Subgroup Analysis Stratified by Baseline Pancreatic ß-cell Function in a Japanese Study of Dulaglutide in Patients with Type 2 Diabetes.

INTRODUCTION: This analysis investigated the relationship between baseline fasting pancreatic ß-cell function and efficacy in Japanese patients with type 2 diabetes (T2D) treated with once-weekly dulaglutide 0.75 mg (dulaglutide) or once-daily liraglutide 0.9 mg (liraglutide) for up to 52 weeks. METHODS: In a 52-week study of monotherapy in Japanese patients with T2D, patients were categorized into three subgroups defined by tertiles (low, medium, and high) of baseline values of three pancreatic ß-cell function parameters [fasting C-peptide, C-peptide index, and secretory units of islets in transplantation (SUIT) index]. Associations between these parameters and efficacy [defined by changes from baseline in glycated hemoglobin (HbA1c), fasting blood glucose (FBG), postprandial blood glucose (PBG), mean of all meals blood glucose excursion, and body weight] in the dulaglutide group (280 patients) or the liraglutide group (137 patients) were evaluated. RESULTS: Patients in the subgroups with high insulin-secreting ability (based on pancreatic ß-cell function) were younger and had shorter disease duration and higher body mass index compared to those with low insulin-secreting ability. No specific trend was observed between baseline pancreatic ß-cell function and changes in HbA1c or FBG. Reductions from baseline in mean PBG and excursion were greatest for patients in the low ß-cell function tertiles. Inconsistent trends in body weight were observed across the treatment groups and ß-cell function parameters. CONCLUSION: In Japanese patients with T2D, changes in HbA1c and body weight after 52 weeks of treatment with dulaglutide or liraglutide could not be predicted by patients' fasting pancreatic ß-cell function before treatment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT01558271). FUNDING: Eli Lilly K.K. (Kobe, Japan).

Incidence of diabetes mellitus and neoplasia in Japanese short-statured children treated with growth hormone in the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS).

The primary goal of the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) was to assess the safety and effectiveness of Humatrope®, a GH preparation, in the treatment of pediatric patients with short stature. We report our findings in the GH-treated Japanese pediatric population focusing on the incidence of type 2 diabetes (T2D) and occurrence of neoplasms. A total of 2,345 Japanese patients were assessed for safety. During a mean observation period of 3.2 yr, T2D occurred in 3 patients (0.13%) and slowly progressive insulin-dependent diabetes mellitus (SPIDDM) related to underlying mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) in 1 patient (0.04%). Neoplasms were reported in 13 patients (0.56%), including 1 patient with brain tumor (germinoma) and 5 with craniopharyngiomas (4 recurrences); the remainder were benign, typically dermatological, neoplasms. The incidence of diabetes mellitus determined in the study did not differ from previous reports in GH-treated pediatric patients, and there was no apparent increase in the risk of new neoplastic lesions or malignant tumors.

Insulin lispro 25/75 and insulin lispro 50/50 as starter insulin in Japanese patients with type 2 diabetes: subanalysis of the CLASSIFY randomized trial.

In Japan, premixed insulins are commonly used as starter insulin for type 2 diabetes. This subpopulation analysis assessed the efficacy and safety of twice-daily LM25 (25% insulin lispro/75% insulin lispro protamine) and LM50 (50% insulin lispro/50% insulin lispro protamine) as starter insulin in Japanese subjects, and compared these results with the whole-trial populations of East Asian subjects. In this subpopulation analysis of an open-label, phase 4, randomized trial (CLASSIFY), Japanese subjects received LM25 (n = 88) or LM50 (n = 84) twice-daily for 26 weeks. The primary outcome was change from baseline at Week 26 in glycated hemoglobin (HbA1c). Results for Japanese subjects were generally similar to those for the whole-trial population. Similar changes from baseline in HbA1c were observed for LM25 and LM50 groups (least squares [LS] mean difference [95% confidence interval] of LM25 - LM50 = 0.13 [-0.16, 0.41]%, 1.42 [-1.75, 4.48] mmol/mol, p = 0.388). More LM50-treated subjects than LM25-treated subjects achieved HbA1c targets of <7.0% (59.5% versus 43.2%; p = 0.034) or ≤6.5% (45.2% versus 28.4%; p = 0.027). The reduction in postprandial blood glucose concentrations after morning and evening meals was statistically significantly greater for LM50 than for LM25. The incidence of both hypoglycemia and treatment-emergent adverse events were similar between treatment groups. Both LM25 and LM50 twice daily appear to be effective and well tolerated as starter insulin, although LM50 might be more effective for Japanese type 2 diabetes patients.

