Are children with IgA nephropathy different from adult patients?

BACKGROUND: Previously, several studies have indicated that pediatric IgA nephropathy (IgAN) might be different from adult IgAN, and treatment strategies might be also different between pediatric IgAN and adult IgAN. METHODS: We analyzed two prospective cohorts established by pediatric and adult nephrologists, respectively. A comprehensive analysis was performed investigating the difference in clinical and pathological characteristics, treatment, and prognosis between children and adults with IgAN. RESULTS: A total of 1015 children and 1911 adults with IgAN were eligible for analysis. More frequent gross hematuria (88% vs. 20%, p < 0.0001) and higher proteinuria (1.8 vs. 1.3 g/d, p < 0.0001) were seen in children compared to adults. In comparison, the estimated glomerular filtration rate (eGFR) was lower in adults (80.4 vs. 163 ml/min/1.73 m2, p < 0.0001). Hypertension was more prevalent in adult patients. Pathologically, a higher proportion of M1 was revealed (62% vs. 39%, p < 0.0001) in children than in adults. S1 (62% vs. 28%, p < 0.0001) and T1-2 (34% vs. 8%, p < 0.0001) were more frequent in adults. Adjusted by proteinuria, eGFR, and hypertension, children were more likely to be treated with glucocorticoids than adults (87% vs. 45%, p < 0.0001). After propensity score matching, in IgAN with proteinuria > 1 g/d, children treated with steroids were 1.87 (95% CI 1.16-3.02, p = 0.01) times more likely to reach complete remission of proteinuria compared with adults treated with steroids. CONCLUSIONS: Children present significantly differently from adults with IgAN in clinical and pathological manifestations and disease progression. Steroid response might be better in children.

DNA methylation of IFI44L as a potential blood biomarker for childhood-onset systemic lupus erythematosus.

BACKGROUND: IFN-induced protein 44-like (IFI44L) promoter methylation has been demonstrated to serve as an effective blood diagnostic biomarker for adult-onset SLE. However, its utility as a diagnostic marker for childhood-onset SLE (cSLE) remains to be verified. METHODS: Initially, we conducted a differential analysis of gene methylation and mRNA expression patterns in cSLE whole blood samples obtained from the public GEO database to determine IFI44L gene expression and assess the methylation status at its CpG sites. Subsequently, we collected clinical whole blood samples from 49 cSLE patients and 12 healthy children, employing an HRM-qPCR-based IFI44L methylation detection technique to evaluate its diagnostic efficacy in pediatric clinical practice. RESULTS: A total of 26 hypomethylated, highly expressed genes in cSLE were identified by intersecting differentially expressed genes (DEGs) and differentially methylation genes (DMGs). GO enrichment analysis for these 26 genes indicated a robust association with type I IFN. Among the overlapping genes, IFI44L exhibited the most pronounced differential expression and methylation. In subsequent clinical validation experiments, IFI44L methylation was confirmed as an effective blood-based diagnostic biomarker for cSLE, achieving an AUC of 0.867, a sensitivity of 0.753, and a specificity of 1.000. CONCLUSIONS: IFI44L methylation is a promising blood biomarker for cSLE. IMPACT: IFI44L promoter methylation was reported to serve as a highly sensitive and specific diagnostic marker for adult-onset SLE. However, the diagnostic efficacy of IFI44L in childhood-onset SLE (cSLE) still remains to be confirmed. In this study, we utilized bioinformatics analysis and conducted clinical experiments to demonstrate that IFI44L methylation can also serve as a promising blood biomarker for cSLE. The findings of this study can facilitate the diagnosis of cSLE and broaden our understanding of its molecular mechanisms, with a particular focus on those related to type I interferons.

Clinical features and familial mutations in the coexistence of Wilson's disease and Alport syndrome: A case report.

