Serum fibroblast growth factor 23 concentration and the risk of mortality in patients undergoing peritoneal dialysis.

BACKGROUND: Fibroblast growth factor 23 (FGF23) is a phosphate-regulating hormone that is secreted in large amounts early in chronic kidney disease. In this cohort, we aimed to investigate the association between serum FGF23 concentration and mortality in patients undergoing peritoneal dialysis (PD). METHODS: Serum FGF23 level was determined by enzyme-linked immunosorbent assay (ELISA) in a large 15-year prospective cohort study of PD patients with stored serum samples at baseline. Kaplan-Meier survival curves and Cox proportional hazards models were performed to characterise the relationship of FGF23 with mortality. RESULTS: A total of 737 incident PD patients were analysed. The baseline median FGF23 concentration was 683.2 (518.5-896.2) pg/mL. Age, serum phosphorus, high-density lipoprotein cholesterol and high-sensitivity C-reactive protein were independently correlated with serum FGF23 concentration. During a median follow-up of 66.7 (41.1-95.4) months, 171 of the 737 participants (23.2%) died, including 84 (49.1%) cardiovascular disease-related and 50 (29.2%) infection-related deaths. Multivariable Cox regression analysis showed that the adjusted hazard ratios of the highest tertile of serum FGF23 compared with those in the lowest tertile were 1.36 (95% confidence interval (CI): 0.89-2.07; p = 0.154), 0.75 (95% CI: 0.40-1.38; p = 0.353) and 2.66 (95% CI: 1.15-6.15; p = 0.022) for all-cause, cardiovascular disease-related and infection-related mortality, respectively. CONCLUSION: High serum FGF23 concentration is associated with a higher risk of infection-related death for incident PD patients.

Genome-Wide Association Analysis of Protein-Coding Variants in IgA Nephropathy.

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.

RhoA vesicle trafficking-mediated transglutaminase 2 membrane translocation promotes IgA1 mesangial deposition in IgA nephropathy.

Transglutaminase 2 (TGase2) has been shown to contribute to the mesangial IgA1 deposition in a humanized mouse model of IgA nephropathy (IgAN), but the mechanism is not fully understood. In this study, we found that inhibition of TGase2 activity could dramatically decrease the amount of polymeric IgA1 (pIgA1) isolated from patients with IgAN that interacts with human mesangial cells (HMC). TGase2 was expressed both in the cytosol and on the membrane of HMC. Upon treatment with pIgA1, there were more TGase2 recruited to the membrane. Using a cell model of mesangial deposition of pIgA1, we identified 253 potential TGase2-associated proteins in the cytosolic fraction and observed a higher concentration of cellular vesicles and increased expression of Ras homolog family member A (RhoA) in HMC after pIgA1 stimulation. Both the amount of pIgA1 deposited on HMC and membrane TGase2 level were decreased by inhibition of the vesicle trafficking pathway. Mechanistically, TGase2 was found to be coprecipitated with RhoA in the cellular vesicles. Membrane TGase2 expression was greatly increased by overexpression of RhoA, while it was reduced by knockdown of RhoA. Our in vitro approach demonstrated that TGase2 was transported from the cytosol to the membrane through a RhoA-mediated vesicle-trafficking pathway that can facilitate pIgA1 interaction with mesangium in IgAN.

Corrigendum: Functional variant rs12614 in CFB confers a low risk of IgA nephropathy by attenuating complement alternative pathway activation in Han Chinese.

[This corrects the article DOI: 10.3389/fimmu.2022.973169.].

Functional variant rs12614 in CFB confers a low risk of IgA nephropathy by attenuating complement alternative pathway activation in Han Chinese.

