Immunoglobulin heavy chain gene rearrangement in heavy chain deposition disease suggests it is a plasma cell disease: a case report.

Heavy chain deposition disease (HCDD) is characterized by the deposition of truncated monoclonal immunoglobulin heavy chains along glomerular basement membranes. Truncated heavy chains are thought to be associated with plasma cell disease (PCD), but previous bone marrow cytology tests showed that only 30% of HCDD cases are related to PCDs. We report the first known use of immunoglobulin heavy chain (IGH) gene rearrangement to diagnose a patient with γ3-HCDD, although bone marrow morphology test identified no abnormalities. Our findings provide strong evidence for a correlation between PCDs and HCDD, which could help understand the genetic background underlying abnormal heavy chains and assess disease prognosis. Further, concordant with previous findings, bortezomib-based chemotherapy had a good therapeutic effect in our patient. We summarize the experience of diagnosing and treating a case of HCDD, and combine this with a literature review to further explore the correlation between PCDs and HCDD, which has important clinical value.

A mixed-method evaluation of the relationship between Oxford classification scores and longitudinal changes in proteinuria in patients with immunoglobulin A nephropathy.

Introduction: This study aimed to investigate the relationship between Oxford Classification scores and longitudinal changes in proteinuria in patients with immunoglobulin A nephropathy (IgAN). Methods: The study was a single-center retrospective cohort study involving 358 patients with primary IgAN who were treated at the Shenzhen Second People's Hospital, China, between January 2011 and May 2021. Multivariate linear regression and generalized additive mixed models (GAMMs), adjusted for traditional risk confounders, were used to evaluate the correlation between scores for mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), tubular atrophy/interstitial fibrosis (T), and crescents (C) (known as the Oxford Classification MEST-C score system), with proteinuria/creatinine ratio (PCR) at the time of renal biopsy and longitudinal changes in PCR, respectively. Results: The median PCR was 1061 mg/g, and it increased on average by 68.82 mg/g per year in these patients. Among patients with renal insufficiency, compared with patients without relative lesions, those with E present (E1) (1153.44; 95% confidence interval [CI], 188.99-2117.89 mg/g) and C > 0 (C1/2) (1063.58; 95% CI, 185.25-1941.90 mg/g) were associated with increased PCR levels at the time of renal biopsy. What's more, S present (S1) (194.96; 95% CI, 54.50-335.43 mg/g per year) was associated with the fastest PCR increase; C > 0 (C1/2) (147.59; 95% CI, 8.32-286.86 mg/g per year) and T >25% (T1/2) (77.04; 95% CI, 7.18-146.89 mg/g per year), were also correlated with a faster PCR increase. In patients with normal kidney function, associations between S1 (55.46; 95% CI, 8.93-101.99 mg/g per year) and E1 (94.02; 95% CI, 21.47-166.58 mg/g per year) and PCR change could be observed. Additionally, in patients with overweight/obesity, S1 (156.09; 95% CI, 52.41-259.77 mg/g per year), E1 (143.34; 95% CI, 35.30-251.38 mg/g per year), T1/2 (116.04; 95% CI, 22.58-209.51 mg/g per year), as well as C1/2 (134.03; 95% CI, 41.73-226.32 mg/g per year) were associated with noticeably quicker PCR increase. Conclusions: Overall, E1 and C1/2 were independently associated with raised proteinuria levels at the time of renal biopsy, and S1, E1, T1/2, C1/2 were independently associated with a longitudinal increase in proteinuria in the patients with IgAN, especially in those with renal insufficiency or overweight/obesity, suggesting that currently available treatments might not be satisfactory, and weight control might be beneficial. Individual therapy development might benefit from the use of the Oxford Classification system.

The increased miRNA-150-5p expression of the tonsil tissue in patients with IgA nephropathy may be related to the pathogenesis of disease.