Background: Alport syndrome (AS) and Wilson's disease (WD) are genetic diseases that could lead to kidney damage. Herein, we report the clinical features and gene variants in a patient with WD and X-linked AS. Case presentation: The proband was a 12-year-old boy diagnosed with AS coexisting with WD at the age of 11 years. The patient underwent a medical check-up when he was 4 years and 8 months. Laboratory tests revealed elevated liver enzymes, decreased serum ceruloplasmin, increased 24-h urinary copper excretion, and one variant in the ATP7B gene. Then, the patient was diagnosed with WD. After 2 months of treatment with D-penicillamine and zinc salt, his liver function had recovered to normal levels, but he presented with microscopic hematuria. The hematuria did not resolve after switching to dimercaptosuccinic acid from D-penicillamine. In addition, he presented with proteinuria 3 years later. A renal biopsy was performed more than 6 years after the patient was diagnosed with WD, and electron microscopy showed that the basement membrane thickness was uneven, layered, and focal torn. Copper staining was negative. A genetic analysis identified a hemizygous variant (c.1718G > A, p. Gly573Asp) in COL4A5 and a homozygous variant (c.2975C > T, p. Pro992leu) in ATP7B. The patient's urine protein-creatinine ratio was less than 1.0 mg/mg after a 1 year of follow-up, after enalapril was administered for treating AS. Conclusion: This case highlights a lack of improvement in renal function after conventional treatment provides a possible indication for performing renal biopsy or genetic testing to determine the etiology in order to facilitate subsequent clinical management. Clinicians should prevent the occurrence of diagnostic inaccuracies caused by diagnostic anchoring because an accurate diagnosis is essential for achieving precise treatment and improved prognosis.

Real-word adrenocorticotropic hormone treatment for childhood-onset nephrotic syndrome.

Background: Current first-line anti-proteinuric treatments do not produce a satisfactory therapeutic effect in a considerable number of patients with nephrotic syndrome (NS). Interest in adrenocorticotropic hormone (ACTH) for the treatment of NS has recently been revived. The present study investigated the efficacy and safety of ACTH treatment in children with frequent relapsing NS (FRNS), steroid-dependent NS (SDNS), and steroid-resistant NS (SRNS). Method: The ACTH treatment group was comprised of NS patients receiving ACTH treatment. Patients with serum cortisol concentrations <85.3 nmol/L and who had not received ACTH treatment previously were enrolled in the control group from January 2018 to January 2021. The maintenance dose of prednisone, the number of disease recurrences, the time of first disease relapse, immunosuppressant use, serum cortisol levels, and adverse events were recorded in both groups. Results: Fifty-one patients were included in the ACTH group, and twenty-one patients were enrolled in the control group. Concurrent treatment with one or more immunosuppressive and/or cytotoxic treatments occurred in 92.2% and 85.7% of patients in the ACTH and control groups, respectively, throughout the study period. A greater reduction in the prednisone maintenance dose was observed in the ACTH group compared with the control group after 1 year of follow up (0.603 ± 0.445 mg/kg vs. 0.267 ± 0.500 mg/kg, p = 0.006). During the one-year study period, fewer participants experienced one or more disease relapses in the ACTH group (45.1%) compared to the control group (76.2%, odds ratio = 3.896, p = 0.016). The number of disease recurrences per patient in the ACTH group was less than that in the control group (median difference = -1, p = 0.006). The mean length of remission was 8.902 m and 7.905 m in the ACTH group and control group, respectively. A log-rank test showed a longer relapse free survival for patients in the ACTH group (p = 0.046), but the Breslow test showed no significant difference between groups (p = 0.104). Ten patients in the ACTH group successfully discontinued all drug therapies. No patients in the control group were able to discontinue drug therapy as of February 2022. Conclusion: ACTH, combined with multiple drugs, is effective at reducing the prednisone maintenance dose and may effectively prevent disease relapses in childhood NS.

Genetic spectrum of CAKUT and risk factors for kidney failure: a pediatric multicenter cohort study.

