A novel gain-of-function mutation in transient receptor potential C6 that causes podocytes injury.

Podocyte injury plays a vital role in focal segmental glomerulosclerosis (FSGS), and apoptosis is one of its mechanisms. The transient receptor potential channel 6 (TRPC6) is highly expressed in podocytes and mutations mediate podocyte injury. We found TRPC6 gene mutation (N110S) was a new mutation and pathogenic in the preliminary clinical work. The purpose of this study was to investigate the potential mechanism of mutation in TRPC6 (TRPC6-N110S) in the knock-in gene mouse model and in immortalized mouse podocytes (MPC5). Transmission electron microscopy was used to evaluate renal injury morphology. We measured 24-hour urinary albumin-to-creatinine ratios and major biochemical parameters such as serum albumin, urea nitrogen, and total cholesterol. The results of CCK-8 assay and apoptosis experiments showed that the TRPC6-N110S overexpression group had slower proliferative activity and increased apoptosis than the control group. FluO-3 assay revealed increased calcium influx in the TRPC6-N110S overexpression group. Podocin level was decreased in TRPC6-N110S group, while TRPC6 and desmin levels were increased in TRPC6-N110S group. The 24 h uACR at 6 weeks was significantly higher in the pure-zygotes group than in the WT and heterozygotes groups, and this difference was found at 8 and 10 weeks.TRPC6 levels showed no significant difference between homozygote and WT mice. Compared to homozygote group, expression of podocin and nephrin were increased in WT, but levels of desmin was decreased in WT. Our results suggest that this new mutation causes podocyte injury probably by enhancing calcium influx and podocyte apoptosis, accompanied by increased proteinuria and decreased expression of nephrin and podocin.

Clinical Characteristics of Children Infected with SARS-CoV-2 Omicron (B.1.1.529) in China's Shanghai.

Introduction: The pandemic of SARS-CoV-2 brings great challenge and threats to humans worldwide. Multiple variants of SARS-CoV-2 tend to be epidemic, among which Omicron is highly infectious within China. The aim of this study was to analyze the clinical characteristics of children infected with SARS-CoV-2 variant B.1.1.529 (Omicron) in the Shanghai, China. Methods: We included 9378 pediatric patients diagnosed with Omicron and treated in the Shanghai International Convention and Exhibition Center between April 1, 2022 and May 31, 2022. We recorded and summarized the clinical characteristics, infectious conditions and biological features of the children infected with Omicron. Results: A total of 9355 paediatric patients were treated in isolation since Makeshift became available, including 5564 males (59.48%) and 3791 females (40.52%). More than half (55.56%) of the affected children were identified at premises screening. The number of symptomatic or asymptomatic patients was 4530 (48.42%) and 4825 (51.58%), respectively. Initial signs or symptoms in asymptomatic patients included fatigue (3582, 38.29%), cough (560, 5.99%), fever (242, 2.59%) and other (146, 1.56%). Age and number of vaccinations in paediatric patients were negatively associated with the number of days from positive to negative nucleic acid test results. Conclusion: Age and number of vaccinations were key factors influencing the conversion of nucleic acid test results in paediatric patients. Early childhood vaccination is encouraged to establish a complete immune barrier.

Targeting ferroptosis attenuates podocytes injury and delays tubulointerstitial fibrosis in focal segmental glomerulosclerosis.

Ferroptosis is a non-apoptotic form of cell death, involved in chronic kidney diseases (CKD) and acute kidney injury (AKI), so far, the role of ferroptosis in focal segmental glomerulosclerosis (FSGS) remains largely unknown. We aimed to investigate the role of ferroptosis in FSGS, in this study, we found the reduced expression of GPX4 in podocytes, as well as tubular epithelial cells (TECs), from patients with FSGS. Treatment with ferrostatin-1 (Fer-1), a potent and selective ferroptosis inhibitor, significantly reduced proteinuria, prevented glomerulosclerosis, attenuated podocyte injury in ADR-induced FSGS murine model. As expected, ADR treatment caused downregulation of GPX4 in human podocytes, treatment with Fer-1 greatly blocked the downregulation of GPX4, restored the GSH level and attenuated cell death. Furthermore, Fer-1 treatment greatly delayed the development of tubulointerstitial fibrosis in ADR-induced FSGS murine model. Taken together, ferroptosis is involved in the pathogenesis of FSGS, targeting ferroptosis is a promising therapeutic option for patients with FSGS.

