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Introduction: Nephrotic syndrome (NS) is one of the most common childhood kidney diseases. Thromboembolic (TE) events are among the most serious complications of NS in children, with a reported prevalence of 1.8–5%. Venous thromboembolism (VTE) is the predominant type. Most cases of TE are clinically symptomatic, but some may be subclinical, thus, their true incidence may be underestimated. Studies on TE in childhood onset NS are few and varied, this prompted us to conduct the present study. Objective: To study the pattern of thromboembolism in childhood INS. Patients and Methods: This descriptive retrospective study included 225 pediatric patients with idiopathic NS (11 with TE events and 214 with no TE events) regularly following up in Alexandria University Children's Hospital, Egypt from 2013 to 2023. Diagnosis of thromboembolism was based on clinical diagnosis and appropriate diagnostic imaging. Results: The frequency of TE among our cohort was 4.9%.The median age of onset of the first TE event was 5.5 years. Most of the TE events (63.6%) occurred during the 1st 6 months of NS diagnosis. The total number of TE events was 15 events, and the most common site was cerebral sino-venous thrombosis (CSVT). The triglyceride levels were significantly higher in the TE event group. The median urinary protein/creatinine ratio was slightly higher in the TE event group. In the TE event group, 4 patients (36.4%) were steroid-resistant and only one of the 11 patients died. Conclusion: In conclusion, TE events are not uncommon among INS children and most of the events occurred early during the disease. There was no significant relationship between the degree of proteinuria, serum albumin level, and the occurrence of TE events, while the level of triglycerides was significantly higher in patients who developed TE events. [ABSTRACT FROM AUTHOR]

Aims: The primary aim of this study was to characterize the health-related quality of life (HRQoL) and identify the associated factors among children aged 2 to 18 in China diagnosed with idiopathic nephrotic syndrome (INS). Additionally, the study aimed to evaluate the HRQoL and caregiving burden of their caregivers and investigate the correlation between the HRQoL of the children and that of their caregivers. Methods: This study recruited 181 children diagnosed with INS from Children’s Hospital, Zhejiang University School of Medicine in China. The proxy-reported PedsQL Generic Core Module (PedsQL™ 4.0 GCM) was used to measure the HRQoL of children, and the EuroQol five-dimensional questionnaire, five-level version (EQ-5D-5L) was applied to measure caregivers’ HRQoL. Differences in scale scores and total scores of PedsQL™ 4.0 GCM were assessed using t-tests and one-way ANOVA. Multivariate linear regression analysis was used to identify the factors associated with children’s HRQoL. Pearson correlation analysis evaluated the correlation between children’s HRQoL and caregiver’s HRQoL. Results: HRQoL of Children with INS declines with increasing age, and children aged 5-18 had lower scores in physical functioning, emotional functioning, school functioning, psychosocial health summary score, and total PedsQL™ 4.0 GCM score compared to healthy children. Various factors, including the mother filling out the questionnaire, the father being unemployed, and the use of other medications except for steroids, were associated with worse HRQoL of children (p values < 0.05). Additionally, a correlation exists between children’s HRQoL and their caregivers’ HRQoL. Conclusion: This study evaluated the HRQoL of children aged 2-18 years diagnosed with INS in China, along with the HRQoL of their caregivers. Multiple factors potentially influence the HRQoL of children. A significant correlation was observed between the HRQoL of children and their caregivers, who frequently experienced varying levels of caregiving burden. Therefore, it is recommended that healthcare professionals prioritize optimizing HRQoL for children with INS and their caregivers. [ABSTRACT FROM AUTHOR]

Introduction Nephrotic syndrome (NS) is one of the most common childhood kidney diseases. Thromboembolic (TE) events are among the most serious complications of NS in children, with a reported prevalence of 1.8–5%. Venous thromboembolism (VTE) is the predominant type. Most cases of TE are clinically symptomatic, but some may be subclinical, thus, their true incidence may be underestimated. Studies on TE in childhood onset NS are few and varied, this prompted us to conduct the present study.Objective To study the pattern of thromboembolism in childhood INS.Patients and Methods This descriptive retrospective study included 225 pediatric patients with idiopathic NS (11 with TE events and 214 with no TE events) regularly following up in Alexandria University Children’s Hospital, Egypt from 2013 to 2023. Diagnosis of thromboembolism was based on clinical diagnosis and appropriate diagnostic imaging.Results The frequency of TE among our cohort was 4.9%.The median age of onset of the first TE event was 5.5 years. Most of the TE events (63.6%) occurred during the 1st 6 months of NS diagnosis. The total number of TE events was 15 events, and the most common site was cerebral sino-venous thrombosis (CSVT). The triglyceride levels were significantly higher in the TE event group. The median urinary protein/creatinine ratio was slightly higher in the TE event group. In the TE event group, 4 patients (36.4%) were steroid-resistant and only one of the 11 patients died.Conclusion In conclusion, TE events are not uncommon among INS children and most of the events occurred early during the disease. There was no significant relationship between the degree of proteinuria, serum albumin level, and the occurrence of TE events, while the level of triglycerides was significantly higher in patients who developed TE events.

Abstract Idiopathic Nephrotic Syndrome (INS) is a common childhood glomerular disease requiring intense immunosuppressive drug treatments. Prediction of treatment response and the occurrence of relapses remains challenging. Biofluid-derived extracellular vesicles (EVs) may serve as novel liquid biopsies for INS classification and monitoring. Our cohort was composed of 105 INS children at different clinical time points (onset, relapse, and persistent proteinuria, remission, respectively), and 19 healthy controls. The expression of 37 surface EV surface markers was evaluated by flow cytometry in serum (n = 83) and urine (n = 74) from INS children (mean age = 10.1, 58% males) at different time points. Urine EVs (n = 7) and serum EVs (n = 11) from age-matched healthy children (mean age = 7.8, 94% males) were also analyzed. Tetraspanin expression in urine EVs was enhanced during active disease phase in respect to the remission group and positively correlates with proteinuria levels. Unsupervised clustering analysis identified an INS signature of 8 markers related to immunity and angiogenesis/adhesion processes. The CD41b, CD29, and CD105 showed the best diagnostic scores separating the INS active phase from the healthy condition. Interestingly, combining urinary and serum EV markers from the same patient improved the precision of clinical staging separation. Three urinary biomarkers (CD19, CD44, and CD8) were able to classify INS based on steroid sensitivity. Biofluid EVs offer a non-invasive tool for INS clinical subclassification and “personalized” interventions.

Abstract Aims The primary aim of this study was to characterize the health-related quality of life (HRQoL) and identify the associated factors among children aged 2 to 18 in China diagnosed with idiopathic nephrotic syndrome (INS). Additionally, the study aimed to evaluate the HRQoL and caregiving burden of their caregivers and investigate the correlation between the HRQoL of the children and that of their caregivers. Methods This study recruited 181 children diagnosed with INS from Children’s Hospital, Zhejiang University School of Medicine in China. The proxy-reported PedsQL Generic Core Module (PedsQL™ 4.0 GCM) was used to measure the HRQoL of children, and the EuroQol five-dimensional questionnaire, five-level version (EQ-5D-5L) was applied to measure caregivers’ HRQoL. Differences in scale scores and total scores of PedsQL™ 4.0 GCM were assessed using t-tests and one-way ANOVA. Multivariate linear regression analysis was used to identify the factors associated with children’s HRQoL. Pearson correlation analysis evaluated the correlation between children’s HRQoL and caregiver’s HRQoL. Results HRQoL of Children with INS declines with increasing age, and children aged 5-18 had lower scores in physical functioning, emotional functioning, school functioning, psychosocial health summary score, and total PedsQL™ 4.0 GCM score compared to healthy children. Various factors, including the mother filling out the questionnaire, the father being unemployed, and the use of other medications except for steroids, were associated with worse HRQoL of children (p values

