RESUMO
SIGNIFICANCE STATEMENT: Genome-wide association studies have identified nearly 20 IgA nephropathy susceptibility loci. However, most nonsynonymous coding variants, particularly ones that occur rarely or at a low frequency, have not been well investigated. The authors performed a chip-based association study of IgA nephropathy in 8529 patients with the disorder and 23,224 controls. They identified a rare variant in the gene encoding vascular endothelial growth factor A (VEGFA) that was significantly associated with a two-fold increased risk of IgA nephropathy, which was further confirmed by sequencing analysis. They also identified a novel common variant in PKD1L3 that was significantly associated with lower haptoglobin protein levels. This study, which was well-powered to detect low-frequency variants with moderate to large effect sizes, helps expand our understanding of the genetic basis of IgA nephropathy susceptibility. BACKGROUND: Genome-wide association studies have identified nearly 20 susceptibility loci for IgA nephropathy. However, most nonsynonymous coding variants, particularly those occurring rarely or at a low frequency, have not been well investigated. METHODS: We performed a three-stage exome chip-based association study of coding variants in 8529 patients with IgA nephropathy and 23,224 controls, all of Han Chinese ancestry. Sequencing analysis was conducted to investigate rare coding variants that were not covered by the exome chip. We used molecular dynamic simulation to characterize the effects of mutations of VEGFA on the protein's structure and function. We also explored the relationship between the identified variants and the risk of disease progression. RESULTS: We discovered a novel rare nonsynonymous risk variant in VEGFA (odds ratio, 1.97; 95% confidence interval [95% CI], 1.61 to 2.41; P = 3.61×10 -11 ). Further sequencing of VEGFA revealed twice as many carriers of other rare variants in 2148 cases compared with 2732 controls. We also identified a common nonsynonymous risk variant in PKD1L3 (odds ratio, 1.16; 95% CI, 1.11 to 1.21; P = 1.43×10 -11 ), which was associated with lower haptoglobin protein levels. The rare VEGFA mutation could cause a conformational change and increase the binding affinity of VEGFA to its receptors. Furthermore, this variant was associated with the increased risk of kidney disease progression in IgA nephropathy (hazard ratio, 2.99; 95% CI, 1.09 to 8.21; P = 0.03). CONCLUSIONS: Our study identified two novel risk variants for IgA nephropathy in VEGFA and PKD1L3 and helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.
Assuntos
Estudo de Associação Genômica Ampla , Glomerulonefrite por IGA , Humanos , Fator A de Crescimento do Endotélio Vascular/genética , Predisposição Genética para Doença , Glomerulonefrite por IGA/genética , Haptoglobinas/genética , Progressão da Doença , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Background: In recent years, many studies have reported the relationship between non-alcoholic fatty liver disease (NAFLD) and sex hormones, especially total testosterone (TT) and sex hormone-binding globulin (SHBG). However, the relationship between sex hormones and the severity of NAFLD is still unclear. Methods: PubMed, Embase, Cochrane Library, Web of Science, WanFang, China National Knowledge Infrastructure and VIP databases were searched for relevant studies from inception to 31 August 2021. Values of weighted mean differences (WMDs) and odds ratios (ORs) with their 95% confidence intervals (CIs) were combined by Stata 12.0 software to evaluate the relationship between TT, SHBG and the severity of NAFLD in males. Results: A total of 2995 patients with NAFLD from 10 published cross-sectional studies were included for further analysis. The meta-analysis indicated that the moderate-severe group had a lower TT than the mild group in males with NAFLD (WMD: -0.35 ng/ml, 95% CI = -0.50 to -0.20). TT and SHBG were important risk factors of moderate-severe NAFLD in males (ORTT = 0.79, 95% CI = 0.73 to 0.86; ORSHBG = 0.22, 95% CI = 0.12 to 0.39; p < 0.001). Moreover, when the analysis was limited to men older than age 50, SHBG levels were lower in those with moderate-severe disease (WMD: -11.32 nmol/l, 95% CI = -14.23 to -8.40); while for men with body mass index (BMI) >27 kg/m2, moderate-severe NAFLD had higher SHBG levels than those with mild disease (WMD: 1.20 nmol/l, 95% CI = -2.01 to 4.42). Conclusion: The present meta-analysis shows that lower TT is associated with the severity of NAFLD in males, while the relationship between SHBG and severity of NAFLD is still to be further verified.
