Tomoyuki Yamakawa

Glycated Albumin Is a Better Glycemic Indicator than Glycated Hemoglobin Values in Hemodialysis Patients with Diabetes: Effect of Anemia and Erythropoietin Injection

The significance of glycated albumin (GA), compared with casual plasma glucose (PG) and glycated hemoglobin (HbA(1c)), was evaluated as an indicator of the glycemic control state in hemodialysis (HD) patients with diabetes. The mean PG, GA, and HbA(1c) levels were 164.5 +/- 55.7 mg/dl, 22.5 +/- 7.5%, and 5.85 +/- 1.26%, respectively, in HD patients with diabetes (n = 538), which were increased by 51.5, 31.6, and 17.7%, respectively, compared with HD patients without diabetes (n = 828). HbA(1c) levels were significantly lower than simultaneous PG and GA values in those patients in comparison with the relationship among the three parameters in patients who had diabetes without renal dysfunction (n = 365), as reflected by the significantly more shallow slope of regression line between HbA(1c) and PG or GA. A significant negative correlation was found between GA and serum albumin (r = -0.131, P = 0.002) in HD patients with diabetes, whereas HbA(1c) correlated positively and negatively with hemoglobin (r = 0.090, P = 0.036) and weekly dose of erythropoietin injection (r = -0.159, P < 0.001), respectively. Although PG and GA did not differ significantly between HD patients with diabetes and with and without erythropoietin injection, HbA(1c) levels were significantly higher in patients without erythropoietin. Categorization of glycemic control into arbitrary quartile by HbA(1c) level led to better glycemic control in a significantly higher proportions of HD patients with diabetes than those assessed by GA. Multiple regression analysis demonstrated that the weekly dose of erythropoietin, in addition to PG, emerged as an independent factor associated with HbA(1c) in HD patients with diabetes, although PG but not albumin was an independent factor associated with GA. In summary, it is suggested that GA provides a significantly better measure to estimate glycemic control in HD patients with diabetes and that the assessment of glycemic control by HbA(1c) in these patients might lead to underestimation likely as a result of the increasing proportion of young erythrocyte by the use of erythropoietin.

Role of fibroblast growth factor-23 in peripheral vascular calcification in non-diabetic and diabetic hemodialysis patients.

Introduction:Fibroblast growth factor (FGF) 23 is a recently identified circulating factor that regulates phosphate (Pi) metabolism. Since the derangement of Pi control is an important risk factor for vascular calcification, we investigated the importance of plasma FGF-23 in the development of vascular calcification in the aorta and peripheral artery in hemodialysis patients with and without diabetes mellitus (DM).Methods:Male hemodialysis patients with DM (n=32) and without DM (n=56) were examined. Plasma samples were obtained before the start of dialysis sessions, and the FGF-23 levels were determined by enzyme-linked immunosorbent assay. Roentgenography of the aorta and hand artery was performed, and visible vascular calcification was evaluated by one examiner, who was blinded to the patient characteristics.Results:In the 56 non-DM hemodialysis patients, vascular calcification was found in the hand artery in 5 patients (8.9%) and in the aorta in 23 patients (41.1%). These levels were significantly lower (p<0.05) than in the 32 DM patients, of whom, 19 (59.4%) and 21 (65.6%) had vascular calcification of the hand artery and aorta, respectively. Multiple regression analyses performed separately in the non-DM and DM patients showed that the plasma FGF-23 level, Ca×Pi product, and body weight are independent factors significantly associated with hand-artery calcification and that diastolic blood pressure is associated with aorta calcification in non-DM patients. In DM patients, the plasma FGF-23 level and hemodialysis duration emerged as independent factors associated with hand-artery calcification and diastolic blood pressure was associated with aorta calcification. The independent association of the plasma FGF-23 level with hand-artery calcification was retained in both non-DM and DM patients when adjusted for the Ca×Pi product.Conclusion:Our findings show that the plasma FGF-23 level is an independent factor negatively associated with peripheral vascular calcification in the hand artery, but not in the aorta, in both male non-DM and DM hemodialysis patients, even when adjusted for the Ca×Pi product. This study raises the possibility that the plasma FGF-23 level may provide a reliable marker for Moenckeberg’s medial calcification in male hemodialysis patients, independent of its regulatory effect on Pi metabolism.

Significant association between the presence of peripheral vascular calcification and lower serum magnesium in hemodialysis patients.

