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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.

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.

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.

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.

Summary Background/Purpose Human oxoguanine-DNA glycosylase 1 (hOGG1) is the enzyme that has DNA repairing capacity. C1245 G substitution of the hOGG1 gene results in reduced enzyme activity. Peritoneal dialysis (PD) is known to cause oxidative DNA damage. We investigated the effect of hOGG1 polymorphism on the clinical outcomes of PD patients. Methods We studied the hOGG1 polymorphism in 441 new PD patients (232 men, age 56.6 ± 13.5 years). The patients were followed for 41.4 ± 18.2 months for cardiovascular events. Results For the entire cohort, there was no significant difference in the 5-year event-free survival between the CC and CG/GG groups (42.9% vs. 33.2%; p = 0.1). However, for patients with baseline serum C-reactive protein (CRP) levels ≤ 5.0 mg/L, 5-year event-free survival of the CC group was significantly better than that of CG/GG group (50.3% vs. 31.9%, p = 0.046). Multivariate analysis showed that hOGG1 polymorphism was an independent predictor of the survival (p = 0.008). In contrast, for patients with baseline CRP > 5.0 mg/L, there was no significant difference in 5-year event-free survival between the CC and CG/GG groups (26.7% vs. 30.2%, p = 0.9). Conclusion In PD patients with no systemic inflammation, hOGG1 1245CC genotype confers a survival benefit as compared to CG or GG genotype, but the protective effect disappears in patients with systemic inflammation. Our results suggest a complex interaction between hOGG1 and inflammation in the pathogenesis of cardiovascular disease in PD patients. 背景 人類oxoguanine-DNA glycosylase 1 (hOGG1)是一種具DNA修復能力的酵素，其酵素活動在hOGG1基因的C1245G替換後會有所下降。此外，腹膜透析(PD)已知會導致DNA的氧化性損害。本研究調查了hOGG1多態性對PD患者的影響。 方法 研究人員對441位剛開始接受PD的病人(男232人, 年齡56.6 ± 13.5歲)，作出hOGG1多態性的調查，並對心血管事件的發生進行共41.4 ± 18.2個月的追蹤。 結果 在整體病人中，CC與CG/GG組別之間在5年無事件存活率上無明顯差異(42.9% vs. 33.2%, p = 0.1)；然而，在基線血清C-反應蛋白(CRP)水平 ≤ 5.0 mg/L的病人中，CC組的5年無事件存活率明顯高於CG/GG組(50.3% vs. 31.9%, p = 0.046)。多變數分析顯示，hOGG1多態性是存活的獨立預測因子(p = 0.008)。相反，在基線CRP > 5.0 mg/L的病人中， CC與CG/GG組別之間在5年無事件存活率上並無明顯差異(26.7% vs. 30.2%, p = 0.9)。 結論 在不具系統性發炎的PD患者間，相比於CG或GG基因型，hOGG1 1245CC基因型具備若干的存活效益，但其效益並未出現於系統性發炎患者間。這些結果意味著，在PD患者的心血管致病過程中，hOGG1與發炎之間存在著複雜的交互關係。

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.

Atherosclerosis is an important medical problem of the 21st century, but traditional risk factors could only account for 50% of the problem. Hyperhomocysteinemia is emerging as an independent atherosclerosis risk factor, associated with folate deficiency, renal failure, and relative deficiency of MTHFR (C677T polymorphism) or other enzymes depending on gender, age, and smoking status. Hyperhomocysteinemia has been reported to occur in 11-22% of western people, in 3-5% of normal asymptomatic Chinese subjects aged 18-70 years in Hong Kong, Macau, Sydney, and San Francisco, 23-36% of Chinese in Hong Kong with premature coronary artery disease, and 29% of a nonselective series of coronary subjects in Hong Kong. Evidence is accumulating that documents its associations with atherosclerosis disease in both case-control observations and prospective cohort studies, in vitro experiments, and in vivo experimental models in both animals and human subjects, as well as the successful improvement by homocysteine-lowering of endothelial function as surrogate atherosclerosis endpoints in asymptomatic human and coronary patients (secondary prevention). A number of large scale homocysteine-lowering trials are currently underway for stroke and heart attacks prevention. Collectively these trials will include more than 65,000 patients at high-risk for cardiovascular and stroke events, and should provide a reliable evidence-base for prevention.