RESUMO
The relationship between serum lipid profiles and related clinicopathologic features of IgA nephropathy (IgAN) and c-Maf-inducing protein (CMIP) gene polymorphisms is unclear. The present study was designed to examine the effect of CMIP single-nucleotide polymorphisms (SNPs) on dyslipidaemia and clinicopathologic features of IgAN. Clinical and pathological data from patients with IgAN diagnosed at the First Affiliated Hospital of Guangxi Medical University were collected. DNA was extracted from blood samples. CMIP rs2925979 and CMIP rs16955379 genotypes were determined by PCR and direct sequencing. Among 543 patients, 281 had dyslipidaemia (51.7%). Compared with the non-dyslipidaemia group, the dyslipidaemia group exhibited higher blood pressure, blood urea nitrogen, uric acid, and body mass index; higher prevalence of oedema, haematuria, tubular atrophy, and interstitial fibrosis; and lower albumin and estimated glomerular filtration rate. In the dyslipidaemia group, the frequency of C allele carriers was higher than that of non-C allele carriers for rs16955379. Multivariate linear regression analysis showed that total cholesterol, low-density lipoprotein and high-density lipoprotein were associated with rs16955379C allele carriers. Apolipoprotein B was associated with A allele carriers of rs2925979. Linkage disequilibrium was observed between rs16955379 and rs2925979, and rs2925979G-rs16955379T was the most common haplotype. The frequencies of the four CMIP SNP haplotypes differed between dyslipidaemia and non-dyslipidaemia groups in IgAN (P<0.05, for all above). Dyslipidaemia is a common complication in IgAN patients, and those with dyslipidaemia present poor clinicopathologic features. CMIP SNPs and their haplotypes are closely correlated with the occurrence of dyslipidaemia and clinicopathologic damage in IgAN patients.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Dislipidemias/genética , Glomerulonefrite por IGA/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Biópsia , China/epidemiologia , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Feminino , Predisposição Genética para Doença , Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/patologia , Haplótipos , Humanos , Glomérulos Renais/patologia , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Eighteen known susceptibility loci for IgAN account for only a small proportion of IgAN risk. METHODS: Genome-wide meta-analysis was performed in 2628 patients and 11,563 controls of Chinese ancestry, and a replication analysis was conducted in 6879 patients and 9019 controls of Chinese descent and 1039 patients and 1289 controls of European ancestry. The data were used to assess the association of susceptibility loci with clinical phenotypes for IgAN, and to investigate genetic heterogeneity of IgAN susceptibility between the two populations. Imputation-based analysis of the MHC/HLA region extended the scrutiny. RESULTS: Identification of three novel loci (rs6427389 on 1q23.1 [P=8.18×10-9, OR=1.132], rs6942325 on 6p25.3 [P=1.62×10-11, OR=1.165], and rs2240335 on 1p36.13 [P=5.10×10-9, OR=1.114]), implicates FCRL3, DUSP22.IRF4, and PADI4 as susceptibility genes for IgAN. Rs2240335 is associated with the expression level of PADI4, and rs6427389 is in high linkage disequilibrium with rs11264799, which showed a strong expression quantitative trail loci effect on FCRL3. Of the 24 confirmed risk SNPs, six showed significant heterogeneity of genetic effects and DEFA showed clear evidence of allelic heterogeneity between the populations. Imputation-based analysis of the MHC region revealed significant associations at three HLA polymorphisms (HLA allele DPB1*02, AA_DRB1_140_32657458_T, and AA_DQA1_34_32717152) and two SNPs (rs9275464 and rs2295119). CONCLUSIONS: A meta-analysis of GWAS data revealed three novel genetic risk loci for IgAN, and three HLA polymorphisms and two SNPs within the MHC region, and demonstrated the genetic heterogeneity of seven loci out of 24 confirmed risk SNPs. These variants may explain susceptibility differences between Chinese and European populations.
Assuntos
Povo Asiático/genética , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Glomerulonefrite por IGA/genética , Polimorfismo de Nucleotídeo Único/genética , População Branca/genética , Adulto , Estudos de Casos e Controles , China , Feminino , Estudo de Associação Genômica Ampla , Humanos , Fatores Reguladores de Interferon/genética , Masculino , Pessoa de Meia-Idade , Proteína-Arginina Desiminase do Tipo 4/genética , Receptores Imunológicos/genéticaRESUMO
BACKGROUND: Studies have shown that the occurrence and development of IgA nephropathy (IgAN) are genetically susceptible, but the relationship between vitamin D receptor (VDR) gene polymorphisms and renal function in IgAN patients is unclear. METHODS: We investigated the relationship between VDR FokI (rs2228570) single nucleotide polymorphism (SNP) and renal function and related clinicopathologic parameters in IgAN patients. Clinical and pathological data of 282 IgAN patients treated at the First Affiliated Hospital of Guangxi Medical University were collected, and FokI genotypes were determined by PCR and direct sequencing. Patients were divided into the renal dysfunction group and normal renal function (control) group by estimated glomerular filtration rate (eGFR) and serum creatinine level. RESULTS: Frequencies of TT genotype and T allele in the renal dysfunction group were higher than those of the control group. Blood urea nitrogen, serum phosphorus (P), proportions of mesangial cell proliferation, interstitial fibrosis/tubular atrophy and crescents in T allele carriers were higher than those in non-T allele carriers, while eGFR and 25-Hydroxyvitamin D3 were lower in T allele carriers than non-T allele carriers. Multiple linear regression analysis showed that eGFR was affected by FokI genotypes in IgAN patients. Logistics regression analysis showed that middle and elderly age, elevated P, intact parathyroid hormone and TT genotype were independent risk factors for renal dysfunction in IgAN patients; the odds ratio of carrying the TT genotype was as high as 84.77 (P < 0.05 for all). CONCLUSIONS: IgA nephropathy patients carrying the VDR FokI TT genotype have an increased risk of renal dysfunction. VDR FokI SNP is closely related to renal function, calcium-phosphate metabolism, and related pathological damage in IgAN patients.