Activation of the alternative pathway (AP) of complement is thought to play an important role in Immunoglobin A nephropathy (IgAN). Our previous study showed that rs4151657 within the complement factor B (CFB) gene increased the risk of IgAN. The protein encoded by the CFB gene is an initial factor that promotes AP activation. The aim of this study was to investigate whether other variants of CFB confer susceptibility to IgAN and elucidate their potential roles in AP activation. A total of 1,350 patients with IgAN and 1,420 healthy controls were enrolled and five tag single-nucleotide polymorphisms were selected for genotyping. The levels of key AP components, such as CFB, complement factor H and complement split product C3a, were measured by enzyme-linked immunosorbent assay. Molecular docking and molecular dynamic simulation were carried out to characterize the mutation of residues in the protein structure and the dynamic properties of wide type and mutation models of CFB protein. The allele-specific effect on CFB expression and its binding affinity to C3b were investigated through cell transfection and surface plasmon resonance analysis, respectively. We found that rs12614 significantly reduced the risk of IgAN (OR = 0.69, 95% CI = 0.52-0.91, P = 0.009), and the rs12614-T (R32W mutation) was correlated with lower CFB levels, higher serum C3 level, and less mesangial C3 deposition in patients with IgAN. The structural model showed that the R32W mutation reduced the structural stability of CFB protein. Furthermore, in vitro study revealed that rs12614-T decreased the expression of CFB and reduced its binding affinity to C3b by four-fold compared with rs12614-C. In conclusion, the rs12614-T in CFB was associated with low risk of IgAN probably by attenuating AP activation.

Corrigendum to "Upregulated Expression of Intestinal Antimicrobial Peptide HD5 Associated with Renal Function in IgA Nephropathy".

[This corrects the article DOI: 10.1155/2020/2078279.].

Neutrophil to high-density lipoprotein ratio associates with higher all-cause mortality and new onset cardiovascular events in peritoneal dialysis patients.

BACKGROUND: Neutrophil to high-density lipoprotein ratio (NHR), a new inflammatory marker, is associated with poor clinical prognosis. However, the correlation of NHR and adverse outcomes in peritoneal dialysis (PD) patients remains unclear. METHODS: In this retrospective cohort study, a total of 1051 PD patients were recruited from three centers during Jan 1, 2009 to Dec 31, 2017. Eligible patients were distributed according to quartiles of the NHR. Kaplan-Meier cumulative incidence curves, multivariate COX regression, competitive risk analysis and restricted cubic spline (RCS) were applied to analyze the relationship between NHR and all-cause mortality as well as cardiovascular events (CVE). In addition, forest plots were used to calculate the interaction between different subgroups. RESULTS: During follow-up, a total of 240 all-cause mortality and 157 new-onset CVE were recorded. The all-cause mortality in the highest quartile of NHR (> 5.43) were higher than those in the other groups. RCS showed a non-linear relationship between NHR and adverse outcomes. Multivariate COX regression indicated elevated NHR was an independent risk factor for all-cause mortality. Compared to the highest quartile, hazard ratio (HR) of new-onset CVE equals to 0.522 (95% CI 0.321-0.849) in the secondary quartile (2.43 < NHR ≤ 3.57), and the HR of all-cause mortality analysis is 0.551 (95% CI 0.378-0.803) in the third quartile (3.57 < NHR ≤ 5.43). Kaplan-Meier analysis suggested there were significant differences in all-cause mortality and new-onset CVE among four NHR groups. CONCLUSIONS: NHR was a new independent risk factor for all-cause mortality in PD patients.

Downregulation of the endothelial histone demethylase JMJD3 is associated with neointimal hyperplasia of arteriovenous fistulas in kidney failure.

Jumonji domain-containing protein-3 (JMJD3), a histone H3 lysine 27 (H3K27) demethylase, promotes endothelial regeneration, but its function in neointimal hyperplasia (NIH) of arteriovenous fistulas (AVFs) has not been explored. In this study, we examined the contribution of endothelial JMJD3 to NIH of AVFs and the mechanisms underlying JMJD3 expression during kidney failure. We found that endothelial JMJD3 expression was negatively associated with NIH of AVFs in patients with kidney failure. JMJD3 expression in endothelial cells (ECs) was also downregulated in the vasculature of chronic kidney disease (CKD) mice. In addition, specific knockout of endothelial JMJD3 delayed EC regeneration, enhanced endothelial mesenchymal transition, impaired endothelial barrier function as determined by increased Evans blue staining and inflammatory cell infiltration, and accelerated neointima formation in AVFs created by venous end to arterial side anastomosis in CKD mice. Mechanistically, JMJD3 expression was downregulated via binding of transforming growth factor beta 1-mediated Hes family transcription factor Hes1 to its gene promoter. Knockdown of JMJD3 enhanced H3K27 methylation, thereby inhibiting transcriptional activity at promoters of EC markers and reducing migration and proliferation of ECs. Furthermore, knockdown of endothelial JMJD3 decreased endothelial nitric oxide synthase expression and nitric oxide production, leading to the proliferation of vascular smooth muscle cells. In conclusion, we demonstrate that decreased expression of endothelial JMJD3 impairs EC regeneration and function and accelerates neointima formation in AVFs. We propose increasing the expression of endothelial JMJD3 could represent a new strategy for preventing endothelial dysfunction, attenuating NIH, and improving AVF patency in patients with kidney disease.

