Steroid-resistant Nephrotic Syndrome Research Articles

Nephrotic Syndrome Throughout Childhood: Diagnosing Podocytopathies From the Womb to the Dorm.

The etiologies of podocyte dysfunction that lead to pediatric nephrotic syndrome (NS) are vast and vary with age at presentation. The discovery of numerous novel genetic podocytopathies and the evolution of diagnostic technologies has transformed the investigation of steroid-resistant NS while simultaneously promoting the replacement of traditional morphology-based disease classifications with a mechanistic approach. Podocytopathies associated with primary and secondary steroid-resistant NS manifest as diffuse mesangial sclerosis, minimal change disease, focal segmental glomerulosclerosis, and collapsing glomerulopathy. Molecular testing, once an ancillary option, has become a vital component of the clinical investigation and when paired with kidney biopsy findings, provides data that can optimize treatment and prognosis. This review focuses on the causes including selected monogenic defects, clinical phenotypes, histopathologic findings, and age-appropriate differential diagnoses of nephrotic syndrome in the pediatric population with an emphasis on podocytopathies.

Comparison of different genetic testing modalities applied in paediatric patients with steroid-resistant nephrotic syndrome

BackgroundSteroid-resistant nephrotic syndrome (SRNS) are monogenic in some cases, however, there are still no clear guidelines on genetic testing in the clinical practice of SRNS in children.MethodsThree hundred thirty-two children were diagnosed with SRNS, and all children underwent genetic testing, including gene panels and/or whole-exome/genome sequencing (WES/WGS), during treatment. We analysed the relationship between clinical manifestation and genotype, and compared different genetic testing methods’ detection rates and prices.ResultsIn this study, 30.12% (100/332) of children diagnosed with SRNS had monogenic causes of the disease. With 33.7% (122/332) of children achieving complete remission, 88.5% (108/122) received steroids combined with tacrolimus (TAC). In detectability, WES increased by 8.69% (4/46) on gene panel testing, while WGS increased by 4.27% (5/117) on WES, and WES was approximately 1/7 of the price of WGS for every further 1% increase in pathogenicity.ConclusionsWe verified that steroids combined with TAC were the most effective option in paediatric SRNS. In detection efficiency, we found that WGS was the highest, followed by WES. The panel was the lowest, but the most cost-effective method when considering the economic-benefit ratio, and thus it should be recommended first in SRNS.

Mutations in the NUP93, NUP107 and NUP160 genes cause steroid-resistant nephrotic syndrome in Chinese children

BackgroundThe variants of nucleoporins are extremely rare in hereditary steroid-resistant nephrotic syndrome (SRNS). Most of the patients carrying such variants progress to end stage kidney disease (ESKD) in their childhood. More clinical and genetic data from these patients are needed to characterize their genotype–phenotype relationships and elucidate the role of nucleoporins in SRNS.MethodsFour patients of SRNS carrying biallelic variants in the NUP93, NUP107 and NUP160 genes were presented. The clinical and molecular genetic characteristics of these patients were summarized, and relevant literature was reviewed.ResultsAll four patients in this study were female and initially presented with SRNS. The median age at the onset of the disease was 5.08 years, ranging from 1 to 10.5 years. Among the four patients, three progressed to ESKD at a median age of 7 years, ranging from 1.5 to 10.5 years, while one patient reached stage 3 chronic kidney disease (CKD3). Kidney biopsies revealed focal segmental glomerulosclerosis in three patients. Biallelic variants were detected in NUP93 in one patient, NUP107 in two patients, as well as NUP160 in one patient respectively. Among these variants, five yielded single amino acid substitutions, one led to nonsense mutation causing premature termination of NUP107 translation, one caused a single nucleotide deletion resulting in frameshift and truncation of NUP107. Furthermore, one splicing donor mutation was observed in NUP160. None of these variants had been reported previously.ConclusionThis report indicates that biallelic variants in NUP93, NUP107 and NUP160 can cause severe early-onset SRNS, which rapidly progresses to ESKD. Moreover, these findings expand the spectrum of phenotypes and genotypes and highlight the importance of next-generation sequencing in elucidating the molecular basis of SRNS and allowing rational treatment for affected individuals.