Analysis of efficacy and safety of dulaglutide 0.75 mg stratified by sex in patients with type 2 diabetes in 2 randomized, controlled phase 3 studies in Japan.

We analyzed the efficacy and safety of once weekly dulaglutide 0.75 mg by sex in 2 randomized, controlled phase 3 studies in Japanese patients with type 2 diabetes (a 52-week monotherapy study [comparator liraglutide 0.9 mg] and a 26-week combination therapy study [comparator insulin glargine]). Females comprised 18% of patients in the monotherapy study and 29% of patients in the combination therapy study. Mean reductions from baseline in glycated hemoglobin (HbA1c) were similar between the sexes for dulaglutide- and liraglutide-treated patients (range -1.17% to -1.49%). Females had numerically greater weight loss or less weight gain than males across all treatment groups. The percentages of patients with reductions in both HbA1c and weight from baseline were also greater for females than for males in all treatment groups. In all treatment groups, the incidences of treatment-emergent adverse events tended to be greater among females than among males. No differences in the incidences of total or nocturnal hypoglycemia were observed between the sexes in any treatment group. Overall, in 2 studies in Japan, across all treatment groups it appeared that HbA1c lowering was unaffected by patient sex, while female patients had greater weight loss or less weight gain and greater incidence of adverse events, including nausea, compared to male patients. Incidences of patients discontinuing dulaglutide early due to adverse event were low (<10%) for both sexes, and no new safety concerns related to dulaglutide were identified for either sex. Therefore, the benefit/risk ratio for dulaglutide remains unchanged, positive for both sexes.

Impact of diet on the efficacy of insulin lispro mix 25 and insulin lispro mix 50 as starter insulin in East Asian patients with type 2 diabetes: Subgroup analysis of the Comparison Between Low Mixed Insulin and Mid Mixed Insulin as Starter Insulin For Patients with Type 2 Diabetes Mellitus (CLASSIFY Study) randomized trial.

AIMS/INTRODUCTION: The pathophysiology of diabetes differs between Asian and Western patients in many ways, and diet is a primary contributor. The present study examined the effect of diet on the efficacy of 25% insulin lispro/75% insulin lispro protamine suspension (LM25) and 50% insulin lispro/50% insulin lispro protamine suspension (LM50) as starter insulin in Chinese and Japanese patients with type 2 diabetes and inadequate glycemic control with oral antidiabetic medication. MATERIALS AND METHODS: This was a predefined subgroup analysis of a phase 4, open-label, 26-week, parallel-arm, randomized (computer-generated random sequence) trial (21 January 2013 to 22 August 2014). Nutritional intake was assessed from food records kept by participants before study drug administration. Outcomes assessed were changes from baseline in self-monitored blood glucose, 1,5-anhydroglucitol and glycated hemoglobin. RESULTS: In total, 328 participants were randomized to receive twice-daily LM25 (n = 168) or LM50 (n = 160). Median daily nutritional intake (by weight and percentage of total energy) was 230.8 g of carbohydrate (54%), 56.5 g of fat (31%) and 66 g of protein (15%). Improvements in self-monitored blood glucose were significantly greater (P ≤ 0.028) in the LM50 group than in the LM25 group, regardless of nutritional intake. When carbohydrate (by weight or percentage energy) or fat (by weight) intake exceeded median levels, LM50 was significantly more efficacious than LM25 (P ≤ 0.026) in improving 1,5-anhydroglucitol and glycated hemoglobin. CONCLUSIONS: Glycemic control improved in both LM25 and LM50 groups, but LM50 was significantly more efficacious under certain dietary conditions, particularly with increased carbohydrate intake.

Comparison of insulin lispro mix 25 with insulin lispro mix 50 as an insulin starter in Asian patients with type 2 diabetes: a phase 4, open-label, randomized trial (CLASSIFY study).

