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Secondary hyperparathyroidism (SHPT) remains a serious complication in patients with chronic kidney disease, and some patients require parathyroidectomy. The Parathyroid Surgeons' Society of Japan (PSSJ) evaluated parathyroidectomy for SHPT and tertiary hyperparathyroidism (THPT) in Japan. The annual numbers of parathyroidectomies between 2004 and 2013 were evaluated using questionnaires. Since 2010, the PSSJ has registered the patients. In total, 826 patients from 42 institutions were registered. The annual number of parathyroidectomies for SHPT and THPT in Japan increased from 2004 to 2007 and then decreased markedly after 2007, with 296 operations performed in 2013. The number of women and men was almost equal (397/427). Median (interquartile range) age of these patients was 59.0 (24-87) years, the duration of hemodialysis before parathyroidectomy was 10.83 (0.0-38.7) years, and diabetic nephropathy was 87/826 (10.5%). Of these patients 59.6% were treated with cinacalcet at undergoing parathyroidectomy. In 75.3% of patients, a total parathyroidectomy with forearm autograft was performed. In 77.7% of patients, four or more parathyroid glands were removed during the initial operation. The incidences of husky voice and wound hemorrhage were 2.9% and 1.1%, respectively. The number of parathyroidectomies for SHPT in Japan decreased markedly after the introduction of cinacalcet. Based on the evaluation of registered patients, parathyroidectomies have been successfully performed at the institutions participating in the PSSJ.

Background Unlike the n-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), n-3-PUFAs such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) appear to have beneficial effects on inflammation, thrombosis, and cardiovascular disease (CVD). We examined possible alterations in serum PUFA profiles in patients on maintenance hemodialysis therapy and its association with CVD risk. Study Design An observational study including cross-sectional and longitudinal analyses. Setting & Participants Single-center study of 517 maintenance hemodialysis patients in an urban area in Japan. Predictors Serum EPA, DHA, and AA concentrations and EPA:AA, DHA:AA, and (EPA+DHA):AA ratios. Outcomes CVD events, including ischemic heart disease, stroke, peripheral artery disease, pulmonary edema, and valve disease. Results Hemodialysis patients showed lower (EPA+DHA):AA, EPA:AA, and DHA:AA ratios than 122 controls similar in age and sex. During follow-up, 190 CVD events were recorded. (EPA+DHA):AA ratio was not associated significantly with CVD in unadjusted analysis, but was associated significantly and inversely with CVD in Cox models adjusted for age and other confounding variables, with HRs in the range of 1.71-1.99 in the lowest versus highest quartile of (EPA+DHA):AA ratios. Similarly, EPA:AA and DHA:AA ratios showed inverse associations with CVD, whereas serum EPA, DHA, and AA concentrations were not predictive of CVD. Limitations No information for dietary intake, use of dietary supplements, or cell membrane PUFA content. Conclusions In hemodialysis patients, serum PUFA profile is unfavorably altered, and the low n-3-PUFA:AA ratios are independent predictors of CVD.

Elemental concentrations in hair from hemodialysis (HD) patients have not been well investigated. We examined the relationships between the elemental concentrations in scalp hair and health-related quality of life (HRQOL) and nutritional status in HD patients. Twenty six elemental concentrations were measured in scalp hair samples from 60 male HD patients using inductively-coupled plasma mass spectrometry. To evaluate HRQOL, the Short Form 36 item health survey (SF36) was used. As indices of nutritional status, body mass index, serum parameters, and geriatric nutritional risk index (GNRI) were used. Phosphorus correlated positively with serum creatinine, blood urea nitrogen (BUN), GNRI and the physical domains of the SF36. Zinc correlated positively with serum creatinine, BUN and the physical domains of the SF36. Mercury and arsenic correlated positively with BUN. Cadmium correlated negatively with serum albumin, BUN and GNRI. Copper correlated positively with the physical domains of the SF36. Iodine correlated negatively with the physical domains of the SF36. Selenium correlated negatively with the mental domains of the SF36. In conclusion, phosphorus and zinc concentrations in scalp hair can be additional biomarkers of HRQOL and/or nutritional status in HD patients. Cadmium accumulation correlated with malnutrition. Iodine and selenium accumulation may adversely affect HRQOL. Further investigation is necessary to determine precisely how these elements affect these measures.