BACKGROUND: The microRNA (miRNA) expression of the tonsil tissues in patients with immunoglobulin A (IgA) nephropathy (IgAN) has not been reported in the literature. METHODS: In this study, the expression of nine miRNAs was measured in the tonsil tissues of patients with IgAN, including miRNA-21-5p, miRNA-29a-3p, miRNA-34a-5p, miRNA-146a-5p, miRNA-146b-5p, miRNA-148b-3p, miRNA-150-5p, miRNA-155-5p, and miRNA-181a-5p. Forty patients with proved primary IgA nephropathy were enrolled in our study, 20 IgAN patients with gross hematuria, which induced by tonsillitis (GH-IgAN group) and 20 IgAN patients without gross hematuria in the history (non-GH-IgAN group). Another 20 patients recruited as the control group (CT group) were chronic tonsillitis without kidney disease. RESULTS: Compared to the CT group, the expression level of miRNA-150-5p in the tonsils was significantly upregulated in the GH-IgAN group, but not in the non-GH-IgAN group (P = 0.031 and P = 0.122, respectively). A correlation analysis was performed between the expression of miRNAs in the tonsils and the clinical data of IgAN patients. The results showed that in the GH-IgAN group, the miRNA-150 expression was positively correlated with systolic blood pressure (ß = 2.36, 95% CI 1.11-3.61, P = 0.0016), diastolic blood pressure (ß = 1.02, 95% CI 0.22-1.82, P = 0.0224), uric acid (ß = 7.43, 95% CI 1.81-13.04, P = 0.0184), leukocyte count (ß = 0.22, 95% CI 0.09-0.35, P = 0039), neutrophil count (ß = 0.19, 95% CI 0.06-0.32, P = 0.0096), cholesterol (ß = 0.09, 95% CI 0.02-0.16, P = 0.0207) and triglyceride level (ß = 0.16, 95% CI 0.10-0.22, P < 0.000). Besides, it was negatively correlated with the estimated glomerular filtration rate (eGFR) (ß = -2.06, 95% CI: -3.90 - -0.21, P = 0.0421) in the GH-IgAN group; however, no significant correlation was found in the non-GH-IgAN group. CONCLUSION: The present findings suggest that miRNA-150-5p may be important in the pathogenesis of IgAN, especially in mucosal immunity against the disease.

The Association of the Oxford Classification Score with Longitudinal Estimated Glomerular Filtration Rate Decline in Patients with Immunoglobulin A Nephropathy: A Mixed-Method Study.

INTRODUCTION: The Oxford Classification score, which predicts renal outcomes for immunoglobulin A nephropathy (IgAN), is widely used in clinical practice. Nevertheless, the relationship between these markers and longitudinal changes in renal function are poorly understood. METHODS: This was a population-based retrospective cohort study of 280 adults with biopsy-proven primary IgAN from 2011 to 2018. We used generalized additive mixed models to control for traditional kidney disease risk factors to analyze the associations between Oxford Classification MEST-C scores (mesangial hypercellularity, M; endocapillary hypercellularity, E; segmental glomerulosclerosis, S; tubular atrophy/interstitial fibrosis, T; crescents, C) and longitudinal changes in the estimated glomerular filtration rate (eGFR) after renal biopsy. RESULTS: The median eGFR was 78.2 mL/min/1.73 m2 at baseline, and then it decreased on average by 1.3 mL/min/1.73 m2 per year in the entire cohort. In adjusted models, compared with patients without relative lesions, the presence of T > 50% (T2) (-5.7; 95% confidence interval [CI], -9.5 to -2.0 mL/min/1.73m2 per year) was associated with the fastest eGFR decline. S present (S1) (-2.9; 95% CI, -4.6 to -1.1 mL/min/1.73m2 per year) and C > 25% glomeruli (C2) (-3.4; 95% CI, -6.4 to -0.5 mL/min/1.73m2 per year) also demonstrated steeper eGFR declines. However, we found no association between M > 0.5 (M1), E present (E1), T 26%-50% (T1), and C present ≥ 1 glomerulus (C1), and progressive eGFR decline (p > 0.05). CONCLUSION: The Oxford Classification scores, S1, T2, and C2, were independently associated with the longitudinal decreases in renal function in patients with IgAN. These findings suggested therapies targeted at improving early damage to these lesions might be essential to delay renal progression.

