Published papers

Background: As there is no established standard of care for non-tuberculous mycobacterium (NTM) peritoneal dialysis (PD)-related peritonitis, its treatments have to be case-dependent, which is often difficult. Additionally, several reported cases were accompanied by encapsulated ascites, adhesive ileus, and encapsulating peritoneal sclerosis, suggesting treatment difficulties. We report two cases of PD-related peritonitis with encapsulated ascites due to Mycobacterium abscessus subsp. massilience and subsp. bolletii. To the best of our knowledge, this is the first case series to report PD-related peritonitis caused by Mycobacterium abscessus subsp. bolletii. Case presentation: The first case is that of a 74-year-old male patient who started PD six years ago for end-stage renal failure due to diabetic nephropathy. In February 2021, he presented with signs of infection at the exit-site and swelling of the tunnel. Mycobacterium abscessus subsp. massilience was detected in the culture of the exit-site exudate; thus, he was diagnosed with tunnel infection (caused by NTM). Subsequently, fever, abdominal pain, and increased cell counts in the PD drainage fluid were observed, and he was judged to have NTM peritonitis. His general condition improved after PD catheter removal in addition to antimicrobial treatment and encapsulated ascites drainage. The second case is that of a 52-year-old man who commenced PD for end-stage renal failure due to nephrosclerosis 12 years ago. In May 2022, he was diagnosed with PD-related peritonitis based on signs of infection at the exit-site, encapsulated ascites on computed tomography, and a cloudy PD drainage fluid. Mycobacterium abscessus subsp. bolletii was detected in the culture of the exit-site exudate, which led to the diagnosis of NTM peritonitis. In addition to antimicrobial treatment, PD catheter removal and encapsulated ascites drainage were performed. The patient also had adhesive bowel obstruction due to peritonitis and required decompression therapy with the insertion of a gastric tube. Conclusions: PD catheter removal and encapsulated ascites drainage might have improved inflammation and treatment outcomes. Additionally, Mycobacterium abscessus might be prone to forming encapsulated cavities and/or intestinal adhesions; however, further accumulation of cases clarifying “subspecies” of Mycobacterium abscessus is necessary to confirm this hypothesis.

Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global pandemic. Although several vaccines targeting SARS-CoV-2 spike proteins protect against COVID-19 infection, mutations affecting virus transmissibility and immune evasion potential have reduced their efficacy, leading to the need for a more efficient strategy. Available clinical evidence regarding COVID-19 suggests that endothelial dysfunction with thrombosis is a central pathogenesis of progression to systemic disease, in which overexpression of plasminogen activator inhibitor-1 (PAI-1) may be important. Here we developed a novel peptide vaccine against PAI-1 and evaluated its effect on lipopolysaccharide (LPS)-induced sepsis and SARS-CoV-2 infection in mice. Administration of LPS and mouse-adapted SARS-CoV-2 increased serum PAI-1 levels, although the latter showed smaller levels. In an LPS-induced sepsis model, mice immunized with PAI-1 vaccine showed reduced organ damage and microvascular thrombosis and improved survival compared with vehicle-treated mice. In plasma clot lysis assays, vaccination-induced serum IgG antibodies were fibrinolytic. However, in a SARS-CoV-2 infection model, survival and symptom severity (i.e., body weight reduction) did not differ between vaccine- and vehicle-treated groups. These results indicate that although PAI-1 may promote the severity of sepsis by increasing thrombus formation, it might not be a major contributor to COVID-19 exacerbation.

As life expectancy continues to increase, age-related kidney diseases are becoming more prevalent. Chronic kidney disease (CKD) is not only a consequence of aging but also a potential accelerator of aging process. Here we report the pivotal role of podocyte ERCC1, a DNA repair factor, in maintaining glomerular integrity and a potential effect on multiple organs. Podocyte-specific ERCC1-knockout mice developed severe proteinuria, glomerulosclerosis, and renal failure, accompanied by a significant increase in glomerular DNA single-strand breaks (SSBs) and double-strand breaks (DSBs). ERCC1 gene transfer experiment in the knockout mice attenuated proteinuria and glomerulosclerosis with reduced DNA damage. Notably, CD44+CD8+ memory T cells, indicative of T-cell senescence, were already elevated in the peripheral blood of knockout mice at 10 weeks old. Additionally, levels of senescence-associated secretory phenotype (SASP) factors were significantly increased in both the circulation and multiple organs of the knockout mice. In older mice and human patients, we observed an accumulation of DSBs and an even greater buildup of SSBs in glomeruli, despite no significant reduction in ERCC1 expression with age in mice. Collectively, our findings highlight the crucial role of ERCC1 in repairing podocyte DNA damage, with potential implications for inflammation in various organs.

