Abstract: BACKGROUND: Full, as compared with partial, correction of anaemia did not reduce the mortality risk in patients with chronic kidney disease (CKD), although the underlying mechanisms are unknown. Since CKD is a high-risk population for cardiovascular disease (CVD), we tested a hypothesis that the presence of atherosclerosis affects the relationship between anaemia and mortality risk. METHODS: We performed a single-centre 10-year follow-up study with an observational cohort of 505 haemodialysis patients to analyse the relationship between haematocrit and all-cause mortality. Baseline haematocrit levels did not differ between the 153 patients with CVD and the 352 patients without CVD. RESULTS: During the follow-up, 268 patients died. Both Kaplan-Meier and univariate Cox analyses showed that higher haematocrit levels were a significant predictor of lower risk of death in the CVD (-) group, whereas haematocrit did not predict death in the CVD (+) group. In multivariate Cox analyses, the inverse relationship between haematocrit and mortality in the CVD (-) group remained significant and independent of 14 covariates including the use of erythropoietin. In contrast, using the same Cox models, the CVD (+) group did not show such a beneficial effect of higher haematocrit. Similar observations were made when the subjects were divided based on carotid artery intima-media thickness instead of the presence of CVD. CONCLUSIONS: These results support the hypothesis that the presence of atherosclerosis alters the relationship between anaemia and mortality risk in haemodialysis patients.

Abstract: Vascular calcification is highly prevalent in dialysis patients, and significantly increases cardiovascular mortality. The presence and progression of vascular calcification is significantly associated with chronic inflammation and malnutrition. Disorders of mineral metabolism, particularly hyperphosphatemia, have been emphasized as risk factors for vascular calcification. Although vascular calcification has been reported to be highly prevalent in diabetic patients with end-stage renal disease (ESRD), the risk factors for vascular calcification in these patients have not been fully explored. Through a review of the literature and our recent studies examining vascular calcification in ESRD patients, hyperphosphatemia is significantly associated with vascular calcification in nondiabetic ESRD patients, while it may not be a significant risk factor for vascular calcification in diabetic ESRD patients. In diabetic patients, vascular calcification occurs long before the initiation of dialysis therapy, and the factors associated with vascular calcification in non-uremic diabetics appear to be hyperglycemia and related metabolic disorders, such as increased glycation and oxidative stress. In diabetic ESRD patients, hyperglycemia is also suggested to be a significant factor associated with the progression of vascular calcification. Thus, the importance of glycemic and phosphate control is suggested to be emphasized in diabetic and nondiabetic ESRD patients, respectively, for prevention of the progression of vascular calcification.

Abstract: Impaired activation of vitamin D in renal failure results in bone and mineral abnormalities, and causes renal osteodystrophy or chronic kidney disease mineral and bone disorder (CKD-MBD). Recent studies suggest that deficiency of active vitamin D is also involved in abnormalities in blood pressure, cardiac hypertrophy, atherosclerosis, glucose intolerance and immune dysfunction that are known as complications of uremia. This article reviews these extra-renal actions of vitamin D and its impact on survival of dialysis patients.

Abstract: OBJECTIVE: Fetuin-A is a circulating glycoprotein which is well characterized as an inhibitor of ectopic calcification. Vascular calcification commonly found in chronic kidney disease (CKD) patients is a predictor of cardiovascular death. Recently, several groups have demonstrated that low fetuin-A levels are associated with mortality in uraemic patients, possibly through regulation of vascular calcification. However, the physiological significance of fetuin-A in atherosclerosis remains unknown, except in specific conditions, such as vascular calcification in CKD patients. The objective of this study was to investigate the association between serum fetuin-A levels and arterial stiffness, a functional property of atherosclerosis, in healthy subjects. PATIENTS AND MEASUREMENTS: The study subjects comprised 141 healthy subjects. We measured serum fetuin-A levels and stiffness parameter beta for the common carotid artery, which was assessed by ultrasound using a phase-locked echo-tracking system. RESULTS: Simple regression analyses indicated that serum fetuin-A levels were significantly correlated with stiffness parameter beta (r = 0.200, P = 0.018). Multiple regression analyses showed that, besides age, fetuin-A (beta = 0.166, P = 0.033) independently contribute to the stiffness parameter beta (R(2) = 0.310, P < 0.0001). CONCLUSIONS: Serum fetuin-A level is associated with carotid arterial stiffness, independent of known atherogenic factors in healthy subjects.

Abstract: OBJECTIVE: Receptor for advanced glycation end-products (RAGE) is involved in diabetic vascular complications. We have recently shown that plasma endogenously secretory RAGE (esRAGE), an alternatively spliced form of RAGE, is closely associated with metabolic syndrome and atherosclerosis. Here, we evaluated if plasma esRAGE is a predictor of cardiovascular mortality in a cohort of 206 (171 nondiabetic) patients with end-stage renal diseases (ESRD). METHODS AND RESULTS: The cohort was followed for a median of 111 months, and 74 deaths including 34 cardiovascular deaths were recorded. Plasma esRAGE was measured at baseline. Cumulative incidence of cardiovascular death by Kaplan-Meier estimation was significantly higher in subjects in the lowest tertile of plasma esRAGE than those in the middle or the highest tertile both in all and nondiabetic subjects alone. In all subjects, as compared with the lowest tertile of plasma esRAGE, the hazards ratios for the highest and middle tertile were 0.40 (95% CI, 0.18 to 0.89) and 0.26 (0.10 to 0.66), respectively. The higher risk for lower esRAGE was still significant even after adjusted either with body mass index, hypertension, dyslipidemia and vascular complications, but was confounded by age and diabetes. CONCLUSIONS: Low circulating esRAGE is a predictor for cardiovascular mortality in ESRD patients.

Abstract: BACKGROUND: Angiopoietin-like protein 3 (ANGPTL3) is a liver-derived plasma protein that modulates plasma triglyceride clearance, angiogenesis and atherosclerosis in experimental models. So far, no study has examined its role in atherosclerosis in human subjects. We evaluated the possible association between plasma ANGPTL3 level and carotid artery intima-media thickness (CA-IMT) and femoral artery intima-media thickness (FA-IMT) in healthy human subjects. METHODS: The subjects were 381 healthy volunteers. Plasma ANGPTL3 was determined by a specific ELISA. CA-IMT and FA-IMT were measured by high-resolution B-mode ultrasonography. RESULTS: The plasma ANGPTL3 level was 764 +/- 291 ng/ml (mean +/- SD). CA-IMT showed a significant positive correlation with plasma ANGPTL3 and other classical risk factors such as age, blood pressure, and plasma glucose and lipid levels. The positive association between ANGPTL3 and CA-IMT remained significant after adjustment for age, sex, smoking, body mass index, systolic blood pressure, plasma glucose, insulin resistance index, triglyceride, and high-density and low-density lipoprotein cholesterol levels. ANGPTL3 also showed a positive association with FA-IMT independent of these factors. CONCLUSIONS: These results demonstrate for the first time that ANGPTL3 is closely associated with arterial wall thickness in human subjects.

Abstract: BACKGROUND: A close relationship has been reported between microalbuminuria and atherosclerosis in patients with diabetes mellitus. The aim of this study was to determine which of the 2 aspects of atherosclerosis, arterial thickening or stiffness, has more effect on levels of microalbuminuria in type 2 diabetic patients. METHODS: Twenty-four-hour urine samples of 167 Japanese type 2 diabetic patients (aged 58 +/- 12 years) without overt proteinuria were collected for quantitative analysis of urinary albumin excretion (UAE). Arterial stiffness was evaluated by measuring aortic pulse-wave velocity (PWV), and arterial thickness was measured by the intima-media thickness (IMT) of the carotid artery. RESULTS: The aortic PWV and carotid IMT were both significantly positively correlated with logarithmically transformed UAE (r=0.269, p<0.001; and r=0.188, p<0.05, respectively). Although there was a significant positive correlation between aortic PWV and carotid IMT (r=0.263, p<0.001), multiple regression analyses demonstrated that aortic PWV, but not carotid IMT, was a significant factor associated with log UAE, independent of other confounding factors (R2=0.246, p<0.0001). CONCLUSIONS: These results suggest that increased arterial stiffness, but not arterial thickness, is significantly associated with the increase in albuminuria, and that decreased arterial distensibility due to increased stiffness caused by atherosclerosis may be related to the progression of diabetic nephropathy in type 2 diabetic patients.

Abstract: PURPOSE OF REVIEW: The paradoxical and inverse association between body mass index and mortality risk in patients with end-stage renal disease has raised a question of whether an increased fat mass is good or bad for patients with chronic kidney disease. The purpose of this review is to update the concept on body fat in patients with chronic kidney disease. RECENT FINDINGS: A greater fat mass is an independent predictor of better survival in patients on maintenance hemodialysis. Following the initiation of dialysis, chronic kidney disease patients gain body weight due mainly to increased fat mass. Fat mass gain over time predicts better survival in hemodialysis patients. In predialysis chronic kidney disease, there is also an inverse association between body mass index and mortality risk. The metabolic syndrome and a high body mass index are independent predictors for development of chronic kidney disease and end-stage renal disease, respectively. In diabetic patients with chronic kidney disease, however, a high initial body mass index is associated with a slower decline in glomerular filtration rate. SUMMARY: The impacts of fat mass on survival and renal function appear to vary depending upon the absence or presence, and stages of chronic kidney disease. Further research is required for optimal nutritional management and improved outcomes of patients with chronic kidney disease.

Abstract: AIM: The present study aimed to clarify the clinical impact of modified NCEP-ATP III criteria for metabolic syndrome (MS) and Framingham Risk Score (FRS) on carotid atherosclerosis in 615 Japanese adults (319 men and 296 women) including 307 with type 2 diabetes. METHODS: Waist circumference was the only component from the original NCEP-ATP III criteria based on Japanese criteria. The intima-medial thickness (IMT) and stiffness parameter beta of the carotid artery were measured by ultrasound. RESULTS: Both IMT and stiffness parameter beta were significantly increased with the number of coexisting components of MS, and higher in subjects with MS than in those without MS (all Ps < 0.0001). In a logistic regression analysis with each component of MS as independent factors, hyperglycemia and hypertension had the highest odds ratio for progressors of IMT and stiffness parameter beta , respectively. Univariate odds ratios of MS for both IMT and stiffness parameter beta were comparable with that of an increase of 10% in 10-year coronary heart disease (CHD) risk by FRS (CHD risk/ 10%) but inferior to CHD risk by FRS >/= 20%. CONCLUSION: The modified NCEP-ATP III criteria for MS revealed an additive predictive impact on carotid atherosclerosis but no superiority to FRS.

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Abstract: Adiponectin, an adipokine secreted specifically from adipose tissue, has plurifunctions including antidiabetic, antiatherosclerotic, and antiinflammatory functions. Recently, platelet activation and the subsequent local inflammation have been implicated in progression of atherosclerosis. The aim of the study is to examine the interrelation among plasma adiponectin levels, platelet activation status and quantitatively determined carotid atherosclerosis. Subjects (n = 277) including 136 type 2 diabetic, 138 hypertensive, and 203 hypercholesterolemic patients participated in the study. Platelet activation was determined as percentage of polymorphonuclear cells (PMNs) or monocytes aggregated with platelets analyzed by CD41-positivity determined by whole-blood flow cytometry. PMN-platelet aggregates were significantly and positively associated with carotid atherosclerosis (intimal-medial thickness, IMT) with the interaction stronger than that of monocyte-platelet aggregates. Stepwise regression analyses revealed that PMN-platelet aggregates were the third strongest determinant of carotid IMT, with age and HbA1c stronger independent determinants. Simple and stepwise regression analyses of the factors associated with PMN-platelet aggregates revealed that HbA1c (r = 0.423), serum adiponectin levels (r = -0.289) and age (r = -0.184) were the three independent determinants. Thus, our data unveil novel link between hypoadiponectinemia and platelet activation.

Abstract: Adiponectin plays important roles in protecting against both insulin resistance and the development of atherosclerosis. The aim of the present study was to investigate the clinical impact of plasma adiponectin on arterial stiffness, a functional property of atherosclerosis, in type 2 diabetic and nondiabetic subjects. We evaluated plasma adiponectin levels and stiffness index beta for the common carotid artery assessed by ultrasound using a phase-locked echo-tracking system for 98 type 2 diabetic subjects and 116 nondiabetic subjects as controls. Plasma adiponectin levels were significantly lower in the diabetic than in the nondiabetic group. The stiffness index beta was significantly higher in the diabetic than in the nondiabetic group. Plasma adiponectin level was significantly correlated with stiffness index beta in the group of all subjects (r=-0.189, P=.006) and the nondiabetic group (r=-0.187, P=.045), but not in the diabetic group (r=0.045, P=.665). On multiple regression analysis, plasma adiponectin level was found to be a significant independent contributor to stiffness index beta in the group of all subjects (beta=-0.232, P=.020) and the nondiabetic group (beta=-0.337, P=.016), but not in the diabetic group. In conclusion, adiponectin is significantly but weakly associated with carotid arterial stiffness independently of known atherogenic factors in the nondiabetic group and that of all subjects, although no significant association between these variables was found in the group of diabetic subjects.

Abstract: Patients with advanced stages of chronic kidney disease (CKD) have an increased risk of death from cardiovascular disease (CVD). Dyslipidemias are associated with atherosclerotic vascular changes and the risk of occurrence of acute myocardial infarction in hemodialysis patients. However, management of dyslipidemia in hemodialysis patients does not appear to be actively carried out in routine practice. Presumably, there are three reasons for this reluctance to lipid-lowering in hemodialysis patients. First, there are epidemiological data showing the inverse relationship between cholesterol and mortality rate; a high cholesterol predicts a better survival. Second, lipids are not usually measured using standard fasting serum, but a non-fasting specimen. Third, although hypertriglyceridemia is the most common abnormality, fibrates are contraindicated in patients with renal failure because of a high risk of rhabdomyolysis. These issues are discussed in the current review article. Based on published work, lipid lowering would not increase the death rate if carried out without worsening malnutrition. The National Kidney Foundation K/DOQI Clinical Practice Guidelines recommend a reduction in fasting LDL-C below 100 mg/dL for the prevention of CVD in dialysis patients. Practically, however, the use of non-HDL-C measured by casual blood samples might be sufficient for the risk assessment in many hemodialysis patients. Statins are a good choice for lipid-lowering in dialysis patients. Furthermore, lipoprotein profile might be improved by an inventive use of dialyzer membranes, dialysate solutions, and other dialysis-related medications. For severe hypercholesterolemia, LDL-apheresis is another choice for consideration. Further studies are needed to clearly prove the benefit of lipid reduction in hemodialysis patients and those with CKD at earlier stages.

Abstract:

Abstract: CONTEXT: Impaired nonoxidative glucose disposal and decrease in mitochondrial glucose oxidation both contribute to insulin resistance in diabetic subjects. OBJECTIVE: In the present study, we investigated whether plasma adiponectin is associated with glucose oxidation and nonoxidative glucose disposal in subjects with and without type 2 diabetes. DESIGN: Euglycemic-hyperinsulinemic clamp was performed in 42 type 2 diabetic (T2DM) and 13 nondiabetic (non-DM) subjects. The whole-body glucose disposal rate (GDR) was evaluated as the mean of the glucose infusion rate during steady state of the clamp. Glucose and fat oxidation rates were assessed by indirect calorimetry, and nonoxidative glucose disposal rate was calculated by subtracting glucose oxidation rate from GDR. RESULTS: Plasma adiponectin level was significantly lower in T2DM than non-DM (2.87 +/- 1.40 vs. 3.96 +/- 2.39 microg/ml, P = 0.045). GDR (3.39 +/- 1.53 vs. 4.83 +/- 1.70 mg/kg x min, P = 0.006) and nonoxidative glucose disposal rate (1.89 +/- 1.39 vs. 3.11 +/- 1.76 mg/kg x min, P = 0.012) were significantly lower in T2DM, compared with non-DM, although no difference was found in glucose oxidation rate between the two groups. In all subjects, plasma adiponectin level was positively correlated with GDR (r = 0.351, P = 0.009) and nonoxidative glucose disposal rate (r = 0.324, P = 0.016) but not glucose oxidation rate. There was no significant correlation between plasma adiponectin level and fat oxidation, either before or during the clamp. CONCLUSIONS: In conclusion, plasma adiponectin level is associated with nonoxidative glucose disposal, which is reduced in type 2 diabetic subjects. Our results suggest that adiponectin controls insulin sensitivity by modulating the glycogen synthetic process in human skeletal muscle.

Abstract: OBJECTIVE: To investigate the impact of glycemic control during regular hemodialysis on the survival of diabetic patients with chronic kidney disease (CKD) in a longitudinal observational study. RESEARCH DESIGN AND METHODS: A total of 114 diabetic CKD patients on hemodialysis at Inoue Hospital (Suita, Japan) were surveyed from May 1995 to December 2002 (survey period 45.5 +/- 29.3 [means +/- SD] months). All subjects were categorized into three groups by mean HbA(1c) (A1C) level during the 3-month period on hemodialysis preceding entry, as follows: good (A1C <6.5%, 5.7 +/- 0.4%, n = 34), fair (6.5 <or= A1C < 8.0%, 7.2 +/- 0.4%, n = 39), and poor (A1C >or=8.0%, 9.2 +/- 0.9%, n = 41) A1C groups. RESULTS: There were no significant differences in age at entry, initiation of hemodialysis, duration of hemodialysis, blood pressure, cardiothoracic ratio, serum creatinine level, or hemoglobin level among the three groups. The cumulative survival of the poor A1C group during the survey was significantly lower than that of the fair and good A1C groups as determined by Kaplan-Meier estimation (P = 0.041, log-rank test). In a multivariate Cox proportional hazard model, both poor A1C group (hazard ratio 2.889, P = 0.010) and mean A1C (1.260 per 1.0%, P = 0.003) were significant predictors of survival. CONCLUSIONS: In diabetic CKD patients on regular hemodialysis, poor glycemic control is an independent predictor of prognosis. This finding indicates the importance of careful management of glycemic control even after initiation of hemodialysis.

Abstract: A higher body mass index (BMI) is a predictor of better survival in hemodialysis patients, although the relative importance of body fat and lean mass has not been examined in the dialysis population. We performed an observational cohort study in 808 patients with end-stage renal disease on maintenance hemodialysis. At baseline, fat mass was measured by dual-energy X-ray absorptiometry and expressed as fat mass index (FMI; kg/m2). Lean mass index (LMI) was defined as BMI minus FMI. During the mean follow-up period of 53 months, 147 deaths, including 62 cardiovascular (CV) and 85 non-CV fatal events, were recorded. In univariate analysis, LMI was not significantly associated with CV or non-CV death, whereas a higher FMI was predictive of lower risk for non-CV death. Analyses with multivariate Cox models, which took other confounding variables as covariates, indicated the independent associations between a higher LMI and a lower risk of CV death, as well as between a higher FMI and a lower risk of non-CV death. These results indicate that increased fat mass and lean mass were both conditions associated with better outcomes in the dialysis population.