BACKGROUND: Congenital anomalies of the kidney and urinary tracts (CAKUT) are the leading cause of kidney failure in children with phenotypic and genotypic heterogeneity. Our objective was to describe the genetic spectrum and identify the risk factors for kidney failure in children with CAKUT. METHODS: Clinical and genetic data were derived from a multicenter network (Chinese Children Genetic Kidney Disease Database, CCGKDD) and the Chigene database. A total of 925 children with CAKUT who underwent genetic testing from 2014 to 2020 across China were studied. Data for a total of 584 children wereobtained from the CCGKDD, including longitudinal data regarding kidney function. The risk factors for kidney failure were determined by the Kaplan-Meier method and Cox proportional hazards models. RESULTS: A genetic diagnosis was established in 96 out of 925 (10.3%) children, including 72 (8%) with monogenic variants, 20 (2%) with copy number variants (CNVs), and 4 (0.4%)with major chromosomal anomalies. Patients with skeletal abnormalities were more likely to have large CNVs or abnormal karyotypes than monogenic variants. Eighty-two patients from the CCGKDD progressed to kidney failure at a median age of 13.0 (95% confidence interval, 12.4-13.6) years, and twenty-four were genetically diagnosed with variants of PAX2, TNXB, EYA1, HNF1B and GATA3 or the 48, XXYY karyotype. The multivariate analysis indicated that solitary kidney, posterior urethral valves, bilateral hypodysplasia, the presence of certain variants and premature birth were independent prognostic factors. CONCLUSIONS: The genetic spectrum of CAKUT varies among different subphenotypes. The identified factors indicate areas that require special attention.

Lipid metabolism contribute to the pathogenesis of IgA Vasculitis.

BACKGROUND AND OBJECTIVES: The underlying mechanism of IgA vasculitis (IgAV) and IgA vasculitis with nephritis (IgAVN) remains unclear. Therefore, there are no accurate diagnostic methods. Lipid metabolism is related to many immune related diseases, so this study set out to explore the relationship of lipids and IgAV and IgAVN. METHODS: Fifty-eighth patients with IgAV and 28 healthy controls were recruited, which were divided into six separate pools to investigate the alterations of serum lipids according to the clinical characteristics: healthy controls group (HCs) and IgAV group (IgAVs), IgAVN group (IgAV-N) and IgAV without nephritis group (IgAV-C), initial IgAV group (IgAV0) and IgAV in treatment with glucocorticoids group (IgAV1). RESULTS: 31 identified lipid ions significantly changed in IgAVs with p < 0.05, variable importance of the projection (VIP) > 1 and fold change (FC) > 1.5. All these 31 lipid ions belong to 6 classes: triacylglycerols (TG), phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylserine, ceramide, and lysophosphatidylcholine. TG (16:0/18:1/22:6) +NH4 over 888875609.05, PC (32:1) +H over 905307459.90 and PE (21:4)-H less than 32236196.59 increased the risk of IgAV significantly (OR>1). PC (38:6) +H was significantly decreased (p < 0.05, VIP>1 and FC>1.5) in IgAVN. PC (38:6) less than 4469726623 conferred greater risks of IgAV (OR=45.833, 95%CI: 6.689~341.070). CONCLUSION: We suggest that lipid metabolism may affect the pathogenesis of IgAV via cardiovascular disease, insulin resistance, cell apoptosis, and inflammation. The increase of TG(16:0/18:1/22:6) + NH4, and PC(32:1) + H as well as PE (21:4)-H allow a good prediction of IgAV. PE-to-PC conversion may participate in the damage of kidney in IgAV. PC (38:6) + H may be a potential biomarker for IgAVN.

Case Report: A case of recurrent thrombosis in pediatric antiphospholipid syndrome associated with pediatric onset systemic lupus.

Systemic lupus erythematosus (SLE) is an autoimmune disease with multi-system involvement as the main manifestation, and has complex and diverse clinical features. Studies on large samples have revealed that SLE patients have a significantly increased risk of thrombotic events, which are also one of the important causes of morbidity and mortality in SLE patients. Antiphospholipid syndrome (APS) is a rare autoimmune disorder characterized by recurrent arterial and venous thrombosis, pregnancy-related complications, and the persistence of antiphospholipid antibodies at a 12-week interval. There are few reports about SLE coexisting with APS in children. This paper reported a school-age patient who started the disease with gross hematuria after bumping into the waist. The initial diagnosis of renal contusion was then confirmed by color Doppler ultrasound as renal vein and inferior vena cava embolism. She suddenly developed severe chest pain and dyspnea 3 days after hospitalization. And imaging supported pulmonary embolism with massive proteinuria, hypoalbuminemia, and hypercholesterolemia. The initial diagnosis was nephrotic syndrome (NS) with arteriovenous embolization, and popliteal vein embolism occurred again 5 years later, and she was thus diagnosed with SLE coexisting with APS. Afterwards, we discussed the possible mechanism and therapeutic strategies of SLE&APS that started with nephrotic syndrome, in order to achieve early identification and treatment of the disease and improve the prognosis of children.