RESUMO
BACKGROUND: Peritoneal fibrosis is the primary reason that patients with end-stage renal disease (ESRD) have to cease peritoneal dialysis. Peritonitis caused by Gram-negative bacteria such as Escherichia coli (E. coli) were on the rise. We had previously shown that matrine inhibited the formation of biofilm by E. coli. However, the role of matrine on the epithelial-mesenchymal transition (EMT) in peritoneal mesothelial cells under chronic inflammatory conditions is still unknown. METHODS: We cultured human peritoneal mesothelial cells (HPMCs) with lipopolysaccharide (LPS) to induce an environment that mimicked peritonitis and investigated whether matrine could inhibit LPS-induced EMT in these cells. In addition, we investigated the change in expression levels of the miR-29b and miR-129-5p. RESULTS: We found that 10âµg/ml of LPS induced EMT in HPMCs. Matrine inhibited LPS-induced EMT in HPMCs in a dose-dependent manner. We observed that treatment with matrine increased the expression of E-cadherin (Fâ=â50.993, Pâ<â0.01), and decreased the expression of alpha-smooth muscle actin (Fâ=â32.913, Pâ<â0.01). Furthermore, we found that LPS reduced the expression levels of miR-29b and miR-129-5P in HPMCs, while matrine promoted the expression levels of miR-29b and miR-129-5P. CONCLUSIONS: Matrine could inhibit LPS-induced EMT in HPMCs and reverse LPS inhibited expressions of miR-29 b and miR-129-5P in HPMCs, ultimately reduce peritoneal fibrosis. These findings provide a potential theoretical basis for using matrine in the prevention and treatment of peritoneal fibrosis.
Assuntos
Alcaloides/uso terapêutico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose/induzido quimicamente , Lipopolissacarídeos/toxicidade , Quinolizinas/uso terapêutico , Actinas/metabolismo , Caderinas/metabolismo , Células Cultivadas , Epitélio/efeitos dos fármacos , Fibrose/genética , Fibrose/metabolismo , Humanos , MicroRNAs/metabolismo , Fibrose Peritoneal/tratamento farmacológico , MatrinasRESUMO
AIM: Anti-glomerular basement membrane (GBM) disease is an autoimmune disorder with rapidly progressive glomerulonephritis and alveolar haemorrhage. Fever symptoms and prodromal infections have been reported in many cases, but still not been elucidated. METHODS: Our study enrolled 140 consecutive patients with anti-GBM disease and retrospectively analyzed the characteristics of fever symptoms and the possible reasons. RESULTS: Among the 140 patients, 94 (67.1%) patients presented with fever (over 37.5°C) prior to admission or within 48 h of hospitalization. Among those with fever, 74 (78.7%) patients had infections, 15 (16.0%) patients had positive serum anti-neutrophil cytoplasmic antibodies, all towards myeloperoxidase, which was comparable to the patients without fever (17.4%, P = 0.830). There were 93/140 patients suffered from infections, with 47.3% in lungs and 31.2% on upper respiratory tract. In some cases, we identified the microbes of infections, including Candida albicans, Escherichia coli, Acinetobacter baumannii, Enterococcus faecalis, Klebsiella pneumoniae, Hemolytic staphylococci, Pseudomonas aeruginosa and Citrobacter braakii. Patients with fever had higher levels of serum anti-GBM antibodies (154.9 ± 58.4 vs. 106.0 ± 63.2 IU/mL, P < 0.001), higher serum creatinine (733.4 ± 402.5 vs. 580.6 ± 368.1 µmol/L, P = 0.032), higher percentage of crescents (87.0 ± 15.6 vs. 67.4 ± 37.6%, P = 0.021), and higher frequency of progression to end stage renal disease (ESRD) (80.9% vs. 60.9%, P = 0.011). CONCLUSION: We concluded that fever is a common symptom in anti-GBM disease and associates with more severe glomerulonephritis. The majority of patients at presentation had fever with respiratory tract infections, which needs further investigation to reveal their role in the pathogenesis of anti-GBM disease.