Background: Usingsteroids as a medical line of treatment for pediatric idiopathic nephrotic syndrome (INS) has a noxious aftereffect on the course of bone mineralization in the targeted children. Searching for new markers of bone mineralization seems to be an imperative issue. Sclerostin (Scl), a glycoprotein which is coded by the SOST gene, is noted as a pivotal controller of bone setup via its repressing outcome on Wnt signaling. The aim of this study was to assess the concentration of Scl level in children with INS and to correlate Scl level with other existing markers of bone metabolism. Method: A case control study achieved on 70 children including 35 patients with INS on corticosteroid therapy and 35apparently well age and sex alike children as a control group. Kidney function testing, bone markers, parathyroid hormone, and serum sclerostin, were assayed in both research groups. Results: There was a statistically significant difference in serum Scl level between the studied groups, being higher in the nephrotic children than the control group (mean ± SD: 10.07 ± 3.650 vs. 5.29 ± 1.92, respectively with p<0.001). Among factors significantly correlated with serum sclerostin, only serum calcium was significantly independently associated with it (unstandardized β=-1.356). There was a statistically significant relation between serum Scl, steroid response and disease activity (p value= 0.001, 0.001 respectively). Conclusion: The sclerostin serum level can serve as an indicator of bone mineralization in children with INS utilizing corticosteroids as a therapeutic agent. [ABSTRACT FROM AUTHOR]

Aim: Saliva can reflect an individual's physiological status or susceptibility to systemic disease. However, little attention has been given to salivary analysis in children with idiopathic nephrotic syndrome (INS). We aimed to perform a comprehensive analysis of saliva from INS children. Methods: A total of 18 children (9 children with INS and 9 normal controls) were recruited. Saliva was collected from each INS patient in the acute and remission phases. 16S rRNA gene sequencing, widely targeted metabolomics, and 4D‐DIA proteomics were performed. Results: Actinobacteria and Firmicutes were significantly enriched in the pretreatment group compared with the normal control group, while Bacteroidota and Proteobacteria were significantly decreased. A total of 146 metabolites were identified as significantly different between INS children before treatment and normal controls, which covers 17 of 23 categories. KEGG enrichment analysis revealed three significantly enriched pathways, including ascorbate and aldarate metabolism, pentose and glucuronate interconversions, and terpenoid backbone biosynthesis (P < 0.05). A total of 389 differentially expressed proteins were selected between INS children before treatment and normal controls. According to the KEGG and GO enrichment analyses of the KOGs, abnormal ribosome structure and function and humoral immune disorders were the most prominent differences between INS patients and normal controls in the proteomic analysis. Conclusion: Oral microbiota dysbiosis may modulate the metabolic profile of saliva in children with INS. It is hypothesized that children with INS might have "abnormal ribosome structure and function" and "humoral immune disorders". Summary at a glance: This study performed a comprehensive analysis of saliva from INS children and revealed that oral microbiota dysbiosis may modulate the metabolic profile of saliva in children with INS. It is hypothesized that children with INS might have "abnormal ribosome structure and function" and "humoral immune disorders". [ABSTRACT FROM AUTHOR]

Background Idiopathic nephrotic syndrome (INS) is a heterogenous disease and current classification is based on observational responses to therapies or kidney histology. The National Unified Renal Translational Research Enterprise (NURTuRE)-INS cohort aims to facilitate novel ways of stratifying INS patients to improve disease understanding, therapeutics and design of clinical trials. Methods NURTuRE-INS is a prospective cohort study of children and adults with INS in a linked biorepository. All recruits had at least one sampling visit collecting serum, plasma, urine and blood for RNA and DNA extraction, frozen within 2 hours of collection. Clinical histology slides and biopsy tissue blocks were also collected. Results A total of 739 participants were recruited from 23 centres to NURTuRE-INS, half of whom were diagnosed in childhood [ n  = 365 (49%)]. The majority were white [ n  = 525 (71%)] and the median age at recruitment was 32 years (interquartile range 12–54). Steroid-sensitive nephrotic syndrome (SSNS) was the most common clinical diagnosis [ n  = 518 (70%)]. Of patients diagnosed in childhood who underwent a kidney biopsy, for SSNS (n  =103), 76 demonstrated minimal change disease (MCD), whereas for steroid-resistant nephrotic syndrome (n  =80), 21 had MCD. Almost all patients diagnosed in adulthood had a kidney biopsy [ n  = 352 (94%)]; 187 had MCD and 162 had focal segmental glomerulosclerosis. Conclusions NURTuRE-INS is a prospective cohort study with high-quality biosamples and longitudinal data that will assist research into the mechanistic stratification of INS. Samples and data will be available through a Strategic Access and Oversight Committee. [ABSTRACT FROM AUTHOR]

Background: Idiopathic nephrotic syndrome (INS) is the most common glomerular disease in children. We performed this study to report histopathological findings, the correlation between clinical and histopathological features, and the response to steroids and other immunosuppressive drugs and outcomes in Syrian children with INS. Methods: A single-center retrospective observational cohort study was conducted at Children's University Hospital in Damascus, and included all patients aged 1–14 years, admitted from January 2013 to December 2022, with INS and who underwent kidney biopsy. Results: The study included 109 patients, with a male/female ratio of 1.13:1, and a median age of 5 years with interquartile range (2.8–10). The main indication of kidney biopsy was steroid-resistant nephrotic syndrome (SRNS) (57.8%). The main histopathological patterns were minimal change disease (MCD) (45%) and focal segmental glomerulosclerosis (FSGS) (37.6%). FSGS was the most common histopathological pattern in SRNS (44.3%). In SRNS, we used calcineurin inhibitors to induce remission. Tacrolimus was used in 49 patients with response rate (complete remission of proteinuria) of 69.4% and cyclosporine in 20 patients with response rate of 50%. In steroid-dependent nephrotic syndrome (SDNS), we used mycophenolate mofetil (MMF) and cyclophosphamide to prevent relapses; MMF was used in 9 patients with response rate (maintaining sustained remission) of 89% and cyclophosphamide in 3 patients with response rate of 66.7%. Rituximab was used in four patients with FSGS, two SRNS patients and two SDNS patients, with sustained remission rate of 100%. Fifteen patients (13.7%) progressed to chronic kidney disease stage 5. Of them, 7 patients had FSGS and 8 patients had focal and global glomerulosclerosis;14 of them were steroid-resistant and one patient was steroid-dependent with persistent relapses. The most common outcome was sustained remission (47%) in MCD and frequent relapses (31.7%) in FSGS. Conclusions: FSGS was the most common histopathological pattern in idiopathic SRNS and had the worst prognosis. Calcineurin inhibitors could be an effective therapy to induce complete remission in SRNS. Rituximab may be an effective treatment to achieve sustained remission in SDNS and frequently relapsing NS and may have a potential role in SRNS with further studies required. [ABSTRACT FROM AUTHOR]

Anamnestic 13-valent pneumococcal conjugate vaccine immunization did not affect the relapse risk in pediatric idiopathic nephrotic syndrome. Pneumococcal serotype (PS)-specific antibody titers increased significantly in all groups. Children receiving immunomodulatory treatments (IMTs) displayed significantly lower levels of PS-specific antibodies for 3/8 serotypes tested. PS-specific B-cell counts significantly increased only in healthy controls and patients receiving corticosteroids. [ABSTRACT FROM AUTHOR]

Background: Childhood idiopathic nephrotic syndrome is one of the most common conditions pediatric nephrologists encounter globally. Nephrotic syndrome is characterized by proteinuria, hyperlipidemia, and edema. The degree and duration of proteinuria have an impact on serum electrolyte levels. However, local data is limited. Objectives: To assess and compare the degree of electrolyte imbalance and its relationship to kidney function indicators during relapse and remission in children with idiopathic nephrotic syndrome. Methods: In this case-control study, blood samples were collected from 80 Iraqi children with an age range of (2-14) years. They were divided into three groups: Group I (20 individuals with steroid-sensitive nephrotic syndrome (SSNS)), Group II (20 individuals with steroid-resistant nephrotic syndrome (SRSN)), and Group III (40 healthy individuals as the control group). Serum electrolyte levels (Na, Ca, Cl, and K) were measured by an ion-selective electrode (9180 electrolyte analyzer). Blood creatinine and urea were measured by a Cobas c311 autoanalyzer during the relapse and remission phase. The patients were clients of the pediatric nephrology consultation center at the Children's Teaching Hospital / Baghdad Medical City and Al-Batoul Teaching Hospital for Women and Children from 15 February to 20 August 2022. The controls were healthy children whose medical history was reviewed to eliminate a history of kidney disease and underwent a comprehensive physical examination. Controls were recruited from a network of family, friends, relatives, and the National Autism Center/ Child Protection Teaching Hospital affiliated with Medical City/Baghdad. Results: Serum Calcium levels showed a clear decrease in all SSNS and SRSN patients compared to the control group. The levels of Sodium and Chloride were significantly lower than the control group during the relapse phase. The results of the relapse phase of SRNS patients indicated higher serum potassium concentration compared with the control group and the SSNS patient group, with a statistically significant difference). Conclusion: All children with idiopathic nephrotic syndrome had hypocalcemia in the relapse and remission phase. SRNS cases had hyperkalemia, Sodium, and chloride fluctuated between low levels during the relapse phase and normal levels during the remission phase.