Correlation Analysis between Gut Microbiota and Metabolites in Children with Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune-mediated diffuse connective tissue disease characterized by immune inflammation with an unclear aetiology and pathogenesis. This work profiled the intestinal flora and faecal metabolome of patients with SLE using 16S RNA sequencing and gas chromatography-mass spectrometry (GC-MS). We identified unchanged alpha diversity and partially altered beta diversity of the intestinal flora. Another important finding was the increase in Proteobacteria and Enterobacteriales and the decrease in Ruminococcaceae among SLE patients. For metabolites, amino acids and short-chain fatty acids were enriched when long-chain fatty acids were downregulated in SLE faecal samples. KEGG analysis showed the significance of the protein digestion and absorption pathway, and association analysis revealed the key role of 3-phenylpropanoic acid and Sphingomonas. Sphingomonas were reported to be less abundant in healthy periodontal sites of SLE patients than in those of HCs, indicating transmission of oral species to the gut. This study contributes to the understanding of the pathogenesis of SLE disease from the perspective of intestinal microorganisms, explains the pathogenesis of SLE, and serves as a basis for exploring potential treatments for the disease.

Astragaloside IV Inhibits Galactose-Deficient IgA1 Secretion via miR-98-5p in Pediatric IgA Nephropathy.

Purpose: The factor associated with IgA nephropathy (IgAN) is an abnormality of IgA known as galactose-deficient IgA1 (Gd-IgA1). The purpose of this study was to determine the molecular role played by miRNAs in the formation of Gd-IgA1 in IgAN and investigate the regulatory role of Astragaloside IV (AS-IV) in miRNAs. Patients and methods: Bioinformatics analysis, along with functional and mechanistic experiments, were used to investigate the relationship and function of miRNA, ß-1, 3-galactosyltransferase (C1GALT1), Gd-IgA1, and AS-IV. Analyses involved a series of tools, including quantitative real-time polymerase chain reaction (qRT-qPCR), Western blot, enzyme-linked immunosorbent assay (ELISA), Vicia Villosa lectin-binding assay (VVA), Cell counting kit-8 assay (CCK-8), and the dual-luciferase reporter assay. Results: miRNA screening and validation showed that miR-98-5p was significantly upregulated in the peripheral blood mononuclear cells (PBMCs) of pediatric patients with IgAN compared with patients diagnosed with mesangial proliferative glomerulonephritis (MsPGN) and immunoglobulin A vasculitis nephritis (IgAV-N), and healthy controls (p < 0.05). Experiments with the dual-luciferase reporter confirmed that miR-98-5p might target C1GALT1. The overexpression of miR-98-5p in DAKIKI cells decreased both the mRNA and protein levels of C1GALT1 and increased the levels of Gd-IgA1 levels; these effects were reversed by co-transfection with the C1GALT1 plasmid, and vice versa. In addition, AS-IV downregulated the levels of Gd-IgA1 level in DAKIKI cells by inhibiting miR-98-5p. Conclusions: Our results revealed that AS-IV could inhibit Gd-IgA1 secretion via miR-98-5p. Increased levels of miR-98-5p in pediatric IgAN patients might affect the glycosylation of IgA1 by targeting C1GALT1. In addition, our analyses suggest that the pathogenesis of IgAN may differ from that of IgAV-N. Collectively, these results provide significant insight into the pathogenesis of IgAN and identify a potential therapeutic target.

Integrated Analyses of Gut Microbiome and Host Metabolome in Children With Henoch-Schönlein Purpura.

