Published papers

＜文献概要＞Point　◆副腎静脈サンプリング(AVS)は原発性アルドステロン症における病型・局在診断のゴールドスタンダードと位置づけられており,外科的治療を含む局所治療の適応を考慮する際に必要な検査である.◆区域別副腎静脈支脈採血(segmental AVS)はより高精度な副腎内ホルモンマッピングを可能とし,詳細な病型診断や副腎機能温存のための副腎部分切除/ラジオ波焼灼術の適応判断に有用である.◆AVS結果解釈,副腎機能温存手術の適応,再AVS・segmental AVS・別導出静脈からの採血の要否などを含めた治療方針の決定には,泌尿器科・内分泌内科・放射線診断科などの多診療科カンファレンスで議論することが望ましい.

＜文献概要＞Point　◆褐色細胞腫を疑ったら,メタネフリン測定検査を行う.◆褐色細胞腫の診断にCTやMRIによる腫瘍の診断が重要である.◆褐色細胞の機能確認検査には123I-MIBGシンチグラフィーや18F-FDG-PETが存在する.

＜文献概要＞はじめに　慶應義塾大学病院(以下,当院)では1990年代よりDSDクラスターとしてわが国で初めて活動を開始し,2019年に性分化疾患(DSD:Disorders/Differences of Sex Development)センターを開設した。小児科,小児外科,泌尿器科,産婦人科,形成外科,内分泌代謝内科,精神神経科,臨床心理士などで定期的な会議を行い,総排泄腔遺残を含む性分化疾患の症例の検討を行っている。

原発性アルドステロン症患者81例のCT画像から腎周囲脂肪(PAT)容量を計測し、心代謝疾患の危険因子やミネラルコルチコイド受容体拮抗薬による治療開始後初期の腎機能の変化との関連について検討した。その結果、%PAT(腎周囲脂肪容量-内臓脂肪容量比)は原発性アルドステロン症の診断時のbody mass index(BMI)、血清クレアチニン濃度、eGFR値、血清尿酸濃度、血清中性脂肪濃度などの心代謝疾患の危険因子と有意な相関関係を認めた。年齢、性別、BMI、病型・局在などの交絡因子で調整した線形重回帰分析でも、PATの蓄積はミネラルコルチコイド受容体拮抗薬による治療開始後初期の腎機能低下と有意に相関した。原発性アルドステロン症において、PAT蓄積は心代謝機能障害およびミネラルコルチコイド受容体拮抗薬による治療開始後初期の腎機能低下に関与することが示唆された。

The biological clock enables organisms to align their intrinsic rhythms with daily environmental cycles thereby maintaining homeostasis and imparting resilience against metabolic derangements. Endocrine hormones and neural networks are key mediators of temporal coordination across remote tissues. The potential impact of maternal-fetal synchronization during pregnancy has been extensively studied, as alterations in maternal circadian rhythms because of mistimed food intake, sleep disturbances, and jet-lagged conditions appear to influence organ development, maturation, and behavior, leading to enduring metabolic consequences in offspring. In support, the in utero environment and maternal nutritional state influence long-term health outcomes, as proposed in the developmental origins of health and disease. While the molecular mechanisms connecting maternal circadian disruption to sustained alterations in progeny are still under investigation, endocrine hormones and metabolites may engage in temporal communication between the mother and fetus and induce epigenetic changes. This review outlines recent discoveries on maternal circadian rhythms as an external input for the fetus and discusses future strategies to strengthen metabolic fitness in subsequent generations.

The handle region peptide (HRP), a (pro)renin receptor (P)RR blocker, did not prevent the acute nephropathy occurring 2 weeks after clipping in renovascular hypertensive rats. This study was performed to examine the effects of HRP, its scramble peptide, or a saline vehicle on slowly progressive nephropathy occurring in the kidneys of two-kidney, one-clip Goldblatt hypertensive rats. At 2 weeks after clipping, the renal morphology in the clipped and non-clipped kidneys was similar in the three groups of rats. At 12 weeks after clipping, however, the glomerulosclerosis index (GI) and the tubulointerstitial damage (TD) of the non-clipped kidneys of the HRP-treated rats were significantly lower than those of vehicle-treated rats, although the GI and the TD were similar in the rats treated with scramble peptide and vehicle. The GI and the TD of the clipped kidneys were similar in the three groups of rats at 12 weeks after clipping. In the non-clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and transforming growth factor (TGF)-β mRNA levels of HRP-treated rats were significantly lower than those of vehicle-treated rats, although they were similar in the non-clipped kidneys from the rats treated with scramble peptide and vehicle. In the clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and TGF-β mRNA levels were similar in the three groups of rats. These results suggest that the ((P)RR)-dependent activation of prorenin contributes to the pathogenesis of slowly progressive nephropathy in the intact kidney in a rat model of renovascular hypertension.

