies and conducted a quality assessment of randomized controlled trials (RCTs) and non-randomized studies with the Cochrane collaboration tool and the Newcastle Ottawa Scale, respectively. We qualitatively synthesized the extracted data to validate the review's objective. Eight full-text articles were selected, comprising four RCTs and four observational analytical studies. Two of the RCTs had a high risk of bias in three parameters of the Cochrane collaboration tool, while three non-randomized studies had low methodological quality. A total of 621 pediatric patients with SSNS were investigated in the eight studies: six participants dropped out in one study. Three RCTs indicate that zinc supplementation may lead to sustained remission or reduction in relapse rate. Similarly, three observational analytical studies suggest a significant relationship between reduced serum zinc levels and disease severity. Despite the association of zinc deficiency with increased morbidity in SSNS and the reduction of relapse rates with zinc supplementation, there is no robust evidence to recommend its use as a therapeutic adjunct. We recommend more adequately-powered RCTs to strengthen the current evidence.

FC038: Efficacy of Levamisole for Maintaining Remission after the First Flare of Steroid Sensitive Nephrotic Syndrome in Children: The Nephrovir-3 Randomized Controlled Trial

Abstract BACKGROUND AND AIMS In children with Steroid Sensitive Nephrotic Syndrome (SSNS), relapse after the first flare occurs in 80% of cases, whatever the dosage or duration of initial steroid therapy. Therefore, there is an unmet need for early interventions to reduce the incidence of relapse and subsequent steroids and immunosuppressive drug exposure. Levamisole is an antihelmintic drug with an immunomodulatory action that reduces relapses in children with frequent relapses or steroid-dependant NS. NEPHROVIR-3 is the first trial to assess the efficacy of levamisole in increasing duration of initial remission after the diagnosis of INS. METHOD NEPHROVIR-3 is a multicentric placebo-controlled randomized trial (1:1), in 38 centres of the Paris area, France. Patients were included at INS diagnosis and randomized, when steroid sensitive within 4 weeks, to receive either levamisole 2.5 mg/kg/48 h or placebo for 6 months, in addition to the French steroid protocol (18 weeks-3990 mg/m2). Primary outcome was the relapse-free survival at 1 year. The effect of the study drug was analysed by a Cox proportional hazard model stratified on centre. RESULTS Between September 2017 and February 2020, 86 patients were included, median age at INS onset was 5 years (IQ 3–7), with 69% of boys. At 4 weeks, 68 of them were randomized. Median time to remission was 8.5 days (IQ 6–12). Relapse-free survival at 12 months was 53.8% [95 confidence interval (95% CI) 34.7–69.5] in the levamisole group versus 20.9% (7.2–39.4) in the placebo group (P = .007). The risk of relapse associated with levamisole was HR = 0.37 (95% CI 0.15–0.89). CONCLUSION Early treatment with levamisole at the first flare of childhood SSNS significantly improves relapse-free survival at 1 year.

Patterns, triggers, and predictors of relapses among children with steroid-sensitive idiopathic nephrotic syndrome at the University of Abuja Teaching Hospital, Gwagwalada, Abuja, Nigeria

Background Childhood steroid-sensitive idiopathic nephrotic syndrome (SSINS) is plagued with relapses that contribute to its morbidity and the cost of treatment. Patients and methods This is a retrospective review of relapses among children with SSINS at the University of Abuja Teaching Hospital from January 2016 to July 2020. Triggers related to relapse incidents were noted. χ 2 test was deployed for predictors (factors at the first clinical presentations that associate with subsequent relapses) of relapses. Predictors with P values of less than 0.05 were considered significant, and 95% confidence intervals (CI) and odd ratio (OR) were described. Results A total of 60 patients with SSINS, comprising 52 (86.7%) males, aged 23 months to 18 years, with a mean age of 7.04±4.16 years, were studied. A total of 38 (63.3%) participants had 126 relapses, including infrequent relapses in 30 (78.9%) and frequent relapses in eight (21.1%). The commonest triggers were acute upper respiratory tract infections (68, 53.9%) and urinary tract infections in 25 (19.8%) relapses. In four (3.2%) relapses, no trigger was identified. The time-to-first relapse ranged 14–365 days, with a median time of 60 days. The significant predictors were hypertension (OR=3.4, 95% CI; 1.04–11.09, P=0.038), urinary tract infections (OR=9.9, 95% CI; 1.16–80.71, P=0.014), malaria fever (OR=8.0, 95% CI; 2.45–26.38, P&lt;0.001), microhematuria (OR=4.9, 95% CI; 11.58–15.16, P=0.004), elevated serum creatinine (OR=12.3, 95% CI; 1.48–101.20, P=0.005), and hypercholesterolemia (OR=4.1, 95% CI; 1.35–12.63, P=0.011). Conclusion Although the pathogenesis of relapses remains unknown, it is prudent to consider relapse-specific preventive strategies against triggers and predictors of relapses in our setting.

