Gut permeability, circulating bacterial fragments and measures of congestion in peritoneal dialysis.

Background: Limited data exist on the association between gut permeability, circulating bacterial fragment and volume overload in peritoneal dialysis (PD) patients. We measured circulating bacterial fragments, N-terminal pro B-type natriuretic peptide (NT-proBNP), calprotectin and zonulin levels, and evaluate their association with the clinical outcomes in PD patients. Methods: This was a single-center prospective study on 108 consecutive incident PD patients. Plasma endotoxin and bacterial DNA, and serum NT-proBNP, calprotectin and zonulin levels were measured. Primary outcomes were technique and patient survival, secondary outcomes were hospitalization data. Results: There was no significant correlation between plasma endotoxin and bacterial DNA, and serum NT-proBNP, calprotectin and zonulin levels. The Homeostatic Model Assessment for Insulin Resistance (HOMA)-2ß index, which represents insulin resistance, positively correlated with plasma bacterial DNA (r = 0.421, P < .001) and calprotectin levels (r = 0.362, P = .003), while serum NT-proBNP level correlated with the severity of volume overload and residual renal function. Serum NT-proBNP level was associated with technique survival even after adjusting for confounding factors [adjusted hazard ratio (aHR) 1.030, 95% confidence interval 1.009-1.051]. NT-proBNP level was also associated with patient survival by univariate analysis, but the association became insignificant after adjusting for confounding factors (aHR 1.010, P = .073). Similarly, NT-proBNP correlated with the number of hospitalizations and duration of hospitalization by univariate analysis, but the association became insignificant after adjusting for confounding factors. Conclusion: There was no correlation between markers of gut permeability, circulating bacterial fragments and measures of congestion in PD patients. Bacterial fragments levels and gut permeability are both associated with insulin resistance. Serum NT-proBNP level is associated with the severity of volume overload and technique survival. Further studies are required to delineate the mechanism of high circulating bacterial fragment levels in PD patients.

Urinary Long Non-Coding RNA Levels as Biomarkers of Lupus Nephritis.

BACKGROUND: Emerging evidence suggests that long non-coding RNA (lncRNA) plays important roles in the regulation of gene expression. We determine the role of using urinary lncRNA as a non-invasive biomarker for lupus nephritis. METHOD: We studied three cohorts of lupus nephritis patients (31, 78, and 12 patients, respectively) and controls (6, 7, and 24 subjects, respectively). The urinary sediment levels of specific lncRNA targets were studied using real-time quantitative polymerase chain reactions. RESULTS: The severity of proteinuria inversely correlated with urinary maternally expressed gene 3 (MEG3) (r = -0.423, p = 0.018) and ANRIL levels (r = -0.483, p = 0.008). Urinary MEG3 level also inversely correlated with the SLEDAI score (r = -0.383, p = 0.034). Urinary cancer susceptibility candidate 2 (CASC2) levels were significantly different between histological classes of nephritis (p = 0.026) and patients with pure class V nephritis probably had the highest levels, while urinary metastasis-associated lung carcinoma transcript 1 (MALAT1) level significantly correlated with the histological activity index (r = -0.321, p = 0.004). Urinary taurine-upregulated gene 1 (TUG1) level was significantly lower in pure class V lupus nephritis than primary membranous nephropathy (p = 0.003) and minimal change nephropathy (p = 0.04), and urinary TUG1 level correlated with eGFR in class V lupus nephritis (r = 0.706, p = 0.01). CONCLUSIONS: We identified certain urinary lncRNA targets that may help the identification of lupus nephritis and predict the histological class of nephritis. Our findings indicate that urinary lncRNA levels may be developed as biomarkers for lupus nephritis.

Longitudinal Changes of NF-κB Downstream Mediators and Peritoneal Transport Characteristics in Incident Peritoneal Dialysis Patients.