BACKGROUND: Lispro Mix 25% insulin lispro/75% insulin lispro protamine (LM25) and Lispro Mix 50% insulin lispro/50% insulin lispro protamine (LM50) were compared as starter insulins in East Asian patients with type 2 diabetes. METHODS: Phase 4, open-label, randomized trial conducted in China, Japan, Korea, and Turkey. Subjects received twice-daily LM25 (n = 207) or LM50 (n = 196) for 26 weeks. The primary outcome was the HbA1c change from baseline. RESULTS: The least squares mean changes from baseline in HbA1c are -1.52% and -1.69% for LM25 and LM50, respectively, and the least squares mean difference [95% CI] is 0.17% [-0.01, 0.35]. More subjects in the LM50 group than in the LM25 group achieved HbA1c targets of <7.0% (59.7% versus 45.9%, respectively; p = 0.007). LM50 was more effective than LM25 in reducing postprandial glucose after the morning (mean difference in change from baseline, 0.56 mmol/L; p = 0.038) and evening (1.11 mmol/L; p < 0.001) meals. The reduction in fasting blood glucose was significantly greater (p = 0.046) in the LM25 group (LS mean [95% CI] change from baseline: -2.37 mmol/L [-2.68, -2.06]) than in the LM50 group (-1.99 mmol/L [-2.30, -1.68]). LM50 was more effective than LM25 in reducing HbA1c in subjects with baseline HbA1c , postprandial glucose, or carbohydrate intake levels greater than the median levels. Hypoglycemia rates and weight gain were similar between groups. CONCLUSIONS: LM25 and LM50 were noninferior to each other in improving glycemic control in Asian patients with type 2 diabetes. In addition, LM50 was more efficacious than LM25 with respect to the percentage of subjects reaching target HbA1c levels. Copyright © 2016 John Wiley & Sons, Ltd.

Pancreatic safety in Japanese patients with type 2 diabetes treated with once weekly dulaglutide 0.75 mg up to 52 weeks in phase 3 clinical trials.

The effects of incretin therapies on pancreatic safety are currently being evaluated. In 3 phase 3 clinical studies of once weekly dulaglutide 0.75 mg (dulaglutide) in Japanese patients with type 2 diabetes (T2D), symptoms suggestive of acute pancreatitis as well as pancreatic enzymes were assessed and the risk of acute pancreatitis was evaluated. Patients who met any of the predefined criteria (clinical signs/symptoms of acute pancreatitis, confirmed amylase or lipase level ≥3 times the upper limit of normal [ULN], abdominal imaging of the pancreas) were adjudicated for acute pancreatitis by a blinded external committee. A total of 43 events in 40 patients (dulaglutide, 35/917 patients; liraglutide, 2/137 patients; insulin glargine, 2/180 patients; and placebo, 2/70 patients) were adjudicated (1 patient had events adjudicated during both placebo and dulaglutide treatment); 2 patients treated with dulaglutide had acute pancreatitis confirmed (2/917 [0.2%]; 2.651 patients/1,000 patient-years). One of these patients was diagnosed by the investigator with acute pancreatitis related to dulaglutide, but there was no typical abdominal pain. The event in the other patient occurred following an endoscopic ultrasound-guided fine needle aspiration. Transient increases in lipase ≥3×ULN were observed in 2% of patients in both the dulaglutide and liraglutide groups; the incidence in dulaglutide-treated patients was not significantly different from the incidences in liraglutide, placebo-, or insulin glargine-treated patients. Results of systematic assessments of pancreatic safety in 3 phase 3 studies for up to 52 weeks do not suggest an increased risk of acute pancreatitis in Japanese patients treated with dulaglutide.

Caveolin-1 facilitates internalization and degradation of ABCA1 and probucol oxidative products interfere with this reaction to increase HDL biogenesis.