Assuntos
Doença Antimembrana Basal Glomerular/epidemiologia , Febre/epidemiologia , Infecções Respiratórias/epidemiologia , Adulto , Doença Antimembrana Basal Glomerular/diagnóstico , Doença Antimembrana Basal Glomerular/imunologia , Doença Antimembrana Basal Glomerular/terapia , Biomarcadores/sangue , China/epidemiologia , Progressão da Doença , Feminino , Febre/diagnóstico , Febre/imunologia , Febre/terapia , Humanos , Falência Renal Crônica/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Sintomas Prodrômicos , Prognóstico , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/imunologia , Infecções Respiratórias/terapia , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fatores de TempoRESUMO
Immunoglobulin A nephropathy (IgAN) is among the most common primary glomerular diseases. The prognosis in IgAN is affected by dyslipidemia, a risk factor for cardiovascular disease. The c-Maf inducing protein (CMIP) gene has been found to be associated with lipid metabolism. But the association between the CMIP rs16955379 single nucleotide polymorphism (SNP) and dyslipidemia or the related clinicopathological features in IgAN have not been reported thus far. The present study investigated the correlation between them. The CMIP rs16955379 SNP genotypes of 300 subjects with IgAN recruited from the First Affiliated Hospital of Guangxi Medical University were identified by polymerase chain reaction and direct sequencing. Compared with the control (normal lipid) group, the dyslipidemia group with IgAN had higher blood uric acid, serum creatinine, blood urea nitrogen and urinary protein quantity, higher proportions of mesangial cell proliferation and renal tubular atrophy/interstitial fibrosis (IFTA), and a lower estimated glomerular filtration rate and serum albumin. The frequencies of the CMIP rs16955379 SNP TT genotype and T allele in the dyslipidemia group were higher than in the control group. Triglyceride, apolipoprotein A1 (ApoA1), ApoA1/B, incidences of mesangial cell proliferation, and IFTA were higher in TT genotype carriers than in CC/CT genotype carriers. Serum lipid profiles and dyslipidemia were significantly associated with renal dysfunction and IFTA. IgAN patients with the TT genotype were more likely to have dyslipidemia, renal dysfunction and IFTA (P < 0.05 for all above). These results indicate that CMIP rs16955379 SNP may be a genetic susceptibility gene for dyslipidemia and poor renal outcome in IgAN.
RESUMO
Goodpasture's disease is closely associated with HLA, particularly DRB1*1501. Other susceptible or protective HLA alleles are not clearly elucidated. The presentation models of epitopes by susceptible HLA alleles are also unclear. We genotyped 140 Chinese patients and 599 controls for four-digit HLA II genes, and extracted the encoding sequences from the IMGT/HLA database. T-cell epitopes of α3(IV)NC1 were predicted and the structures of DR molecule-peptide-T-cell receptor were constructed. We confirmed DRB1*1501 (OR = 4·6, P = 5·7 × 10-28 ) to be a risk allele for Goodpasture's disease. Arginine at position 13 (ARG13) (OR = 4·0, P = 1·0 × 10-17 ) and proline at position 11 (PRO11) (OR = 4·0, P = 2·0 × 10-17 ) on DRß1, encoded by DRB1*1501, were associated with disease susceptibility. α134-148 (HGWISLWKGFSFIMF) was predicted as a T-cell epitope presented by DRB1*1501. Isoleucine137 , tryptophan140 , glycine142 , phenylalanine143 and phenylalanine145 , were presented in peptide-binding pockets 1, 4, 6, 7 and 9 of DR2b, respectively. ARG13 in pocket 4 interacts with tryptophan140 and forms a hydrogen bond. In conclusion, we propose a mechanism for DRB1*1501 susceptibility for Goodpasture's disease through encoding ARG13 and PRO11 on MHC-DRß1 chain and presenting T-cell epitope, α134-148 , with five critical residues.
Assuntos
Doença Antimembrana Basal Glomerular/imunologia , Autoantígenos/metabolismo , Colágeno Tipo IV/metabolismo , Epitopos de Linfócito T/metabolismo , Cadeias HLA-DRB1/metabolismo , Linfócitos T/imunologia , Alelos , Autoantígenos/genética , China , Colágeno Tipo IV/genética , Simulação por Computador , Mapeamento de Epitopos , Epitopos de Linfócito T/genética , Predisposição Genética para Doença , Genótipo , Cadeias HLA-DRB1/genética , Humanos , Polimorfismo Genético , Ligação Proteica , Conformação Proteica , Receptores de Antígenos de Linfócitos T/metabolismo , RiscoRESUMO
Epitopes of phospholipase A2 receptor (PLA2R), the target antigen in idiopathic membranous nephropathy (iMN), must be presented by the HLA-encoded MHC class II molecules to stimulate autoantibody production. A genome-wide association study identified risk alleles at HLA and PLA2R loci, with the top variant rs2187668 within HLA-DQA1 showing a risk effect greater than that of the top variant rs4664308 within PLA2R1. How the HLA risk alleles affect epitope presentation by MHC class II molecules in iMN is unknown. Here, we genotyped 261 patients with iMN and 599 healthy controls at the HLA-DRB1, HLA-DQA1, HLA-DQB1, and HLA-DPB1 loci with four-digit resolution and extracted the encoded amino acid sequences from the IMGT/HLA database. We predicted T cell epitopes of PLA2R and constructed MHC-DR molecule-PLA2R peptide-T cell receptor structures using Modeler. We identified DRB1*1501 (odds ratio, 4.65; 95% confidence interval [95% CI], 3.39 to 6.41; P<0.001) and DRB1*0301 (odds ratio, 3.96; 95% CI, 2.61 to 6.05; P<0.001) as independent risk alleles for iMN and associated with circulating anti-PLA2R antibodies. Strong gene-gene interaction was noted between rs4664308(AA) and HLA-DRB1*1501/DRB1*0301. Amino acid positions 13 (P<0.001) and 71 (P<0.001) in the MHC-DRß1 chain independently associated with iMN. Structural models showed that arginine13 and alanine71, encoded by DRB1*1501, and lysine71, encoded by DRB1*0301, facilitate interactions with T cell epitopes of PLA2R. In conclusion, we identified two risk alleles of HLA class II genes and three amino acid residues on positions 13 and 71 of the MHC-DRß1 chain that may confer susceptibility to iMN by presenting T cell epitopes on PLA2R.