Association Between Serum IgG Concentrations and Prognosis in IgA Nephropathy.

INTRODUCTION: To investigate the relationship between serum IgG (sIgG) concentration and the prognosis of IgA nephropathy (IgAN). METHODS: A total of 309 patients with biopsy-proven IgAN in the Second Referral Hospital of Shenzhen were enrolled between 2010/01 and 2017/06. Patients were divided into 3 groups on the basis of sIgG tertiles: < 8.99 g/L (Group G1), 8.99 to 11.17 g/L (Group G2), and > 11.17 g/L (Group G3). RESULTS: As the level of sIgG increased, there was a decrease in DBP, serum creatinine, 24h urine proteinuria and an increase in serum albumin (all P < .05). In terms of pathological manifestations, with increasing sIgG levels, there was a tendency of decline in the Lee's grading system or high-grade tubular atrophy/interstitial fibrosis or in the proportion of glomerular sclerosis and the ratio of crescent (all P < .05). Kaplan-Meier analysis indicated that the cumulative renal survivals rates were significantly higher in patients with elevated sIgG (P < .05). Cox regression analysis showed that after adjusting for gender, age, BMI, and clinical indicators (BP, 24h urine proteinuria, eGFR, M, E, S, T, and the ratio of crescent), decreased sIgG level at the time of renal biopsy is an independent risk factor for unfavorable outcomes in IgAN. Furthmore, every 1 g/L decrease in sIgG level was associated with a 1.74-fold (95% CI: 1.30 to 5.38) increased risk of the incidence of composite renal outcomes. CONCLUSIONS: Decreased serum IgG level at baseline might be a kind of predictive marker for the poor prognosis of IgAN.

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.

The protective effect of Cordycepin on diabetic nephropathy through autophagy induction in vivo and in vitro.

BACKGROUND: Diabetic nephropathy (DN) is one of the most serious chronic complications of diabetes mellitus (DM). Autophagy is an important physiological function for podocytes to maintain stability of intracellular environment. In this study, we planned to clarify the effect of Cordycepin, a traditional Chinese medicine, on DN and the related mechanisms. METHODS: All rats were randomly divided into normal control group, diabetic controls, low-dose group (10 mg/kg), medium-dose group (100 mg/kg), and high-dose group (500 mg/kg). The level of cholesterol, blood sugar, triglyceride, creatinine, and urine protein was examined through an automatic biochemistry analyser. Enzyme-linked immunosorbent assay (Elisa) was used to detect the level of IL-1ß, IL-6, and IL-18. HE staining was used to examine histopathologic changes. TUNEL staining was used to detected cell apoptosis. The expression of fibrosis markers α-SMA, t-TG, and TIMP-1, apoptosis-related proteins cleaved-caspase3, Bax and Bcl-2, autophagy markers Beclin1, light chain 3 (LC3)I/II, and p62 were evaluated by western blot. RESULTS: The level of cholesterol, blood sugar, triglyceride, creatinine, and urine protein in the diabetic controls was much higher than that in the normal control group. Obvious histopathology injuries were also found in DN model group. After Cordycepin treatment, all the above indexes were improved compared with the DN group and tissue damages were also alleviated. Further studies showed that Cordycepin suppressed cell apoptosis and renal fibrosis and rescued cell autophagy in DN rat model. Moreover, the results of our in vitro experiments showed that the addition of 3-methyladenine (3-MA, specific autophagy inhibitor) successfully abolished the protective effect of Cordycepin on renal fibrosis through inducing apoptosis and renal fibrosis. The above protective effects of Cordycepin were exhibited in a dose-dependent manner. CONCLUSION: Cordycepin participated in the modulation of cell apoptosis, fibrosis, and autophagy induction in DN. Our study for the first time revealed that Cordycepin had a certain therapeutic effect on DN in rats through autophagy induction.

