Adiponectin in renal disease: relationship to phenotype and genetic variation in the gene encoding adiponectin

BACKGROUND: The prevalence of cardiovascular disease (CVD) and inflammation is high in patients with end-stage renal disease (ESRD). Adiponectin is an adipocytokine that may have significant anti-inflammatory and anti-atherosclerotic effects. Low adiponectin levels have previously been found in patients with high risk for CVD. METHODS: In a cohort of 204 (62% males) ESRD patients aged 52 +/- 1 years the following parameters were studied: presence of CVD, body composition, plasma adiponectin (N= 107), cholesterol, triglycerides, HDL-cholesterol, serum leptin, high-sensitivity C-reactive protein (hs-CRP), urinary albumin excretion (UAE), and single-nucleotide polymorphisms (SNPs) in the apM1 gene at positions -11391, -11377, 45, and 276. Thirty-six age- (52 +/- 2 years) and gender-matched (64% males) healthy subjects served as control subjects. RESULTS: Markedly (P < 0.0001) elevated median plasma adiponectin levels were observed in ESRD patients (22.2 microg/mL), especially type 1 diabetic patients (36.8 microg/mL), compared to control subjects (12.2 microg/mL). Log plasma adiponectin correlated to visceral fat mass (R=-0.29; P < 0.01) and Log hs-CRP (R=-0.26; P < 0.01). In a stepwise (forward followed by backward) multiple regression model only type-1 diabetes (P < 0.001) and visceral fat mass (P < 0.05) were independently associated with plasma adiponectin levels. The adiponectin gene -11377 C/C genotype was associated with a lower prevalence of CVD (25 vs. 42%) compared to the G/C genotype. CONCLUSION: The present cross-sectional study demonstrates that, whereas genetic variations seem to have a minor impact on circulating adiponectin levels, lower visceral fat mass and type 1 diabetes mellitus are associated with elevated plasma adiponectin levels in ESRD patients. Furthermore, low levels of adiponectin are associated with inflammation in ESRD.     

Plasma adiponectin concentration before and after successful kidney transplantation

BACKGROUND: Adiponectin, a protein secreted exclusively by adipocytes, is presumed to be involved in the pathogenesis of atherosclerosis and insulin resistance. An elevated plasma adiponectin concentration was found in ESRD patients on hemodialysis (HD). However, the role of kidneys in adiponectin biodegradation/elimination is unknown. Therefore, we assessed plasma adiponectin concentrations in ESRD patients before and after successful kidney transplantation. METHODS: Among 44 hemodialyzed patients (29 men, 15 women; mean age 39 +/- 11 years; mean body mass index [BMI] 23.6 +/- 3.5 kg/m(2); mean duration of HD treatment before kidney transplantation 27 +/- 26 months), plasma adiponectin concentrations and insulin resistance indices (HOMA-R) were measured twice: immediately before kidney transplantation (Tx) and 1-2 days before patient discharge from the hospital with stable kidney transplant function (mean serum creatinine level 191 +/- 105 micromol/L). The control group consisted of 22 normotensive healthy subjects (12 men, 10 women). RESULTS: Among uremic patients, before Tx, plasma adiponectin concentrations were significantly higher than in healthy subjects (20.8 +/- 8.3 vs 8.7 +/- 4.8 microg/mL; P <.001) After successful Tx, plasma adiponectin concentrations decreased significantly (20.8 +/- 8.3 vs 15.7 +/- 7.0 microg/mL before and after Tx, respectively; P <.001). Simultaneously, after successful kidney transplantation, an increase in HOMA-R was observed (1.01 +/- 0.61 vs 1.43 +/- 0.83; P =.002). However, changes in adiponectinemia did not significantly correlate with serum creatinine or HOMA-R. CONCLUSION: The kidneys seem to play an important role in adiponectin biodegradation and/or elimination.     

Association of TGF-beta1 polymorphisms with chronic renal disease

BACKGROUND: Transforming growth factor beta1 (TGF-beta1) plays an important role in tissue fibrosis and has been found to participate in cardiovascular disease (CVD). This study aimed to evaluate the association of TGF-beta1 polymorphisms with chronic renal disease (CRD), and its progression to dialysis in a retrospective longitudinal study of an end-stage renal disease (ESRD) cohort. METHODS: The Arg/Pro (codon 25) and Leu/Pro (codon 10) polymorphisms were genotyped in 104 ESRD patients aged 64 +/- 14 yrs (mean +/- SD), 62 males, and in 104 matched controls. RESULTS: The genotype distribution of Leu10Pro and Arg25Pro polymorphisms was different between patients and controls: Leu/Leu, Leu/Pro, Pro/Pro: 0.35, 0.50, 0.15 vs. 0.30, 0.24, 0.46 (p=0.001) and Arg/Arg, Arg/Pro, Pro/Pro: 0.79, 0.21, 0 vs. 0.87, 0.10, 0.03 (p=0.019). Similarly, haplotypes constructed with the combination of both polymorphisms were different among groups. There were no differences in CRD progression rate among genotypes. Codon 10 Leu allele was associated with the presence of clinical CVD in the ESRD patients (Leu/Leu, Leu/Pro, Pro/Pro: with CVD 0.49, 0.49, 0.02 vs. without CVD 0.27, 0.51, 0.22 (p=0.01). Combined polymorphism haplotypes were also significantly different between ESRD patients with and without CVD. This association was independent from other risk factors. CONCLUSIONS: TGF-beta1 polymorphisms are associated with ESRD, particularly in patients with associated clinical CVD, and could be useful as genetic markers of CRD and higher cardiovascular risk.     

