Risk factors for renal outcomes in children with antineutrophil cytoplasmic antibody-associated vasculitis: a nationwide retrospective study in China.

BACKGROUND: Pediatric antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a life-threatening systemic vasculitis featured by liability to renal involvement. However, there are few studies on the risk factors and predictive models for renal outcomes of AAV in children. METHODS: Data from 179 AAV children in multiple centers between January 2012 and March 2020 were collected retrospectively. The risk factors and predictive model of end-stage renal disease (ESRD) in AAV were explored. RESULTS: Renal involvement was the most typical manifestation (95.5%), and the crescent was the predominant pathological lesion (84.9%). The estimated glomerular filtration rate (eGFR) was evaluated in 114 patients, of whom 59.6% developed ESRD, and the median time to ESRD was 3.20 months. The eGFR [P = 0.006, odds ratio (OR) = 0.955, 95% confidence interval (CI) = 0.924-0.987] and the percentages of global glomerulosclerosis (pGGS; P = 0.018, OR = 1.060, 95% CI = 1.010-1.112) were independent risk factors for ESRD of renal biopsy. Based on the pGGS and eGFR at renal biopsy, we developed three risk grades of ESRD and one predictive model. The Kaplan‒Meier curve indicated that renal outcomes were significantly different in different risk grades (P < 0.001). Compared with serum creatinine at baseline, the predictive model had higher accuracy (0.86 versus 0.58, P < 0.001) and a lower coefficient of variation (0.07 versus 0.92) in external validation. CONCLUSIONS: Renal involvement is the most common manifestation of pediatric AAV in China, of which more than half deteriorates into ESRD. The predictive model based on eGFR at renal biopsy and the pGGS may be stable and accurate in speculating the risk of ESRD in AAV children. Supplementary file 2 (MP4 18937 KB).

Association between HLA alleles and sub-phenotype of childhood steroid-sensitive nephrotic syndrome.

BACKGROUND: Few studies have addressed the effects of human leukocyte antigen (HLA) alleles on different clinical sub-phenotypes in childhood steroid-sensitive nephrotic syndrome (SSNS), including SSNS without recurrence (SSNSWR) and steroid-dependent nephrotic syndrome/frequently relapse nephrotic syndrome (SDNS/FRNS). In this study, we investigated the relationship between HLA system and children with SSNSWR and SDNS/FRNS and clarified the value of HLA allele detection for precise typing of childhood SSNS. METHODS: A total of 241 Chinese Han individuals with SSNS were genotyped using GenCap-WES Capture Kit, and four-digit resolution HLA alleles were imputed from available Genome Wide Association data. The distribution and carrying frequency of HLA alleles in SSNSWR and SDNS/FRNS were investigated. Additionally, logistic regression and mediating effects were used to examine the relationship between risk factors for disease process and HLA system. RESULTS: Compared with SSNSWR, significantly decreased serum levels of complement 3 (C3) and complement 4 (C4) at onset were detected in SDNS/FRNS (C3, P < 0.001; C4, P = 0.018). The average time to remission after sufficient initial steroid treatment in SDNS/FRNS was significantly longer than that in SSNSWR (P = 0.0001). Low level of C4 was further identified as an independent risk factor for SDNS/FRNS (P = 0.008, odds ratio = 0.174, 95% confidence interval 0.048-0.630). The HLA-A*11:01 allele was independently associated with SSNSWR and SDNS/FRNS (P = 0.0012 and P = 0.0006, respectively). No significant HLA alleles were detected between SSNSWR and SDNS/FRNS. In addition, a mediating effect among HLA-I alleles (HLA-B*15:11, HLA-B*44:03 and HLA-C*07:06), C4 level and SDNS/FRNS was identified. CONCLUSIONS: HLA-I alleles provide novel genetic markers for SSNSWR and SDNS/FRNS. HLA-I antigens may be involved in steroid dependent or frequent relapse in children with SSNS as mediators of immunoregulation.

[Expression of glomerular heparan sulfate domains in pediatric patients with minimal change nephrotic syndrome].