Abstract: Angiogenic response is impaired in diabetes. Here, we examined the involvement of receptor for advanced glycation end products (RAGE) in diabetes-related impairment of angiogenesis in vivo. Angiogenesis was determined in reconstituted basement membrane protein (matrigel) plugs containing vascular endothelial growth factor (VEGF) implanted into nondiabetic or insulin-deficient diabetic wild-type or RAGE(-/-) mice. The total, endothelial, and smooth muscle (or pericytes) cells in the matrigel were significantly decreased in diabetes, with the regulation dependent on RAGE. In the matrigel, proangiogenic VEGF expression was decreased, while antiangiogenic thrombospondin-1 was upregulated in diabetic mice, regardless of the presence of RAGE. In wild-type mice, proliferating cell nuclear antigen (PCNA)-positive cells in the matrigel were significantly less in diabetic than in nondiabetic mice, while the numbers of transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells were significantly higher. This alteration in PCNA- and TUNEL-positive cells in diabetes was not observed in RAGE(-/-) mice. Similarly, the percentage of nuclear factor kappaB-activated cells is enhanced in diabetes, with the regulation dependent on the presence of RAGE. Importantly, adenovirus-mediated overexpression of endogenous secretory RAGE, a decoy receptor for RAGE, restores diabetes-associated impairment of angiogenic response in vivo. Thus, RAGE appears to be involved in impairment of angiogenesis in diabetes, and blockade of RAGE might be a potential therapeutic target.

Abstract: Active vitamin D plays important roles not only in bone and mineral metabolism but also in the cardiovascular system. Cohort studies in hemodialysis patients demonstrated that use of active vitamin D analogs was associated with reduced risk of death, particularly death from cardiovascular disease. Treatment with vitamin D had beneficial effects on cardiac and immune functions in dialysis patients, and inflammatory markers in non-renal subjects. Also, anti-proteinuric effect was recently shown in chronic kidney disease. Experimentally, active vitamin D inhibits atherogenic cellular behaviors and activation of the renin-angiotensin system. Thus, active vitamin D is a regulator of cardiovascular and kidney functions.

Abstract: Arterial stiffness is increased in type 2 diabetes mellitus, and diabetes preferentially affects arterial stiffness of the central (elastic, capacitive) over peripheral (muscular, conduit) arteries. We hypothesized that arterial stiffness of the central artery may be more closely associated with ischemic heart disease (IHD) than stiffness of peripheral arteries in type 2 diabetes mellitus. The subjects were 595 type 2 diabetes patients including 70 with IHD. Arterial stiffness was measured as pulse wave velocity (PWV) in the heart-carotid, heart-femoral, heart-brachial, and femoral-ankle regions. The PWV values of the four segments correlated with each other in patients without IHD. However, the correlations were less impressive in those with IHD, suggesting unequal stiffening of regional arteries in IHD. As compared with patients without IHD, the IHD group showed significantly higher PWV values of the four arterial segments, particularly of the heart-femoral region. The presence of IHD was significantly associated with higher heart-femoral PWV, and this association remained significant and independent of other factors in a multiple logistic regression analysis. Pulse pressure was more strongly correlated with PWV of the heart-femoral than other arterial regions. Thus, diabetic patients with IHD have increased stiffness of arteries, particularly of the aorta, supporting the concept that central arterial stiffness plays an important role in the development of IHD.

Abstract: Death rate is unacceptably elevated in end-stage renal disease patients treated with hemodialysis. Excessive body fat, or obesity, is the well-known risk factor for cardiovascular disease and other health problems in the general population. However, hemodialysis patients with a higher body mass index (BMI) have a lower risk of death, as shown by many studies. There are several explanations for the paradox of BMI in dialysis patients. First, although body mass is composed of fat mass and fat-free mass (lean mass), it is unknown which is more important, fat mass or lean mass, in predicting outcome of hemodialysis patients. Second, it is also possible that functions of adipose tissue are altered in renal failure so that accumulation of body fat leads to less atherogenicity and beneficial properties become predominant. Third, an increased fat mass may be protective against death after harmful events. In this article, we explore these possibilities using either the data of our own cohort of hemodialysis patients or the existing registry data of Japan. We conclude that in hemodialysis patients, fat mass rather than lean mass plays a protective role against mortality, that the fat mass-adipocytokine relationship is altered, and that a low BMI is associated with increased risk of fatality after cardiovascular events rather than the risk of occurrence of such events.

Abstract: Increased arterial stiffness is an independent predictor of death from cardiovascular disease, and aortic stiffness is more predictive than stiffness of other arterial regions. Because little is known about the effect of chronic kidney disease (CKD) on regional arterial stiffness, pulse wave velocity (PWV) of four different arterial segments was measured in patients who had type 2 diabetes with and without various stages of CKD. A total of 434 patients had type 2 diabetes, and there were 192 healthy control subjects who were comparable in age and gender. GFR was estimated by the abbreviated Modification of Diet in Renal Disease equation. The patients with diabetes were classified into CKD stages by the definition of the Kidney Disease Outcomes Quality Initiative guidelines. PWV was measured in the heart-femoral, heart-carotid, heart-brachial, and femoral-ankle segments simultaneously using an automatic pulse wave analyzer. PWV of each arterial region was increased in patients who had diabetes without kidney damage and was increased further in a stepwise manner with the advanced stages of CKD. The increase in PWV was greater in the heart-femoral and heart-carotid regions than in the heart-brachial and femoral-ankle segments. However, after adjustment for age, BP, and other confounding factors using a multiple regression model, decreased GFR was independently associated with increased PWV of the heart-femoral region but not with PWV of other arterial segments. In type 2 diabetes, CKD was associated with increased stiffness of arteries, particularly of the aorta. The cross-sectional result may explain the increased risk for cardiovascular disease in CKD, although longitudinal studies are needed to confirm it.

Abstract: Adiponectin, an adipocyte-specific plasma protein, has been reported to exhibit protective effects against atherosclerosis as well as an insulin-sensitizing effect. This study was designed to investigate the effect of adiponectin on carotid arterial stiffness in type 2 diabetic patients treated with pioglitazone and metformin. Twenty type 2 diabetic patients were enrolled and divided into 2 groups, a pioglitazone-treated group (n = 10) and a metformin-treated group (n = 10). Before and after intervention, plasma adiponectin levels were measured by enzyme-linked immunosorbent assay and carotid arterial stiffness was evaluated by the stiffness parameter beta, measured by ultrasound equipped with a phase-locked echo-tracking system. In the pioglitazone group, plasma adiponectin level significantly increased and stiffness parameter beta significantly decreased, whereas in the metformin group neither of these parameters changed significantly. The changes in stiffness parameter beta were significantly and inversely correlated with change in plasma adiponectin level after treatment with pioglitazone or metformin in the group of all subjects (r = -0.472, P = .036). In conclusion, the present study is the first to demonstrate that increase in adiponectin level after treatment with the insulin sensitizers pioglitazone and metformin may improve arterial stiffness in patients with type 2 diabetes mellitus.

Abstract: BACKGROUND: Certain metabolic disorders, such as hyperphosphatemia induce vascular calcification in haemodialysis patients; it is unclear, however, whether these disorders contribute to aortic calcification in diabetic haemodialysis patients. This study examined the risk factors of aortic calcification in a large number of haemodialysis patients, and compared risk factors between diabetic and non-diabetic patients. METHODS: The subjects were 667 patients on maintenance haemodialysis: 184 with type 2 diabetes and 483 without. Aortic calcification was measured semi-quantitatively using a plain computed tomography image of the abdominal aorta, and an aortic calcification index (ACI) was calculated. RESULTS: The ACI of the diabetic subjects was significantly higher than that of those without diabetes (57.3+/-22.1 vs 44.8+/-28.3%, P < 0.0001), although the dialysis vintage of the former was significantly shorter (P < 0.001). Multiple regression analyses showed that diabetes was a significant independent risk factor for increased ACI. Multiple regression analyses, performed separately in diabetics and non-diabetics, revealed that advanced age, higher systolic blood pressure, smoking and longer haemodialysis vintage were common independent risk factors significantly associated with increased ACI in both patient groups (R2 = 0.296, P < 0.0001 for non-diabetics; R2 = 0.193, P < 0.0001 for diabetics). Higher serum phosphate concentration was not significantly associated with increased ACI in diabetic patients (P = 0.429), although it was a significant independent factor in non-diabetic patients (beta = 0.150, P < 0.0005). CONCLUSION: Aortic calcification in diabetic haemodialysis patients is more advanced, compared with non-diabetic patients, even with short haemodialysis vintage. Since disorders of mineral metabolism are not significantly associated with aortic calcification in diabetic haemodialysis patients, aortic calcification in these patients could be affected by metabolic abnormalities associated with the diabetic state per se, independent of other confounding factors; and aortic calcification may be advanced even before haemodialysis induction.

Abstract: Sevelamer hydrochloride (SH) is widely used for the treatment of hyperphosphatemia in patients with renal failure who are on maintenance hemodialysis. In this study, we investigated the clinical effects of SH, administered as either monotherapy or combined with a calcium carbonate formulation, on the metabolism of calcium (Ca) and phosphorus (P) in patients who had been taking a Ca-based binder. Patients were divided into three groups (i): switched completely from a Ca-based binder to SH (complete switch); (ii) dosage of the Ca-based binder was reduced, and SH introduced (partial switch); and (iii) dosage of the Ca-based binder was not reduced and SH introduced (combination therapy). We also examined the effects of the introduction of SH on the lipid profile and parathyroid hormone (PTH) concentration. Comparison between groups of the numbers of successfully treated cases (reaching target concentrations of serum P=5.5 mg/dL and Ca x P product=55 mg2/dL2 within 6 months of treatment) showed that the likelihood of reaching target levels was higher if Ca-based binder was maintained as much as possible (combination therapy>partial changeover>complete changeover). Furthermore, treatment with SH decreased total cholesterol and non-HDL cholesterol concentrations significantly, and also increased HDL cholesterol and PTH concentrations compared to pre-treatment. These results suggest that when a calcium carbonate formulation is already in use, as far as compliance allows, the dosage should not be reduced when SH is added. Despite its beneficial effects on the lipid and PTH concentrations, preventing an excessive increase in the PTH concentration is essential when using SH.

Abstract: OBJECTIVE: A statin, a potent lipid-lowering drug, improves pain-free walking distance in patients with peripheral arterial disease (PAD) without increasing the ankle-brachial pressure index (ABI). Arterial stiffness affects the blood flow of peripheral arteries. The purpose of this study was to evaluate the effect of cholesterol-lowering with atorvastatin on regional arterial stiffness in patients with type 2 diabetes mellitus. METHODS: The subjects were 22 type 2 diabetic patients with hypercholesterolemia, who received atorvastatin at a daily dose of 10 mg for 6 months. Before and after the treatment with atorvastatin, we measured pulse wave velocity (PWV) in the heart-brachial, heart-carotid, heart-femoral and femoral-ankle segments. RESULTS: Following treatment with atorvastatin, femoral-ankle PWV showed a significant reduction. The PWV of other arterial segments tended to decrease, although the changes were not statistically significant. We found no significant changes in blood pressure, heart rate, ABI, or plasma concentrations of glucose, L-arginine and asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial function. CONCLUSIONS: Atorvastatin treatment was associated with an improvement in the stiffness of leg arteries in type 2 diabetes mellitus. This may partly explain the statin-mediated improvement of walking performance in those with PAD.

Abstract: BACKGROUND: Although an increased serum phosphate concentration is a significant risk factor for vascular calcification, it is unclear whether serum phosphate level is a risk factor for increased arterial wall thickness in hemodialysis patients. METHODS: Using B-mode ultrasonography, we examined intima-medial thickness (IMT) of the carotid artery of hemodialysis patients and analyzed risk factors for increased IMT with regard to the effect of serum phosphate. Seven hundred sixteen hemodialysis patients were enrolled (547 patients without diabetes, 169 patients with diabetes; 441 men, 275 women; age, 60 +/- 8.5 years). RESULTS: IMT of patients with diabetes was significantly greater than that of patients without diabetes (0.859 +/- 0.250 versus 0.783 +/- 0.178 mm; P < 0.0001). For the group of all patients, IMT correlated weakly, but significantly, with serum phosphate level (r = 0.093; P = 0.0127). In multiple regression analysis of the group of all patients, greater serum phosphate level (beta = 0.166; P < 0.0001) was shown to be a significant independent risk factor for increased carotid IMT, in addition to other significant independent risk factors, including advanced age, higher blood pressure, greater non-high-density lipoprotein cholesterol level, and the presence of diabetes (R2 = 0.1119; P < 0.00001). In multiple regression analyses performed separately for hemodialysis patients without and with diabetes, greater phosphate level and advanced age were significant independent risk factors for increased IMT, independent of other confounding risk factors. CONCLUSION: These results show that in addition to advanced age, greater serum phosphate level is a significant and independent factor associated with advanced arteriosclerosis in hemodialysis patients with and without diabetes, suggesting that phosphate levels should be controlled appropriately to prevent an increase in arterial wall thickness in hemodialysis patients.

Abstract: Intercellular adhesion molecule-1 (ICAM-1) is involved in inflammation and development of atherosclerotic change of vascular endothelium. The aim of the present study is to investigate whether K469E polymorphism of the ICAM-1 gene is associated with various clinical factors including plasma fibrinogen in patients with type 2 diabetes. ICAM-1 gene polymorphism was examined using polymerase chain reaction and restriction enzyme analysis in 360 type 2 diabetic patients. Plasma fibrinogen levels and other clinical variables were measured as well as circulating soluble ICAM-1 (sICAM-1) levels by enzyme-linked immunosorbent assay. The distribution of ICAM-1 genotypes, EE, EK, and KK, was not significantly different between type 2 diabetes and 152 healthy control subjects. Among 3 groups according to ICAM-1 genotypes in type 2 diabetes, no difference was found in adiposity, glycemic control, lipid profile, insulin sensitivity evaluated by homeostasis model assessment, or sICAM-1. Regarding fibrinogen, the patients with E allele showed significantly lower plasma fibrinogen levels in a dose-dependent manner (P = .033). Spearman rank correlation analyses revealed that ICAM-1 genotype showed significant correlation with plasma fibrinogen level (P < .001). In multiple regression analysis, ICAM-1 genotype was independent contribution factor of plasma fibrinogen level as well as high-density lipoprotein-cholesterol and urinary albumin excretion (R2 = 0.148, P < .001). In conclusion, K469E polymorphism of the ICAM-1 gene had impact on plasma fibrinogen level independently of other clinical factors in 360 type 2 diabetic patients, suggesting that fibrinogen is a candidate which links the ICAM-1 gene polymorphism to atherosclerosis.

Abstract: OBJECTIVE: Advanced glycation endproducts, AGEs, and its specific receptor, RAGE, are involved in diabetic vascular complications. Endogenous secretory RAGE, esRAGE, has been identified as an alternatively spliced form of RAGE, and shown to act as a decoy receptor for AGE. Here, we measured plasma esRAGE level with a recently developed enzyme-linked immunosorbent assay (ELISA) and examined its association with atherosclerosis in age- and gender-matched 203 type 2 diabetic and 134 nondiabetic subjects. METHODS AND RESULTS: Plasma esRAGE was inversely associated with carotid or femoral atherosclerosis, as quantitatively measured as intimal-medial thickness (IMT) by arterial ultrasound. Stepwise regression analyses revealed that plasma esRAGE was the third strongest and independent factor associated with carotid IMT, following age and systolic blood pressure. Plasma esRAGE was significantly lower in diabetic patients (0.176+/-0.092 ng/mL) than nondiabetic controls (0.253+/-0.111). Of note, in all, diabetic or nondiabetic group, plasma esRAGE was significantly and inversely correlated with components of the metabolic syndrome including body mass index, blood pressure, triglyceride, HbA1c, or an insulin resistance index. Stepwise regression analyses showed that body mass index or insulin resistance index was the major factor determining plasma esRAGE in all, nondiabetic or diabetic population. CONCLUSIONS: esRAGE is a novel and potential protective factor for the metabolic syndrome and atherosclerosis.

Abstract: The aim of this cross-sectional study was to investigate whether physical activity and local arterial thickening may affect bone metabolism. To analyze the effects of physical activity and atherosclerosis on bone in healthy Japanese people, health-related quality of life (HRQL) and local arterial thickening were assessed by means of the Medical( )Outcomes Study 36-item Short Form (SF-36), and intimal-medial thickness (IMT) in common carotid artery (CA) and femoral artery (FA), respectively. Bone mineral density (BMD) in lumbar spine was measured by dual X-ray absorptiometry and the osteo-sono assessment index (OSI) of the calcaneus by ultrasound. Healthy subjects (106 male and 154 female) were recruited from those who participated in a local health check program at the Osaka City University Hospital. A significant correlation existed between lumbar spine BMD and calcaneus OSI (r=0.551, P<0.0001). Among various scores in SF-36, only physical functioning score correlated weakly but significantly in a positive manner with lumbar spine BMD (rho=0.156, P=0.0147) and calcaneus OSI (rho=0.190, P=0.0024). Lumbar spine BMD correlated negatively with FA IMT (rho=-0.191, P=0.0027) whereas calcaneus OSI with FA IMT (rho=-0.199, P=0.0014). Multiple regression analyses revealed a significant association between FA IMT and calcaneus OSI, whereas lumbar spine BMD did not correlate significantly with FA or CA IMT. When subjects were restricted to female, FA IMT, but not CA IMT, still showed tendency against independent factors negatively associated with calcaneus OSI. Furthermore, lumbar spine BMD, but not calcaneus OSI, was weakly but significantly associated with increased physical functioning score independently. In conclusion, it was suggested that physical activity may affect bone strength in lumbar spine and calcaneus and that FA IMT might be a significant determinant of bone strength in calcaneus, but not in lumbar spine, in healthy Japanese subjects.

Abstract: Patients with chronic kidney disease (CKD) have an increased risk for death from cardiovascular disease (CVD). They have multiple metabolic abnormalities that may accelerate atherosclerosis, such as hypertension, insulin resistance, and dyslipidemia, along with other CKD-related risk factors. In addition, a considerable proportion of patients with advanced stages of CKD are malnourished, presenting "metabolic syndrome with malnutrition". The presence of malnutrition/inflammation dramatically changes the apparent relationship between CVD death risk and some risk factors. For example, in stage 5 CKD patients on hemodialysis, a higher body mass index and a higher plasma cholesterol are predictors of better survival. To understand the paradoxic epidemiology, we should recognize risk factors for occurrence of CVD events and risk factors of fatality after an event. In this article, we review the unique situation of CKD, emphasizing the need of more strict control of both types of risk factors to improve survival of CKD patients.