BACKGROUND Interaction of receptor for advanced glycation end products (RAGE) with advanced glycation end products (AGEs) is an important pathogenic mechanism of diabetic complications. Three mutations in the promoter region of the RAGE gene (T-429C, T-374A and a 63 bp deletion spanning from -407 to -345 nucleotides) were known to have increased transcriptional activities. We investigated the relationship between these polymorphisms and the risk of cardiovascular diseases in Chinese subjects with overt diabetic nephropathy. METHODS A total of 219 Type 2 diabetic subjects with nephropathy were recruited. Genotyping of the three polymorphisms in the genomic DNA was done by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Patients were followed for 8 years for the development of cardiovascular events and survival. RESULTS The T-429 C and T-374 A polymorphism had no effect on the event-free survival of the subjects. For the 63 bp deletion polymorphism, the event-free survival was 37.0% and 63.2% at 96 months for del-/- and del-/+ genotypes, respectively (log-rank test, p = 0.034). After adjusting for confounders, the 63 bp deletion polymorphism had a marginal effect on event-free survival (adjusted hazard ratio: 3.517, 95% CI: 0.852 - 14.521, p = 0.082). Subjects without any mutation of the three polymorphisms have significantly higher risk of first ischemic heart disease than those with any of the three mutations (adjusted hazard ratio: 0.218, 95% CI: 0.062 - 0.764, p = 0.017). CONCLUSION The 63 bp del-/+ genotype of the RAGE gene has a marginal benefit on the cardiovascular event-free survival in subjects with diabetic nephropathy. Subjects with any of the three mutations have a lower risk of ischemic heart disease. The role of RAGE in the pathogenesis of cardiovascular disease in diabetic patients requires further study.

SUMMARY: 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.

Background: Peroxisome proliferator-activator receptor-gamma (PPAR-γ) is a nuclear receptor that serves important roles in intermediate metabolism. We examined the relationship between two PPAR-γ 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-γ 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-γ gene are important predictors of cardiovascular event in patients with diabetic nephropathy. Further studies are needed to examine the interaction of PPAR-γ gene polymorphisms and thiazolidinedione treatment on the cardiovascular risk in this group of patients.

Environmental and genetic factors may both affect the risk of vascular cognitive impairment developing after a stroke. To identify factors affecting this risk, the cognitive status of 121 patients was examined 3 months after an ischemic stroke. In all patients and in 270 control subjects, 7 polymorphisms reported to affect risk of vascular ischemic disease were genotyped. In 51 patients (42.1%), vascular cognitive impairment resulted, defined by a Mini-Mental State Examination score of less than 24. These patients were older and more likely to be women. Alleles of none of the polymorphisms differed between patients with or without vascular cognitive impairment, except for glutamate-cysteine ligase modifier (GCLM) (odds ratio = 2.8, P = .006). When all stroke patients were considered, the GCLM genotype did not affect Mini-Mental State Examination scores. Testing the GCLM genotype in an independent group of stroke patients may determine whether this association with vascular cognitive impairment is genuine. ( J Geriatr Psychiatry Neurol 2007;20:93-99)

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.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.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.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.

