GIV/Girdin Links Vascular Endothelial Growth Factor Signaling to Akt Survival Signaling in Podocytes Independent of Nephrin

Podocytes are critically involved in the maintenance of the glomerular filtration barrier and are key targets of injury in many glomerular diseases. Chronic injury leads to progressive loss of podocytes, glomerulosclerosis, and renal failure. Thus, it is essential to maintain podocyte survival and avoid apoptosis after acute glomerular injury. In normal glomeruli, podocyte survival is mediated via nephrin-dependent Akt signaling. In several glomerular diseases, nephrin expression decreases and podocyte survival correlates with increased vascular endothelial growth factor (VEGF) signaling. How VEGF signaling contributes to podocyte survival and prevents apoptosis remains unknown. We show here that Gα–interacting, vesicle-associated protein (GIV)/girdin mediates VEGF receptor 2 (VEGFR2) signaling and compensates for nephrin loss. In puromycin aminonucleoside nephrosis (PAN), GIV expression increased, GIV was phosphorylated by VEGFR2, and p-GIV bound and activated Gαi3 and enhanced downstream Akt2, mammalian target of rapamycin complex 1 (mTORC1), and mammalian target of rapamycin complex-2 (mTORC2) signaling. In GIV-depleted podocytes, VEGF-induced Akt activation was abolished, apoptosis was triggered, and cell migration was impaired. These effects were reversed by introducing GIV but not a GIV mutant that cannot activate Gαi3. Our data indicate that after PAN injury, VEGF promotes podocyte survival by triggering assembly of an activated VEGFR2/GIV/Gαi3 signaling complex and enhancing downstream PI3K/Akt survival signaling. Because of its important role in promoting podocyte survival, GIV may represent a novel target for therapeutic intervention in the nephrotic syndrome and other proteinuric diseases.     

Surgery for hepatocellular carcinoma with tumor thrombus extending into the right atrium: report of a successful resection without the use of cardiopulmonary bypass

Hepatocellular carcinomas, of which the tumor thrombus extends into the right atrium via the inferior vena cava, may soon cause fatal complications. Only surgery can be an effective treatment. This procedure usually needs the aid of cardiopulmonary bypass. We recently experienced a successful surgery to remove thrombus combined with hepatectomy. Reporting the detailed technique, both associated diagnosis and intraoperative management are discussed herein. We were able to perform hepatectomy of tumor thrombus in the right atrium without the use of cardiopulmonary bypass or veno-venous bypass. The tumor thrombus was removed from the right atrium into the suprahepatic inferior vena cava by reducing the liver on the tail side. And after total hepatic vascular exclusion was achieved, the intracaval tumor thrombus and the right lobe of the liver were removed en bloc. The operation took 545 minutes and the total hepatic vascular exclusion period was 32 minutes. The postoperative course was uneventful. There are some key points for this procedure. Preoperative or intraoperative US is essential in judging whether tumor thrombus can be removed from the right atrium into the inferior vena cava by reducing the liver or not. Test clamping of the inferior vena cava prior to total hepatic vascular exclusion will enable us to judge whether veno-venous bypass during total hepatic vascular exclusion is needed or not. Surgery without the use of cardiopulmonary bypass is safe and can be minimally invasive when it is performed with a reliable diagnosis and technique.     

Effect of Intensive Salt‐Restriction Education on Clinic,Home, and Ambulatory Blood Pressure Levels in Treated Hypertensive Patients During a 3‐Month Education Period

The authors tested the hypothesis that low‐salt diet education by nutritionists would lower blood pressure (BP) levels in treated hypertensive patients. The amount of urinary salt excretion and clinic, home, and ambulatory BP values at baseline and at 3 months were measured in 95 patients with hypertension. After randomization to a nutritional education group (E group, n=51) or a control group (C group, n=44), the C group received conventional salt‐restriction education and the E group received intensive nutritional education aimed at salt restriction to 6 g/d by nutritionists. From baseline to the end of the study, 24‐hour urinary sodium excretion was significantly lowered in the E group compared with the C group (6.8±2.9 g/24 h vs 8.6±3.4 g/24 h, P<.01). Morning home systolic BP tended to be lowered in the E group (P=.051), and ambulatory 24‐hour systolic BP was significantly lowered in the E group (−4.5±1.3 mm Hg) compared with the C group (2.8±1.3 mm Hg, P<.001). Intensive nutritional education by nutritionists was shown to be effective in lowering BP in treated hypertensive patients.