Malnutrition-inflammation-atherosclerosis (MIA) syndrome components in hemodialysis and peritoneal dialysis patients

BACKGROUND: Malnutrition, inflammation, and atherosclerosis (MIA syndrome) are common in end-stage renal disease (ESRD) patients. Each component of MIA syndrome is the predictor of outcomes in ESRD patients. In this cross-sectional study, we aimed to compare both dialysis modalities for MIA syndrome components. MATERIAL AND METHODS: Thirty hemodialysis (HD) (mean age 44 +/- 11 years, 14 male and 16 female, mean time on dialysis: 31.0 +/- 19.0 months) and 30 continuous ambulatory peritoneal dialysis (CAPD) patients (41 +/- 9 years, 12 male and 18 female, mean time on dialysis: 25.5 +/- 21.5 months) were included. In order to determine malnutrition in ESRD patients, serum albumin level and anthropometric measurements were used. For inflammation, serum C-reactive protein level, erythrocyte sedimentation rate, and fibrinogen levels were measured. Mean-carotid artery intima media thickness (m-CIMT), presence of carotid plaque and serum homocysteine level were used to determine atherosclerosis. RESULTS: Five CAPD patients (16%) and one HD patient (3%) was hypoalbuminemic. HD and CAPD groups were similar for inflammation. Mean-CIMT and serum homocysteine level were higher in HD patients than CAPD patients. There was a positive correlation between homocysteine and m-CIMT. CONCLUSION: Before choosing renal replacement therapy, malnutrition, inflammation, and atherosclerosis parameters must be investigated in ESRD patients. Hemodialysis seems to be more advantageous for malnutrition components than CAPD. Both dialysis modalities seem to be similar for inflammation, and CAPD modality has superiority for atherosclerosis. Before choosing the type of renal replacement therapy, assessment of MIA syndrome components could be useful for individualization of the decision on which dialytic modality is appropriate in ESRD patients.     

Hyperhomocysteinemia, diabetes mellitus, and carotid atherosclerosis independently increase atherosclerotic vascular disease outcome in Japanese patients with end-stage renal disease

BACKGROUND: Patients with end-stage renal disease (ESRD) have high mortality from atherosclerotic/atherothrombotic vascular disease (AVD). However, the role of an elevated plasma total homocysteine (tHcy) level as a risk factor is uncertain in ESRD. METHODS: We enrolled 55 ESRD patients in a prospective follow-up study in order to evaluate the prognostic significance of their tHcy levels, common methylenetetrahydrofolate reductase (MTHFR) gene polymorphism, and other atherosclerotic risk factors, in combination with the results of B mode ultrasound for carotid arteries. RESULTS: Mean intima-media thickness of the common carotid artery (CCA-IMT) in ESRD patients was thicker than that in 102 age- and sex-matched healthy controls. Carotid plaque was more frequently present in patients compared with controls, as was calcified plaque more common in patients (p < 0.001). Plasma tHcy levels (mean +/- SD) in patients (39.1 +/- 27.2 nmol/ml) were higher than that (8.8 +/- 2.7 nmol/ml) in controls (p < 0.001). Folic acid was the major determinant of elevated tHcy levels in ESRD patients. During the follow-up period of 31 +/- 3 months, 14 patients had one or more AVD complications, and 10 consequently died from AVD causes. Proportional hazards modeling showed that 5-year intervals of age (relative risk of 2.95, 95% CI 1.62 - 5.37), 10 nmol/ml intervals of tHcy levels (relative risk of 2.31, 95% CI 1.31 - 4.08), and presence of diabetes mellitus (relative risk of 6.62, 95% CI 1.07 +/- 40.8) were independent predictors of future AVD events, and tHcy levels (relative risk of 2.67, 95% CI 1.29 - 5.52) and age (relative risk of 2.10, 95% CI 1.15 - 3.83) were those of AVD mortality. We also found a significant association between carotid plaque prevalence and AVD events (X(2) = 11.6, p = 0.001). CONCLUSION: Hyperhomocysteinemia, diabetes mellitus, and carotid atherosclerosis appeared to contribute independently to increase the risk of AVD outcome in Japanese patients with ESRD.     