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

BackgroundFew 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.MethodsA 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.ResultsCompared 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.ConclusionsHLA-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.

Thyroid profile in idiopathic childhood steroid-sensitive nephrotic syndrome

Thyroid profile in idiopathic childhood steroid-sensitive nephrotic syndrome

Thyroid Profile in Idiopathic Childhood Steroid-Sensitive Nephrotic Syndrome

Background: Nephrotic syndrome (NS), the most common glomerular disease of childhood, characterized by massive proteinuria which may have a negative impact on the circulating thyroid hormone status necessitating thyroid hormone supplementation in these children. Aim: The aim was to determine the thyroid status in steroid-sensitive NS during the time of relapse and remission. Materials and Methods: In this single-center prospective observational study, we documented thyroid hormone profile (thyroid-stimulating hormone [TSH], thyroxine, and triiodothyronine) in fifty children at presentation (first attack or relapse) and again 4 weeks after remission. Baseline characteristics were noted in the prestructured proforma. Results: Out of the total fifty children analyzed, 29 were male and 21 females. Although both T3 and T4 levels were within the normal range in all participants during attack/relapse and in remission, there was a statistically significant difference in absolute levels of both T3 and T4 at relapse and remission (P = 0.001). There was a significant rise of TSH levels during attack/relapse which normalized to normal values after 4 weeks of remission (13.08 ± 7.9 vs. 2.43 ± 1.00 mIU/L,P = 0.0001). None required thyroid hormone replacement therapy. Conclusion: The rise of TSH level during relapse is mostly transient and usually does not require thyroid hormone supplementation.

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 < 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 < 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.

Mycophenolate Mofetil Treatment in Childhood Steroid-sensitive Nephrotic Syndrome: Single Center Experience

Objective : We aimed to investigate the efficacy of mycophenolate mofetil (MMF) for maintaining remission and reduce the number of relapses in childhood steroid-sensitive nephrotic syndrome. The effects of MMF on growth and blood pressure parameters were also evaluated. Material and Methods: This retrospective, single-center observational study included patients with steroid-sensitive nephrotic syndrome who were treated using MMF between 2009 and 2019 in the Department of Pediatric Nephrology in our hospital. Results: Ten patients had steroid-dependent nephrotic syndrome; six patients frequently had relapsing nephrotic syndrome in this study. The mean duration of the disease was 93.3 ± 25.0 months and the mean duration of the MMF onset was 33.9 ± 16.7 months after diagnosis. Ten patients showed a 50% or greater reduction in the relapse rate and the prednisolone treatment was discontinued in eight patients for six months or more. Compared to the previous year, before the start of the MMF treatment, there was a 52.7% reduction in the relapse rate and a 36.6% reduction in the cumulative annual dose of steroid after 12 months of MMF treatment. The height z score and the median office systolic blood pressure standard deviation scores of the patients improved after MMF treatment (respectively p = 0.003, p = 0.01). Conclusion: The findings suggest that MMF may lead to decreased relapse rates and cumulative steroid dose, which has a positive effect on growth and blood pressure parameters in steroid-sensitive nephrotic syndrome.

Rituximab in children with steroid sensitive nephrotic syndrome: in quest of the optimal regimen.

Rituximab has emerged as an effective and important therapy in children with complicated frequently relapsing and steroid-dependent nephrotic syndrome to induce long-term disease remission and avoid steroid toxicities. The optimal rituximab regimen is not totally well defined, and there are many varying practices worldwide. We will in this review describe how patient factors, rituximab dose, and use of maintenance immunosuppression affect treatment outcomes. Specifically, low-dose rituximab without concomitant immunosuppression is associated with shorter relapse-free duration while other regimens have comparable outcomes. Patients with more severe disease generally have worse response to rituximab. Although rituximab appears to be generally safe, there are growing concerns of chronic hypogammaglobulinemia and impaired immunity especially in young children. Reliable prognostications and biomarkers for guiding subsequent treatments to avoid excessive treatments are yet to be identified. In this review, we will outline the, as we see it, best approach of rituximab in childhood steroid sensitive nephrotic syndrome at the present state of knowledge.

Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome

To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P=4.94E-20, odds ratio (OR)=1.90) and TNFSF15 (rs6478109, P=2.54E-8, OR=0.72) regions achieved genome-wide significance and were replicated in Korean, South Asian and African populations. Trans-ethnic meta-analyses including Japanese, Korean, South Asian, African, European, Hispanic and Maghrebian populations confirmed the significant associations of variants in NPHS1-KIRREL2 (Pmeta=6.71E-28, OR=1.88) and TNFSF15 (Pmeta=5.40E-11, OR=1.33) loci. Analysis of the NPHS1 risk alleles with glomerular NPHS1 mRNA expression from the same person revealed allele specific expression with significantly lower expression of the transcript derived from the risk haplotype (Wilcox test p=9.3E-4). Because rare pathogenic variants in NPHS1 cause congenital nephrotic syndrome of the Finnish type (CNSF), the present study provides further evidence that variation along the allele frequency spectrum in the same gene can cause or contribute to both a rare monogenic disease (CNSF) and a more complex, polygenic disease (SSNS).

Centromere protein I (CENPI) is a candidate gene for X-linked steroid sensitive nephrotic syndrome.

Individuals with proteinuria in association with hypoalbuminemia, edema, and hyperlipidemia are considered as having nephrotic syndrome (NS). NS is the most common kidney disease seen in the paediatric age group. NS is usually classified into steroid resistant nephrotic syndrome (SRNS) and steroid sensitive nephrotic syndrome (SSNS). More than 58 genes have been identified as a monogenic cause of SRNS, however, the genetic architecture of childhood SSNS remains poorly understood. Here in this study, we performed sequencing of 66 NS candidate genes followed by whole genome SNP genotyping and whole exome sequencing in SSNS families with multiple affected individuals. NS candidate genes sequencing did not identify any pathogenic variant in the known genes. Homozygosity mapping based on an autosomal recessive model failed to detect any shared loss of heterozygosity region in the genome. An unbiased and hypothesis-free exome data analysis identified a missense variant (c.383G>A; p.Arg128Gln) in the CENPI gene. Sanger sequencing of both parents, unaffected and affected individuals confirmed an X-linked inheritance pattern of the variant (c.383G>A) with SSNS phenotype. The variant (c.383G>A) is very rare and is potentially damaging. Collectively, these observations suggest that a specific pathogenic link between SSNS development and alteration in CENPI exists. However, human mutations in CENPI causing SSNS have not been reported hitherto. Identification of genetic defects underlying SSNS will help in understanding the precise aetiology of SSNS and improved management of children with NS.

Lower prednisone dosing for steroid-sensitive nephrotic syndrome relapse: a prospective randomized pilot study.

Relapses of steroid-sensitive nephrotic syndrome are traditionally treated with prednisone 2mg/kg/day or 60mg/m2/day. Retrospective data support the use of lower doses. We designed a prospective randomized pilot study to investigate the efficacy of different doses in achieving remission of steroid sensitive nephrotic syndrome relapse. The cohort included 30 children with relapsed steroid sensitive nephrotic syndrome, mean age 6.3 ± 3years and mean disease duration 2.2 ± 1.8years. The children were randomized to receive 2, 1.5, or 1mg/kg/day prednisone. The corresponding times to response, defined as the first of 3 consecutive days without proteinuria, were 7.2 ± 1.4, 10.2 ± 5.1, and 9 ± 3.3days; the difference between the 1.5 and 2mg/kg/day groups was statistically significant. One patient each in the 1mg/kg/day and the 1.5mg/kg/day groups failed to respond and were switched to 2mg/kg/day, leading to a response after 3 and 10days, respectively. Mean cumulative prednisone doses in the 3 groups were 45.5 ± 3.4, 42.7 ± 25.9, and 24.9 ± 7.4mg/kg, respectively (P < 0.05).Conclusion: In the present study, treatment of childhood steroid sensitive nephrotic syndrome relapse with prednisone 1-1.5mg/kg/day led to a significantly lower cumulative dose than the standard dose. Treatment with a lower dose may be equally safe and effective to the standard dose.What is Known:• Relapses of steroid-sensitive nephrotic syndrome are traditionally treated with standard-dose steroids.• Treatment with corticosteroids may have significant adverse effects mainly with long-term use.What is New:• Treatment of steroid sensitive nephrotic syndrome relapse with 1-1.5mg/kg/day prednisone may lead to a significantly lower cumulative dose.• Treatment with a lower steroid dose may be as effective as the standard dose in achieving remission of steroid sensitive nephrotic syndrome relapse.

Genetics of Childhood Steroid Sensitive Nephrotic Syndrome: An Update.

