Steroid-sensitive Nephrotic Syndrome Patients Research Articles

Lipidomic profiles in serum and urine in children with steroid sensitive nephrotic syndrome

BackgroundSteroid-sensitive nephrotic syndrome (SSNS) accounts for approximately 80% of cases of nephrotic syndrome. The involvement of aberrant lipid metabolism in early SSNS is poorly understood, warranting further investigation. This study aimed to explore alterations in lipid metabolism associated with SSNS pathogenesis. MethodsA screening cohort containing serum (50 SSNS, 37 controls) and urine samples (27 SSNS, 26 controls) was analyzed by untargeted lipidomic profiling using UHPLC-QTOF-MS. Then, a validation cohort (20 SSNS, 56 controls) underwent further analysis to check the potential clinical application by ROC curve analysis. ResultsLipidomic profiling of serum and urine samples revealed significant lipid alterations in SSNS patients, with the alterations in the serum samples being more significant. An elevated concentration of PE and PG and downregulated concentration of FA were observed in SSNS serum. A total of 38 dysregulated lipids and 5 lipid metabolic pathways were identified in the serum samples in SSNS patients. Validation in the second cohort confirmed differential regulation of nine kinds of lipids, including 5 up-regulated substances [SM d33:2 (m/z = 686.5361), SHexCer d34:1 (m/z = 779.521), PI 20:4_22:4 (m/z = 934.5558), Cer_NS d18:1_23:0 (m/z = 635.6216), and GM3 d36:1 (m/z = 1180.7431)], as well as 4 down-regulated substances: [CE 18:1 (m/z = 650.601), PE 38:6 (m/z = 763.5205), PC 17:0_20:4 (m/z = 795.5868) and EtherPC 16:2e_20:4 (m/z = 763.5498)]. ConclusionsUntargeted lipidomic analysis successfully identified specific lipid class changes in patients with SSNS, providing a deeper understanding of lipid alterations and underlying mechanisms associated with SSNS.

Comparison of Urinary Beta-2 Microglobulin Levels in Children with SSNS and Calcineurin Inhibitor-Treated SRNS.

While the utility of beta-2 microglobulin (β2M) has been explored in various renal conditions to identify tubulointerstitial damage, it has not been adequately studied in nephrotic syndrome. The primary objective of the study was to compare urinary β2M levels in children with steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS) in disease remission. This cross-sectional study was done at a tertiary care hospital between April 2019 and March 2020. Sixty children (2-18 years) with SSNS and SRNS (30 in each group) in remission were enrolled. SRNS patients were included after ≥1 year of treatment with calcineurin inhibitors (CNIs). Biochemical investigations were done to confirm remission; spot samples for urinary β2M were collected and estimation was done by an enzyme-linked immunosorbent assay (ELISA)-based kit. Of the 60 children, 63% were boys. The median (interquartile range [IQR]) age at enrollment for SSNS and SRNS patients was 7 (4.1-9) and 11 (8.3-12) years, respectively. Urinary β2M levels were significantly higher in SRNS patients compared to SSNS patients (2.6 vs. 0.75 mg/ml, P < 0.0001). Patients who received cyclosporine for >2 years had higher median urinary β2M levels compared to those who received it for a shorter period (2.63 vs. 1.83 mg/ml, P = 0.03). Median β2M levels were higher in focal segmental glomerulosclerosis than minimal change disease (3.5 vs. 2.5 mg/ml). Urinary β2M levels were higher in SRNS compared to SSNS disease in remission, and β2M levels correlated well with CNI use of >2 years. It appears to be a promising noninvasive tool to identify early tubular damage and progression in patients with nephrotic syndrome, especially SRNS.

Long-term outcomes in children with idiopathic nephrotic syndrome: a single center experience

