Published papers

Background: Fechtner syndrome, also referred to as nonmuscle myosin heavy chain 9-related disease (MYH9-RD), is an autosomal-dominant genetic disorder. It is caused by abnormalities in the MYH9 gene, which encodes the nonmuscle conventional (class II) myosin heavy chain A (NMMHC-IIA). Its clinical manifestations include mild macrothrombocytopenia with leukocyte inclusions, hearing loss, cataracts, and renal failure. Case presentation: We present the case of a 34-year-old female patient with Fechtner syndrome in whom end-stage renal disease (ESRD) developed. During childhood, she presented with the typical symptoms of MYH9-RD, including thrombocytopenia, leukocyte inclusion bodies, onset of nephropathy, sensorineural hearing loss, and cataracts, wherein a clinical diagnosis of Fechtner syndrome was established. Her renal function deteriorated during adolescence. Furthermore, the patient underwent renal biopsy at the age of 18 years, which revealed focal segmental glomerulosclerosis. She was started on hemodialysis at the age of 33 years, followed by a living-donor renal transplantation after 5 months. She achieved a target platelet count of 50 × 109/L for arteriovenous fistula creation and 100 × 109/L for renal transplantation via platelet transfusions. Heparin use was avoided as an anticoagulant during hemodialysis. Since the patient expressed a desire for childbearing, genetic testing was performed, revealing an in-frame deletion of 21 nucleotides at 3195–3215 in exon 25 (A1065_A1072 del) of NMMHC-IIA, which has been reported to correlate with mild renal dysfunction. Our patient’s condition progressed into ESRD. Although genetic testing techniques have made great strides in recent years, our case clearly presents the difficulty in assuming an association between genetic abnormalities and clinical manifestations. Conclusions: Our case may provide further understanding of the management of ESRD in patients with MYH9-RD-related thrombocytopenia based on the results of genetic testing.

OBJECTIVES: Using a dataset from a survey on national health and productivity management, we identified health and productivity factors associated with organizational profitability. METHODS: The Ministry of Economy, Trade and Industry conducted an annual survey on Health and Productivity Management between 2014 and 2021. We assessed the associations of organizational health and productivity management using survey questions collected in 2017 and 2018, with the rate of change in profits from 2017 and 2018 to 2020. We identified factors associated with organizational profitability using eXtreme Gradient Boosting, and calculated SHapley Additive exPlanation (SHAP) values for each factor. RESULTS: Among 1,593 companies (n= 4,359,834 employees), the mean age of employees at baseline was 40.3 years and the proportion of women was 25.8%. A confusion matrix for evaluating model performance had an accuracy of 0.997, precision of 0.993, recall of 0.997, and area under the precision-recall curve of 0.999. The most important factors related to an increase in corporate profits were the percentage of current smokers (SHAP value, 0.121), per-employee cost of health services (0.084) and medical services (0.050); the percentage of full-time employees working in sales departments (0.074) and distribution or customer service departments (0.054); the percentage of employees who slept well (0.055); and the percentage of employees within a company who regularly exercised (0.043). CONCLUSIONS: Employees' lifestyle-related health risk factors and organizations' management systems were associated with organizational profitability. Lifestyle medicine professionals may demonstrate a significant return on investment by creating a healthier and more productive workforce.

A decreased body mass index (BMI) over time is associated with a poor prognosis for patients on hemodialysis. We aimed to examine whether this association also applies to patients with peritoneal dialysis (PD). BMI change was defined as the percentage change in the BMI between the time of PD catheter insertion and six months after its insertion. The association between the BMI change and all-cause mortality or PD discontinuation from six months after PD catheter insertion until October 2021 was investigated. This retrospective cohort study included 122 patients (aged 61.1 ± 12.1 years; 90 males) who underwent PD catheter insertion between January 2008 and March 2020. The median follow-up period was 43.1 (21.2-78.8) months. The median six-month percentage change in the BMI was -2.14 (-5.56-1.84)%, and patients were categorized into tertiles based on their BMI changes. The fully-adjusted Cox regression analysis revealed a significantly higher rate of PD discontinuation or all-cause mortality (hazard ratio (HR): 2.48; 95%; confidence interval (CI): 1.41-4.37) in patients with the lowest tertile (T1, BMI change: < -4.13%) compared to patients with the middle tertile (T2, BMI change: -4.13%-0.67%). The risk was not significantly higher in patients with the highest tertile (T3, BMI change: >0.67%) than those in the T2 group (HR: 1.18; 95% CI: 0.66-2.11). A decreased BMI over time is independently associated with HD transfer or all-cause mortality among patients initiating PD, which highlights the importance of the 6-month BMI change as a novel prognostic marker.