BACKGROUND: The activation of NAD+-dependent deacetylase, Sirt1, by the administration of nicotinamide mononucleotide (NMN) ameliorates various aging-related diseases. METHODS: Diabetic db/db mice were treated with NMN transiently for 2 weeks and observed for effects on diabetic nephropathy (DN). RESULTS: At 14 weeks after the treatment period, NMN attenuated the increases in urinary albumin excretion in db/db mice without ameliorating hemoglobin A1c levels. Short-term NMN treatment mitigated mesangium expansion and foot process effacement, while ameliorating decreased Sirt1 expression and increased claudin-1 expression in the kidneys of db/db mice. This treatment also improved the decrease in the expression of H3K9me2 and DNMT1. Short-term NMN treatment also increased kidney concentrations of NAD+ and the expression of Sirt1 and nicotinamide phosphoribosyltransferase (Nampt), and it maintained nicotinamide mononucleotide adenyltransferase1 (Nmnat1) expression in the kidneys. In addition, survival rates improved after NMN treatment. CONCLUSIONS: Short-term NMN treatment in early-stage DN has remote renal protective effects through the upregulation of Sirt1 and activation of the NAD+ salvage pathway, both of which indicate NMN legacy effects on DN.

Recent reports have shown the feasibility of measuring biological age from DNA methylation levels in blood cells from specific regions identified by machine learning, collectively known as the epigenetic clock or DNA methylation clock. While extensive research has explored the association of the DNA methylation clock with cardiovascular diseases, cancer, and Alzheimer's disease, its relationship with kidney diseases remains largely unexplored. In particular, it is unclear whether the DNA methylation clock could serve as a predictor of worsening kidney function. In this pilot study involving 20 subjects, we investigated the association between the DNA methylation clock and subsequent deterioration of renal function. Additionally, we noninvasively evaluated DNA damage in urinary shedding cells using a previously reported method to examine the correlation with the DNA methylation clock and worsening kidney function. Our findings revealed that patients with an accelerated DNA methylation clock exhibited increased DNA damage in urinary shedding cells, along with a higher rate of eGFR decline. Moreover, in cases of advanced CKD (G4-5), the DNA damage in urinary shedding cells was significantly increased, highlighting the interplay between elevated DNA damage and eGFR decline. This study suggests the potential role of the DNA methylation clock and urinary DNA damage as predictive markers for the progression of chronic kidney disease.

Context: Aldosterone-producing adenomas are a curable subtype of primary aldosteronism (PA); however, hypertension persists in some patients after adrenalectomy. Objective: To identify factors associated with, and develop prediction models for, blood pressure (BP) normalization or improvement after adrenalectomy. Design: Retrospective analysis of patients treated between 2006 and 2018, with a 6-month follow-up. Setting: A nationwide, 29-center Japanese registry encompassing 15 university hospitals and 14 city hospitals. Patients: We categorized 574 participants in the Japan Primary Aldosteronism Study, who were diagnosed with PA and underwent adrenalectomy, as BP normalized or improved, on the basis of their presentations at 6 months postsurgery. Main Outcome Measure: The rate of complete, partial, and absent clinical success. Predictive factors related to BP outcomes after PA surgery were also evaluated. Results: Complete clinical success was achieved in 32.6% and partial clinical success was achieved in 53.0% of the patients at 6 months postsurgery. The following five variables were independent predictors for BP normalization: ≤7 years of hypertension, body mass index ≤25 kg/m2, no more than one antihypertensive medication, absence of medical history of diabetes, and female sex. The area under the receiver operator characteristic curve was 0.797 in the BP normalization model. Conclusion: We established models that predicted postoperative BP normalization in patients with PA. These should be useful for shared decision-making regarding adrenalectomy for PA.