OBJECTIVES: To investigate the expression of glomerular heparin sulfate (HS) in paediatric patients with minimal change nephritic syndrome (MCNS). METHODS: The kidyney tissues were collected by biopsy from 13 paediatric patients with MCNS, while 5 normal renal biopsy samples were used as control. HS in glomeruli was analysed by indirect immunofluorescence staining using four different monoclonal antibodies, Hepss1, 3G10, JM403 and 10E4, which all recognize distinct HS species and each interacts with a specific HS domain. The concentrations of urine heparan sulfate also were measured by enzyme-linked immunosorbent assay (Elisa). RESULTS: Expression of HS fine domains was aberrant in paediatric patients compared with control subjects. Children with MCNS in replase showed a decreased glomerular expression of 10E4, JM403 and Hepss1 (P < 0.05). The level of urinary HS was significantly increased in peadiatric patients with MCNS when compared with that in control subjects (P < 0.01). CONCLUSION: These results suggest that loss of heparan sulphate in renal tissue may play a role in the pathogenesis of MCNS proteinuria.

[A prospective multicenter clinical control trial on treatment of refractory nephrotic syndrome with mycophenolate mofetil in children].

OBJECTIVE: To evaluate the efficacy and safety of mycophenolate mofetil (MMF) plus prednisone on refractory nephrotic syndrome (RNS) in children. METHODS: One hundred and forty-two children with RNS from ten clinical trial centers were divided into two groups: MMF (n=87) and control (n=55). The MMF group patients were administered with oral MMF (30-40 mg/kg daily) for at least 6 months. Afterwards the patients who responded to MMF received another 6 months MMF treatment at a dosage of 10-20 mg/kg daily. The controls were treated with pulse intravenous infusion of cyclophosphamide (CTX) (10 mg/kg daily) for 2 days every 2 weeks for 3 months. Then CTX was administered at a dosage of 500 mg/m2 once a month 4, 7 and 10 months after treatment. While the patients received MMF or CTX treatment, they were treated with oral prednisone (0.5-1 mg/kg daily) for 2 to 3 months, and then the dosage of prednisone was gradually reduced. Urinary protein, liver and renal functions, and side effects of drugs were examined at regular intervals for one year. RESULTS: Of the 87 patients, 58 achieved complete remission, 16 achieved partial remission, 9 achieved early remission and 4 had no response to treatment. In the control group, 35 achieved complete remission, 9 achieved partial remission, 1 achieved early remission and 10 had no response to treatment. The total remission rate in the MMF group (95.4%) was significantly higher than that in the control group (81.8%) (P<0.01). After treatment 67 patients (65.4%) in the MMF group had negative proteinuria compared with 36 patients (65.4%) in the control group (P>0.05). MMF was found to be more effective in reducing proteinuria, and improving hypoproteinemia, oliguria, hyperlipemia, and edema than CTX. MMF was better tolerated with lower incidences of adverse reactions than CTX. CONCLUSIONS: The combined therapy of MMF and prednisone is more effective and tolerable than pulse intravenous infusion of CTX for treatment of RNS in children.

Characterization of the genomic structures and selective expression profiles of nine class I small heat shock protein genes clustered on two chromosomes in rice (Oryza sativa L.).

The cytosolic class I small heat shock proteins (sHSP-CI) represent the most abundant sHSP in plants. Here, we report the characterization and the expression profile of nine members of the sHSP-CI gene family in rice (Oryza sativa Tainung No.67), of which Oshsp16.9A, Oshsp16.9B, Oshsp16.9C, Oshsp16.9D and Oshsp17.9B are clustered on chromosome 1, and Oshsp17.3, Oshsp17.7, Oshsp17.9A and Oshsp18.0 are clustered on chromosome 3. Oshsp17.3 and Oshsp18.0 are linked by a 356-bp putative bi-directional promoter. Individual gene products were identified from the protein subunits of a heat shock complex (HSC) and from in vitro transcription/ translation products by two-dimensional gel electrophoreses (2-DE). All sHSP-CI genes except Oshsp17.9B were induced strongly after a 2-h heat shock treatment. The genes on chromosome 3 were induced rapidly at 32 and 41 degrees C, whereas those on chromosome 1 were induced slowly by similar conditions. Seven of these genes, except Oshsp16.9D and Oshsp17.9B, were induced by arsenite (As), but only genes on chromosome 3 were strongly induced by azetidine-2-carboxylic acid (Aze, a proline analog) and cadmium (Cd). A similar expression profile of all sHSP-CI genes at a lower level was evoked by ethanol, H2O2 and CuCl2 treatments. Transient expression assays of the promoter activity by linking to GUS reporter gene also supported the in vivo selective expression of the sHSP-CI genes by Aze treatment indicating the differential induction of rice sHSP-CI genes is most likely regulated at the transcriptional level. Only Oshsp16.9A abundantly accumulated in mature dry seed also suggested additionally prominent roles played by this HSP in development.