The association between excessive salt intake and blood pressure (BP) elevation is well‐known, and some interventional studies such as the International Study of Electrolyte Excretion and Blood Pressure (INTERSALT) demonstrated that the amount of salt intake was associated with BP levels.¹ In an international study of 101,945 individuals from 17 countries, it was found that the estimated sodium intake of 3 g/d to 6 g/d was associated with lower incidences of cardiovascular events and death compared with higher or lower levels of salt intake.² In a study of a mildly hypertensive population, clinic and ambulatory BP levels were significantly lowered by low salt intake compared with those in the control group.³ In the same study, lower salt intake was associated with lower excretion of urinary albumin and a lower pulse wave velocity (a measure of arterial stiffness) compared with those in the control group. Taken together, these findings support the importance of salt restriction for the improved control of BP and protection from end‐organ damage, provided that the salt restriction is successfully performed.In the 2014 guidelines from the Japanese Society of Hypertension (JSH), salt restriction to <6 g/d is recommended for all hypertensive populations.⁴ However, this recommendation is mostly based on observational studies⁵ or interventional studies in which the diets of patients were completely controlled, sometimes under hospitalized conditions.⁶ For example, in the Dietary Approaches to Stop Hypertension (DASH) trial,⁷ a low‐salt diet was given to the patients during the study period. Few studies have examined whether intensive nutritional education in an outpatient clinic, especially education on dietary salt restriction, can lower not only clinic BP but also home and ambulatory BP levels. Thus, in the present study, we tested the hypothesis that intensive nutritional education focused on salt restriction and provided by nutritionists in an outpatient clinic lowers clinic, home, and ambulatory BP in treated hypertensive patients.     

Clinical usage of serum ferritin to assess liver fibrosis in patients with non‐alcoholic fatty liver disease: Proceed with caution

Serum ferritin was recently reported to have low diagnostic accuracy for the detection of advanced fibrosis in patients with non‐alcoholic fatty liver disease (NAFLD). To corroborate these findings, we investigated the diagnostic accuracy of serum ferritin levels for detecting liver fibrosis in NAFLD patients utilizing a large Japanese cohort database. A total 1201 biopsy‐proven NAFLD patients, seen between 2001 and 2013, were enrolled into the Japan Study Group of NAFLD. Analysis was performed on data from this cohort comparing between serum ferritin levels and hepatic histology. Serum ferritin increased with increasing histological grade of steatosis, lobular inflammation and ballooning. Multivariate analyses revealed that sex differences, steatotic grade and fibrotic stage were independently associated with serum ferritin levels (P < 0.0001, <0.0001, 0.0248, respectively). However, statistical analyses performed using serum ferritin levels demonstrated that the area under the receiver–operator curve for detecting fibrosis was not adequate for rigorous prediction. Several factors including sex differences, steatosis and fibrosis were found to correlate with serum ferritin levels. Therefore, serum ferritin may have low diagnostic accuracy for specifically detecting liver fibrosis in NAFLD patients due to the involvement of multiple hepatocellular processes.     

Home BP Monitoring Using a Telemonitoring System is Effective for Controlling BP in a Remote Island in Japan

The purpose of this study was to assess whether a home blood pressure (HBP) telemonitoring system could improve BP control and overcome the problems of HBP monitoring in a remote location. The authors enrolled 60 subjects and randomized them to either a Telemonitoring group or a Control group. The outcomes were changes in HBP level, adherence to HBP monitoring, and visual analog scale (VAS; score 0–100) as a measure of the motivation to perform HBP measurements. The reductions in morning systolic BP (−5.5±0.9 mm Hg vs 0.7±0.7 mm Hg, P<.001) and evening systolic BP (−4.6±1.0 mm Hg vs 1.0±1.1 mm Hg, P<.001) and the change in VAS (12.8±3.3 vs −1.6±2.2, P=.001) were significantly greater in the Telemonitoring group than in the Control group. The measure of the adherence to HBP monitoring tended to be better (P=.064) in the Telemonitoring group than in the Control group. These results indicate that an HBP telemonitoring system would be a beneficial healthcare measure in remote geographical locations.