Assuntos
Alelos , Aminoácidos/fisiologia , Genes MHC da Classe II/fisiologia , Glomerulonefrite Membranosa/genética , Glomerulonefrite Membranosa/imunologia , Antígenos HLA-DR/fisiologia , Humanos , Receptores da Fosfolipase A2/fisiologia , Fatores de RiscoRESUMO
BACKGROUND: Experimental studies showed that 25-hydroxy-vitamin D [25(OH)D] deficiency (defined as 25-hydroxy-vitamin D < 15 ng/ml) has been associated with CKD progression. Patients with IgA nephropathy have an exceptionally high rate of severe 25(OH)D deficiency; however, it is not known whether this deficiency is a risk factor for progression of IgA nephropathy. We conducted this study to investigate the relationship between the plasma level of 25(OH)D and certain clinical parameters and renal histologic lesions in the patients with IgA nephropathy, and to evaluate whether the 25(OH)D level could be a good prognostic marker for IgA nephropathy progression. METHODS: A total of 105 patients with biopsy-proven IgA nephropathy were enrolled between 2012 and 2015. The circulating concentration of 25(OH)D was determined using serum samples collected at the time of biopsy. The primary clinical endpoint was the decline of estimated glomerular filtration rate (eGFR; a 30 % or more decline compared to the baseline). RESULTS: Mean eGFR decreased and proteinuria worsened proportionally as circulating 25(OH)D decreased (P < 0.05). The 25(OH)D deficiency was correlated with a higher tubulointerstitial score by the Oxford classification (P = 0.008). The risk for reaching the primary endpoint was significantly higher in the patients with a 25(OH)D deficiency compared to those with a higher level of 25(OH)D (P = 0.001). As evaluated using the Cox proportional hazards model, 25(OH)D deficiency was found to be an independent risk factor for renal progression [HR 5.99, 95 % confidence intervals (CIs) 1.59-22.54, P = 0.008]. CONCLUSION: A 25(OH)D deficiency at baseline is significantly correlated with poorer clinical outcomes and more sever renal pathological features, and low levels of 25(OH)D at baseline were strongly associated with increased risk of renal progression in IgAN.
Assuntos
Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/patologia , Deficiência de Vitamina D/sangue , Vitamina D/análogos & derivados , Adulto , Biomarcadores/sangue , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Glomerulonefrite por IGA/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteinúria/etiologia , Fatores de Risco , Vitamina D/sangue , Deficiência de Vitamina D/complicações , Adulto JovemRESUMO
IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis. Previously identified genome-wide association study (GWAS) loci explain only a fraction of disease risk. To identify novel susceptibility loci in Han Chinese, we conduct a four-stage GWAS comprising 8,313 cases and 19,680 controls. Here, we show novel associations at ST6GAL1 on 3q27.3 (rs7634389, odds ratio (OR)=1.13, P=7.27 × 10(-10)), ACCS on 11p11.2 (rs2074038, OR=1.14, P=3.93 × 10(-9)) and ODF1-KLF10 on 8q22.3 (rs2033562, OR=1.13, P=1.41 × 10(-9)), validate a recently reported association at ITGAX-ITGAM on 16p11.2 (rs7190997, OR=1.22, P=2.26 × 10(-19)), and identify three independent signals within the DEFA locus (rs2738058, P=1.15 × 10(-19); rs12716641, P=9.53 × 10(-9); rs9314614, P=4.25 × 10(-9), multivariate association). The risk variants on 3q27.3 and 11p11.2 show strong association with mRNA expression levels in blood cells while allele frequencies of the risk variants within ST6GAL1, ACCS and DEFA correlate with geographical variation in IgAN prevalence. Our findings expand our understanding on IgAN genetic susceptibility and provide novel biological insights into molecular mechanisms underlying IgAN.