Purpose: Idiopathic nephrotic syndrome (INS) is a common glomerular disease observed in children. Depending on their response to steroids, patients can be classified either as having steroid-sensitive nephrotic syndrome (SSNS) or steroid-resistant nephrotic syndrome (SRNS). Whereas SSNS patients respond favorably to steroid treatment and achieve a complete remission with normal renal functions, SRNS patients do not, and are at high risk of developing end-stage renal diseases (ESRD). The aim of this study was to analyze the long-term outcomes of patients with INS.&#x0D; Materials and Methods: In our medical center, records of children diagnosed with INS were evaluated. Demographic information, laboratory results, response to treatment, and clinical progression were analyzed.&#x0D; Result: Ninety-one children (64% male) with a mean age of 11.1±4.1 years (3.5-18) were included in the patient cohort, with a mean age of diagnosis of 5.2±3.8 years (1-16.2) and a mean follow-up period of 5.7±2.8 years (2-12). Sixty-eight (75%) patients had SSNS, and 23 (25%) patients had SRNS. Among the SSNS patients, 18 (31%) were steroid-dependent, 12 (20%) were frequently relapsing, and 29 (49%) were infrequently relapsing. Renal biopsy was performed on 29 (32%) patients, 59% had focal segmental glomerulosclerosis. The complete remission rate was 94% for all patients, with 100% for SSNS and 74% for SRNS. ESRD was developed for 9% of patients with SRNS.&#x0D; Conclusion: The response to steroid treatment serves as a valuable prognostic indicator for INS as it plays a pivotal role in mitigating the risk of progression toward end-stage renal failure.

Urinary Apolipoprotein A1 and Neutrophil Gelatinase-associated Lipocalin in Children with Idiopathic Nephrotic Syndrome

Urinary biomarkers are a promising diagnostic modality whose role was explored in nephrotic syndrome (NS). We estimated urinary apolipoprotein A1 (Apo A1) and neutrophil gelatinase-associated lipocalin (NGAL) in children with first-episode NS (FENS) and controls with a longitudinal follow-up to see the serial changes during remission. The study groups comprised 35 children with FENS and an equal number of age- and sex-matched controls. Patients were followed up at regular intervals, and 32 patients were classified as having steroid-sensitive NS (SSNS) and 3 as having steroid-resistant NS (SRNS). The mean follow-up period was 8.7 ± 4.2 months. Three patients in the SSNS group were labeled as having frequent relapses or steroid-dependent disease during follow-up. Of the three children with SRNS, two had minimal changes in the disease and one had idiopathic membranous nephropathy. The levels of Apo A1:creatinine, NGAL:creatinine, and spot urinary protein:urinary creatinine ratios were significantly higher in children with FENS compared with controls. The levels of the urine biomarkers decreased significantly at subsequent follow-up with remission. The Apo A1 and NGAL levels in SSNS patients were significantly high compared with both the controls and FENS patients. Urinary Apo A1 levels in SRNS patients were lower at initial presentation. This longitudinal study revealed changes in the urinary Apo A1 and NGAL in NS over the course of the disease.

T-cell and B-cell repertoire diversity are selectively skewed in children with idiopathic nephrotic syndrome revealed by high-throughput sequencing.

Clinical studies suggest that the dysfunction of T cells and B cells may play an essential role in the pathogenesis of idiopathic nephrotic syndrome (INS), but laboratory evidence is lacking. Therefore, this study explored T-cell receptor (TCR) and B-cell receptor (BCR) profiling in children with idiopathic nephrotic syndrome. High-throughput sequencing technology was used to profile the TCR and BCR repertoires in children with INS. Peripheral blood was collected from ten INS patients, including five vinculin autoantibody-positive patients and five vinculin autoantibody-negative patients, before and after treatment. TCR and BCR libraries were constructed by 5'-RACE and sequenced by a DNBSEQ-T7 sequencer, and sequence analyses were performed using ReSeqTools, FastP, MiXCR, and VDJtools. The TRA (T-cell receptor α), TRG (T-cell receptor γ), and IGH (immunoglobulin heavy chain) repertoires of the INS group were occupied by highly abundant clonotypes, whereas small clonotypes occupied the healthy group, especially TRA. A significant increase in the Shannon-Weaver index was observed for the TRA and TRG repertoires after treatment in vinculin autoantibody-negative patients, but a significant increase in the IGH repertoire after treatment was observed in vinculin autoantibody-positive patients. The frequency of some V-J pairs was significantly enriched in steroid-sensitive nephrotic syndrome patients. The usage frequency of the V and J genes was skewed in patients, which seemed not related to immunosuppressive therapy. However, after effective treatment, dynamic changes in the size of the individual clonotype were observed. T-cell and B-cell immunity contribute to the pathogenesis of different INSs. Video: (MP4 99,786KB).

Association of Catalase Gene Polymorphisms with Idiopathic Nephrotic Syndrome in a Chinese Pediatric Population.