Abstract: Patients with end-stage renal disease (ESRD) show an inverse association between body mass index and risk of death from cardiovascular disease. Paradoxical epidemiology may suggest some beneficial effects of body fat in ESRD. Because an antiatherogenic adipocytokine adiponectin is increased in uremic plasma, we tested a hypothesis that, in ESRD, plasma adipocytokine profile may be less atherogenic or that the relationship between body fat and adipocytokines may be altered. The subjects were 103 patients with ESRD undergoing hemodialysis and 166 healthy subjects comparable in age and sex. We measured body fat mass by dual-energy x-ray absorptiometry and plasma levels of adiponectin and leptin by enzyme-linked immunosorbent assay. The ESRD group showed a significant increase in plasma adiponectin, leptin, and adiponectin/leptin ratio than the healthy subjects. Although sex and fat mass were significant factors correlating with plasma adiponectin level in the healthy group, none of these were significantly associated with plasma adiponectin in the patients with ESRD. In contrast, leptin showed significant relationships with sex and fat mass regardless of the presence of ESRD. Plasma adiponectin correlated negatively with plasma triglycerides and positively with high-density lipoprotein cholesterol in both healthy and ESRD groups, suggesting that uremic adiponectin retains its actions in favor of its antiatherogenicity. Thus, plasma adipocytokine profile was altered in ESRD, and the effects of body fat and sex on adiponectin were less significant in the patients with ESRD.

Abstract: It is well-known that secondary hyperparathyroidism of uremia influences not only bone and mineral metabolism but also cardiovascular complications. Here we reported the effects of the level of serum intact PTH and its gene polymorphism on cardiovascular and non-cardiovascular mortality in hemodialysis patients. We analyzed the association between clinico-molecular parameters and 3-year survival in 508 hemodialysis patients among whom 90 patients died. The multivariate Cox proportional hazards models showed that the presence of diabetes mellitus, levels of albumin and intact PTH, and BstB I genotype were indicated as independent predictors of cardiovascular mortality, whereas age and albumin level were indicated as those of non-cardiovascular mortality, suggesting that the level of intact PTH and its gene polymorphism effect cardiovascular mortality in hemodialysis patients.

Abstract: Recent evidence suggests important roles for platelet activation in the progression of atherosclerosis. We have recently shown that P-selectin expression or the presence of platelet-monocyte aggregates, a well-characterized marker of platelet activation, is associated with carotid atherosclerosis in the general population. It is not clear, however, whether platelet activation is also associated with carotid atherosclerosis in patients with type 2 diabetes. In the present study, we measured circulating levels of platelet-monocyte aggregates in 120 patients with type 2 diabetes and 120 age- and gender-matched non-diabetic subjects, and examined their association with carotid atherosclerosis determined by arterial ultrasound. The percentage of platelet-monocyte aggregates was analyzed by CD41-positivity determined by whole-blood flow cytometry. Diabetic subjects (7.73 +/- 4.04%, mean +/- SD) showed significantly higher percentages of platelet-monocyte aggregates than non-diabetic subjects (6.03 +/- 4.38%). The percentage of these aggregates was significantly and positively correlated with HbA(1c) in both diabetic and non-diabetic subjects, with the association independent of other clinical factors. Logistic multiple regression analyses revealed that platelet-monocyte aggregates were significantly associated with the presence of carotid plaques independent of the status of glycemic control in diabetic subjects. Thus, an increase in platelet-monocyte aggregation in type 2 diabetic patients appears to be involved in the pathophysiology of carotid atherosclerosis.

Abstract: BACKGROUND: It is difficult to predict the hypoglycemic effect of pioglitazone (a thiazolidinedione) as an insulin sensitizer. The purpose of the present study was to investigate whether insulin resistance index, homeostasis model assessment index (HOMA-IR) is a useful predictor of hypoglycemic effect of pioglitazone in comparison with body mass index (BMI). METHODS: Thirty-four type 2 diabetic patients (14 men and 20 women, mean age 60 +/- 14 years) were treated with pioglitazone, 15 mg per day for 3 months. Eighteen subjects showed a decrease of 0.5% or more in HbA1C after treatment and were considered responders while 16 subjects were non-responders. A receiver operating characteristic (ROC) analysis was performed to determine HOMA-IR and BMI sensitivity and the false positive rate (1-specificity) for discriminating responders from non-responders. RESULTS: Although there was no significant difference in age, sex, fasting plasma glucose, HbA1C and BMI between responders and non-responders, fasting insulin levels and HOMA-IR prior to treatment were significantly higher in the responders than in the non-responders. In ROC analysis, the sensitivity, false positive rate, and efficiency for HOMA-IR at the cut-off value, 4.6, with the highest efficiency were 81.2%, 22.2%, and 79.4%, respectively, and those for BMI at the cut-off value, 29.1, were 87.5%, 53.3%, and 67.7%, respectively. CONCLUSION: HOMA-IR is a useful predictor of pioglitazone treatment in type 2 diabetic patients.

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Abstract: BACKGROUND: Fibroblast growth factor (FGF)-23 is a recently identified circulating factor which causes renal phosphate wasting disorders. Although the mechanism of regulation of FGF-23 secretion is unknown, plasma FGF-23 level may be regulated or affected by serum phosphate levels because of its hypophosphatemic effect. METHODS: We tested the hypothesis that plasma FGF-23 levels may be increased in hyperphosphatemia in patients with end-stage renal disease (ESRD) on maintenance hemodialysis. We measured plasma FGF-23 levels in 158 male uremic patients on maintenance hemodialysis. Plasma samples were obtained before starting dialysis sessions to determine FGF-23 levels by enzyme-linked immunosorbent assay (ELISA). RESULTS: Plasma FGF-23 level exhibited significant and positive correlations with inorganic phosphate, intact parathyroid hormone (PTH), corrected calcium, and duration of hemodialysis on simple regression analyses. All these associations remained significant in multiple regression analyses. CONCLUSION: Serum phosphate, calcium, and intact PTH could be regulators of FGF-23 levels in uremic patients on maintenance hemodialysis. Our results may provide new insights into the pathophysiologic effects of FGF-23 on calcium-phosphate homeostasis.

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Abstract: Atherosclerosis has two key components, thickening and stiffening of arterial wall. These parameters are quantified ultrasonographically by IMT (intima-media thickness) and PWV (pulse wave velocity). In the present study, we determined the FA IMT (IMT of the bilateral femoral artery) and PWV of femoral-ankle (PWV fa) and brachial-ankle (PWV ba) segments in order to examine whether the degree of atherosclerosis is different between paretic and non-paretic lower limbs in 24 patients with hemiparesis. The values of PWV fa, PWV ba and FA IMT were all significantly greater on the paretic than the non-paretic side. Furthermore, significant decreases in masses of muscle, bone and fat, determined by dual-energy X-ray absorptiometry, were observed in paretic lower limbs compared with the non-paretic side. PWV fa correlated significantly and negatively with muscle mass ( r =-0.488, P =0.0004) and tended to correlate negatively with BMC (bone mineral content; r =-0.264, P =0.069) when statistical analyses were performed with the paretic and non-paretic sides together. Multiple regression analysis elucidated that the muscle mass was associated significantly with PWV fa and PWV ba, independent of age, duration after cerebrovascular accident, gender, bone and fat mass and FA IMT. The muscle mass was still associated with increased PWV fa and PWV ba when multivariate analysis was conducted independently in the paretic and non-paretic sides. In summary, our results indicated that arterial thickening and stiffening were greater on the paretic than the non-paretic side and suggested that a decrease of muscle mass might be associated with increased arterial stiffening in the paretic lower limb.

Abstract: BACKGROUND: Renal failure results in deficiency of active vitamin D3 that has diverse effects on metabolism and organ functions. Treatment with active forms of vitamin D(3) ameliorates abnormalities in bone and mineral metabolism, cardiac function, immune response and others. We hypothesized that treatment with vitamin D(3) may be beneficial for survival in patients with end-stage renal disease (ESRD). METHODS: We compared the risk of death between regular users (n = 162) and non-users (n = 80) of oral 1alpha-hydroxyvitamin D3 (alfacalcidol) in a cohort of ESRD patients undergoing haemodialysis for a follow-up of 61 +/- 23 months. The daily dose of alfacalcidol ranged from 0.25 to 1.5 microg, with a median of 0.5 microg. RESULTS: The alfacalcidol users showed a lower risk of death from cardiovascular disease than the non-users in a univariate Cox model [hazards ratio (HR) 0.287, 95% confidence interval (CI) 0.127-0.649, P = 0.003], whereas the risk for death from non-cardiovascular disease was not different between the two groups. Stepwise multivariate Cox analysis showed that cardiovascular mortality was significantly associated with age, presence of diabetes mellitus and treatment with alfacalcidol (HR 0.377, 95% CI 0.246-0.578, P = 0.022). CONCLUSIONS: These results indicate that use of oral alfacalcidol was associated with reduced risk for cardiovascular death in this cohort of ESRD patients. The result of this observational study warrants further randomized controlled trials with 1alpha-hydroxy vitamin D3 to confirm the possibility that such medication improves survival of ESRD patients.

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Abstract: BACKGROUND: Hemodialysis patients have advanced arterial wall stiffening as shown by increased aortic pulse wave velocity (PWV), an independent predictor of cardiovascular mortality. We compared aortic PWV of uremic patients before starting hemodialysis treatment with that of patients on maintenance hemodialysis. METHODS: The subjects were 71 patients with end-stage renal disease (ESRD) before starting hemodialysis (predialysis group), 144 patients on maintenance hemodialysis, and 140 healthy control subjects. These three groups were all nondiabetic and comparable in age and gender. RESULTS: The hemodialysis group had greater aortic PWV than the healthy subjects, and the predialysis patients showed a still higher value than the hemodialysis group. Multiple regression analysis in the total subjects revealed that the presence of renal failure was significantly associated with increased aortic PWV independent of age, gender, blood pressure, body mass index, smoking, high-density lipoprotein (HDL) and nonhigh-density lipoprotein (non-HDL) cholesterol levels. In contrast, hemodialysis was associated with decreased aortic PWV independent of renal failure and the other factors. Further analyses in the combined uremic patients again indicated the favorable impact of hemodialysis on aortic PWV independent of the classical risk factors, use of antihypertensive medications, including angiotensin-converting enzyme inhibitors and calcium channel blockers, hematocrit, serum calcium, phosphorus, parathyroid hormone levels, and the use of calcium carbonate. Insulin resistance using homeostasis model assessment (HOMA-IR) was associated with increased aortic PWV. CONCLUSION: Aortic stiffening was present in uremic patients before starting hemodialysis treatment and no adverse effect of hemodialysis was observed, suggesting the important roles of renal failure and/or metabolic alterations secondary to renal failure in arterial stiffness in patients with uremia.

Abstract: The purpose of the study was to investigate whether quantitative insulin sensitivity check index (QUICKI) and the reciprocal index of homeostasis model assessment (1/HOMA-IR) are excellent surrogate indexes of insulin resistance in type 2 diabetic patients with various ranges of fasting plasma glucose. One hundred eight type 2 diabetic patients were divided into tertiles according to fasting levels of plasma glucose (FPG) [T1: 4.2 < or = FPG (mmol/liter) < 6.5, n = 36; T2: 6.5 < or = FPG < 8.1, n = 36; T3: 8.1 < or = FPG < or = 11.1, n = 36]. The association between QUICKI or 1/HOMA-IR and insulin resistance index assessed by euglycemic hyperinsulinemic clamp (Clamp-IR) was investigated in each group. QUICKI was strongly correlated with Clamp-IR in all groups (r = 0.615 in T1, r = 0.659 in T2, and r = 0.788 in T3; all subjects, r = 0.691; all P < 0.001). Reciprocal of HOMA-IR also highly correlated with Clamp-IR in all groups (r = 0.600, r = 0.721, and r = 0.730, respectively; all subjects, r = 0.685; all P < 0.001). In conclusion, QUICKI and the reciprocal index of HOMA were highly correlated with Clamp-IR in type 2 diabetic patients with relatively wide ranges of fasting plasma glucose.

Abstract:

Abstract: OBJECTIVE: To investigate whether: (1) aerobic exercise decreases arterial stiffness and (2) reduction in arterial stiffness is associated with improvement in insulin resistance in type 2 diabetes. METHODS: Common carotid and femoral arterial stiffness was ultrasonographically evaluated using stiffness index beta in 23 type 2 diabetic subjects before and after a 3-week exercise protocol including ergometer and walking. Insulin sensitivity (Clamp-IR) was assessed using euglycemic-hyperinsulinemic clamp before and after the protocol. Arterial stiffness was also examined in steady hyperinsulinemic state during clamp. RESULTS: Anthropometrical factors did not change following exercise. Clamp-IR tended to increase after exercise protocol (P = 0.061). Stiffness index beta decreased following exercise in both common carotid and femoral arteries (P = 0.020 and P < 0.001, respectively). DeltaClamp-IR was significantly correlated with the changes in stiffness index beta of both common carotid (P = 0.040) and femoral artery (P = 0.016). Divided into tertiles according to DeltaClamp-IR, decreases in stiffness index beta for both common carotid (P = 0.009) and femoral (P = 0.037) arteries was greater in tertile group with a higher DeltaClamp-IR. Hyperinsulinemia during clamp decreased stiffness index beta in both common carotid (P = 0.031) and femoral (P = 0.025) arteries before exercise, but these effects disappeared after the exercise protocol. CONCLUSIONS: Short-term aerobic exercise significantly decreased arterial stiffness in both common carotid and femoral arteries, and the reduction of stiffness was associated with improvement of insulin resistance in type 2 diabetes.

Abstract: Vitamin D receptors are expressed not only in the classical target organs (bone, parathyroid glands, kidneys and intestine) but also in other non-classical targets including arteries, heart, immune system, endocrine organs, and nervous system. Therefore, the deficiency of active forms of vitamin D in uremia may explain various abnormalities in biological functions and survival disadvantage in this disease condition. Previous studies reported that treatment with vitamin D had beneficial effects on cardiac and immune functions in dialysis patients. A recent observational cohort study indicated that the mortality risk was different between the groups taking different types of vitamin D analogues. We found that patients on a low-dose oral alfacalcidol showed a significantly lower risk for cardiovascular death than those without vitamin D supplementation. Although these observations need further confirmation by randomized controlled studies, appropriate use of active forms of vitamin D may improve the outcomes of patients with chronic kidney disease.

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Abstract: Although evidence has accumulated indicating a close relationship between inflammation and atherosclerosis, the relationship between inflammation and vascular calcification in patients with chronic renal failure is unclear. In the present study, the relationship between C-reactive protein (CRP) and vascular calcification in dialysis patients was examined. Vascular calcification of the aorta and hand arteries of 512 hemodialysis patients without significant infection (age 58.8 +/- 10.1 y; 305 men, 207 women) were examined by roentgenography of the lateral abdomen and hands, respectively. Patients with a mean CRP level greater than 1.0 mg/L (n = 254) were older than those with a CRP level less than or equal to 1.0 mg/L (n = 258) and had a longer duration of dialysis, lower serum albumin level, and higher phosphate level ( P < .01, P < .05, P < .001, and P < .01, respectively). Prevalence of vascular calcification of aorta and hand arteries in the former group was significantly higher than in the latter (65.0% versus 43.8% for aorta, P < .0001; and 25.0% versus 14.7% for hand arteries, P < .01). In a multivariate logistic regression analysis adjusted for age, hemodialysis duration, sex, levels of calcium and phosphate, and presence of diabetes, CRP level was a significant predictor for the presence of aortic calcification (odds ratio for highest versus lowest quartile, 2.669; 95% confidence interval, 1.539-5.421, P = .0010) and of calcification of hand arteries (odds ratio, 2.243; 95% confidence interval, 1.039-4.841; P = .0395). In conclusion, the present study shows that increased levels of CRP are significantly associated with the presence of vascular calcification in both aorta and hand arteries (ie, with both atheromatous and medial forms of calcification), indicating evidence for a relationship between inflammation and vascular calcification in hemodialysis patients.

Abstract: Patients with end-stage renal disease have markedly increased risk for death from cardiovascular disease. Renal failure is associated with multiple metabolic and endocrinologic abnormalities, and these alterations are involved in advanced atherosclerosis and high cardiovascular risk. Increased insulin resistance index by homeostasis model assessment (HOMA-IR), a simple index of insulin resistance, was an independent predictor of cardiovascular mortality in nondiabetic patients on maintenance hemodialysis. Renal failure impairs lipoprotein metabolism leading to the atherogenic lipoprotein profile characterized by increased triglyceride-rich remnant lipoproteins such as intermediate-density lipoprotein, an independent factor of increased aortic stiffness. Non-high-density lipoprotein cholesterol, the sum of cholesterol of intermediate-density lipoprotein and other apoB-containing lipoproteins, is an independent factor associated with increased arterial thickness and a predictor of cardiovascular death in hemodialysis patients. The risk for cardiovascular death in hemodialysis patients is associated closely with hypertension and malnutrition, but not with obesity. The constellation of insulin resistance, dyslipidemia, hypertension, and malnutrition in renal failure suggests the presence of another type of metabolic syndrome promoting cardiovascular disease. In addition, vitamin D deficiency and abnormalities in calcium, phosphate, and parathyroid hormone levels increase the death risk from cardiovascular disease in renal failure. It is expected that treatment of these metabolic and endocrinologic alterations would improve the survival of patients with renal failure.

Abstract: BACKGROUND: Recent genetic animal models reveal important roles of platelet P-selectin on progression of atherosclerosis. In the present study, we examine the relation between platelet P-selectin expression and atherosclerotic parameters in 517 subjects. METHODS AND RESULTS: Unrelated subjects (n=517; 235 male and 282 female), including 187 with type 2 diabetes, 184 with hypertension, and 366 with hyperlipidemia, were enrolled in the study. P-selectin expression was determined by whole-blood flow cytometry. Arterial stiffness (stiffness index beta) and arterial wall thickness (intima-media thickness [IMT]) were determined by carotid ultrasound. P-selectin expression was significantly and positively correlated with carotid IMT and stiffness index beta. Multiple regression analyses showed that the association of the percentage of P-selectin-positive platelets with carotid IMT was independent of other clinical factors. Moreover, the percentage of P-selectin-positive platelets was higher in subjects with carotid plaque and was an independent factor associated with occurrence of carotid plaque analyzed by multiple logistic regression analysis. Finally, the percentage of P-selectin-positive platelets was positively associated with age, body mass index, systolic and diastolic blood pressure, and HbA1c and inversely associated with HDL cholesterol. CONCLUSIONS: Platelet P-selectin is independently associated with atherosclerotic arterial wall changes in human subjects.