Imagination-Based Loving-Kindness and Compassion Meditation: A New Meditation Method Developed from Chinese Buddhism.

Many loving-kindness and compassion meditation methods used in psychological research are derived from Theravada and Tibetan Buddhism. Zhiyi (), a representative figure of Chinese Buddhism, proposed a different meditation method, namely, imagination-based loving-kindness and compassion meditation. The current article introduces the imagination-based loving-kindness and compassion meditation proposed by Zhiyi and compares it with meditation methods from Theravada and Tibetan Buddhism. Zhiyi's method limits the content of imagination during meditation, which can be an essential supplement to the free association method derived from Theravada Buddhism. Zhiyi's method of helping others entirely through imagination differs significantly from the tonglen method derived from Tibetan Buddhism and may be more suitable for participants without religious beliefs. Based on Zhiyi's source text and previous psychological studies, a mental-health training program for imagination-based loving-kindness and compassion meditation is proposed. The limitations of Zhiyi's method and the future directions for empirical research on Zhiyi's method are also discussed. The differences between Zhiyi's method and other methods in terms of effects and applicable populations need to be examined in future studies.

Association between urinary VEGFA and renal pathology of IgA nephropathy patients.

BACKGROUND: Renal biopsy remains the golden standard for diagnosing and monitoring IgA nephropathy (IgAN). Vascular endothelial growth factor A (VEGFA) was crucial for the survival of glomerular cells. Our aim was to screen the expression pattern of urinary, circulating and renal VEGFA in IgAN patients to reveal their relationship with renal pathology and outcomes. METHODS: Baseline VEGFA levels were determined with ELISA, real-time PCR and immunohistochemistry. Associations between VEGFA expression and clinical-pathological parameters, and renal outcomes were evaluated. RESULTS: Compared with healthy controls, urinary VEGFA level was obviously elevated in IgAN patients (76.19 ± 63.67 pg/mg Cr vs 146.67 ± 232.71 pg/mg Cr, p = 0.0291) and not correlated with serum VEGFA level. Baseline urinary VEGFA was significantly associated with gender and tubular atrophy/interstitial fibrosis by stepwise multivariate regression analysis. Urinary VEGFA was higher in male patients accompanied with higher serum creatinine, larger proportion of hypertension and recurrent hematuria than in female patients. In the kidney of IgAN patients, VEGFA were robustly expressed in the parietal epithelial cells, podocytes, mesangial cells and tubular epithelial cells. After a follow-up duration of 38.53 ± 27.14 months, IgAN patients with higher urinary VEGFA level were found to have a poorer renal outcome of renal replacement therapy (HR = 1.027, p = 0.037) or composite outcome (HR = 1.023, p = 0.039) after adjusting for confounders. CONCLUSIONS: Increased urinary VEGFA might reflect certain renal pathology and, although not fully specific, still could be served as a valuable noninvasive indicator in predicting renal progression of IgAN.

Expression profile of Fc receptor-like molecules in patients with IgA nephropathy.