Our aim was to investigate the association between gene polymorphisms in catalase (CAT), a well-known oxidative stress regulator, and susceptibility to idiopathic nephrotic syndrome (INS) or responses to steroid therapy in a Chinese pediatric population. We analyzed 3 CAT single-nucleotide polymorphisms (SNVs; rs7943316, rs769217, and rs12270780) using multi-polymerase chain reaction combined with next-generation sequencing in 183 INS patients and 100 healthy controls. For the allele and genotype frequencies of the CAT SNVs, no significant differences were observed between INS patients and controls. Patients with C allele of CAT rs769217 had a higher risk of developing steroid-dependent nephrotic syndrome than the steroid-sensitive nephrotic syndrome patients (P = 0.018; odds ratio = 1.76). Our data suggests that genetic variations in CAT were unlikely to confer susceptibility to INS in Chinese children, whereas the C allele of the CAT rs769217 polymorphism showed a strong association with steroid-dependent responses in Chinese INS children.

MO1040: Idiopathic Nephrotic Syndrome After 10 Years of Age: Is Systematic Renal Biopsy Appropriate?

Abstract BACKGROUND AND AIMS Renal biopsy (RB) is recommended at diagnosis for children presenting with isolated nephrotic syndrome (NS) after the age of 10–12 years, unlike in younger children, because of a higher frequency of other diagnoses than MCD or FSGS. Recent reports, local practices and new serological biomarkers for membranous nephropathy now question this approach. Therefore, the objective of our study was to evaluate the causes of NS and indications for RB in a population-based cohort of adolescents with NS. METHOD We conducted a retrospective multicenter study, including children aged 10–18 years diagnosed with Idiopathic-like NS between December 2007 and June 2020 in 35 paediatric and 3 paediatric nephrology (PN) departments of the Paris area (NEPHROVIR network) and patients with Idiopathic-looking NS biopsied in the three PN departments. RESULTS A total of 103 children were included (54 males). The mean age at diagnosis was 13.4 ± 2 years. A renal biopsy was performed in 76 patients: at presentation because of atypical symptoms (such as hypertension, macroscopic haematuria, organic renal failure) in 15 or for no other reason than age in 39 and after 4 weeks for steroid resistance +/– atypies in 22 patients. Histological findings were MCD (n = 49), FSGS (n = 13), mesangial proliferation (n = 3), membranous nephropathy (n = 6) and IgAN (n = 5). CONCLUSION NS was secondary in only 11% of adolescents presenting with Idiopathic-like NS, and first-line treatment with oral prednisone was appropriate in all cases. In addition, more than 40% of RB could have been avoided in steroid-sensitive NS patients. Finally, we propose that RB should only be performed in case of atypical clinical or biological history or steroid resistance after 4 weeks, as in the younger population.

STUDY ON RISK FACTORS FOR RELAPSE IN CHILDHOOD NEPHROTIC SYNDROME IN A TERTIARY CARE CENTRE OF EASTERN INDIA

Background: Nephrotic syndrome is a common renal disease in children characterised by massive proteinuria,hypoalbuminemia(serum albumin &lt;2.5g/dl),hyperlipidemia(serum cholesterol&gt;200mg/dl) and edema.It has high propensity for relapse.Approximately 80-90%of steroid sensitive nephrotic syndrome patients experience one or more relapses during their lifetime. So,the main problem in such disease is relapses and their association with complications of disease or side effects of drugs like steroid used in treatment.An understanding of risk factors that determine the course,is useful in taking decisions regarding therapy and counselling of parents.Ascarcity of reported data on risk factors for relapse from eastern India prompted to carry out this study in a tertiary care hospital. Aims And Objectives:To determine different risk factors for relapse in childhood nephrotic syndrome. Materials And Method: A retrospective analysis of medical records of children with steroid sensitive nephrotic syndrome of 1-12 years of age,with history of disease onset atleast 1 year back,attending inpatient and outpatient department of Pediatric medicine,IPGME&amp;R,Kolkata was carried out from February 2016 –July 2017 after obtaining ethical clearance from Instituitional Ethics committee and written informed consent from parents. Results: Records of 60 children with SSNS were reviewed.The mean age of the study population was7.3±2.7 years. Boys constituted 63.3% &amp; girls constituted 36.7% of total study population. 23 patients were included in FRNS/SDNS group,rest 37 patients were in IFRNS/No relapse group.Data were analyzed by using SPSS 20.0.1 programme and Graph Pad Prism version 5. Chi-square test &amp; Two-sample t-tests were used as statistical test &amp; p value &lt;0.05 was taken as signicant.Compared to IFRNS/No relapse,patients with FRNS/SDNS had signicantly more infections during 1st episode,more association with massive edema, more number of patients with inadequate duration of treatment (&lt;8weeks or irregular) and longer achievement of remission(14.3±2.7 days vs10±2.1),shorter steroid free time interval between completion of treatment of 1st attack &amp; onset of 1st relapse.FRNS group had signicantly less serum albumin(1.68±0.202 vs 2.05±0.17g/dl) during disease onset than IFRNS/No relapse group. Conclusion: Presence of infection &amp; massive edema during disease onset, inadequate initial treatment,prolonged achievement of remission,low serum albumin during disease onset ,short steroid free time interval between completion of treatment of 1st attack &amp;onset of 1st relapse were observed as statistically signicant risk factors for frequently relapse.These observations need to be validated by multicenter prospective study with larger sample size.