Vascular endothelial growth factor (VEGF) plays a pivotal role in the capillary endothelial cell growth and proliferation and has known effects on glomerular microvascular permeability. Because certain VEGF polymorphisms are correlated with alterations in VEGF expression, we hypothesized that VEGF genetic polymorphisms may affect the renal survival and progression of primary IgA nephropathy.The study population consisted of 195 biopsy-proven IgA nephropathy patients at our center between 1984 and 2004. VEGF genotype polymorphism at -2578 positions was determined from peripheral blood leukocytes DNA using polymerase chain reaction methodologies. The primary end point was kidney survival as measured by the time interval from renal biopsy to end-stage renal disease or the requirement of renal replacement therapy.In total, we studied 119 women (61%) and 76 men (39%), with a mean age of 35 +/- 10 yr at the time of renal biopsy. Observed genotype frequency was 55.6%, 38.8%, and 5.1% for CC, CA, and AA genotypes respectively. Baseline characteristics did not differ significantly between three genotype groups for patient age, sex, prevalence of hypertension, degree of proteinuria, initial serum creatinine concentration, and the histological grading. After a median follow-up period of 11 yr, doubling of the baseline serum creatinine occurred in 107 of them; 99 patients reached end-stage renal disease requiring renal replacement therapy with a median renal survival of 88 months. The kidney survival in the CC genotype subgroup was similar to that of the CA/AA genotype subgroup during the first 2 yr but became worse than the latter thereafter (log-rank test P = 0.023). The kidney survival rates at the end of 6 yr were 76.8% in the CA genotype, 67.0% in the CC, and 50.0% in the AA genotype groups. Unadjusted hazard ratio of developing end-stage renal disease was 2.65 (95% CI, 1.16 to 6.06) for the CC group as compared to the CA/AA group. The influence of VEGF genotype upon renal survival, however, was not significant after multivariate Cox regression analysis.Our preliminary results raise the concern that the CC genotype of the VEGF promoter at -2578 position might be associated with increased risk of renal progression in patients with IgA nephropathy.

Cytokine transforming growth factor (TGF) is involved in regulation of tissue repair after injury. More recently, TGF-beta1 codon 10 gene polymorphism has been shown to be associated with circulating TGF-beta levels. We tested whether TGF-beta1 genotype polymorphism was predictive of renal allograft function decline.The study population consisted of 129 consecutive cadaveric or living related renal transplant recipients at our center between 1985 and 2001. The recipient TGF-beta1 genotype polymorphism was determined from peripheral blood leucocytes DNA. The primary endpoint was rate of glomerular filtration rate decline between the first year and the third year of transplant.Baseline glomerular filtration rate as estimated by MDRD study equation at 1 year measured 50+/-17 mL/min/1.73 m2. At the end of the 3-year follow-up period, 52 patients (40%) experienced biopsy-confirmed acute rejections. Frequency and severity of allograft rejection did not differ with TGF-beta genotypes. However, the decline in glomerular filtration rate was significantly greater in Leu/Leu (TT) than Leu/Pro (CT) recipients, 6.3+/-16.9 mL/min/1.73 m2 versus 0.1+/-10.2 mL/min/1.73 m2, p=0.04.Our results demonstrate that recipient TGF-beta1 codon 10 Leu/Leu homozygosity is a potential risk factor of kidney allograft function decline.