BACKGROUND: Fc receptor-like (FCRL) molecules were considered to play a role in the pathogenesis of certain autoimmune diseases. Nonetheless, the clinical significance of FCRLs in IgA nephropathy (IgAN) remains unclear. OBJECTIVE: This study is aimed at investigating the expression levels of FCRLs molecules in IgAN patients and determining its relevance to disease activity. METHODS: The mRNA expression levels of FCRLs were determined in peripheral blood mononuclear cells (PBMCs) of 42 IgAN patients and 48 healthy controls by quantitative real-time PCR (qRT-PCR). FCRLs proteins expression in B cells of 25 IgAN patients, 14 patients with non-IgAN glomerulonephritis, and 29 healthy controls were detected by Flow cytometry. The Spearman correlation test was used to assess the correlation of FCRLs expression with clinical parameters of IgAN patients. RESULTS: Our results indicated significant down-regulation of FCRL2 and FCRL3 mRNA levels in IgAN patients compared to healthy subjects. Surface protein expression of FCRLs molecules confirmed the qRT-PCR results. But FCRL2 and FCRL3 protein levels did not correlate with clinicopathologic phenotypes of IgAN patients. However, we found a significant positively correlation of FCRL2 and FCRL3 mRNA expression with the core 1 ß1,3-galactosyltransferase (C1GALT1) and its molecular chaperone (Cosmc) mRNA levels in IgAN patients. CONCLUSIONS: FCRL2 and FCRL3 expression levels in IgAN patients are significantly decreased and correlated with CIGALT1 and Cosmc mRNA expression.

Vitamin D (1,25-(OH)2D3) Improves Endothelial Progenitor Cells Function via Enhanced NO Secretion in Systemic Lupus Erythematosus.

It has been proven that vitamin D was decreased and function of circulating endothelial progenitor cells (EPCs) was injured in systemic lupus erythematosus (SLE) patients. However, the effect of vitamin D on the function of EPCs in vitro and its mechanism need further study. Therefore, we investigated whether vitamin D improved the function of EPCs in vitro. The peripheral blood mononuclear cells of the participants were isolated from SLE patients and control subjects and cultured to EPCs. After the EPCs were treated with vitamin D (1,25-(OH)2D3), we evaluated the number, migratory and proliferative activities, and nitric oxide (NO) production of EPCs in vitro and detected vascular endothelial function by flow-mediated dilatation (FMD). We found that vitamin D in a dose-dependent manner improved number and migratory and proliferative activities of EPCs from SLE patients. Additionally, vitamin D upregulated NO production from EPCs in vitro. A significant correlation between the FMD and plasma NO level was found. There was also a correlation between number, migration, and proliferation of EPCs and NO production. Thus, the present findings indicated that vitamin D improved the function of EPCs from SLE patients via NO secretion.

Serum lipoprotein(a) and risk of mortality in patients on peritoneal dialysis.

BACKGROUND: Elevated serum lipoprotein(a) [Lp(a)] level is an independent risk factor for atherosclerotic diseases in the general population and hemodialysis patients. However, the association between Lp(a) levels and mortality has received little attention in peritoneal dialysis (PD) patients. OBJECTIVE: The objective of the study was to evaluate the association of Lp(a) levels with all-cause and cardiovascular (CV) mortality in PD patients. METHODS: This retrospective cohort study was conducted in PD patients enrolled from January 1, 2006 to December 31, 2015, and followed until December 31, 2018. Cox regression models were performed to assess the association of serum Lp(a) levels with all-cause and CV mortality in PD patients. RESULTS: In total, 1492 incident PD patients were eligible for the study. During a median follow-up period of 45.1 months, 402 all-cause and 210 CV deaths occurred. Multivariate Cox regression analysis revealed that the first and third tertiles of Lp(a) levels were significantly associated with increased risk for all-cause mortality [hazard ratio (HR) = 1.33, 95% confidence interval (95% CI) = 1.01-1.75, P = .041; HR = 1.53, 95% CI = 1.18-1.98, P = .001, respectively] when compared with the second tertile, and the third tertile of Lp(a) level was independently associated with an 80% increased risk of CV mortality (HR = 1.80, 95% CI = 1.26-2.56, P = .001). Moreover, our results showed that the HRs per log unit higher Lp(a) level for all-cause and CV mortality were 1.53 (95% CI = 1.05-2.22, P = .027) and 2.41 (95% CI = 1.44-4.03, P < .001), respectively. CONCLUSIONS: Our results suggest that both low and high serum Lp(a) levels are risk markers for all-cause death, but only a higher baseline serum Lp(a) level is an independent risk factor for CV mortality in PD patients.

Upregulated Expression of Intestinal Antimicrobial Peptide HD5 Associated with Renal Function in IgA Nephropathy.