The role of intra-peritoneal mediators in the regulation peritoneal transport is not completely understood. We investigate the relation between longitudinal changes in dialysis effluent level of nuclear factor kappa-B (NF-κB) downstream mediators and the change in peritoneal transport over 1 year. We studied 46 incident PD patients. Their peritoneal transport characteristics were determined after starting PD and then one year later. Concomitant dialysis effluent levels of interleukin-6 (IL-6), cyclo-oxygenase-2 (COX-2) and hepatocyte growth factor (HGF) are determined. There were significant correlations between baseline and one-year dialysis effluent IL-6 and COX-2 levels with the corresponding dialysate-to-plasma creatinine level at 4 hours (D/P4) and mass transfer area coefficient of creatinine (MTAC). After one year, patients who had peritonitis had higher dialysis effluent IL-6 (26.6 ± 17.4 vs 15.1 ± 12.3 pg/ml, p = 0.037) and COX-2 levels (4.97 ± 6.25 vs 1.60 ± 1.53 ng/ml, p = 0.007) than those without peritonitis, and the number of peritonitis episode significantly correlated with the IL-6 and COX-2 levels after one year. In contrast, dialysis effluent HGF level did not correlate with peritoneal transport. There was no difference in any mediator level between patients receiving conventional and low glucose degradation product solutions. Dialysis effluent IL-6 and COX-2 levels correlate with the concomitant D/P4 and MTAC of creatinine. IL-6 and COX-2 may contribute to the short-term regulation of peritoneal transport.

Relationship between Plasma Endocan Level and Clinical Outcome of Chinese Peritoneal Dialysis Patients.

BACKGROUND: Endocan is associated with endothelial dysfunction. In peritoneal dialysis (PD) patients, cardiovascular disease is a common cause of mortality. We examined the relationship between serum endocan level and clinical outcome of PD patients. METHODS: We recruited 193 new PD patients (118 males, mean age 58.8 ± 11.6 years). Serum endocan levels were determined and stratified into tertile 1 (lowest) to 3 (highest). Nutritional status, arterial pulse wave velocity (PWV) and serum C-reactive protein (CRP) levels were measured. The patients were followed for at least 4 years for clinical outcomes. RESULTS: For the whole cohort, patients with higher serum endocan levels had lower serum albumin and subjective global assessment score, higher carotid-femoral PWV, and higher serum CRP. For patients with suboptimal blood pressure (BP) control, cardiovascular event-free survival was 95.0, 95.5, and 78.5% for tertiles 1, 2, and 3 at 60 months respectively (p = 0.019). Multivariate Cox regression analysis showed that serum endocan level was an independent predictor of cardiovascular event-free survival. No association with cardiovascular event-free survival was found for patients with adequate BP control (95.0, 92.3, and 100% for tertile 1, 2, and 3 at 60 months, respectively, p = 0.6). CONCLUSIONS: Higher serum endocan level is associated with unfavourable nutritional, arterial and inflammatory conditions in PD patients. In patients with suboptimal BP control, higher serum endocan is also associated with worse cardiovascular outcome.

Peritoneal inflammation and fibrosis in C-reactive protein transgenic mice undergoing peritoneal dialysis solution treatment.

AIM: C-reactive protein (CRP) is a mediator of systemic inflammation. Peritoneal dialysis (PD) is known to cause peritoneal inflammation and fibrosis. We compare the degree of peritoneal inflammation and fibrosis in wild-type (WT) and CRP-transgenic (Tg) mice after PD treatment. METHODS: WT (n = 7) and CRP-Tg (n = 10) C57BL/6 J mice (all male, 10-12 weeks old) were injected intra-peritoneally with 4.25% dextrose PD solution (3 mL/mouse) daily for 28 days, followed by a 2-h peritoneal equilibration test (PET). The mice were then killed. Parietal peritoneal and omental tissues were collected for the assessment of inflammation and fibrosis. RESULTS: After 28 days of PD treatment, CRP-Tg mice had higher dialysate-to-plasma (D/P) creatinine ratio than that of WT mice. Parietal peritoneum of the CRP-Tg mice was more cellular and thicker than that of the WT mice. CRP-Tg mice also had higher connective tissue growth factor (CTGF), intercellular adhesion molecule 1 (ICAM1) and tumor necrosis factor α (TNFα) RNA expressions as well as immunohistochemical staining in the parietal peritoneum than that of the WT mice. CONCLUSIONS: CRP-Tg mice have significantly more inflammation and fibrosis than WT mice after PD treatment. Our results suggest that CRP play a role in inflammation and fibrosis induced by PD. The implication of our results to human PD therapy needs further investigations.