A clinicopathological and prognostic study of 18 children with C1q nephropathy and focal segmental glomerulosclerosis: an 18-year experience from a single center.

BACKGROUND: C1q nephropathy is a relatively rare glomerulonephritis characterized by dominant mesangial deposition of C1q. Even though C1q nephropathy has been described for more than three decades, the clinicopathological features and renal outcomes remain unclear. C1q nephropathy may present diverse morphological patterns, including focal segmental glomerulosclerosis and, the notion of C1q nephropathy as a separate disease entity is still debated. This study aimed to describe the clinical and prognostic relevance of C1q nephropathy in children with primary focal segmental glomerulosclerosis. METHODS: Three hundred eighty-nine children were diagnosed with primary focal segmental glomerulosclerosis in Jinling Hospital from 2003 to 2020. Among them, 18 cases fulfilled the criteria for C1q nephropathy. We then selected as a control group 18 children with primary focal segmental glomerulosclerosis without C1q nephropathy matched to those with C1q nephropathy for age, sex, and period of renal biopsy. Clinical and prognostic parameters were compared in children with and without C1q nephropathy. Renal end-point was defined as a ≥ 40% reduction in estimated glomerular filtration rate or end-stage renal disease. RESULTS: Four point sixty-three percent (18/389) of primary focal segmental glomerulosclerosis cases were diagnosed with C1q nephropathy. The male-to-female ratio of patients diagnosed with C1q nephropathy was 1:1. The median age at biopsy and age at onset was 15.63 (13.00-16.50) years and 14.50 (9.00-16.00) years, respectively. The prevalence of nephrotic syndrome, hematuria, and hypertension was 38.90% (7/18), 72.20% (13/18), and 33.30% (5/18), respectively. Four (22.2%) patients were steroid-dependent, 13 (72.2%) patients were steroid-resistant, and 1 (5.6%) patient developed secondary steroid-resistance. During a follow-up of 52.24 (25.00-72.47) months, 10 (55.6%) patients achieved remission, and 5 (27.8%) progressed to the end-point [including 2 (11.11%) patients who developed end-stage kidney disease]. There was no significant difference in the estimated end-stage renal disease-free survival rates, the estimated end-point-free survival rates, and the long-term remission rate between patients with and without C1q nephropathy (Kaplan-Meier, Log-rank, all P > 0.05). CONCLUSIONS: C1q nephropathy was rare in pediatric patients with focal segmental glomerulosclerosis. These patients usually had poor response to steroids. The long-term renal outcomes and remission of children with primary focal segmental glomerulosclerosis with C1q nephropathy were comparable to those without C1q nephropathy.

Glomerular capillary C3 deposition as a risk factor for unfavorable renal outcome in pediatric primary focal segmental glomerular sclerosis.

Introduction: Some patients with primary focal segmental sclerosis (FSGS) demonstrate complement 3 (C3) deposition in glomerular capillary loops (Cap-C3) and/or mesangial area (Mes-C3). The clinicopathological and prognostic significance of C3 deposition remains incompletely investigated, especially in the pediatric cohort. Methods: We retrospectively analyzed 264 children of biopsy-proven primary FSGS between January 2003 and December 2020. The correlation between Cap-C3 and renal outcome was evaluated by the Kaplan-Meier method and Cox multivariate regression analysis. Renal end-point event was defined as the development of end-stage renal disease, death for renal disease, or an estimated glomerular filtration rate reduction by at least 50% from baseline. Results: Among the 264 patients, 30 (11.4%) had Cap-C3. Kaplan-Meier analysis showed that patients with Cap-C3 had significantly lower renal survival rates than patients without Cap-C3 (60.17% vs. 84.71% at 5 years, 39.49% vs. 65.55% at 10 years, P < 0.01). Cox multivariate regression analysis showed that Cap-C3 was an independent risk factor for poor renal outcome (HR 3.53, 95% CI 1.22-10.19, P = 0.02). Conclusion: Glomerular capillary C3 deposition was an independent risk factor for unfavorable renal outcome in children with primary FSGS.

Predictors of long-term outcomes in pediatric focal segmental glomerulosclerosis.