Numbers of endothelial progenitor cells (EPCs) have been shown to be decreased in subjects with end-stage renal disease (ESRD), the mechanism of which remained poorly understood. In this study, mutual association among circulating EPC levels, carotid atherosclerosis, serum pentosidine, and skin autofluorescence, a recently established noninvasive measure of advanced glycation end products accumulation, was examined in 212 ESRD subjects undergoing hemodialysis. Numbers of circulating EPCs were measured as CD34+ CD133+ CD45(low) VEGFR2+ cells and progenitor cells as CD34+ CD133+ CD45(low) fraction by flow cytometry. Skin autofluorescence was assessed by the autofluorescence reader; and serum pentosidine, by enzyme-linked immunosorbent assay. Carotid atherosclerosis was determined as intimal-medial thickness (IMT) measured by ultrasound. Circulating EPCs were significantly and inversely correlated with skin autofluorescence in ESRD subjects (R = -0.216, P = .002), but not with serum pentosidine (R = -0.079, P = .25). Circulating EPCs tended to be inversely associated with IMT (R = -0.125, P = .069). Intimal-medial thickness was also tended to be correlated positively with skin autofluorescence (R = 0.133, P = .054) and significantly with serum pentosidine (R = 0.159, P = .019). Stepwise multiple regression analyses reveal that skin autofluorescence, but not serum pentosidine and IMT, was independently associated with low circulating EPCs. Of note, skin autofluorescence was also inversely and independently associated with circulating progenitor cells. Thus, tissue accumulated, but not circulating, advanced glycation end products may be a determinant of a decrease in circulating EPCs in ESRD subjects.

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

The management of hemodialysis patients with chronic kidney disease-mineral bone disorder includes treatment to control levels of calcium, phosphorus and parathyroid hormone, so as to prevent bone and soft-tissue complications. Recently, pleiotropic effects of active vitamin D have attracted much attention, and its effect on outcome has also gained recognition. However, administration of active vitamin D may cause hypercalcemia and hyperphosphatemia. Now, the use of a novel class of drugs, cinacalcet hydrochloride, has been proposed as a strategy to reduce parathyroid hormone secretion, while decreasing levels of serum calcium, phosphorus, and calcium x phosphorus products. Among subjects with secondary hyperparathyroidism undergoing hemodialysis, combined therapy with cinacalcet and vitamin D sterols improved achievement of the biochemical targets for chronic kidney disease-mineral bone disorder recommended by the guidelines.

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.

Treating hyperphosphatemia without increasing the calcium load in chronic kidney disease patients on dialysis is important, as conventional treatment frequently results in ectopic calcification. Sevelamer, a monotherapy for hyperphosphatemia is frequently associated with gastrointestinal disorders, often resulting in discontinuation of treatment. Lanthanum carbonate is a novel non-calcium-based phosphate binder for the treatment of chronic kidney disease. Here, its clinical efficacy and safety were assessed in Japanese dialysis patients. A placebo-controlled, randomized, double-blind, parallel group, multicenter study was performed in Japanese dialysis patients. Patients were treated with various dosages of lanthanum carbonate or a placebo daily for six weeks. The primary efficacy endpoint was the change in serum phosphate level from the baseline. Secondary endpoints included achievement rates to target serum phosphate levels and changes in serum calcium levels. Safety was evaluated by the incidence of drug-related and treatment-emergent adverse events. A significant reduction in serum phosphate level was demonstrated for all dosages from Week 1. This dose-dependent effect was also observed in the changes in serum calcium x phosphate product, yet there was no notable difference in serum calcium or serum intact parathyroid hormone levels. The incidence of drug-related adverse events was dose-dependent, with the most common being gastrointestinal symptoms. Lanthanum carbonate effectively controls serum phosphate levels and is generally tolerable to Japanese chronic kidney disease patients on dialysis, as reported for the Caucasian population. The optimal dosage in Japanese patients needs to be confirmed using a flexible-dose titration schedule.

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.

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 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.

Clinical studies have been performed to determine the effect of cinacalcet HCl (cinacalcet), an allosteric modulator of the calcium-sensing receptor (CaR), on primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism of uremia (SHPT). However, no in vitro studies on human parathyroid cells have been reported to date. In this study, the inhibitory effect of cinacalcet on PTH secretion was analyzed in primary cultured parathyroid cells obtained from patients. The investigation involved three PHPT and three SHPT patients subjected to therapeutic parathyroidectomy. Notably, all SHPT patients were resistant to intravenous vitamin D analogue therapy. Removed parathyroid tumors were used for immunohistochemistry and parathyroid cell primary culture. Immunohistochemical analyses revealed diminished expression of CaR and vitamin D receptor (VDR) in all parathyroid tumors. PTH secretion from cultured parathyroid cells of PHPT and SHPT patients was suppressed by extracellular Ca2+ and cinacalcet in a dose-dependent manner. Rates of suppression of PTH secretion in PHPT and SHPT by cinacalcet (1000 nmol/l) were 61% +/- 21% and 61% +/- 19%, respectively. Cinacalcet demonstrates significant potency in the suppression of PTH secretion in primary cultured human parathyroid cells in vitro, despite reduced levels of the target protein, CaR. Data from this in vitro analysis support the clinical application of cinacalcet in PHPT and SHPT therapy.