AIM Vascular calcification, which significantly increases cardiovascular and other causes of mortality, is highly prevalent in hemodialysis patients. The aim of the present study was to examine the association between serum magnesium levels and vascular calcification in hemodialysis patients. METHODS 390 nondiabetic patients on maintenance hemodialysis (226 males and 164 females, 59 +/- 13 years) were examined. Hand roentgenography was performed in each patient, and visible vascular calcification of the hand arteries was evaluated. Blood was drawn to measure serum calcium, phosphate, magnesium and intact parathyroid hormone levels. RESULTS There were 52 patients (38 males and 14 females) with vascular calcification, and 338 (188 males and 150 females) without. Serum phosphate was significantly higher in the former compared with the latter group (p < 0.005); serum intact parathyroid hormone was significantly higher (p < 0.05), whereas serum calcium was not statistically different between the two groups. Serum magnesium was significantly lower in patients with vascular calcification than in those without (2.69 +/- 0.28 vs. 2.78 +/- 0.33 mg/dl, p < 0.05). Multivariate logistic regression analysis revealed that serum magnesium concentration was a significant independent factor associated with the presence of vascular calcification in hemodialysis patients (odds ratio 0.28, 95% CI 0.09 - 0.92/1 mg/dl increase in serum magnesium, p = 0.036) after adjustment for age, gender, duration of hemodialysis, calcium, phosphate and intact parathyroid hormone concentrations. CONCLUSION Hypomagnesemia is significantly associated with the presence of vascular calcification of the hand arteries, independent of serum calcium and phosphate levels. These results suggest that higher serum magnesium concentrations may play an important protective role in the development of vascular calcification in hemodialysis patients, and that magnesium concentration of dialysis fluid may be reconsidered in view of preventing vascular calcification in hemodialysis patients.

Serum β2-microglobulin level is a significant predictor of mortality in maintenance haemodialysis patients

BACKGROUND Beta(2)-microglobulin (beta(2)-M) is recognized as a surrogate marker of middle-molecule uraemic toxins and is a key component in the genesis of dialysis-associated amyloidosis. Few studies have evaluated the association of beta(2)-M levels with clinical outcome in dialyzed patients. METHODS The prognostic implication of serum beta(2)-M levels for the survival of haemodialysis patients was examined in 490 prevalent haemodialysis patients (60.1 +/- 11.8 years, haemodialysis duration of 87.4 +/- 75.7 months, 288 males and 202 females; 24% diabetics). The patients were divided into two groups according to their serum beta(2)-M levels: lower beta(2)-M group (n = 245) with serum beta(2)-M <32.2 mg/L (the median serum beta(2)-M) and higher beta(2)-M group (n = 245) with that >or=32.2 mg/L. RESULTS During the follow-up period of 40 +/- 15 months, there were 91 all-cause deaths, and out of them, 36 were from cardiovascular diseases. Kaplan-Meier analysis revealed that all-cause mortality in the higher beta(2)-M group was significantly higher compared to that in the lower beta(2)-M group (P < 0.001). Multivariate Cox proportional hazards analyses showed that serum beta(2)-M level was a significant predictor for all-cause mortality (hazard ratio, 1.05; 95% CI, 1.01-1.08; P = 0.005), and for non-cardiovascular mortality (hazard ratio, 1.06; 95% CI, 1.02-1.10; P = 0.006), after adjustment for age, gender, haemodialysis duration, the presence of diabetes, serum albumin and serum C-reactive protein. CONCLUSION These results demonstrate that the serum beta(2)-M level is a significant predictor of mortality in haemodialysis patients, independent of haemodialysis duration, diabetes, malnutrition and chronic inflammation, suggesting the clinical importance of lowering serum beta(2)-M in these patients.

Geriatric Nutritional Risk Index, a simplified nutritional screening index, is a significant predictor of mortality in chronic dialysis patients