Introduction: The clinical evolution of steroid-sensitive forms of pediatric idiopathic nephrotic syndrome (INS) is highly heterogeneous following the standard treatment with prednisone. To date, no prognostic marker has been identified to predict the severity of the disease course starting from the first episode. Methods: In this monocentric prospective cohort study we set up a reproducible and standardized flow cytometry panel using two sample tubes (one for B-cell and one for T-cell subsets) to extensively characterized the lymphocyte repertoire of INS pediatric patients. A total of 44 children with INS at disease onset were enrolled, sampled before and 3 months after standard induction therapy with prednisone and followed for 12 months to correctly classify their disease based on relapses. Age-matched controls with non immune-mediated renal diseases or with urological disorders were also enrolled. Demographical, clinical, laboratory and immunosuppressive treatment data were registered. Results: We found that children with INS at disease onset had significantly higher circulating levels of total CD19+ and specific B-cell subsets (transitional, maturenaïve, plasmablasts/plasmacells, CD19+CD27+, unswitched, switched and atypical memory B cells) and reduced circulating levels of Tregs, when compared to age-matched controls. Prednisone therapy restored most B- and T-cell alterations. When patients were subdivided based on disease relapse, relapsing patients had significantly more transitional, CD19+CD27+ memory and in particular unswitched memory B cells at disease onset, which were predictive of a higher risk of relapse in steroid-sensitive patients by logistic regression analysis, irrespective of age. In accordance, B-cell dysregulations resulted mainly associated with steroid-dependence when patients were stratified in different disease severity forms. Of note, Treg levels were reduced independently from the disease subgroup and were not completely normalized by prednisone treatment. Conclusion: We have set up a novel, reproducible, disease-specific flow cytometry panel that allows a comprehensive characterization of circulating lymphocytes. We found that, at disease onset, relapsing patients had significantly more transitional, CD19+CD27+ memory and unswitched memory B cells and those who are at higher risk of relapse had increased circulating levels of unswitched memory B cells, independently of age. This approach can allow prediction of clinical evolution, monitoring of immunosuppression and tailored treatment in different forms of INS. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of idiopathic nephrotic syndrome (INS) has not been fully explained. Among the likely factors, tumor necrosis factor - alpha (TNF-α) is considered. We aimed to evaluate the TNF-α (sTNF-α, uTNF-α) levels in the serum and urine of INS children, with the aim of determining its association with proteinuria, and of determining its usefulness as a marker of the disease severity. Methods: Fifty-one examined patients were divided into subgroups depending on the number of relapses as follows: group IA—first episode; group IB—more than two relapses, and according to treatment modality; group IIA—glucocorticosteroids (GS) alone; and group IIB—GS with immunosuppressants. Healthy age-matched children served as the control group. Results: sTNF-α and uTNF-α levels were significantly increased in active phases in the whole INS group compared to the control group. They decreased in remission, but remained significantly higher when compared to the control group. During remission in the IB group, sTNF-α levels were significantly higher than in IA, whereas, in the relapse phase, these values were similar. In the IA group, a positive correlation between proteinuria and sTNF-α was demonstrated. Conclusions: Our findings suggest that TNF-α plays a role in the development of INS, and may be used as a prognostic marker, as well as an indicator for the continuation of therapy. Additional research is required to verify this statement. [ABSTRACT FROM AUTHOR]

Background Posterior subcapsular cataracts (PSC) and raised intraocular pressure (IOP) are the most common ocular complications of oral steroid administration, particularly following long-term use or treatment with high doses. Objective To evaluate the association between cumulative steroid dose and duration of treatment with the occurrence of PSC and raised IOP, as well as its associated factors in children with idiopatic nephrotic syndrome (INS). Methods This cross-sectional study included children aged 4–18 years with INS who received oral steroid therapy for at least six consecutive months. Patients underwent complete eye examinations by an ophthalmologist to evaluate their visual acuity as well as the occurrence of PSC and/or raised IOP. Results Of 92 subjects, 19.6% had PSC, 12% had raised IOP, and one had a best corrected visual acuity (BCVA) of

Abstract Background Nephrotic syndrome is a chronic disorder characterized by heavy proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Idiopathic minimal-change disease is the most common form encountered in children. Corticosteroids are the cornerstone for the treatment of idiopathic nephrotic syndrome (INS), with different regimens depending on the response to therapy and frequency of relapses. This case report presents complications after implant treatment in patient with INS. Case presentation 20 years old female patient presented for implant consultation. Medical history includes INS since early childhood, and she is on different medications to control her condition, including long-term steroid use. Dental history revealed that implant treatment was unsuccessful after multiple attempts. She presented with an implant on the area of lower left first mandibular molar, that shows increased mobility and radiolucency on radiographic examination. A diagnosis of implant failure was made, the implant was removed, and the area was cleaned and sutured. The patient decided to replace her missing teeth with fixed partial denture and was referred for prosthodontist. The potential adverse effect of steroid use and the possible underlying mechanism that could affect bone metabolism and implants osseointegration are reviewed. Conclusion Clinical practice guidelines are needed for the management of dental implants in chronic steroid users.

Background: Nephrotic syndrome is a common pediatric kidney condition t. It happens in young children and adolescents. The goal of this research was to investigate the diagnostic value of urinary MCP-1 in pediatric patients with idiopathic nephrotic syndrome. Methods: At the pediatric nephrology outpatient clinic and the pediatric nephrology unit, this case-control study was carried out at Zagazig University hospitals on children attending at pediatric inpatient and outpatient clinics. They were divided into three groups: group A, which consisted of 27 nephrotic patients in remission; group B, which consisted of 27 nephrotic patients who were active and experiencing either their first attack or relapses; and group C, which consisted of 27 sex- and age-matched healthy children who were present at a general pediatric clinic. Results: There is a statistically significant difference in urinary monocyte chemotactic Protein 1. The best cutoff of urinary monocyte chemotactic protein 1 in the diagnosis of nephrotic syndrome is ≥79 with the area under curve 1, sensitivity 100%, specificity 96.3%, positive predictive value 98.2%, negative predictive value 100%, and overall accuracy 98.8%. The best cutoff steroid-resistant nephrotic syndrome by using urine monocyte chemotactic protein 1 as a diagnostic marker is ≥512 with area under curve 0.992, sensitivity 96.3%, specificity 88.9%, positive predictive value 89.7%, negative predictive value 96%, and overall accuracy 92.6%. Conclusions: The findings imply that urine MCP-1 levels can differentiate between patients with active disease and those who are in remission, as well as between cases of steroid-resistant nephrotic syndrome and cases of steroid-sensitive nephrotic syndrome. [ABSTRACT FROM AUTHOR]