Association of ITGAX and ITGAM gene polymorphisms with susceptibility to IgA nephropathy.

Previous genome-wide association studies have discovered significant association at ITGAX-ITGAM on 16p11.2 for IgA nephropathy (IgAN). In this study, we performed a two-stage association study that enrolled 1700 IgAN cases and 2400 controls to further investigate the relationship of ITGAX and ITGAM gene polymorphisms with IgAN. Seven single-nucleotide polymorphisms (SNPs) were selected for genotyping in 1000 IgAN cases and 1000 healthy controls in the discovery stage, and the significant SNP was further validated in additional 700 IgAN cases and 1400 healthy controls. We found that four SNPs (rs11150619, rs11150614, rs7190997, and rs4597342) showed potential associations with IgAN susceptibility in the discovery stage, but only SNP rs11150619 was further genotyped in the validation stage after multiple testing. The results indicated that rs11150619 was significantly associated with IgAN in the combined samples (OR = 0.81, 95%CI = 0.71-0.91, and dominant P = 6.68 × 10-4). Moreover, patients with TT genotype of rs11150619 exhibited increased estimated glomerular filtration rate levels and a reduced proportion of global sclerosis compared with those with TC and CC genotypes. Our results suggested that ITGAX and ITGAM gene polymorphisms were associated with IgAN in a Chinese Han population, and the rs11150619-T allele showed a potential protective role for IgAN.

Association of body mass index and uncontrolled blood pressure with cardiovascular mortality in peritoneal dialysis patients.

The association of body mass index (BMI) and blood pressure (BP) control and their interaction with cardiovascular (CV) mortality in continuous ambulatory peritoneal dialysis (CAPD) patients is unclear. We retrospectively analyzed a consecutive series of 1595 incident CAPD patients with hypertension from 2006 to 2013, and followed up through December 2015. The BMI was categorized according to the World Health Organization classification for Asian population. Binary logistic regression was used to assess the relationship between BMI and BP control. Cox's proportional hazards models and competing risk analyses were performed to examine the nassociation of BMI and BP control with CV mortality. In the entire cohort, obesity was unlikely related to increased risk of uncontrolled BP. However, the adjusted hazard ratio (AHR) of CV mortality was increased in individuals with obesity when compared to those with normal weight (AHR 1.56; 95% confidence interval (CI) 1.04-2.34) and in individuals with uncontrolled BP when compared to those with controlled BP (AHR 1.39; (1.02-1.89)). Subgroup analyses showed that the combination of obesity and uncontrolled BP was associated with an increased risk for CV death, when compared to normal weight subjects with uncontrolled BP (AHR 2.35; (1.43-3.86)). Further, subjects with obesity and uncontrolled BP had a nearly threefold increase in risk (AHR 2.57; (1.57-4.20)) for CV death compared to subjects with neither risk factor. These associations persisted in competing risk analyses. In conclusion, the association of obesity with CV mortality was likely to vary with hypertension status among CAPD patients.

Association Analysis of the MHC in Lupus Nephritis.