Identification of Nephrin gene variants in Indian children associated with Steroid sensitive and Steroid resistant nephrotic syndrome

Nephrotic syndrome (NS) remains the most frequent indication of glomerular disease in childhood. The NPHS1 gene encoding nephrin protein is one of the common mutant genes in SRNS (Steroid Resistant Nephrotic syndrome) patients. These gene mutations are more likely to progress into ESKD (end-stage kidney disease). In the present study, we investigated the pathogenesis of the NPHS1 gene in Indian patients with SSNS and SRNS. Ninety-six children have been involved in the present study in which 37 belong to Steroid Sensitive Nephrotic syndrome (SSNS), 27 belong to Steroid Resistant Nephrotic syndrome (SRNS) 32 are healthy individuals. We designed a panel of NPHS1 gene (CDS- Coding sequence) and performed Illumina sequencing (MiSeq). We found a total of 45 variants in the NPHS1 gene. In addition, we found novel pathogenic c.2441A > G and two likely pathogenic missense variants, p.Gly395Ser, p.Ser400Pro in SSNS and SRNS patients by ACMG criteria. Therefore, early diagnosis of steroid resistant nephrotic syndrome in the Indian population can be made by identifying genetic variants using a customized gene panel.

The immune cell landscape of peripheral blood mononuclear cells from PNS patients

Existing research suggests that the human immune system and immune cells are involved in the pathogenesis of nephrotic syndrome, but there is still a lack of direct evidence. This study tried to analyze the profiling of immune cells in the peripheral blood of steroid-sensitive nephrotic syndrome (SSNS) patients and steroid-resistant nephrotic syndrome (SRNS) patients before and after standard steroid treatment to clarify the immunological mechanism of nephrotic syndrome patients. The number and proportion of CD4 + T cells in patients with nephrotic syndrome remained unchanged. However, there is an imbalance of Th1 and Th2 and an excessive increase of Th17 cells. The number of CD8 + T cells and the number of effector CD8 + T cells in them increased significantly, but only in SSNS, the number of activated CD8 + T cells increased, and the number of activated Treg cells decreased significantly. Nephrotic syndrome patients also have B cell disorder, and it is more prominent in SSNS patients. Compared with the normal control, only the number of B cells and plasmablast in SSNS patients increased significantly (Z = − 2.20, P = 0.028). This study also observed that transitional B cells decreased in both SSNS and SRNS patients, but SSNS patients' decrease was lower than in SRNS patients. Compared with normal controls, monocytes in patients with nephrotic syndrome decreased significantly. The main reason was that Non-classical Monocyte decreased, while Classical Monocyte increased slightly. The total number of NK cells did not change, but the internal cell subgroups' composition occurred. Changes, realized as CD56hi NK cells increased, CD56low NK cells decreased; and the above trend is more evident in SSNS patients. Patients with nephrotic syndrome have immune disorders, including T cells, B cells, Monocytes, and NK cells. It can be confirmed that immune factors are involved in the pathogenesis of the nephrotic syndrome.