BACKGROUND: Available data on primary focal segmental glomerulosclerosis (FSGS) in children usually report on short follow-up and small samples. Furthermore, the application of the Columbia classification for FSGS in children has not yet been fully agreed. We aimed to confirm the prognosis and risk factors of FSGS in a large cohort of Chinese children. METHODS: Two hundred seventy-four children with primary FSGS from a single center were enrolled from 2003 to 2018. Long-term renal survival and related risk factors were evaluated by the Kaplan-Meier method and Cox multivariate regression analysis. Receiver operating characteristic (ROC) curve analysis further tested the effect of various risk factors in predicting renal outcomes. The composite end-point included ≥ 50% reduction in estimated glomerular filtration rate and/or end-stage renal disease or death. RESULTS: One hundred twenty-five children were diagnosed with not otherwise specified (NOS) (45.6%) variant; 79 with tip lesions (28.8%), 32 with collapsing (11.7%), 31 with cellular (11.3%), and 7 with perihilar lesions (2.6%). The renal survival rate was 80.73% at 5 years, 62.58% at 10 years and 34.66% at 15 years. Multivariate analysis showed that chronic tubulointerstitial damage ≥ 25% (HR 4.14, 95% CI 1.49-11.50, P < 0.01), collapsing variant [(reference: NOS) HR 2.16, 95% CI 1.10-4.27, P = 0.03], segmental sclerosis (HR 1.03, 95% CI 1.01-1.04, P < 0.01) and age at biopsy (HR 0.91, 95% CI 0.85-0.98, P = 0.01) were significantly associated with renal outcomes. ROC curve analysis showed an excellent diagnostic yield of the Columbia classification. The combination of Columbia classification, CTI ≥ 25% and segmental sclerosis had the best predictive value for renal outcomes (AUC = 0.867, sensitivity = 77.78%, specificity = 82.27%, P < 0.01). CONCLUSIONS: This study reports a renal survival rate of Chinese children with FSGS of 62.58% at 10 years and 34.66% at 15 years. Prognosis is poorer in patients with collapsing variant or CTI ≥ 25% and good in patients with tip variant. The Columbia classification is confirmed as a valuable tool for predicting prognosis of Chinese children with FSGS.

IgM deposition is a risk factor for delayed remission and early relapse of the pediatric minimal change disease.

Background: Minimal change disease (MCD) is the most common pathological subtype of pediatric idiopathic nephrotic syndrome (INS). It has been suggested that IgM deposition might predict kidney function deterioration in the course of MCD. However, the specific role of IgM deposition in the prognosis of MCD is still controversial. This study aims to investigate the clinical significance of IgM deposition on delayed remission and early relapse in a pediatric population. Methods: This study enrolled 283 children diagnosed with MCD by renal biopsy in a single center from 2010 to 2022. These cases were divided into two groups according to the histopathological deposition of IgM. Patients' demographics, clinical parameters, and follow-up data were collected and analyzed. The primary and secondary outcomes were defined as the time to the first remission and the first relapse. Results: The IgM-positive group had a weaker response to steroids (steroid-sensitive: 23.5% vs. 40.8%; steroid-dependent: 74.0% vs. 51.0%; steroid-resistant: 18.4% vs. 8.2%, P = 0.001), and showed more recurrent cases (47.2% vs. 34.4%, P = 0.047) compared with the IgM-negative group. The Kaplan-Meier analysis showed that the IgM-positive group had a lower cumulative rate of the first remission (Log-rank, P < 0.001) and a higher rate of the first relapse (Log-rank, P = 0.034) than the IgM-negative group. Multivariate Cox analysis showed that IgM deposition was independently associated with the delayed first remission (hazard ratio [HR] = 0.604, 95% confidence interval [CI] = 0.465-0.785, P < 0.001) and the early first relapse (HR = 1.593, 95% CI = 1.033-2.456, P = 0.035). Conclusion: IgM deposition was associated with a weaker steroid response. MCD children with IgM deposition were prone to delayed first remission and early first relapse.

Two Children With Steroid-Resistant Significant Proteinuria Due to Nonsense Mutations of the TRIM8 Gene: A Case Report and Literature Review.