Lupus nephritis (LN) is one of the most prevalent and serious complications of SLE, with significant effects on patient and renal survival. Although a large number of genetic variants associated with SLE have been identified, biomarkers that correlate with LN are extremely limited. In this study, we performed a comprehensive sequencing analysis of the whole MHC region in 1331 patients with LN and 1296 healthy controls and validated the independent associations in another 950 patients with LN and 1000 controls. We discovered five independent risk variants for LN within the MHC region, including HLA-DRß1 amino acid 11 (Pomnibus<0.001), HLA-DQß1 amino acid 45 (P<0.001; odds ratio, 0.58; 95% confidence interval, 0.52 to 0.65), HLA-A amino acid 156 (Pomnibus<0.001), HLA-DPß1 amino acid 76 (Pomnibus<0.001), and a missense variant in PRRC2A (rs114580964; P<0.001; odds ratio, 0.38; 95% confidence interval, 0.30 to 0.49) at genome-wide significance. These data implicate aberrant peptide presentation by MHC classes 1 and 2 molecules and sex hormone modulation in the development of LN.

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.

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.

Clinicopathologic features of IgA nephropathy patients with different levels of proteinuria.

AIMS: To investigate the clinicopathologic features of IgA nephropathy (IgAN) patients with different levels of proteinuria and its clinical significance. METHODS: This was a single-center retrospective cohort study. Patients with biopsy-proven primary IgAN were enrolled from January 2006 to December 2011 in The First Affiliated Hospital of Sun Yat-sen University, divided into six groups based on proteinuria at biopsy (≤ 0.30 g/d, 0.31 - 0.50 g/d, 0.51 - 1.00 g/d, 1.01 - 2.00 g/d, 2.01 - 3.00 g/d, and > 3.00 g/d). Demographic and clinicopathologic data were collected and analyzed. RESULTS: 1,413 patients were enrolled in this study, with the median proteinuria being 0.61 g/d (interquartile range 0.30 - 1.29). Patients with proteinuria > 0.50 g/d showed significant differences in their clinicopathologic characteristics with higher prevalence of hypertension, hypoalbuminemia, hyperuricemia, hypercholesterolemia and hypertriglyceridemia, worse renal function, higher proportions of segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, and interstitial inflammation. Even the patients with proteinuria 0.31 - 0.50 g/d exhibited higher uric acid, lower total serum protein and albumin, higher proportions of crescents, and global glomerulosclerosis. Furthermore, multiple risk factors linear regression analysis has shown that there were significant associations between proteinuria and serum albumin, uric acid, total cholesterol, triglyceride, systolic blood pressure, degrees of segmental glomerulosclerosis, proportions of crescents, and global glomerulosclerosis. CONCLUSION: Clinicopathologic features were significantly worse in IgAN patients with increasing of proteinuria.

Deep sequencing of the MHC region in the Chinese population contributes to studies of complex disease.

The human major histocompatibility complex (MHC) region has been shown to be associated with numerous diseases. However, it remains a challenge to pinpoint the causal variants for these associations because of the extreme complexity of the region. We thus sequenced the entire 5-Mb MHC region in 20,635 individuals of Han Chinese ancestry (10,689 controls and 9,946 patients with psoriasis) and constructed a Han-MHC database that includes both variants and HLA gene typing results of high accuracy. We further identified multiple independent new susceptibility loci in HLA-C, HLA-B, HLA-DPB1 and BTNL2 and an intergenic variant, rs118179173, associated with psoriasis and confirmed the well-established risk allele HLA-C*06:02. We anticipate that our Han-MHC reference panel built by deep sequencing of a large number of samples will serve as a useful tool for investigating the role of the MHC region in a variety of diseases and thus advance understanding of the pathogenesis of these disorders.

Identification of new susceptibility loci for IgA nephropathy in Han Chinese.

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.

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.

High peritoneal transport status was not associated with mortality in peritoneal dialysis patients with diabetes.