BACKGROUND AND AIMS: Expression of ATP binding cassette transporter (ABC) A1, a key membrane protein for biogenesis of high-density lipoprotein (HDL), is regulated not only by its gene transcription but also by its intracellular degradation to modulate plasma HDL concentration. We previously showed that inhibition of ABCA1 degradation by probucol oxidative products, spiroquinone (SQ) and diphenoquinone (DQ), increased HDL biogenesis and reverse cholesterol transport, and achieved reduction of atherosclerosis in animal models. The background mechanism has thus been investigated. METHODS: Involvement of caveolin-1, a protein of multiple functions in cell biology, particularly in cholesterol trafficking, has been examined for its roles in ABCA1 degradation as well as the effects of SQ and DQ on the reaction. RESULTS: ABCA1 protein was increased in caveolin-1-deficient mouse embryonic fibroblasts, not by increase of transcription but by decrease in its internalization and degradation. Transfection and expression of caveolin-1 normalized the protein level and the rate of degradation of ABCA1. Immunoprecipitation experiments demonstrated association between ABCA1 and caveolin-1 and SQ and DQ disrupted this interaction. The effects of SQ and DQ to increase ABCA1 and cell cholesterol release induced by apolipoprotein A-I were dependent on expression of caveolin-1. Fluorescence imaging of ABCA1 and caveolin-1 in cultured cells demonstrated their co-localization as well as its disruption by SQ and DQ, being consistent with the biochemical findings. CONCLUSIONS: Caveolin-1 enhances internalization and degradation of ABCA1 by its association with ABCA1. Interference of this interaction by probucol oxidative products suppresses ABCA1 degradation and increase HDL biogenesis.

Laparoscopy Reveals a Diversity of Peritoneal Change in Patients with Long-Term Vintage of Peritoneal Dialysis.

BACKGROUND: Although laparoscopy may provide more detailed morphological and histological information about peritoneal damage, its significance in patients with long vintage of peritoneal dialysis (PD) is not elucidated. METHODS: Findings in 12 patients with PD vintage of 7.3 (5.0-8.4) years who had undergone laparoscopy between 2007 and 2011 were reviewed. Macroscopic (peritoneal change, hypervascular change, adhesion, encapsulation) and histopathological peritoneal findings (interstitial fibrosis, microvascular change, fibrin deposition, inflammatory cell infiltration) were scored and summed as Macro-total score (Macro-TS) and Micro-total score (Micro-TS), respectively. Factors associated with these scores and the relationship between these scores were investigated. RESULTS: Neither Macro-TS nor Micro-TS were related to PD vintage (p = 0.069 and p = 0.769, respectively); moreover, Macro-TS varied from patient to patient regardless of similar PD vintage. However, Macro-TS showed a significant association with duration of acidic dialysate (p = 0.003). CONCLUSION: Macroscopic and microscopic findings via laparoscopy may help the assessment of peritoneal damage in patients with long PD vintage.

Low parathyroid hormone levels after parathyroidectomy reduce cardiovascular mortality in chronic hemodialysis patients.

BACKGROUND: The aim of the study is to elucidate whether parathyroid hormone (PTH) levels after parathyroidectomy affect the prognosis of patients with secondary hyperparathyroidism. SUBJECTS AND METHODS: Two hundred and ninety-five patients, who underwent PTx without autotransplantation from July 1998 to December 2011, were divided into the low (n = 148) and high (n = 147) PTH groups, using the median value of each mean value of intact PTH after surgery (16.6 pg/mL). After observation for 5.00 years, we evaluated demographic factors, influences of postoperative mineral metabolism, magnitude of uremia, and vitamin D receptor activators on their prognosis, with the multivariate Cox proportional hazard model. RESULTS: While overall survival rates in the high and low PTH groups were 54.9 and 74.2 %, respectively (P = 0.1500), cardiovascular survival rates were 71.6 and 94.4 %, respectively (P = 0.0256). The hazard ratio for cardiovascular mortality in the high PTH group (≥16.6 pg/mL) was 3.132 (P = 0.0470), and those in groups with the median age more than 59 years and with cardiovascular disease were 2.654 (P = 0.0589) and 3.377 (P = 0.0317), respectively. The intact PTH level 6 days after surgery and the mean postoperative intact PTH value showed a strong correlation (Spearman ρ = 0.9007, P < 0.0001, y = 0.4725x + 30.395, R 2 = 0.51798). CONCLUSION: The present study suggests that maintaining low PTH levels after parathyroidectomy reduces cardiovascular mortality and improves the prognosis. Total parathyroidectomy (more than 4 glands) without autotransplantation seems to be one of the treatment options for managing severe secondary hyperparathyroidism.