Inflammation in end-stage renal disease: sources,consequences, and therapy

Cardiovascular disease (CVD) remains the main cause of morbidity and mortality in patients with end-stage renal disease (ESRD). Although traditional risk factors are common in ESRD patients, they alone may not be sufficient to account for the high prevalence of CVD in this condition. Recent evidence demonstrates that chronic inflammation, a nontraditional risk factor which is commonly observed in ESRD patients, may cause malnutrition and progressive atherosclerotic CVD by several pathogenetic mechanisms. The causes of inflammation in ESRD are multifactorial and, while it may reflect underlying CVD, an acute-phase reaction may also be a direct cause of vascular injury by several pathogenetic mechanisms. Available data suggest that proinflammatory cytokines play a central role in the genesis of both malnutrition and CVD in ESRD. Thus it could be speculated that suppression of the vicious cycle of malnutrition, inflammation, and atherosclerosis (MIA syndrome) would improve survival in dialysis patients. Recent evidence has demonstrated strong associations between inflammation and both increased oxidative stress and endothelial dysfunction in ESRD patients. As there is not yet any recognized, or even proposed, treatment for ESRD patients with chronic inflammation, it would be of obvious interest to study the long-term effect of various anti-inflammatory treatment strategies on the nutritional and cardiovascular status as well as outcome in these patients.     

A comparative analysis of nutritional parameters as predictors of outcome in male and female ESRD patients.

BACKGROUND: Many patients with end-stage renal disease (ESRD) are malnourished and cross-sectional studies show that markers of malnutrition may predict death. Serum albumin (S-albumin), the commonest nutritional marker, has been criticized because it is so closely related to the effects of inflammation and other non-nutritional factors. Consequently, we need other nutritional markers that can predict outcome. However, males and females differ as regards body composition and it is not known how this may influence the predictive power of different nutritional markers. METHODS: In 206 ESRD patients (126 males) aged 52+/-1 years, we evaluated the relationship between survival and five estimates of nutritional status (S-albumin, subjective global assessment (SGA), lean body mass (LBM), body fat mass (FM) assessed by dual-energy X-ray absorptiometry, and handgrip strength (HGS)) close to start of renal replacement therapy (RRT). The patients were also classified as regards the presence of cardiovascular disease (CVD), diabetes mellitus (DM), and inflammation (CRP> or = 10 mg/l). Mortality was monitored over mean follow-up period of 37+/-2 months. RESULTS: In the whole patient group, the presence of CVD, DM, inflammation, and malnutrition (SGA >1) close to start of RRT all predicted poor outcome. However, whereas inflammation strongly predicted (P<0.0001) poor outcome in males, no such effect was observed in females. Also, differences were found between males and females regarding the predictive value of the five different nutritional estimates. Whereas HGS, SGA, and S-albumin independently predicted poor outcome in males, only SGA predicted outcome (independently of age, CVD, and DM) in females. CONCLUSIONS: Mild to moderate malnutrition, as assessed by SGA, was present in 39% of the patients and predicted outcome independently of age and co-morbidity in both males and females. However, the predictive power of various other nutritional markers differed markedly between male and female patients. Whereas a low HGS was an excellent independent outcome predictor in males, no predictive power of this parameter was found in females. S-albumin is more closely related to co-morbidity and inflammation than nutritional status in patients close to start of RRT. We conclude that sex is an important factor that must be taken into account in studies on nutrition and nutritional interventions in ESRD patients.     

Association of the circulating adiponectin concentration with coronary in-stent restenosis in haemodialysis patients.

BACKGROUND: Success of coronary stenting is limited by in-stent restenosis. We aimed to determine whether circulating levels of the cytokines, which have anti-inflammatory properties such as adiponectin or interleukin-10, could be associated with the occurrence of coronary in-stent restenosis in patients with end-stage renal disease (ESRD). METHODS: We enrolled 71 consecutive ESRD patients undergoing haemodialysis (mean age: 64.9+/-8.9 years; 19 women, 52 men; mean haemodialysis duration: 78.2+/-87.5 months), who received stenting for a single coronary lesion. Plasma concentrations of adiponectin and IL-10 were measured within one week before coronary stenting. RESULTS: Of the 71 patients who had received stenting, in-stent restenosis occurred in 37 patients (52.1%) within 6 months after stenting. In univariate logistic analysis, the homeostasis model assessment index of insulin resistance, blood haemoglobin, serum concentrations of high density lipoprotein-cholesterol or triglycerides and plasma concentrations of insulin or adiponectin were significantly associated with coronary in-stent restenosis. In a multiple logistic regression analysis among these variables, however, only the plasma adiponectin concentration was associated with the coronary in-stent restenosis: the odds ratio of the increase in 1 microg/ml of plasma adiponectin concentration for having restenosis was 0.651 (P = 0.001, 95% confidence interval: 0.506-0.839). Patients with restenosis had lower plasma adiponectin concentrations than those without [6.2+/-2.2 microg/ml (2.1-10.4 microg/ml; n = 37) vs 27.2+/-10.8 microg/ml (17.9-79.8 microg/ml; n = 34); P = 0.0001]. CONCLUSIONS: Circulating adiponectin concentrations may be associated with the occurrence of coronary in-stent restenosis in ESRD patients undergoing maintenance haemodialysis.     