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 investigated the prevalence of hypertensive patients and treated hypertensive patients using a Japanese nationwide administrative claims database. We analyzed national database data from 2014, including all claims data, provided by the Ministry of Health, Labour and Welfare of Japan. Hypertensive diseases were identified using Japanese standardized disease codes. Among hypertensive patients, treated hypertensive patients were defined by the prescription of any antihypertensive medication, identified using national health insurance price listing codes. We calculated and compared the number and age-adjusted prevalence of hypertensive patients and treated hypertensive patients by prefecture and the proportion of these patients by the size of medical facilities. In 2014, approximately 27 million Japanese people were identified as hypertensive, among which 89.6% were treated. The age-adjusted prevalence of hypertensive patients (per 100,000 persons) among women and men was 21,414 and 21,084, respectively. The age-adjusted prevalence of treated hypertensive patients (per 100,000 persons) among women and men was 19,118 and 18,974, respectively. While the prevalence of hypertensive and treated hypertensive patients varied geographically, the prevalence remained similar between the sexes. Approximately 59% of hypertensive patients visited clinics (0 to 19 beds) in Japan. In Japan, 27 million people were diagnosed with hypertensive diseases, and approximately 90% of these patients were treated with any antihypertensive medication in 2014. The distribution of hypertensive patients varied geographically throughout Japan.

Because end-stage renal disease patients undergoing hemodialysis frequently take acid suppressants for the treatment or prevention of gastrointestinal diseases, it is important to clarify the drug-interactions between acid suppressants and phosphate binders on the control of serum phosphate levels. In the present study, we examined whether the phosphate-lowering effects of three phosphate binders, lanthanum carbonate (LC), ferric citrate hydrate (FCH), and sucroferric oxyhydroxide (SFOH), were affected by proton pump inhibitors (PPIs) in maintenance hemodialysis patients. Laboratory data for 71 patients who had been newly prescribed one of the three phosphate binders were examined. LC at a dosage of 500 ± 217 mg/day significantly decreased serum phosphate levels by -18% in the absence of a PPI (n = 9), while a dosage of 700 ± 230 mg/day only decreased it by -3% in the presence of a PPI (n = 10). Thus, the efficacy of LC in reducing serum phosphate levels was significantly hindered by the presence of PPIs. FCH significantly decreased serum phosphate levels by -18% in the absence of a PPI (n = 7, FCH: 571 ± 189 mg/day) and by -17% in the presence of a PPI (n = 20, FCH: 638 ± 151 mg/day). The decrease in serum phosphate levels by SFOH (393 ± 197 mg/day) was -7% in the absence of a PPI (n = 7), and SFOH at a dosage of 556 ± 316 mg/day significantly decreased serum phosphate levels by -13% in the presence of a PPI (n = 18). These results suggest that the phosphate-lowering effect of LC, but not of FCH or SFOH, is diminished in the presence of PPIs in hemodialysis patients.

The small GTPase protein RhoA has two effectors, ROCK (Rho-associated protein kinase 1) and mDIA1 (protein diaphanous homolog 1), which cooperate reciprocally. However, temporal regulation of RhoA and its effectors in obesity-induced kidney damage remains unclear. Here, we investigated the role of RhoA activation in the proximal tubules at the early and late stages of obesity-induced kidney damage. In mice, a three-week high-fat-diet induced proximal tubule hypertrophy and damage without increased albuminuria, and RhoA/mDIA1 activation without ROCK activation. Conversely, a 12-week high-fat diet induced proximal tubule hypertrophy, proximal tubule damage, increased albuminuria, and RhoA/ROCK activation without mDIA1 elevation. Proximal tubule hypertrophy resulting from cell cycle arrest accompanied by downregulation of the multifunctional cyclin-dependent kinase inhibitor p27Kip1 was elicited by RhoA activation. Mice overexpressing proximal tubule-specific and dominant-negative RHOA display amelioration of high-fat diet-induced kidney hypertrophy, cell cycle abnormalities, inflammation, and renal impairment. In human proximal tubule cells, mechanical stretch mimicking hypertrophy activated ROCK, which triggered inflammation. In human kidney samples from normal individuals with a body mass index of about 25, proximal tubule cell size correlated with body mass index, proximal tubule cell damages, and mDIA1 expression. Thus, RhoA activation in proximal tubules is critical for the initiation and progression of obesity-induced kidney damage. Hence, the switch in the downstream RhoA effector in proximal tubule represents a transition from normal to pathogenic kidney adaptation and to body weight gain, leading to obesity-induced kidney damage.