Expansion of the genotypic and phenotypic spectrum and treatment of four children with Steroid-resistant nephrotic syndrome due to variants of TRPC6 gene

To summarize the clinical and genetic characteristics, treatment and prognosis of four children with Steroid-resistant nephrotic syndrome (SRNS) due to variants of TRPC6 gene. Clinical data of four children with SRNS admitted to Children's Hospital Affiliated to Zhengzhou University between May 2020 and August 2022 were collected. Peripheral blood samples were collected from the children and their parents, and whole exome sequencing was carried out. Sanger sequencing was used to verify the pathogenicity of the candidate variants among the children and their parents. All of the four children were found to harbor heterozygous variants of the TRPC6 gene, including c.523C>T (p.R175W), c.1327T>A (p.F443I), c.430G>C (p.E144Q) (unreported previously), and c.523C>T (p.R175W), which were all missense variants. Two of the children have shown a simple type, whilst two have shown a nephritis type, none had extrarenal phenotype. Comprehensive renal pathology of three children revealed focal segmental glomerulosclerosis (FSGS). Two children were treated with steroids combined with calcineurin inhibitors (CNIs), among whom one showed significant improvement in symptoms. Discoveries of the novel c.430G>C variant and the new SRNS phenotype of the c.1327T>A variant have expanded the mutational and phenotypic spectrum of the TRPC6 gene, which has provided a reference for clinical diagnosis and genetic counseling for the families.

WCN24-1789 The use of rituximab in childhood steroid-resistant nephrotic syndrome: an international, multi-centre study

WCN24-1789 The use of rituximab in childhood steroid-resistant nephrotic syndrome: an international, multi-centre study

National Unified Renal Translational Research Enterprise: Idiopathic Nephrotic Syndrome (NURTuRE-INS) study

Abstract 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 with 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 In total, 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 (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 MCD and 162 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.

Clinical Profile of Pediatric Patients with Steroid-resistant Nephrotic Syndrome Treated by Cyclophosphamide, Cyclosporin A, Mycophenolate Mofetile and Tacrolimus in Hasan Sadikin General Hospital

BackgroundSteroid-resistant nephrotic syndrome is a major cause of chronic kidney disease in children and adolescents. These diseases require appropriate management, while in some developing countries, the availability of agents recommended by international guidelines is very limited.Research objectivesTo determine and describe the patient profiles of pediatric Steroid Resistant Nephrotic Syndrome (SRNS) that use Cyclophosphamide(CPA), Cyclosporine(CyA), Tacrolimus, and Mycofenolat Mofetil (MMF) in Dr. Hasan Sadikin Hospital (RSHS), Bandung as a tertiary hospital in West Java, Indonesia.Methods and materialsThis research used a retrospective study with cross-sectional study design, total sampling method and medical record of pediatric (1-18 years old) patients from January 1st 2017–September 31st 2019 who were diagnosed as SRNS .Results : From 99 subjects that belonged to inclusion criteria, 35.4% pediatric SRNS patients were in the age group 6-10 years and 60.6% were males. Laboratorium profiles showed among all population, ureum <100 mg/dL were found as high as 97%, creatinine 0.3-1.0 mg/dL (71.7%) albumin >2,5 gr/dL (51.5%), negative hematuria (68.7%) , protein dipstick < 3 (50.5%), and LFG > 90 mL/min/1.73 m2 (79.8%).. The patients generally had use CPA (87.9%) and remission <6 month (51.5%).Conclusion: Profiles of pediatric patients are important to diagnose and prognose SRNS. By using these approaches, it is feasible to access and detect the most effective treatment for SRNS.

Estimation of the Age of the Kashubian-Specific Pathogenic NPHS2 Variant Responsible for Hereditary Steroid-Resistant Nephrotic Syndrome Points to Its Recent Local Origin

Steroid-resistant nephrotic syndrome (SRNS) is a highly heterogenic kidney disorder resulting from genetic abnormalities or immune system dysfunction affecting the establishment and maintenance of the glomerular filtration barrier. The most common cause of genetic SRNS is biallelic pathogenic variants in NPHS2 gene, especially in individuals with an infantile or childhood onset. The type of the NPHS2 defect implies the course of the disease and the stage of its onset and differs across populations. In a cohort of Polish patients with SRNS, a unique profile of the disease-related NPHS2 variants was identified in patients from northern Poland inhabited by Kashubs, a minority West-Slavic ethnic group known for a local increase of the frequency of several pathogenic variants. Among Kashubian families, the compound heterozygotes c.686G>A/c.1032delT and a single c.1032delT homozygote were the only underlying cause of SRNS. The restricted, Kashubian-only pattern of c.1032delT occurrence, suggesting the founder effect, prompted us to conduct a detailed analysis of its haplotype background to estimate the age of the c.1032delT origin. Eight Kashubian SRNS families were genotyped using the Infinium Global Screening Array-24. The haplotype background analysis was performed using an in-house pipeline designed to solve the phase of the heterozygous genotype data. The age of the c.1032delT mutation was calculated using the gamma method based on the genetic length of ancestral haplotypes shared between two or more individuals carrying this variant. The results of our study indicated a very recent origin of the c.1032delT mutation (~240 years). Genetic screening performed in the general Polish population control corroborates the assumption that the mutation occurred on the specific Kashubian haplotype background. The identification of ancestry-specific Kashubian pathogenic variant can help to develop effective screening and diagnostic strategies as a part of personalized medicine approach in the region.