PURPOSE: It was reported that gut-kidney axis may play an important role in IgA nephropathy (IgAN). Previous five GWASs of different populations for IgAN have discovered several genes related to intestinal immunity, including DEFA gene. However, the roles of the encoded proteins of DEFA5/6 which were called intestinal antimicrobial peptides HD5 and HD6 were not clear in kidney disease, such as IgAN. The purpose of this study was to clarify the association of HD5 and HD6 with IgAN. METHODS: We measured HD5 and HD6 in serum, urine, and kidney of IgAN patients and normal controls by ELISA, Western blot, and immunofluorescence. The association of HD5 or HD6 levels with clinical and pathologic phenotypes was analyzed. RESULTS: Serum levels of HD5 and HD6 were significantly higher in IgAN patients than those in normal controls. Baseline serum HD5 levels were significantly associated with eGFR (P = 0.002) and tubular atrophy/interstitial fibrosis (P = 0.002) and tubular atrophy/interstitial fibrosis (P = 0.002) and tubular atrophy/interstitial fibrosis (P = 0.002) and tubular atrophy/interstitial fibrosis (. CONCLUSIONS: In IgAN patients, an elevated serum HD5 level at the time of renal biopsy was associated with poor renal outcomes. HD5 rather than HD6 was probably associated with renal function of IgAN patients.

Decreased Jagged1 expression in vascular smooth muscle cells delays endothelial regeneration in arteriovenous graft.

AIMS: It is well-established that endothelial dysfunction promotes activation of vascular smooth muscle cell (VSMC). Whether decreased accumulation of VSMCs affects endothelial regeneration and functions in arteriovenous graft (AVG) remodelling has not been studied. We sought to identify mechanisms by which the Notch ligand, Jagged1, in VSMCs regulates endothelial cell (EC) functions in AVGs. METHODS AND RESULTS: AVGs were created in transgenic mice bearing VSMC-specific knockout (KO) or overexpression of Jagged1. VSMC migration, EC regeneration, and its barrier functions as well as AVG remodelling were evaluated. Jagged1 expression was induced in VSMCs of neointima in the AVGs. Jagged1 KO in VSMCs inhibited the accumulation of extracellular matrix as well as VSMC migration. Fewer α-SMA-positive VSMCs were found in AVGs created in VSMC-specific Jagged1 KO mice (VSMCJagged1 KO mice) vs. in WT mice. Decreased VSMCs in AVGs were associated with deterioration of EC functions. In AVGs created in transgenic mice bearing Jagged1 KO in VSMCs exhibited delayed EC regeneration and impaired EC barrier function. Barrier dysfunction of ECs increased inflammatory cell infiltration and dysregulation of AVG remodelling and arterialization. The increased expression of IL-1ß in macrophages was associated with expression of adhesion markers in ECs in AVGs created in VSMCJagged1 KO mice. In contrast, AVGs created in mice with overexpression of Jagged1 in VSMCs exhibited improved EC regeneration plus decreased macrophage infiltration. This led to AVG remodelling and arterialization. In co-cultures of ECs and VSMCs, Jagged1 deficiency in VSMCs suppressed N-cadherin and integrin ß3 expression in ECs. Inhibition of integrin ß3 activation delayed EC spreading and migration. Notably, Jagged1 overexpression in VSMCs or treatment with recombinant Jagged1 stimulated the expression of N-cadherin and integrin ß3 in ECs. Jagged1-induced responses were blocked by inhibition of Notch signalling. CONCLUSIONS: Jagged1 expression in VSMCs maintains EC barrier functions and blocks infiltration of macrophages. These responses promote remodelling and arterialization of AVGs.

Association of FCRL3 Gene Polymorphisms with IgA Nephropathy in a Chinese Han Population.