IntroductionThe clinical evolution of steroid-sensitive forms of pediatric idiopathic nephrotic syndrome (INS) is highly heterogeneous following the standard treatment with prednisone. To date, no prognostic marker has been identified to predict the severity of the disease course starting from the first episode.MethodsIn this monocentric prospective cohort study we set up a reproducible and standardized flow cytometry panel using two sample tubes (one for B-cell and one for T-cell subsets) to extensively characterized the lymphocyte repertoire of INS pediatric patients. A total of 44 children with INS at disease onset were enrolled, sampled before and 3 months after standard induction therapy with prednisone and followed for 12 months to correctly classify their disease based on relapses. Age-matched controls with non immune-mediated renal diseases or with urological disorders were also enrolled. Demographical, clinical, laboratory and immunosuppressive treatment data were registered.ResultsWe found that children with INS at disease onset had significantly higher circulating levels of total CD19+ and specific B-cell subsets (transitional, mature-naïve, plasmablasts/plasmacells, CD19+CD27+, unswitched, switched and atypical memory B cells) and reduced circulating levels of Tregs, when compared to age-matched controls. Prednisone therapy restored most B- and T-cell alterations. When patients were subdivided based on disease relapse, relapsing patients had significantly more transitional, CD19+CD27+ memory and in particular unswitched memory B cells at disease onset, which were predictive of a higher risk of relapse in steroid-sensitive patients by logistic regression analysis, irrespective of age. In accordance, B-cell dysregulations resulted mainly associated with steroid-dependence when patients were stratified in different disease severity forms. Of note, Treg levels were reduced independently from the disease subgroup and were not completely normalized by prednisone treatment.ConclusionWe have set up a novel, reproducible, disease-specific flow cytometry panel that allows a comprehensive characterization of circulating lymphocytes. We found that, at disease onset, relapsing patients had significantly more transitional, CD19+CD27+ memory and unswitched memory B cells and those who are at higher risk of relapse had increased circulating levels of unswitched memory B cells, independently of age. This approach can allow prediction of clinical evolution, monitoring of immunosuppression and tailored treatment in different forms of INS.

Xinmiao Hu,1– 3,&ast; Qian Wu,1,2,&ast; Qunfeng Lu,4,5,&ast; Jiangao Zhang,6 Xiaowei Yang,7 Wenjian Chen,3 Ping Wang,3 Qinglin Yu,3 Jingan Dong,3 Yan Sang8 1School of Medicine, Tong University, Shanghai, People’s Republic of China; 2Department of Nursing, Shanghai Tenth People’s Hospital Affiliated to Tongji University, Shanghai, People’s Republic of China; 3Department of Nephrology and Rheumatology, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 4Department of Nursing, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 5School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 6Nantong Visionland Eye Hospital, Jiangsu, People’s Republic of China; 7School of Medicine, Nantong University, Jiangsu, People’s Republic of China; 8Department of Nursing, Department of Computer Technology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Sang, Department of Computer Technology, Affiliated Hospital of Nantong University, No. 20 Xisi Road, Nantong, Jiangsu, 226001, People’s Republic of China, Tel +86 13862915051, Email sangyan_cn@126.comPurpose: To identify the difficulties and burdens related to the experience of caring for children.Methods: A phenomenological approach was used in this qualitative study. Semi-structured and adolescents with idiopathic nephrotic syndrome (INS) in mainland China. Interviews lasting 35– 90 minutes were conducted with 13 parental caregivers of youth with INS. The Colaizzi’s analysis was used in data analysis.Results: The mean age of parental caregivers was 40.3 ± 6.1 years, and the average caregiving year of 3.2 ± 3.3 years. Most INS patients were male (69.2%), had a mean age of 7.6 ± 4.2 years. Based on the analysis of the data, five major themes emerged. These were: persistent emotional burden; neglected physical burden; overwhelming financial burden; absence of social support system and burden related to loss of normal life.Conclusion: Health professionals must develop strategies to provide stage-by-stage, targeted health education and psychological support services to parental caregivers of INS youth in China. The government must subsidize routine medications and frequent hospitalizations to minimize the financial burden on parental caregivers of INS youth. Moreover, anti-discrimination policies must be established to protect caregivers from explicit discrimination in public places.Keywords: caregiver, burden, idiopathic nephrotic syndrome, youth

Background: During the coronavirus disease-2019 (COVID-19) pandemic, there was a lack of access to outpatient facilities for other diseases. Conversely, few studies have reported changes in clinical features of idiopathic nephrotic syndrome (INS) in children before and after the COVID-19 pandemic. Methods: Thirty-two children with primary INS, who were admitted to four Showa University-affiliated hospitals between January 2017 and December 2022, were enrolled in this retrospective study. Children were divided according to the onset of INS into a post-COVID-19 group (onset in 2020–2022, n = 25) and a pre-COVID-19 group (onset in 2017–2019, n = 32). We compared the clinical characteristics and features of initial INS between two groups. Results: In the post-COVID-19 group, these patients had interval between noticing symptoms of INS, such as edema and INS diagnosis was significantly longer (7 days versus 3.5 days; p = 0.0047), and had significantly raised serum LDL cholesterol levels at the time of INS diagnosis than in the pre-COVID-19 group (314 mg/dL versus 260 mg/dL; p = 0.028). Likewise, steroid-resistant nephrotic syndrome was significantly more common in the post-COVID-19 group [32% (n = 8) versus 6% (n = 2); p = 0.016]. A correlation analysis revealed a moderate positive correlation between the interval from symptom to diagnosis and LDL cholesterol (r = 0.460015, p = 0.0003). Conclusions: Children with INS after the COVID-19 pandemic showed a longer time between noticing symptoms of INS and diagnosis, increased serum LDL cholesterol and more steroid resistance than before the pandemic. [ABSTRACT FROM AUTHOR]

Levamisole (LMS) is a small molecule used in the treatment of idiopathic nephrotic syndrome (INS). The pathogenesis of INS remains unknown, but evidence points toward an immunological basis of the disease. Recently, LMS has been shown to increase the relapse‐free survival in INS patients. While LMS has been hypothesized to exert an immunomodulatory effect, its mechanism of action remains unknown. Here, we show that LMS decreased activation and proliferation of human T cells. T‐cell activation‐associated cytokines such as IL‐2, TNF‐α, and IFN‐γ were reduced upon LMS treatment, whereas IL‐4 and IL‐13 were increased. Gene expression profiling confirmed that the suppressive effects of LMS as genes involved in cell cycle progression were downregulated. Furthermore, genes associated with p53 activation were upregulated by LMS. In agreement, LMS treatment resulted in p53 phosphorylation and increased expression of the p53 target gene FAS. Accordingly, LMS sensitized activated T cells for Fas‐mediated apoptosis. LMS treatment resulted in a mid‐S phase cell cycle arrest accompanied by γH2AX‐foci formation and phosphorylation of CHK1. Our findings indicate that LMS acts as an immunosuppressive drug that directly affects the activation and proliferation of human T cells by induction of DNA damage and the activation of a p53‐dependent DNA damage response. [ABSTRACT FROM AUTHOR]

The pathogenetic mechanisms underlying the onset and the post-transplant recurrence of primary focal segmental glomerulosclerosis (FSGS) are complex and remain yet to be fully elucidated. However, a growing body of evidence emphasizes the pivotal role of the immune system in both initiating and perpetuating the disease. Extensive investigations, encompassing both experimental models and patient studies, have implicated T cells, B cells, and complement as crucial actors in the pathogenesis of primary FSGS, with various molecules being proposed as potential "circulating factors" contributing to the disease and its recurrence post kidney-transplantation. In this review, we critically assessed the existing literature to identify essential pathways for a comprehensive characterization of the pathogenesis of FSGS. Recent discoveries have shed further light on the intricate interplay between these mechanisms. We present an overview of the current understanding of the engagement of distinct molecules and immune cells in FSGS pathogenesis while highlighting critical knowledge gaps that require attention. A thorough characterization of these intricate immune mechanisms holds the potential to identify noninvasive biomarkers that can accurately identify patients at high risk of post-transplant recurrence. Such knowledge can pave the way for the development of targeted and personalized therapeutic approaches in the management of FSGS. [ABSTRACT FROM AUTHOR]

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Background: Idiopathic nephrotic syndrome (INS) is one of the chronic diseases in children and it is important to identify its related factors. The present study aimed at investigating the relationship between H. pylori infection and the incidence and recurrence of idiopathic nephrotic syndrome in children. Methods: The total number of case participants was 40 and the total number of control participants was 41. Based on the number of cases of nephrotic syndrome (NS), the same number of healthy children of the same age and gender were selected as the control group. The information and data collected include demographic characteristics of patients, duration of disease, number of recurrences, blood pressure and blood excretion in urine, height, and weight, and presence of gastrointestinal symptoms on the checklist. The data were entered into SPSS and analyzed at a significance level of 05. Results: From 81 participants in the study, 11 (13.75%) cases were H. pylori positive, of whom 7 (17.5%) cases were in the control group and 4 (10%) cases were in the patients’ group. There was no significant difference between the two groups in terms of H. pylori infection rate (P = 0.863). Moreover, there were no significant differences between the patients suffering from the nephrotic syndrome in terms of height, weight, blood pressure, hematuria, duration and recurrence of the disease (p>0.05). Conclusion: According to the evaluations performed in the present study, there was no relationship between low birth weight, blood pressure, disease duration, and disease recurrence with NS.

