A functional polymorphism in the promoter region of TLR3 is associated with susceptibility to end-stage renal disease.

BACKGROUND/AIMS: End-stage renal disease (ESRD) is simultaneously associated with immune activation, systemic inflammation and immune deficiency. Toll-like receptor 3 (TLR3), a receptor for viral double-stranded RNA, is involved in immune cell activation in renal diseases and may contribute to chronic inflammatory disease progression. To date, effects of TLR3 polymorphisms on ESRD remain unknown. Therefore, we determined the predictive value of TLR3 polymorphisms and further functionally studied ESRD. METHODS: We performed a case-control association study and genotyped 616 ESRD patients and 813 healthy controls. Patients were genotyped for -7C/A, 1377C/T and 1234C/T polymorphisms of TLR3 using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The Haplotype association analysis was performed using the Haploview package. A luciferase reporter assay and real-time PCR were used to test the function of the -7C/A promoter polymorphism in TLR3 expression in human embryonic kidney 293 (HEK293) cells. RESULTS: Genotype distributions of -7C/A and 1377C/T in TLR3 were significantly different in ESRD patients and healthy controls. The ATC haplotype of TLR3 was associated with a decreased risk of ESRD. We also found significant differences in TLR3 expression by dexamethasone treatment between various genotypes of -7C/A (p = 0.02). TLR3 transcriptional activity of the variant -7 C allele was higher than that of the -7 A allele after dexamethasone treatment. CONCLUSION: RESULTS indicate that, in our population, the presence of the C allele of -7C/A in TLR3 increases the susceptibility to ESRD. In vitro studies demonstrated that -7C/A may be involved in ESRD development through transcriptional modulation of TLR3.

Gene-gene interactions in renin-angiotensin-aldosterone system contributes to end-stage renal disease susceptibility in a Han Chinese population.

OBJECTIVE: In this study, we investigated whether RAAS gene single nucleotide polymorphisms (SNPs) and their interactions were associated with end-stage renal stage (ESRD). METHODOLOGY AND RESULTS: This was a case-control study for 647 ESRD cases and 644 controls. AGT (M235T (rs699) and T174M (rs4762)), AGTR1 (A1166C (rs5186) and C573T (rs5182)), ACE (I/D (rs1799752) and G2350A (rs4343)), and CYP11B2 C-344T (rs1799998) were genotyped and compared between cases and controls to identify SNPs associated with ESRD susceptibility. Multifactor dimensionality reduction (MDR) was used to identify gene-gene interactions. Several RAAS genes were associated with ESRD: AGT M235T, ACE I/D, ACE G2350A, and CYP11B2 C-344T. By MDR analysis, a three-locus model (ACE ID/ACE G2350A/CYP11B2 C-344T) of gene-gene interaction was the best for predicting ESRD risk, and its maximum testing accuracy was 56.08% and maximum cross-validation consistency was 9/10. ESRD risk was higher with the simultaneous occurrence of ACE I/D DD-ACE G2350A AA. AGT, ACE, and CYP11B2 gene polymorphisms are associated with ESRD. CONCLUSIONS: The gene-gene interaction effects of ACE I/D, ACE G2350A, and CYP11B2 C-344T polymorphisms are more important than individual factors for ESRD development among Han Chinese.

The T-1237C polymorphism of the Toll-like receptor-9 gene is associated with chronic kidney disease in a Han Chinese population.

Chronic kidney disease (CKD) is increasingly recognized as a global public health problem. As inflammatory processes and genetic factors are involved in the pathogenesis of CKD, we have investigated the potential genetic contribution of Toll-like receptor (TLR) gene polymorphisms in CKD. In a case-control association study, 149 CKD patients and 429 healthy controls were genotyped by real-time polymerase chain reaction. CKD patients were defined as kidney damage (albuminuria, proteinuria or hematuria) or glomerular filtration rate < 60 ml/min/1.73 m(2) for 3 months or more. Single nucleotide polymorphisms (SNPs) at TLR-2 G2408A, TLR-4 A12874G and C13174T, and TLR-9 T-1237C, T-1486C, and G1635A were assessed, and linkage disequilibrium calculations and haplotype association analysis were undertaken. The functions of TLR-9 have been documented to recognize the viral and bacterial CpG DNA sequences, whereas detects microbe-derived peptidoglycan and lipopeptides and TLR-4 binds lipopolysaccharides. SNPs within the TLR genes may influence promoter activity, mRNA conformation and subcellular localization, and/or protein structure and function. Our results show that only the TLR-9 T-1237C and G1635A gene polymorphisms demonstrate an association with CKD (p = 0.002 and p = 0.04, respectively). The TLR-9 TCA haplotype at T-1237C, T-1486C, and G1635A was associated with a lower risk of CKD, whereas the TTA haplotype was associated with a higher risk of CKD. In the Han Chinese population, those who carry the C and A alleles at SNPs T-1237C and G1635A in the TLR-9 gene appear to be more susceptible to the development of CKD.