COMPARISON OF HIGH SENSITIVITY C-REACTIVE PROTEIN VALUE FOR STEROID SENSITIVE NEPHROTIC SYNDROME PATIENTS WITH STEROID RESISTANT

Backgroud : Nephrotic syndrome (NS) is the most common glomerulopathy in childhood. The incidence of NS in the United States and United Kingdom is 2-7 new cases per 100,000 children per year, with a prevalence ranging from 16 cases per 100,000 children, and is found to be higher in developing countries. Nephrotic syndrome is a chronic disease that requires long-term monitoring because one of the complications that can be caused is cardiovascular complications caused by hyperlipidemia. High Sensitivity C-Reactive Protein (hs-CRP) can be used as a cardiovascular predictor in NS patients. Objective : To determine the differences in the value of hs-CRP in steroid sensitive nephrotic syndrome patients with steroid resistance. Methods : Case control design in 36 pediatric patients with nephrotic syndrome who came to the outpatient and inpatient unit of H. Adam Malik Hospital Medan from August 2020 to December 2020. Sampling using consecutive sampling technique, conducted interviews with parents, physical and laboratory examinations to confirm the diagnosis of steroid sensitive and steroid resistant nephrotic syndrome. An unpaired t-test and Mann-Whitney test were analyzed to assess the comparison between variables. Result : All NS patients were 36 subjects, 25 subjects (69.4%) were male and 11 subjects (30.5%) were female. The mean age of the study subjects for steroid sensitive NS patients was 8.4 (SD 4.8) years, whereas for steroid-resistant NS patients was 10.4 (SD 4.7) years. There was no significant difference between the hs-CRP value of steroid sensitive nephrotic syndrome patients with steroid resistance. Conclusion : There is no significant difference between the hs-CRP value of steroid sensitive nephrotic syndrome patients with steroid resistance.

MO248P-GLYCOPROTEIN EXPRESSING IL-17A+IFN-GAMA+ TH17/1 CELLS ARE REFRACTORY TO GLUCOCORTICOID IN NEPHROTIC SYNDROME*

Abstract Background and Aims Th17 cells are critical effectors mediating the autoimmunity in nephrotic syndrome (NS). Elevated IFN-γ has also been involved in NS; however, it remains unclear to what extent Th1 cells contribute to glucocorticoids resistance in NS. P-glycoprotein (P-gp) effluxes glucocorticoids outside the cells and selectively expressed differentially on T cell subtypes. In this study, we investigated the role of P-gp and cellular source of IFN-γ and assessed its contribution to glucocorticoids resistance in NS. Method We analyzed the frequency of pathogenic IL-17A+IFN-γ+ Th17/1 lymphocytes and P-gp expression on their surface by flow cytometry in SSNS (n = 32; mean age: 9.06 ± 5.84) and SRNS (n = 28; mean age: 11.29 ± 3.73) patients. We also included 15 age- and sex-matched healthy controls. All patients were of biopsy proven minimal change disease and all patients were treated with steroids. All patients were recruited as per the criteria of ISKDC. Results We found a significant IL-17A+IFN-γ+ Th17/1 population (P &amp;lt; 0.001) in steroid resistant NS (SRNS) as compared to steroid sensitive NS (SSNS) patients. IL-12 and IL-23 are significantly higher in SRNS as compared to SSNS patients which are require for transition of pathogenic Th17 cells to IFN-γ producers. Of the IL-17A+IFN-γ+ Th17/1 population 95.8% cells were expressed P-gp on their surface in SRNS; however only 30.1% cells expressed P-gp in SSNS group (Figure 1). We also observed that P-gp expression correlate positively with IL-17A+IFN-γ+ Th17/1 population (r= 0.739, p&amp;lt; 0.001) significantly. Conclusion The above findings clearly show that higher expression of P-gp on IL-17A+IFN-γ+ Th17/1 cells associated with steroid resistance in nephrotic syndrome through both IL-17A and IFN-γ.

Decreased Circulating Transitional B-Cell to Memory B-Cell Ratio Is a Risk Factor for Relapse in Children with Steroid-Sensitive Nephrotic Syndrome