Background: TRIM8 gene mutations have been reported as the genetic basis of autosomal dominant (AD) neuro-renal syndrome in children, which presents with epileptic encephalopathy, focal segmental glomerulosclerosis (FSGS), developmental delay, and mental retardation. In this study, we report the cases of two children with significant proteinuria due to de novo nonsense mutations of the TRIM8 gene. Case Presentation: Case 1 was a 7-year-old girl who presented with proteinuria and developmental delay, and her renal biopsy showed FSGS. She developed end-stage renal disease (ESRD) 3 years after onset. Case 2 was another 7-year-old girl who developed proteinuria only at age 3, and renal biopsy showed glomerular segmental mesangial proliferative lesions. The two girls underwent genetic testing but we did not find a positive result in the whole exon. However, cluster analysis revealed two new nonsense mutations of the TRIM8 gene (c.1461C>A, p.Tyr 487* and c.1453C>T, p.Gln485*). Conclusions: We reported the clinical manifestation of this neuro-renal syndrome for the first time in China. It is necessary to perform genetic testing in children with steroid-resistant significant proteinuria to identify its etiology and avoid the side effects of immunosuppressants.

Human bone marrow mesenchymal stem cells-derived exosomes protect against nerve injury via regulating immune microenvironment in neonatal hypoxic-ischemic brain damage model.

Neonatal hypoxic-ischemic (HI) brain injury is a serious injury caused by various perinatal factors, which has become a heavy mental burden to the family. The molecular mechanism underlying neonatal hypoxic-ischemic brain injury remains largely unknown. Human bone marrow mesenchymal stem cells (hBMSCs) have caused wide public concern due to the immunomodulatory properties. Exosomes can polarize human microglia and thus changed it into an anti-inflammatory phenotype to reduce the release of pro-inflammatory factors. However, it is unclear whether hBMSCs-exosomes have effect on neonatal hypoxic-ischemic brain injury. In this study, we aimed at investigating the role of hBMSCs-exosomes in regulating immune response and nerve injury in neonatal hypoxic-ischemic brain damage model. In the research, we identified the exosome secretion of hBMSCs could transferred into human microglia (HMC). Moreover, we determined the importance of hBMSCs-exosomes in regulating HMC polarization and inflammatory response. Our research findings might provide a new insight into slowing the disease progression of neonatal hypoxic-ischemic brain injury.

Value of magnetic resonance imaging indices of left renal vein entrapment in the diagnosis of nutcracker syndrome in children.

BACKGROUND: Nutcracker syndrome (NCS) is also known as left renal vein (LRV) compression syndrome. Magnetic resonance imaging (MRI) can better depict the anatomical structure of soft tissues in the area of compression. Diagnosis of NCS using MRI in adults is not uncommon. However, there are few studies on the diagnosis of NCS using MRI in children. Therefore, we conducted this study to evaluate the clinical value of the MRI indices of the LRV in the diagnosis of NCS in children. METHODS: This study was a single-center retrospective analysis. One hundred seventy-four patients with suspected NCS were enrolled from January 2017 to July 2020. The inclusion criteria for suspected NCS were mainly based on clinical symptoms or signs, laboratory examinations and imaging reports. Other diseases that may cause hematuria and/or proteinuria were excluded. We grouped the patients based on the diagnostic criteria for NCS into a nutcracker group and a control group. The receiver operating characteristic (ROC) curve was constructed for evaluating the value of MRI indices in the diagnosis of NCS. RESULTS: The majority of NCS patients presented with orthostatic proteinuria (OP) (67.2%), followed by hematuria (55.2%), abdominal pain (19.0%), and left flank pain (15.5%). The areas under the curve (AUCs) for the superior mesenteric artery (SMA) angle, beak sign, and compression ratio (CR) in the diagnosis of NCS were 0.870, 0.895, and 0.878, respectively, and the best cutoff values of the SMA angle and CR were 36.8 and 3.99, respectively. The specificities of SMA angle <36.8°, beak sign, CR >3.99, SMA angle <36.8° and beak sign, SMA angle <36.8° and CR >3.99, and beak sign and CR >3.99 were 82.5%, 93.8%, 93.8%, 97.9%, 95.9% and 97.9%, respectively. CONCLUSIONS: Children with SMA angles less than 36.8°, beak signs and CR greater than 3.99 should be highly suspected of having NCS. Among these parameters, "beak sign" showed the highest diagnostic accuracy by MRI, and the combination of any two of the above parameters achieved a higher specificity than the single parameters.

Using MEST-C Scores and the International Study of Kidney Disease in Children Classification to Predict Outcomes of Henoch-Schönlein Purpura Nephritis in Children.