Quantitative phenotyping of Nphs1 knockout mice as a prerequisite for gene replacement studies.

Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of chronic kidney disease before the age of 25 yr. Nephrin, encoded by NPHS1, localizes to the slit diaphragm of glomerular podocytes and is the predominant structural component of the glomerular filtration barrier. Biallelic variants in NPHS1 can cause congenital nephrotic syndrome of the Finnish type, for which, to date, no causative therapy is available. Recently, adeno-associated virus (AAV) vectors targeting the glomerular podocyte have been assessed as a means for gene replacement therapy. Here, we established quantitative and reproducible phenotyping of a published, conditional Nphs1 knockout mouse model (Nphs1tm1.1Pgarg/J and Nphs2-Cre+) in preparation for a gene replacement study using AAV vectors. Nphs1 knockout mice (Nphs1fl/fl Nphs2-Cre+) exhibited 1) a median survival rate of 18 days (range: from 9 to 43 days; males: 16.5 days and females: 20 days); 2) an average foot process (FP) density of 1.0 FP/µm compared with 2.0 FP/µm in controls and a mean filtration slit density of 2.64 µm/µm2 compared with 4.36 µm/µm2 in controls; 3) a high number of proximal tubular microcysts; 4) the development of proteinuria within the first week of life as evidenced by urine albumin-to-creatinine ratios; and 5) significantly reduced levels of serum albumin and elevated blood urea nitrogen and creatinine levels. For none of these phenotypes, significant differences between sexes in Nphs1 knockout mice were observed. We quantitatively characterized five different phenotypic features of congenital nephrotic syndrome in Nphs1fl/fl Nphs2-Cre+ mice. Our results will facilitate future gene replacement therapy projects by allowing for sensitive detection of even subtle molecular effects.NEW & NOTEWORTHY To evaluate potential, even subtle molecular, therapeutic effects of gene replacement therapy (GRT) in a mouse model, prior rigorous quantifiable and reproducible disease phenotyping is necessary. Here, we, therefore, describe such a phenotyping effort in nephrin (Nphs1) knockout mice to establish the basis for GRT for congenital nephrotic syndrome. We believe that our findings set an important basis for upcoming/ongoing gene therapy approaches in the field of nephrology, especially for monogenic nephrotic syndrome.

Lipoprotein glomerulopathy: a rare cause of steroid-resistant nephrotic syndrome in a child.

Lipoprotein glomerulopathy (LPG) is a rare condition of renal lipidosis characterized by lipoprotein thrombi in glomeruli, an abnormal plasma lipoprotein profile, and a marked increase in serum apolipoprotein E (apo E) levels. It is a monogenic disorder with autosomal dominant inheritance and the average age of presentation is 32years (4-69years). It is rare in children. The presentation can be nephrotic syndrome, hematuria, or progressive renal failure. Here we report the first described case of LPG in an Indian 7.5-year-old boy who presented with steroid-resistant nephrotic syndrome with normal renal function. A renal biopsy was suggestive of lipoprotein glomerulopathy. The detection of a pathogenic variant in apo E, Kyoto type, by exome sequencing, confirmed the diagnosis of lipoprotein glomerulopathy. Complete response was achieved with Angiotensin-converting Enzyme inhibitor and fenofibrates.