Association between concurrent antidepressant and hypnotic treatment and the risk of dementia: A nationwide cohort study.

OBJECTIVE: This study aimed to investigate the risk of dementia among subgroups of patients receiving concurrent antidepressant and hypnotic treatment, antidepressants alone, and hypnotics alone. METHODS: Multivariate Cox proportional hazards regression models were used to determine the effects of antidepressants and hypnotics on dementia risk after adjusting for potential confounders. RESULTS: Compared with the reference group, patients receiving concurrent antidepressant and hypnotic treatment had the highest adjusted hazard ratio (aHR: 2.390, 95% CI: 2.224-2.536; P < 0.001) for all-cause dementia, followed by those receiving antidepressants alone (aHR: 1.919, 95% CI: 1.811-2.012; P < 0.001) and hypnotics alone (aHR: 1.458, 95% CI: 1.397-1.527; P < 0.001). With regard to dementia subtypes, trends similar to those for all-cause dementia were observed for Alzheimer's dementia, vascular dementia and other types of dementia. The sensitivity analysis conducted also found the robustness of findings. Notably, inconsistent findings were observed in subgroup with depression, revealing a null association between concurrent antidepressant and hypnotic treatment (aHR: 0.496; 95% CI: 0.183-1.343; P = 0.175) or hypnotics alone (aHR: 2.750; 95% CI: 0.797-9.482; P = 0.102) and the risk of dementia, and a negative association between antidepressants alone (aHR: 0.351; 95% CI: 0.130-0.942; P = 0.032) and the risk of dementia. CONCLUSION: A null or negative association was observed between concurrent antidepressant and hypnotic treatment, antidepressants alone, hypnotics alone, and the dementia risk in the subgroup of patients with depression, suggesting the absence of an association between dementia risk and antidepressants alone or hypnotics alone.

Dental restorative treatment expenditure and resource utilization in patients with chronic kidney disease: A nationwide population-based study.

BACKGROUND/PURPOSE: There is a variety of pathological alterations occurring in the oral cavity are strongly associated with chronic kidney disease (CKD) or CKD therapy. The aim of this study is to conduct a retrospective analysis to examine the possible correlation between the dental restorative treatment modalities and the progression of kidney disease in CKD population. MATERIALS AND METHODS: A total of 10,457 individuals were divided into three groups: (HC) group (n = 1438), high risk (HR) group (n = 3392), and CKD group (n = 5627). HR group were defined for those with an eGFR ≥60 (mL/min/1.73 m2) in addition to fulfilling one of the following requirements: (1) being diagnosed diabetes mellitus (DM), hypertension, or cardiovascular disease; (2) having a family member diagnosed with CKD or receiving dialysis treatment. Demographic characteristics, dental restorative treatment utilization and expenditures, including amalgam filling, composite resin filling on anterior teeth or posterior teeth, were analyzed retrospectively (2000-2008) among these groups using a nationwide database. RESULTS: The utilization and expenditures for various restorative treatments were significantly different among investigated groups, and the health insurance usage exhibited an inverse relationship with CKD stages, especially at CKD stages 4 and 5. A sustained decline in utilization and expenditures for restorative treatment was associated with the deterioration of kidney function. The lowest usage of these restorative modalities was noted in the CKD group and a marked difference was noted among investigated groups. CONCLUSION: The findings do, however, provide indirect evidence that if patients with progressive renal failure and receive less dental care.

The Association of Losartan and Ramipril Therapy With Kidney and Cardiovascular Outcomes in Patients With Chronic Kidney Disease: A Chinese Nation-Wide Cohort Study in Taiwan.

