Difficulty in activities of daily living and falls in patients undergoing hemodialysis: A cross-sectional study with nondialysis controls.

INTRODUCTION: Impaired activities of daily living (ADL) and falls are important issues in hemodialysis patients. So far, information is limited regarding self-reported difficulty with ADL (ADL difficulty) in hemodialysis patients. Then, we compared the degree of ADL difficulty and the prevalence of fallers between hemodialysis patients and a nondialyzed control group. Also, the possible association between ADL difficulty and falls was examined. METHODS: This was a single center, cross-sectional study including two groups of outpatients aged 50 years or older; 209 prevalent hemodialysis patients, and 139 nonrenal patients with diabetes mellitus, hypertension, and/or dyslipidemia (control group). ADL difficulty score was evaluated by a 48-item questionnaire including six subscales of ADLs namely locomotion, eating, toileting, dressing, bathing, and grooming. Experience of falls in the previous year period was examined by a questionnaire. FINDINGS: The two groups did not differ significantly in age or sex. The hemodialysis group had a higher median (interquartile range) total score of ADL difficulty than the control group [10 (2-39) vs. 2 (0-10); p < 0.001] and a higher prevalence of fallers (73/209, 34.9% vs. 16/139, 11.5%; p < 0.001). In multivariable-adjusted linear regression analyses, history of falls was independently associated with a higher score of ADL difficulty for total or each of the six subscales. DISCUSSION: The hemodialysis patients had a significantly higher ADL difficulty and a higher prevalence of fallers than the control group. Self-reported ADL difficulty and falls were closely linked regardless of the patient group.

Oxidative Stress and Inflammation as Predictors of Mortality and Cardiovascular Events in Hemodialysis Patients: The DREAM Cohort.

AIM: Both oxidative stress and inflammation are involved in the pathogenesis of cardiovascular disease (CVD). The serum level of derivatives of reactive oxygen metabolites (d-ROMs) is a measure of the total amount of hydroperoxides serving as a marker of oxidative stress. We investigated whether d-ROMs could predict the clinical outcomes in hemodialysis patients and whether the associations of d-ROMs with the outcomes are independent of a marker of inflammation, C-reactive protein (CRP). METHODS: This was a prospective cohort study in hemodialysis patients. The key exposures were the serum levels of d-ROMs and CRP. The outcome measures were all-cause mortality and new CVD events. RESULTS: A total of 517 patients were analyzed. d-ROMs correlated positively with CRP. During follow-up for 5 years, 107 patients died, and 190 patients experienced new CVD events. In the Kaplan-Meier analyses, both higher d-ROMs and higher CRP levels predicted higher risks for mortality and CVD events. By Cox proportional-hazard regression analysis adjusted for potential confounders excluding CRP, d-ROMs exhibited a significant association with all-cause mortality, but this association was no longer significant after further adjustment for CRP. Using the same model, CRP exhibited a significant association with all-cause mortality, but this association was no longer significant after further adjustment for d-ROMs. When we analyzed new CVD events as the outcome, CRP was a significant predictor, whereas the level of d-ROMs was not. CONCLUSIONS: Although d-ROMs predicted mortality and CVD events in unadjusted models, the associations of d-ROMs with these outcomes were not independent of CRP. Oxidative stress and inflammation appear to share common causal pathways.

Clinical impact of the leptin to soluble leptin receptor ratio on subclinical carotid atherosclerosis in patients with type 2 diabetes.

AIM: The adipocyte-derived hormone leptin plays a key role in the regulation of food intake and energy expenditure. Recent studies have suggested that leptin is also involved in the pathogenesis of obesity-associated atherosclerosis and cardiovascular disease. In this study, we investigated the associations of leptin and the soluble leptin receptor (sOb-R) with atherosclerosis in patients with type 2 diabetes. METHODS: Three hundred seventeen type 2 diabetic subjects were enrolled in this cross-sectional study. Fasting plasma leptin and sOb-R concentrations were measured by enzyme-linked immunosorbent assays. The intima-media thickness (IMT) of the common carotid artery was measured by ultrasound. RESULTS: The IMT was significantly associated with sOb-R concentrations, age, diabetes duration, serum creatinine (sCre) levels, and systolic blood pressure (SBP), but not with leptin concentrations or the leptin/sOb-R ratio. The concentrations of leptin (r=0.478, p<0.001) and the sOb-R (r= -0.404, p<0.001) and the leptin/sOb-R ratio (r=0.501, p<0.001) were strongly correlated with IMT in subjects treated with insulin for glycemic control, but not in those treated with diet alone or oral hypoglycemic agents. Multiple regression analysis, including age, sex, diabetes duration, body mass index, SBP, HbA1c, triglycerides, LDL-cholesterol, sCre, smoking, and insulin therapy, revealed that plasma leptin and the leptin/sOb-R ratio were independently associated with IMT in subjects treated with insulin. CONCLUSIONS: Plasma leptin and the leptin/sOb-R ratio are associated with atherosclerosis in patients with type 2 diabetes on insulin therapy, and these associations were independent of obesity and other cardiovascular risk factors.