Assuntos
Povo Asiático/genética , Glomerulonefrite por IGA/genética , Adulto , Antígenos CD/genética , Antígeno CD11b/genética , Antígeno CD11c/genética , Estudos de Casos e Controles , China , Proteína DEFICIENS/genética , Fatores de Transcrição de Resposta de Crescimento Precoce/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Proteínas de Choque Térmico/genética , Humanos , Fatores de Transcrição Kruppel-Like/genética , Liases/genética , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Sialiltransferases/genética , Adulto JovemRESUMO
Spinal cord injury (SCI)induced osteoporosis may cause mild trauma to bone and increase the risk of bone fracture. The present study aimed to investigate the efficacy of coenzyme Q (CoQ10) on SCIinduced osteoporosis in rats. SCI was induced by surgical transection of the cord at the T1012 level. Animals were treated with CoQ10 (10 mg/kg; intragastrically) daily from 12 h after the surgery and over 10 subsequent days. At the end of the experimental period, blood was collected from the animals and femurs and tibiae were removed for evaluation using biochemical assays. Treatment with CoQ10 prevented SCIinduced bone loss by rescuing the decreased levels of bone mineral density and bone mineral content observed in the SCI rats. Furthermore, CoQ10 administration reduced bone malondialdehyde levels with a concomitant increase in superoxide dismutase levels, thus alleviating SCIinduced oxidative injury. In addition, serum inflammatory cytokine levels were markedly increased in rats postSCI, which was attenuated by treatment with CoQ10. Finally, the osteoclastspecific genes receptor activator of nuclear factor kappaB ligand and cathepsin K were significantly upregulated and the osteoblastspecific gene corebinding factor alpha 1 in the femur was downregulated following SCI, which was effectively restored following treatment with CoQ10. The results suggested that CoQ10 treatment may be effective in attenuating SCIinduced osteoporosis.
Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Osteoporose/prevenção & controle , Traumatismos da Medula Espinal/tratamento farmacológico , Ubiquinona/análogos & derivados , Animais , Avaliação Pré-Clínica de Medicamentos , Fêmur/efeitos dos fármacos , Fêmur/metabolismo , Fêmur/patologia , Expressão Gênica , Interleucina-6/sangue , Masculino , Osteoblastos/fisiologia , Osteoclastos/fisiologia , Osteoporose/etiologia , Estresse Oxidativo , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/complicações , Tíbia/efeitos dos fármacos , Tíbia/metabolismo , Tíbia/patologia , Fator de Necrose Tumoral alfa/sangue , Ubiquinona/administração & dosagemRESUMO
AIM: Numerous studies have examined and reported a high prevalence of chronic kidney disease (CKD) in the general population in various countries including China. However, the situation may be different in undeveloped rural minority regions in China because of China's economic diversity. The aim of the present study was to estimate the prevalence of CKD and to analyze its associated factors in a Zhuang ethnic minority area in Southwest China. METHODS: A cross-sectional survey of a rural minority area populated by people of Zhuang ethnicity in Southwest China using multistage, cluster random sampling methods was performed. The prevalence of indicators of kidney damage and CKD were calculated and risk factors associated with the presence of CKD were analyzed. RESULTS: In total, 7588 people participated in the study. After adjustment for age and gender, the prevalence of albuminuria, haematuria and reduced estimated glomerular filtration rate were 2.7%, 3.7%, and 2.2%, respectively. After adjustment for age and gender, the prevalence of CKD was 8.3%, while recognition of the disease was 3.6%. Independent risk factors associated with CKD were age, gender, and hypertension. Risk factors independently associated with kidney damage were age, gender, hyperuricaemia, and hypertension. CONCLUSION: Our data exhibited a lower prevalence and awareness of CKD in undeveloped rural minority regions, especially exhibited a low prevalence of albuminuria. This result attributed to the low prevalence of metabolic disorders in the local region. Risk factors associated with CKD in our study is similar to surveys in other regions of China.
Assuntos
Povo Asiático , Grupos Minoritários , Saúde das Minorias/etnologia , Insuficiência Renal Crônica/etnologia , Saúde da População Rural/etnologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Albuminúria/etnologia , China/epidemiologia , Análise por Conglomerados , Comorbidade , Estudos Transversais , Feminino , Taxa de Filtração Glomerular , Inquéritos Epidemiológicos , Hematúria/etnologia , Humanos , Hipertensão/etnologia , Hiperuricemia/etnologia , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prevalência , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Fatores Sexuais , Adulto JovemRESUMO
AIM: Vitamin D deficient patients present an increased risk of cardiovascular disease. We conducted this systematic review and meta-analysis to evaluate the effect of active vitamin D analogue on cardiovascular outcomes in predialysis chronic kidney disease. METHODS: Pubmed, Embase, the Cochrane Library, CNKI, and article reference lists were searched for randomized controlled trials (RCTs) that compared active vitamin D analogues with placebo or no treatment for patients with predialysis chronic kidney disease. A meta-analysis was conducted using the standard methods consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Reviewer Manager Software, ver. 5.2, was used. RESULTS: Seven RCTs (five studies with paricalcitol and two studies with calcitriol, 731 patients) were included. Compared with control groups, active vitamin D reduced the incidence of cardiovascular events (RR, 0.27; 95% CI, 0.13-0.59), induced an increase in those with proteinuria reduction (RR, 1.9; 95% CI, 1.34-2.71), but did not alter left ventricular mass index and systolic function (MD, 0.42 g/m2.7 ; 95% CI, -0.23-1.07 g/m2.7 , P = 0.21 for left ventricular mass index and MD, -0.33; 95% CI, -0.74-0.07, P = 0.1 for left ventricular ejection fraction). Neither systolic blood pressure nor diastolic blood pressure was reduced by active vitamin D (MD, 0.3 mmHg; 95% CI, -4.95-5.56 mmHg; MD, -0.24 mmHg; 95% CI: -6.21-5.72 mmHg, respectively). Increased probability of hypercalcaemia after paricalcitol therapy was found (RR, 7.85; 95% CI, 2.92-21.10). CONCLUSION: Active vitamin D reduced the incidence of cardiovascular events and induced a reduction in proteinuria, but its long-term effect on cardiac structure and function needed further confirmation. Increased probability of hypercalcaemia after paricalcitol therapy was found.