Introduction: Henoch-Schönlein purpura nephritis (HSPN) and IgA nephropathy (IgAN) bear similarities in some aspects. The histological classification of HSPN was built on the International Study of Kidney Disease in Children (ISKDC) criteria, while IgAN was established on the 2016 Oxford classification (MEST-C scores). The purpose of this paper was to discuss the predictive value of the ISKDC classification and MEST-C scores in children with HSPN. Methods: We performed a retrospective study of 877 children with HSPN in a single center between 2001 and 2019. The primary outcome was defined as chronic kidney disease-estimated glomerular filtration rate (eGFR) <90 ml/min/1.73 m2. Results: During the follow-up period of 23.3 (10.9-47.9) months, 51 (5.8%) patients reached the primary outcome. As revealed in a Kaplan-Meier plot, segmental glomerulosclerosis (S) (P < 0.001) and tubular atrophy/interstitial fibrosis (T) (P < 0.001) significantly predict poor renal outcome. Other Oxford lesions and the ISKDC classification, however, did not show a significant difference in a worse outcome. In a multivariate Cox model adjusted for pathological and clinical factors, eGFR [hazard ratio (HR) = 2.831, 95% confidence interval (95% CI) = 1.359-5.896], S lesion (HR = 3.936, 95% CI = 2.078-7.457), and T lesion (HR = 4.002, 95% CI = 1.733-9.242) were independent risk factors for the renal outcome. Conclusion: This series constitutes the largest series reported so far in the literature of such patients. According to our findings, S and T of the Oxford classification, which are ignored by the ISKDC classification, could be applied to predict the renal prognosis of children with HSPN.

Use of liquid chromatography-tandem mass spectrometry to perform urinary proteomic analysis of children with IgA nephropathy and Henoch-Schönlein purpura nephritis.

The emerging technology of urinary proteomics has become an efficient biological approach for identifying biomarkers and characterizing pathogenesis in renal involvement. In this study, we attempted to elucidate the relationship between IgAN and HSPN in children, employing LC-MS/MS to perform urinary proteomic analyses using the DIA method. Early-morning spot urine was collected from patients with biopsy-proven IgAN (n = 19) and HSPN (n = 19) prior to treatment and renal biopsy in the Department of Pediatrics, Jinling Hospital, Nanjing, China, and did healthy volunteers (n = 14), from June 2018 to December 2019. Two hundred seventy-six urinary proteins and 125 urinary proteins were determined to be differentially expressed in children with IgAN (n = 4) and HSPN (n = 4), respectively, compared to the urinary proteins of healthy children (n = 4) (p < 0.05). GO analysis demonstrated that the differentially expressed proteins of the two groups, which were located in the extracellular matrix and cell membrane, were primarily involved in biological processes, including metabolic processes, immune system processes, cellular adhesion, cell proliferation, signaling, and biological regulation. KEGG analysis revealed that the differentially expressed proteins of the two groups were associated with cell adhesion molecules, ECM-receptor interactions, the PI3K-Akt signaling pathway, the complement and coagulation cascades, regulation of actin cytoskeleton, cholesterol metabolism, and platelet activation. The target proteins (alpha-1B-glycoprotein (A1BG) and afamin (AFM)), which participated in the complement and coagulation cascades and the regulation of complement activation, were further investigated in the independent validation cohort by ELISA. These proteins were significantly increased in children with IgAN (n = 15) and HSPN (n = 15) compared with the proteins observed in healthy controls (n = 10, P < 0.05). The validated results were consistent with the mass spectrometry results. SIGNIFICANCE: IgAN and HSPN both result from the glomerular deposition of abnormally glycosylated IgA1 with mesangial proliferative changes, and both diseases are common glomerulopathies in the pediatric population that are believed to be correlated. Interestingly, our data, by combining urinary proteomic analyses, showed that several uniform enrichment pathways played an important role in the progression of IgAN and HSPN, suggesting that we might reduce the renal involvement of the two diseases in children through these pathways. The same urinary proteins along these pathways were observed to be differentially expressed in children with IgAN and HSPN, implying that these proteins may be potential biomarkers to identify the two diseases. Future studies examining larger cohorts are warranted to confirm the validity of our findings.

Long-term renal survival and related risk factors for primary membranous nephropathy in Chinese children: a retrospective analysis of 217 cases.

