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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.

OBJECTIVE: We aimed to evaluate the association between platelet (PLT) count and the risk and progression of hand, foot, and mouth disease (HFMD). METHODS: In total, 122 HFMD patients and 40 healthy controls were enrolled in the study. The differences between variables among the different subgroups were compared. Logistic regression analyses were performed to assess the relationship between various parameters and HFMD risk/progression. Sensitivity analysis was conducted by detecting the trend of the association between PLT count quartiles and HFMD risk/progression. A generalized additive model was used to identify the nonlinear relationship between PLT count and HFMD risk/progression. The relationship between gender and PLT count as well as the risk/progression of HFMD was detected using a stratified logistic regression model. RESULTS: Significant differences were observed in terms of age, male/female ratio, white blood cell (WBC) count, and PLT count between patients with stage I-II, III-IV HFMD and healthy controls. Moreover, the alanine aminotransferase and magnesium levels between patients with stage I-II and III-IV HFMD significantly differed. Moreover, a significant difference was noted in the male/female ratio among the different PLT groups. The group with a low PLT count had a lower risk of HFMD progression than the group with a high PLT count (Q4) (p=0.039). Lower age, male gender, and WBC count were found to be associated with HFMD risk. Meanwhile, PLT count was correlated to HFMD progression. The sensitivity analysis yielded a similar result using the minimally adjusted model (p for trend=0.037), and minimal changes were observed using the crude and fully adjusted model (p for trend=0.054; 0.090). A significant nonlinear relationship was observed between PLT count and HFMD progression after adjusting for age, gender, and WBC (p=0.039). CONCLUSIONS: PLT was independently associated with HFMD progression in a nonlinear manner.

The activation of transcription factors such as nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1) plays an important role in regulating the expression of target genes, including those for cytokines involved in pathogenesis of minimal change nephrotic syndrome (MCNS). The therapeutic effects of glucocorticoids depend on the glucocorticoid receptor (GR) acting on gene transcription and interacting with certain transcription factors. To explore the role of transcription factors in the pathogenesis of MCNS and the therapeutic effects of glucocorticoids, we examined the DNA-binding abilities of NF-kappaB, AP-1, and GR in peripheral blood mononuclear cells (PBMC) from 6 children with MCNS and 6 healthy controls by electrophoretic mobility shift assay (EMSA). NF-kappaB and AP-1 DNA-binding abilities were significantly increased both at baseline and after stimulation by phorbol 12-myristate 13-acetate (TPA) in PBMC from MCNS patients compared with controls, but declined to normal levels after treatment with dexamethasone (DEX). GR DNA-binding abilities were significantly reduced at baseline and after treatment with TPA, but were enhanced markedly by DEX. There were strong correlations between urinary protein and the baseline DNA binding ability of NF-kappaB or AP-1, or GR. These results suggested that the abnormal activation of NF-kappaB and AP-1 and the reduction of GR DNA-binding abilities may be involved in the pathogenesis of MCNS. Inhibition of NF-kappaB and AP-1 and enhancement of GR DNA-binding abilities by DEX may form the molecular basis of the effects of glucocorticoids in MCNS.