Published papers

OBJECTIVE: Obesity is a risk factor of chronic kidney disease (CKD), contributing to the rising incidence of cardiometabolic diseases. Renal sinus fat (RSF) is an ectopic fat depot located at the renal cavity that could impair renal function and hemodynamic through compression of renal structures. The major purpose of this study was to explore the relationship between RSF accumulation and renal dysfunction in CKD patients. METHODS: We evaluated the associations between computed tomography measured RSF volume and key clinical and histologic parameters involved in renal function and hemodynamics in 132 well-characterized CKD patients who underwent renal biopsy (median age: 62 years; 63.6% men). RESULTS: RSF volume normalized by renal volume (RSF%) positively correlated with obesity-related traits such body mass index and visceral fat volume (VFV) (all P < 0.001) whereas it negatively correlated with estimated glomerular filtration rate (eGFR) (ρ = -0.42, P < 0.001) and 24-h urinary creatinine clearance (CCr) (ρ = -0.34, P < 0.001). Notably, we found robust positive correlations between RSF% and renal resistive index (RRI) measured by the Doppler ultrasound (ρ = 0.40, P < 0.001), and the histological severity of global glomerular sclerosis (ρ = 0.48, P < 0.001) and interstitial fibrosis and tubular atrophy (IFTA) (ρ = 0.35, P < 0.001). In the multivariate linear regression models, after accounting for potential confounders including VFV, RSF% remained significantly associated with CCr (β = -0.26, P < 0.001), RRI (β = 0.17, P = 0.022), global glomerular sclerosis (β = 0.21, P = 0.002), and IFTA (β = 0.17, P = 0.012). CONCLUSION: RSF accumulation is associated with renal dysfunction and hemodynamic abnormalities independent of visceral adiposity. Our results suggest that RSF may have a potential unique role in the pathogenesis of CKD.

Type 2 diabetes (T2DM) is characterized by insulin resistance and β-cell dysfunction. Because patients with T2DM have inadequate β-cell mass (BCM) and β-cell dysfunction worsens glycemic control and makes treatment difficult, therapeutic strategies to preserve and restore BCM are needed. In rodent models, obesity increases BCM about 3-fold, but the increase in BCM in humans is limited. Besides, obesity-induced changes in BCM may show racial differences between East Asians and Caucasians. Recently, the developmental origins of health and disease hypothesis, which states that the risk of developing noncommunicable diseases including T2DM is influenced by the fetal environment, has been proposed. It is known in rodents that animals with low birthweight have reduced BCM through epigenetic modifications, making them more susceptible to diabetes in the future. Similarly, in humans, we revealed that individuals born with low birthweight have lower BCM in adulthood. Because β-cell replication is more frequently observed in the 5 years after birth, and β cells are found to be more plastic in that period, a history of childhood obesity increases BCM. BCM in patients with T2DM is reduced by 20% to 65% compared with that in individuals without T2DM. However, since BCM starts to decrease from the stage of borderline diabetes, early intervention is essential for β-cell protection. In this review, we summarize the current knowledge on regulatory factors of human BCM in health and diabetes and propose the β-cell-centric concept of diabetes to enhance a more pathophysiology-based treatment approach for T2DM.

This study investigated the mechanism underlying the beneficial effects of mineralocorticoid receptor (MR) antagonists in patients with resistant hypertension and diabetic nephropathy by examining post-translational modification of the MR by O-linked-N-acetylglucosamine (O-GlcNAc), which is strongly associated with type 2 diabetes. Coimmunoprecipitation assays in HEK293T cells showed that MR is a target of O-GlcNAc modification (O-GlcNAcylation). The expression levels and transcriptional activities of the receptor increased in parallel with its O-GlcNAcylation under high-glucose conditions. Liquid chromatography-tandem mass spectrometry revealed O-GlcNAcylation of the MR at amino acids 295-307. Point mutations in those residues decreased O-GlcNAcylation, and both the protein levels and transcriptional activities of MR. In db/db mouse kidneys, MR protein levels increased in parallel with overall O-GlcNAc levels of the tissue, accompanied by increased SGK1 mRNA levels. The administration of 6-diazo-5-oxo-L-norleucin, an inhibitor of O-GlcNAcylation, reduced tissue O-GlcNAc levels and MR protein levels in db/db mice. Thus, our study showed that O-GlcNAcylation of the MR directly increases protein levels and transcriptional activities of the receptor under high-glucose conditions in vitro and in vivo. These findings provide a novel mechanism of MR as a target for prevention of complications associated with diabetes mellitus.