Vaccines represent the most important medical evolution in the last two centuries allowing prevention and formally eradication of a wide number of infectious diseases. Safety and effectiveness are main issues that still require an open discussion. A few clinical reports described a critical temporal relationship between vaccination and acute nephrotic syndrome, indirectly suggesting an association. For this review, the literature was reviewed to identify articles reporting associations of nephrotic syndrome with vaccines against a vast array of infectious diseases (including bacteria, virus and Sars-Cov-2). As specific aims, we evaluated effectiveness and safety in terms of occurrence of either "de novo" nephrotic syndrome in health subjects or "relapse" in those already affected by the disease. In total, 377 articles were found; 166 duplicates and 71 non-full text, animal studies or non-English language were removed. After excluding another 50 articles not containing relevant data on generic side effects or on relapses or new onset nephrotic syndrome, 90 articles met the search criteria. Overall, studies reported the effect of vaccines in 1015 patients, plus 4 nationwide epidemiologic investigations. Limited experience on vaccination of NS patients with measles, mumps, and rubella live attenuated vaccines does not allow any definitive conclusion on their safeness. VZV has been administered more frequently without side effects. Vaccines utilizing virus inactivated, recombinant, and toxoid can be utilized without risks in NS. Vaccines for influenza reduce the risk of infections during the pandemic and are associated with reduced risk of relapse of NS typically induced by the infection. Vaccines for SARS-CoV-2 (all kinds) offer a concrete approach to reduce the pandemic. "De novo" NS or recurrence are very rare and respond to common therapies. [ABSTRACT FROM AUTHOR]

Background: Nephrotic syndrome is common in children and adults worldwide, and steroid‐sensitive nephrotic syndrome (SSNS) accounts for 80%. Aberrant metabolism involvement in early SSNS is sparsely studied, and its pathogenesis remains unclear. Therefore, the goal of this study was to investigate the changes in initiated SSNS patients‐related metabolites through serum and urine metabolomics and discover the novel potential metabolites and metabolic pathways. Methods: Serum samples (27 SSNS and 56 controls) and urine samples (17 SSNS and 24 controls) were collected. Meanwhile, the non‐targeted analyses were performed by ultra‐high‐performance liquid chromatography‐quadrupole time of flight‐mass spectrometry (UHPLC‐QTOF‐MS) to determine the changes in SSNS. We applied the causal inference model, the DoWhy model, to assess the causal effects of several selected metabolites. An ultraperformance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) was used to validate hits (D‐mannitol, dulcitol, D‐sorbitol, XMP, NADPH, NAD, bilirubin, and α‐KG‐like) in 41 SSNS and 43 controls. In addition, the metabolic pathways were explored. Results: Compared to urine, the metabolism analysis of serum samples was more clearly discriminated at SSNS. 194 differential serum metabolites and five metabolic pathways were obtained in the SSNS group. Eight differential metabolites were identified by establishing the diagnostic model for SSNS, and four variables had a positive causal effect. After validation by targeted MS, except XMP, others have similar trends like the untargeted metabolic analysis. Conclusion: With untargeted metabolomics analysis and further targeted quantitative analysis, we found seven metabolites may be new biomarkers for risk prediction and early diagnosis for SSNS. [ABSTRACT FROM AUTHOR]

Background: Prospective research of children receiving heterogeneous vaccines has shown that immunization is not associated with pediatric idiopathic nephrotic syndrome (NS) relapses. However, prospective data concentrating only on influenza (flu) virus vaccines are not available. Methods: This multicenter prospective study was conducted in children with NS who received inactivated flu vaccines from June 2017 to July 2018. The day of flu vaccination was defined as day 0, and the period between prevaccination and postvaccination days was defined as − X to + Y (period from day − 180 to 0 as the precontrolled period). The primary outcome was the NS relapse rate from day 0 to + 30 as a direct association with vaccination compared with those in the precontrolled period. Exacerbation was defined as children experiencing more NS relapses after vaccination compared with those in the precontrolled period, or children starting any new immunosuppressants due to NS relapse after vaccination. Results: Sixty-three children were included. Relapse rates were not significantly different between the precontrolled period and 0 to + 30 periods (0.38 vs. 0.19 times/person-year, p = 0.95). Although the exacerbation rate during the 0 to + 180 period in children without NS relapse in the precontrolled period was very low (4/54 [7.4 %]), children with at least one NS relapse in the precontrolled period showed a remarkable increase in the rate (4/9 [44.4%]; p = 0.01). Conclusions: Flu vaccination did not significantly precipitate the direct relapse of NS in children. However, it might increase the disease activity in children with at least one NS relapse within a half year before vaccination. [ABSTRACT FROM AUTHOR]

Background: Idiopathic nephrotic syndrome (INS) is one of the chronic diseases in children and it is important to identify its related factors. The present study aimed at investigating the relationship between H. pylori infection and the incidence and recurrence of idiopathic nephrotic syndrome in children. Methods: The total number of case participants was 40 and the total number of control participants was 41. Based on the number of cases of nephrotic syndrome (NS), the same number of healthy children of the same age and gender were selected as the control group. The information and data collected include demographic characteristics of patients, duration of disease, number of recurrences, blood pressure and blood excretion in urine, height, and weight, and presence of gastrointestinal symptoms on the checklist. The data were entered into SPSS and analyzed at a significance level of 05. Results: From 81 participants in the study, 11 (13.75%) cases were H. pylori positive, of whom 7 (17.5%) cases were in the control group and 4 (10%) cases were in the patients' group. There was no significant difference between the two groups in terms of H. pylori infection rate (P = 0.863). Moreover, there were no significant differences between the patients suffering from the nephrotic syndrome in terms of height, weight, blood pressure, hematuria, duration and recurrence of the disease (p>0.05). Conclusion: According to the evaluations performed in the present study, there was no relationship between low birth weight, blood pressure, disease duration, and disease recurrence with NS. [ABSTRACT FROM AUTHOR]

Abstract Objective We aimed to investigate the renal prognosis of patients with idiopathic nephrotic syndrome (INS) complicated with steroid-induced diabetes mellitus (SIDM), the association of high-density lipoprotein cholesterol (HDL-C) before glucocorticoid treatment with renal prognosis, and the risk for persistent diabetes among patients with INS who had withdrawn from steroid therapy. Materials and methods We retrospectively analyzed 239 patients with INS complicated with SIDM at the National Clinical Research Center of Kidney Diseases, Jinling Hospital, from January 2008 to December 2019. The primary endpoint was the composite renal outcome defined as the development of end-stage renal disease (ESRD) or a 50% decrease in estimated glomerular filtration rate (eGFR) for more than 24 months after glucocorticoid withdrawal. The secondary endpoint was persistent diabetes, defined as fulfilling the criteria for diagnosing diabetes or using antidiabetic medications for at least 24 months after glucocorticoid withdrawal. Results After glucocorticoid withdrawal for over 24 months, 35 (14.6%) patients reached the composite renal endpoint: end-stage renal disease (n = 14) or a 50% decrease in eGFR (n = 21). Before glucocorticoid therapy, a level of HDL-C greater than 1.45 mmol/L worsened renal survival in patients with INS complicated with SIDM. The log10 the level of HDL-C before glucocorticoid treatment was an independent risk factor for the renal outcome. A prediction model was generated: Hazard ratio (renal outcome) = 0.94 * hypertension before glucocorticoid therapy + 2.29 * log10 level of HDL-C before glucocorticoid treatment + 0.90 * the grade of interstitial tubule injury (AUROC, 0.75; 95% CI, 0.63 to 0.87; P