Relationship between HSP70-2 A+1267G Polymorphism and Cardiovascular Events of Chinese Peritoneal Dialysis Patients.

BACKGROUND: Heat shock proteins (HSPs) are expressed by cells in response to various environmental stresses. A single-nucleotide polymorphism A+1267G of the HSPA1B gene affects the expression of HSP70-2, with the A allele being protective against inflammatory conditions. We investigated the relation between the HSP A+1267G polymorphism and the clinical outcomes of Chinese peritoneal dialysis (PD) patients. METHODS: We studied 347 new PD cases (181 males, age 56.6 ± 13.7 years). Genotyping was done by standard methods. Patients were followed for 40.5 ± 20.7 months for survival analysis. RESULTS: For the entire cohort, there was no difference in the 5-year survival between genotype groups. However, there was a significant interaction between HSP polymorphism and diabetic status on the cardiovascular event-free survival. In patients without pre-existing diabetes, 5-year cardiovascular event-free survival of the GG/AG genotype group was significantly better than that of the AA genotype group (57.2 vs. 32.1%, p = 0.011). CONCLUSION: The G allele of the HSP70-2 A+1267G polymorphism confers survival advantages in non-diabetic PD patients. The role of HSP in the pathogenesis of cardiovascular disease in renal failure patients needs further investigation.

Relationship between myeloid-related protein 8/14 and survival of Chinese peritoneal dialysis patients.

BACKGROUND: Myeloid-related protein 8/14 (MRP8/14) is released by cells of myeloid lineage upon inflammatory challenges. Experimental data suggested that MRP8/14 is important in the initiation and progression of inflammation and cardiovascular diseases. We examined the relation between serum MRP8/14 level and cardiovascular disease in Chinese peritoneal dialysis (PD) patients. METHODS: We studied 102 new PD patients (58 males, mean age 57.3 ± 11.9 years). Baseline serum MRP8/14 was determined and grouped to quartiles for analysis. All patients were then followed for an average of 23.9 ± 6.9 months. RESULTS: There was a trend of lower 3-year cardiovascular event-free survival for patient quartiles with high serum MRP8/14 levels (log-rank test, p = 0.064). The 3-year actuarial survival was significantly lower for quartile groups with higher MRP8/14 levels (96.0, 94.7, 72.9, and 62.5% for quartiles 1-4, respectively, p = 0.003). Cox regression analysis showed that serum MRP8/14 level and Kt/V were independent predictors of actuarial survival; in this model, every 1 µg/ml increase in serum MRP8/14 level confers a 25.1% increase in risk of death (95% confidence interval, 1.3-54.4%, p = 0.037). There was no significant difference in technique survival between the MRP8/14 quartile groups. CONCLUSION: A high baseline serum MRP8/14 level was associated with a lower actuarial survival in Chinese PD patients. The pathogenic role of MRP8/14 in the cardiovascular disease of PD patients needs further investigation.

Relationship between serum levels of tumour necrosis factor-related apoptosis-inducing ligand and the survival of Chinese peritoneal dialysis patients.

AIM: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) can counteract inflammation and atherosclerosis, both common causes of morbidity in peritoneal dialysis (PD) patients. We examined the relation between serum soluble TRAIL (sTRAIL) levels and the outcome of Chinese PD patients. METHODS: We studied 116 new PD patients (67 males, age 56.7 ± 13.4 years). Baseline serum sTRAIL level was determined and grouped to tertiles 1 (lowest) to 3 (highest). All patients were followed for 20.9 ± 7.0 months. RESULTS: Patient survival was 83.4%, 74.2% and 100% for tertiles 1 to 3, respectively, at 24 months (P = 0.021). Multivariate Cox regression analysis showed that serum sTRAIL level was an independent predictor of patient survival after adjusting for confounding factors (adjusted hazard ratio 0.962, 95% confidence interval [CI] 0.935-0.991, P = 0.010). CONCLUSION: A higher baseline serum sTRAIL level was associated with a better survival of PD patients. The detailed mechanism deserves further investigation.

Relationship between CRP polymorphism and cardiovascular events in Chinese peritoneal dialysis patients.