A 71-year-old man complained of nausea and loss of appetite for eight months prior to admission. He was transported to a hospital with disorientation and diagnosed with primary hyperparathyroidism by laboratory examinations. However, ultrasonography, computed tomography, and technetium-99m labeled methoxyisobutyl isonitrile (99mTc-MIBI) with single-photon emission computed tomography did not yield definite results. In contrast, somatostatin receptor scintigraphy successfully identified the lesion responsible for the over-secretion of parathyroid hormone within the middle mediastinum. The tumor was successfully resected by surgery, and a histopathological analysis confirmed the parathyroid adenoma nature of the tumor.

An intradialytic systolic blood pressure (SBP) decline, which defines intradialytic hypotension, may be associated with higher all-cause mortality. However, in Japanese patients on hemodialysis (HD), the association between intradialytic SBP decline and patient outcomes is unclear. This retrospective cohort study included 307 Japanese patients undergoing HD over 1 year in three dialysis clinics and evaluated the association between the mean annual intradialytic SBP decline (predialysis SBP-nadir intradialytic SBP) and clinical outcomes, including major adverse cardiovascular events (MACEs; cardiovascular death, nonfatal myocardial infarction or unstable angina, stroke, heart failure, and other severe cardiovascular events requiring hospitalization) by following up for 2 years. The mean annual intradialytic SBP decline was 24.2 (25-75th percentile, 18.3-35.0) mmHg. In the model fully adjusted for intradialytic SBP decline tertile group (T1, <20.4 mmHg; T2, 20.4 to <29.9 mmHg; T3, ≥29.9 mmHg), predialysis SBP, age, sex, HD vintage, Charlson comorbidity index, ultrafiltration rate, use of renin-angiotensin system inhibitors, corrected calcium, phosphorus, human atrial natriuretic peptide, geriatric nutritional risk index, normalized protein catabolism rate, C-reactive protein, hemoglobin, and use of pressor agents, Cox regression analyses showed that the hazard ratio (HR) was significantly higher for T3 than for T1 for MACEs (HR, 2.38; 95% confidence interval 1.12-5.09) and all-cause hospitalization (HR, 1.68; 95% confidence interval 1.03-2.74). Therefore, in Japanese patients on HD, a greater intradialytic SBP decline was associated with worse clinical outcomes. Further studies are warranted to investigate whether interventions to attenuate the intradialytic SBP decline will improve the prognosis of Japanese patients on HD.

Patients with end-stage renal disease are less likely to choose peritoneal dialysis (PD) as renal replacement therapy (RRT). The reasons for this biased selection are still poorly understood. In this study, we evaluated the effect of the timing of RRT education on PD selection. This single-center retrospective observational study included patients who initiated maintenance dialysis at our hospital between April 2014 and July 2021. A logistic regression analysis was performed to investigate the association of RRT education timing with PD selection. Among the 355 participants (median age [IQR] 70 (59−79) years; 28.7% female), 53 patients (14.9%) and 302 patients (85.1%) selected PD and hemodialysis, respectively. Multivariate analysis demonstrated that high estimated glomerular filtration (eGFR) at RRT education positively predicted PD selection (p < 0.05), whereas old age (p < 0.01) and high Charlson comorbidity index (p < 0.05) were negative predictors of PD selection. Female sex (p = 0.44), welfare public assistance (p = 0.78), living alone (p = 0.25), high geriatric nutritional risk index (p = 0.10) and high eGFR at first visit to the nephrology department (p = 0.83) were not significantly associated with PD selection. Late RRT education could increase the biased selection of dialysis modality.