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

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 × 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.

Hypothyroidism is associated with increased morbidity from cardiovascular disease, and an increase in serum osteoprotegerin (OPG) has recently been reported to be associated with the severity of coronary heart disease and cardiovascular mortality. The present study was designed to examine whether hypothyroidism causes an increase in serum OPG, and to determine whether levothyroxine (L-T4) replacement therapy might suppress serum OPG levels in hypothyroid patients. Fifty-three hypothyroid patients with chronic thyroiditis and age- and sex-matched normal control subjects were examined for the levels of serum OPG and plasma von Willebrand factor (vWF), a vascular injury marker. Thirty-seven of the hypothyroid patients were further monitored for changes in these markers during 1 year in a euthyroid state induced by L-T4 replacement therapy. Baseline OPG was significantly higher in hypothyroid patients than in normal controls (4.51 ± 0.50 vs 3.72 ± 0.23 pmol/l (mean ± S.E.); P = 0.0182). In multivariate analysis, baseline OPG was significantly associated with baseline levels of TSH (r = 0.280, P = 0.0162) and vWF (r = 0.626, P < 0.0001). During one year of L-T4 replacement therapy, hypothyroid patients showed a significant decrease in OPG levels from 4.35 ± 0.51 to 3.48 ± 0.26 pmol/l (P = 0.0166), a level comparable to normal controls. The change in serum OPG levels during L-T4 replacement therapy was significantly and independently associated in a negative fashion with baseline vWF (r = −0.503, P = 0.0014). This study suggested that the severity of hypothyroidism and vascular injury might have important independent roles in increasing the serum OPG level in hypothyroid patients. Furthermore, it was demonstrated that a sustained euthyroid state might have the potential to decrease the serum OPG level in hypothyroid patients and that the degree of vascular injury in the hypothyroid state is independently associated with a decrease in serum OPG during a 1-year normalization of thyroid function.

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 D3 ameliorates abnormalities in bone and mineral metabolism, cardiac function, immune response and others. We hypothesized that treatment with vitamin D3 may be beneficial for survival in patients with end-stage renal disease (ESRD). Methods. We compared the risk of death between regular users (n ¼ 162) and non-users (n ¼ 80) of oral 1-hydroxyvitamin D3 (alfacalcidol) in a cohort of ESRD patients undergoing haemodialysis for a followup of 61 ± 23 months. The daily dose of alfacalcidol ranged from 0.25 to 1.5mg, with a median of 0.5mg. 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 ¼ 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 ¼ 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 1-hydroxy vitamin D3 to confirm the possibility that such medication improves survival of ESRD patients.

Summary 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. patients and methods Intima-media thickness (IMT) in the common carotid artery (CCA) was measured from digitalized still images taken during scanning by high-resolution ultrasonography as an indicator of early atherosclerosis. Thirty-five hypothyroid patients were examined for their CCA IMT before and 1 year after normalization of thyroid function by L-T4 replacement. As control, 35 healthy subjects were enrolled from among the participants in a local health-check programme conducted at the Osaka City University Hospital. results Basal CCA IMT was significantly higher in hypothyroid patients [0·635 ± 0·018 (mean ± SE) mm] than in control subjects (0·559 ± 0·021 mm, P

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.