BACKGROUND Malnutrition is a common complication in haemodialysis patients. Recently, the Geriatric Nutritional Risk Index (GNRI) has been reported as a simple and accurate tool to assess nutritional status of haemodialysis patients. Our objective was to examine the association between GNRI and mortality in chronic haemodialysis patients. METHODS We examined the GNRI of 490 maintenance haemodialysis patients (60 ± 12 years, 293 males and 197 females) and followed up these patients for 60 months. Predictors for all-cause death were examined using Kaplan-Meier analysis and Cox proportional analyses. RESULTS The GNRI was 98.0 ± 6.0, and was significantly and negatively correlated with age and haemodialysis duration. During the 60-month follow-up period, 129 patients died. According to the highest positive likelihood and risk ratios, the cutoff value of GNRI for mortality was set at 90. Kaplan-Meier analysis revealed that patients with a GNRI <90 (n = 50) had a significantly lower survival rate, compared to those with GNRI ≥90 (n = 440) (log-rank test, P < 0.0001). Multivariate Cox proportional hazards analyses demonstrated that GNRI was a significant predictor for mortality [hazard ratio (HR) 0.962, 95% confidence interval (CI) 0.931-0.995, P < 0.05], after adjustment for age, gender, C-reactive protein, presence of diabetes and haemodialysis duration. CONCLUSIONS These results demonstrated that GNRI is a significant predictor for mortality in haemodialysis patients. The simple method of GNRI is considered to be a clinically useful marker for the assessment of nutritional status in haemodialysis patients.

Serum Levels of TRAP5b, a New Bone Resorption Marker Unaffected by Renal Dysfunction, as a Useful Marker of Cortical Bone Loss in Hemodialysis Patients

Tartrate-resistant acid phosphatase (TRAP) 5b is a new marker of bone resorption that is unaffected by renal dysfunction. The significance of TRAP5b was assessed in hemodialysis (HD) patients. Serum concentrations of TRAP5b and cross-linked N-telopeptide of type I collagen (NTX) were determined as bone resorption markers, and those of bone alkaline phosphatase (BAP) and intact osteocalcin (OC) were measured as bone formation markers in 58 HD patients. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry twice in the distal third of the radius, with a 2-year interval between measurements. Serum TRAP5b correlated significantly with BAP, intact OC, intact parathyroid hormone (PTH), and especially serum NTX. TRAP5b, NTX, BAP, and intact OC all correlated significantly with BMD at the time of the second measurement; and TRAP5b, NTX, and intact OC, but not BAP and intact PTH, correlated significantly with the annual change in BMD during the 2-year period. Among the bone markers, patients in the highest tertile for serum TRAP5b and intact OC showed the fastest rate of cortical bone loss. The sensitivity and specificity for detection of rapid bone loss were 57.9% and 76.9%, respectively, for serum TRAP5b. Measurement of serum TRAP5b, as well as intact OC, may be a clinically relevant assay for estimation of bone metabolic status in HD patients, although serum intact OC accumulates in uremic serum.

Increased Incidence of Vertebral Fracture in Older Female Hemodialyzed Patients with Type 2 Diabetes Mellitus

Bone disease in hemodialysis (HD) patients with type 2 diabetes mellitus (DM) is characterized by low bone turnover (Inaba M, et al. Am J Kidney Dis 2002; 39:1261-1269), although their bone quality is yet to be determined. The present study was designed to examine whether the prevalence of vertebral fracture in female HD patients with type 2 DM, age 65 years and older, might be increased, and the relation of this fracture to bone mineral density (BMD) determined by dual X-ray absorptiometry (DXA), since few data are available on the effect of DM on bone strength at lumbar spine. The prevalence of vertebral fracture in type 2 DM HD patients was 32.3%, which was greater than that of non-DM HD patients (13.3%) when adjusted for age and HD duration. Logistic regression analysis elucidated the presence of DM and age as independent risk factors for an increased prevalence of vertebral fracture in HD patients. In non-DM HD patients, those with vertebral fracture showed age significantly higher and BMD in either lumbar spine or distal one third of radius significantly lower than the respective value in those without fracture. However, in DM HD patients, neither BMD in lumbar spine nor distal one third of radius was significantly lower in those with vertebral fracture than in those without. Furthermore, age did not differ significantly between DM HD patients with and without fracture. In conclusion, female type 2 DM HD patients, age 65 years and older, showed significantly higher incidence of vertebral fracture than non-DM HD patients. Although age and low BMD emerged as independent risk factors for vertebral fracture in non-DM HD patients, those factors failed to be a risk factor in DM HD patients, suggesting that BMD determined by DXA might not be reliable in assessing bone strength in DM HD patients.