Introduction: A significant proportion of children with SSNS (steroid-sensitive nephrotic syndrome) experience recurrence. Reliable biomarkers to predict flare are currently lacking because the pathogenesis of SSNS remains obscure. Objective: Since B cells may be involved in the pathogenesis of SSNS, we aimed to identify perturbations of B-cell subsets that might predict SSNS relapse. Methods: We measured levels of circulating B-cell subsets in 69 SSNS children by flow cytometry, between 2018 and 2019. We divided them into a relapse group and a nonrelapse group according to whether a relapse occurred within 1 year of follow-up. We used Cox survival analysis to assess correlations between B-cell subsets and relapse. In addition, recurrence-free survival curves were calculated using the Kaplan-Meier method. Results: The proportion of transitional B cells was significantly lower in the relapse group (5.3 ± 5.1% vs. 8.7 ± 4.3% in nonrelapse group, p = 0.007), while the proportion of memory B cells was significantly higher (8.4 ± 3.0% vs. 5.8 ± 3.3% in nonrelapse, p = 0.002). There was a significant decrease in the transitional B-cell to memory B-cell ratio (T/M) in the relapse group (p < 0.001). Univariate analysis revealed that transitional B cells, memory B cells, and the T/M ratio were significantly correlated with relapse in SSNS patients (p < 0.05). Multivariate analysis revealed that only T/M ratio (hazard ratio 0.278, 95% confidence interval 0.085–0.908, p = 0.034) was an independent risk factor for recurrence-free survival in SSNS patients. A cutoff value for the T/M ratio of 1.16 resulted in a sensitivity of 90% and specificity of 80% (area under the curve 0.909; p < 0.001). Kaplan-Meier curves of cumulative relapse-free survival, stratified by this cutoff value, were constructed, which showed that the cumulative relapse-free rates for cutoff values of >1.16 (n = 38) and ≤1.16 (n = 31) were 76.3 and 29.0%, respectively (χ² = 18.416, p < 0.001). Conclusions: Decreased transitional B/memory B ratio is associated with SSNS recurrence in the reported cohort. Thus, it may prove to be a useful marker to predict SSNS relapse in children.

Cardiac functions in children with steroid-sensitive nephrotic syndrome.

The aim of the present study was to evaluate the presence of cardiac systolic and diastolic dysfunction in pediatric patients with steroid-sensitive nephrotic syndrome (NS). The study population consisted of 19 patients with debut-relapse of NS aged 1-18years and 30 sex and age-matched healthy controls. Blood and urine samples, two M-mode conventional echocardiograms and tissue Doppler velocity imaging were evaluated in both attack and remission periods. With regard to conventional pulse wave Doppler (cPWD), steroid-sensitive NS patients (both in debut / relapse and in remission periods) had a higher peak of late diastolic flow velocities (A peak), and patients in debut / relapse had a lower E/A ratio than the control group, indicating diastolic dysfunction (overall P = 0.003 and P = 0.006, respectively). Based on tissue Doppler velocity imaging echocardiography results, patients in debut/relapse had a higher A' and a lower E'/A' ratio (overall P < 0.001 and P = 0.001, respectively). There was also a significant difference in the cPWD E/TDI E' ratio between the patients showing an increased cPWD E/TDI E' ratio in remission periods compared to in debut/relapse periods (P = 0.09). The albumin levels were positively correlated with E'/A' and E/ E' ratio (r = 0.609; P = 0.007, r = 0.472; P = 0.041 respectively). Systolic cardiac functions are preserved but diastolic functions are affected in steroid-sensitive NS patients both in debut/relapse and in remission periods in a relatively short time. The persistence of left ventricular (LV) dysfunction during the remission period requires special attention during the follow up for early detection of cardiac abnormalities.

Impaired thiol/disulphide homoeostasis in children with steroid-sensitive nephrotic syndrome.

Abnormal thiol/disulphide homoeostasis (TDH) is responsible for the pathogenesis of various diseases. We aimed to examine the TDH in children with steroid-sensitive nephrotic syndrome (SSNS). A total of 131 children, 60 with SSNS and 71 healthy controls, participated in the study. Plasma total thiol (TT), native thiol (SH) and disulphide (SS) levels in the SSNS during remission and control groups were estimated using a new method developed by Erel and Neselioglu. Albumin, TT, SH levels and SH/TT ratio were decreased, whereas SS/SH and SS/TT ratios were elevated in SSNS group compared with control group. However, there was no significant difference in SS levels between the two groups. Albumin level was positively correlated with TT, SH and SS levels in the SSNS group. We found that TDH shifts in favour of oxidants in children with SSNS in remission. This shift indicates that SSNS patients are exposed to augmented oxidative stress.