Abstract: The aim of the present study is to investigate whether Met416Val (M416V) polymorphism of glycogen synthase (GYS1) gene is associated with insulin resistance in type 2 diabetes. In 100 type 2 diabetic subjects (66 men and 34 women), the M416V polymorphism of GYS1 gene was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) as previously reported, and insulin resistance was assessed by euglycemic hyperinsulinemic clamp represented as M/I value, the mean of glucose infusion rate (M value) adjusted by steady state plasma insulin level. The means of age and body mass index (BMI) of the subjects were 53.1+/-11.6 (SD) years and 23.3+/-3.5 kg/m2. The allele frequencies of M416V polymorphism were 82.0% for MM, 16.0% for MV, and 2.0% for VV, and subjects were subsequently divided into V(+) group (n=18) and V(-) group (n=82) according to the presence or absence of V allele. There were no significant differences in age, BMI, blood pressure, fasting plasma glucose or insulin levels or glycosylated hemoglobin (HbA1c) levels between the V(+) and V(-) groups. No significant differences in either M or M/I value were found between the V(+) and V(-) groups (M value, 5.06+/-2.20 v 5.12+/-2.04 mg x kg(-1) x min(-1), P=.841; M/I value, 5.24+/-3.07 v 5.39+/-2.87 mg x kg(-1) x min(-1) x mU(-1) x L, P=.576). BMI showed the strongest independent contribution to M/I value, but the presence of V allele did not in multiple regression analysis. In conclusion, the M416V polymorphism of GYS1 gene is not associated with insulin resistance in type 2 diabetes.

Abstract: OBJECTIVE: To investigate whether the quantitative insulin sensitivity check index (QUICKI) and the reciprocal index of homeostasis model assessment (1/HOMA-IR) derived from fasting plasma glucose and insulin level are excellent surrogate indices of insulin resistance in both normal range-weight and moderately obese type 2 diabetic and healthy subjects. RESEARCH DESIGN AND METHODS: The association between QUICKI or 1/HOMA-IR and insulin resistance index assessed by euglycemic-hyperinsulinemic clamp (clamp-IR) was investigated in 121 type 2 diabetic and 29 healthy subjects recruited from among 120 (age 55 +/- 11, 48 +/- 15, and 52 +/- 15 years [means +/- SD], respectively). Type 2 diabetic subjects were divided into groups of 76 normal range-weight and 45 moderately obese subjects (BMI 21.4 +/- 2.3 vs. 27.2 +/- 2.2 kg/m(2), P < 0.0001). RESULTS: QUICKI and 1/HOMA-IR were significantly lower in the moderately obese group than in the normal range-weight type 2 diabetic and healthy groups (n = 120) (QUICKI, 0.338 +/- 0.030, 0.371 +/- 0.037, and 0.389 +/- 0.041, respectively, P < 0.0001; 1/HOMA-IR, 0.50 +/- 0.33, 0.92 +/- 0.55, and 1.24 +/- 0.82, P < 0.0001). QUICKI was strongly correlated with clamp-IR in normal range-weight, moderately obese type 2 diabetic, and healthy subjects (r = 0.641, 0.570, and 0.502, respectively; all subjects, r = 0.608, P < 0.01) and 1/HOMA-IR exhibited correlations comparable to those of QUICKI with clamp-IR (r = 0.637, 0.530, and 0.461, respectively; all subjects, r = 0.589, P < 0.001). In multiple regression models including QUICKI or 1/HOMA-IR as an independent variable, the estimation formula accounted for 55% of the variability of clamp-IR for the group of all type 2 diabetic subjects (R(2) = 0.547 and 0.551, respectively, P <or= 0.0001). CONCLUSIONS: QUICKI and 1/HOMA-IR were highly correlated with clamp-IR, with comparable coefficients in both normal range-weight and moderately obese type 2 diabetic patients and nondiabetic subjects. The latter can probably be applied clinically in view of its convenience.

Abstract: OBJECTIVE: Hyperglycemia and hypertension are known to be risk factors for the development of proteinuria in patients with diabetes. Little is known, however, about predictors of progression of renal failure in diabetic patients. RESEARCH DESIGN AND METHODS: We investigated factors affecting progression of renal failure by measuring the doubling of serum creatinine (s-Cr) as an end point in a cohort of 85 type 2 diabetic patients with chronic renal insufficiency/failure (s-Cr >1.5 and <3.7 mg/dl, 61 +/- 11 years old, 51 men and 34 women, mean s-Cr 2.3 +/- 0.6 mg/dl). RESULTS: The survey period (mean +/- SD) was 14.2 +/- 10.8 months. The cumulative incidence of the end point in patients with insulin therapy (n = 41) was significantly lower than that in patients without it (n = 44) (P = 0.0022, P values by log-rank test). Multivariate Cox analysis revealed insulin therapy (hazard ratio [HR] 0.435, 95% CI 0.252-0.750, P = 0.0027), serum albumin (0.484, 284-0.823, P = 0.0074), mean blood pressure (1.023, 1.004-1.043, P = 0.017), and hemoglobin (0.841, 0.728-0.972, P = 0.0194) to be independent and significant predictors of progression to renal failure, whereas HbA(1c) or serum cholesterol were not. CONCLUSION: In type 2 diabetic patients with renal failure, hypoalbuminemia, anemia, higher mean blood pressure, and lack of use of insulin predict rapid progression of renal failure, but HbA(1c) does not, and insulin therapy may be possibly an indicator of the delay in progression of renal failure.

Abstract: BACKGROUND: Patients with end-stage renal disease (ESRD) often show lipid abnormalities that may promote atherosclerosis. Although the standard lipid marker is low-density lipoprotein cholesterol (LDL-C) in official recommendations, the need of fasting blood sampling has prevented routine screening for plasma lipids in hemodialysis patients. METHODS: We therefore evaluated the power of non-high-density lipoprotein cholesterol (non-HDL-C) in predialysis (non-fasting) serum as a predictor of cardiovascular mortality in a cohort of 525 hemodialysis patients. RESULTS: During the mean follow-up of 64 months, 120 deaths, including 44 fatal cardiovascular events, occurred. Patients in the highest tertile of non-HDL-C (137 to 285 mg/dL) had a significantly higher risk for cardiovascular mortality (HR, 3.065; 95% CI, 1.357 to 6.925; P = 0.007) [correction] in a univariate Cox analysis. The association between non-HDL-C and cardiovascular mortality remained significant in multivariate Cox models, which included HDL-C, age, gender, duration of hemodialysis, blood pressure, presence of diabetes mellitus, serum albumin, C-reactive protein, and body mass index. CONCLUSION: Non-HDL-C in predialysis serum was a significant and independent predictor of cardiovascular mortality in hemodialysis patients. Non-HDL-C may be a useful marker for risk assessment in routine practice, although predictive powers of this and the standard fasting LDL-C should be compared in future studies.

Abstract: BACKGROUND: Immune response to oxidized low-density lipoprotein (oxLDL) may modulate atherogenesis. We recently reported that a high titer of serum anti-oxLDL antibody was an independent predictor of a low risk for cardiovascular death in patients with end-stage renal disease (ESRD). In the present study, we examined a possible association between anti-oxLDL antibody titer and arterial wall thickness in ESRD patients. METHODS: The subjects were 103 ESRD patients treated with hemodialysis. A high resolution B-mode ultrasound method was used to measure intima-media thickness of carotid (CA-IMT) and femoral arteries (FA-IMT). RESULTS: In univariate analysis, anti-oxLDL antibody showed a significant negative correlation with FA-IMT. The inverse association between anti-oxLDL antibody and FA-IMT remained significant in multiple regression analysis, including age, gender, blood pressure, plasma lipids, smoking, C-reactive protein, calcium-phosphate product, serum albumin, body mass index, and duration of dialysis as covariates. The antibody titer showed an inverse trend with CA-IMT without statistical significance. CONCLUSION: These results show for the first time that titer of anti-oxLDL antibody is an independent factor inversely associated with arterial thickness in ESRD, supporting the concept that immunity against oxLDL plays an anti-atherogenic role.

Abstract: BACKGROUND: Although vitamin D has been reported to be useful in the treatment of patients with secondary hyperparathyroidism, it is not effective in some of them. The goal of this study was to see whether a relationship could be found between maxacalcitol responsiveness and parathyroid gland size. METHODS: Parathyroid gland size was measured by ultrasonography in 25 patients with secondary hyperparathyroidism [serum intact parathyroid hormone (PTH) >300 pg/ml, 58.1 +/- 2.8 years old, 15 males and 10 females], who were treated with maxacalcitol. Patients were divided into two groups according to the mean value of the maximum diameter of the glands: group S with a diameter <11.0 mm and group L with a diameter >or =11.0 mm. Between the two groups there were no significant differences in serum intact PTH, calcium or phosphate level or duration of haemodialysis. RESULTS: Mean (+/- SE) maximal diameter of detectable parathyroid glands was 11.0 +/- 0.7 mm before treatment. At 4-24 weeks after administration of maxacalcitol, intact PTH concentrations decreased significantly in group S (from 546 +/- 39 to 266 +/- 34 pg/ml at 24 weeks; P < 0.01), but did not significantly change in group L (from 481 +/- 39 to 403 +/- 49 pg/ml at 24 weeks). At 24 weeks after maxacalcitol administration, the number of detectable parathyroid glands was significantly decreased in group S (from 2.2 +/- 0.3 to 1.8 +/- 0.4; P < 0.05), but not in group L. Serum calcium increased significantly in group L (from 9.6 +/- 0.2 to 10.2 +/- 0.3 mg/dl; P < 0.05), but not in group S. There was a significant correlation between reduction in PTH and parathyroid gland size (r = -0.42, P < 0.05). CONCLUSIONS: These results indicate that the responsiveness to maxacalcitol therapy of secondary hyperparathyroidism is dependent on parathyroid gland size and that the simple measurement of maximum parathyroid gland diameter by ultrasonography may be useful for predicting responsiveness to maxacalcitol treatment.

Abstract:

Abstract: BACKGROUND: Cardiovascular disease is the leading cause of death in patients with end-stage renal disease (ESRD). Previous studies showed that patients with ESRD had increased intima-media thickness of the carotid artery (CA-IMT). In the present study, we examined whether CA-IMT would predict cardiovascular mortality in patients with ESRD. METHODS: The cohort consisted of 438 patients with ESRD treated with hemodialysis. CA-IMT was measured by high-resolution B-mode ultrasonography. RESULTS: During the follow-up period of 30 months, 82 deaths, including 44 cardiovascular fatal events, occurred. Compared with those with CA-IMT less than 1.0 mm, those with moderately increased CA-IMT (1.0 to 2.0 mm) and those with severely increased CA-IMT (>or=2.0 mm) showed a significantly greater risk for death from cardiovascular causes; odds ratios were 3.17 (95% confidence interval [CI], 1.41 to 7.17; P = 0.005) and 10.20 (95% CI, 3.67 to 28.3; P < 0.0001), respectively, in a multivariate Cox analysis including age, sex, duration of hemodialysis therapy, presence of diabetes mellitus, blood pressure, body mass index, and high-density lipoprotein and non-high-density lipoprotein cholesterol levels as covariates. Conversely, CA-IMT was not significantly associated with noncardiovascular mortality. CONCLUSION: These results indicate that increased CA-IMT is an independent predictor of cardiovascular mortality in the hemodialysis population.

Abstract: OBJECTIVE: We recently reported that rheumatoid arthritis (RA) patients had increased intima-media thickness (IMT) of the common carotid artery (CCA). The present longitudinal study was performed to determine whether the change in arterial thickness was accelerated in RA patients and to determine which factor was important in the progression of arterial wall changes. METHODS: We studied 62 female RA patients with stable disease activity and 63 healthy female controls. IMT of the CCA was measured twice by high-resolution B-mode ultrasonography. The second examination was performed 18-36 months after the first, and changes were expressed as millimeters of increase per year. Baseline examinations included blood markers of inflammation and urinary calcium excretion (expressed as the calcium-to-creatinine ratio). RESULTS: RA patients showed a significantly greater increase in IMT of the CCA compared with controls. In univariate analyses of the RA patient data, the C-reactive protein (CRP) level correlated with the increase in CCA IMT. Other markers of inflammation (the erythrocyte sedimentation rate and white blood cell and platelet counts) also showed significant positive associations with the annual increase in CCA IMT in multiple regression models when adjusted for age, smoking status, blood pressure, and serum cholesterol level. The urinary calcium-to-creatinine ratio was also significantly associated with an increase in CCA IMT. Moreover, both the CRP level and the urinary calcium-to-creatinine ratio were significantly and independently associated with the increase in IMT of the CCA. CONCLUSION: Patients with RA have a higher rate of increase in thickening of the arterial wall. Inflammation and calcium mobilization are factors closely associated with the accelerated arterial wall changes.

Abstract: OBJECTIVE: Patients with type 2 diabetes mellitus are at an increased risk of atherosclerosis including peripheral arterial disease (PAD). The purpose of this study was to examine the possible alteration in pulse wave velocity (PWV) in lower-limb arteries among diabetic patients with PAD. METHODS: We measured brachial-ankle PWV (baPWV) using an automatic device in 101 healthy control subjects and 102 type 2 diabetic patients including those with PAD. RESULTS: Diabetic patients without PAD showed a higher baPWV than the healthy control subjects. There was no significant difference in baPWV between the right and left legs in these groups. In contrast, among diabetic patients with PAD, baPWV was significantly lower in the affected legs than in the non-affected legs, and the reduction in baPWV was greater in those with lower ankle-brachial pressure index (ABI). In the patients with PAD who received percutaneous transluminal angioplasty, both baPWV and ABI were increased following successful vessel dilatation. CONCLUSIONS: These results suggest that baPWV is increased in diabetic patients, whereas it is decreased in the affected legs in diabetic patients with PAD. Widening of the right-left difference in baPWV may be a novel marker of PAD.

Abstract: The aim of the present study was to investigate the independent association of the intimal-medial thickness of carotid and femoral arteries (CA-IMT and FA-IMT), a marker of atheroscelosis, with insulin resistance in type 2 diabetic patients. We evaluated CA-IMT and FA-IMT by high-resolution ultrasonography and insulin resistance determined by euglycemic hyperinsulinemic clamp in 119 type 2 diabetic subjects, 71 males and 48 females (age, 54 +/- 12 (SD) years). In simple regression analyses, CA-IMT and FA-IMT were significantly inversely correlated with insulin sensitivity index (CA-IMT, r = -0.225, p = 0.010; FA-IMT, r = -0.186, p = 0.043, respectively). Multiple regression analysis was performed with the logarithm of CA-IMT or FA-IMT as a dependent variable and insulin sensitivity index as an independent variable along with known clinical risk factors. Insulin sensitivity index exhibited a significant independent contribution to log (CA-IMT) (beta = -0.204, p = 0.033) and to log (FA-IMT) (beta = -0.237, p = 0.010) in these models (CA-IMT, R(2) = 0.347, p < 0.0001; FA-IMT, R(2) = 0.398, p < 0.0001, respectively). In conclusion, insulin resistance is associated with both CA-IMT and FA-IMT in type 2 diabetic patients, suggesting that it is an independent risk factor for the development of atherosclerosis in type 2 diabetes.

Abstract: The prevalence of peripheral vascular disease (PVD) in diabetic patients is manyfold higher than that of age- and sex-matched nondiabetic subjects. This study was designed to evaluate the relationship between quantitatively determined peripheral circulation in the lower extremities and arterial wall thickness or stiffness in 68 patients with type 2 diabetes. Peripheral circulation during treadmill-exercise was monitored by transcutaneous oxygen tension (TcPO2) and was expressed as percentage of post-exercise TcPO2 adjusted by that of pre-exercise (TcPO2 index). Arterial wall thickness (intima-media thickness; IMT) and stiffness (stiffness beta) were measured by ultrasonography. TcPO2 index was negatively (r=-0.350, P=0.0007) correlated with stiffness beta, not with IMT, of the femoral artery. In patients without insulin therapy (n=52), both fasting plasma insulin concentration (r=-0.323, P=0.0023) and HOMA IR, an insulin resistance index, (r=-0.281, P=0.0084) were negatively correlated with TcPO2 index. Multiple regression analyses showed that association of stiffness beta of the femoral artery or HOMA IR with the TcPO2 index was independent of other factors including age, smoking index, ankle brachial pressure index and IMT of femoral artery. Thus, arterial wall stiffness of femoral artery appears to be a major determinant of peripheral circulation in patients with type 2 diabetes.

Abstract: BACKGROUND: Changes in body fat mass in a large number of hemodialysis patients is unknown. METHODS: Body fat mass and lean body mass were measured by dual x-ray absorptiometry (DXA) in 561 patients with hemodialysis duration less than 180 months (62.3 +/- 11.5 years old; mean +/- SD). RESULTS: Fat mass tended to increase during the first 3 years of hemodialysis, and it tended to decrease thereafter. Between hemodialysis duration and the fat mass index, there was a significant positive correlation within the first 36-month period of hemodialysis (r = 0.124; P < 0.05; n = 245), and a significant negative correlation during the period of 36 to 180 months. (r = -0.192; P < 0.001; n = 316). There was no tendency of change in the lean body mass index. CONCLUSION: Considering the results together with the authors previous prospective study results, which show significant fat mass increase in the first year of hemodialysis, the present cross-sectional study may suggest that fat mass gradually increases in the first 3 years and decreases thereafter. Fat mass is suggested to be a nutritional parameter in hemodialysis patients.

Abstract: Arterial stiffness affects cardiac functions, peripheral circulation, and cardiovascular mortality. We examined whether arterial stiffness in different regions is equally affected by diabetes and other factors. The subjects were 161 patients with type 2 diabetes and 129 healthy subjects comparable in age and sex. Arterial stiffness was evaluated by measuring pulse wave velocity (PWV) in the heart-carotid, heart-brachial, heart-femoral, and femoral-ankle segments using an automatic device. The diabetic patients had greater PWV than the healthy subjects in the four arterial regions, and the effect of diabetes on PWV was greater in the heart-carotid and heart-femoral segments (central) than in the heart-brachial and femoral-ankle regions (peripheral). PWV increased with age in the four arterial regions, and the effect of age on PWV was greater in the central than in peripheral arteries. In multiple regression analysis, age and systolic blood pressure had significant impacts on PWV of the four regions, whereas diabetes was significantly associated only with PWV of the central arteries. In contrast, sex was associated with PWV of the peripheral arteries. Thus, type 2 diabetes had greater impact on PWV of the central arteries, and different factors were involved in PWV among different arterial regions.