Genetic polymorphism of VEGF: Impact on longitudinal change of peritoneal transport and survival of peritoneal dialysis patients. Background Vascular endothelial growth factor (VEGF) plays a pivotal role in the peritoneal angiogenesis and hyperpermeability in patients on peritoneal dialysis. We hypothesis that VEGF genetic polymorphism may affect the longitudinal change of peritoneal transport and clinical outcome of peritoneal dialysis patients. Methods We studied 135 consecutive new peritoneal dialysis patients. VEGF genetic polymorphism at –1154 and –2578 positions were determined by polymerase chain reaction (PCR) methodologies. Standard peritoneal test and dialysis adequacy and transport test (DATT) were performed at the initiation of peritoneal dialysis. After 12 months, DATT was repeated in 83 patients. In 35 patients, VEGF production in vivo was determined by its levels in serum and peritoneal dialysis effluent, and mRNA expression in peritoneal dialysis effluent. Patients were followed for 19.4 ± 8.5 months for survival study. Results There was no relation between VEGF genotype and baseline peritoneal transport group. The changes in 24-hour dialysate-to-plasma (D/P) creatinine after 12 months were 0.028 ± 0.159, -0.013 ± 0.137, and 0.141 ± 0.231 for CC, CA, and AA genotype at –2578 position, respectively [one-way analysis of variance (ANOVA), P = 0.028]. The AA genotype had significantly higher increase in 24-hour D/P creatinine than the other genotypes. Similar results were found with the genotype at -1154 position, which had marked linkage disequilibrium with the genotype at –2578 position. Actuarial patient survival was 90.3% and 74.9% at 24 months for CC and CA/AA genotypes at –2578 position, respectively (P = 0.036). After correcting for confounding covariates, the adjusted hazard ratio of death was 3.04 (95% CI, 1.10 to 8.36) for the CA/AA group as compared to CC group. Although baseline serum VEGF level was higher in patients with CC genotype than those with CA/AA genotype at –2578 position (541.5 ± 322.8 pg/mL vs. 298.8 ± 209.4 pg/mL, P = 0.012), VEGF mRNA expression in peritoneal dialysis effluent was significantly lower in patients with CC genotype (1.82 ± 2.77 vs 4.48 ± 3.28, P = 0.021). VEGF protein level in peritoneal dialysis effluent was also marginally lower in patients with CC genotype, although the difference was not significant. Genotype at –1154 position was not associated with VEGF production in vivo or patient survival. Conclusion We conclude that in peritoneal dialysis patients, the AA genotype of VEGF promoter at –2578 position was associated with progressive increase in peritoneal transport. The CA/AA genotype at –2578 position was also associated with an excess mortality. Our finding also suggests that systemic and local peritoneal VEGF production may be differentially regulated.

Association of transforming growth factor-beta (TGF-β) T869C (Leu 10Pro) gene polymorphisms with type 2 diabetic nephropathy in Chinese.IntroductionTransforming growth factor-β (TGF-β) is known to play a pivotal role in the regulation of extracellular matrix (ECM) accumulation. Since diabetic nephropathy (DMN) is characterized by basement membrane thickening and mesangial expansion, control of ECM deposition is believed to be important in the pathogenesis of the disease. Recently, TGF-β T869C (Leu 10Pro) gene polymorphism has been identified which may be associated with circulating TGF-β levels.MethodsIn order to examine the relationship between TGF-β gene polymorphism with DMN in Chinese, we carried out a case-control study, which recruited 123 Chinese type 2 diabetic patients with an average duration of diabetes for 12 years. A total of 58 patients who developed DMN (micro- or macroalbuminuria, with or without renal impairment) were compared with 65 diabetic patients without DMN despite similar duration of disease (normoalbuminuric and creatinine

Background. Plasma level of plasminogen activator inhibitor (PAI)-1 is genetically determined by a polymorphism in the promoter region, involving two alleles, 4G and 5G. Plasma PAI-1 concentrations are higher in subjects homozygous for the 4G allele than other genotypes (5G/5G and 4G/5G). Such genetic variation in fibrinolytic system may affect the long-term renal transplant outcome. Methods. We determined PAI-1 4G/5G-promoter genotype polymorphism among our renal transplant recipients between 1985 and 2001. Primary event was defined as doubling of baseline serum-creatinine level. Results. Over a median period of 79 months, 130 patients with 132 kidney grafts were assessed. Baseline clinical variables were comparable among three genotype groups. There was no association between primary event and PAI-1 genotype among the entire cohort. However, among subjects with prior acute rejection episodes, those homozygous for 4G had significantly higher risk of serum creatinine doubling than the other two genotypes (relative risk 2.45, 95% confidence interval 1.19–5.04). PAI-1 genotype does not predict primary events in patients without rejection (relative risk 0.57, 95% confidence interval 0.07–4.17). Conclusions. PAI-1 4G/5G-promoter polymorphism modulates the risk of renal transplant outcomes after acute rejection(s). Recipients homozygous for PAI-1 4G allele have a higher risk of progressive renal damage after acute rejection episode(s). PAI-1 promoter polymorphisms are potentially important determinants of renal response to rejection.