Aim:Idiopathic nephrotic syndrome (NS) is the most common glomerular disorder of childhood. Its prognosis is correlated with treatment responsiveness and not renal histopathology. Most of the children who suffer from NS experience multiple relapses and there is a risk of long-term drug dependence with possible side effects. Hence, there is always a need for markers to assess its long-term outcome even in steroid responders. Urine neutrophil gelatinase-associated lipocalin (uNGAL) is an early risk marker of acute kidney injury and also a marker of progression of chronic kidney disease. Our aim was to determine if urine NGAL could predict steroid responsiveness at the onset of NS, which would help in the planning and monitoring of the treatment in idiopathic NS. The aims of this study were to determine the levels of uNGAL in children who were having their first episode of NS and to study its relation with steroid resistance at 3 months.Materials and Methods:A prospective observational study was conducted in children diagnosed with their first episode of idiopathic NS in a tertiary care teaching hospital from January, 2019 to July, 2020. Urinary NGAL measurements were conducted before starting steroids.Results:Seventy-nine children satisfying the inclusion criteria were included in this study. Their mean age was 7.18 (±2.86) years. The male to female ratio was 1.25:1. All 63 children who had urine NGAL less than 10 ng/mL responded to the standard dose of steroids at 8 weeks and attained remission. Out of the 16 children with NGAL over 10 ng/mL, 56.3% (n=9) responded to steroids within 8 weeks (intermediate or late steroid responders) and 43.8% (n=7) were steroid resistant NS (SRNS). Urine NGAL below 10 ng/mL was associated with steroid responsiveness in the first episode of NS at 3 months (p

Idiopathic nephrotic syndrome (INS) is a chronic glomerular disease in children, characterized by severe proteinuria, hypoalbuminemia, and/or presence of edema and hyperlipidemia. The pathogenesis, however, has not been yet established. The clinical course of the disease is characterized by frequent relapses. Interleukin-15 (IL-15) is a pro-inflammatory cytokine, that apart from its involvement in the immune system, was found to be playing a vital role in various cells' functioning, including renal tissue. It is desirable to look for new predictors of INS. Our study aimed to evaluate IL-15 as a potential marker in the early diagnosis of the disease. The cohort participating in the study consisted of patients hospitalized in Clinical Hospital No. 1 in Zabrze, from December 2019 to December 2021, including study group with INS (n = 30) and control group (n = 44). Results: The concentration of IL-15 in both serum and urine was significantly elevated in patients with INS, compared to healthy controls. The cytokine might serve as a marker of the disease, however, further research on larger study groups is needed. [ABSTRACT FROM AUTHOR]

Background: Children with underlying kidney diseases display a mild course of SARS-CoV-2 infection, but they only accounted for a minority of cases until the spread of the Omicron variant. Nonetheless, idiopathic nephrotic syndrome (INS) has been advocated as a predictor of worse outcome. Methods: We investigated the spread, severity, and risk of relapse related to SARS-CoV-2 infection among children with INS. The incidence and characteristics of SARS-CoV-2 infections, immunosuppression, and vaccination status were retrospectively collected from the beginning of the pandemic to May 31, 2022. Results: We enrolled 176 patients (73 females, median age 10.22 years); 28 had a steroid-resistant disease, and 108 (61.4%) were on immunosuppressive therapy. Sixty-one (34.7%) patients reported a SARS-CoV-2 infection, with incidence peaking between December 2021 and January 2022. No hospitalization or deaths were reported, and symptoms were absent or mild. The rate of SARS-CoV-2 infection was similar in children with and without immunosuppression (33.8% vs 35.2%; p = 0.85). None of the 38 immunosuppressed patients discontinued the therapy, but they had a longer time to negativization (13.31 vs. 10.04 days; p = 0.03). Proteinuria was detected in 7 patients, but only one had a relapse requiring steroid therapy, with prompt remission and a mild course. Conclusions: After the spread of the Omicron variant, the rate of SARS-CoV-2 infection in children with INS was much higher than previously reported. In this large cohort, symptoms were mild, even in immunosuppressed patients and those with proteinuria. During the infection, transient proteinuria was common with a low rate of relapses. [ABSTRACT FROM AUTHOR]

Background: Viral upper respiratory tract infections trigger nephrotic syndrome relapses. Few data exist on the impact of the SARS-CoV-2 pandemic on the risk of relapse in children with idiopathic nephrotic syndrome (INS). Methods: In a Belgian and Italian cohort of children with INS, we performed a retrospective analysis on the number and duration of relapses observed in 3 different periods in 2020: first COVID period, February 15–May 31; second COVID period, June 1–September 14; third COVID period, September 15–December 31. Relapse rates were compared to those of the previous 5 years (PRECOVID period). For the years 2019 and 2020, all causes and INS relapse-related hospitalizations were recorded. Hospitalizations and deaths due to SARS-CoV-2 infection were also recorded. In the Belgian cohort, SARS-CoV-2 serologies were performed. Results: A total of 218 patients were enrolled, and 29 (13.3%) were diagnosed with new-onset INS during the COVID period. Relapse rates per 1000 person-days were as follows: 3.2 in the PRECOVID period, 2.7 in the first COVID period, 3.3 in the second COVID period, and 3.0 in the third COVID period. The incidence rate ratio for the total COVID period was 0.9 (95%CI 0.76 to 1.06; P = 0.21) as compared to the PRECOVID period. During 2020, both the proportion of patients hospitalized for recurrence (14.2% vs. 7.6% in 2019; P = 0.03) and the rate of hospitalization for recurrence (IRR 1.97 (95%CI 1.35 to 2.88); P = 0.013) were higher compared to 2019. In December 2020, anti-SARS-CoV-2 antibodies were detected in 31% of the Belgian cohort. Patients with positive and negative SARS-CoV-2 serology did not differ significantly in relapse rate (2.4 versus 4.2 per 1000 person-days). The number of new INS cases remained similar between 2020, 2019, and 2018. Conclusion: The first year of the SARS-CoV-2 pandemic did not significantly affect the relapse rate in children with INS. No serious infections were reported in this population of immunosuppressed patients. A higher resolution version of the Graphical abstract is available as Supplementary information [ABSTRACT FROM AUTHOR]

The pathogenetic mechanisms underlying the onset and the post-transplant recurrence of primary focal segmental glomerulosclerosis (FSGS) are complex and remain yet to be fully elucidated. However, a growing body of evidence emphasizes the pivotal role of the immune system in both initiating and perpetuating the disease. Extensive investigations, encompassing both experimental models and patient studies, have implicated T cells, B cells, and complement as crucial actors in the pathogenesis of primary FSGS, with various molecules being proposed as potential “circulating factors” contributing to the disease and its recurrence post kidney-transplantation. In this review, we critically assessed the existing literature to identify essential pathways for a comprehensive characterization of the pathogenesis of FSGS. Recent discoveries have shed further light on the intricate interplay between these mechanisms. We present an overview of the current understanding of the engagement of distinct molecules and immune cells in FSGS pathogenesis while highlighting critical knowledge gaps that require attention. A thorough characterization of these intricate immune mechanisms holds the potential to identify noninvasive biomarkers that can accurately identify patients at high risk of post-transplant recurrence. Such knowledge can pave the way for the development of targeted and personalized therapeutic approaches in the management of FSGS.