Abstract: OBJECTIVE: ACE inhibitors are known to be effective in preventing the progression of diabetic nephropathy. Activation of the renin-angiotensin system (RAS) is reported to contribute to intrarenal hemodynamic abnormality in diabetic patients. We examined whether RAS blockade by captopril induces intrarenal hemodynamic changes in normotensive patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The patients ranged in age from 40 to 65 years (20 men and 20 women). A total of 15 age- and sex-matched healthy individuals served as control subjects. Resistive index (RI) of interlobar arteries was examined by duplex Doppler sonography before and after the oral captopril (25 mg) test. RESULTS: At baseline, no significant differences in RI values or plasma renin activity (PRA) were seen between the patients and healthy subjects. In healthy subjects, the RI values after the captopril test were significantly higher than baseline values (P < 0.01). However, in patients with type 2 diabetes, both with normoalbuminuria and microalbuminuria, RI values after the test were significantly lower than baseline values (P < 0.001). There were significant negative correlations between DeltaRI value and HbA1c (r = -0.458, P < 0.005) and between DeltaRI value and baseline PRA in diabetic patients (r = -0.339, P < 0.05). Multiple regression analysis showed that HbA1c and baseline PRA significantly and independently affected the magnitude of decrease in RI values after captopril administration in diabetic patients (R2 = 0.391, P < 0.0001). CONCLUSIONS: These results indicate that the intrarenal RAS may be activated in diabetic patients, that such activation may be affected by poor glycemic control, and that blockade of RAS activation by ACE inhibitor reduces intrarenal vascular resistance in diabetic patients. The results emphasize the beneficial effects of ACE inhibition in improving intrarenal hemodynamics in diabetic patients.

Abstract: Polymorphism of alpha2 integrin (C807T) is shown to be associated with an increased incidence of thrombotic cardiovascular events. However, it is not clear whether this polymorphism is associated with atherosclerotic arterial wall thickening. In this study, we examined the association of C807T polymorphism with arterial wall thickness in 265 control subjects and 272 patients with type 2 diabetes. In all subjects, intima-media thickness of the right carotid artery in the 807TT group (0.649 +/- 0.028 mm [SE]) was significantly (P = 0.0228, Scheffe's F test) less than in the 807CC group (0.767 +/- 0.033). This effect of polymorphism is gene dose dependent (P = 0.0227, ANOVA). The similar association was also observed in patients with diabetes but not in control subjects. Multiple regression analysis in all subjects revealed that the T allele was inversely (beta = -0.095, P = 0.021) associated with intima-media thickness independent of age, HbA(1c), and HDL cholesterol. Finally, an inverse relation between the occurrence of carotid plaque and the T allele was observed in patients with diabetes with an adjusted odds ratio of 0.487 (P = 0.031) in multiple logistic regression analyses. These results suggest that the number of 807T alleles in alpha2 integrin is protective against atherosclerotic arterial wall thickening and the occurrence of plaque in patients with type 2 diabetes.

Abstract: BACKGROUND: Atherosclerosis is advanced in hemodialysis patients as shown by increased intima-media thickness of carotid arteries (CA-IMT), although it is not established whether the advanced atherosclerosis results from hemodialysis treatment or from chronic renal failure. The purpose of this study was to evaluate the effects of hemodialysis and renal failure on CA-IMT in patients with chronic renal failure. METHODS: CA-IMT was measured by high-resolution B-mode ultrasonography in 110 patients with chronic renal failure before starting dialysis (CRF group), and compared with CA-IMT of 345 hemodialysis patients (HD group) and 302 healthy control subjects. They were all nondiabetic and the three groups were comparable in age and gender. RESULTS: As compared with the healthy control subjects, the CRF and HD groups had greater CA-IMTs, whereas CA-IMTs of the CRF and HD groups were not statistically different. There was no significant correlation between duration of hemodialysis and CA-IMT in the HD group. Multiple regression analysis in the total subjects indicated that presence of renal failure, but not being treated with hemodialysis, was a significant factor associated with increased CA-IMT independent of age, gender, blood pressure, smoking, high-density lipoprotein (HDL) and non-HDL cholesterol levels. CONCLUSIONS: These results demonstrate that thickening of arterial wall is present in patients with chronic renal failure before starting hemodialysis treatment, and support the concept that advanced atherosclerosis in hemodialysis patients is due not to hemodialysis treatment, but to renal failure and/or metabolic abnormalities secondary to renal failure.

Abstract: BACKGROUND: Few studies have addressed the effect of vasodilatory stimuli on the intrarenal arterial system in type 2 diabetes mellitus (DM), and factors affecting its responsiveness. METHODS: One hundred twenty-four patients with type 2 DM without renal failure were enrolled, and 25 subjects served as controls. Using duplex Doppler sonography, resistive indices (RI) of interlobar arteries were measured before and after sublingual nitroglycerine (NTG) (0.3 mg) spray over a 10-min period. RESULTS: Per cent changes in RI (%DeltaRI) in the DM group were significantly less than in controls (P<0.05), as was the area over the %DeltaRI-time curve (AOC-%DeltaRI, total responsiveness to nitroglycerine) (P<0.05). In the DM group, significant negative correlations were found between AOC-%DeltaRI and age (r=-0.492, P<0.0001). AOC-%DeltaRI in DM patients with proteinuria was significantly lower than without it (P<0.003). AOC-%DeltaRI in smokers was also significantly lower than in nonsmokers (P<0.05). By multiple regression analysis of the DM group, AOC-%DeltaRI was found to be significantly and independently affected by age (beta=-0.394), smoking (beta=-0.211), and the presence of proteinuria (beta=-0.270; R(2)=0.354, P<0.0001). CONCLUSIONS: Diabetic patients have a lower level of responsiveness to NTG. Advanced age, smoking, and proteinuria significantly affect response to NTG in DM patients, suggesting that advanced intrarenal arteriosclerosis may be contributory. Smoking is suggested to be a risk factor for progression of diabetic nephropathy, likely contributing to poor responsiveness of the intrarenal arterial system to vasodilatory stimuli.

Abstract: Cholesteryl ester transfer protein (CETP) is a key regulating factor of lipid metabolism, and the polymorphism of its gene may therefore be a candidate for modulating the lipid parameters, altering the susceptibility to atherosclerosis in type 2 diabetic subjects. In a group of 443 unrelated Japanese patients with type 2 diabetes, we studied the B1B2 polymorphism at the CETP locus, which is detectable with the restriction enzyme TaqI. Patients were separated into three groups according to genotype and compared based on their clinical characteristics, lipid parameters, and macrovascular complications. The B2 allele was associated in a dose-dependent fashion with higher HDL cholesterol and apolipoprotein AI levels, together with lower CETP concentrations. Furthermore, the prevalence of macrovascular complications, such as coronary heart disease, arteriosclerosis obliterans, and cerebral vascular disease, was significantly higher in subjects with the B1B1 genotype. Multiple logistic regression analysis also showed that the B1 allele of CETP genotype was associated with the incidence of these three complications independently of other risk factors. Thus, in type 2 diabetic patients, the B1B2 polymorphism of CETP gene is likely to be a strong genetic predictor of macrovascular complications.

Abstract: Insulin resistance is closely associated with atherosclerosis and cardiovascular mortality in the general population. Patients with end-stage renal disease (ESRD) are known to have insulin resistance, advanced atherosclerosis, and a high cardiovascular mortality rate. We evaluated whether insulin resistance is a predictor of cardiovascular death in a cohort of ESRD. A prospective observational cohort study was performed in 183 nondiabetic patients with ESRD treated with maintenance hemodialysis. Insulin resistance was evaluated by the homeostasis model assessment method (HOMA-IR) using fasting glucose and insulin levels at baseline, and the cohort was followed for a mean period of 67 mo. Forty-nine deaths were recorded, including 22 cardiovascular deaths. Cumulative incidence of cardiovascular death by Kaplan-Meier estimation was significantly different between subjects in the top tertile of HOMA-IR (1.40 to 4.59) and those in the lower tertiles of HOMA-IR (0.28 to 1.39), and the hazard ratio (HR) was 2.60 (95% confidence interval [CI], 1.12 to 6.01; P = 0.026) in the univariate Cox proportional hazards model. In multivariate Cox models, the positive association between HOMA-IR and cardiovascular mortality remained significant (HR, 4.60; 95% CI, 1.83 to 11.55; P = 0.001) and independent of age, C-reactive protein, and presence of preexisting vascular complications. Further analyses showed that the effect of HOMA-IR on cardiovascular mortality was independent of body mass index, hypertension, and dyslipidemia. In contrast, HOMA-IR did not show such a significant association with noncardiovascular mortality. These results indicate that insulin resistance is an independent predictor of cardiovascular mortality in ESRD.

Abstract: We have experienced rare cases of membranoproliferative glomerulonephritis (MPGN)-like nephritis, which was seen in siblings. Both the brothers had asymptomatic hematuria and proteinuria at an age before 10, 7 and 4 years old, respectively. Renal biopsy revealed proliferative glomerulonephritis, resembling MPGN type III. The family history showed that their father and grandfather suffered from end-stage renal disease, suggesting that MPGN seen in the present sibling cases is hereditary. A review of the literature revealed that familial MPGN is rare, that most of the cases have urinary abnormalities at an age of less than 10 years, and that male preponderance is seen in familial MPGN.

Abstract: Diabetic bone disease is characterized by low bone turnover resulting from either impaired secretion of parathyroid hormone (PTH) or refractoriness of osteoblasts to PTH. The present study was performed to elucidate which factor contributes more to the reduction in bone turnover by comparison between 64 hemodialyzed patients with diabetes mellitus and 106 hemodialyzed patients without diabetes mellitus. Only men were enrolled to avoid the influence of the menstrual cycle on bone metabolism. Serum intact PTH (iPTH) levels were significantly lower in hemodialyzed patients with diabetes than those without diabetes, although no significant difference existed in age, duration of hemodialysis therapy, or serum calcium or phosphate levels. Of the biochemical markers measured, serum intact osteocalcin (iOC) and deoxypyridinoline levels were significantly lower in patients with diabetes, although serum bone-specific alkaline phosphatase (BAP) and pyridinoline levels did not differ significantly between the two groups of patients. When patients were restricted to those with serum iPTH levels greater than 180 pg/mL, this parameter correlated significantly in a positive manner with both serum iOC and BAP levels and negatively with bone mineral density at distal radius 1/3. Regression slopes between iPTH levels and these parameters were not significantly different between the two groups of patients, indicating the absence of refractoriness of bone to PTH in patients with diabetes. In conclusion, our findings suggest that impaired PTH secretion, but not refractoriness of osteoblasts to PTH, may be responsible for the low bone turnover in hemodialyzed patients with diabetes.

Abstract: OBJECTIVE: To determine whether arterial wall thickening is advanced in rheumatoid arthritis (RA) patients compared with healthy controls by measuring the intima-media thickness (IMT) of the common carotid and femoral arteries, and to evaluate the factors associated with arterial IMT in patients with RA. METHODS: We studied 138 RA patients and 94 healthy controls (matched for age, sex, and other major risk factors for atherosclerosis). IMT was measured on digitized still images of the common carotid and femoral arteries obtained by high-resolution ultrasonography (10-MHz in-line Sectascanner). Laboratory variables relevant to RA activity were measured by routine methods. The degree of RA progression was assessed by scoring (Larsen method) metacarpophalangeal (MCP) joints on hand radiographs. Activities of daily living were determined by a modified Health Assessment Questionnaire (M-HAQ) score, and physical activity levels were assessed by ultrasound measurement of the calcaneus (expressed as the osteo-sono assessment index [OSI] Z score). RESULTS: Common carotid and femoral artery IMTs were significantly higher (P < 0.05) in RA patients (mean +/- SD 0.641 +/- 0.127 and 0.632 +/- 0.125 mm, respectively) compared with controls (0.576 +/- 0.115 and 0.593 +/- 0.141 mm, respectively). Multiple regression analysis revealed a significant association between RA and the common carotid artery IMT. Moreover, the common carotid artery IMT in RA patients was positively associated with disease duration, the MCP joint Larsen score, and the M-HAQ score, and was negatively associated with the calcaneus OSI Z score. No significant association was found between corticosteroid treatment and common carotid artery IMT. CONCLUSION: RA patients exhibited greater thickness of the common carotid and femoral arteries than healthy controls. The duration and severity of RA and decreased activities of daily living, but not corticosteroid treatment, were independently associated with the increased arterial wall thickness.

Abstract: Elevated intermediate-density lipoprotein (IDL), a remnant lipoprotein, is an independent risk factor for atherosclerosis in patients with end-stage renal disease (ESRD). Since the presence of diabetes mellitus further increases the risk of cardiovascular mortality in ESRD, we examined the effect of diabetes on IDL among ESRD patients. The subjects were 330 healthy control subjects and 287 patients with end-stage renal disease including 80 patients with type 2 diabetes. As compared with the healthy subjects, the nondiabetic ESRD patients had increased plasma triglyceride and IDL cholesterol. Diabetic patients with ESRD showed a further increase in plasma triglyceride and IDL cholesterol compared with the nondiabetic group. However, the difference in IDL levels between the ESRD groups was no longer significant when subjects were stratified by plasma triglyceride. Plasma triglyceride was correlated with IDL cholesterol. Increased hemoglobin A(1c) was significantly associated with IDL cholesterol in a multiple regression model including age, gender, and the presence of ESRD. Such an association was no longer significant in another model including plasma triglyceride as an additional covariate. Further analysis indicated the positive effects of diabetes and hyperglycemia on plasma triglyceride. These results indicate that increased IDL in ESRD is further deteriorated in the presence of diabetes, and that the adverse effect is accounted for at least partly by hypertriglyceridemia associated with chronic hyperglycemia.

Abstract: AIM/HYPOTHESIS: Although derangements of calcium and phosphate control have been emphasized as important risk factors for vascular calcification in non-diabetic haemodialysis patients, similar risk factors for diabetic haemodialysis patients are not known. We compared factors affecting peripheral vascular calcification between haemodialysis patients with and without diabetes. METHODS: We examined 421 patients on maintenance haemodialysis. There were 89 patients with Type II (non-insulin-dependent) diabetes mellitus (53 men and 36 women, 62+/-10 years old) and 332 patients without diabetes (192 men and 140 women, 59+/-13 years old). Hand roentgenography was carried out, and visible vascular calcification of the hand arteries was evaluated. RESULTS: There were 42 diabetic patients and 45 non-diabetic patients with vascular calcification. The prevalence of vascular calcification in diabetic patients (47.1%) was higher than in non-diabetic patients (13.6%) ( p<0.001). In multivariate logistic regression, the main factors affecting vascular calcification in non-diabetic patients were advanced age, longer duration of haemodialysis, increased phosphate concentrations, male gender, and lower predialysis diastolic pressure. In diabetic patients, predictors for vascular calcification were higher values of HbA(1C) and longer duration of haemodialysis. In diabetic patients, a 1% increase in HbA(1C) increased the risk of calcification by 2.1-fold (95% CI 1.282-3.575, p=0.0029). CONCLUSION/INTERPRETATION: We have shown that poor glycaemic control, rather than calcium and phosphate concentrations, is a predictor of peripheral vascular calcification in diabetic patients on haemodialysis. This study emphasizes that glycaemic control remains critical even in diabetic patients with end-stage renal disease.

Abstract: BACKGROUND: Immune response to oxidized low-density lipoprotein (oxLDL) may modulate the process of atherogenesis and cardiovascular disease. METHODS: We performed a prospective, observational cohort study in 249 patients with end-stage renal disease (ESRD) to examine whether the serum titer of anti-oxLDL antibody can predict cardiovascular mortality. RESULTS: The median anti-oxLDL antibody titer was 320 mU/mL at baseline. During the follow-up (63 +/- 23 months), 72 deaths including 34 cardiovascular deaths occurred. When the subjects were divided into two groups by the median titer, the high titer group showed a lower risk for cardiovascular mortality (P = 0.040 by Kaplan-Meier analysis and log-rank test). Multivariate Cox proportional hazards model indicated that the lower risk of cardiovascular death in the high titer group remained significant (hazard ratio of 0.46, 95%CI 0.23-0.95, P = 0.037) and independent of age, presence of vascular complications, presence of diabetes mellitus, and elevated C-reactive protein. In contrast, anti-oxLDL antibody titer was not associated with non-cardiovascular mortality. CONCLUSIONS: These results demonstrate, to our knowledge for the first time, that serum anti-oxLDL antibody titer is an independent predictor of cardiovascular mortality in a cohort of patients with ESRD.

Abstract: The peroxisome proliferator-activated receptor (PPAR) gamma is an important regulator of adipocyte differentiation and a modulator of intracellular insulin-signaling events. We examined the roles of the Pro12Ala variant of PPAR gamma2 in obesity and insulin resistance in 402 Japanese patients with type 2 diabetes and 116 control subjects. Among the diabetes subjects, the Pro12Pro homozygotes showed significantly higher body mass index (BMI) than those with the Pro12Ala variant (p = 0.020), while there was no association between genotype and BMI in the controls. Furthermore, diabetic subjects with Pro12Pro showed significantly higher fat body mass index (FBMI) than those with Pro12Ala (p = 0.016), while no association between genotype and lean body mass index (LBMI) was observed. Regarding insulin resistance, there was no difference in the HOMA index or in clamp index between Pro12Ala and Pro12Pro variants. These data suggest that the Pro12Ala polymorphism of PPAR gamma2 does not influence insulin resistance but body composition in Japanese diabetic subjects.

Abstract: The association between endothelial constitutive nitric oxide synthase (ecNOS) gene polymorphism and vascular endothelial function has not been clarified. We investigated the impact of ecNOS gene polymorphism on endothelial function in 95 patients with Type 2 diabetes (ecNOS genotype: 4b/b, n = 62; 4b/a, n = 30; 4a/a, n = 3). Flow-mediated (endothelium dependent, FMD) and nitroglycerin-induced (endothelium independent, NTG) vasodilations of the right brachial artery were studied using a phase-locked echotracking system. There were no significant differences in clinical characteristics among the ecNOS genotypes. The FMD was significantly lower in the patients with ecNOS4a allele than in those without ecNOS4a allele (P < 0.05). Multiple regression analysis showed that ecNOS4a allele and mean blood pressure were significant independent determinants for reduced FMD in all patients (R(2) = 0.122, P = 0.0025). The ecNOS4a allele was an independent determinant for reduced FMD in smokers but not in nonsmokers. These results suggest that ecNOS4a allele is a genetic risk factor for endothelial dysfunction in diabetic patients, especially in smokers.