Expanding the spectrum of novel candidate genes using trio exome sequencing and identification of monogenic cause in 27.5% of 320 families with steroid-resistant nephrotic syndrome

Expanding the spectrum of novel candidate genes using trio exome sequencing and identification of monogenic cause in 27.5% of 320 families with steroid-resistant nephrotic syndrome

Risk factors and renal outcomes of AKI in children with secondary steroid-resistant nephrotic syndrome

Background Acute kidney injury (AKI) is increasingly prevalent in children with nephrotic syndrome (NS). It is associated with adverse outcomes in NS, especially steroid-resistant nephrotic syndrome (SRNS). The incidence, risk factors and outcomes of AKI in secondary SRNS remain undefined. The main objectives of this study were to determine the risk factors and prognosis of AKI in hospitalized children with secondary SRNS. Material and methods This retrospective study was conducted from January 2014 to December 2019, involving 172 hospitalizations with secondary SRNS admitted to the First Affiliated Hospital of Sun Yat-sen University. AKI was defined and classified in accordance with the 2012 Kidney Disease Improving Global Outcomes (KDIGO) guidelines. Results AKI was found in 67 (39.0%) of 172 hospitalizations with secondary SRNS. Average age of onset in our group is 4.4 (3.1, 6.7) years with AKI and 3.7 (1.8, 5.6) years without AKI. Urea nitrogen level is 5.9 (4.1, 10.0) mmol/L with AKI and 5.1 (3.7, 7.0) mmol/L. Uric acid level is 446.0 (340.0, 567.0) umol/L with AKI and 401.0 (303.0, 496.0) umol/L. 24-h urinary protein level is 4.14 (2.9, 6.5) g with AKI and 2.5 (1.3, 5.3) without AKI. Multivariate logistic regression revealed that infection (OR = 5.287; 95% confidence interval, 2.349 to 11.899; p < 0.001), age at onset (OR = 1.180; 95% confidence interval, 1.032 to 1.349; p = 0.015) and uric acid level (OR = 1.003; 95% confidence interval, 1.000 to 1.006; p = 0.031) were significantly associated with the development of AKI in children with secondary SRNS. Among 72 children with secondary SRNS, six went to end-stage kidney disease (ESKD). Children in the AKI group were more likely to progress to ESKD compared with children in the non-AKI group (p = 0.017) with a median follow‐up of 48.5months. Conclusion AKI occurred in 39.0% of total hospitalizations associated with secondary SRNS. Risk factors including infection, age of onset, and uric acid level are associated with AKI in children with secondary SRNS. Furthermore, AKI was identified as a risk factor for the progression of secondary SRNS to ESKD.

Clinicopathological features and outcome of secondary steroid resistant nephrotic syndrome: A retrospective analysis.

To determine the clinico-pathological features and long-term outcome of secondary steroid-resistant nephrotic syndrome treated with steroids and calcineurin inhibitors. The retrospective cohort study was conducted at the Sindh Institute of Urology and Transplant, Karachi, in June and July 2023, and comprised data from January 1, 2008, to December 31, 2020, of children aged 1-18 years who developed steroid resistance after initial sensitivity to steroids with at least 1-year of follow-up. Demographics as well as time taken to secondary steroid response were documented. Renal biopsy of all patients with secondary steroid resistance had been performed. Eventual outcomes after treatment with calcineurin inhibitors based on the degree of proteinuria and serum albumin levels were used to categorise complete remission, partial remission and no response. Kidney function, as determined by estimated glomerular filtration rate, was recorded. Data was analysed using SPSS 22. Of the 1,000 patients who underwent renal biopsy for steroid resistance, 48(4.8%) had idiopathic steroid-resistant nephrotic syndrome; 32(66.7%) males, 16(33.3%) females and median age of 5 years (interquartile range: 4-7.3 years). Median age at diagnosis of nephrotic syndrome was 5 years (interquartile range: 3.6-7.3 years). The median time from nephrotic syndrome to secondary steroid-resistant nephrotic syndrome was 23 months (interquartile range: 8.75-44.5 months). Biopsy results at diagnosis showed that 27(56.3%) had minimal change disease. The mean follow-up time was 6.1±3.2 years. Of the 43(89.5%) patients who received cyclosporin for 1 year, 29(67%) obtained complete remission, 5(12%) attained partial remission and no response was seen in 9(21%) patients. Majority of the children had minimal change disease at the time of diagnosis of secondary steroid-resistant nephrotic syndrome. The long-term response with calcineurin inhibitors was favourable at 1 year.