ObjectivePrevious studies have indicated a decrease in T regulatory cells (Tregs) among patients with steroid-resistant nephrotic syndrome. CCL22 and Leptin influenced the immune function of Tregs through their respective pathways. This study aimed to compare patients with steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS) in terms of CCL22 and Leptin levels.MethodsThis prospective study included 117 children diagnosed with idiopathic nephrotic syndrome (INS). Peripheral blood samples were collected before initiating steroid therapy, and serum levels of CCL22 and Leptin were measured. Patients were categorized into three groups based on their response to steroid treatment. Renal biopsies were recommended for all children diagnosed with INS, with higher acceptance rates in glucocorticoid resistance patients.ResultsBased on the response to steroid treatment, 117 children were divided as groups of SSNS (82 cases), frequent relapse nephrotic syndrome (FRNS) (10 cases), and SRNS (25 cases). A total of 41 patients underwent kidney biopsy, 11 cases (13.4%) in SSNS, 7 cases (70.0%) in FRNS and 24 cases (96.0%) in SRNS. 30 cases were minimal change disease (MCD), 9 cases were mesangial proliferative glomerulonephritis (MsPGN) and 3 cases were focal segmental glomerulosclerosis (FSGS). The levels of Leptin were significantly higher in SR patients (1208.1 ± 1044.1 pg/ml) compared to SS patients (515.4 ± 676.9 pg/ml) and controls (507.9 ± 479.8 pg/ml), regardless of the pathological type. CCL22 levels were significantly elevated in SRNS (92.2 ± 157.0 pg/ml), but the difference seemed to be attributed to the specific type of pathology, such as Minimal change disease (MCD) (127.4 ± 206.7 pg/ml) and focal segmental glomerulosclerosis (FSGS) (114.8 ± 22.0 pg/ml). For SRNS prediction, the AUC of Leptin, CCL22, and the joint prediction index were 0.764, 0.640, and 0.806, respectively.ConclusionSerum levels of CCL22 and Leptin, detected prior to steroid therapy, were associated with steroid resistance in childhood INS.

Slamet Wardoyo,1 Taufik Anwar,2 Alkausyari Aziz3 1Department of Environmental Health, Poltekkes Kemenkes Surabaya, Surabaya, Indonesia; 2Department of Environmental Health, Poltekkes Kemenkes Pontianak, Pontianak, Indonesia; 3Department of Nutrition, Poltekkes Kemenkes Riau, Pekanbaru, IndonesiaCorrespondence: Slamet Wardoyo, Tel +62 857 8754 9486, Email slaametwardoyo91@gmail.com

Abstract Background and objectives Children with multi-drug resistant idiopathic nephrotic syndrome (MDR-INS) usually progress to end-stage kidney disease with a consistent risk of disease recurrence after transplantation. New therapeutic options are needed for these patients. Mesenchymal stromal cells (MSCs) are multipotential non-hematopoietic cells with several immunomodulatory properties and growing clinical applications. Cord blood-derived MSC have peculiar anti-inflammatory and immunosuppressive properties. We aimed at assessing safety and efficacy of cord-blood-derived MSCs (CB-MSCs) in children with MDR-INS. Design, setting, participants Prospective, open-label, single arm phase I–II pilot study. Pediatric patients with MDR-INS, resistant to at least two lines of therapy, were enrolled. Allogenic CB-MSCs were administered intravenously on days 0, 14, and 21 at a dose of 1.5 × 106 cells/kg. Patients were followed for at least 12 months. The primary outcomes were safety and toxicity. The secondary outcome was remission at 12 months evaluated by urinary protein/urinary creatinine ratio (uPr/uCr). Circulating regulatory T cells (Tregs) were monitored. Results Eleven pediatric patients with MDR-INS (10 females, median age 13 years) resistant to a median of 3 previous lines of therapy were enrolled. All patients completed the CB-MSC infusion schedule. No patient experienced any infusion-related adverse event or toxicity. Nine patients were assessable for efficacy. At the 12 months follow-up after the treatment, the median uPr/uCr did not change significantly from baseline (8.13 vs. 9.07; p = 0.98), while 3 patients were in partial or complete remission. A lower baseline uPr/uCr was a predictor of remission (2.55 vs. 8.74; p = 0.0238). Tregs count was not associated with CB-MSCs therapy. Conclusions CB-MSCs are safe and may have a role in the immunosuppressive therapy of pediatric patients with MDR-INS. This preliminary experience paves the way toward further phase II studies addressing MSC efficacy in immune-mediated kidney diseases.

Introduction: Steroid dependent nephrotic syndrome (SDNS) is a difficult and troublesome presentation of idiopathic nephrotic syndrome (INS) in children, with complicated management and increased morbidity. Objectives: The aim of this study was to identify the predictive clinical and laboratory characteristics of patients with SDNS, for parents counseling, appropriate management and improving outcome. Patients and Methods: A total of 374 children with steroid sensitive INS were evaluated in two groups as steroid dependent (group 1=199) and non-steroid dependent (group 2= 175) INS. SDNS was defined as ≥2 relapses during steroid reducing treatment or 15 days after discontinuation of corticosteroids. Results: Mean age at presentation was significantly lower in children with SDNS than those without steroid dependency (P=0.022). Diagnostic age less than two years (P=0.016), total relapses (P

Introduction: Immune dysfunction contributes to the progression of idiopathic nephrotic syndrome (INS), but the details of the pathogenesis of progression remain unknown. This study of children with INS investigated the relationship of activation of the mechanistic target of rapamycin (mTOR) pathway (PI3K/AKT/mTOR/p70S6K) with the levels of T helper 2/regulatory T (Th2/Treg) cells. Materials and Methods: Twenty children with active INS (before steroid treatment), 20 children with remitting INS (INS-R, after steroid treatment), and 20 healthy control children (Ctrl) were enrolled. The levels of Th2/Treg cells in their peripheral circulatory systems were measured using flow cytometry, and the concentration of interleukin (IL)-4 was determined using a cytometric bead array (CBA). The levels of PI3K, AKT, mTOR, p70S6K, and transcription factors associated with Th2/Treg cells were measured using real-time polymerase chain reaction. Results: The INS group had a greater proportion of circulating Th2 cells; level of IL-4 protein; and levels of GATA, PI3K, AKT, mTOR, and p70S6K mRNAs than the Ctrl group (all P < 0.05), but a lower proportion of circulating Tregs and expression of Foxp3 (both P < 0.05). Patients in the INS-R group had normalization of these markers (all P < 0.05). Patients in the INS group had negative correlation in the percentage of Treg cells with Th2 cells and with IL-4 level and a negative correlation in the levels of GATA3 and Foxp3 mRNAs. Conclusions: Patients with active INS had an imbalance of Th2/ Treg cells, which might result from the aberrant signaling of the mTOR pathway (PI3K/AKT/mTOR/ p70S6K). [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusion: T-cell and B-cell immunity contribute to the pathogenesis of different INSs. 93jrUr7xWzcKs_m7ApEaSR Video: (MP4 99,786 KB) [ABSTRACT FROM AUTHOR]

Background: In the absence of effective measures to predict steroid responsiveness, patients with nonhereditary steroid-resistant nephrotic syndrome (SRNS) have a significantly increased risk of progression to end-stage renal disease. In view of the poor outcomes of SRNS, it is urgent to identify the steroid responsiveness of idiopathic nephrotic syndrome (INS) early. Methods: To build a prediction model for SRNS, we collected 91 subjects; 57 of them had steroid-sensitive nephrotic syndrome, and the others had SRNS. For each subject, 87 clinical variables were measured. In general, only a small part of these variables is informative to SRNS. Thus, we proposed a new variable selection framework including a penalized regression approach (named MLR+TLP) to select variables having a linear effect on the SRNS and a nonparametric screening method (MAC) to select variables having a nonlinear marginal (joint) effect on the SRNS. Thereafter, considering the correlation between selected clinical variables, we used a stepwise method to build our final model for predicting SRNS. In addition, a statistical testing procedure is proposed to test the overfitting of the proposed model. Results: Twenty-six clinical variables were selected to be informative to SRNS, and an SVM model was built to predict SRNS with a leave-one-out cross-validation (LOO-CV) accuracy of 95.2% (overfitting p value<0.005). To make the model more useful, we incorporate prior medical information into the model and consider the correlation between selected variables. Then, a reduced SVM model including only eight clinical variables (erythrocyte sedimentation rate, urine occult blood, percentage of neutrophils, immunoglobulin A, cholesterol, vinculin autoantibody, aspartate aminotransferase, and prolonged prothrombin time) was built to have a LOO-CV accuracy of 92.8% (overfitting p value<0.005). The validation cohort showed that the reduced model obtained an accuracy of 94.0% (overfitting p value<0.005), with a sensitivity of 90.0% and a specificity of 96.7%. Notably, vinculin autoantibody is the only podocyte autoantibody included in this model. It is linearly related to steroid responsiveness. Finally, our model is freely available as a user-friendly.Conclusion: The SRNS prediction model constructed in this study comprehensively and objectively evaluates the internal conditions and disease status of INS patients and will provide scientific guidance for selecting treatment methods for children with nonhereditary SRNS. [ABSTRACT FROM AUTHOR]