BACKGROUND: Primary membranous nephropathy (PMN) is a rare pathological finding in paediatric patients. Data on PMN in children have been restricted to studies with small samples and fairly short follow-up periods. Therefore, we conducted this single-centre study to evaluate the long-term renal survival and related risk factors for PMN in children, and the clinical and histological characteristics were also described. METHOD: Two hundred and seventeen children with PMN were enrolled from July 2008 to September 2017. Patients with follow-up durations < 12 months were excluded, except for patients who progressed to end-stage kidney disease (ESKD) or experienced a related death within 12 months. Long-term renal survival and related risk factors were analysed. RESULT: The sex ratio was 1.33:1 (male vs female), and the median age was 15.0 (14.0-17.0) years old. The most prominent clinical manifestation was nephrotic syndrome (130 59.9%), which was accompanied by various degrees of oedema (142 65.4%), hyperlipidaemia (151 69.6%), hypoalbuminemia (130 59.9%), and nephrotic proteinuria (135 62.2%). Hypertension occurred in 36.4% of children with PMN. After a median follow-up of 45.0 (23.5-74.0) months, 11 patients (5.1%) developed ESKD, and the cumulative kidney survival rates of ESKD at 5 and 10 years after renal biopsy were 95.3% and 67.8%, respectively. The cumulative kidney survival rates of the combined event of ESKD and/or 30% decline in estimated glomerular filtration rate (eGFR) at 5 and 10 years after renal biopsy were 92.6% and 59.5%, respectively. Cox multivariate regression and Kaplan-Meier analysis demonstrated that hypertension and proteinuria ≥ 50 mg/kg/day were associated with renal outcome. CONCLUSION: In this study, the 5-year and 10-year cumulative renal survival rates of ESKD in children with PMN were reported for the first time as 95.3% and 67.8%, respectively. In addition, this is the first report to find that hypertension and proteinuria ≥ 50 mg/kg/day are associated with renal outcome in children with PMN.

MiR-139 protects against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced nerve injury through targeting c-Jun to inhibit NLRP3 inflammasome activation.

BACKGROUND: Cerebral ischemia/reperfusion (I/R) injury after ischemic stroke is usually accompanied with the activation of inflammasome which seriously impairs neurological function. MiR-139 has been reported to be associated with inflammatory regulation in multiple diseases. However, its effect and mechanism on inflammation regulation after cerebral I/R injury are still poorly understood. METHODS: An in vitro model of cerebral I/R injury was constructed with oxygen-glucose deprivation/reoxygenation (OGD/R) treatment. TargetScan bioinformatics analysis and dual luciferase reporter assay were utilized to confirm the targeted relationship between miR-139 and c-Jun. Cell pyroptosis was verified by flow cytometry and Caspase-1 Detection Kit. qRT-PCR assay was performed to detect the expression levels of miR-139, c-Jun, NLRP3 and ASC. Western blotting was applied to measure the protein levels of c-Jun and pyroptosis-related markers NLRP3, ASC, caspase-1, GSDMDNterm. The ELISA assay was applied to measure the release of IL-1ß, IL-18 and LDH. RESULTS: MiR-139 was significantly downregulated whereas c-Jun was obviously upregulated after OGD/R treatment. TargetScan analysis predicted that c-Jun was a potential target of miR-139, which was verified by the dual-luciferase reporter assay. Also, overexpression of miR-139 repressed c-Jun expression. Furthermore, miR-139 inhibited OGD/R-induced cell pyroptosis and the upregulation of NLRP3, caspase-1, ASC, GSDMDNterm, and the release of IL-1ß, IL-18 and LDH, while miR-139 inhibition exerted the opposite effects. However, overexpression of c-Jun aggravated OGD/R-induced nerve injury and partly abolished the neuroprotective effect of miR-139. CONCLUSION: Upregulation of miR-139 exerted neuroprotection against OGD/R-induced nerve injury by negatively regulating c-Jun/NLRP3 inflammasome signaling. This study offered insights for providing potential therapeutic targets for treating cerebral I/R injury.

The correlation analysis between the Oxford classification of Chinese IgA nephropathy children and renal outcome - a retrospective cohort study.