Steroid-resistant minimal change nephrotic syndrome associated with thymoma treated effectively with rituximab following thymectomy and cyclosporine: a case report

BackgroundMinimal change nephrotic syndrome (MCNS) can be complicated by thymoma; however, no standard therapy for thymoma-associated MCNS has yet been established. We herein describe a case of steroid-resistant MCNS associated with thymoma, treated effectively with rituximab.Case presentationA 71-year-old Japanese man was referred to our department with severe proteinuria (20 g/gCr). Renal biopsy showed minimal change disease and computed tomography revealed an anterior mediastinal mass. Based on these findings, he was diagnosed with thymoma-associated MCNS. He was treated with oral prednisolone (50 mg/day) and cyclosporine, and underwent thymectomy and plasma exchange. However, no improvement in proteinuria was observed. He therefore received intravenous rituximab 500 mg, resulting in a marked decrease in proteinuria from 5328 to 336 mg/day after 1 week.ConclusionsThis case suggests that rituximab might be an effective therapy in patients with steroid-resistant MCNS associated with thymoma.

WT1-related disorders: more than Denys-Drash syndrome.

Historically, specific mutations in WT1 gene have been associated with distinct syndromes based on phenotypic characteristics, including Denys-Drash syndrome (DDS), Frasier syndrome (FS), Meacham syndrome, and WAGR syndrome. DDS is classically defined by the triad of steroid-resistant nephrotic syndrome (SRNS) onset in the first year of life, disorders of sex development (DSD), and a predisposition to Wilms tumor (WT). Currently, a paradigm shift acknowledges a diverse spectrum of presentations beyond traditional syndromic definitions. Consequently, the concept of WT1-related disorders becomes more precise. A genotype-phenotype correlation has been established, emphasizing that the location and type of WT1 mutations significantly influence the clinical presentation, the condition severity, and the chronology of patient manifestations. Individuals presenting with persistent proteinuria, with or without nephrotic syndrome, and varying degrees of kidney dysfunction accompanied by genital malformations should prompt suspicion of WT1 mutations. Recent genetic advances enable a more accurate estimation of malignancy risk in these patients, facilitating a conservative nephron-sparing surgery (NSS) approach in select cases, with a focus on preserving residual kidney function and delaying nephrectomies. Other key management strategies include kidney transplantation and addressing DSD and gonadoblastoma. In summary, recent genetic insights underscore the imperative to implement individualized, integrated, and multidisciplinary management strategies for WT1-related disorders. This approach is pivotal in optimizing patient outcomes and addressing the complexities associated with these diverse clinical manifestations.

Low Birth Weight is Associated with More Severe Course of Steroid-Sensitive Nephrotic Syndrome in Children, Multicentric Study.

Several previous studies have reported a more severe course of nephrotic syndrome in children with low birth weight. Cohort of 223 children with idiopathic nephrotic syndrome. We aimed to investigate the association between course of nephrotic syndrome and low birth weight. Data from seven paediatric nephrology centres were used. Children with low birth weight had 3.84 times higher odds for a more severe course of steroid-sensitive nephrotic syndrome (95% CI 1.20-17.22, P=0.041), and those with low birth weight and remission after 7 days had much higher odds for a more severe course of disease (OR 8.7). Low birth weight children had a longer time to remission (median 12 vs. 10 days, P=0.03). They had a higher need for steroid-sparing agents (OR for the same sex=3.26 [95% CI 1.17-11.62, P=0.039]), and the odds were even higher in females with low birth weight (OR 6.81). There was no evidence of an association either between low birth weight and focal segmental glomerulosclerosis or between low birth weight and steroid-resistant nephrotic syndrome. We conducted the first multicentric study confirming the worse outcomes of children with NS and LBW and we found additional risk factors. Low birth weight is associated with a more severe course of steroid-sensitive nephrotic syndrome, while being female and achieving remission after 7 days are additional risk factors.

Endothelial Dysfunction in Children With Nephrotic Syndrome: A Cross-Sectional Study.