Association of endothelial and vascular smooth muscle dysfunction with cardiovascular risk factors, vascular complications, and subclinical carotid atherosclerosis in type 2 diabetic patients.

AIM: Atherosclerosis and arteriosclerosis are mainly caused by the dysfunction of arterial components, namely, vascular endothelial cells, smooth muscle cells, and the extracellular matrix. Endothelial dysfunction is well established as a predictive surrogate marker of cardiovascular events; however, little is known regarding the clinical implications of vascular smooth muscle dysfunction for cardiovascular disease and microangiopathy. In the present study, we aimed to clarify the association of arterial dysfunction with micro-/macroangiopathy and conventional cardiovascular risk factors in 181 type 2 diabetic patients (T2DM; age ± SD, 64 ± 10 years; duration of diabetes, 12 ± 10 years). METHODS: Flow-mediated dilatation (FMD) and nitroglycerin-mediated dilatation (NMD) were assessed to evaluate endothelial dysfunction and vascular smooth muscle dysfunction, respectively, by using a novel ultrasound device, UNEXEF18G (Unex Co. Ltd., Japan). RESULTS: The FMD and NMD were 6.4 ± 3.9% and 13.4 ± 6.6%, respectively. No significant differences in FMD were noted between T2DM with and without micro- or macroangiopathy; however, NMD in T2DM patients with micro- and macroangiopathy was significantly lower than that in T2DM patients without angiopathy. NMD decreased with the progression of chronic kidney disease (CKD) stage (p = 0.005), but not FMD (p = 0.071). On multiple regression analysis, significant independent contributors to FMD were age, smoking, systolic blood pressure, glycosylated hemoglobin, and serum total cholesterol, while those for NMD were age, systolic blood pressure, and waist circumference. CONCLUSION: The relationship of vascular complications and cardiovascular risk factors with NMD is different from that with FMD in type 2 diabetic patients.

Brachial-ankle pulse wave velocity as an index of central arterial stiffness.

AIM: Stiffness of the central arteries plays an important role in the pathophysiology of cardiovascular disease, and pulse wave velocity (PWV) of the aorta has been used as the standard measure of central arterial stiffness. An automated device for brachial-ankle (ba) PWV is available, although information is limited whether baPWV reflects the stiffness of central or peripheral arteries. We therefore addressed this question in the present study. METHODS: The subjects were 2,806 consecutive participants in our non-invasive vascular laboratory, excluding those with an ankle-brachial index (ABI) lower than 0.95. PWV measurements were simultaneously performed using an automated device for the ba, heart-femoral (hf, aorta), heart-carotid (hc), heart-brachial (hb), and femoral-ankle (fa) segments. Correlational analyses were performed (1) among these PWV values, (2) between PWV and individual risk factors, and (3) between PWV and the Framingham risk score (FRS), a surrogate index for integrated cardiovascular risk. RESULTS: The correlation of baPWV was the highest with hfPWV (r=0.796) and the lowest with hcPWV (r=0.541). Among the known factors preferentially affecting central arterial stiffness, higher age, diabetes mellitus, and chronic kidney disease (CKD) were also closely associated with increased baPWV. Finally, FRS was more closely correlated with hfPWV (r=0.613) and baPWV (r=0.609) than with hbPWV (r=0.523), hcPWV (r=0.509), and faPWV (r=0.393). CONCLUSION: These results indicate that baPWV is an index of arterial stiffness showing similar characteristics to those of aortic PWV.

Central versus peripheral arterial stiffness in association with coronary, cerebral and peripheral arterial disease.