Recent studies have shown that intestinal microbes and metabolites are involved in the pathogenesis of many diseases. However, whether and how they are related to Henoch-Schönlein purpura (HSP) has yet to be understood. This work is designed to detect gut microbes, intestinal and serum metabolites in children with HSP, trying to discover the etiology and pathogenesis of HSP. A total of 86 children were recruited in this study, namely, 58 children with HSP (HSP group) and 28 healthy children as control groups (CON group). 16S rDNA amplicon sequencing technology and UPLC-QTOF/MS non-targeted metabolomics analysis were used to detect the intestinal microbes and metabolites, and also multi-reaction monitoring technology for detecting serum arachidonic acid (AA) and its metabolites. Then, correlation analysis was performed to explore the possible interaction between the differential gut microbes and metabolites. As a result, at the microbiota family level, the CON group had an advantage of Coriobacteriaceae while the HSP group had a dominant Bacteroidaceae. Five kinds of bacteria in the HSP group were significantly enriched at the genus level, and seven kinds of bacteria were significantly enriched in the CON group. A total of 59 kinds of gut metabolites significantly differ between the two groups, in which most are lipids and peptides. Spearman correlation analysis showed that Bacteroides, Dialister, and Agathobacter were associated with unsaturated fatty acids, especially AA metabolism. Then, we tested the AA related metabolites in serum and found thromboxane B2, leukotriene B4, prostaglandin D2, 9S-hydroxyoctadecadienoic acid, and 13S-hydroxyoctadecadienoic acid significantly changed. In conclusion, children with HSP had dominant Bacteroidaceae and decreased Coriobacteriaceae in the family level of gut microbes, and also lipids and peptides changed most in the gut metabolites. Our data suggested that the biosynthesis and metabolism of unsaturated fatty acids, especially AA and its metabolites, might participate in the occurrence and development of HSP.

Genetic Architecture of Childhood Kidney and Urological Diseases in China.

Kidney disease is manifested in a wide variety of phenotypes, many of which have an important hereditary component. To delineate the genotypic and phenotypic spectrum of pediatric nephropathy, a multicenter registration system is being implemented based on the Chinese Children Genetic Kidney Disease Database (CCGKDD). In this study, all the patients with kidney and urological diseases were recruited from 2014 to 2020. Genetic analysis was conducted using exome sequencing for families with multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early-onset or extrarenal features. The genetic diagnosis was confirmed in 883 of 2256 (39.1%) patients from 23 provinces in China. Phenotypic profiles showed that the primary diagnosis included steroid-resistant nephrotic syndrome (SRNS, 23.5%), glomerulonephritis (GN, 32.2%), congenital anomalies of the kidney and urinary tract (CAKUT, 21.2%), cystic renal disease (3.9%), renal calcinosis/stone (3.6%), tubulopathy (9.7%), and chronic kidney disease of unknown etiology (CKDu, 5.8%). The pathogenic variants of 105 monogenetic disorders were identified. Ten distinct genomic disorders were identified as pathogenic copy number variants (CNVs) in 11 patients. The diagnostic yield differed by subgroups, and was highest in those with cystic renal disease (66.3%), followed by tubulopathy (58.4%), GN (57.7%), CKDu (43.5%), SRNS (29.2%), renal calcinosis /stone (29.3%) and CAKUT (8.6%). Reverse phenotyping permitted correct identification in 40 cases with clinical reassessment and unexpected genetic conditions. We present the results of the largest cohort of children with kidney disease in China where diagnostic exome sequencing was performed. Our data demonstrate the utility of family-based exome sequencing, and indicate that the combined analysis of genotype and phenotype based on the national patient registry is pivotal to the genetic diagnosis of kidney disease. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-021-00014-1.

A novel likely pathogenic variant in the UMOD gene in a family with autosomal dominant tubulointerstitial kidney disease: a case report.

BACKGROUND: Autosomal dominant tubulointerstitial kidney disease (ADTKD) caused by a pathogenic variant in UMOD (ADTKD-UMOD) is a rare group of diseases characterized by hyperuricaemia with decreased urinary excretion of urate, gout and progressive chronic kidney disease. The mundane clinical characteristics often result in a failure to diagnose ADTKD-UMOD. CASE PRESENTATION: In this report, we describe a 12-year-old boy who presented with polyarthritis, hyperuricaemia and tophi with a family history of 8 affected individuals. Clinical data, blood and urine samples of 3 affected members and 8 unaffected members were collected. Genetic testing of the eight genes (UMOD, HPRT1, PRPS1, MTHFR, REN, HNF1b, URAT1 and G6PC) was performed using Sanger sequencing. A heterozygous missense variant (c.674C > G; p.T225R) in UMOD was found in this boy, his older brother with the same phenotype and his mother with hyperuricaemia, gout and chronic kidney disease. CONCLUSION: This case highlights the importance of family history and genetic testing for definite diagnosis. This novel variant extends the spectrum of known UMOD gene variants and further supports the allelic heterogeneity of ADTKD-UMOD.