Background Children with nephrotic syndrome (NS) have a higher risk of cardiovascular morbidity. Studies on the evaluation of arterial stiffness and endothelial function and its predictive risk factors in these children are limited. Objective The primary objective of the study was to determine arterial stiffness by measuring carotid intimal medial thickness, flow-mediated dilatation, and physiological parameters in children with nephrotic syndrome to predict the risk of premature atherosclerosis as compared to controls. Participants A total numberof 33 children with NS in the age group of 2-14 years in remission and 39 healthy controls were enrolled in the study. Out of 33 children with nephrotic syndrome, five were infrequently relapsing NS, eight were frequently relapsing, 16 were steroid dependent, and four were steroid-resistant NS. Intervention Relevant history, physical examination, anthropometric measurements, and laboratory investigations were done. Carotid intimal medial thickness (cIMT), flow-mediated dilatation (FMD), and other physiological parameters were measured in both children with NS and control groups. Outcome Carotid intimal medial thickness (cIMT), flow-mediated dilatation (FMD), and other physiological parameters were compared between children with NS and healthy controls for detecting arterial stiffness and endothelial dysfunction. Results Dyslipidaemia was seen in more than 50% of children during remission. There was neither significant difference in mean cIMT in the common carotid artery nor FMD between the control and study groups. There was a trend of lower Reactive Hyperemia Index (RHI) in children with NS. Conclusion Dyslipidemia persists even during the remission phase in NS. No statistically significant difference is observed in cIMT and percentage proportionate change in FMD in both the study and control groups. Nevertheless, RHIis notably lower in children with NS. These findings need further validation in future studies.

Low-density Lipoprotein Receptor Activities, Lipids, Apolipoprotein, and Clinical Course of Patients with Steroid-resistant Nephrotic Syndrome Treated with Low-density Lipoprotein Apheresis: A Case Series.

We herein report three cases of steroid-resistant nephrotic syndrome successfully treated with low-density lipoprotein apheresis (LDL-A). All patients were treated with a combination of steroids, cyclosporine, and LDL-A. In all cases, the serum concentrations of LDL, total and high-density lipoprotein cholesterol, and triglycerides were significantly lowered following LDL-A administration. Furthermore, the estimated LDL receptor activity increased, while both serum LDL and total cholesterol levels decreased, suggesting that LDL-A increases LDL receptor activity by driving changes in serum cholesterol concentration. This case series suggests that LDL-A increases LDL receptor activity, which may improve the intracellular uptake of cyclosporine.

Nephrotic syndrome sera induce different transcriptomes in podocytes based on the steroid response.

As the molecular mechanism of nephrotic syndrome remains largely undiscovered, patients continue to be exposed to the pros and cons of uniform glucocorticoid treatment. We explored whether the exposure of invitro-cultivated podocytes to sera from children with steroid-sensitive or steroid-resistant nephrotic syndrome induces differences in gene expression profiles, which could help to elucidate the pathogenesis of the steroid response. Human immortalized podocytes were cultivated with patient sera for 3 days. After cell lysis, RNA extraction, 3'-mRNA libraries were prepared and sequenced. There were 34 significantly upregulated and 14 downregulated genes (fold difference <0.5 and >2.0, respectively, and false discovery rate-corrected p < 0.05) and 22 significantly upregulated and 6 downregulated pathways (false discovery rate-corrected p < 0.01) in the steroid-sensitive (n = 9) versus steroid-resistant group (n = 4). The observed pathways included upregulated redox reactions, DNA repair, mitosis, protein translation and downregulated cholesterol biosynthesis. Sera from children with nephrotic syndrome induce disease subtype-specific transcriptome changes in human podocytes invitro. However, further exploration of a larger cohort is needed to verify whether clinically distinct types of nephrotic syndrome or disease activity may be differentiated by specific transcriptomic profiles and whether this information may help to elucidate the pathogenesis of the steroid response.

Nephrotic Syndrome in a Child With NPHS2 Mutation.

Steroid resistant nephrotic syndrome (SRNS) accounts for 30% of all cases of nephrotic syndrome (NS) in children and frequently leads to end stage kidney disease (ESKD). About 30% of children with SRNS demonstrate causative mutations in podocyte- associated genes. Early identification of genetic forms of SRNS is critical to avoid potentially harmful immunosuppressive therapy. A 2-year-old male patient with NS and no family history of renal disease did not respond to 4-week steroid treatment. Kidney biopsy demonstrated mesangial proliferative glomerulopathy with basement membrane dysmorphism. Tacrolimus and Lisinopril were added to therapy pending results of genetic testing. Kidney Gene panel showed a NPHS2 c.413G>A (p.Arg138Gln) homozygous pathogenic variant. This missense variant is considered a common pathogenic founder mutation in European populations. A diagnosis of autosomal-recessive form of nonsyndromic SRNS due to NPHS2 causative variant was made. Immunosuppresive therapy was stopped, Lizinopril dose was increased and weekly infusions of Albumin/furosemide were initiated to manage edema. This case demonstrates that early genetic testing in children with SRNS avoids prolonged potentially harmful immunosuppressive therapy, allows for timely genetic family counseling, and allows earlier consideration for future living related donor kidney transplantation.