Subgroup analysis of phase 3 studies of dulaglutide in Japanese patients with type 2 diabetes.

The efficacy and tolerability of once weekly dulaglutide 0.75 mg in Japanese patients with type 2 diabetes (T2D) were evaluated by subgroups defined by key demographic characteristics. This post hoc analysis included data from patients who received dulaglutide 0.75 mg for up to 26 weeks in three phase 3 trials (one open-label, randomized; one double-blind and open-label, randomized; one open-label, nonrandomized). Patients were classified into subgroups on the basis of sex (male, female), age (<65, ≥65 years), body weight (<70, ≥70 kg), body mass index (BMI; <25, ≥25 kg/m(2)), duration of diabetes (<7, ≥7 years), HbA1c (≤8.5, >8.5%), use of concomitant sulfonylurea (yes, no), and use of concomitant biguanide (yes, no). Efficacy measures analyzed were changes from baseline in HbA1c and body weight and percentages of patients achieving HbA1c <7.0%. Safety measures analyzed were incidence of hypoglycemia and nausea and change from baseline in seated pulse rate. A total of 855 patients were analyzed. Once weekly dulaglutide 0.75 mg improved blood glucose control as measured by HbA1c regardless of patient characteristics; patients with higher baseline HbA1c values had greater improvements compared to patients with lower baseline values. Weight loss was greater in patients with lower baseline HbA1c and in patients taking concomitant biguanides. Concomitant use of sulfonylureas had the greatest effect on the incidence of hypoglycemia. Treatment of T2D with once weekly dulaglutide 0.75 mg for 26 weeks was associated with significant improvement in glycemic control irrespective of age, sex, duration of diabetes, body weight, BMI, or concomitant medication.

Deficiency in the Lipid Exporter ABCA1 Impairs Retrograde Sterol Movement and Disrupts Sterol Sensing at the Endoplasmic Reticulum.

Cellular cholesterol homeostasis involves sterol sensing at the endoplasmic reticulum (ER) and sterol export from the plasma membrane (PM). Sterol sensing at the ER requires efficient sterol delivery from the PM; however, the macromolecules that facilitate retrograde sterol transport at the PM have not been identified. ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol and phospholipid export to apolipoprotein A-I for the assembly of high density lipoprotein (HDL). Mutations in ABCA1 cause Tangier disease, a familial HDL deficiency. Several lines of clinical and experimental evidence suggest a second function of ABCA1 in cellular cholesterol homeostasis in addition to mediating cholesterol efflux. Here, we report the unexpected finding that ABCA1 also plays a key role in facilitating retrograde sterol transport from the PM to the ER for sterol sensing. Deficiency in ABCA1 delays sterol esterification at the ER and activates the SREBP-2 cleavage pathway. The intrinsic ATPase activity in ABCA1 is required to facilitate retrograde sterol transport. ABCA1 deficiency causes alternation of PM composition and hampers a clathrin-independent endocytic activity that is required for ER sterol sensing. Our finding identifies ABCA1 as a key macromolecule facilitating bidirectional sterol movement at the PM and shows that ABCA1 controls retrograde sterol transport by modulating a certain clathrin-independent endocytic process.

Possible predictors for QOL improvement following GH replacement therapy in adult GHD.

In addition to impaired physical activity, adult GH deficiency (GHD) can decrease quality of life (QOL). Hence, assessment of QOL is important to evaluate the efficacy of GH replacement therapy. This study aimed to identify factors that may be predictive of long-term improvement in QOL among clinical/laboratory variables during GH replacement therapy. The analysis included 83 Japanese adults with GHD who participated in the Hypopituitary Control and Complications Study (HypoCCS). Correlations between the change from baseline in clinical/laboratory variables at 6 months and the change from baseline in Quality of life (Short-Form 36 [SF-36] component scores) at 12 months were examined. Unexpectedly, all component scores were negatively correlated with the change in fasting plasma glucose concentration (FPG) (physical component summary [PCS], r = -0.456; mental component summary [MCS], r = -0.523; role/social component summary [RCS], r = -0.433). The change in MCS was positively correlated with the change in insulin-like growth factor-1 standard deviation score (IGF-1 SDS) (r = 0.417). The change in PCS was positively correlated with the change in body fat (r = 0.551). The change in RCS was positively correlated with the change in waist circumference (r = 0.528). Short-term changes in several clinical/laboratory variables, most notably FPG and IGF-1 SDS, were correlated with long-term changes in QOL. The clinical importance of these correlations for predicting GH replacement treatment efficacy warrants further investigation.