The aim of this nation-wide cohort study was to assess the association of using an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) therapy on the prognosis of hypertensive patients with chronic kidney disease (CKD). We used Cox's proportional hazard regression model to estimate hazard ratios (HRs) for the risk of end-stage renal disease (ESRD), all-cause mortality, cardiovascular mortality, and first hospitalization for cardiovascular disease (CVD) for losartan and ramipril versus conventional antihypertensive agents. In total, 136,266 hypertensive patients with CKD in Taiwan were followed up from 2001 to 2008. In an average follow-up of 5.9 years, 7364 (5.40%) patients reached ESRD, 4165 (3.06%) patients died, and 6163 (4.52%) patients had their first hospitalization for CVD. Use of losartan or ramipril was associated with a lower risk of the endpoints compared with the conventional group. In the losartan group, the risks of ESRD, all- and cardiovascular-cause mortality, and first hospitalization for CVD were decreased by 9.2% (P = 0.01), 24.6% (P < 0.001), 12.4% (P = 0.03), and 36.0% (P = 0.01), respectively. In the ramipril group, these risks decreased by 7.6% (P = 0.02) for ESRD, 56.9% (P < 0.001) for all-cause mortality, 7.5% (P = 0.04) for cardiovascular mortality, and 24.7% (P < 0.001) for first hospitalization. This study indicated that losartan and ramipril had distinct association on the prognosis of hypertensive patients with CKD, and was first to disclose that the mean time to reach each endpoint for patients in the losartan, ramipril, and conventional group was not significantly different. However, further study is needed to confirm results of the present study.

Use of traditional Chinese medicine (Ren Shen Yang Rong Tang) against microinflammation in hemodialysis patients: An open-label trial.

BACKGROUND: Complementary and alternative medicine such as traditional Chinese medicine (TCM) is now frequently used combined with Western medicine for treatment in chronic kidney disease (CKD). OBJECTIVE: We designed an open-label trial to investigate the safety and potential therapeutic effects of Ren Shen Yang Rong Tang (R-S-Y-R-T) in hemodialysis (HD) patients. METHODS: The experimental group was treated with additional R-S-Y-R-T combined with routine western medicine, while the control group was treated only with routine western medicine. The duration of study was 6 months. Primary outcomes were to evaluate the changes in serum hematocrit and albumin levels. Secondary outcomes including blood inflammatory markers (c-reactive protein [CRP], interleukin-6 [IL-6], and tumor necrosis factor-α [TNF-α]) were checked. Finally we also followed up the change of quality of life (QOL) in our subjects. RESULTS: Sixty nine respondents were enrolled in this trial. Finally a total of 59 patients (27 R-S-Y-R-T group, 32 control group) completed the 6-month follow-up. Primary outcomes showed no significant statistical change of hematocrit in either 2 group (P>0.05). But the R-S-Y-R-T group had a statistical increase in serum albumin (P<0.05). Secondary outcomes were that both TNF-α (P=0.003) and IL-6 (P=0.001) showed evident decrease in the R-S-Y-R-T group. CRP was identified without statistical difference in both groups (P=0.226). The R-S-Y-R-T group also had a significant improvement in QOL (P<0.05). CONCLUSIONS: Our study suggests that R-S-Y-R-T could decrease chronic inflammation and increase the life quality in HD patients. Further larger clinical trial of long-term treatment with R-S-Y-R-T is necessary for evaluating treatment use.

Impact of interaction of cigarette smoking with angiotensin-converting enzyme polymorphisms on end-stage renal disease risk in a Han Chinese population.

BACKGROUND: Several polymorphisms in the angiotensin-converting enzyme (ACE) and ACE2 genes are associated with the development of end-stage renal disease (ESRD). Certain genetic polymorphisms may modify the deleterious effects of environmental factors such as cigarette smoking and may also modify the inherited risk. We investigated the association of six ACE and ACE2 polymorphisms with ESRD to determine whether a relationship exists between gene-smoking interactions and ESRD. MATERIALS AND METHODS: We performed a case-control association study and genotyped 683 ESRD patients and 653 healthy controls. All subjects were genotyped for ACE (I/D, G2350A and A-240T) and ACE2 (G8790A, A1075G and G16854C) gene polymorphisms by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: Significant associations were observed between ACE I/D and G2350A polymorphisms and ESRD. There was no difference in ACE2 genotype distribution between ESRD patients and healthy controls. Haplotype analysis showed that DAA and DAT haplotypes were risk factors for ESRD. Moreover, a gene-environment interaction was observed between ACE I/D polymorphism and cigarette smoking. CONCLUSION: ACE I/D and ACE G2350A polymorphisms were associated with the development of ESRD. The interaction between ACE I/D polymorphism and smoking is also associated with an enhanced risk of ESRD.

A retrospective case-control analysis of the outpatient expenditures for western medicine and dental treatment modalities in CKD patients in Taiwan.