BACKGROUND: The 2016 Oxford Classification's MEST-C scoring system predicts outcomes in adults with IgA nephropathy (IgAN), but it lacks tremendous cohort validation in children with IgAN in China. We sought to verify whether the Oxford classification could be used to predict the renal outcome of children with IgAN. METHODS: In this retrospective cohort study, 1243 Chinese IgAN children who underwent renal biopsy in Jinling Hospital were enregistered from 2000 to 2017. The combined endpoint was defined as either a ≥ 50% reduction in estimated glomerular filtration rate (eGFR) or end-stage renal disease (ESRD). We probed into the relevance betwixt the Oxford classification and renal prognosis. RESULTS: There were 29% of children with mesangial proliferation(M1), 35% with endocapillary proliferation (E1), 37% with segmental sclerosis/adhesion lesion (S1), 23% with moderate tubular atrophy/interstitial fibrosis (T1 25-50% of cortical area involved), 4.3% with severe tubular atrophy/interstitial fibrosis (T2 > 50% of cortical area involved), 44% with crescent in< 25% of glomeruli(C1), and 4.6% with crescent in> 25% of glomeruli (C2). All children were followed for a medial of 7.2 (4.6-11.7) years, 171 children (14%) arrived at the combined endpoint. The multivariate COX regression model revealed that the presence of lesions S (HR2.7,95%CI 1.8 ~ 4.2, P<0.001) and T (HR6.6,95%CI 3.9 ~ 11.3, P<0.001) may be the reason for poorer prognosis in the whole cohort. In contrast, C lesion showed a significant association with the outcome only in children received no immunosuppressive treatment. CONCLUSIONS: This study revealed that S and T lesions were useful as the long-term renal prognostic factors among Chinese IgAN children.

Two Children With Novel TRPC6 Spontaneous Missense Mutations and Atypical Phenotype: A Case Report and Literature Review.

Background: The phenotypes of TRPC6 mutations have been reported mainly in familial and sporadic focal segmental glomerulosclerosis (FSGS), which can occur in both adults and children. Herein, we report on two children with novel TRPC6 spontaneous missense mutations associated with immune complex-mediated glomerulonephritis and minor glomerular abnormality (MGA) that showed to be resistant to corticosteroids and other immunosuppressants. Case Presentation: A 9-year-old girl presented with steroid-resistant nephrotic syndrome (SRNS), while another 11-year-old boy developed proteinuria at 7 years old. Treatment with a variety of immunosuppressants had no effect, and the renal biopsy showed immune complex-mediated glomerulonephritis and MGA. No members of their family were clinically affected. Genetic testing was performed in the two patients, revealing two novel spontaneous missense mutations in TRPC6-N110S and P112R. The girl developed end-stage renal disease (ESRD) 5 months after onset while the boy continued to have sub-nephrotic range proteinuria and normal creatinine. Conclusions: Two novel TRPC6 mutations were associated with the atypical phenotype-immune complex-mediated glomerulonephritis and MGA, rather than FSGS as previously reported. Their rates of disease progression are different. Genetic testing is helpful to identify the etiology and avoid the side effects brought on by immunosuppressants.

Hypertonic saline mediates the NLRP3/IL-1ß signaling axis in microglia to alleviate ischemic blood-brain barrier permeability by downregulating astrocyte-derived VEGF in rats.

INTRODUCTION: The aim of this study was to explore whether the antibrain edema of hypertonic saline (HS) is associated with alleviating ischemic blood-brain barrier (BBB) permeability by downregulating astrocyte-derived vascular endothelial growth factor (VEGF), which is mediated by microglia-derived NOD-like receptor protein 3 (NLRP3) inflammasome. METHODS: The infarct volume and BBB permeability were detected. The protein expression level of VEGF in astrocytes in a transient focal brain ischemia model of rats was evaluated after 10% HS treatment. Changes in the NLRP3 inflammasome, IL-1ß protein expression, and the interleukin-1 receptor (IL1R1)/pNF-кBp65/VEGF signaling pathway were determined in astrocytes. RESULTS: HS alleviated the BBB permeability, reduced the infarct volume, and downregulated the expression of VEGF in astrocytes. HS downregulates IL-1ß expression by inhibiting the activation of the NLRP3 inflammasome in microglia and then downregulates VEGF expression by inhibiting the phosphorylation of NF-кBp65 mediated by IL-1ß in astrocytes. CONCLUSIONS: HS alleviated the BBB permeability, reduced the infarct volume, and downregulated the expression of VEGF in astrocytes. HS downregulated IL-1ß expression via inhibiting the activation of the NLRP3 inflammasome in microglia and then downregulated VEGF expression through inhibiting the phosphorylation of NF-кBp65 mediated by IL-1ß in astrocytes.