Phospholipid plasmalogen, a surrogate marker of oxidative stress, is associated with increased cardiovascular mortality in patients on renal replacement therapy.

BACKGROUND: There is a high incidence of premature cardiovascular disease (CVD) in patients with end-stage renal disease (ESRD). Free radical-induced tissue damage is thought to play a major role in the pathogenesis of atherosclerosis, and there are several reports indicating an increased oxidative stress in ESRD. However, it is not well established that increased oxidative stress predicts cardiovascular mortality in ESRD. Plasmalogens, a group of phospholipids with a vinyl ether bond in the sn-1 position, are considered to be sensitive markers of oxidative stress. METHODS: Cardiovascular and non-cardiovascular mortality was recorded (follow-up time 1860+/-94 days) in 105 ESRD patients (mean age 51+/-2 years) in whom the fasting ratio of the erythrocyte levels of plasmalogens (DMA 16/C16:0 and DMA 18/C18:0) had been determined at the start of renal replacement therapy (RRT). The prevalence of malnutrition (subjective global assessment), diabetes mellitus (DM), smoking habits and CVD was also determined. RESULTS: Thirty-eight patients who died of CVD (0.066+/-0.003) had a significantly lower DMA 16/C16:0 ratio than 15 patients who died of non-cardiovascular causes (0.078+/-0.005; P<0.05) and 52 patients alive at follow-up (0.075+/-0.003; P<0.05). A Cox proportional hazard model analysis showed that a low (相似文献   

Association of adiponectin mutation with type 2 diabetes: a candidate gene for the insulin resistance syndrome

Adiponectin, also referred to as AdipoQ or ACRP30, is a plasma protein produced and secreted exclusively from adipose tissue. The protein contains a collagen-like domain and a C1q-like globular domain. A protease-generated globular segment enhances fatty acid oxidation in muscles, thereby modulating lipid and glucose metabolism. Plasma adiponectin levels are inversely correlated with the severity of insulin resistance. A recent genome-wide scan study mapped a susceptibility locus for type 2 diabetes and the metabolic syndrome to chromosome 3q27, where the adiponectin gene is located. Here, we screened Japanese patients with type 2 diabetes and age- and BMI-matched nondiabetic control subjects for mutations in adiponectin gene. We identified four missense mutations (R112C, I164T, R221S, and H241P) in the globular domain. Among these mutations, the frequency of I164T mutation was significantly higher in type 2 diabetic patients than in age- and BMI- matched control subjects (P < 0.01). Furthermore, plasma adiponectin concentrations of subjects carrying I164T mutation were lower than those of subjects without the mutation. All the subjects carrying I164T mutation showed some feature of metabolic syndrome, including hypertension, hyperlipidemia, diabetes, and atherosclerosis. Our findings suggest that I164T mutation is associated with low plasma adiponectin concentration and type 2 diabetes.     

The evaluation incidence and risk factors of mortality among patients with end stage renal disease in southeast Turkey

AIM: End stage renal disease (ESRD) presents with higher morbidity and mortality with respect to the general population. In recent study, the causes of mortality and associated risk factors in ESRD have been evaluated. MATERIALS AND METHODS: In this study, 1538 patients diagnosed with ESRD in 10-year period were evaluated retrospectively. The patients were divided as dead (group 1) and alive (group 2). The patients' demographic features, causes of death, comorbidity at hospitalization, hematological and biochemical analyses, creatinine clearance at the beginning of hospitalization, daily urine volume, blood gas results, CRP value as inflammatory marker, ejection fraction, interventricular septum diameter, left ventricle posterior wall end-diastolic diameter, and left atrium diameter determined with echocardiography were recorded. RESULTS: Mortality ratio of ESRD patients in a 10-year period was 14.1%. While the general mean age of all patients was 54.7 +/- 16.6 and male/female ratio was 781/757, these ratios were 66.3 +/- 21.8 and 114/103 in Group 1 and 52.8 +/- 21.7 and 667/654 in Group 2. One or more comorbid pathologies were present in 82.9% of Group 1. The most common cause of mortality was cardiovascular diseases (CVD), and the most common cause of comorbidity was infections. Older age, anemia, absence of residual renal function, hypoalbuminemia, inflammation, impaired Ca and P metabolism, and left ventricular hypertrophy were significantly higher in Group 1 than in Group 2. CONCLUSION: CVD are the most important preventable causes of morbidity and mortality in all stages of chronic kidney disease. Taking precaution against CVD and the associated complications will provide a positive contribution in reducing morbidity and mortality among ESRD patients.     