Fatigue Is a Predictor for Cardiovascular Outcomes in Patients Undergoing Hemodialysis

BACKGROUND AND OBJECTIVES Despite potential significance of fatigue and its underlying components in the occurrence of cardiovascular diseases, epidemiologic data showing the link are virtually limited. This study was designed to examine whether fatigue symptoms or fatigues underlying components are a predictor for cardiovascular diseases in high-risk subjects with ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS 788 volunteer patients under hemodialysis therapy (506 male, 282 female) completed the survey between October and November 2005, with the follow-up period up to 26 months to monitor occurrence of fatal or nonfatal cardiovascular events. The questionnaire consisted of 64 questions, and promax rotation analysis of the principal component method conceptualized eight fatigue-related factors: fatigue itself, anxiety and depression, loss of attention and memory, pain, overwork, autonomic imbalance, sleep problems, and infection. RESULTS 14.7% of the patients showed fatigue scores higher than twice the SD of the mean for healthy volunteers. These highly fatigued patients exhibited a significantly higher risk for cardiovascular events (hazard ratio: 2.17; P < 0.01), with the relationship independent of the well-known risk factors, including age, diabetes, cardiovascular disease history, and inflammation and malnutrition markers. Moreover, comparisons of the risk in key subgroups showed that the risk of high fatigue score for cardiovascular events was more prominent in well-nourished patients, including lower age, absence of past cardiovascular diseases, higher serum albumin, and high non-HDL cholesterol. CONCLUSIONS Fatigue can be an important predictor for cardiovascular events in patients with ESRD, with the relationship independent of the nutritional or inflammatory status.

Inhibition of intimal hyperplasia after vein grafting by in vivo transfer of human senescent cell-derived inhibitor-1 gene

The senescent cell-derived inhibitor (sdi)-1 (p21) protein has been identified as a downstream mediator of the tumor suppressor p53 in the cell cycle regulation. In this study, we focused on the function of sdi-1 gene in inhibiting vascular smooth muscle cell (VSMC) proliferation after vein grafting in a rabbit model. To test the hypothesis, we transfected human sdi-1 gene by an intra-operative approach. Accompanied by markedly increased sdi-1 protein, the significant increase in PCNA-stained VSMCs in vein grafts was inhibited by transfection of sdi-1 gene. Moreover, at 2 weeks after transfection, transfer of sdi-1 gene resulted in a significant inhibition in neointimal formation, compared with control vector. Of importance, immunohistological studies determining the expression pattern of myosin heavy isoforms, adult type specific SM2 and embryonic specific SMemb/NMHC-B, demonstrated expression of the adult phenotype of VSMCs in the neointima of sdi-1 gene-transfected vein grafts at 2 weeks after the operation, while the neointima was predominantly composed of embryonic phenotype of VSMCs in the control grafts. Overall, these results demonstrate that a single intraluminal incubation of human sdi-1 gene can result in a significant inhibition of neointimal formation after vein grafting, associated with phenotypic change of VSMCs from neonatal to adult type in a rabbit model. Inhibition of hyperplasia in a graft model by transfection of sdi-1 gene may be due to the change in VSMC phenotype from neonatal to adult, in addition to the inhibition of VSMC growth.

Arterial stiffness predicts cardiovascular death independent of arterial thickness in a cohort of hemodialysis patients

OBJECTIVE Both arterial thickness and stiffness are predictors of cardiovascular disease (CVD). Although these arterial changes develop in parallel, no study has ever tested a hypothesis that arterial stiffness can predict mortality from CVD independent of arterial thickness. This study tested this possibility. METHODS This was an observational cohort study in 423 hemodialysis patients (CKD stage 5D). We simultaneously measured intima-media thickness (CA-IMT) and stiffness parameter beta (CA-beta) by carotid ultrasonography at baseline, and the cohort was followed-up for a mean period of 70 months. RESULTS During the follow-up, 216 all-cause deaths occurred including 124 deaths from CVD. Univariate analyses indicated both CA-IMT and CA-beta were significant predictors for CVD death. Kaplan-Meier analysis, in which the total subjects were divided into four groups by the medians of CA-IMT and CA-beta, showed that the hazards ratio (95% confidence interval) was 5.87 (3.43-10.05) for the group with higher CA-IMT/higher CA-beta as compared to the group with lower CA-IMT/lower CA-beta. The hazards ratios for the group with lower CA-IMT/higher CA-beta (2.22, 1.16-4.25) and the group with higher CA-IMT/lower CA-beta (2.85, 1.52-5.33) were comparable. Multivariate Cox analysis revealed that both CA-IMT and CA-beta were independently predictive of CVD mortality even after adjustment for other relevant covariates. CONCLUSION Increased arterial stiffness predicted cardiovascular mortality independent of arterial thickness in this cohort, implicating the distinct roles of stiffness and thickness of arterial wall in the pathogenesis of CVD.