Objective: We aimed to investigate the renal prognosis of patients with idiopathic nephrotic syndrome (INS) complicated with steroid-induced diabetes mellitus (SIDM), the association of high-density lipoprotein cholesterol (HDL-C) before glucocorticoid treatment with renal prognosis, and the risk for persistent diabetes among patients with INS who had withdrawn from steroid therapy. Materials and methods: We retrospectively analyzed 239 patients with INS complicated with SIDM at the National Clinical Research Center of Kidney Diseases, Jinling Hospital, from January 2008 to December 2019. The primary endpoint was the composite renal outcome defined as the development of end-stage renal disease (ESRD) or a 50% decrease in estimated glomerular filtration rate (eGFR) for more than 24 months after glucocorticoid withdrawal. The secondary endpoint was persistent diabetes, defined as fulfilling the criteria for diagnosing diabetes or using antidiabetic medications for at least 24 months after glucocorticoid withdrawal. Results: After glucocorticoid withdrawal for over 24 months, 35 (14.6%) patients reached the composite renal endpoint: end-stage renal disease (n = 14) or a 50% decrease in eGFR (n = 21). Before glucocorticoid therapy, a level of HDL-C greater than 1.45 mmol/L worsened renal survival in patients with INS complicated with SIDM. The log10 the level of HDL-C before glucocorticoid treatment was an independent risk factor for the renal outcome. A prediction model was generated: Hazard ratio (renal outcome) = 0.94 * hypertension before glucocorticoid therapy + 2.29 * log10 level of HDL-C before glucocorticoid treatment + 0.90 * the grade of interstitial tubule injury (AUROC, 0.75; 95% CI, 0.63 to 0.87; P < 0.01). Meanwhile, a level of fasting plasma glucose (FPG) before glucocorticoid treatment greater than 5.2 mmol/L enhanced the likelihood of persistent diabetes for at least 24 months after glucocorticoid withdrawal. Conclusions: Increased level of HDL-C before glucocorticoid therapy was independently associated with a higher risk for renal outcome and thus may be useful in the renal prognosis of patients with INS complicated with SIDM. [ABSTRACT FROM AUTHOR]

Steroid sensitive nephrotic syndrome is a common condition in pediatric nephrology, and most children have excellent outcomes. Yet, 50% of children will require steroid-sparing agents due to frequently relapsing disease and may suffer consequences from steroid dependence or use of steroid-sparing agents. Several steroid-sparing therapeutic agents are available with few high quality randomized controlled trials to compare efficacy leading to reliance on observational data for clinical guidance. Reported trials focus on short-term outcomes such as time to first relapse, relapse rates up to 1–2 years of follow-up, and few have studied long-term remission. Trial designs often do not consider inter-individual variability, and differing response to treatments may occur due to heterogeneity in pathogenic mechanisms, and genetic and environmental influences. Strategies are proposed to improve the quantity and quality of trials in steroid sensitive nephrotic syndrome with integration of biomarkers, novel trial designs, and standardized outcomes, especially for long-term remission. Collaborative efforts among international trial networks will help move us toward a shared goal of finding a cure for children with nephrotic syndrome. [ABSTRACT FROM AUTHOR]

Objective 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. Methods 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. Results 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). Conclusion 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. [ABSTRACT FROM AUTHOR]

Abstract Background To date, there is insufficient knowledge about the association of air pollution and childhood nephrotic syndrome in the real world. This study aimed to evaluate the effects of the three common gaseous air pollutants, including sulfur dioxide, total hydrocarbon, and methane, on the risk of idiopathic nephrotic syndrome (INS) in children. Methods We collected data from the Taiwan National Health Insurance Research Database and Taiwan Air Quality-Monitoring Database. Children younger than 18 years old, identified from January 1, 2000, were followed up until the first diagnosis of INS was established or until December 31, 2012. We measured the incidence rates and hazard ratios for INS stratified based on the quartiles (Q1–Q4) of air pollutant concentration. Multivariate Cox proportional hazards models were also applied by adjusting age, sex, monthly income, and urbanization. Results Compared with participants exposed to Q1 concentrations, the adjusted hazard ratios (aHRs) for INS increased progressively along the four quartiles of sulfur dioxide, total hydrocarbon, and methane, from 1 (Q1) to 1.78 (Q4), 1 (Q1) to 3.49 (Q4), 1 (Q1) to 7.83 (Q4), respectively. Conclusions Our study revealed that children with exposure to higher concentrations of sulfur dioxide, total hydrocarbon, and methane was associated with an increased risk of INS.

Background: Idiopathic nephrotic syndrome (INS) is one of the most common glomerular diseases in children with different pathological types and different responses to corticosteroids. A definitive diagnosis is essential for planning the treatment and determining the prognosis of these patients and currently, kidney biopsy is the only method for definitive diagnosis. However, this is an invasive procedure. In addition, in some cases, the biopsy is contraindicated or tissue obtained on biopsy is insufficient and may not represent the underlying disease. According to the recent hypothesis about the role of circulating permeability factors in the pathogenesis of INS, urine protein analysis as a noninvasive method to determine the specific biomarkers of the disease is of great interest to nephrologists and can be useful. Methods: In this case − control study, we analyzed urinary CD80 (uCD80) levels in 51 patients with INS using a special CD80 enzyme-linked immunosorbent assay kit and were compared between different groups of patients. Results: The highest urine CD80/creatinine ratio was found in patients with active minimal change disease and steroid-responsive nephrotic syndrome in the relapse stage of the disease. Conclusion: A significant level of uCD80 is correlated with better renal function and a more favorable response to steroids in patients with INS. Therefore, it can be concluded that a high level of uCD80 is correlated with a good prognosis in these patients.

Aim: Idiopathic nephrotic syndrome (NS) is the most common glomerular disorder of childhood. Its prognosis is correlated with treatment responsiveness and not renal histopathology. Most of the children who suffer from NS experience multiple relapses and there is a risk of long-term drug dependence with possible side effects. Hence, there is always a need for markers to assess its long-term outcome even in steroid responders. Urine neutrophil gelatinase-associated lipocalin (uNGAL) is an early risk marker of acute kidney injury and also a marker of progression of chronic kidney disease. Our aim was to determine if urine NGAL could predict steroid responsiveness at the onset of NS, which would help in the planning and monitoring of the treatment in idiopathic NS. The aims of this study were to determine the levels of uNGAL in children who were having their first episode of NS and to study its relation with steroid resistance at 3 months. Materials and Methods: A prospective observational study was conducted in children diagnosed with their first episode of idiopathic NS in a tertiary care teaching hospital from January, 2019 to July, 2020. Urinary NGAL measurements were conducted before starting steroids. Results: Seventy-nine children satisfying the inclusion criteria were included in this study. Their mean age was 7.18 (±2.86) years. The male to female ratio was 1.25:1. All 63 children who had urine NGAL less than 10 ng/mL responded to the standard dose of steroids at 8 weeks and attained remission. Out of the 16 children with NGAL over 10 ng/mL, 56.3% (n=9) responded to steroids within 8 weeks (intermediate or late steroid responders) and 43.8% (n=7) were steroid resistant NS (SRNS). Urine NGAL below 10 ng/mL was associated with steroid responsiveness in the first episode of NS at 3 months (p<0.001). Conclusion: Urine NGAL below 10 ng/mL is an early predictive biomarker of steroid responsiveness in the first episode of idiopathic NS. [ABSTRACT FROM AUTHOR]