P-glycoprotein (P-gly), which is responsible for the phenotypic expression of multidrug resistance in cancerous tissue was stained immunohistochemically in previously untreated alpha-fetoprotein (AFP)-producing (n = 20) and nonproducing gastric cancers (n = 20). P-gly, AEP, and carcinoembryonic antigen(CEA) were stained in formalin-fixed paraffin-embedded tissue sections immunohistochemically using the monoclonal antibody JSB-1, anti-AFP, and anti-CEA, respectively. DNA ploidy pattern was determined by Fluorescence Activated Cell Sorter (FAGS) analyzer.P-gly was significantly overexpressed in AFP producing gastric cancers (60%) than in AFP nonproducing ones (20%) (P < 0.01). When the result of P-gly staining was analyzed among the AFP-positive cases, P-gly positivity did not emerge either as a significant prognostic factor or as a predictor of the metastatic potentiality of the tumor. The intrinsic overexpression of P-gly in AFP producing gastric cancers proves its biological and morphological similarities to hepatocellular carcinoma. The significantly (P < 0.05) higher incidence of P-gly in diploid tumors indicate that expression of this phenotype might be related to the differentiation of the tumor.P-gly was overexpressed in AFP producing gastric carcinoma and the existing drug resistance, frequent recurrence, and poor prognosis might be explained by presence of P-gly in this carcinoma. (C) 1995 Wiley-Liss, Inc.

Two molecular defects have been described in parathyroid adenomas: rearrangement and overexpression of the PRADI/cyclin DI oncogene and allelic loss of chromosome II DNA, often including the multiple endocrine neoplasia type I (MENI) putative tumor suppressor gene region. In an effort to identify additional parathyroid tumor suppressor genes, we examined 25 parathyroid adenomas for tumor-specific allelic loss of polymorphic DNA loci located near known or candidate tumor suppressor genes. Control leukocyte DNA from all 25 patients was heterozygous for I or more of the 9 chromosome I markers examined. Allelic loss at I or more of these informative loci on chromosome I was observed in 10 of 25 (40%) adenomas. Although many tumors lost extensive regions on chromosome I, all but one of these tumors had allelic loss of distal I p (I p32-pter); four tumors also lost loci on Iq. Allelic loss at IIqI3, the site of the MEN I gene, was detected in 5 of 2I (24%) informative cases, including 3 with Ip loss. In contrast, allelic loss was rarely observed at loci on 99 and Iop and was not observed at loci on 3p, 3q. 4p, 5q, I2q, I4q, I8q, 22q, or Xp. In summary, clonal allelic loss of loci on chromosome arm Ip is a frequent feature of parathyroid adenomas, implying that inactivation of a tumor suppressor gene(s) on Ip commonly contributes to their pathogenesis. © 1995 Wiley-Liss, Inc.

Elemental concentrations in hair from hemodialysis (HD) patients have not been well investigated. We examined the relationships between the elemental concentrations in scalp hair and health-related quality of life (HRQOL) and nutritional status in HD patients. Twenty six elemental concentrations were measured in scalp hair samples from 60 male HD patients using inductively-coupled plasma mass spectrometry. To evaluate HRQOL, the Short Form 36 item health survey (SF36) was used. As indices of nutritional status, body mass index, serum parameters, and geriatric nutritional risk index (GNRI) were used. Phosphorus correlated positively with serum creatinine, blood urea nitrogen (BUN), GNRI and the physical domains of the SF36. Zinc correlated positively with serum creatinine, BUN and the physical domains of the SF36. Mercury and arsenic correlated positively with BUN. Cadmium correlated negatively with serum albumin, BUN and GNRI. Copper correlated positively with the physical domains of the SF36. Iodine correlated negatively with the physical domains of the SF36. Selenium correlated negatively with the mental domains of the SF36. In conclusion, phosphorus and zinc concentrations in scalp hair can be additional biomarkers of HRQOL and/or nutritional status in HD patients. Cadmium accumulation correlated with malnutrition. Iodine and selenium accumulation may adversely affect HRQOL. Further investigation is necessary to determine precisely how these elements affect these measures.

Lanthanum carbonate is a non-aluminum, non-calcium phosphate binder. Its efficacy and its safety profile up to 1 year have been reported in Japanese hemodialysis patients. The present study was an extension of the earlier study. One hundred and forty-five patients were enrolled in the original 1 year observational Phase III study. After 1 year of treatment, 63 patients continued with further lanthanum treatment. Lanthanum carbonate was administered at 750–4,500 mg/day for up to 156 weeks (3 years). The reduction in serum phosphate was used to evaluate efficacy, and laboratory markers of bone turnover were monitored. The serum phosphate level was maintained at a significantly lower level (P