Postischemic vasodilation, endothelial activation, and cardiovascular remodeling in end-stage renal disease

BACKGROUND: Cardiovascular complications are the major cause of death in end-stage renal disease (ESRD) patients. These complications are associated with concomitant cardiac and vascular remodeling, including left ventricular (LV) hypertrophy and hypertrophy of arterial walls. The endothelium influences the process of arterial remodeling. ESRD patients are characterized by the development of both cardiovascular remodeling and endothelial dysfunction. METHODS: Common carotid artery (CCA) intima-media thickness (IMT), CCA diameter, CCA distensibility, LV mass, and function were determined in 60 stable ESRD patients on hemodialysis and 34 age-, sex-, and blood pressure (BP)-matched controls, and their relationships with endothelial alterations were estimated by forearm postischemic vasodilation [flow debt repayment (FDR)] measured by venous plethysmography. We also evaluated the relationships between FDR and several cardiovascular risk factors or markers of inflammatory response or endothelial activation, for example, duration of dialysis, BP, smoking habits, cholesterol, parathormone (PTH), serum albumin, plasma fibrinogen, C-reactive protein (CRP), plasma homocysteine, plasminogen activator inhibitor (PAI-1), and von Willebrand factor (vWF). RESULTS: ESRD patients had increased LV mass, CCA diameter and CCA IMT, and had decreased CCA distensibility (P < 0.05). While the postischemic peak flow was comparable in controls and ESRD patients (29.2 +/- 9.1 vs. 27.9 +/- 0.2 mL/100 mL/min), FDR was lower in ESRD patients (116 +/- 31 vs. 88 +/- 32%, P < 0.001) because of the shorter duration of vasodilation (127 +/- 36 vs. 96 +/- 32 s, P < 0.001). The time to complete FDR was longer in ESRD patients (110 +/- 54 vs. 162 +/- 72 s, P < 0.001). ESRD patients had lower high-density lipoprotein cholesterol and serum albumin (P < 0.01) and higher triglycerides, fibrinogen, plasma homocysteine, vWF (P < 0.01), and PAI-1 (P < 0.05). For ESRD patients, significant negative age- and pressure-independent correlations were established between FDR and CCA diameter, duration of dialysis, and PAI-1. FDR was positively correlated with serum albumin. FDR and time to FDR were negatively correlated with CCA IMT and LV mass. CCA distensibility was positively associated with FDR (P < 0.001) and negatively with time to FDR (P < 0.001). The PAI-1 concentration was positively correlated with CCA IMT (P < 0.01) and negatively with CCA distensibility (P < 0.001). CONCLUSIONS: Our data provide the first evidence that cardiac and arterial remodeling in ESRD patients are inversely related to forearm reactive hyperemia. The diminished hyperemic response is due to the shorter duration of hyperemia and is associated with higher concentrations of serum markers of endothelial activation, suggesting that, in ESRD patients, endothelial dysfunction may be a factor influencing cardiovascular changes.     

Association of endothelial nitric oxide synthase Glu298Asp polymorphism with end-stage renal disease

BACKGROUND: Impairment of nitric oxide generation caused by gene polymorphism is considered as a major factor in the deterioration of progressive renal disease, including diabetic nephropathy and hypertension. The aim of the present study was to examine the Glu298Asp polymorphism of endothelial nitric oxide synthase (eNOS) in patients with end-stage renal disease (ESRD). METHODS: The Glu298Asp polymorphism in exon 7 was determined in 100 ESRD patients who were maintained on hemodialysis at Dr. Soetomo Hospital, Surabaya, Indonesia, and in a control group of 100 unrelated healthy individuals. In the patient group, 39 patients had Type 2 diabetes mellitus (DM), 44 hypertension (HT) and 17 miscellaneous conditions. The mean length of time from onset of ESRD to the start of this study was 24.37 +/- 32.37 months (Mean +/- SD). RESULTS: The positivity of Glu298Asp in the ESRD group was significantly higher than that in the control group (p < 0.0001). The odds ratio for this group was 4.57 (95% confidence interval 2.52 - 8.31). The positivity of 298Asp in Type 2 DM ESRD with subgroup was significantly higher than that in healthy controls (p < 0.0001). The positivity of 298Asp in the subgroup of patients with HT-derived ESRD was also significantly higher (males p < 0.036, females p < 0.005) than that in healthy control group. Homozygotes with glutamate to aspartate substitution at nucleotide position 7702 showed a single band at 457 bp. CONCLUSION: It appears that Glu298Asp may be a predisposing factor in DM-derived and HT-derived ESRD.     