BACKGROUND AND OBJECTIVES: The single-nucleotide polymorphism (SNP) -717A→G substitution, rs2794521, was found in the promoter of the C-reactive protein (CRP) gene. Functional studies showed that A allele promoter has higher transcriptional activity than the G allele. This study investigated the association between this SNP and the outcome of Chinese patients undergoing peritoneal dialysis (PD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The study included 441 new PD patients (232 men; mean age ± SD, 56.7±13.5 years). CRP genotyping was determined; patients were followed for 41.3±18.3 months for cardiovascular events. RESULTS: For the entire cohort, 5-year event-free survival rates did not differ between the AA and AG/GG groups (35.7% and 31.9%, respectively; P=0.64). However, there was significant interaction between plasma cholesterol levels and CRP genotype groups on event-free survival (P=0.04 for interaction). For patients with cholesterol levels of 200 mg/dl or greater, the 5-year event-free survival rate in the AG/GG group was significantly better than that in the AA group (54.7% versus 40.0%; P=0.04), whereas there was no difference in event-free survival between genotype groups for patients with cholesterol levels less than 200 mg/dl. CONCLUSIONS: CRP gene -717AG or GG genotypes is associated with cardiovascular benefit to Chinese PD patients with cholesterol levels of 200 mg/dl or greater. These findings suggest a complex interaction among cholesterol, CRP, and cardiovascular disease in PD patients.

Relationship between glutathione S-transferase M1 polymorphism and clinical outcomes in Chinese peritoneal dialysis patients.

BACKGROUND: Oxidative stress contributes to cardiovascular diseases in peritoneal dialysis (PD) patients. Glutathione S-transferase M1 is an antioxidative enzyme encoded by the GST M1 gene. The GST M1 (-) genotype causes deficiency of the enzyme when compared with the GST M1 (+) genotype. We investigated the effects of the GST M1 (-)/(+) polymorphism on the clinical outcomes of Chinese PD patients. METHODS: We studied 441 new PD patients (232 men, age 56.6 ± 13.5 years). GST M1 (-)/(+) polymorphism was determined by multiplex polymerase chain reaction. The patients were followed for 41.4 ± 18.2 months. RESULTS: The GST M1 polymorphism was not associated with 5-year patient and technique survival in the whole cohort. However, there were significant interactions between age group and the GST M1 polymorphism on 5-year patient survival (p=0.046) and technique survival (p=0.049). Post hoc analysis showed that for patients =70 years old, those with the GST M1 (+) genotype had significantly better 5-year patient survival (62.5% vs. 26.2%; log rank test, p=0.012) and technique survival (55.1% vs. 21.9%; log rank test, p=0.024) than the GST M1 (-) group. For patients younger than 70 years, the GST M1 polymorphism did not affect 5-year patient or technique survival. CONCLUSION: The GST M1 (+) genotype is associated with better survival in elderly PD patients, who may have heavy oxidative stress as a result of the aging and PD processes.

Relationship between beta1-adrenergic receptor polymorphisms and cardiovascular disease in patients with diabetic nephropathy.

AIM: Activation of beta1-adrenergic receptor (beta1AR) enhances contractility and heart rate. The polymorphism Arg389Gly in the beta1AR gene was found to be functionally important in determining receptor activity. The relationship between this polymorphism and the risk of cardiovascular disease was investigated in Chinese subjects with overt diabetic nephropathy. METHODS: A total of 219 type 2 diabetic subjects with nephropathy were recruited. Genotyping of the beta1AR Arg389Gly polymorphism was determined. Patients were followed up to 96 months for the development of cardiovascular events. RESULTS: There were 122, 86 and 11 patients with Arg/Arg, Arg/Gly and Gly/Gly genotype, respectively. At 96 months, the event-free survival of primary composite cardiovascular end-point was 33.0% and 44.3% for Gly(+) and Gly(-) groups, respectively (log-rank test, P = 0.105), while the event-free survival for first ischaemic heart disease was 62.4% and 75.9%, respectively (log-rank test, P = 0.038). However, with multivariate analysis by the Cox proportional hazard model to adjust for confounders, only low-density lipoprotein and baseline glomerular filtration rate were independent predictors of first ischaemic heart event. CONCLUSION: The beta1AR Arg389Gly polymorphism is not an independent predictor of cardiovascular events in subjects with overt diabetic nephropathy.