Treatment with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and incubation with lipopolysaccharide (LPS) induces interleukin 1 beta (IL-1 beta) production in the histiocytic lymphoma cell line U937. Here we investigated the effect of treatment with both TPA and 1 alpha, 25-dihydroxyvitamin D3 (1,25(OH)2D3) on LPS-induced IL-1 beta production in U937 cells. To clarify the mechanism of IL-1 beta production, the possible role of polyamines in this process was examined. Combined treatment with TPA and 1,25(OH)2D3 for 72 h followed by incubation with LPS for 24 h caused synergistic induction of both IL-1 beta release and mRNA expression. On the other hand, TPA increased the numbers of vitamin D3 receptors, which may be one mechanism of this synergistic induction. Ornithine decarboxylase (ODC), a rate-limiting enzyme for polyamine biosynthesis, was also induced by these compounds biphasically: the first peak of ODC activity was observed at 4 h of the incubation with the two compounds and the second peak was at 4 h after the addition of LPS. To find whether these peaks were related to IL-1 beta production, DL-alpha-difluoromethylornithine (DFMO), a specific irreversible inhibitor of ODC, was added together with TPA and 1,25(OH)2D3. DFMO decreased the cellular levels of putrescine and spermidine and suppressed IL-1 beta release and IL-1 beta mRNA expression by 65%. Exogenous putrescine, but not spermidine, abrogated these kinds of inhibition. Similar results were obtained with DFMO and the polyamines during the differentiation of the cells up to the monocyte or macrophage stage. These results thus suggest that changes in either of these intracellular polyamines, especially putrescine, help to regulate the differentiation of U937 cells, resulting in partial control of the regulation of IL-1 beta production.

Recently, we have reported two cases with endothelin (ET)-secreting tumor presenting with hypertension and elevated plasma endothelin-1 (ET-1) levels. The present study examines the histopathology of the ET-secreting tumor in one of these cases. The neoplasm was located in the skin and microscopically characterized as a malignant hemangioendothelioma by remarkable intravascular proliferations of atypical endothelium with the expression of Factor VIII-related antigen in the tumor cells. The tumor enlarged rapidly with rising ET-1 and blood pressure levels. The ET-1 content and its messenger RNA expression in the tumor extract were higher than those from normal parts of skin. ET-1 may play a pathophysiological role in patients with ET-secreting malignant hemangioendothelioma.

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.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 (A1C6.5%, 5.7 +/- 0.4%, n = 34), fair (6.5or= A1C8.0%, 7.2 +/- 0.4%, n = 39), and poor (A1Cor=8.0%, 9.2 +/- 0.9%, n = 41) A1C groups.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.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.

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.Intima-media thickness (IMT) in the common carotid artery (CCA) was measured from digitalized still images taken during scanning by high-resolution ultrasonography as an indicator of early atherosclerosis. Thirty-five hypothyroid patients were examined for their CCA IMT before and 1 year after normalization of thyroid function by L-T4 replacement. As control, 35 healthy subjects were enrolled from among the participants in a local health-check programme conducted at the Osaka City University Hospital.Basal CCA IMT was significantly higher in hypothyroid patients [0.635 +/- 0.018 (mean +/- SE) mm] than in control subjects (0.559 +/- 0.021 mm, P0.005). After 1 year of euthyroidism, 34 out of 35 patients showed a significant decrease of CCA IMT, to 0.552 +/- 0.015 mm (P0.0001), a level comparable to normal controls. CCA IMT change was closely associated with basal levels of total cholesterol (r = -0.472, P= 0.0031), low-density lipoprotein (LDL) cholesterol (r = -0.441, P= 0.0076) and the total/HDL cholesterol ratio (r =-0.435, P= 0.0057), but not with any of the other variables measured except for age (r = -0.353, P= 0.0296).This study demonstrated that L-T4 treatment might have the potential to reverse the progression of atherosclerosis in hypothyroid patients. Furthermore, it suggests that increased levels of LDL cholesterol and the total/HDL cholesterol ratio have an important role in the increased common carotid intima-media thickness in hypothyroid patients.

The expression of the connective tissue growth factor ( ctgf) gene increases along with the differentiation of growth cartilage cells, and the highest expression is observed in the hypertrophic stage. Similarly, recent reports demonstrated c- fos expression in chondrocytes in the early hypertrophic zone of growth cartilage, and suggested that the c- fos gene may play a crucial role in the regulation of hypertrophic differentiation. A chondrocytic human cell line, HCS-2/8, is known to retain a variety of chondrocytic phenotypes. When such cells were kept overconfluent, they expressed increasing levels of c- fos transcripts along a time course phenotypically similar to that of hypertrophic differentiation. Moreover, by using a competitive electromobility-shift assay, we found that AP-1, a Fos/Jun heterodimer, in HCS-2/8 was capable of binding not only to a typical AP-1-binding DNA fragment but also to the enhancer fragment of the ctgf gene. Based on the findings above, we hypothesize that, prior to hypertrophic differentiation, AP-1-related oncogenes are activated and that their gene products subsequently activate ctgf gene expression, which might eventually induce hypertrophy.