Abstract: OBJECTIVE: To investigate the impact of glycemic control on the survival of diabetic subjects with end-stage renal disease (ESRD) starting hemodialysis treatment. RESEARCH DESIGN AND METHODS: This single-center prospective observational study enrolled 150 diabetic ESRD subjects (109 men and 41 women; age at hemodialysis initiation, 60.5 +/- 10.2 years) at start of hemodialysis between January 1989 and December 1997. The subjects were divided into groups according to their glycemic control level at inclusion as follows: good HbA1c <7.5%, n = 93 (group G), and poor HbA1c > or = 7.5%, n = 57 (group P); and survival was followed until December 1999, with a mean follow-up period of 2.7 years. RESULTS: Group G had better survival than group P (the control group) (P = 0.008). At inclusion, there was no significant difference in age, sex, systolic blood pressure (SBP), BMI, cardio-to-thoracic ratio (CTR) on chest X-ray, and serum creatinine (Cre) or hemoglobin (Hb) levels between the two groups. After adjustment for age and sex, HbA1c was a significant predictor of survival (hazard ratio 1. 133 per 1.0% increment of HbA1c, 95% CI 1.028-1.249, P = 0.012), as were Cre and CTR. CONCLUSIONS: Good glycemic control (HbA1c <7.5%) predicts better survival of diabetic ESRD patients starting hemodialysis treatment.

Abstract: Cardiovascular risk is increased in patients with diabetic nephropathy. The aim of this study was to examine the relative impacts of albuminuria and renal failure, the two important features of diabetic nephropathy, on potentially atherogenic lipoprotein changes in this condition. The subjects were 160 non-diabetic healthy controls and a total of 200 type 2 diabetes patients with various degrees of nephropathy. The diabetic patients were divided into four groups by urinary albumin/creatinine ratio (U-ACR) and serum creatinine (S-Cr) levels: DM-1 (U-ACR< 30 mg/g, N=85), DM-2 (U-ACR=30-300 mg/g, N=48), DM-3 (U-ACR > 300 mg/g, N=29) and DM-4 (S-Cr>177 micromol/l or 2.0mg/dl, N=38). Lipids in very low (VLDL), intermediate (IDL), low (LDL), and high density (HDL) lipoproteins were measured following ultracentrifugation. VLDL-cholesterol (VLDL-C) was elevated (by 73-100%) in diabetic patients and it did not differ among the stages of nephropathy. IDL-C was higher as the nephropathy stage was advanced, and the elevation was significant in the DM-3 (by 75%) and DM-4 (by 131%) groups. LDL-C was not elevated in diabetic patients and was not different among the stages of nephropathy. Reduction of HDL-C was significant in DM-1, DM-2 and DM-3 (by 12-16%) and it was more exaggerated in DM-4 (by 35%). Multiple regression analyses indicated that elevated S-Cr, but not U-ACR, was an independent factor associated with raised IDL-C and lowered HDL-C in diabetic patients. These results indicate that diabetic patients with nephropathy show multiple lipoprotein changes, and that renal failure has greater impact than albuminuria on abnormalities in IDL and HDL. These lipoprotein alterations may contribute to an increased cardiovascular risk in diabetic nephropathy, especially in diabetic renal failure.

Abstract: OBJECTIVE: To assess the impacts of insulin resistance and renal function on plasma total homocysteine (tHcy) levels in patients with type 2 diabetes with a wide range of nephropathy. RESEARCH DESIGN AND METHODS: Plasma tHcy levels were measured using the enzyme immunoassay method in 75 patients with type 2 diabetes and compared with those in 54 healthy control subjects. Insulin sensitivity indexes were assessed in patients with type 2 diabetes by hyperinsulinemic-euglycemic clamp using artificial pancreas. RESULTS: Plasma tHcy levels and their log-translormed values (log tHcy) were significantly higher in all patients with diabetes than in control subjects (tHcy, 12.0 +/- 0.7 [SE] vs. 8.7 +/- 0.3 micromol/l, P < 0.0001; log tHcy, 1.040 +/- 0.021 vs. 0.920 +/- 0.016 micromol/l, P < 0.0001). Plasma tHcy levels in patients with diabetes were significantly increased according to degree of nephropathy (P < 0.0001). On simple regression analyses, log tHcy correlated with insulin sensitivity indexes (r = -0.319, P = 0.005) as well as creatinine clearance (r = 0.634, P < 0.0001) in all patients with diabetes. Multiple regression analyses showed that insulin sensitivity indexes (beta = -0.245) as well as creatinine clearance were independent contributors to log tHcy in all patients with diabetes (R2 = 0.750, P < 0.0001). For the 59 patients with diabetes with creatinine clearance >60 ml/min, insulin sensitivity indexes were also shown to be a significant contributor to log tHcy (beta = -0.438, R2 = 0.561, P < 0.001). CONCLUSION: Insulin resistance and renal function are independent determinants of tHcy levels in patients with type 2 diabetes.

Abstract: MRI and bone scintigraphy of a 64-year-old woman admitted with severe lumbago showed multiple metastatic bone cancer mainly on vertebrae, and breast cancer was found by mammography. After enucleation was performed, treatment with tegafur, tamoxifen and oral bisphosphonate/etidronate was started. Because symptoms associated with bone metastasis worsened, we began to administer 30 mg of pamidronate intravenously every 4 weeks. Since that time the extent of metastasis has been inhibited, resulting in ameliorated lumbodynia and improved quality of life.

Abstract: Paraoxonase is a high-density lipoprotein (HDL)-bound esterase that hydrolyzes various organophosphorus compounds and protects low-density lipoprotein (LDL) against accumulation of lipid peroxides. Paraoxonase activity is strongly affected by the polymorphism of the paraoxonase gene (PON1) at position 192. In addition, the enzyme activity shows a great variation within each genotype, although the underlying mechanism is unknown. Because paraoxonase activity is decreased in subjects with type 2 diabetes mellitus who have insulin resistance, we investigated the association between paraoxonase activity and insulin resistance in a nondiabetic population. The subjects were 237 healthy Japanese adults with fasting plasma glucose less than 7.0 mmol/L. Paraoxonase activity was measured using paraoxon as a routine substrate. Insulin resistance was assessed by homeostasis model assessment index (HOMA index). Paraoxonase activity was affected by HDL level. To reduce the effect of HDL on paraoxonase, paraoxonase activity/HDL ratio was used. When the subjects were divided into tertiles by HOMA index, the subjects with higher HOMA values had higher paraoxonase/HDL ratios, although the 3 groups were comparable in age, gender and the PON1 genotype distribution. Paraoxonase/HDL ratio showed significant positive correlations not only with HOMA index, but also with body mass index, waist-to-hip ratio (WHR), whereas it correlated inversely with age at borderline significance. Multiple regression analysis indicated that the association between HOMA index and paraoxonase/HDL ratio was significant and independent of PON1 genotype, age, and adipocity. The positive association between HOMA index and HDL-corrected enzyme activity was again significant when the enzyme activity was measured with diazoxon as an alternative substrate. These results suggest that insulin resistance or hyperinsulinemia is a factor contributing to the intragenotype variability of paraoxonase activity in a population without overt hyperglycemia.

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Abstract: Cardiovascular mortality is substantially higher in patients with end-stage renal disease (ESRD). Lipoprotein abnormality in ESRD is one of the possible risk factors for advanced atherosclerosis. Uremic dyslipidemia is characterized by increased plasma triglycerides due to elevated very low density lipoprotein (VLDL) and decreased high-density lipoprotein (HDL). Plasma total or low-density lipoprotein (LDL) cholesterol is rarely elevated in hemodialysis patients. The "LDL" by standard assay methods consists of intermediate-density lipoprotein (IDL) and LDL devoid of IDL. Although "LDL" is not increased, IDL is markedly elevated in uremic plasma. We previously showed that aortic stiffness of hemodialysis patients was associated positively with VLDL, IDL, and LDL devoid of IDL and that IDL is the best lipoprotein predictor of aortic stiffness. The IDL level is correlated positively with plasma total cholesterol, triglyceride, and "LDL" levels. Importantly, increased IDL is found in ESRD patients with "normal" "LDL"cholesterol levels, indicating that the target "LDL" level should be lower than that for the general population. More than 40% of hemodialysis patients exceeded the upper limit (15 mg/dL, 95th percentile level) of IDL cholesterol in healthy subjects. Based on a linear relationship between IDL and "LDL," the normal range of IDL cholesterol (<15 mg/dL) corresponds to "LDL" cholesterol by the Friedewald equation below 100 mg/dL in hemodialysis patients. Statins effectively and safely reduce "LDL," including IDL in patients treated with hemodialysis or peritoneal dialysis. The effect of lipid-lowering therapy on cardiovascular mortality in ESRD, however, awaits the results of ongoing prospective trials.

Abstract: Diabetes mellitus is a strong risk factor for the progression of atherosclerosis. In patients with chronic renal failure on hemodialysis, advanced atherosclerosis is reported to be present. We examined how renal insufficiency affects intima-medial thickness (IMT) of the carotid and femoral arteries in patients with type 2 diabetes mellitus. IMT was measured by B-mode ultrasonography in 115 patients with type 2 diabetes mellitus (65 men, 50 women; 58 +/- 13 years old). The IMT of the carotid and the femoral artery of patients with creatinine clearance less than 80 mL/min (n = 55) were significantly greater than those of patients with creatinine clearance 80 mL/min or greater (n = 60; P < 0.01 and P < 0.05). Linear regression analyses showed that there was a significant negative correlation between creatinine clearance and IMT of the carotid artery (r = -0.330; P < 0.001) and femoral artery (r = -0.336; P < 0.001). Multiple regression analyses revealed that age and creatinine clearance significantly and independently affected the IMT of the carotid artery (R(2) = 0.176; P < 0.0001), and age, duration of diabetes, and smoking affected the IMT of the femoral artery (R(2) = 0.287; P < 0.0001). These findings show that decreased renal function accelerates atherosclerosis in patients with type 2 diabetes mellitus and that chronic renal failure is a significant, independent risk factor for carotid atherosclerosis in these patients.

Abstract: Stiffening and thickening of arterial wall are two important components of atherosclerosis. The purpose of this study was to evaluate the effects of femoral artery wall stiffness on clinical manifestation of peripheral vascular disease (PVD) in type 2 diabetes mellitus. The subjects were 315 patients with type 2 diabetes. Presence of intermittent claudication and/or leg pain at rest and reduced ankle-brachial blood pressure index (ABI<0.9) were used as a subjective and an objective index of PVD, respectively. Femoral artery intima-media thickness (FA-IMT) and stiffness parameter beta (FA-stiffness beta) were measured by ultrasound methods. Symptomatic patients (N=58) showed greater values for both FA-IMT and FA-stiffness beta than those without symptom (N=257). Similarly, patients with reduced ABI (N=56) had greater FA-IMT and FA-stiffness beta than those without (N=259). However, correlation between FA-IMT and FA-stiffness beta was not impressive, especially in the symptomatic patients. To evaluate the effect of FA-stiffness beta on PVD symptoms, the subjects were divided into three subgroups according to FA-IMT, and then FA-stiffness beta was compared between those with and without PVD symptoms in each subgroup. The symptomatic patients had greater FA-stiffness beta values than the asymptomatic subjects in all the three subgroups. Multiple logistic regression analysis indicated that the presence of PVD symptoms was associated more closely with increased FA-stiffness beta than with increased FA-IMT, whereas reduced ABI was associated more closely with FA-IMT than with FA-stiffness beta. These data suggest that stiffening of arterial wall has a significant impact on PVD manifestations, particularly on the leg symptoms, in patients with type 2 diabetes.

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Abstract: Patients with chronic uremia have a substantially elevated risk of death from cardiovascular disease than do the general population. Although uremic and nonuremic groups share some of the risk factors for cardiovascular mortality, such as older age, diabetes, and inflammation, other factors appear to affect cardiovascular mortality in the opposite direction. For example, being overweight and having hyperlipidemia are established risk factors in the general population, whereas lower body mass index and lower plasma cholesterol have been shown to be risk factors for cardiovascular mortality in end-stage renal disease (ESRD). This paradoxical phenomenon is explained by two facts: (1) that malnutrition is a strong predictor of cardiovascular mortality in ESRD and (2) that plasma lipid levels are lowered in malnutrition. However, it is not known whether atherosclerosis is promoted by malnutrition or by low cholesterol level. Because the cardiovascular mortality rate is theoretically the product of event rate and fatality rate after an event, risk factors for cardiovascular mortality could fall into two categories: those raising the event rate and those affecting the fatality rate. Some factors could work both ways. Patients with ESRD show a significant increase in both event rate and fatality rate. Dyslipidemia is an independent factor affecting atherosclerotic arterial wall changes and cardiovascular events in ESRD. Other factors affecting the cardiovascular event rate in ESRD include diabetes and an elevated homocysteine level. In contrast, factors associated with poor survival after an event include diabetes and anemia. Malnutrition could be a factor causing the fatality rate to rise, although there is no direct evidence supporting this possibility. Further studies are needed to show the differential effects of a risk factor on event rate and fatality rate. Patients with ESRD would have a better chance of living longer by better management of the two categories of risk factors.

Abstract: Nutritional status affects well-being and survival in patients who are undergoing hemodialysis. It was examined how maintenance hemodialysis altered body fat mass. In 72 patients with chronic renal failure (age, 62 +/- 12 yr; 42 men, 30 women), body fat was measured by dual x-ray absorptiometry 1 mo after initiation of maintenance hemodialysis and approximately 1 yr later (mean +/- SD, 11 +/- 2 mo). The second measurement showed significantly greater body fat mass than the first (11.38 +/- 3.84 versus 10.09 +/- 4.12 kg; P < 0.0001). After calculation of the change in body fat mass per month, no significant differences were evident in relation to gender or to presence of diabetes. Changes in body fat mass per month correlated negatively with baseline serum albumin concentration (r = -0.449, P < 0.0001) and baseline body fat mass (r = -0.423, P < 0.001). These factors independently influenced the change according to multiple regression analysis (R(2) = 0.323, P < 0.0001). In conclusion, body fat mass increases significantly in the first year of maintenance hemodialysis, especially in patients with poor nutritional status. More general, dual x-ray absorptiometry assessment of body fat mass was found to be useful for evaluating the nutritional status of hemodialysis patients.

Abstract: Cardiovascular mortality is elevated in patients with end-stage renal disease (ESRD), especially in those with diabetes mellitus. Although the higher cardiovascular death rate in diabetic ESRD patients may be the result of more advanced atherosclerotic changes of the arterial wall, this has not been documented previously. Aortic stiffness was compared between ESRD patients with and without diabetes, and the impact of aortic stiffness on cardiovascular mortality was examined in a prospective, observational cohort study. The cohort consisted of 265 ESRD patients on hemodialysis, including 50 diabetic patients studied between June 1992 and December 1998. At baseline, the diabetic ESRD patients had significantly higher aortic pulse wave velocity (PWV), a noninvasive measure of aortic stiffness, than the nondiabetic patients. During a mean follow-up period of 63 mo, 81 deaths, including 36 cardiovascular deaths, were recorded. Kaplan-Meier analysis revealed higher all-cause or cardiovascular mortality rates in the diabetic as compared with the nondiabetic patients and also in those with higher aortic PWV than those with lower aortic PWV. The effect of diabetes on cardiovascular death was significant in the Cox model, including age, years on hemodialysis, gender, smoking, C-reactive protein, hematocrit, and body mass index as covariates. However, when aortic PWV was included as a covariate, the impact of diabetes was no longer significant, whereas aortic PWV was a significant predictor. In a model including 13 covariates, aortic PWV remained a significant predictor for cardiovascular and overall mortality but not for non-cardiovascular death. These results demonstrate that the increased aortic stiffness of the ESRD patients with diabetes mellitus contributed to the higher all-cause and cardiovascular mortality rates.

Abstract: Oxidized low density lipoprotein (oxLDL) has been implicated in the pathogenesis of atherosclerosis. Recent studies have shown that immunization of animals with oxLDL results in suppression of atherogenesis. Antibody against oxLDL (oxLDL Ab) is detectable in human sera, although its biological significance is not well established. We examined the relationship between oxLDL Ab titer and circulating oxLDL level in 130 healthy Japanese subjects. OxLDL was measured as apolipoprotein (apo) B-containing lipoproteins carrying oxidized phosphatidylcholines by a sensitive ELISA. IgG class oxLDL Ab titer was measured by ELISA. Plasma oxLDL concentration was very low and it corresponded on average to one to two out of 1000 apoB-containing lipoproteins in plasma. Plasma oxLDL correlated positively with LDL cholesterol and inversely with oxLDL Ab titer. These associations remained significant and independent in multiple regression analysis including age, gender, smoking, and high-density lipoprotein cholesterol. These data indicate that healthy subjects have a very low concentration of oxLDL in the circulation, and that oxLDL Ab titer is in an inverse relationship with plasma oxLDL concentration in this population. Although these results suggest that oxLDL Ab may play a role in maintaining the low level of plasma oxLDL, its role in atherogenesis awaits further studies.

Abstract: Oxidation of LDLs plays an important role in atherosclerosis, and immune response to oxidized LDL (oxLDL) may modulate atherogenesis. Although immunization with oxLDL is shown to suppress atherogenesis in animal models, the role of the immune response to oxLDL is not well established in humans. We investigated the relationship between the titer of anti-oxLDL antibody (oxLDL Ab) and arterial wall thickness in a healthy population with no clinical signs of atherosclerosis. Intima-media thickness of the carotid arteries (CA-IMT) was measured by high-resolution B-mode ultrasonography in 446 healthy subjects. The titer of IgG-class oxLDL Ab was measured by a solid-phase ELISA. In univariate analysis, CA-IMT correlated positively with age, systolic blood pressure, total cholesterol, triglyceride, LDL cholesterol, body mass index, and waist-to-hip ratio, whereas it correlated negatively with HDL cholesterol and oxLDL Ab titer. The inverse association between oxLDL Ab titer and CA-IMT remained significant in multiple regression analysis, which took other confounding variables into account. These results indicate an independent inverse relationship between oxLDL Ab titer and CA-IMT in healthy subjects, supporting the hypothesis that immune response to oxLDL may have a protective role at an early stage of human atherosclerosis.

Abstract: Duplex Doppler sonography has been reported to be useful in examining the intrarenal hemodynamic abnormalities in various renal diseases. We investigated the impact of diabetes on intrarenal hemodynamics in patients with chronic renal failure (CRF). The resistive index and pulsatility index of the renal interlobar arteries were measured using duplex Doppler sonography in 90 CRF patients (serum creatinine >130 and <800 mmol/l, mean age 59 +/- 11 years). Forty-eight patients had type 2 diabetes and 42 did not. Twenty-nine age-matched, healthy subjects served as controls. Both resistive index and pulsatility index were greater in CRF patients than in the controls (p < 0.0001). No significant differences existed in age, sex, body mass index, total serum cholesterol, serum creatinine, estimated creatinine clearance, or mean blood pressure between the diabetic CRF and nondiabetic CRF groups. Resistive index and pulsatility index were significantly increased in the diabetic CRF patients compared to the nondiabetic CRF patients (p < 0.0001). Multiple regression analysis of all CRF patients revealed that resistive index was independently affected by the presence of type 2 diabetes (F = 44.535), as well as decreased creatinine clearance (F = 18.157) and age (F = 15.160) (R(2) = 0.559, p < 0.0001). These results clearly demonstrated that intrarenal arterial resistance is significantly increased in CRF patients with type 2 diabetes compared to similar patients without diabetes. The impact of diabetes mellitus and advanced age on intrarenal hemodynamics may be due to intrarenal arteriosclerosis and interstitital lesions. Measurements of RI values in addition to conventional ultrasound imaging may add further information on such renal lesions.

