Tsuguru Hatta

Klotho is associated with VEGF receptor-2 and the transient receptor potential canonical-1 Ca2+ channel to maintain endothelial integrity

Klotho is a circulating protein, and Klotho deficiency disturbs endothelial integrity, but the molecular mechanism is not fully clarified. We report that vascular endothelium in Klotho-deficient mice showed hyperpermeability with increased apoptosis and down-regulation of vascular endothelial (VE)-cadherin because of an increase in VEGF-mediated internal calcium concentration ([Ca2+]i) influx and hyperactivation of Ca2+-dependent proteases. Immunohistochemical analysis, the pull-down assay using Klotho-fixed agarose, and FRET confocal imaging confirmed that Klotho protein binds directly to VEGF receptor 2 (VEGFR-2) and endothelial, transient-receptor potential canonical Ca2+ channel 1 (TRPC-1) and strengthens the association to promote their cointernalization. An in vitro mutagenesis study revealed that the second hydrolase domain of Klotho interacts with sixth and seventh Ig domains of VEGFR-2 and the third extracellular loop of TRPC-1. In Klotho-deficient endothelial cells, VEGF-mediated internalization of the VEGFR-2/TRPC-1 complex was impaired, and surface TRPC-1 expression increased 2.2-fold; these effects were reversed by supplementation of Klotho protein. VEGF-mediated elevation of [Ca2+]i was sustained at higher levels in an extracellular Ca2+-dependent manner, and normalization of TRCP-1 expression restored the abnormal [Ca2+]i handling. These findings provide evidence that Klotho protein is associated with VEGFR-2/TRPC-1 in causing cointernalization, thus regulating TRPC-1–mediated Ca2+ entry to maintain endothelial integrity.

Plasma S100A12 Level Is Associated with Cardiovascular Disease in Hemodialysis Patients

BACKGROUND AND OBJECTIVES S100A12 is an endogenous receptor ligand for advanced glycation end products. Cardiovascular disease remains a major cause of morbidity and mortality in patients with chronic kidney disease. In this study, we report cross-sectional data on 550 hemodialysis patients and assess the relationship between plasma S100A12 level and cardiovascular disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A cross-sectional study of 550 maintenance hemodialysis patients was conducted. We investigated the past history of cardiovascular disease and quantified the plasma level of S100A12 protein in all participants. RESULTS Plasma S100A12 level was higher in hemodialysis patients with cardiovascular disease (n=197; 33.8 ± 28.1 ng/ml) than in those without it (n=353; 20.2 ± 16.1 ng/ml; P<0.001). In multivariate logistic regression analysis, the plasma S100A12 level (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.13 to 1.44; P<0.001) was identified as an independent factor associated with the prevalence of cardiovascular disease. The other factors associated with the prevalence of cardiovascular diseases were the presence of diabetes mellitus (OR, 2.81; 95% CI, 1.79 to 4.41; P < 0.001) and high-sensitivity CRP level (OR, 1.02; 95% CI, 1.00 to 1.05; P=0.046). Furthermore, the plasma S100A12 level (OR, 1.30; 95% CI, 1.09 to 1.54; P=0.004) was significantly associated with cardiovascular disease even in hemodialysis patients without diabetes mellitus (n=348). CONCLUSIONS These results suggest that the plasma S100A12 protein level is strongly associated with the prevalence of cardiovascular disease in hemodialysis patients.

Target for Glycemic Control in Type 2 Diabetic Patients on Hemodialysis: Effects of Anemia and Erythropoietin Injection on Hemoglobin A1c

In hemodialysis (HD) patients the glycated hemoglobin (HbA1c) level may underestimate glycemic control. The aim of this study is to estimate accurate glycemic control in type 2 diabetic patients on HD. Type 2 diabetes patients (N = 87) who had been receiving maintenance HD for at least one year were enrolled. HbA1c and the percentage of glycated albumin relative to total the serum albumin (%GA) were measured in blood samples and the factors that affected the %GA/HbA1c ratio were examined. There were significant and positive correlations between the plasma glucose and either the HbA1c levels (r = 0.539, P < 0.01) or the %GA level (r = 0.520, P < 0.01). No relationship between the serum albumin levels and %GA levels was observed. A weekly dose of erythropoietin (EPO) was positively correlated with the ratio of %GA/HbA1c and hematocrit (Ht) correlated negatively. There was no significant correlation between the %GA/HbA1c level and the EPO dose in patients with Ht ≥ 30%, although a significant correlation was found between those parameters in the Ht < 30% group. The mean of the %GA/HbA1c ratios in patients with Ht ≥ 30%, with Ht < 30% and treated with EPO < 100 IU/kg/week, and with Ht < 30% and treated with EPO ≥ 100 IU/kg/week were 3.41, 3.56 and 4.13, respectively. In HD patients, accurate glycemic control may be estimated as: HbA1c × 1.14 if Ht ≥ 30%; HbA1c × 1.19 if Ht < 30% and treated with low dosages of EPO; and HbA1c × 1.38 if Ht < 30% and treated with high dosages of EPO.