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.

Heparin shows a blood pressure-lowering effect in various hypertensive rat models. This study was designed to examine the effect of heparin on vasoconstrictor endothelin-1 (ET-1) production by cultured human umbilical vein endothelial cells (HUVECs). ET-1 and cyclic GMP levels in the medium were determined by radioimmunoassay. ET-1 mRNA was quantified by densitometric Northern blot analysis. ET-1 was released into the medium in a time-dependent manner, and its release was augmented by thrombin (10 U/ml). Heparin suppressed both basal and thrombin-stimulated ET-1 secretion and its mRNA expression in a dose-dependent manner. Heparin suppressed ET-1 mRNA expression in a time-dependent fashion. Heparin did not suppress both basal and thrombin-stimulated ET-1 production in the presence of NG-monomethyl-L-arginine (L-NMMA) (10(-5) M). The production of cGMP stimulated by thrombin was significantly enhanced by heparin, but not in the presence of L-NMMA (10(-5) M). Heparin may suppress vasoconstrictor ET-1 production mediated by the enhancement of endothelium-derived nitric oxide in HUVECs.

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.

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.

Antibody to oxidized low-density lipoprotein and cardiovascu- expressing immunoglobulin mRNA (4), suggesting local lar mortality in end-stage renal disease. production of antibodies. OxLDL is detected in athero- Background. Immune response to oxidized low-density lipo- matous lesions (5-7), and it can activate lymphocyte clones protein (oxLDL) may modulate the process of atherogenesis (8). Immunoglobulins extracted from plaques recognize and cardiovascular disease. oxLDL (9), and antibody against oxLDL is present in Methods. We performed a prospective, observational cohort study in 249 patients with end-stage renal disease (ESRD) to serum (6, 10-19). To date it has not been established examine whether the serum titer of anti-oxLDL antibody can whether immune response to oxLDL is atherogenic or predict cardiovascular mortality. anti-atherogenic. Results. The median anti-oxLDL antibody titer was 320 Atherosclerosis is advanced (20-23) and the cardiovas- mU/mL at baseline. During the follow-up (63 23 months), cular mortality rate is substantially elevated among pa- 72 deaths including 34 cardiovascular deaths occurred. When the subjects were divided into two groups by the median titer, tients with end-stage renal disease (ESRD) (24, 25). Some the high titer group showed a lower risk for cardiovascular studies showed that ESRD patients had a higher titer mortality (P 0.040 by Kaplan-Meier analysis and log-rank of anti-oxLDL antibody than healthy subjects (26, 27). test). Multivariate Cox proportional hazards model indicated Elevated anti-oxLDL antibody also was reported in pa- that the lower risk of cardiovascular death in the high titer tients with coronary artery disease (11), severe carotid group remained significant (hazard ratio of 0.46, 95%CI 0.23- 0.95, P 0.037) and independent of age, presence of vascular atherosclerosis (10), and peripheral artery disease (12). complications, presence of diabetes mellitus, and elevated Although some studies failed to confirm such elevation in C-reactive protein. In contrast, anti-oxLDL antibody titer was anti-oxLDL antibody in patients with acute myocardial not associated with non-cardiovascular mortality. infarction (16), cerebral infarction (15), diabetic macro- Conclusions. These results demonstrate, to our knowledge angiopathy (14), and familial hypercholesterolemia (17), for the first time, that serum anti-oxLDL antibody titer is an independent predictor of cardiovascular mortality in a cohort most of these observations suggest that titer of anti- of patients with ESRD. oxLDL antibody is elevated in those with advanced ath- erosclerosis. In contrast to the comparison between groups with and Since oxidized low-density lipoprotein (oxLDL) plays without advanced atherosclerosis, a few studies focused on a central role in the initiation and progression of athero- the variation of anti-oxLDL antibody titer within healthy sclerosis (1), immune response to oxLDL may modulate subjects. Recently, we found an inverse association be- atherogenesis (2) and cardiovascular mortality. In ather- tween serum anti-oxLDL antibody and circulating oxLDL omatous plaques, there are immune competent cells in- levels in healthy human subjects (18). We also showed cluding macrophages, activated T (3), and B lymphocytes an independent and inverse association between anti- oxLDL antibody titer and intima-media thickness of ca- rotid artery in a healthy population (19). These results