Advances in genome science in the last 20 years have led to the discovery of over 50 single gene causes and genetic risk loci for steroid resistant nephrotic syndrome (SRNS). Despite these advances, the genetic architecture of childhood steroid sensitive nephrotic syndrome (SSNS) remains poorly understood due in large part to the varying clinical course of SSNS over time. Recent exome and genome wide association studies from well-defined cohorts of children with SSNS identified variants in multiple MHC class II molecules such as HLA-DQA1 and HLA-DQB1 as risk factors for SSNS, thus stressing the central role of adaptive immunity in the pathogenesis of SSNS. However, evidence suggests that unknown second hit risk loci outside of the MHC locus and environmental factors also make significant contributions to disease. In this review, we examine what is currently known about the genetics of SSNS, the implications of recent findings on our understanding of pathogenesis of SSNS, and how we can utilize these results and findings from future studies to improve the management of children with nephrotic syndrome.

A longitudinal study on the effects of psychological stress on proteinuria in childhood steroid-sensitive nephrotic syndrome

ObjectiveSteroid-sensitive nephrotic syndrome (SSNS) in children is often complicated by one or more relapses, as manifested by the appearance of proteinuria. Besides health-related triggers, psychological stress might be related to relapse. This longitudinal study examined the link between perceived stress, emotional valence (feeling happy vs. unhappy) and daily reported proteinuria, and investigated the temporal relation between stressful events and proteinuria. MethodSixteen children (4–13 years) diagnosed with SSNS were included. Patients kept an online diary for an average of 124 days, wherein they reported proteinuria (n = 1985 urine samples), perceived stress, emotional valence, medication use and health complaints. Stressful days were determined at the start of the study. Using multilevel analysis, the following associations were tested: (1) the relation between perceived stress, emotional valence and proteinuria, and (2) the temporal relation between stressful days and proteinuria. ResultsAppearance of proteinuria was reported in 410/1985 urine samples. Perceived stress and not emotional valence significantly predicted proteinuria (95% CI [0.11, 0.27]), even five days later. There was a significant temporal association between stressful days and proteinuria (95% CI [0.22, 1.14]). The effect sizes of these associations were small, f = 0.04 and f = 0.12, respectively. ConclusionsOur findings suggest that psychological stress may trigger proteinuria in children with SSNS. Future research in larger samples is needed to support our findings.

Childhood onset steroid-sensitive nephrotic syndrome continues into adulthood

Childhood steroid-sensitive nephrotic syndrome (SSNS) has previously been assumed to be a disease of childhood. This has been challenged by few studies reporting that some patients with childhood SSNS may continue to relapse into adulthood. The aim of this study was to investigate the long-term outcome of childhood SSNS presenting data from an unselected well-defined cohort of Danish patients. We conducted a retrospective study of the clinical outcome from a population of patients consecutively admitted to the pediatric departments in the central and northern region of Denmark from 1998 to 2015. Patients were followed until August 2017. Data were collected from the patient's medical records. Long-term outcome was studied in 39 adult patients with childhood onset SSNS. A total of 31% (12/39) had active disease in adulthood. Univariate analysis showed that more severe forms of SSNS (e.g., steroid dependent/frequent relapsing (SD/FR) nephrotic syndrome) in childhood were associated with active disease in adulthood. Comparing adult patients with SD/FR showed a significantly higher number of relapses/patient/year from late childhood and adolescence in the group with active disease vs. non-active disease (1.06 (95%CI: 0.32-1.81) vs. 0.19 (95%CI: 0.06-0.31, p = 0.005). In general, one third of all patients with SSNS during childhood continue to have active disease during early adulthood, in particular patients with SD/FR continue to suffer from active disease. The present data illustrates that SSNS is not just a disease of childhood but persists in adulthood in a significant number of patients.

Genetic Basis of Health Disparity in Childhood Nephrotic Syndrome

Nephrotic syndrome is the most common glomerular disease in children. There is wide variation in the incidence of nephrotic syndrome in different populations, with a higher incidence in children of South Asian descent. However, nephrotic syndrome with a more indolent course and poor prognosis is more common in African American children. The disparity in the prevalence and severity of nephrotic syndrome is likely due to complex interactions between environmental and biological factors. Recent advances in genome science are providing insight into some of the biological factors that may explain these disparities. For example, risk alleles in the gene encoding apolipoprotein L1 (APOL1) have been established as the most important factor in the high incidence of chronic glomerular diseases in African Americans. Conversely, the locus for childhood steroid-sensitive nephrotic syndrome in the gene encoding major histocompatibility complex-class II-DQ-alpha 1 (HLA-DQA1) is unlikely to be the explanation for the high incidence of steroid-sensitive nephrotic syndrome in Asian children because the same variants are equally common in whites and African Americans. There is a need for collaborative large-scale studies to identify additional risk loci to explain disparities in disease incidence and response to therapy. Findings from such studies have the potential to lead to the identification of new therapeutic targets for nephrotic syndrome.