Sodium restriction improves the gustatory threshold for salty taste in patients with chronic kidney disease

Sodium restriction is important in the treatment of chronic kidney disease; however, it is sometimes difficult to achieve. Decreased taste sensitivity may be a factor influencing inadequate control of oral salt intake and subsequent high blood pressure. To measure this, the gustatory threshold (recognition and detection) for salty taste was determined in 29 patients with chronic kidney disease using a sodium-impregnated test strip and relevant factors determining taste sensitivity were analyzed. Compared with 11 healthy volunteers, recognition and detection thresholds were increased in the patients with chronic kidney disease. Oral sodium intake correlated positively but serum zinc correlated negatively with the recognition threshold. Patients with diabetic nephropathy had a higher detection threshold than non-diabetic patients. Both recognition and detection thresholds were increased in patients with diuretic administration. After 1 week of sodium restriction, the average recognition threshold decreased significantly. Our study verified that latent taste dysfunction and zinc deficiency are common in patients with chronic kidney disease. Further, the recognition threshold for salty taste improved even after a short period of salt restriction.

Association of Nocturnal Hypoxemia with Progression of CKD

BACKGROUND AND OBJECTIVES Nocturnal hypoxemia is highly prevalent among patients with CKD. Nocturnal hypoxemia contributes to systemic inflammation, oxidative stress, endothelial cell dysfunction, and activation of the renin-angiotensin system, which are common pathologic mechanisms of CKD progression. This study investigated whether nocturnal hypoxemia is independently associated with CKD progression. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This two-center retrospective cohort study included 161 patients with stages 3-4 CKD enrolled from January of 2009 to July of 2011 with a body mass index less than 25.0 kg/m(2). The 4% oxygen desaturation index, the number of events per hour in which oxygen saturation decreases by >4% during sleep, was measured, and the declining rate of the estimated GFR was followed over 1 year. The severity of nocturnal hypoxemia was categorized as none (oxygen desaturation index<5.0), mild (5.0≤oxygen desaturation index<15.0), or moderate to severe (15.0≤oxygen desaturation index). RESULTS The mean estimated GFR of the total cohort at baseline was 31 ml/min per 1.73 m(2). Eighty patients (49.7%) were diagnosed with nocturnal hypoxemia; 64 patients were diagnosed with mild nocturnal hypoxemia, and 16 patients were diagnosed with moderate-to-severe nocturnal hypoxemia. The estimated GFR declined three- to fourfold faster in patients with moderate-to-severe nocturnal hypoxemia than patients with no or mild nocturnal hypoxemia (the mean values [95% confidence intervals] were -2.14 [-1.06 to -3.21], -3.02 [-1.31 to -4.74], and -8.59 [-2.00 to -15.2] ml/min per 1.73 m(2) per year in the no, mild, and moderate-to-severe nocturnal hypoxemia groups, respectively; P=0.003). Nocturnal hypoxemia remained a significant predictor of decline in estimated GFR after adjustment for various baseline clinical factors. CONCLUSIONS In nonobese patients with CKD, nocturnal hypoxemia is an independent risk factor of a rapid decline in kidney function.

Blockade of angiotensin II receptors inhibits the increase in blood pressure induced by insulin

To elucidate whether hyperinsulinemia increases blood pressure by increasing sympathetic outflow via the activation of the central angiotensin system, insulin was infused into urethane-anesthetized rats intravenously (i.v.) or intracerebroventricularly (i.c.v.) under euglycemic conditions. Infusion (i.v.) of insulin elicited pressor effects in a dose-dependent manner (13, 20, and 40 mU/min). Although depressor responses to i.v. injections of hexamethonium were significantly greater in insulin-infused than in saline-infused rats, i.v. captopril and d(CH2)5Tyr(Me)-arginine vasopressin did not show any differences between the groups. Infusions (i.c.v.) of insulin (8 mU/10 microl) also induced cardiovascular acceleration and augmented the depressor response to i.v. hexamethonium in insulin-infused rats. The i.c.v. pretreatment with the angiotensin II antagonist losartan inhibited the pressor responses to both the i.c.v. and i.v. infusion of insulin. These results suggest that the increase in blood pressure induced by euglycemic hyperinsulinemia is elicited by sympathetic activation and that hyperinsulinemia stimulates the angiotensin system in the brain to increase sympathetic nerve activity.