Association of interleukin-18 promoter polymorphism and atherosclerotic diseases in Chinese patients with diabetic nephropathy.

AIM: Interleukin-18 (IL-18) is a pro-inflammatory cytokine and possibly plays an important role in the pathogenesis of cardiovascular disease. The relationship between two IL-18 gene polymorphisms, namely C-607A and G-137C, and cardiovascular disease in patients with diabetic nephropathy was examined. METHODS: Two hundred and twenty patients (91 male) with diabetic nephropathy were studied. The IL-18 promoter genotypes were determined. All patients were then prospectively followed for the cardiovascular events. Cardiovascular mortality and all-cause mortality were also compared. RESULTS: Mean age was 64.3 +/- 10.6 years; average follow up was 73.9 +/- 33.6 months. The frequencies of CC, CA and AA genotypes of the C-607A polymorphism were 25.5%, 48.2% and 26.8%, respectively; GG, GC and CC genotypes of the G-137C polymorphism were 71.8%, 25.0% and 3.2%, respectively. Neither of the polymorphisms were associated with the development of primary cardiovascular end-point. Cardiovascular survival was 84.8% and 70.6% at 60 months for GG and GC/CC genotypes of the G-137C polymorphism, respectively (P = 0.027); the corresponding actuarial survival was 69.0% and 54.8%, respectively (P = 0.053). However, the G-137C genotype was not an independent predictor of cardiovascular or actuarial survival after adjusting for confounders by multivariate analysis with the Cox model. The C-607A polymorphism had no significant effect on cardiovascular or actuarial survival. CONCLUSION: The G-137C polymorphism of the IL-18 promoter is associated with the cardiovascular mortality, and a trend of association with all-cause mortality, in patients with diabetic nephropathy. The association, however, becomes insignificant after adjusting for confounding factors. Further studies are needed to test other genetic determinants of the association between systemic inflammation and cardiovascular disease in renal failure patients.

Peroxisome proliferator-activated receptor-gamma gene polymorphism and risk of cardiovascular disease in patients with diabetic nephropathy.

BACKGROUND: Peroxisome proliferator-activator receptor-gamma (PPAR-gamma) is a nuclear receptor that serves important roles in intermediate metabolism. We examined the relationship between two PPAR-gamma gene polymorphisms, namely the P12A and C161T, and cardiovascular disease in patients with diabetic nephropathy. METHODS: We studied 170 predialysis and 50 peritoneal dialysis patients with diabetic nephropathy. The PPAR-gamma genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism assay. The patients were then followed prospectively for the development of cardiovascular events. Cardiovascular mortality and all-cause mortality were also compared. RESULTS: There were 91 male cases. The mean age was 64.3 +/- 10.6 years. The frequencies of Pro/Pro and Pro/Ala genotypes of the P12A polymorphism were 95 and 5%, respectively; CC, CT and TT genotypes of the C161T polymorphism were 55.5, 39.5 and 5.0%, respectively. For the P12A polymorphism, the event-free survival was 56.5 and 9.1% at 60 months for Pro/Pro and Pro/Ala genotypes, respectively (p = 0.0005). For the C161T polymorphism, the event-free survival was 61.5 and 44.9% for CC and CT/TT genotypes, respectively (p = 0.0044). By multivariate analysis with the Cox proportional hazard model to adjust for confounders, the independent factors for event-free survival were P12A and C161T polymorphisms, age and diastolic blood pressure. In this model, the Pro/Ala genotype conferred 7.6-fold (95% CI 2.1- to 28.0-fold, p = 0.002) excess hazard of developing primary cardiovascular end point as compared to the Pro/Pro genotype, while each T allele at the 161 position conferred 83.4% (95% CI 15.2-291.9%, p = 0.011) excess hazard. CONCLUSIONS: We conclude that P12A and C161T polymorphisms of the PPAR-gamma gene are important predictors of cardiovascular event in patients with diabetic nephropathy. Further studies are needed to examine the interaction of PPAR-gamma gene polymorphisms and thiazolidinedione treatment on the cardiovascular risk in this group of patients.