Traditional and non-traditional risk factors as contributors to atherosclerotic cardiovascular disease in end-stage renal disease

Cardiovascular disease (CVD) remains the main cause of morbidity and mortality in patients with end-stage renal disease (ESRD). Although traditional risk factors, such as diabetes mellitus, hypertension, dyslipidemia and advanced age, are prevalent in ESRD patients they may not be sufficient by themselves to account for the high prevalence of CVD in patients with this condition. Thus, the search for other, non-traditional, risk factors that may be involved in the pathogenesis of uremic CVD has been an area of intense study. Data suggest that the accelerated atherosclerotic process of ESRD may involve several interrelated processes, such as oxidative stress, endothelial dysfunction and vascular calcification, in a milieu of constant low-grade inflammation. The cause(s) of inflammation in ESRD are multifactorial and, while it may reflect underlying CVD, an acute-phase reaction may also be a direct cause of vascular injury via several pathogenetic mechanisms. Available data suggest that pro-inflammatory cytokines play a central role in the genesis of both malnutrition and CVD in ESRD. Thus, it could be speculated that suppression of the vicious cycle of malnutrition, inflammation and atherosclerosis (MIA syndrome) would improve survival in dialysis patients. Recent evidence has demonstrated strong associations between inflammation and both increased oxidative stress and endothelial dysfunction in ESRD patients. As there is not yet any recognized, or even proposed, treatment for ESRD patients with chronic inflammation it would be of obvious interest to study the long-term effect of various anti-inflammatory treatment strategies on the nutritional and cardiovascular status as well as outcome of these patients.     

Low fetuin-A levels are associated with cardiovascular death: Impact of variations in the gene encoding fetuin

BACKGROUND: Vascular calcification is common among end-stage renal disease (ESRD) patients and a central characteristic of the atherosclerotic cardiovascular disease observed in dialysis patients. Fetuin-A, a circulating calcium-regulatory glycoprotein that inhibits vascular calcification, is associated with inflammation and outcome in dialysis patients. In the present study, we evaluated the association between fetuin-A, clinical phenotype, and outcome, as well as the impact of fetuin gene (AHSG) polymorphisms on the protein product and outcome. METHODS: In a cohort of 258 (161 males) ESRD patients starting renal replacement therapy [glomerular filtration rate (GFR) 6.8 +/- 0.2 mL/min] aged 52 +/- 1 years the following parameters were studied: presence of malnutrition (subjective global assessment), comorbidity [diabetes mellitus and clinical manifest cardiovascular disease (CVD)], carotid plaques (N= 101), hs-CRP, fetuin-A, S-albumin, interleukin (IL)-6, and single nucleotide polymorphisms (SNPs) in the AHSG gene (N= 215) at amino acid positions Thr248Met (C-->T), Thr256Ser (C-->G), Asp276Asn (G-->A), and Arg317Cys (C-->T). RESULTS: Both all-cause (P < 0.001) and cardiovascular (P < 0.001) mortality were associated with low fetuin-A levels independently of age, smoking, diabetes, S-albumin, CVD, and inflammation (CRP > or =10 mg/L). Inflamed (0.199 vs. 0.247 g/L; P < 0.01) and malnourished (0.207 vs. 0.262 g/L; P < 0.05) patients had significantly lower median fetuin-A than noninflamed and well-nourished ESRD patients, respectively. In a logistic regression model (N= 101), fetuin-A was significantly (P < 0.05) associated with the presence of carotid plaques independently of age, CVD, diabetes, S-albumin, gender, and inflammation. Significant correlations were observed between fetuin-A and both S-albumin (Rho = 0.30; P < 0.0001) and IL-6 (Rho =-0.21; P < 0.01). Patients with the AHSG 256Ser allele had lower serum fetuin-A levels, and higher all-cause and cardiovascular mortality rate if they were inflamed. CONCLUSION: The present study shows that a low fetuin-A level is associated with malnutrition, inflammation, and atherosclerosis (carotid plaques), as well as with increased cardiovascular and all-cause mortality. Because the present study demonstrates an effect of variations in the AHSG gene on both circulating fetuin-A levels and outcome, this indicates that ESRD patients with the AHSG 256Ser allele are at risk of accelerated vascular calcification.     

Serum ionic fluoride levels in haemodialysis and continuous ambulatory peritoneal dialysis patients