Incremental prognostic value of myocardial perfusion single photon emission computed tomography for patients with diabetes and chronic kidney disease

PurposeThis study estimates whether myocardial perfusion single photon emission computed tomography (SPECT) can predict the prognostic risk of cardiac events among patients with diabetes and relatively mild chronic kidney disease (CKD). MethodsData from 2423 patients in the Japanese Assessment of Cardiac Events and Survival Study were examined. Patients were classified into group A (diabetes−, CKD−), B (diabetes−, CKD+), C (diabetes+, CKD−), and D (diabetes+, CKD+). After 3 years of follow-up, the incidence of cardiac events and the ability of myocardial perfusion SPECT to estimate prognosis were evaluated. ResultsA total of 119 (4.9%) events (28 cardiac deaths, 25 myocardial infarctions, and 66 severe heart failures) occurred. Each type of event occurred more frequently in CKD compared with non-CKD groups with both diabetic and nondiabetic populations. Risk was higher in patients with high summed stress scores. Risk gradually increased in nondiabetic groups according to the decrease in the estimated glomerular filtration rate and roughly consisted of two diabetic groups with a cutoff of eGFR equal to 50 ml/min. ConclusionA high incidence of cardiac events is associated with CKD in both nondiabetic and diabetic patients. Summed stress scores obtained by myocardial perfusion SPECT have a highly incremental value for predicting the cardiac prognosis of patients with diabetes and CKD. These scores are useful for the risk stratification of asymptomatic patients with relatively mild renal dysfunction requiring neither dialysis nor renal transplantation.

Augmented response of endothelin-A and endothelin-B receptor stimulation in coronary arteries of hypertensive hearts.

To determine whether the vasoconstrictor response to endothelin-1 (ET-1) is altered in coronary vessels of hypertensive hearts and the role of ETA and ETB receptors in these responses to ET-1, the vasoconstrictor response to ET-1 in coronary vessels was measured with or without ETA and ETB receptor antagonists. In isolated hearts of spontaneously hypertensive rat (SHR) and normotensive Wistar-Kyoto (WKY) rat, the coronary perfusion pressure was measured on a Langendorff apparatus with constant pressure (75 mm Hg). Coronary perfusion resistance (CPR) (mm Hg/ml/min/g) was calculated. ET-1 elicited dose-dependent increases of CPR in both normotensive and SHR rat hearts. However, the responses were significantly greater in SHR than those of WKY. Pretreatment with the ETA antagonist FR139317 and the ETB antagonist BQ788 inhibited CPR increases with ET-1 infusion. However, vasoconstrictor responses to ET-1 were still greater in SHR than in WKY after FR139317 or BQ788 infusion. These findings suggest that the augmented vasoconstrictor response of coronary artery to ET-1 is mediated by both ETA and ETB receptors. These changes may contribute to the impaired coronary circulation in hypertension.

Plasma S100A12 Levels and Peripheral Arterial Disease in End-Stage Renal Disease

Background: S100A12 is an endogenous ligand of the receptor for advanced glycation end products (RAGE). Plasma S100A12 levels are high in end-stage renal disease (ESRD) patients undergoing maintenance hemodialysis (HD). Peripheral arterial disease (PAD) is common in HD patients and is associated with increased cardiovascular morbidity and mortality rates in this population. To date, however, no study has specifically assessed the relationship between plasma S100A12 and PAD in HD patients. Methods: We conducted a cross-sectional study of 152 HD patients in our affiliated hospital. We investigated PAD history and patient characteristics and quantified plasma S100A12 levels in all participants. Results: HD patients with PAD (n = 26; 21.9 [13.6–33.4] ng/ml) showed significantly higher plasma S100A12 levels than HD patients without PAD (n = 126; 11.8 [7.5–17.6]ng/ml; p < 0.001). In multivariate logistic regression analysis, the plasma S100A12 level (odds ratio [OR] 5.71; 95% confidence interval [CI] 1.29–25.3; p = 0.022) was identified as an independent factor associated with PAD prevalence. Another factor associated with PAD prevalence was the ankle-brachial index (OR 0.54; 95% CI 0.40–0.74; p < 0.001). Conclusion: These results suggest that plasma S100A12 levels are strongly associated with PAD prevalence in ESRD patients undergoing HD.

A Case Report of Mycobacterium Abscessus Peritonitis in a Peritoneal Dialysis Patient

Abstract:  Peritonitis due to nontuberculous mycobacterium in peritoneal dialysis (PD) patients is rare. However, when it occurs, PD catheter removal is required in most cases because of resistance to antibiotic therapy. We report a case of Mycobacterium abscessus peritonitis subsequent to tunnel infection after PD catheter‐replacement surgery. The patient underwent this surgery as her tunnel infection had not resolved following the usual 3 month course of antibiotic therapy. After surgery, tunnel infection of the second catheter and peritonitis occurred. Nontuberculous mycobacteria were detected on acid‐fast stain from both the old and new exit‐site drainage and the peritoneal effluent. The mycobacteria were identified as M. abscessus. Removal of the new catheter and surgical excision of the previous catheter tunnel were performed and multiple antibiotics were started. After 3 months the postsurgical wounds had healed completely. This case demonstrates the importance of further evaluation of unidentified PD catheter‐related infections, including an examination for nontuberculous mycobacterium.