Our previous genome-wide association study has identified a suggestive association at rs11264799 within FCRL3 (Fc receptor-like 3) locus on 1q23.1 for IgA nephropathy (IgAN) in a Chinese Han population. This study aims to investigate the association of FCRL3 variants with the susceptibility, clinicopathological phenotypes and prognosis of IgAN. Eleven FCRL3 single-nucleotide polymorphisms (SNPs) were selected and analyzed in this two-stage case/control study with a total of 1750 IgAN cases and 2500 healthy controls in a Chinese Han population. Unconditional logistic regression models were used to estimate odds ratios and 95% confidence intervals (CIs) as implemented in the PLINK software. Luciferase assays were applied to detect the allelic effect of rs11264794 on gene expression regulation. We found that four SNPs (rs11264794, rs7865684, rs11264799, and rs6691569) were significantly associated with IgAN susceptibility after Bonferroni correction in the combined samples. Genotype/phenotype association analysis observed that two SNPs (rs11264794 and rs11264793) were associated with less disease severity. After adjusting for confounders, rs11264794 was independently correlated with renal outcome in IgAN patients (hazard ratio = 0.64, 95% CI = 0.43-0.97, p = 0.033). In addition, the protective allele A of rs11264794 was significantly associated with higher FCRL3 gene expression. Furthermore, luciferase reporter gene assays demonstrated that the minor allele of rs11264794 obviously reduced the specific binding between miR-183-5p.1 and FCRL3 3'-untranslated region. Our results indicate that FCRL3 gene polymorphisms are associated with the development and progression of IgAN, and the rs11264794-A allele showed a protective role for IgAN.

Association of TNFSF13 polymorphisms with IgA nephropathy in a Chinese Han population.

BACKGROUND: Our previous genome-wide association study of IgA nephropathy (IgAN) in a Chinese Han population suggested that the TNFSF13 gene may be a novel susceptibility gene for IgAN. In the present study, we aimed to further evaluate the associations of single-nucleotide polymorphisms (SNPs) and expression level of the TNFSF13 gene with the risk and clinical parameters of IgAN. METHODS: Six candidate SNPs were selected for genotyping by Sequenom MassARRAY iPLEX in 1000 IgAN cases and 1000 controls. Unconditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (95% CI) with adjustment for age and sex. Serum APRIL (encoded by the TNFSF13 gene) level was detected by an enzyme-linked immunosorbent assay. RESULTS: We found that rs3803800 was significantly associated with the susceptibility of IgAN after Bonferroni correction [padditive  = 0.0009, OR (95% CI) = 1.25 (1.09-1.42); precessive  = 0.0006, OR (95% CI) = 1.54 (1.20-1.96)]; however, the association remained only in women after further sex-stratified analysis. Genotype-phenotype correlation analysis showed significant associations of rs3803800 with severe clinicopathological manifestations in IgAN patients after adjusting for age and sex, as well as the other two SNPs (rs4246413 and rs4968210) that were also associated with specific clinical phenotypes. Compared with healthy controls, serum APRIL levels were significantly higher in IgAN patients (p = 0.0001) and associated with severity of disease. CONCLUSIONS: The results of the present study indicate that the genetic variations and gene expression level of TNFSF13 are associated with the susceptibility and severity of IgAN in a Han Chinese population.

New strategy for renal fibrosis: Targeting Smad3 proteins for ubiquitination and degradation.

PURPOSE: Smad3 is a critical signaling protein in renal fibrosis. Proteolysis targeting chimeric molecules (PROTACs) are small molecules designed to degrade target proteins via ubiquitination. They have three components: (1) a recognition motif for E3 ligase; (2) a linker; and (3) a ligand for the target protein. We aimed to design a new PROTAC to prevent renal fibrosis by targeting Smad3 proteins and using hydroxylated pentapeptide of hypoxia-inducible factor-1α as the recognition motif for von Hippel-Lindau (VHL) ubiquitin ligase (E3). METHODS: Computer-aided drug design was used to find a specific ligand targeting Smad3. Surface plasmon resonance (SPR) was used to verify and optimize screening results. Synthesized PROTAC was validated by two-stage mass spectrometry. The PROTAC's specificity for VHL (E3 ligase) was proved with two human renal carcinoma cell lines, 786-0 (VHL(-)) and ACHN (VHL(+)), and its anti-fibrosis effect was tested in renal fibrosis cell models. RESULTS: Thirteen small molecular compounds (SMCs) were obtained from the Enamine library using GLIDE molecular docking program. SPR results showed that #8 SMC (EN300-72284) combined best with Smad3 (KD=4.547×10(-5)M). Mass spectrometry showed that synthesized PROTAC had the correct peptide molecular weights. Western blot showed Smad3 was degraded by PROTAC with whole-cell lysate of ACHN but not 786-0. Degradation, but not ubiquitination, of Smad3 was inhibited by proteasome inhibitor MG132. The upregulation of fibronectin and Collagen I induced by TGF-ß1 in both renal fibroblast and mesangial cells were inhibited by PROTAC. CONCLUSION: The new PROTAC might prevent renal fibrosis by targeting Smad3 for ubiquitination and degradation.