T-cell receptor (TCR) proteins recognize a complex of an antigen-derived peptide bound to the cell surface products of the major histocompatibility complex (MHC) that could be of importance in the immunopathogenesis of IgA nephropathy (IgAN). Previous studies found no difference on TCR constant beta chain gene frequencies in IgAN compared with control. Yet no study on the TCR alpha gene in IgAN was reported. We studied the TCR C alpha gene polymorphisms by restriction fragment length polymorphism (RFLP) in 53 patients with IgAN and in comparison with 67 healthy controls. The patients were also classified into different histopathological grading (I, II, and III with increasing histological severity) and renal functions. The extracted DNA were digested with Taq I enzymes and probed with a full-length TCR-alpha cDNA clone p1.2alpha probe. A 7-kb C-alpha Taq 1 fragment is found in 32 of 53 patients (60.3%) compared with 26 of 67 controls (38.8%) (P0.05). There was no association of any polymorphic fragment, including the 7-kb fragment, with either the histological grading or renal function. It is concluded that the TCR C-alpha gene is associated with IgAN but not with the prognosis of the disease.

We investigated the total cell count and cell population of the overnight peritoneal dialysis effluent (PDE) by flow cytometry in 76 stable continuous ambulatory peritoneal dialysis (CAPD) patients. The mean percentage of mesothelial cells and macrophages was 4.4% and 57%, respectively. A higher percentage of dead cells among the mesothelial cells compared with other cell populations in the PDE was observed. Peritoneal transport properties were studied in every patient by determining the dialysate to plasma ratio of creatinine concentration (D/P) at the fourth hour of the peritoneal equilibration test, and the mass transfer area coefficient of creatinine (MTACCr) or glucose. Cancer antigen 125 (CA125), suggested as a bulk marker for the mesothelial mass in stable peritoneal dialysis patients, was determined in the PDE. No correlation was demonstrated between CA125 and the number of mesothelial cells, lymphocytes, or macrophages in the PDE. A significant correlation was observed between CA125 and different parameters of peritoneal transport (D/P and MTACCr). On the contrary, neither the history of peritonitis nor the duration of CAPD appeared to affect the CA125 concentration in the PDE. The lack of correlation between CA125 in the PDE and the duration of CAPD may be related to the early loss of peritoneal transport properties as a result of the use of hypertonic dialysate in the majority of our patients with small-volume CAPD (3 x 2 L daily exchange). Our findings suggest that CA125 may not necessarily correlate well with the number of mesothelial cells in PDE. In patients with vanishing of the mesothelial layer, the measurement of CA125 (as a bulk marker for the mesothelial mass in the peritoneum) may reflect the change of peritoneal transport properties.

Summary 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.

Background: Pre-clinical studies showed that carnosine may have a beneficial cardiovascular effect. We studied the effect of tri-nucleotide repeat (CTGs) polymorphisms in exon 2 of the CNDP1 gene, which codes for carnosinase and is responsible for the degradation of carnosine, on the clinical outcome of Chinese peritoneal dialysis (PD) patients. Methods: We studied 442 PD subjects. Genotyping was done by direct sequencing of genomic DNA. Patients were followed for 43.5 ±16.2 months. Results: The prevalence of 6-6, 5-6, 5-5 and 4-6 CTGs genotypes was 80.3%, 18.6%, 0.9% and 0.2%, respectively. A total of 270 patients (61.1 %) developed the primary composite end point during follow-up. The 5-year event-free survival of the 6-6 CTGs and non 6-6 group was 37.1% and 21.3%, respectively (log rank test, p = 0.3). Conclusion: The CTGs polymorphism of the CNDP1 gene does not affect survival of Chinese PD subjects. The role of carnosine and CNDP1 gene polymorphism in the pathogenesis of cardiovascular disease requires further study.

Aim: Activation of β1-adrenergic receptor (β1AR) enhances contractility and heart rate. The polymorphism Arg389Gly in the β1AR 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 β1AR 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 β1AR Arg389Gly polymorphism is not an independent predictor of cardiovascular events in subjects with overt diabetic nephropathy.