High serum fluoride (F-) in patients with chronic renal failure (CRF) and end-stage renal disease (ESRD) is associated with risk of renal osteodystrophy and other bone changes. This study was done to determine F- in normal healthy controls and patients with ESRD on haemodialysis (HD) or peritoneal dialysis (PD). Seventeen healthy controls (12 males, 5 females) and 39 ESRD patients on dialysis (17 males, 22 females) were recruited in the study in a community with 47.4 +/- 3.28 microM/l (range 44-51 microM/l) of F- content in drinking water. Control subjects showed a mean serum F- concentration of 1.08 +/- 0.350 microM/l. Males in control group showed slightly higher F- levels (1.15 +/- 0.334, range 0.55-1.9 microM/l) than females (0.92 +/- 0.370, range 0.6-1.5 microM/l). Mean serum F- concentration did not correlate significantly with age and sex among control subjects, whereas such correlation was observed in patients with ESRD on dialysis. Mean serum F- concentration was significantly higher in patients on dialysis (2.67 +/- 1.09, range 0.8-5.2 microM/l) than normal controls. When grouped according to sex, the mean serum F- concentration in males (3.05 +/- 1.04, range 1.8-5.2 microM/l) was significantly higher than females (2.38 +/- 1.08, range 0.8-5.2 microM/l). When patients were grouped according to age, it was observed that F- concentration was significantly higher in patients with age groups 21-70 (2.86 +/- 1.05) than those with age group 13-20 years (1.42 +/- 0.531). Thus F- concentration correlated with age and sex, being higher in males and above 20 years. Despite appreciable clearance of F- (39-90%) across the peritoneum, patients on CAPD showed higher serum F- concentration than those on HD (3.1 +/- 1.97 vs 2.5 +/- 1.137 microM/l). Of the total 39 patients on dialysis 39% had their serum F- concentration above 3.0 microM/l, posing the risk of renal osteodystrophy.      

Renin-angiotensin gene polymorphism in children with uremia and essential hypertension

The M235T polymorphism of the angiotensinogen (ANG) gene, the I/D polymorphism of the angiotensin converting enzyme (ACE) gene, and the A1166C polymorphism of the angiotensin II type 1 receptor (AT1R) gene were identified in 70 patients with end-stage renal disease [20 pediatric ESRD, aged 14.9+/-3.1, years blood pressure (BP) 139+/-14/91+/-13 mmHg, 50 adult ESRD, aged 48.7+/-18.7 years, BP 149.1+/-24/96.9+/-12 mmHg], 35 with juvenile essential hypertension (JEHT, aged 14.4+/-2.7 years, 24-h mean BP 135.37+/-7.37/72.4+/-7.68 mmHg), 130 adult healthy normotensive controls (aged 34.9+/-8.1 years, BP 117.8+/-8.7/78.7+/-8.5 mmHg), and 20 pediatric controls (aged 13.2+/-1.2 years, BP 109+/-6.5/71+/-5.9 mmHg). The ACE gene polymorphism was determined by polymerase chain reaction and the ANG and AT1R gene polymorphisms by single-step LightCycler technology. The ACE gene distribution of the Hungarian controls did not differ from the results of the other Caucasian populations. In JEHT and pediatric ESRD patients, the MT genotype of ANG was more frequent than in controls (JEHT 80%, pediatric ESRD 74% versus controls 50%, P<0.02). The DD genotype of ACE was over-represented in pediatric ESRD compared with controls (ESRD 45% versus controls 22%, P<0.05). There was a non-significant increase in the CC genotype frequency of AT1R in adult patients with ESRD compared with controls. In conclusion, there was an increased frequency of the ACE DD genotype in pediatric ESRD, which could be a genetic risk factor for the development of ESRD. Furthermore, there was a significant increase in MT genotype frequency of ANG M235T polymorphism in pediatric ESRD and JEHT. The role of AT1R gene polymorphism needs further investigation.     

Influence of endothelin-1 gene polymorphisms on the progression of autosomal dominant polycystic kidney disease

BACKGROUND/AIM: A significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD). The variability cannot be fully explained by the genetic heterogeneity of the disease. Endothelin-1 (ET-1) has been suggested to be a major promoting factor in renal diseases. The role of the ET-1 gene locus (EDN1) in the renal function in the general nondiabetic population was evaluated. We examined the influence of three single-nucleotide polymorphisms of the ET-1 gene (EDN1)--K198N, 3A/4A, and T-1370G--on the progression of ADPKD towards end-stage renal disease (ESRD). METHODS: Two hundred and five ADPKD patients (113 males and 92 females) who had reached ESRD were analyzed. The patients were divided into three groups: (1) 48 patients (23 males and 25 females) with ESRD later than 63 years of age (slow progressors), (2) 74 patients (41 males and 33 females) with ESRD before 45 years of age (rapid progressors), and (3) 83 patients (49 males and 34 females) with ESRD between 45 and 63 years old. DNA samples from collected blood were genotyped for three single-nucleotide polymorphisms of EDN1: K198N, 3A/4A, and T-1370G. Haplotype analysis was also done in 200 healthy individuals. We compared the frequencies of the different genotypes between the groups of slow and rapid progressors and the ages at the time of ESRD regarding the EDN1 genotypes. RESULTS: The EDN1 genotype distribution showed no differences among the groups of slow progressors, rapid progressors, the ADPKD group with ESRD between 45 and 63 years old, and the control group. Comparing the ages of ESRD of all patients, we did not find significant differences with regard to the different genotypes. Furthermore, we compared the combinations of the different haplotypes and the ages at the time of ESRD. We found no differences in ages at the time of ESRD in patients with different haplotypes in the endothelin promoter (T-1370G) in combination with 3A/4A or K198N polymorphisms. Comparing the ages at the time of ESRD in patients with different 3A/4A and K198N haplotypes, we found a significantly lower age at the time of ESRD (47.1 +/- 8.7 years) in the carriers of the 4A allele in combination with the 198N allele (4A/4A, 3A/4A + 198KN,NN) than in the carriers of the 4A allele homozygous for the K198 allele (52.9 +/- 10.9 years; 4A/4A, 3A/4A + 198KK; t test: p < 0.01) and in the carriers of the 198N allele homozygous for the 3A allele (53 +/- 11.2 years; 3A/3A + 198KN,NN; t test: p < 0.05). CONCLUSIONS: We excluded an effect of K198N, 3A/4A, and T-1370G polymorphisms of EDN1 on the progression of ADPKD. However, a deleterious effect of the combination of 4A and 198N alleles of EDN1 was observed in APKDK individuals.     