IPDN-China promotes the development of pediatric dialysis in China.

BACKGROUND: In mainland China, dialysis for children with end-stage renal disease (ESRD) was not introduced until the 1980s. To describe the development of pediatric dialysis in different regions of China, a national pediatric dialysis network, namely, International Pediatric Dialysis Network-China (IPDN-China) ( www.pedpd.org.cn ), was launched in 2012. METHODS: Original and updated information from the renal centers registered with the IPDN-China was collected between 2012 and 2016 from two sources, namely, the registry and the survey, and demographic features were analyzed. RESULTS: Due to promotion by the IPDN-China, the number of registered renal centers increased from 12 to 39 between 2012 and 2016, with a significant increase in the coverage of the Chinese administrative divisions (from 26.5 to 67.6%) (p < 0.01); and the coverage of the pediatric (0~14 years old) population increased to nearly 90% in 2016. The distribution of renal centers indicated that East China had the highest average number of registered centers per million population (pmp) 0~14-year-old age group. Seventeen relatively large dialysis centers were distributed across 14 divisions. Various modalities of renal replacement therapy (RRT) were available in most centers. The IPDN-China has promoted collaborations between dieticians, psychologists, and social workers on dialysis teams to provide better service to children with ESRD and their families. The proportion of centers with all three types of paramedic support (i.e., dieticians, psychologists, and social workers) as well as the proportion of centers with a partial paramedic team significantly increased between 2012 (25.0%) and 2016 (69.2%) (p < 0.05). In terms of the point prevalent cases of patients (aged < 18 years), data from the survey of 39 registered centers revealed that the number of children with ESRD who were on RRT was 578 (49% received a kidney transplant) at the end of 2016, which was more than that reported in previous surveys. Data from the registry showed that 349 dialysis patients had been enrolled as of the end of 2016. The median age at RRT start was 9.5 years, and the leading cause of ESRD was congenital abnormalities of the kidney and urinary tract (CAKUT). CONCLUSIONS: The IPDN-China has helped to promote the development of pediatric dialysis for ESRD in China by improving the organization of care for dialysis patients and increasing the availability and the quality of RRT for patients who need it. To improve knowledge about the epidemiology and outcomes of pediatric RRT around the country, a sustained effort needs to be made by the IPDN-China to increase the enrollment of dialysis patients and increase the number of registered centers in the future.

Podocytic infolding in Schimke immuno-osseous dysplasia with novel SMARCAL1 mutations: a case report.

BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive disorder characterized by spondyloepiphyseal dysplasia, progressive renal insufficiency and defective cellular immunity. Podocytic infolding glomerulopathy (PIG) is a newly proposed disease entity characterized by microspheres or microtubular structures associated with podocytes infolding into the glomerular basement membrane (GBM) on electron microscopy (EM). CASE PRESENTATION: A 4-year-old boy was admitted to our ward due to proteinuria and edema lasting 1 month. He had a short trunk and demonstrated subtle dysmorphology, with a triangular shape, a broad nasal bridge and a bulbous nasal tip. The laboratory findings were as follows: lymphocytes, 0.5 × 109/L; urine protein, 3.67 g/d; albumin, 9.8 g/L; and cholesterol, 11.72 mmol/L. Skeletal X rays showed small iliac wings, small ossification centers of the capital femoral epiphyses, shallow dysplastic acetabular fossae and mildly flattened vertebrae. The specimen for light microscopy (LM) suggested focal segmental glomerulosclerosis (FSGS). EM revealed a focal thickness of the GBM with some cytoplasmic processes of podocyte infolding into the GBM. Gene sequencing showed novel compound heterozygous mutations in the SMARCAL1 gene (c.2141 + 5G > A; c.2528 + 1G > A) that were inherited from his parents. Finally, we established the diagnosis of SIOD and treated him with diuretics and angiotensin-converting enzyme inhibitors (ACEIs). CONCLUSION: The pathogenic mechanism of PIG has not been clarified. Further studies are required to understand whether gene mutations, especially those related to podocytes, contribute to the pathogenesis of podocytic infolding.