Selenium level in steroid-resistant and steroid-sensitive nephrotic syndrome

Background The mechanisms of pathogenesis of steroid-resistant nephrotic syndrome (SRNS) and steroid-sensitive nephrotic syndrome (SSNS) are not well understood. Antioxidants, such as glutathione peroxidase enzyme (GPx) and its cofactor, selenium, are thought to slow the progress of nephrotic syndrome (NS).&#x0D; Objective To compare selenium levels in SRNS and SSNS pediatric patients.&#x0D; Methods This cross-sectional study was conducted in 51 SRNS and 30 SSNS patients, aged 2 to 18 years, who visited the Pediatric Nephrology Outpatient Clinic at Cipto Mangunkusumo Hospital, Jakarta. Subjects were included by consecutive sampling. Selenium was measured on venous blood using GC tools MS ™ (Agilent technologies, inc.).&#x0D; Results Median selenium levels in SRNS patients were 92 (range 42-154) μg/L and in SSNS patients were 93 (range 69-193) μg/L.&#x0D; Conclusion Selenium levels in SRNS and SSNS patients were not significantly different.

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).

P1817DOES EPIGENETIC FACTORS LIKE HDAC2 PLAYS ROLE IN STEROID RESISTANCE VIA REGULATION OF P-GP AND MRP-1 IN CHILDHOOD IDIOPATHIC NEPHROTIC SYNDROME?

Abstract Background and Aims The action of glucocorticoids is to switch off activated inflammatory genes. The activated glucocorticoid receptors (GR) interact with co-repressor molecules to impair NFκB-associated co-activator activity, reducing histone acetylation, chromatin remodelling. Reduction in histone acetylation occurs via recruitment of histone deacetylase (HDAC) 2 to the activated inflammatory gene complex by activated GR, resulting in efficacious suppression of activated inflammatory genes within the nucleus. To evaluate the effect HDAC 2 on P-gp and MRP-1 expression and function. Method Total of 78 subjects were considered in the study out of which 50 were steroid sensitive nephrotic syndrome (SSNS), and 28 were steroid resistant nephrotic syndrome (SRNS) patients. mRNA expression was analyzed on peripheral blood mononuclear cells (PBMCs) in SRNS patients (mean age 8.43±3.8 years), SSNS patients (mean age 7.54±3.5 years). PBMCs were treated with 1µM of Theophylline (HDAC2 stimulator) and 0.8µM of Trichostatin A (HDAC2 inhibitor) for a period of 48 hours. Quantitative PCR was performed using light cycler LC480 using SYBR green PCR technology with SYBR premix relative gene expression levels were calculated and normalized to the corresponding levels of the housekeeping gene (GAPDH). Results Expression of P-gp (4.79±0.970 v/s 2.13±0.72, p&amp;lt;0.0001) and MRP-1 (3.99 ±0.8 v/s 1.99 ±0.91, p&amp;lt;0.0001) on PBMCs was increased in SRNS as compared to that of SSNS. HDAC2 mRNA levels were significantly decreased in SRNS patients as compared to that of SSNS patients (2.97 ± 0.95 v/s 6.02 ± 1.13, p&amp;lt;0.0001). Theophylline(HDAC stimulator) for a period of 48 hours decreased mRNA levels of P-gp and MRP-1 in PBMCs of SRNS with maximal induction at 1µM (fold change 2.65 and 2.21, *p&amp;lt;0.0001) However HDAC2 mRNA expression increased significantly (fold change5.67, *p&amp;lt;0.0001). In SSNS patients P-gp and MRP-1 mRNA expression decreased at1µM (fold change 1.25, 1.24, *p&amp;lt;0.0001) while the mRNA expression was increased (fold change 6.93, *p&amp;lt;0.0001). TSA(HDAC inhibitor) for a period of 48 hours increased mRNA levels of P-gp and MRP-1 in PBMCs of SRNS with maximal induction at 0.8µM (fold change 7.51, 7.31, *p&amp;lt;0.0001) and significantly decreased the level of HDAC2 (fold change1.50, *p&amp;lt;0.0001) similarly in SSNS patients P-gp and MRP-1 mRNA expression increased at 0.8µM (fold change 3.49, 3.35, *p&amp;lt;0.0001) and HDAC2 decreased (fold change2.53, *p&amp;lt;0.0001) at 0.8µM. The functional activity of P-gp and MRP-1 was significantly higher in SRNS group as compared to SSNS group (p&amp;lt;0.001), whereas enzymatic activity of HDAC2 was increased in SSNS group as compared to SRNS group (p&amp;lt;0.001) Conclusion As we observed that HDAC2 regulates P-gp and MRP-1 efflux pumps, Inducer of HDAC2 may be a probable treatment stratergy for patients of Idiopathic Nephrotic Syndrome.