Low α-defensin gene copy number increases the risk for IgA nephropathy and renal dysfunction.

Although a major source of genetic variation, copy number variations (CNVs) and their involvement in disease development have not been well studied. Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. We performed association analysis of the DEFA1A3 CNV locus in two independent IgAN cohorts of southern Chinese Han (total of 1189 cases and 1187 controls). We discovered three independent copy number associations within the locus: DEFA1A3 [P = 3.99 × 10(-9); odds ratio (OR), 0.88], DEFA3 (P = 6.55 × 10(-5); OR, 0.82), and a noncoding deletion variant (211bp) (P = 3.50 × 10(-16); OR, 0.75) (OR per copy, fixed-effects meta-analysis). While showing strong association with an increased risk for IgAN (P = 9.56 × 10(-20)), low total copy numbers of the three variants also showed significant association with renal dysfunction in patients with IgAN (P = 0.03; hazards ratio, 3.69; after controlling for the effects of known prognostic factors) and also with increased serum IgA1 (P = 0.02) and galactose-deficient IgA1 (P = 0.03). For replication, we confirmed the associations of DEFA1A3 (P = 4.42 × 10(-4); OR, 0.82) and DEFA3 copy numbers (P = 4.30 × 10(-3); OR, 0.74) with IgAN in a Caucasian cohort (531 cases and 198 controls) and found the 211bp variant to be much rarer in Caucasians. We also observed an association of the 211bp copy number with membranous nephropathy (P = 1.11 × 10(-7); OR, 0.74; in 493 Chinese cases and 500 matched controls), but not with diabetic kidney disease (in 806 Chinese cases and 786 matched controls). By explaining 4.96% of disease risk and influencing renal dysfunction in patients with IgAN, the DEFA1A3 CNV locus may be a potential therapeutic target for developing treatments for this disease.

High glucose concentrations in peritoneal dialysate are associated with all-cause and cardiovascular disease mortality in continuous ambulatory peritoneal dialysis patients.

BACKGROUND: The effect of high peritoneal dialysate glucose concentration (PDGC) on all-cause and cardiovascular disease (CVD) mortality in peritoneal dialysis (PD) patients is unclear. OBJECTIVE: Our study aimed to investigate the effect of high PDGC on all-cause and CVD mortality in continuous ambulatory PD (CAPD) patients. METHODS: The study enrolled 716 patients newly initiated on CAPD therapy between January 2006 and December 2010. We allocated the patients to low (< 1.56%), medium (≥ 1.56% to < 1.74%), and high (≥ 1.74%) average PDGC groups according to the tertile of average PDGC in the first 6 months after PD initiation. Cox regression and ordinal logistic regression were used to analyze determinants of mortality and of PDGC use respectively. RESULTS: Mean follow-up in the study cohort was 31 ± 15 months. The all-cause mortality was 4.7 events per 100 patient-years, and the leading cause of death was CVD. Patients with a higher PDGC had significantly higher cumulative rates of all-cause (log-rank p < 0.001) and CVD mortality (log-rank p < 0.001). In Cox regression analysis, high PDGC independently predicted higher all-cause (hazard ratio: 2.63; p = 0.004) and CVD mortality (hazard ratio: 2.78; p = 0.01). Compared with a lower PDGC, a higher PDGC was significantly associated with older age [odds ratio (OR): 1.02; p < 0.001], low residual renal function (OR: 0.91; p < 0.001), and high dialysate-to-plasma ratio of creatinine (OR: 28.61; p < 0.001) in ordinal logistic regression. CONCLUSIONS: Higher PDGC is associated with higher allcause and CVD mortality in CAPD patients.