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Abstract: BACKGROUND/AIM: In patients with type 2 diabetes mellitus, the relationship between glomerular filtration rate (GFR) and urinary albumin excretion remains an unresolved issue. In order to investigate the early renal function abnormalities, GFR and urinary albumin excretion were assessed, and their relationship was examined in normotensive patients with type 2 diabetes mellitus. METHODS: In a cross-sectional study of 85 nonhypertensive Japanese patients with type 2 diabetes mellitus not showing overt proteinuria, the GFR was measured using (99m)Tc-diethylenetriamine pentaacetate renography. Fifty-one diabetic patients lacked microalbuminuria (albumin excretion <30 mg/day), while 34 patients showed microalbuminuria (between 30 and 300 mg/day). Fifteen healthy subjects served as controls. RESULTS: The three groups were well matched with regard to gender, age, and body mass index. The GFR in microalbuminuric patients (134 +/- 23 ml/min/1.48 m(2)) was significantly higher than in patients without microalbuminuria (108 +/- 21 ml/min/1.48 m(2)) and in controls (109 +/- 18 ml/min/1.48 m(2); p < 0.0001). In type 2 diabetic patients, the GFR positively correlated with the logarithmically transformed urinary albumin excretion. Multiple regression analysis showed that the urinary albumin excretion was significantly and independently affected by GFR (beta = 0.548), duration of diabetes (beta = 0.297), and systolic blood pressure (beta = 0.232; R(2) = 0.409; p < 0.0001). CONCLUSION: It is suggested that one of the mechanisms underlying increased urinary albumin excretion in early nephropathy in normotensive type 2 diabetes is glomerular hyperfiltration.

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Abstract: OBJECTIVE: To investigate whether the insulin resistance index (IR) assessed by homeostasis model assessment (HOMA) is associated with the insulin resistance index assessed by euglycemic-hyperinsulinemic clamp (clamp IR) in type 2 diabetic patients who received sulfonylureas (SUs), as well as in those treated by diet alone. RESEARCH DESIGN AND METHODS: Retrospectively, the association between HOMA IR and clamp IR was analyzed in 80 type 2 diabetic subjects (53 subjects treated with SUs and 27 subjects treated with diet alone). The 80 subjects, selected because they had not received insulin therapy, were among 111 diabetic participants in a clamp study for evaluation of insulin resistance from May 1993 to December 1997 in Osaka City University Hospital. RESULTS: The HOMA IR showed a hyperbolic relationship with clamp IR. The log-transformed HOMA IR (all subjects, r = -0.725, P < 0.0001; SU group, r = -0.727, P < 0.0001; diet group, r = -0.747, P < 0.0001) correlated more strongly with clamp IR than did HOMA IR per se (all subjects, r = -0.594, P < 0.0001; SU group, r = -0.640, P < 0.0001; diet group, r = -0.632, P = 0.0004). The univariate regression line between log-transformed HOMA IR and clamp IR in the SU group did not differ from that in the diet group (slope, -6.866 vs. -5.120, P > 0.05; intercept, 6.566 vs. 5.478, P > 0.05). Stepwise multiple regression analyses demonstrated that the log-transformed HOMA IR was the strongest independent contributor to clamp IR (R2 = 0.640, P < 0.0001). CONCLUSIONS: The HOMA IR strongly correlated with the clamp IR in type 2 diabetic patients treated with SUs as well as in those treated with diet alone.

Abstract: The adipocyte-derived hormone leptin is the 16-kd product of the ob gene that regulates food intake and body weight. Plasma leptin level is elevated in patients with chronic renal failure, partly because of impaired clearance through the kidney. In this study, we examined whether leptin is cleared into peritoneal dialysate in patients with end-stage renal disease treated by continuous ambulatory peritoneal dialysis (CAPD). The subjects were 46 CAPD patients and 67 age- and gender-matched healthy subjects. Leptin concentration in peritoneal dialysate from CAPD patients was measurable by a sensitive enzyme-linked immunosorbent assay (ELISA), and the daily loss of leptin by the peritoneal route was estimated to correspond to the amount contained in approximately 2 L plasma. Dialysate leptin concentration correlated positively with plasma leptin level and with percent body fat measured by dual-energy X-ray absorptiometry. The dialysate-to-plasma (D/P) ratio of leptin concentration was twice higher than expected from its molecular weight. D/P ratios of beta2-microglobulin, albumin, and transferrin showed strong correlations with each other (r = 0.768 to 0.801), whereas the correlation between D/P ratios of leptin and beta2-microglobulin was less impressive (r = 0.378). This was also the case with the relationship between apparent peritoneal clearances of these macromolecules, suggesting that dialysate leptin had some origins other than passive transport of plasma leptin. To test the hypothesis that abdominal visceral fat may contribute to the unexpectedly raised peritoneal dialysate leptin concentration, multiple regression analysis was performed. Leptin concentration in peritoneal dialysate showed significant association with plasma leptin level and D/P ratio of beta2-microglobulin, and it also showed an independent association with abdominal visceral fat but not with subcutaneous fat assessed by ultrasonography. These results showed that peritoneal dialysate from CAPD patients contained a significant amount of leptin, which derived presumably from both plasma and local visceral fat tissue.

Abstract: BACKGROUND: Patients with chronic renal failure often have alterations in lipoprotein profile including elevated very-low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL), and reduced high density lipoprotein (HDL) levels. Among these changes, raised IDL has been shown as an independent risk factor for atherosclerosis in hemodialysis patients. There are a limited number of studies reporting pharmacological approaches to IDL reduction in a uremic population. METHODS: We therefore summarize the effects of lipid-lowering drugs on IDL levels in patients with chronic renal failure treated by hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). RESULTS: First, a nicotinic acid analog niceritrol was given to hemodialysis patients. The drug increased HDL-cholesterol by 11%, but the reductions in VLDL-, IDL- and LDL-cholesterol were not significant. Second, CAPD patients were treated with a fibric acid derivative clinofibrate, which was excreted mainly into bile unlike other drugs in this class. The fibrate resulted in a remarkable reduction in VLDL-triglycerides, although it did not reduce IDL-cholesterol. Finally, an HMG-CoA reductase inhibitor (statin) pravastatin was used in HD and CAPD patients. Pravastatin reduced IDL- and LDL-cholesterol to the same extent (by 31%). None of these treatments caused serious adverse effects. CONCLUSIONS: We propose that IDL is an important target in the management of uremic dyslipidemia. To date, statins have been shown to be suitable for this purpose, although it remains to be clarified whether such an intervention reduces the risk for atherosclerotic vascular events in the uremic population.

Abstract: OBJECTIVE: The aim of this study was to assess the relationship between atherotic (structural) and sclerotic (functional) changes in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Aortic distensibility and carotid intimal-media thickness (IMT) were evaluated using carotid-femoral aortic pulse-wave velocity (a-PWV) and high-resolution B-mode ultrasonography in 271 patients with type 2 diabetes and 285 age-matched control subjects. RESULTS: a-PWV and carotid IMT were significantly higher in the patients than in the control subjects in all age-groups (P < 0.0001, respectively). The carotid IMT and a-PWV were significantly correlated with age in both the patients with type 2 diabetes and control subjects. There was a significant positive relationship between the carotid IMT and a-PWV in both the patients (r = 0.482, P < 0.0001) and control subjects (r = 0.424, P < 0.0001). The slope of the regression line for the carotid IMT to the a-PWV was significantly steeper in the diabetic patients than in the control subjects (P < 0.05). Multiple regression analysis in all subjects showed that age, diabetic state, and cigarette smoking were independently common risk factors for the increase in carotid IMT and a-PWV. In the diabetic patients, the independent risk factors associated with the carotid IMT were age, hyperlipidemia, and duration of diabetes (R2 = 0.232, P < 0.0001), while those associated with a-PWV were age and duration of diabetes (R2 = 0.334, P < 0.0001). CONCLUSIONS: The results indicated that diabetic patients showed more advanced changes in atherosis than that in sclerosis as compared with age- and sex-matched control subjects. Such atherotic changes in diabetic patients may be associated with hyperlipidemia.

Abstract: OBJECTIVE: To assess the relationship between the insertion (I)/deletion (D) polymorphism of the ACE gene and arterial distensibility in patients with type 2 diabetes and healthy control subjects. RESEARCH DESIGN AND METHODS: Aortic and carotid arterial distensibility were evaluated by measuring aortic pulse-wave velocity (a-PWV) and carotid stiffness beta using an echo-tracking system in 137 patients with type 2 diabetes and 260 age-matched control subjects. RESULTS: a-PWV and carotid stiffness beta were significantly higher in patients with type 2 diabetes than in age-matched control subjects (P < 0.05). Both stiffness beta and a-PWV were significantly higher in the patients with the II genotype than in those with the DD genotype (P < 0.001). In the control subjects, multiple regression analysis showed that age and decreased HDL cholesterol were independently associated with increased a-PWV (R2 = 0.244, P < 0.0001) and that age, systolic and diastolic blood pressure, and BMI were independently associated with increased carotid stiffness beta (R2 = 0.454, P < 0.0001). In the patients with type 2 diabetes, age, gene dose of the I allele, and systolic and diastolic blood pressure were independently associated with increased a-PWV (R2 = 0.545, P < 0.0001), and age, gene dose of the I allele, and systolic blood pressure were associated with increases in carotid stiffness beta (R2 = 0.314, P < 0.0001). CONCLUSIONS: These results suggested that ACE polymorphism is associated with the impairment of aortic and carotid distensibility in patients with type 2 diabetes.

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Abstract: OBJECTIVE: To investigate the association between arterial wall stiffness indexes beta of the common carotid artery (CCA) and the femoral artery (FA) and insulin resistance in NIDDM subjects in a cross-sectional study. RESEARCH DESIGN AND METHODS: We evaluated the arterial stiffness indexes beta of CCA and FA using an ultrasonic phase-locked echo-tracking system in 60 NIDDM subjects attending the diabetes center in Osaka City University Hospital, compared with 120 age- and sex-matched control subjects. Insulin sensitivity indexes were evaluated using a euglycemic-hyperinsulinemic clamp. RESULTS: Stiffness indexes beta of both CCA and FA were significantly higher in NIDDM subjects than in control subjects (CCA 18.1 +/- 0.9 vs. 11.7 +/- 0.3, respectively, P < 0.001; FA 35.7 +/- 2.3 vs. 23.7 +/- 0.8, respectively, P < 0.001). The mean insulin sensitivity index in NIDDM subjects was 4.69 +/- 0.29 mg.kg-1.min-1.mU-1.l. The stiffness indexes beta of both CCA and FA were inversely correlated with insulin sensitivity indexes (CCA r = -0.393, P = 0.002; FA r = -0.329, P = 0.010), as well as with age, duration of diabetes, and mean blood pressure. In stepwise multiple regression analyses, insulin sensitivity index and duration of diabetes were identified as significant independent variables for stiffness indexes beta in both CCA and FA (CCA R2 = 0.249, P = 0.0003; FA R2 = 0.336, P < 0.001). CONCLUSIONS: Arterial stiffness indexes beta of CCA and FA were associated with insulin resistance in NIDDM subjects.

Abstract: Patients with chronic renal failure often show accumulation of intermediate-density lipoprotein (IDL). Because recent studies have emphasized the atherogenicity of IDL in the general population, we evaluated the relationship between this lipoprotein and aortic atherosclerosis in uremic patients treated with hemodialysis. Aortic pulse wave velocity (PWV) was measured as a noninvasive index of sclerotic change of aorta in 205 hemodialysis patients and 184 age- and gender-matched healthy subjects. Fasting plasma lipoproteins were fractionated by ultracentrifugation into very low-density lipoprotein (VLDL), IDL, LDL, and HDL. Plasma lipoprotein (a) (Lp(a)) was measured by a latex immunoturbidimetric assay. Aortic PWV was significantly higher in the hemodialysis patients than in the control subjects. The hemodialysis group showed a significant increase in VLDL and IDL cholesterol, whereas their LDL and HDL cholesterol were lower than the control levels. Lp(a) levels did not differ between the two groups. In the hemodialysis population, VLDL, IDL, and LDL cholesterol correlated positively with aortic PWV adjusted for age, gender, smoking, and BP, whereas Lp(a) did not. Multiple regression analyses indicated that plasma triglycerides, independent of HDL cholesterol, had a significant association with aortic PWV in the hemodialysis patients but not in the control subjects. Further analyses revealed that aortic PWV in the hemodialysis patients had a significant and independent association with IDL cholesterol, whereas aortic PWV in the control subjects had significant and independent associations with HDL cholesterol and Lp(a). These results demonstrate that IDL is the lipoprotein fraction most closely associated with aortic PWV in the hemodialysis patients.

Abstract: Leptin is a newly found hormone secreted by adipocytes that regulates food intake, thermogenesis, and body fat. We measured plasma leptin levels in 103 patients with chronic renal failure treated by hemodialysis and 167 age- and gender-matched healthy control subjects to examine the impact of renal failure on plasma leptin levels and the influence of leptin on body composition measured by dual-energy X-ray absorptiometry. Hemodialysis patients showed a significant decrease in both body fat mass and lean body mass compared with those of the control subjects. Plasma leptin was significantly elevated in the hemodialysis group over the controls. In both groups, leptin was higher in female than male subjects, and it correlated positively with percent body fat. The subjects were divided into six categories according to percent body fat, and plasma leptin levels were compared between the two groups in the same category. Leptin of hemodialysis patients was significantly higher than that of the control subjects in the percent body fat categories of 30 or greater, whereas there was no statistically significant difference in leptin concentrations in the lower percent body fat categories. This was also true in the comparison in each gender, and leptin levels in female subjects showed a more remarkable difference between the hemodialysis and control groups in obese categories. Multiple regression analysis in all subjects indicated that plasma leptin levels were independently affected by percent body fat, plasma insulin concentration, gender, and renal failure. The positive impact of renal failure on leptin remained significant in the subjects with percent body fat of 30 or greater in the multiple regression model, whereas it was no longer significant in the remaining lean subjects. In multiple regression analysis of factors affecting fat mass index and lean mass index, leptin level was selectively associated with fat mass index, but not with lean mass index, regardless of percent body fat ranges. These results indicate that renal failure is an important factor affecting plasma leptin levels, especially in obese female subjects, and that hyperleptinemia was closely related to fat mass but not to lean body mass in hemodialysis patients.

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Abstract: We compared plasma lipid and lipoprotein parameters between 210 chronic renal failure patients treated by hemodialysis and 223 age- and sex-matched healthy control subjects to examine whether atherogenic lipoprotein changes were present in hemodialysis patients in the absence of hyperlipidemia. The hemodialysis group showed higher levels of plasma triglycerides, very low density lipoprotein (VLDL) cholesterol, and intermediate density lipoprotein (IDL) cholesterol and a lower level of high density lipoprotein (HDL) cholesterol. Low density lipoprotein (LDL) cholesterol of the hemodialysis group was not elevated but their LDL was significantly more triglyceride-enriched than that of controls. Subjects were then divided into five categories according to their plasma triglyceride levels at an interval of 50 mg/dl, and comparison was made between the two groups in the same range of plasma triglycerides. Hemodialysis patients again showed higher levels of VLDL- and IDL-cholesterol, and lower levels of HDL-cholesterol than the control group even in the plasma triglycerides-matched comparisons. Similarly, higher VLDL- and IDL-cholesterol levels in hemodialysis patients were significant in plasma total cholesterol-matched subgroup comparisons. Multiple regression analysis indicated that the relationship between plasma lipid concentrations and individual lipoprotein levels were substantially altered in uremic state. The 95th percentile level of IDL-cholesterol in the nonuremic controls was 15 mg/dl, and 45% of hemodialysis patients exceeded this level. Decreased HDL-cholesterol levels < or = 35 mg/dl were seen in 6% of the control and 38% of the hemodialysis group. Elevated IDL-cholesterol and decreased HDL-cholesterol were persistently found in hemodialysis patients with normal lipid levels. It is concluded that hemodialysis patients exhibited more atherogenic lipoprotein profile than nonuremic subjects with comparable levels of plasma triglycerides and total cholesterol. Especially, increased IDL- and decreased HDL-cholesterol levels in hemodialysis patients persisted even at very low levels of plasma lipids. Since elevated IDL and decreased HDL-cholesterol are implicated in the progression of atherosclerosis, these findings are of clinical importance in the diagnosis of lipoprotein disorder in chronic renal failure.

Abstract: We examined the association between the polymorphism of the apolipoprotein E (apoE) and the ACE genes and the intima-media thickness (IMT) of the carotid and femoral arteries measured using ultrasonography. The values of IMT of each artery were significantly higher in NIDDM patients (n = 356) than in control subjects (n = 235). The E4 allele or the D allele did not affect clinical characteristics, including age, fasting plasma glucose, total cholesterol, HDL cholesterol, LDL cholesterol, or blood pressure, in NIDDM or control subjects. No difference in the carotid IMT value was noted among the apoE genotypes in control or diabetic subjects. The carotid IMT was significantly higher in diabetic patients with the DD genotype (1.200 +/- 0.586 mm) than in those with the II genotypes (0.990 +/- 0.364 mm). Neither the E4 allele nor the D allele affected the femoral IMT in control or diabetic subjects. Multiple regression analysis demonstrated that the carotid IMT of NIDDM patients was associated with age, the D allele, and LDL cholesterol but not with the E4 allele, whereas that of control subjects was associated with age, sex, systolic blood pressure, LDL cholesterol, and HDL cholesterol, inversely. These results suggested that the E4 allele was not associated with the carotid or femoral IMTs, but that the D allele was statistically associated with carotid IMT in NIDDM patients but not control subjects. However, since the association was weak (2.3% explanatory power), its biological significance remains to be determined.