Association of the T-G polymorphism in adiponectin (exon 2) with obesity and insulin sensitivity: interaction with family history of type 2 diabetes.

The adipocyte-derived hormone adiponectin seems to protect from insulin resistance, a key factor in the pathogenesis of type 2 diabetes. Genome-wide scans have mapped a susceptibility locus for type 2 diabetes and the metabolic syndrome to chromosome 3q27, where the adiponectin gene is located. A common silent T-G exchange in nucleotide 94 (exon 2) of the adiponectin gene has been associated with increased circulating adiponectin levels. Metabolic abnormalities associated with the G allele have not been reported. We therefore assessed whether this polymorphism alters insulin sensitivity and/or measures of obesity using the Tübingen Family Study database (prevalence of the G allele, 28%). In 371 nondiabetic individuals, we found a significantly greater BMI in GG + GT (25.5 +/- 0.7 kg/m(2)) compared with TT (24.1 +/- 0.3 kg/m(2); P = 0.02). Insulin sensitivity (determined by euglycemic clamp, n = 209) was significantly lower in GG + GT (0.089 +/- 0.007 units) compared with TT (0.112 +/- 0.005 units; P = 0.02). This difference disappeared completely on adjustment for BMI. Because our population contains a relatively high proportion of first-degree relatives of patients with type 2 diabetes, we stratified by family history (FHD). Much to our surprise, the genotype differences in BMI and insulin sensitivity in the whole population were attributable entirely to differences in the subgroup without FHD, whereas in the subgroup with FHD, the G allele had absolutely no effect. Moreover, individuals without FHD had a significantly lower BMI than individuals with FHD (25.2 +/- 0.4 vs. 26.2 +/- 0.5 kg/m(2); P = 0.01), which was not the case for the GG + GT subgroup without FHD (27.0 +/- 0.9 kg/m(2); NS). This suggests that in individuals without familial predisposition for type 2 diabetes, the adiponectin polymorphism may mildly increase the obesity risk (and secondarily insulin resistance). In contrast, in individuals who are already burdened by other genetic factors, this small effect may be very hard to detect.     

Homocysteine and methionine metabolism in ESRD: A stable isotope study.

BACKGROUND: Hyperhomocysteinemia has a high prevalence in the end-stage renal disease (ESRD) population, which may contribute to the high cardiovascular risk in these patients. The cause of hyperhomocysteinemia in renal failure is unknown, and therapies have not been able to normalize plasma homocysteine levels. Insight into methionine-homocysteine metabolism in ESRD is therefore necessary. METHODS: Using a primed, continuous infusion of [2H3-methyl-1-13C]methionine, we measured whole body rates of methionine and homocysteine metabolism in the fasting state in four hyperhomocysteinemic hemodialysis patients and six healthy control subjects. RESULTS: Remethylation of homocysteine was significantly decreased in the hemodialysis patients: 2.6+/-0.2 (SEM) vs. 3.8+/-0.3 micromol. kg(-1)x hr(-1) in the control subjects (P = 0.03), whereas transsulfuration was not 2.5+/-0.3 vs. 3.0+/-0.1 micromol. kg(-1) x hr(-1) (P = 0.11). The transmethylation rate was proportionally and significantly lower in the ESRD patients as compared with controls: 5.2+/-0.4 vs. 6.8+/-0.3 micromol. kg(-1) x hr(-1) (P = 0.02). Methionine fluxes to and from body protein were similar. CONCLUSIONS: The conversion of homocysteine to methionine is substantially (approximately 30%) decreased in hemodialysis patients, whereas transsulfuration is not. Decreased remethylation may explain hyperhomocysteinemia in ESRD. This stable isotope technique is applicable for developing new and effective homocysteine-lowering treatment regimens in ESRD based on pathophysiological mechanisms.