Abnormalities of Serum Fatty Acids in Children With Henoch-Schönlein Purpura by GC-MS Analysis.

Purpose: The objectives of this work were to test the levels of serum medium- and long- chain fatty acids (MLCFAs) in children and to discover their possible relationship with Henoch-Schönlein Purpura (HSP), also known as Immunoglobulin A vasculitis. Methods: A total of 57 children with HSP (HSP group) and 28 healthy children (CON group) were recruited for this study. Serum specimens were collected to detect the compositions and contents of MLCFAs by gas chromatography with mass spectrometry (GC-MS) analysis. Results: The contents of all detected 37 MLCFAs in the HSP group were higher than the healthy group. Thirty-one species of MLCFAs were discovered to have a significant difference (p < 0.05) in two groups. Comparing to healthy controls, there were 31, 31, 18 fatty acids showed a statistical difference in the untreated group, regular treated group, and withdrawal group of HSP, respectively. The trend of fatty acids in the three HSP groups was similar to the healthy controls, as well as the untreated group and regular treated group changed more obviously than the withdrawal group. Almitate (C16:0) and 18 carbon atoms (C18) of fatty acids were abundant in all three HSP groups, divided according to the treatment of glucocorticoid. Some fatty acids were found having considerable differences (p < 0.05) in three groups. Monounsaturated fatty acids (MUFAs), including elaidate (C18:1T), cis-11,14,17-eicosatrienoic acid ester (C20:1), and cis-15-tetracosenoate (C24:1), were distinctly higher in HSP children with renal damage. Conclusion: Our study revealed that the abnormalities in MLCFA may be associated with the development of HSP. Another interesting finding was that fatty acids contents were changing during the glucocorticoid treatment. Meanwhile, long-chain MUFAs may have an impact on renal damage in HSP patients. Further studies need to be carried out in order to explore the specific mechanism of fatty acids in the course of HSP.

Multicenter study of the clinical features and mutation gene spectrum of Chinese children with Dent disease.

Dent disease is a rare X-linked recessive inherited tubular disease. In this multicenter study, the clinical presentation and genetic background of Chinese children with Dent disease are studied to improve the cognition and diagnostic ability of pediatricians. In this prospective cohort, we described the genotype and phenotype of a national cohort composed of 45 pediatric probands with Dent disease belonging to 45 families from 12 different regions of China recruited from 2014 to 2018 by building up the multicenter registration system. The CLCN5 gene from 32 affected families revealed 28 different mutations. The OCRL gene from 13 affected families revealed 13 different mutations. The incidence of low-molecular-weight proteinuria (LMWP) in both Dent disease type 1 populations and Dent disease type 2 populations was 100.0%; however, the incidence of other manifestations was not high, which was similar to previously reported data. Therefore, LMWP is a key clinical feature that should alert clinicians to the possibility of Dent disease. A high amount of LMWP combined with positive gene test results can be used as the diagnostic criteria for this disease. The diagnostic criteria are helpful in reducing the missed diagnosis of this disease and are beneficial for protecting the renal function of these patients through early diagnosis and early intervention.

A Systematic Analysis of Major Susceptible Genes in Childhood-onset Steroid-resistant Nephrotic Syndrome.