Suppression of peritoneal thickening by histamine in a mouse model of peritoneal scraping.

BACKGROUND: Inflammatory reactions play an important role in peritoneal sclerosis in patients on peritoneal dialysis. Since histamine affects inflammatory reactions and immune responses, we investigated effects of intraperitoneal administration of histamine on peritonitis induced by mechanical scraping in mice. METHODS: After anesthesia, the right peritoneum was scraped 90 times over 1 min, and bilateral peritonea were observed by light microscopy after 7 days. RESULTS: Thickness of the peritoneal membrane on the right side was 174 ± 77 µm (mean ± SD, n = 8), while that on the left side was 24 ± 19 µm. Intraperitoneal administration of histamine (0.3 or 1.0 mmol/L, 0.5 mL each) twice daily for 7 days after scraping decreased thickness of the right peritoneum to 42 and 43 % of that in saline-injected animals, respectively (P < 0.01), although histamine (0.1 mmol/L) did not affect it. Promethazine (5 nmol, twice daily for 7 days), a histamine H1 receptor antagonist, abolished the amelioration caused by histamine (1.0 mmol/L). Neither ranitidine (15 nmol), a histamine H2 receptor antagonist, nor thioperamide (7.5 nmol), a histamine H3/H4 receptor antagonist, affected the outcome in histamine-treated mice. CONCLUSION: These findings indicate that histamine H1 action partly prevents the development of peritoneal fibrosis caused by mechanical scraping.

Effect of growth hormone treatment on quality of life in Japanese children with growth hormone deficiency: an analysis from a prospective observational study.

The aim of this study was to assess changes in quality of life (QoL) in Japanese children with GH deficiency (GHD) after 12 mo of GH treatment or with idiopathic short stature (ISS) after 12 mo without treatment. Children with GHD were treated with GH after enrollment. Outcome measures included the parent-rated Child Behavior Checklist (CBCL), the Youth Self-Report Form (YSR), and height standard deviation scores (SDS). Total CBCL scores significantly decreased in children with GHD (n = 152, mean change (standard deviation [SD]) = -3.42 [11.21]) and ISS (n = 129, mean change = -4.82 [10.09]) after 12 mo (p < 0.001). Total YSR scores (mean change = -9.21 [14.07]) and height SDS (mean change = 0.35 [0.38]) significantly decreased in children with GHD (p < 0.001), but were unchanged in children with ISS. The change in total YSR score was significantly correlated with the change in height SDS in children with GHD (r = -0.516, p = 0.003). Our findings demonstrate that GH treatment can improve QoL in Japanese children with GHD. The correlation between the changes in total YSR score and height SDS demonstrated that increased height resulted in improved QoL.

Proteomic analysis of proteins eliminated by low-density lipoprotein apheresis.

Low-density lipoprotein apheresis (LDL-A) treatment has been shown to decrease serum LDL cholesterol levels and prevent cardiovascular events in homozygous patients with familial hypercholesterolemia. Recently, LDL-A treatment has been suggested to have beneficial effects beyond the removal of LDL particles. In this study, to clarify the preventive effects of LDL-A treatment on atherosclerosis, the waste fluid from the adsorption columns was analyzed. The waste fluid of LDL adsorption columns was analyzed by two-dimensional electrophoresis followed by mass spectrometry. Serum concentrations of the newly identified proteins before and after LDL-A treatment were measured by enzyme-linked immunosorbent assay. We identified 48 kinds of proteins in the waste fluid of LDL adsorption columns, including coagulation factors, thrombogenic factors, complement factors, inflammatory factors and adhesion molecules. In addition to the proteins that were reported to be removed by LDL-A treatment, we newly identified several proteins that have some significant roles in the development of atherosclerosis, including vitronectin and apolipoprotein C-III (Apo C-III). The serum levels of vitronectin and Apo C-III decreased by 82.4% and 54.8%, respectively, after a single LDL-A treatment. While Apo C-III was removed with very low-density lipoprotein (VLDL) and LDL, vitronectin was removed without association with lipoproteins. The removal of proteins observed in the waste fluid has a certain impact on their serum levels, and this may be related to the efficacy of LDL-A treatment. Proteomic analysis of the waste fluid of LDL adsorption columns may provide a rational means of assessing the effects of LDL-A treatment.