Long-term renal survival and undetected risk factors of IgA nephropathy in Chinese children-a retrospective 1243 cases analysis from single centre experience.

BACKGROUND: The long-term renal outcome for IgA nephropathy (IgAN) in large cohorts of children remains unclear. IgAN is a progressive disease, to explore novel biomarkers is necessary for predicting the disease activity and progression of IgAN. In addition, there is a hot debate on when to treat with immunosuppression in children. We aimed to confirm the long-term renal survival, find some undetected risk factors and investigate when to treat with immunosuppression can benefit for renal outcome in Chinese children. METHODS: 1243 Children with IgAN were enrolled and a follow-up of at least 1 year after a biopsy from 2000 to 2017. Long-term renal survival, undetected risk factors and the renal survival of immunosuppressive and non-immunosuppressive therapy were evaluated. The primary endpoint of the study was a combined outcome of either ≥50% reduction in estimated glomerular filtration rate (eGFR) or end-stage renal disease (ESRD) or death. RESULTS: The median follow-up time were 86.8 months (interquartile range 54.7-140.2 months). The 5-, 10- and 15-year renal survival rates were 95.3%, 90.3% and 84%, respectively. Cox multivariate regression and Kaplan-Meier analysis showed that hypertension, hyperuricemia, high 24 h urine protein (24 h-UP) levels, lower initial eGFR, high urine C3 levels, high retinol-binding protein (RBP) levels, segmental glomerulosclerosis (S) and tubular atrophy and interstitial fibrosis (T) were associated with renal outcome. The statistically significant predictive perfect power for renal outcome was RBP ≥ 0.7µg/ml (AUC = 0.899, sensitivity = 84.00%, specificity = 86.00%), 24 h-UP ≥ 1 g/24 h (AUC = 0.722, sensitivity = 84.20%, specificity = 52.70%), eGFR < 60 ml/min/1.73 m2 (AUC = 0.718, sensitivity = 81.30%, specificity = 39.20%) and S1 lesion (AUC = 0.703, sensitivity = 75.50%, specificity = 65.10%).Children with urinary RBP ≥ 0.7µg/ml were associated with a 2.513-fold risk than patients with urinary RBP < 0.7µg/ml (P = 0.003). Our study suggested that immunosuppressive therapy may reduce the risk of progression in IgAN children had both eGFR > 50 ml/min/1.73 m2 and proteinuria of at least 1 g/day. CONCLUSIONS: This is the first report that the 15-year renal survival rate of children with IgAN in China was 84%. At the same time, this is the first study to reveal that urinary RBP ≥ 0.7µg/ml may indicate a poor renal outcome. In addition, this study supports immunosuppressive therapy for IgAN children had both proteinuria ≥1 g/day and initial eGFR > 50 ml/min/1.73m2.

Urinary proteomics of Henoch-Schönlein purpura nephritis in children using liquid chromatography-tandem mass spectrometry.

BACKGROUND: Henoch-Schönlein purpura nephritis (HSPN) is the principal cause of morbidity and mortality in children with Henoch-Schönlein purpura (HSP). However, the criteria for risk assessment currently used is not satisfactory. The urine proteome may provide important clues to indicate the development of HSPN. METHODS: Here, we detected and compared the urine proteome of patients with HSPN and healthy controls by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the data-independent acquisition (DIA) mode. The differentially expressed proteins were analysed by gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. For validation, enzyme-linked immunosorbent assay (ELISA) was used to analyse the selected proteins. RESULTS: A total of 125 proteins (29 upregulated and 96 downregulated) were found to be differentially expressed in children with HSPN compared with the controls. Forty-one proteins were predicted to have direct interactions. The enriched pathways mainly included focal adhesion, cell adhesion molecules, the PI3K-Akt signalling pathway, ECM-receptor interactions and so on. Cell adhesion related to the pathogenesis of HSPN was the main biological process identified in this study. The decrease in two proteins (integrin beta-1 and tenascin) was validated by ELISA. CONCLUSIONS: Our study provides new insights into the assessment of HSPN progression in children, as well as new potential biomarkers. The data confirm the value of the urinary proteome in capturing the emergence of HSPN.