BACKGROUND: Although stiffness of central arteries is more preferentially associated with coronary artery disease (CAD) than that of peripheral arteries, less is known for cerebrovascular disease (CVD) and peripheral artery disease (PAD). We measured pulse wave velocity (PWV) in four arterial segments, and examined the relative changes in the four regional PWVs in patients with CAD, CVD or PAD. METHODS: The 2798 subjects were selected from 3300 consecutive participants of our non-invasive vascular lab. 342 subjects had one or more pre-existing atherosclerotic diseases including 128 CAD (N=128), CVD (N=195) and PAD (N=83). PWVs were simultaneously measured using an automated pulse wave analyzer (model BP-203RPE, Colin) in the heart-femoral (hf, aorta), heart-carotid (hc), heart-brachial (hb), and femoral-ankle (fa) segments. RESULTS: As compared to the subjects without atheroscletoric disease, those with CAD, CVD, or PAD showed higher levels of PWV in the four arterial segments, particularly in hfPWV. The relative increase in hfPWV remained significant after adjustment for age, sex, hypertension, pulse rate, smoking, diabetes mellistus, dyslipidemia, and chronic kidney disease. CONCLUSION: This study indicates that the preferential increase in central arterial stiffness is found not only in CAD but CVD and PAD as well.

Serum C-reactive protein and thioredoxin levels in subjects with mildly reduced glomerular filtration rate.

BACKGROUND: Chronic kidney disease (CKD) is a newly recognized high-risk condition for cardiovascular disease (CVD), and previous studies reported the changes in inflammation and oxidative stress in advanced stages of CKD. We compared the levels of serum biomarkers for inflammation and oxidative stress between subjects with normal and mildly reduced glomerular filtration rate (GFR). METHODS: The subjects were 182 participants of a health check-up program including those with normal (>or= 90 mL/min/1.73 m2, N = 79) and mildly reduced eGFR (60-89 mL/min/1.73 m2, N = 103) which was calculated based on serum creatinine, age and sex. We excluded those with reduced eGFR < 60 mL/min/1.73 m2. No one had proteinuria. We measured serum levels of C-reactive protein (CRP) and thioredoxin (TRX) as the markers of inflammation and oxidative stress, respectively. RESULTS: As compared with subjects with normal eGFR, those with mildly reduced eGFR had increased levels of both CRP and TRX. Also, eGFR was inversely correlated with these biomarkers. The associations of eGFR with these biomarkers remained significant after adjustment for age and sex. When adjustment was done for eight possible confounders, CRP showed significant association with systolic blood pressure, high density lipoprotein cholesterol (HDL-C) and non-HDL-C, whereas TRX was associated with sex significantly, and with eGFR and systolic blood pressure at borderline significance. CONCLUSIONS: We showed the increased levels of CRP and TRX in subjects with mildly reduced eGFR. The eGFR-CRP link and the eGFR-TRX link appeared to be mediated, at least partly, by the alterations in blood pressure and plasma lipids in these subjects.

Fetuin-A and atherosclerotic calcified plaque in patients with type 2 diabetes mellitus.

Fetuin-A is a multifunctional circulating glycoprotein. Among its roles, inhibition of ectopic calcification is a prominent feature. Low fetuin-A levels in dialysis patients are associated with cardiovascular mortality, possibly via accelerating vascular calcification. However, except for dialyzed conditions, a correlation between fetuin-A levels and vascular calcification remains controversial. Furthermore, any inhibitory effect of fetuin-A on atherosclerotic calcified plaques (CPs) remains unclear compared with its effect on medial artery calcification that is often found in dialyzed patients. Therefore, we examined the association between fetuin-A levels and atherosclerotic CPs. For this study, 416 consecutive patients with type 2 diabetes mellitus and without renal dysfunction were examined. We measured serum fetuin-A levels and investigated for the presence of CP in the common carotid and femoral arteries using ultrasonography. Fetuin-A levels were significantly lower in patients with CP than those without CP (262.6 +/- 56.7 and 281.5 +/- 64.6 microg/mL, respectively; P = .001). Multivariate logistic regression analysis showed that fetuin-A levels were inversely associated with the presence of CP (odds ratio = 0.753; 95% confidence interval, 0.608-0.933; P = .010). These results suggest that fetuin-A may inhibit the calcification of atherosclerotic plaques independently of the dialyzed condition.

Plasma angiopoietin-like protein 3 (ANGPTL3) concentration is associated with uremic dyslipidemia.