P0238LONG-TERM OUTCOME OF CHILDHOOD IDIOPATHIC NEPHROTIC SYNDROME

Abstract Background and Aims Little is known about the long-term outcome of childhood idiopathic nephrotic syndrome (INS), in particular long-term complications, rate of relapses, frequency of prolonged steroid (S) and immunosuppressive treatment (IS). The choice of immunosuppressive drug remains discussed. Our aim was to study the long-term outcome in adulthood of patients with INS diagnosed during childhood. Method In this monocentric retrospective study, we included all adult patients (&amp;gt;18 years) admitted in our nephrology department between 2013 and 2019 with INS diagnosed during childhood. Patients who reached ESRD during childhood were excluded. Data regarding the outcome in adulthood were obtained through clinical database and medical charts. Results Eighty-two patients (M/F = 2/1) were included. Sixty-height patients had steroid-sensitive nephrotic syndrome (SSNS), including 52 with steroid-dependant nephrotic syndrome (SDNS). The other 14 patients had steroid-resistant nephrotic syndrome (SRNS). The median age at diagnosis was 3.9 years (1.2-16.5). The median number of relapses during childhood was 12 (0-52), 0.9/patient/year. 89% of patients received IS therapy in addition to S during childhood: median number of successive therapeutic lines was 3 (0-10) per child. Median follow-up during adulthood was 4.6 (0.1-25) years. 67% of patients experienced at least one relapse during adulthood, with a median number of relapses of 0.53 (0-3.7)/patient/year. Risk of relapse during adulthood was significantly associated with the total number of relapses during childhood (p=0.015) and with the number of relapses per year during childhood (p=0.007). 45% of patients received IS in addition to S during adulthood, mainly mycophenolate mofetil (23/82), calcineurin inhibitors (21/82) and rituximab (12/82). High blood pressure was observed in 22% of patients. At last follow-up, median eGFR was 90 (64-117) mL/min/1.73m in SSNS patients, 86 (57-126) mL/min/1.73m in SDNS patients and 70 (23-113) mL/min/1.73m in SRNS patients. Only 4/82 patients presented with eGFR lower than 60 mL/min/1.73m. Among them, 3 had SRNS. Only 1 thrombo-embolic event and 3 severe infections were reported. Bone densitometry was performed in 26 adult patients and osteopenia was found in 19 of them (73%). Conclusion The incidence of relapses in adulthood was relatively high in our study. However bias related to inclusion criteria could play a role. Whereas renal function remained normal in most patients, high blood pressure and osteopenia were frequent but major complications were rarely reported.

Physical development and idiopathic nephrotic syndrome in children

INTRODUCTION.Study of physical development (PD) of children with idiopathic nephrotic syndrome (INS) includes mainly assessment of body height and weight during corticosteroid (CS) therapy; specifics of these criteria before and after the treatment are not sufficiently studied. THE AIM: to study PD of children with INS debut during CS therapy and upon its completion.PATIENTS AND METHODS.A retrospective analysis of PD was performed in 89 patients with INS in Voronezh Regional Children's Clinical Hospital No.1 during 1998-2014 using method of Z-score of body height and weight in comparison with regional standards.RESULTS.At the INS debut body height of 38.2% of the children and body weight of 41.2% accordingly were less than those of healthy children, p&lt;0.001. Children with steroid-sensitive nephrotic syndrome (SSNS) had no difference in body height Z-score during CS therapy (0.17±1.06) and upon its completion (0.28±1.22), p=0.794. Body height was less in steroiddependent patients (SDNS) compared to SSNS patients. Z-score body weight values in children with SSNS were higher during maximum doses of CS (0.94±1.59) and returned to previous values after the therapy (-0.24±1.33), р=0,040. Patients with a frequent relapsing SSNS and SDNS had overweight and obesity remained after prednisone treatment (p=0.009).CONCLUSION.Physical development of children with INS has differences associated with CS therapy. Since body height and weight of children with INS were different from the norms before CS therapy, this could be influenced by genetic factors, which to be studied further. The results can be used to prognose CS therapy influence on PD of patients and assess prognosis of INS.