Background The histology and function of the kidney deteriorates with age and progressive renal failure, but the mechanisms involved in renal ageing are not known. In vitro studies suggest that telomere shortening is important in replicative senescence, and is accelerated by stress factors that increase replication. We investigated whether IgA nephropathy, a prototype chronic kidney disease, is associated with localized intrarenal cellular ageing. Methods We studied the mean length of terminal restriction fragments (TRF), a measure of average telomere size, in the DNA of peripheral blood mononuclear cells and urinary sediment of 15 patients with IgA nephropathy. Results The mean TRF lengths in peripheral blood is 7043.8 +/- 1 182.8 base pairs, and in urinary sediment is 6 749.7 +/- 636.5 base pairs. The mean TRF lengths of urinary DNA significantly correlate with the serum creatinine (r = -0.525, p = 0.044) and estimated glomerular filtration rate (GFR) (r = 0.651, p = 0.009). The mean TRF lengths of urinary DNA had an insignificant inverse correlation with patient age (r = -0.364, p = 0.2), and do not correlate with the degree of glomerulosclerosis (r = 0.004, p = 0.9) or tubulointerstitial scarring in renal biopsy (r =-0.032, p = 0.9). After 30 months of follow-up, the rate of decline of estimated GFR has an inverse correlation with the mean TRF lengths of urinary DNA (r = -0.699, p = 0.004). The TRF lengths of peripheral blood DNA do not correlate with any clinical or histological parameter or the rate of renal function decline. Conclusions Although this is a pilot study, our observation indicates that the TRF lengths of genomic DNA extracted from urinary sediment is related to the degree of renal impairment. However, a long telomere length of genomic DNA in urinary sediment is associated with a more rapid decline of renal function. Our findings might be relevant to the pathogenesis of progressive renal failure.

The 5,10-methylenetetrahydrofolate reductase ( MTHFR ) gene 677C --T polymorphism causes an A222V amino acid change which affects MTHFR enzyme activity and can increase homocysteine, a vascular disease risk factor. This polymorphism was examined for association with stroke. In a case-control study of 241 ischemic stroke patients and 304 controls in Hong Kong, the V allele increased in stroke [28% vs. 20%, odds ratio (OR) 1.5, p=0.003]. A lack of significance for the increase in the VV genotype (7.5% vs. 4.6%, OR 1.7, p = 0.16) may be due to its rarity in this region. V -allele carriers had more severe strokes (according to the NIH stroke scale). The association of the V allele with stroke occurred mostly in women or older subjects and was due to decreasing V allele frequency with age, as seen in other studies. This V frequency decline with age might be due to a loss of V -carrying controls from a higher risk of cancer, vascular disease, bone fracture, and kidney failure when folate is sparse. Examination of previous studies revealed that the association of VV genotype with stroke appeared stronger in Japan than elsewhere, possibly due to dietary differences. Perhaps folate supplementation for stroke prevention would particularly benefit VV individuals in such high-risk regions.

There is evidence that type 1 plasminogen activator inhibitor (PAI-1) may have an important role in peritoneal function. We studied the effect of physiologically relevant PAI-1 promotor polymorphisms on peritoneal permeability. We performed a standard peritoneal equilibration test (PET) in 100 new continuous ambulatory peritoneal dialysis (CAPD) patients. We studied another 48 prevalent CAPD patients who had a baseline PET performed 2 years before; a standard PET was repeated on enrollment. The PAI-1 promotor polymorphism was examined. All patients then were followed up for 16.7 ± 15.0 months. Prevalences of 4G/4G, 4G/5G, and 5G/5G genotypes were 31.8%, 46.6%, and 21.6%, respectively. Of the 100 new CAPD patients, there was no difference in net ultrafiltration (UF), dialysate-plasma (D/P) creatinine ratio at 4 hours, or mass transfer area coefficient (MTAC) of creatinine among the three genotype groups. D/P creatinine ratios at 4 hours were 0.595 ± 0.133, 0.607 ± 0.137, and 0.627 ± 0.142 for the 4G/4G, 4G/5G, and 5G/5G groups, respectively (one way analysis of variance, P = 0.715). Of the 48 prevalent patients, PAI-1 genotype did not affect the longitudinal change in net UF, D/P creatinine ratio at 4 hours, or MTAC of creatinine. During follow-up, 16 patients developed peritonitis episodes that required Tenckhoff catheter removal. One patient died, 8 patients returned to long-term CAPD therapy after peritonitis resolved, and the other 7 patients developed peritoneal failure and were switched to long-term hemodialysis therapy. PAI-1 promotor genotype did not predict peritoneal failure after an episode of severe peritonitis (chi-square test, P = 0.328). We conclude that PAI-1 promotor polymorphism is not associated with peritoneal transport characteristics in stable peritoneal dialysis patients, longitudinal change in peritoneal transport, or development of peritoneal failure after an episode of severe peritonitis. © 2002 by the National Kidney Foundation, Inc.