RESUMO
Linear deposition of IgG and complement 3 (C3) along glomerular basement membrane (GBM) is generally revealed in the kidneys of human anti-GBM disease. Our recent studies demonstrated the pathogenic role of complement activation in renal damage of this disease. However, the pathways of complement activation were still paradoxical. In this study, renal biopsy tissues from 10 patients with anti-GBM disease were used to investigate the pathways of complement activation by detecting the deposition of various complement components, including C1q, factor B, factor P (properdin), mannose-binding lectin (MBL), C3d, C4d and C5b-9, using immunohistochemistry and immunofluorescence. We found that C1q, factor B, properdin, C3d, C4d and C5b-9 were detected in all the glomeruli of our patients, along GBM with a linear and/or granular staining pattern. Furthermore, C1q, factor B and properdin co-localized well with C5b-9. The properdin also co-localized well with C3d. However, the deposition of MBL was diffusive in mesangium, GBM, Bowman's capsule and within crescents and was not co-localized with C5b-9 but partially co-localized with C4d. The intensity of factor B deposition (3.3 vs. 1.2, P<0.001) and C5b-9 deposition (3.2 vs. 1.6, P<0.001) was significantly stronger in the glomeruli with crescent formation, compared with the glomeruli without crescents. The complement system is overall activated via both the alternative pathway and classical pathway in the kidneys of human anti-GBM disease. The alternative pathway might play an important role in complement activation induced renal damage.
Assuntos
Doença Antimembrana Basal Glomerular/patologia , Ativação do Complemento , Rim/patologia , Adulto , Idoso , Doença Antimembrana Basal Glomerular/metabolismo , Complemento C3/metabolismo , Feminino , Imunofluorescência , Humanos , Imunoglobulina G/metabolismo , Rim/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: Clinical trials have shown that niacin and its analog, niacinamide, significantly reduce serum phosphate in patients undergoing dialysis. This review aimed to assess the benefits and harm of niacin and niacinamide in renal dialysis patients. METHODS: PubMed, EMBASE, and Cochrane Library were searched, without language limitation, randomized controlled trials (RCTs). Standard methods, consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, were used. Reviewer Manager software, version 5.2, was used for meta-analysis. RESULTS: Five RCTs with a sample size of 230 patients were included. The meta-analysis showed that niacin and niacinamide significantly decreased serum phosphorus levels [weight mean difference (WMD) -0.88; 95 % confidence interval (CI) -1.19 to -0.57] as well as the calcium × phosphorus product (Ca × P) (WMD -9.15; 95 % CI -13.23 to -5.08), and increased high-density lipoprotein (HDL) levels (WMD 9.30; 95 % CI 5.86-12.74) in renal dialysis patients. Niacin significantly increased the risk of flushing [relative risk (RR) 33; 95 % CI 4.71-232.12] in these patients, while the risk of thrombocytopenia was significantly increased in the niacinamide group (RR 2.82; 95 % CI 1.14-6.94). However, sensitivity analysis showed that our finding regarding thrombocytopenia should be regarded with a low degree of certainty. CONCLUSION: Niacin and its analog effectively improved phosphorus metabolism in renal dialysis patients. However, niacin can cause flushing and niacinamide probably cause thrombocytopenia. Further larger sample size and well-designed RCTs are needed.