AIM: Nephrotic syndrome is a urinary disease, causing high morbidity and mortality. However, the mutation prevalence of major susceptible genes in childhood-onset steroid-resistant nephrotic syndrome (SRNS) in China is limited. In this study, we performed a systematic analysis of the mutations in 18 major SRNS-susceptible genes in Chinese SRNS children. METHODS: Mutation analysis was performed to sequence 18 major SRNS-susceptible genes (NPHS1, NPHS2, CD2AP, PLCE1, ACTN4, TRPC6, INF2, WT1, LMX1B, LAMB2, LAMB3, GLA, ITGB4, SCARB2, COQ2, PDSS2, MTTL1, and SMARCAL1) using a PCR-based MassArray technology in 38 childhood-onset SRNS patients in China. This cohort included 10 sporadic cases and 28 familial cases from 7 SRNS families with disease onset between the ages of 1-13 years. RESULTS: Our analysis detected a heterozygous missense mutation (p.E447K, pathogenic) in NPHS1 in 3/28 familial patients (10.7%) and 1/10 (10.0%) patient without a family history. In addition, two NPHS2 mutations (p.R138X and p.R291W, pathogenic) were identified in 2 patients from another family (7.1% familial cases, 0% sporadic cases, 5.2% overall). Pathogenic mutations of remaining 16 SRNS-susceptible genes were not detected. CONCLUSION: Our results have verified the significant prevalence of pathogenic NPHS1 and NPHS2 mutations in childhood-onset SRNS in China, while the other 16 SRNS-susceptible genes seem to have lesser contribution to child-onset SRNS. Therefore, our study indicates that it is very necessary to make more efforts to target NPHS1 and NPHS2 for childhood-onset SRNS treatment, especially in China.

Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system.

To explore the approaches and diagnostic yield of genetic testing for renal disease in children, we describe the genotype and phenotype of the national cohort of children with renal disease from 13 different regions of China recruited from 2014 to 2018 by building up the multicenter registration system (Chinese Children Genetic Kidney Disease Database, CCGKDD). Genetic diagnosis was confirmed in 42.1% of our cohort of 1001 pediatric patients with clinical suspicion of a genetic renal disease. Of the 106 distinct monogenetic disorders detected, 15 accounted for 60.7% of genetic diagnoses. The diagnostic yield was 29.1% in steroid resistant nephritic syndrome (SRNS), 61.4% in cystic renal disease, 17.0% in congenital anomalies of the kidney and urinary tract (CAKUT), 62.3% in renal tubular disease/renal calcinosis, and 23.9% for chronic kidney disease (CKD) 3 to 5 stage with unknown origin. Genetic approaches of target gene sequence (TGS), singleton whole-exome sequencing (WES) and trio-WES were performed with diagnostic rates of 44.8%, 36.2%, and 42.6%, respectively. The early use of trio-WES could improve the diagnostic rate especially in renal tubular disease and calcinosis. We report the genetic spectrum of Chinese children with renal disease. Establishment of the CCGKDD will improve the genetic work on renal disease.

Usefulness of mizoribine administration in children with frequently relapsing nephrotic syndrome, and the relationship between pharmacokinetic parameters and efficacy: a multicenter prospective cohort study in China.

BACKGROUND: Mizoribine (MZR) is an immunosuppressant used to treat adult nephropathy. There is little experience with the drug in treating Chinese children with frequently relapsing nephrotic syndrome (FRNS). We investigated the efficacy and safety for treating MZR with FRNS. Furthermore, the relationship between efficacy and serum concentration was investigated. METHODS: A prospective multicenter observational 12-month study was performed for evaluating the usefulness of MZR with FRNS. Serum MZR concentration was measured, and the relationships between pharmacokinetic parameters (Cmax, AUC), number of relapses, and urinary protein were evaluated. RESULTS: Eighty-two pediatric patients from four hospitals were treated with MZR and prednisone. MZR treatment significantly reduced the number of relapses and steroid doses. A correlation between pharmacokinetic parameters and relapses was observed, which fits well with the sigmoidal Emax model. Even in the relationship between pharmacokinetic parameters and urinary proteins, it was recognized that there was a threshold in the pharmacokinetic parameters for the therapeutic effect similar to the results obtained with the sigmoidal Emax model. Eleven patients (13.4%) experienced mild adverse events. CONCLUSIONS: MZR therapy was effective in reducing the number of relapses and steroid doses. No severe adverse reactions were observed. Therapeutically effective serum concentrations were estimated to be Cmax ≥ about 2 µg/mL or AUC ≥ about 10 µg h/mL. MZR and steroid treatment were effective and safe for pediatric FRNS.