BACKGROUND: Continuous ambulatory peritoneal dialysis (CAPD) patients with diabetes are at increased risk of mortality and high peritoneal transporters appear to contribute to poor survival. However, little is known about the combined impacts of high peritoneal transporters and diabetes on mortality. METHODS: This was a prospective observational cohort study. 776 incident CAPD patients were enrolled. Unadjusted and adjusted Cox proportional regression models were used to evaluate the association and interaction of peritoneal transport and diabetic status with mortality. RESULTS: In the entire cohort, high peritoneal transport status was associated with an increased risk of all-cause mortality in unadjusted model [hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.30 to 4.25, P = 0.01], but this association was not significant in multivariable model. There was an interaction between peritoneal membrane transport status and diabetes (P = 0.028). Subgroup analyses showed that compared to low and low average transporters, high transporters was associated with a higher risk of all-cause mortality (adjusted HR 1.78, 95% CI 1.07 to 4.70, P = 0.04) in CAPD patients without diabetes, but not in those with diabetes (adjusted HR 0.79, 95%CI 0.33 to 1.89, P = 0.59). Results were similar when transport status was assessed as a continuous variable. CONCLUSIONS: The association between high peritoneal transport and all-cause mortality was likely to vary with diabetes status. High peritoneal transport was associated with an elevated risk of death among CAPD patients without diabetes, but not in those with diabetes.

Polymorphism of DEFA in Chinese Han population with IgA nephropathy.

Our recent genome-wide association study (GWAS) had discovered a new locus at 8p23 (rs2738048) associated with IgA nephropathy (IgAN) in Chinese Han patients, implicating the DEFA gene family within this locus as susceptibility genes. However, it is still unknown whether there are additional variations within these genes associated with the disease susceptibility. The aim of this study is to investigate the polymorphisms of DEFA genes in the susceptibility to IgAN and explore possible disease mechanisms. Sixteen tag single-nucleotide polymorphisms (tag SNPs) were selected for association study in 1,000 IgAN cases and 1,000 controls by using Sequenom MassArray system or TaqMan SNP genotyping assays. We found seven SNPs within DEFA genes that were significantly associated with IgAN, including rs2738048 discovered in our previous GWAS (p = 0.0007, OR = 0.77) and additional 6 SNPs (rs2615787, p = 0.0001, OR = 0.74; rs2738081, p = 0.0003, OR = 0.72; rs2738058, p = 0.0001, OR = 0.73; rs4288398, p = 0.0008, OR = 0.78; rs6984215, p = 0.002, OR = 0.63; rs12716641, p = 0.00002, OR = 0.71). Electrophoretic mobility shift assays and luciferase assays demonstrated that fragments containing rs2738048, rs2738081 and rs6984215 were transcription factor binding sites for CTF, SP1 and CdxA, respectively, and the allele status of rs2738048 and rs6984215 could significantly change the luciferase activity. These results suggest that polymorphisms within DEFA genes are involved in gene transcriptional regulation, and this may have some effect in mediating susceptibility to IgAN in southern Chinese.

Optimization and evaluation of magnetic bead separation combined with matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy (MALDI-TOF MS) for proteins profiling of peritoneal dialysis effluent.

Peritoneal dialysis effluent (PDE) potentially carries an archive of peptides relevant to pathological processes in abdominal and surrounding tissues. Magnetic beads and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry is one such approach that offers a unique tool for profiling of peptides, but this approach has not been used in the PDE analysis. In this study, we developed a strategy for screening PDE proteins <15 kDa and applied this technique to identify potential biomarkers for peritonitis. We examined four kinds of magnetic beads, including a carbon series (C3, C8), weak cation exchange (WCX) and immobilized metal-affinity chromatography (IMAC-Cu) beads. Samples processed with IMAC-Cu magnetic beads consistently showed more MS signals across all beads within the measured mass range. Moreover, there was no difference in the number and morphology of MS signals between concentrated and unconcentrated samples. The PDE peptidome pattern, based on a panel of 15 peaks, accurately recognized peritonitis PD patients from peritonitis-free patients with sensitivity of 90.5% and specificity of 94.7% respectively. Therefore, IMAC-Cu magnetic beads and unconcentrated samples can be used as a fast and cost-effective approach for sample preparation prior to more in-depth discovery of predictive biomarkers of disease in patients on dialysis.