Assuntos
Niacina/uso terapêutico , Niacinamida/uso terapêutico , Fósforo/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/tratamento farmacológico , Complexo Vitamínico B/uso terapêutico , Rubor/induzido quimicamente , Humanos , Lipoproteínas HDL/sangue , Niacina/efeitos adversos , Niacinamida/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/terapia , Trombocitopenia/induzido quimicamente , Complexo Vitamínico B/efeitos adversosRESUMO
OBJECTIVE: To observe the risk factors and prevalence status of hypertension at the Guangxi Zhuang-rural region. METHODS: Through cross-sectional survey, Xinlan village (Ethnic-Zhuang tribe village) in Liangqing District of Nanning was chosen as survey site. Select Zhuang-ethnic villagers (age ≥ 18 years, living time ≥ 6 months per year) as survey subjects. Questionnaire survey and examinations including blood pressure measurement, blood tests, and urine test were made by trained medical professionals. Multivariate logistic regression analysis was used to analyze the risk factors of hypertension. RESULTS: Complete data were obtained in 2036 residents. The hypertension prevalence rate was 11.6% (237/2036) [12.5% (110/883) for male, 11.0% (127/1153) for female], adjusted prevalence rate was 10.7% (11.3% for male, 10.4% for female) based on the population of Guangxi in 2010. Hypertension awareness rate was 36.3% (86/237) , therapy rate was 22.8% (54/237) , and control rate was 11.0% (26/237) . Multivariate logistic regression analysis showed that age (OR = 1.06, 95%CI:1.05-1.08, P < 0.01), alcohol drinking habit (OR = 1.92, 95%CI:1.25-2.95, P < 0.01), high salt diet(OR = 1.48, 95%CI:1.04-2.10, P < 0.05), diabetes(OR = 7.03, 95%CI:1.94-25.44, P < 0.01), obesity(OR = 1.20, 95%CI: 1.15-1.25, P < 0.01) and hypertriglyceridemia(OR = 1.12, 95%CI:1.03-1.22, P < 0.01) were risk factors for hypertension in this cohort. CONCLUSIONS: Prevalence rate is slightly lower in adult of the Guangxi Zhuang-rural areas than national or Guangxi Zhuang Autonomous Region levels, but hypertension awareness, therapy and control rates in this cohort are not satisfactory. Targeted strategies are needed to improve the prevention and therapy of hypertension in this region.
Assuntos
Hipertensão/etnologia , Adulto , Idoso , Determinação da Pressão Arterial , China/epidemiologia , Estudos Transversais , Etnicidade , Feminino , Humanos , Estilo de Vida , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , PrevalênciaRESUMO
AIM: Both enalapril and losartan are effective and widely used in patients with chronic kidney disease (CKD). This review aimed to evaluate the benefits of enalapril and losartan in adults with CKD. METHODS: PubMed, EMBASE, the Cochrane Library and ClinicalTrials.gov were searched, without language limitations, for randomized controlled trials (RCT), in which enalapril and losartan were compared in adults with CKD. Standard methods, consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, were used. Reviewer Manager software, ver. 5.2, was used for meta-analysis. RESULTS: Of 318 citations retrieved, 17 RCT (14 parallel-group and three cross-over) met our inclusion criteria. The pooled analysis for parallel RCT showed that the effects of enalapril and losartan on blood pressure, renal function and serum uric acid (UA) were similar. Meta-analysis indicated that patients taking enalapril had a higher risk of dry cough (risk ratio, 2.88; 95% CI, 1.11-7.48; P=0.03). Sensitivity analysis showed good robustness of these findings. CONCLUSION: Enalapril has similar effects to losartan on systemic blood pressure, renal function and serum UA in patients with CKD, but carries a higher risk of dry cough. Larger trials are required to evaluate the effects of these medications on clinical outcomes.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Enalapril/uso terapêutico , Rim/efeitos dos fármacos , Losartan/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Adulto , Idoso , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Distribuição de Qui-Quadrado , Tosse/induzido quimicamente , Creatinina/sangue , Enalapril/efeitos adversos , Feminino , Humanos , Rim/fisiopatologia , Losartan/efeitos adversos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Resultado do Tratamento , Ácido Úrico/sangueRESUMO
AIM: The options for long-term maintenance therapy in lupus nephritis (LN) remain controversial. This meta-analysis of randomized controlled trials (RCTs) assessed the prognosis and safety of mycophenolate mofetil (MMF) versus azathioprine (AZA) used as maintenance therapy for lupus nephritis. METHODS: The data of Cochrane Library, PubMed, EMBASE were retrieved to search the studies about the RCT studies that compared MMF with AZA used as maintenance therapy for lupus nephritis. We extracted the data reflecting prognosis, which included mortality, end-stage renal failure (ESRF), renal relapse, doubling serum creatinine, and adverse effects, then further analyzed the combined results of data and calculated the relative risk (RR). RESULTS: Four RCT studies including 328 patients were enrolled into our meta-analysis. There was no difference between the patients receiving either MMF or AZA for maintenance therapy in preventing relapse, progression to end-stage renal failure, death and doubling of serum creatinine. MMF is not superior to AZA in terms of the risks of infection and gastrointestinal upset, but fewer patients receiving MMF developed leukopenia (RR 0.12; 95% confidence interval (CI), 0.04-0.39; P = 0.0004) and amenorrhoea (RR 0.17; 95% CI, 0.04-0.72; P = 0.02) than those receiving AZA. CONCLUSION: The current limited evidence suggests that MMF offers similar prognosis as AZA for maintenance therapy, while MMF appears safer than AZA in the treatment of lupus nephritis.