Hypertension is one of the most common risk factors for cardiovascular disease, with a prevalence of approximately 30% to 45% of the general population.¹ Niijima, a small island located 160 km south of Tokyo, has 2933 residents (1410 men and 1523 women), 37% of whom are elderly (older than 65 years). In the 2013 health examination, the prevalence of hypertension was 35% among those older than 40 years. There has been an increasing number of elderly people living alone or living with elderly spouses on Niijima as a result of out‐migration of the young. In cases of acute illness, such as myocardial infarction or cerebral infarction, patients must be transported to a specialized medical center in Tokyo via 3‐hour flight by helicopter. In addition, there is no way off the island in the case of typhoons or other severe storms. Therefore, primary prevention by aggressive control of cardiovascular risk factors, especially hypertension, is of paramount importance.Home blood pressure (HBP) monitoring has been reported to be superior to office BP monitoring in predicting future cardiovascular events or mortality.², ³, ⁴, ⁵ When there is a discrepancy between the levels of HBP and office BP, HBP is superior to office BP in predicting cardiovascular risk.⁶, ⁷ However, in clinical practice, HBP monitoring is sometimes difficult to carry out adequately, especially in the elderly. With regard to HBP measurements, the biggest concern is the limited accuracy of the measurement techniques reporting by the subjects. With respect to the reporting of HBP measurements, the major problems are excess reports, insufficient reports, and reports of phantom records.⁸ In addition, patients sometimes forget to bring their log books in which the results of HBP measurements are written. On Niijima Island, it has been estimated that only 10% to 20% of hypertensive outpatients measure their HBP correctly.To overcome these shortcomings of HBP, the HBP telemonitoring system was developed.⁹ In the HBP telemonitoring system, HBP data are stored and transmitted to a secure Web site and doctors can check them in real time. Subjects do not need to manually record their BP data and physicians can check all of their data on the Web site. Studies have shown that the HBP telemonitoring system improves BP control, self‐efficacy, and adherence to antihypertensive medication.¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵ However, it has not been established whether an HBP telemonitoring system would be effective in an elderly population, most of whom are living alone or with elderly spouses, in a remote geographical location.In this study, we hypothesized that an HBP telemonitoring system would improve BP control and solve the problems of HBP monitoring related to adherence and motivation in the population of Niijima Island, a very remote location off the east coast of Japan.     

Nighttime Home Blood Pressure and the Risk of Hypertensive Target Organ Damage

In ambulatory blood pressure (BP) monitoring, nighttime BP has a superior ability to predict hypertensive target organ damage than awake BP. We evaluated whether nighttime BP, assessed by a home BP monitor, was associated with hypertensive target organ damage. We measured clinic BP, out-of-clinic BP including nighttime home BP, and the urinary albumin:creatinine ratio (UACR) in 854 patients who had cardiovascular risk factors. Nighttime home BP was measured at 2:00, 3:00, and 4:00 am, in addition to clinic, awake ambulatory, nighttime ambulatory, and awake home BP. Nighttime home systolic BP (SBP) was slightly higher than nighttime ambulatory SBP (difference, 2.6 mm Hg; P<0.001). Clinic (r=0.186), awake ambulatory (r=0.173), nighttime ambulatory (r=0.194), awake home (r=0.298), and nighttime home (r=0.311) SBPs were all associated with log-transformed UACR (all P<0.001). The correlation coefficient for the relationship between nighttime home SBP and log-transformed UACR was significantly greater than that for the relationship between nighttime ambulatory SBP and log-transformed UACR (P<0.001). The goodness of fit of the association between SBP and UACR was improved by adding nighttime home SBP to the other SBPs (P<0.001). Nighttime home diastolic BP also improved the goodness-of-fit of the association between diastolic BP and UACR (P=0.001). Similar findings were observed for the left ventricular mass index in the subgroup (N=594). In conclusion, nighttime home BP is slightly different from (but comparable to) nighttime ambulatory BP. The addition of nighttime home BP to other BP measures improves the association of BP with hypertensive target organ damage.