AIMS/HYPOTHESIS: Type 2 diabetes is characterised by reduced beta cell mass (BCM). However, it remains uncertain whether the reduction in BCM in type 2 diabetes is due to a decrease in size or number of beta cells. Our aim was to examine the impact of beta cell size and number on islet morphology in humans with and without type 2 diabetes. METHODS: Pancreas samples were obtained from 64 Japanese adults with (n = 26) and without (n = 38) type 2 diabetes who underwent pancreatectomy. Using pancreatic tissues stained for insulin, we estimated beta cell size based on beta cell diameter. Beta cell number was estimated from the product of fractional beta cell area and pancreas volume divided by beta cell size. The associations of beta cell size and number with islet morphology and metabolic status were examined. RESULTS: Both beta cell size (548.7 ± 58.5 vs 606.7 ± 65.0 μm3, p < 0.01) and number (5.10 × 108 ± 2.35 × 108 vs 8.16 × 108 ± 4.27 × 108, p < 0.01) were decreased in participants with type 2 diabetes compared with those without diabetes, with the relative reduction in beta cell number (37%) being greater than for beta cell size (10%). Beta cell number but not size was positively correlated with BCM in participants with and without type 2 diabetes (r = 0.97 and r = 0.98, both p < 0.01) and negatively correlated with HbA1c (r = -0.45, p < 0.01). CONCLUSIONS/INTERPRETATION: Both beta cell size and number were reduced in participants with type 2 diabetes, with the relative reduction in beta cell number being greater. Decrease in beta cell number appears to be a major contributor to reduced BCM in type 2 diabetes.

The aim of the study was to explore the relationship between daily glycemic variability (GV) and visit-to-visit glycemic variability (VVV) in patients with type 2 diabetes (T2DM). A total of 156 outpatients with T2DM who had undergone continuous glucose monitoring (CGM) for 5 days were included in this study. Indices of GV, i.e., standard deviation and coefficient of variation (CV) of glucose, mean amplitude of glycemic excursion (MAGE) and mean of the daily differences (MODD) were calculated from the CGM data. VVV was calculated as CV of HbA1c or glycated albumin (GA) from HbA1c or GA measured for 3 years. Relationships among clinical parameters, GV and VVV were evaluated. Age was positively, and BMI and C-peptide index were inversely correlated with GV such as CV glucose and MAGE, while BMI was positively correlated with VVV. Mean glucose rather than GV was correlated with VVV. In contrast, time in range (TIR, 70-180 mg/dL) was correlated with both mean HbA1c or GA and VVV. In conclusion, GV and VVV were differently correlated with clinical parameters and were hardly correlated with each other. TIR was correlated with both mean HbA1c and VVV, suggesting that efforts to achieve optimal TIR are practical strategies to reduce VVV in patients with T2DM.

A 23-year-old man presented with severe hypertension. Based on his history of minocycline treatment for over three years and clinical symptoms, such as myalgias and renovascular hypertension with multiple intrarenal aneurysms, he was diagnosed with minocycline-induced renal polyarteritis nodosa (PAN). After minocycline treatment cessation and management of the hypertension, his blood pressure, renin-aldosterone levels, and urinary protein levels gradually improved. Seven and a half years later, repeated angiography found that the aneurysms had resolved. This is the first report in English describing a case of minocycline-induced renal PAN that was reversed functionally and morphologically without steroids or immunosuppressive drugs.