BACKGROUND: To determine if expenditures for dentistry (DENT) correlate with severity of chronic kidney disease (CKD). METHODS: A total of 10,457 subjects were enrolled from January 2008 to December 2010, divided into three groups: healthy control (HC) group (n = 1,438), high risk (HR) group (n = 3,392), and CKD group (n = 5,627). Five stages were further categorized for the CKD group. OPD utilization and expenditures for western medicine (WM), DENT, and TCM (traditional Chinese medicine) were analyzed retrospectively (2000-2008) using Taiwan's National Health Insurance Research Database. Three major areas were analyzed among groups CKD, HR and HC in this study: 1) demographic data and medical history; 2) utilization (visits/person/year) and expenditures (9-year cumulative expenditure, expenditure/person/year) for OPD services in WM, DENT, and TCM; and 3) utilization and expenditures for dental OPD services, particularly in dental filling, root canal and periodontal therapy. RESULTS: OPD utilization and expenditures of WM increased significantly for the CKD group compared with the HR and HC groups, and increased steadily along with the severity of CKD stages. However, overall DENT and TCM utilization and expenditures did not increase for the CKD group. In comparison among different CKD stages, the average expenditures and utilization for DENT including restorative filling and periodontal therapy, but not root canal therapy, showed significant decreases according to severity of CKD stage, indicating less DENT OPD utilization with progression of CKD. CONCLUSIONS: Patients with advanced CKD used DENT OPD service less frequently. However, the connection between CKD and DENT service utilization requires further study.

Angiotensin-converting enzyme insertion/deletion polymorphism contributes high risk for chronic kidney disease in Asian male with hypertension--a meta-regression analysis of 98 observational studies.

BACKGROUND: Associations between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphisms and chronic kidney disease (CKD) have been extensively studied, with most studies reporting that individuals with the D allele have a higher risk. Although some factors, such as ethnicity, may moderate the association between ACE I/D polymorphisms and CKD risk, gender-dependent effects on the CKD risk remain controversial. OBJECTIVES: This study investigated the gender-dependent effects of ACE I/D polymorphisms on CKD risk. DATA SOURCES: PubMed, the Cochrane library, and EMBASE were searched for studies published before January 2013. STUDY ELIGIBILITY CRITERIA PARTICIPANTS AND INTERVENTIONS: Cross-sectional surveys and case-control studies analyzing ACE I/D polymorphisms and CKD were included. They were required to match the following criteria: age >18 years, absence of rare diseases, and Asian or Caucasian ethnicity. STUDY APPRAISAL AND SYNTHESIS METHODS: The effect of carrying the D allele on CKD risk was assessed by meta-analysis and meta-regression using random-effects models. RESULTS: ETHNICITY [ODDS RATIO (OR): 1.24; 95% confidence interval (CI): 1.08-1.42] and hypertension (OR: 1.55; 95% CI: 1.04-2.32) had significant moderate effects on the association between ACE I/D polymorphisms and CKD risk, but they were not significant in the diabetic nephropathy subgroup. Males had higher OR for the association between ACE I/D polymorphisms and CKD risk than females in Asians but not Caucasians, regardless of adjustment for hypertension (p<0.05). In subgroup analyses, this result was significant in the nondiabetic nephropathy group. Compared with the I allele, the D allele had the highest risk (OR: 3.75; 95% CI: 1.84-7.65) for CKD in hypertensive Asian males. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: The ACE I/D polymorphisms may incur the highest risk for increasing CKD in hypertensive Asian males.

Gene polymorphisms of angiotensin-converting enzyme and angiotensin II type 1 receptor among chronic kidney disease patients in a Chinese population.

Chronic kidney disease (CKD) is highly prevalent in Taiwan and an increasing number of patients are affected, with a high risk of progression to end-stage renal disease and huge medical expenses. It has been predicted that the presence of hypertension increases with decreasing renal function due to a decrease in sodium excretion and activation of the renin-angiotensin system (RAS). The aim of this study was to investigate the influence of genetic variants of the RAS gene on CKD. We performed a case control association study and genotyped 135 CKD patients and 270 healthy controls among Han Chinese in Taiwan. All subjects were genotyped for angiotensinogen (AGT-M235T, T174M, A-20C), angiotensin-I converting enzyme (ACE-A2350G) and angiotensin II type 1 receptor (AGTR1-A1166C, C573T, C-521T) polymorphisms of RAS genes by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Significant associations were observed in ACE-A2350G and AGTR1-C573T polymorphism between CKD patients and controls. In regard to ACE-A2350G, compared with the AA genotype the GG genotype protected against CKD (adjusted odds ratio [OR] = 0.34; p = 0.01). In regard to AGTR1-C573T, the CT genotype was a risk for CKD compared with the CC genotype (adjusted OR = 1.82; p = 0.03). We conclude that ACE-A2350G and AGTR1-C573T polymorphisms are likely candidate determinants of CKD.