This study investigated the long-term antihypertensive effects of esaxerenone, a novel nonsteroidal mineralocorticoid receptor blocker, alone or in combination with a calcium channel blocker (CCB) or a renin-angiotensin system (RAS) inhibitor, in Japanese patients with essential hypertension. Patients were treated with esaxerenone starting at 2.5 mg/day increasing to 5 mg/day if required to achieve blood pressure (BP) targets as a monotherapy or with a CCB or RAS inhibitor. After the first 12 weeks of treatment, an additional antihypertensive agent could be added if required to achieve the target BP; the total treatment period was 28 or 52 weeks. The primary endpoint was a change from baseline in sitting BP. Of the 368 enrolled patients, 245 received monotherapy, and 59 and 64, respectively, took a CCB or RAS inhibitor concurrently. Mean changes from baseline in sitting systolic/diastolic BP (95% confidence intervals) at weeks 12, 28 and 52 were -16.1 (-17.3, -14.9)/-7.7 (-8.4, -6.9), -18.9 (-20.2, -17.7)/-9.9 (-10.7, -9.2), and -23.1 (-25.0, -21.1)/-12.5 (-13.6, -11.3) mmHg, respectively (all P < 0.0001 vs baseline). Similar BP reductions at these weeks were observed between all patient subgroups stratified by age, and the observed decreases in 24-h ambulatory BP were consistent with the efficacy observed in sitting BP. Esaxerenone was also well-tolerated with a rate of hyperkalemia at 5.4% (serum potassium ≥5.5 mEq/L), indicating a good safety profile for treatment over the long-term or in combination with a CCB or RAS inhibitor. In conclusion, esaxerenone may be a promising treatment option for patients with hypertension.

AIMS/INTRODUCTION: There have been few reports about the longitudinal changes in pancreas volume (PV) or pancreatic steatosis (PS) in response to obesity. In this longitudinal analysis using health check-up data, we explored changes in PV, PS and glucose metabolic indices that occurred after weight gain in Japanese without diabetes. MATERIALS/METHODS: Clinical data on 37 Japanese subjects with a ≥1 kg/m2 increase in body mass index between two health check-ups and without diabetes were collected. PV, pancreas attenuation (PA) and splenic attenuation (SA) were evaluated using computed tomography (CT) images. The pancreas area was outlined by hand in multiple images with slice thickness of 2 mm, and the PV was computed by summing these areas. PS was defined as the difference between SA and PA (SA-PA). Medical records were collected, including findings on immunoreactive insulin (IRI), homeostasis model assessment of insulin resistance (HOMA-R) and beta cell function (HOMA-β). Paired t-test and Spearman's correlation coefficient were used in the analyses. RESULTS: The median follow-up period was 21.1 months and the mean BMI was increased from 25.5 ± 3.3 kg/m2 to 27.0 ± 3.3 kg/m2. PV (53.5 ± 15.9 cm3 vs. 56.2 ± 16.4 cm3) and SA-PA (8.7 ± 9.1 HU vs. 13.6 ± 10.9 HU) increased significantly after weight gain (both, P < 0.001). There were significant increases of IRI and HOMA-R with the weight gain (both, P < 0.05), whereas HOMA-β exhibited only a nonsignificant trend of increase (55.4％ (41.5-65.5) vs. 56.8％ (46.2-83.7), P = 0.07). CONCLUSIONS: Both PV and PS were increased longitudinally with weight gain in Japanese without diabetes.

Worldwide, hypertension and chronic kidney disease (CKD) are highly prevalent disorders and are strong risk factors for cardiovascular disease and end-stage renal disease (ESRD). The developmental origins of health and disease (DOHAD) concept suggests that undesirable perinatal environmental conditions, such as malnutrition, contribute to disease development in adults. Among the known hypertension and CKD risk factors, DOHAD plays a potential role in determining susceptibility to the onset of these diseases in later adulthood. Since low birth weight (LBW) is a surrogate marker for adverse fetal environmental conditions, the high incidence of LBW in developing countries and its increasing incidence in most developed countries (attributed to multiple pregnancies and prepregnancy maternal factors, such as undernutrition, advanced maternal age, and smoking) is concerning. Thus, LBW is an important public health problem not only because of the associated infant mortality and morbidity but also because it is a risk factor for adult-onset hypertension/CKD. During their reproductive years, pregnant women who were born with LBWs have an increased risk of hypertensive disorders of pregnancy, which contribute to the risk of developing cardiovascular disease and ESRD. The offspring of LBW females are also likely to be LBW, which suggests that susceptibility to hypertension/CKD may reflect transgenerational inheritance. Therefore, there is global concern about the increasing prevalence of LBW-related diseases. This review summarizes the relevance of hypertension and CKD in conjunction with DOHAD and discusses recent studies that have examined the impact of the upward LBW trend on renal function and blood pressure.