Drinking hydrogen (H2)-rich water is a common way to consume H2. Although many studies have shown efficacy of drinking H2-rich water in neuropsychiatric and endocrine metabolic disorders, their authenticity has been questioned because none examined the associated pharmacokinetics of H2. Therefore, we performed the first study to investigate the pharmacokinetics of H2 in pigs given an H2-rich glucose solution with the aim to extrapolate the findings to humans. We inserted blood collection catheters into the jejunal and portal veins, suprahepatic inferior vena cava, and carotid artery of 4 female pigs aged 8 weeks. Then, within 2 min we infused 500 ml of either H2-rich or H2-free glucose solution into the jejunum via a percutaneous gastrostomy tube and measured changes in H2 concentration in venous and arterial blood over 120 min. After infusion of the H2-rich glucose solution, H2 concentration in the portal vein peaked at 0.05 mg/L and remained at more than 0.016 mg/L (H2 saturation level, 1%) after 1 h; it also increased after infusion of H2-free glucose solution but remained below 0.001 mg/L (H2 saturation level, 0.06%). We assume that H2 was subsequently metabolized in the liver or eliminated via the lungs because it was not detected in the carotid artery. In conclusion, drinking highly concentrated H2-rich solution within a short time is a good way to increase H2 concentration in portal blood and supply H2 to the liver.

Aim: The Effect of Intermittent-Scanning Continuous Glucose Monitoring to Glycemic Control Including Hypoglycemia and Quality of Life of Patients with Type 1 Diabetes Mellitus (ISCHIA) study was a randomized, crossover trial that reported the decrease in time below range (TBR) by the use of intermittent-scanning continuous glucose monitoring (isCGM) combined with structured education in adults with type 1 diabetes (T1D) treated by multiple daily injections. The participants were instructed to perform frequent scanning of the isCGM sensor (10 times a day or more) and ingest sugar when impending hypoglycemia is suspected by tracking the sensor glucose levels and the trend arrow. We conducted post-hoc analysis to identify factors affecting difference in TBR (∆TBR), in time in range (∆TIR), and in time above range (∆TAR). Participants and methods: Data from 93 participants who completed the ISCHIA study were used. Multiple regression analyses were performed to identify factors affecting CGM metrics. Results: Pearson’s correlation analysis showed the negative association between log-transformed scan frequency and with ∆TBR (r = − 0.255, P = 0.015), while there was no significant association of log-transformed scan frequency with ∆TIR (r = 0.172, P = 0.102) and ∆TAR (r = 0.032, P = 0.761), respectively. The log-transformed scan frequency was an independent predictor of ∆TBR (Beta = − 7.712, P = 0.022), but not of ∆TIR(Beta = 7.203, P = 0.091) and of ∆TAR (Beta = 0.514, P = 0.925). Conclusions: Our findings suggest that more frequent scanning of isCGM may be beneficial to reduce TBR in T1D adults.

We conducted a randomized, crossover trial to compare intermittent-scanning continuous glucose monitoring (isCGM) device with structured education (Intervention) to self-monitoring of blood glucose (SMBG) (Control) in the reduction of time below range.This crossover trial involved 104 adults with type 1 diabetes mellitus (T1DM) using multiple daily injections. Participants were randomly allocated to either sequence Intervention/Control or sequence Control/Intervention. During the Intervention period which lasted 84 days, participants used the first-generation FreeStyle Libre (Abbott Diabetes Care, Alameda, CA, USA) and received structured education on how to prevent hypoglycemia based on the trend arrow and by frequent sensor scanning (≥10 times a day). Confirmatory SMBG was conducted before dosing insulin. The Control period lasted 84 days. The primary endpoint was the decrease in the time below range (TBR;70 mg/dL).The time below range was significantly reduced in the Intervention arm compared to the Control arm (2.42 ± 1.68 h/day [10.1 %±7.0 %] vs 3.10 ± 2.28 h/day [12.9 %±9.5 %], P = 0.012). The ratio of high-risk participants with low blood glucose index 5 was significantly reduced (8.6 % vs 23.7 %, P  0.001).The use of isCGM combined with structured education significantly reduced the time below range in patients with T1DM.

The prorenin receptor is an accessory subunit of the vacuolar H+-ATPase, suggesting that it has fundamental functions beyond activation of the local renin-angiotensin system. Podocytes express the prorenin receptor, but its function in these cells is unknown. Here, podocyte-specific, conditional, prorenin receptor-knockout mice died of kidney failure and severe proteinuria within 4 weeks of birth. The podocytes of these mice exhibited foot process effacement with reduced and altered localization of the slit-diaphragm proteins nephrin and podocin. Furthermore, the podocytes contained numerous autophagic vacuoles, confirmed by enhanced accumulation of microtubule-associated protein 1 light chain 3-positive intracellular vesicles. Ablation of the prorenin receptor selectively suppressed expression of the V0 c-subunit of the vacuolar H+-ATPase in podocytes, resulting in deacidification of intracellular vesicles. In conclusion, the prorenin receptor is important for the maintenance of normal podocyte structure and function.