Abstract: Plasma leptin level is known to correlate with the degree of obesity. To determine the influences of renal function and insulin resistance on plasma leptin concentrations, we measured plasma leptin concentrations and performed the euglycaemic hyperinsulinaemic clamp studies in 57 patients with non-insulin-dependent diabetes mellitus with a wide range of renal function. In simple regression analyses, plasma leptin concentration showed significant positive correlations with percentage of body fat measured by dual energy X-ray absorptiometry, body mass index, waist to hip ratio and fasting plasma insulin. Leptin level was higher in females than males. Multiple regression analyses indicated that percent body fat, waist to hip ratio, plasma insulin, gender and renal function (1/creatinine), but not insulin sensitivity, were significant and independent determinants of plasma leptin level. These results suggest that plasma leptin level is regulated or affected by multiple factors including renal function. Insulin resistance appeared to increase leptin levels indirectly by raising plasma insulin.

Abstract: Cardiovascular motality is high in patients with chronic renal failure treated with dialysis, and secondary hyperparathyroidism may promote atherosclerogenesis. Recent studies have revealed advanced atherosclerosis in hemodialysis patients by using high-resolution B-mode ultrasonography. Multiple regression analyses indicated that hyperphosphatemia and hyperparathyroidism were associated with increased intima-media thickness (IMT) of the carotid and femoral arteries in hemodialysis patients, respectively. Hypocalcemia and hyperparathyroidism independently and adversely affect the lipoprotein profile by suppressing hepatic triglyceride lipase (HTGL), a lipid-regulating enzyme playing important roles in the metabolism of intermediate density lipoprotein (IDL) and high density lipoprotein (HDL). Plasma IDL is raised markedly, and HDL is lowered in uremia. These lipoprotein changes are closely associated with increased aortic pulse wave velocity (PWV), an index of aortic sclerosis. These findings support the hypothesis that deranged calcium-phosphate homeostasis and secondary hyperparathyroidism promote atherosclerosis in uremia, at least partly by affecting lipoprotein metabolism. Adequate dialysis and efforts to normalize calcium, phosphate and PTH would be beneficial in preventing not only bone disease, but atherosclerosis as well.

Abstract: BACKGROUND: The insertion/deletion (I/D) polymorphism of the ACE gene has been shown to be associated with cardiovascular disease in healthy subjects as well as in patients with non-insulin-dependent diabetes mellitus (NIDDM). We investigated the relationship between the ACE gene polymorphism and the wall thickness of both carotid and femoral arteries in NIDDM patients. METHODS AND RESULTS: We measured the intimal plus medial thickness (IMT) of both carotid and femoral arteries using high-resolution B-mode ultrasonography in 288 Japanese NIDDM patients (160 men, 128 women). No significant differences among the three genotypes were found with respect to age, sex, duration of diabetes, body mass index, blood pressure, plasma glucose, hemoglobin AIC, total cholesterol, triglycerides, HDL cholesterol, or cigarette-years. Plasma ACE levels were strongly associated with I/D polymorphism, with an additive effect of the D alleles. The carotid IMT of the patients carrying the D allele (DD+ID genotype) was significantly higher than that of the patients not carrying the D allele (II genotype) (P = .037), whereas the femoral IMT was not affected by the I/D polymorphism. Multiple regression analysis demonstrated that the risk factors for carotid IMT of patients with NIDDM were age, non-HDL cholesterol, and D allele of the ACE gene (R2 = .155, P < .0001). CONCLUSIONS: The D allele of the ACE gene may be a risk factor for the development of wall thickening of the carotid but not the femoral artery in NIDDM patients.

Abstract: We sought to determine whether artherosclerosis may be accelerated in uremic patients on maintenance hemodialysis and investigated the risk factors for carotid and femoral atherosclerosis in such patients. High-resolution B-mode ultrasonography was used to determine the intima-media thickness (IMT) of the carotid and femoral arteries in 199 hemodialysis patients and 81 age-matched healthy controls subjects. The IMT values of the carotid and femoral arteries in the hemodialysis patients were significantly higher than in age-matched control subjects in most age groups. The IMT values of the carotid or femoral artery were significantly correlated with age in both the hemodialysis patients and the control subjects. There was a significant relationship between the IMT values of the two arteries in the hemodialysis patients (r = 0.418, P = 0.0001) and in the control subjects (r = 0.321, P = 0.0037). Multiple regression analysis showed that age, cigarette smoking, and uremic state were independent risk factors for atherosclerosis of both arteries in the patients and the control subjects (R2 = 0.174, P < 0.0001; R2 = 0.205, P < 0.0001, respectively). In the hemodialysis patients, the independent risk factors associated with the extent of the IMT of the carotid artery were age, cigarette smoking, and serum phosphorus level (R2 = 0.230, P < 0.0001), while those associated with the extent of the IMT of the femoral artery were age, cigarette-smoking, and serum m-PTH level (R2 = 0.230, P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: Elevated plasma intermediate density lipoprotein (IDL) is one of the features of uremic dyslipidemia which is potentially atherogenic. We examined the effects of pravastatin, an HMG-CoA reductase inhibitor, on IDL levels as well as other lipoprotein parameters in 19 uremic patients treated with hemodialysis (HD, n = 11) or continuous ambulatory peritoneal dialysis (CAPD, n = 8). The patients were administered 5 mg/day pravastatin for the initial 4 weeks and 10 mg/day for the subsequent 12 weeks. In the analysis of the total subjects, IDL-cholesterol was reduced by 31% as well as low density lipoprotein (LDL)-cholesterol. Cholesterol in very low density lipoprotein (VLDL) also decreased whereas that in high density lipoprotein (HDL) did not. Significant decrease of serum triglycerides was due mainly to reduced IDL- and LDL-triglycerides. Apolipoprotein (apo) A-I did not change, whereas apo A-II, B, C-II, C-III, E, and B/A-I ratio were significantly lowered. Pravastatin did not affect measured activity of lecithin: cholesterol acyltransferase, post-heparin plasma lipoprotein lipase or hepatic triglyceride lipase. HD and CAPD patients responded almost equally to the treatment. IDL elevation was present independent of serum total cholesterol, and it was lowered by pravastatin even in non-hypercholesterolemic subjects. There was no critical adverse effect besides transient and asymptomatic increase of serum creatine kinase level. We conclude that pravastatin can be a safe and effective approach to the management of dyslipidemia in uremic patients who have an elevated level of IDL.

Abstract: We examined the effects of a fibric acid, clinofibrate, on lipoprotein metabolism in 12 hyperlipidemic patients with uremia treated on continuous ambulatory peritoneal dialysis during a 24 week treatment. Daily dose of clinofibrate was 200 mg for the initial four weeks, 400 mg for the second four weeks, and 600 mg for the subsequent 16 weeks. Serum and very-low density lipoprotein (VLDL) triglyceride were decreased by 36% and 48%, respectively. Neither total cholesterol nor apolipoprotein B changed significantly, whereas cholesterol was decreased in VLDL and increased in low (LDL) and high density lipoprotein (HDL) fractions. Post-heparin plasma lipoprotein lipase (LPL) before treatment was not lower than the normal value, and we found no change in LPL activity following clinofibrate. Hepatic triglyceride lipase also did not change. Apolipoprotein (apo) C-II/C-III ratio was low as compared to the normal value before treatment, and the ratio was increased by 38% after the treatment. Decrease in VLDL triglyceride was associated with increase in apo C-II/C-III ratio in all the cases. Abnormal enrichment with triglyceride of LDL and HDL fractions was improved by clinofibrate. Although one patient had a transient and asymptomatic elevation of serum creatine phosphokinase, no patient had muscle pain. There was no accumulation of the drug in the 24 week trial. These results suggest that clinofibrate is an effective and safe approach to the management of dyslipidemia in CAPD patients.

Abstract: We examined the changes in high-density-lipoprotein (HDL) metabolism in eight female obese patients undergoing a very-low-calorie diet (VLCD). In the first half of the study, HDL cholesterol (HDL-C), apolipoprotein A-I (apo A-I), and apo A-II showed a parallel decrease. Although lipoprotein lipase (LPL) and hepatic lipase (HTGL) did not change, lecithin: cholesterol acyltransferase (LCAT) decreased. In the latter half of the protocol, HDL-C and apo A-I increased whereas apo A-II decreased, resulting in increased apo A-I-A-II ratios. There was no change in LPL, HTGL, or LCAT. LCAT and apolipoprotein composition may be important in HDL-C changes after VLCD.

Abstract: Calcium homeostasis during a very-low-calorie diet (VLCD) was examined. During the treatment, intact parathyroid hormone tended to decrease initially, bone Gla-protein increased significantly in the third week, and tartrate-resistant acid phosphatase decreased during the entire treatment. Serum ketone bodies showed significant correlations with intact parathyroid hormone and bone Gla-protein in some cases. Regarding bone mineral content, bone mineral content of the head increased while that of the legs decreased, resulting in no significant changes in total bone mineral content. These results suggest that VLCD treatment alters calcium homeostasis, which may cause regional bone mineral changes.

Abstract: We measured serum lipoprotein(a) [Lp (a)] concentrations in 50 uremic patients treated on continuous ambulatory peritoneal dialysis (CAPD) and compared them with those in 29 uremic patients on hemodialysis (HD) and those in 62 normal controls. The median values were 47.9 mg/dl in CAPD patients, 25.2 mg/dl in HD patients, and 11.7 mg/dl in controls, respectively. These differences were statistically significant when assessed by Kruskal-Wallis test (p < 0.0001). Thirty-five out of 50 patients on CAPD (70%) and 12 out of 29 patients on HD (41%) had Lp(a) concentrations above 30 mg/dl, whereas these high values were observed in only 15% of normal controls. This difference in prevalence of high Lp(a) was also significant by 2 x 3 chi-square test (p < 0.01). There was a significant positive correlation between Lp(a) and apolipoprotein B (r = 0.517, p < 0.0001). In CAPD patients, 9 with ischemic heart disease had a significantly higher median Lp(a) than those without it (67.4 vs 40.9 mg/dl, p < 0.01 by Mann-Whitney U-test). These results suggest that high levels of serum Lp(a) might contribute to an increased risk for ischemic heart disease in CAPD patients, and that there may be a relationship between Lp(a) and apolipoprotein B metabolism in CAPD patients.

Abstract: 1,5-Anhydro-D-glucitol (AG) is one of the main polyols and its structure resembles glucose. It has been proposed that decreased serum AG concentrations in diabetic patients are a novel indicator of diabetic metabolic derangement. However, the pathway of AG metabolism still remains to be clarified. In this study we investigated the transport of AG into human polymorphonuclear leukocytes (PMNLs) isolated from healthy volunteers and found that 0.1 mM 3-O-methy-D-glucose (3OMG) was equilibrated with a half saturation time of 10 s, while the uptake rate of AG was much slower. The concentration dependence of AG uptake revealed that the AG transport velocity reached a plateau, with a Km of about 50 mM and Vmax of about 25 nmol/min/10(7) cells. Transport of 14C-labeled 3OMG was inhibited by unlabeled D-glucose or AG in a dose-dependent manner. The mean inhibition constant (Ki) for D-glucose and for AG were 1.06 and 4.93 mM, respectively. Cytochalasin B (20 microM) inhibited 3OMG transport by 90% but AG transport by only 50%. S/V for 14C-labeled AG transport plotted against the concentration of unlabeled 3OMG showed a non-linear and biphasic pattern. These results suggest that AG influx into PMNLs is mediated not only by the cytochalasin B-sensitive glucose transport system but also via another facilitated transport system.

Abstract: We measured lipoproteins, apolipoproteins, lipoprotein lipase (LPL), hepatic triglyceride lipase (HTGL), lecithin: cholesterol acyltransferase (LCAT) and parameters of calcium metabolism to evaluate the roles of these enzymes and hypertriglyceridemia for impaired high-density lipoprotein (HDL) metabolism in chronic renal failure, and to examine the impact of altered calcium homeostasis on the lipoprotein-regulating enzymes. The subjects were 25 healthy volunteers and 66 uremic patients, 24 treated with hemodialysis (HD) and 42 with continuous ambulatory peritoneal dialysis (CAPD). Lipoprotein analysis revealed: (1) reduction in HDL cholesterol especially in HDL2 subfraction; (2) increase in HDL triglyceride; and (3) decreased ratio of HDL2 cholesterol to HDL3 cholesterol in both HD and CAPD patients. Simple regression analysis showed: (1) a positive correlation between VLDL triglyceride and triglyceride/cholesterol ratio of HDL; (2) positive correlations of LPL level in post-heparin plasma to cholesterol concentrations in HDL2, HDL3 and total HDL, and to apolipoproteins A-I and A-II; and (3) inverse correlations of HTGL to HDL2 cholesterol and to the ratio of HDL2 cholesterol/HDL3 cholesterol. Multiple regression analysis of HDL cholesterol indicated positive association with LPL and inverse correlation with VLDL triglyceride. Four variables including LPL, HTGL, LCAT and VLDL triglyceride explained 51.5% of the variation of HDL cholesterol. HDL2 cholesterol was associated positively with LPL and negatively with VLDL triglyceride in the model. HDL3 cholesterol was associated positively with LPL, HTGL and LCAT and inversely with VLDL triglyceride. Stepwise multiple regression analysis indicated that independent predictors of HTGL were gender, parathyroid hormone levels by a mid-portion assay, ionized calcium and age, and that those of LCAT were ionized calcium and age.(ABSTRACT TRUNCATED AT 250 WORDS)

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Abstract: To assess the mechanism of serum lipoprotein abnormalities in continuous ambulatory peritoneal dialysis (CAPD), we measured serum lipids, apolipoproteins, and postheparin lipases in 46 patients with end-stage renal disease (ESRD) treated on CAPD, 26 patients on hemodialysis (HD), and 29 healthy subjects. HD patients had higher serum triglyceride levels than the healthy controls, showing type IV and type III phenotypes. They had significantly lower activities of hepatic triglyceride lipase (HTGL) in postheparin plasma compared with controls, and postheparin lipoprotein lipase (LPL) was also decreased by 15%, although the latter change was not statistically significant. CAPD patients had elevated levels in triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein (apo) B, showing type IV, III, and II (IIb and IIa) phenotypes. The mean LPL and HTGL activities in CAPD patients were not different from those of HD patients. CAPD patients with hyperlipoproteinemia had significantly higher serum albumin levels than those with normolipidemia. There was a significant positive correlation between albumin and apo B levels in CAPD patients. In hyperlipidemic CAPD patients, there was no difference in serum albumin concentrations or HTGL activities among lipoprotein phenotypes, whereas LPL activities were significantly higher in the patients with type II than those with type IV hyperlipoproteinemia. These results suggest that there was some linkage between alterations in serum albumin and lipoproteins, and that LPL was related to phenotypic variation of hyperlipoproteinemia in CAPD.

Abstract: Total body and regional bone mineral density (BMD) and bone mineral content (BMC) in obese patients and healthy controls were assessed by dual-photon absorptiometry (DPA) in this study. In both men and women, BMD values in total body, pelvis, upper and lower extremities were significantly (p less than 0.05) higher in the obese group (body mass index greater than 28) than in the non-obese group (body mass index less than 23). These BMD values correlated significantly with body weights and with percentages of body fat. In the obese group, 8 massively obese women were treated with an 8-week very low calorie diet (VLCD), resulting in a 13.4 kg of mean body weight reduction. Although BMC in total body and in pelvis were maintained, significant decreases of BMC in the upper (from 275 +/- 30 to 255 +/- 26 g) and lower (from 871 +/- 47 to 805 +/- 31 g) extremities were observed following the 8-week VLCD treatment. These results suggest that body fat mass affects BMD and BMC preferentially in weight bearing bone, the changes of which are not always associated with changes in total body BMD or BMC.

Abstract: Direct effects of human uremic serum on the production of endothelin-1 in cultured porcine endothelial cells were examined in this study. Uremic serum decreased the level of monomeric endothelin-1 secreted into the culture medium by endothelial cells. This effect occurred at a transcriptional step because uremic serum decreased the endothelin-1 mRNA level in those cells. For the partial characterization of this inhibitory activity, uremic serum was fractionated with a centricut column. Uremic serum contains humoral factor(s) larger than 50 kD which suppress the endothelin-1 mRNA level in cultured endothelial cells.

Abstract: We examined changes in high density lipoprotein (HDL) metabolism during a very low calorie diet weight reduction program in 6 massively obese normolipidemic women. The diet protocol consisted of a 1st low calorie diet (LCD; 1440, 1280, and 880 kcal daily for 1 week, each, in succession), a 1st very low calorie diet (VLCD; 420 kcal daily for 4 weeks, using Optifast 70), intermission (880 kcal daily for 1 week), the 2nd VLCD (4 weeks) and the 2nd LCD (880 and 1280-1440 kcal daily for 1 week, each). Mean body weight reduction was 18.9 kg. HDL-cholesterol, more specifically HDL2-cholesterol, reduced transiently during the 1st VLCD, intermission, and 2nd VLCD periods, and tended to increase in the 2nd LCD. Apolipoprotein (apo) A-I showed a similar change to HDL-cholesterol. However, apo A-II decreased persistently throughout the weight reduction program, and the apo A-I/apo A-II ratio increased significantly in the later part of the program. Serum triglyceride, apo B, and lipoprotein lipase (LPL) activity in post-heparin plasma did not change. These data suggest that the observed decrease in HDL-cholesterol was not due to a reduction in very low density lipoprotein-derived HDL production or to an LPL deficiency, but was consistent with reduction in chylomicron-derived HDL formation following dietary fat restriction.

Abstract: Serum fructosamine levels were investigated in patients with uremia undergoing various modes of treatment. The serum fructosamine levels correlated positively with the blood glucose levels determined a week or two earlier. The fructosamine levels were significantly affected by the protein concentration, and those corrected for protein concentrations had a closer correlation to the blood glucose levels than did the uncorrected levels. The corrected fructosamine levels were not significantly different between healthy volunteers and nondiabetic patients with uremia on conservative treatment. In an in vitro system, fructosamine concentrations were hardly affected by urea, which is known to influence the level of hemoglobin A1. These results suggest that serum fructosamine measurement can provide us with reliable information on a short-term glycemic condition, even in azotemic patients. To be more precise, the serum level of fructosamine corrected for protein concentration can be an excellent glycemic index which is not susceptible to over- or dehydration and is of high clinical value, especially in the management of diabetic patients with chronic renal failure.

Abstract: The immunoregulatory effect of 1 alpha-OHD3, a precursor form of active vitamin D3 1,25 (OH)2D3, was examined in hemodialysis patients. Peripheral blood mononuclear cells (PBM) from hemodialysis patients produced significantly less interleukin-2 (IL-2) than those from normal controls. Four weeks of oral administration of 0.5 micrograms/day of 1 alpha-OHD3 enhanced the IL-2 production of PBM from the patients. This fact suggests that 1 alpha-OHD3 therapy may be useful for the restoration of IL-2 production in hemodialysis patients, and that the vitamin D3 deficiency may be responsible for the impairment of cellular immunity associated with IL-2 production disorder in hemodialysis patients.