Background. Epidemiological studies have suggested a link between chronic Helicobacter pylori infection and ischemic heart disease but the underlying mechanism remains elusive. We hypothesized that H. pylori-associated chronic gastritis causes impairment of absorption of vitamin cofactors that are essential in the metabolism of homocysteine and results in hyperhomocysteinemia. Materials and Methods. Forty-nine dyspeptic patients were studied. H. pylori infection was defined by rapid urease test and histology. Fasting serum homocysteine level, which was measured by a validated commercial fluorescence polarization immunoassay, was correlated with H. pylori infection statuses and gastric histology. H. pylori-infected patients were followed up for 24 weeks post eradication for changes in serum homocysteine concentration. Results. Univariate analyses showed that serum homocysteine level correlated with increasing age (p

Immunoglobulin A nephropathy (IgAN) is characterized by raised serum IgA and predominant mesangial IgA deposits of polymeric nature. The abnormal glycosylation of the carbohydrate moieties in the hinge region of the IgA molecule has recently attracted much attention. In this study we investigated the galactosylation and sialylation of monomeric and polymeric IgA1 isolated from patients with IgAN. Total IgA1 in serum samples from patients with IgAN or from healthy controls was isolated with a jacalin-agarose column as jacalin-bound protein (JBP). Monomeric and polymeric IgA1 were distinctly separated by fast protein liquid chromatography. Lectin binding assays were designed to examine the sialylation and the expression of terminal galactose and N-acetyl galactosamine of the O-linked carbohydrate in the hinge region of the IgA molecule. Reduced terminal galactosylation was demonstrated in serum IgA and monomeric IgA1 isolated from patients with IgAN as compared with results in healthy control subjects. However, a reduction in terminal galactosylation was not found in polymeric IgA1 isolated from patients with IgAN. Instead, increased sialylation of IgA1 (alpha2-3 linked to galactose) was demonstrated in polymeric IgA1. This abnormality of IgA1 could bear considerable implication on the pathogenesis of IgAN, because the masking effect of sialic acid may hinder the clearance of polymeric IgA1 by the asialoglycoprotein receptor (ASGP-R) of the liver cells. An increase in the sialylated content would also render the polymeric IgA from patients with IgAN more anionic. These immunochemical properties may contribute to the selective glomerular deposition of polymeric IgA1 in IgAN.

Association of plasminogen activator inhibitor-1 4G/4G genotype and type 2 diabetic nephropathy in Chinese patients.BackgroundPlasminogen activator inhibitor-1 (PAI-1) is a key regulator of fibrinolytic pathway and extracellular matrix (ECM) turnover. Because diabetic nephropathy is characterized by the presence of basement membrane thickening and mesangial expansion, we examined the role of PAI-1 gene polymorphisms in the development of type 2 diabetic nephropathy. Evidence also suggested that the PA/plasmin system and the renin-angiotensin system (RAS) interact together to affect the risk of fibrosis and thrombosis. Hence, we also studied the synergistic effect between PAI-1 and angiotensin-converting enzyme (ACE) gene polymorphisms.MethodsThe PAI-1 and ACE (D/I) gene polymorphisms were examined in a cohort of Chinese type 2 diabetic patients who had diabetes for an average of 14 years. These patients were sex and age matched. Group A (N = 46) consisted of patients without diabetic nephropathy (normoalbuminuric with creatinine