Hideki Tahara

Insulin Resistance as an Independent Predictor of Cardiovascular Mortality in Patients with End-Stage Renal Disease

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.

Impact of Glycemic Control on Survival of Diabetic Patients on Chronic Regular Hemodialysis: A 7-Year Observational Study

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 HbA1c (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 ≤ A1C < 8.0%, 7.2 ± 0.4%, n = 39), and poor (A1C ≥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.

Hypertension Associated with Endothelin-Secreting Malignant Hemangioendothelioma

Endothelin-1, a potent vasoconstrictor peptide that has recently been isolated from the supernatant of cultured porcine aortic endothelial cells (1), is involved in some vascular disorders (2). Mal...

Platelet P-Selectin Expression Is Associated With Atherosclerotic Wall Thickness in Carotid Artery in Humans

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 &bgr;) 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 &bgr;. 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.

Decrease in carotid intima-media thickness in hypothyroid patients after normalization of thyroid function

objective  This case–control study was carried out to assess whether levothyroxine (L‐T4) replacement might cause regression of the enhanced atherosclerosis seen in hypothyroid patients.

Low Circulating Endogenous Secretory Receptor for AGEs Predicts Cardiovascular Mortality in Patients With End-Stage Renal Disease

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.

Skin autofluorescence, a marker for advanced glycation end product accumulation, is associated with arterial stiffness in patients with end-stage renal disease

Elevated cardiovascular mortality has been shown to be associated with increased arterial stiffness. However, the contribution of tissue accumulation of advanced glycation end products (AGEs) to increased arterial stiffness is unclear. We examined whether skin autofluorescence, a recently developed marker of tissue accumulation of AGEs, is associated with arterial stiffness in 120 Japanese patients with end-stage renal disease (ESRD) and 110 age- and sex-matched control subjects. The ESRD patients had significantly higher pulse wave velocity (PWV), a noninvasive measure of arterial stiffness, and skin autofluorescence than the control subjects. Skin autofluorescence was significantly associated with age in the group of all subjects (R(s) = 0.255, Spearman rank correlation test) and that of control subjects (R(s) = 0.493), but not in the group of ESRD subjects (R(s) = 0.046). The PWV was significantly and positively associated with skin autofluorescence in the group of all subjects (R(s) = 0.335), controls (R(s) = 0.246), and ESRD subjects (R(s) = 0.205). Multiple regression analyses showed that, in the group of all subjects, association of skin autofluorescence with PWV was significant even after adjustment for other covariates including the presence of ESRD and age. Moreover, for ESRD subjects, a significant association between skin autofluorescence and PWV was found, independent of age. Our findings demonstrate the potential usefulness of skin autofluorescence in people of color and demonstrate clinically for the first time the potential involvement of tissue accumulation of AGEs in the pathophysiology of arterial stiffness.

Genetic analyses in patients with familial isolated hyperparathyroidism and hyperparathyroidism–jaw tumour syndrome

Background  A subset of familial isolated primary hyperparathyroidism (FIHP) is a variant of hyperparathyroidism–jaw tumour syndrome (HPT‐JT).

Is the volume of the parathyroid gland a predictor of Maxacalcitol response in advanced secondary hyperparathyroidism

Abstract:  We evaluated the relationship between the volume of parathyroid glands estimated by ultrasonography (US) and response of 22‐oxa calcitriol (Maxacalcitol, OCT) in patients with secondary hyperparathyroidism (2HPT) to evaluate whether the volume can be a predictor of the OCT response. Eleven institutes participated in this study. Ninety‐four patients with advanced 2HPT were enrolled. The volume of the parathyroid glands were estimated by US before and 6 months after OCT treatment. The response of OCT treatment was classified into three groups (Group A: i‐PTH < 300 pg/mL; Group B: 300 pg/mL ≤ i‐PTH < 500 pg/mL; Group C: i‐PTH ≥ 500 pg/mL). Forty‐eight patients were in Group A, 28 patients in Group B, and 18 patients in Group C. The PTH levels at the beginning and 6 months were 458.3–199.1 pg/mL (P < 0.0001) in Group A, 524.6–403.2 pg/mL (P = 0.007) in Group B and 736.7–613.6 pg/mL (ns) in Group C, respectively. The volume of the largest gland in Group B was significantly larger than that in Group A (96.2 vs. 343.2 mm3: P < 0.001). Clinical factors affecting response of OCT was evaluated by logistic regression analysis and only the volume of the largest gland was a significant factor. In the patients whose volume was less than 300 mm3, the OCT response was significantly effective. We conclude that the glandular volume of the largest parathyroid gland estimated by US can be a useful factor to predict the OCT response in patients with moderate or severe renal HPT.

Parathyroid Tumor Suppressor on 1p: Analysis of the p18 Cyclin‐Dependent Kinase Inhibitor Gene As a Candidate

Loss of chromosome arm 1p DNA is the most common molecular defect thus far observed in human parathyroid adenomas, suggesting that 1p is the location of a putative tumor suppressor gene (or genes) whose inactivation contributes frequently to parathyroid tumorigenesis. To narrow the genomic location of this tumor suppressor gene, we analyzed 25 sporadic parathyroid adenomas for allelic loss of polymorphic DNA loci on chromosome 1 using 11 microsatellite markers not previously scored for this set of tumors. Allelic loss on chromosome arm 1p DNA was observed in 8 of 25 adenomas. Marker deletion patterns showed some complexity, with the regions most commonly deleted in these tumors being 1p36 and 1p35–p31. The 1p35–p31 region contains an excellent candidate tumor suppressor gene, p18, whose product is a cell cycle regulator that inhibits the cyclin D1‐associated kinase CDK6. Given that cyclin D1 is a parathyroid oncogene, inactivation of an inhibitor of cyclin D1 function, like p18, might also cause excessive parathyroid growth. To examine the involvement of p18 in parathyroid tumorigenesis, we analyzed 25 parathyroid adenomas for mutations of the p18 coding exons by single strand conformational polymorphism analysis and sequencing. No point mutations were found in any of the 25 adenomas. These observations indicate that inactivating mutation of the p18 gene occurs uncommonly, if at all, in parathyroid adenomas. In addition, the data raise the important possibility that more than a single tumor suppressor gene on 1p could contribute to parathyroid neoplasia.