Reduced renal α-Klotho expression in CKD patients and its effect on renal phosphate handling and vitamin D metabolism.

Renal α-Klotho (α-KL) plays a fundamental role as a co-receptor for fibroblast growth factor 23 (FGF23), a phosphaturic hormone and regulator of 1,25(OH)2 vitamin D3 (1,25VitD3). Disruption of FGF23-α-KL signaling is thought to be an early hallmark of chronic kidney disease (CKD) involving reduced renal α-KL expression and a reciprocal rise in serum FGF23. It remains unclear, however, whether the rise in FGF23 is related to the loss of renal α-KL. We evaluated α-KL expression in renal biopsy samples and measured levels of several parameters of mineral metabolism, as well as soluble α-KL (sKL), in serum and urinary samples from CKD patients (n = 236). We found that although renal α-KL levels were significantly reduced and serum FGF23 levels were significantly elevated in early and intermediate CKD, serum phosphate levels remained within the normal range. Multiple regression analysis showed that the increases in FGF23 were significantly associated with reduced renal function and elevated serum phosphate, but were not associated with loss of renal α-KL. Moreover, despite falling renal α-KL levels, the increase in FGF23 enhanced urinary fractional excretion of phosphate and reduced serum 1,25VitD3 levels in early and intermediate CKD, though not in advanced CKD. Serum sKL levels also fell significantly over the course of CKD, and renal α-KL was a significant independent determinant of sKL. These results demonstrate that FGF23 levels rise to compensate for renal failure-related phosphate retention in early and intermediate CKD. This enables FGF23-α-KL signaling and a neutral phosphate balance to be maintained despite the reduction in α-KL. In advanced CKD, however, renal α-KL declines further. This disrupts FGF23 signaling, and serum phosphate levels significantly increase, stimulating greater FGF23 secretion. Our results also suggest the serum sKL concentration may be a useful marker of renal α-KL expression levels.

Clinical potential of oral nicorandil to improve myocardial fatty acid metabolism after percutaneous coronary intervention in hemodialysis patients.

BACKGROUND/AIMS: The assessment of myocardial fatty acid metabolism impairment by single-photon emission computed tomography (SPECT) using (123)I-ß-methyliodophenyl-pentadecanoic acid (BMIPP) might predict the risk of cardiac death in hemodialysis patients. We investigated the potential of oral nicorandil to improve myocardial fatty acid metabolism after percutaneous coronary intervention (PCI) in this population. METHODS: We evaluated 128 hemodialysis patients who had obtained coronary revascularization by PCI (90 men and 38 women, 66 ± 9 years). Participants for the analysis were randomly assigned to either the nicorandil (n = 63) or control group (n = 65). BMIPP SPECT was performed every year after coronary revascularization by PCI. Uptake on SPECT was graded in 17 segments on a 5-point scale (0, normal; 4, absent) and assessed as BMIPP summed scores (SS). RESULTS: The incidence of cardiac death was lower (p = 0.004) in the nicorandil group (7/63, 11.1%) than in the control group (21/65, 32.3%) during a mean follow-up of 2.7 ± 1.4 years. BMIPP SS reduction rates improved in the nicorandil group compared with the control group from 3 years of administration. In Kaplan-Meier analyses, free survival rate of cardiac death was higher in patients with a ≥20% BMIPP SS reduction rate as compared with those with a <20% BMIPP SS reduction rate (p = 0.0001). In multiple logistic analysis, oral administration of nicorandil was associated with ≥20% reduction rates of BMIPP SS (odds ratio 2.823, p = 0.011). CONCLUSION: Long-term oral administration of nicorandil may improve impaired myocardial fatty acid metabolism after coronary revascularization by PCI in hemodialysis patients.