OBJECTIVE: Angiopoietin-like protein 3, a liver-derived plasma protein, increases plasma triglycerides (TG) in mice by suppressing the activity of lipoprotein lipase, a key enzyme in plasma TG clearance. Uremic dyslipidemia is characterized by increased TG-rich lipoproteins such as very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL), lowered high-density lipoprotein (HDL), and TG-enrichment of low-density lipoprotein (LDL) and HDL. Since the role of angiopoietin-like protein 3 (ANGPTL3) in uremic dyslipidemia is unknown, we examined its possible association with the lipoprotein abnormalities in patients with chronic renal failure (CRF). METHODS: The subjects were 202 hemodialysis patients, 44 predialysis patients with CRF and 148 healthy control subjects comparable in age and sex. Fasting plasma ANGPTL3 was measured by enzyme-linked immunoassay, and lipoproteins were fractioned by ultracentrifugation. RESULTS: Median (25th-75th percentile range) ANGPTL3 levels were 523 (409-645) and 393 (308-511)ng/mL in hemodialysis and predialysis patients, respectively, which were significantly lower than the control level of 700 (570-875)ng/mL. In the total subjects, ANGPTL3 was inversely correlated with VLDL- and IDL-cholesterol levels, and positively with HDL-cholesterol. ANGPTL3 correlated inversely with TG/cholesterol ratios of both LDL and HDL. In multiple regression models, these associations, excluding TG/cholesterol ratio of LDL, remained significant and independent of possible confounders including age, sex, body mass index, insulin resistance index (HOMA-IR), and adiponectin, whereas the associations of ANGPTL3 with the lipoprotein parameters were less significant when apoC-II/C-III ratio was included in the models. CONCLUSION: The reduced ANGPTL3 level in hemodialysis patients was consistently associated with the major components of uremic dyslipidemia. ANGPTL3 may be a novel factor contributing to uremic dyslipidemia.

The combination of IMT and stiffness parameter beta is highly associated with concurrent coronary artery disease in type 2 diabetes.

AIMS: The clinical implications of stiffness of the carotid artery (CA) have not been fully clarified in the prediction of coronary artery disease (CAD), although intima-media thickness (IMT) has been established as a surrogate marker. We examined the associations of stiffness parameter beta (ST) and IMT with concurrent CAD. METHODS: IMT and ST were measured by ultrasound in 439 nondiabetic subjects as a control and 1528 type 2 diabetic subjects (T2DM) with or without CAD in a cross-sectional study. RESULTS: Both IMT and ST significantly increased with age and group category, in the order of control, T2DM without CAD, and T2DM with CAD (p<0.001). The area under the curve on ROC analysis of ST for concurrent CAD was comparable to that for IMT. On multivariate logistic regression analysis, High IMT (>or=1.30 mm) and High stiffness (>or=20.0) had significant odds ratios for concurrent CAD (2.205, p<0.001 and 1.548, p<0.05, respectively). The group with High IMT and High Stiffness exhibited a stronger multivariate odds ratio (3.115, p=0.0001). CONCLUSIONS: ST and IMT are associated with CAD and exhibited significant odds ratios for CAD. Our findings suggest that the combination of IMT and ST is a useful marker of atherosclerosis.

Small dense low-density lipoprotein cholesterol concentration and carotid atherosclerosis.

Low-density lipoprotein cholesterol (LDL-C) and the small dense LDL (SdLDL) phenotype are both predictors for ischemic heart disease. We examined whether cholesterol of SdLDL (SdLDL-C) is more closely associated with carotid artery intima-media thickness (CA-IMT), a surrogate measure of atherosclerosis, than LDL-C and other lipid parameters. The subjects were 326 consecutive participants including those with dyslipidemia, diabetes mellitus, hypertension, chronic kidney disease, and smokers. SdLDL-C was quantified by a newly developed precipitation method, and CA-IMT by high-resolution B-mode ultrasound. In univariate analysis, CA-IMT was most strongly correlated with SdLDL-C (Spearman's r=0.441, P<0.001), followed by apolipoprotein (apo) B, LDL-C, non-high-density lipoprotein cholesterol (Non-HDL-C), and plasma triglycerides (TG). HDL-C and apo A-I correlated inversely with CA-IMT. Non-lipid variables that were associated with CA-IMT were age, sex, presence of diabetes mellitus, presence of hypertension, estimate glomerular filtration rate (eGFR), and C-reactive protein (CRP). Even after adjustment for age, sex, diabetes mellitus, hypertension, smoking, eGFR and CRP, the positive association of CA-IMT with SdLDL-C remained significant, and again stronger than the associations with others lipid parameters. Further analyses revealed that the level of SdLDL-C was elevated in subgroups of the subjects including men, older subjects, smokers, those with higher CRP levels, those with diabetes mellitus, and hypertensive patients. These results indicate that SdLDL-C was the best marker of carotid atherosclerosis among the lipid parameters tested, and suggest that quantitative measurement of SdLDL-C gives useful information in the risk assessment for atherosclerotic disease.