The progression of chronic kidney disease (CKD) cannot be completely inhibited. We first explored factors contributing to CKD progression in patients with CKD in a prospective observational study. In the next phase, we focused on the effects of aldosterone, conducting a single-blinded placebo-controlled study using the selective mineralocorticoid receptor antagonist (MRA), eplerenone (25 mg/day). We recruited patients with CKD stage 2 and 3 whose plasma aldosterone concentration was above 15 ng/dL based on the prior data of a prospective observational study. In the CKD cohort study (n = 141), baseline plasma aldosterone concentration was identified as an independent contributory factor for the future rate of change in estimated glomerular filtration rate (eGFR). When the cut-off value for aldosterone was set at 14.5 ng/dL, the decline rate was significantly higher in patients with higher plasma aldosterone concentration (- 1.22 ± 0.39 ml/min/1.73 m2/year vs. 0.39 ± 0.40 ml/min/1.73 m2/year, p = 0.0047). In the final intervention study, in the eplerenone group, eGFR dropped at 6 months after the initiation of the study, and thereafter eGFR was maintained until the end of the study. At 24 months and 36 months, eGFR was significantly higher in the eplerenone group than in the placebo group. In conclusion, MRA can be an effective strategy in preventing CKD progression, especially in patients with high plasma aldosterone.

Dysregulation of nicotinamide adenine dinucleotide (NAD +) metabolism contributes to the initiation and progression of age-associated diseases, including chronic kidney disease (CKD). Nicotinamide N-methyltransferase (NNMT), a nicotinamide (NAM) metabolizing enzyme, regulates both NAD + and methionine metabolism. Although NNMT is expressed abundantly in the kidney, its role in CKD and renal fibrosis remains unclear. We generated NNMT-deficient mice and a unilateral ureter obstruction (UUO) model and conducted two clinical studies on human CKD to investigate the role of NNMT in CKD and fibrosis. In UUO, renal NNMT expression and the degraded metabolites of NAM increased, while NAD + and NAD + precursors decreased. NNMT deficiency ameliorated renal fibrosis; mechanistically, it (1) increased the DNA methylation of connective tissue growth factor (CTGF), and (2) improved renal inflammation by increasing renal NAD + and Sirt1 and decreasing NF-κB acetylation. In humans, along with CKD progression, a trend toward a decrease in serum NAD + precursors was observed, while the final NAD + metabolites were accumulated, and the level of eGFR was an independent variable for serum NAM. In addition, NNMT was highly expressed in fibrotic areas of human kidney tissues. In conclusion, increased renal NNMT expression induces NAD + and methionine metabolism perturbation and contributes to renal fibrosis.

Glucocorticoid causes hyperglycemia, which is common in patients with or without diabetes. Prolonged hyperglycemia can be experienced even after the discontinuation of glucocorticoid use. In the present study, we examined the time course of blood glucose level in hospital patients who received transient glucocorticoid treatment. In addition, the mechanism of prolonged hyperglycemia was investigated by using dexamethasone (Dexa)-treated mice and cultured cells. The blood glucose level in glucose tolerance tests, level of insulin and glucagon-like peptide 1 (GLP-1), and the activity of dipeptidyl peptidase 4 (DPP-4) were examined during and after Dexa loading in mice, with histone acetylation level of the promoter region. Mice showed prolonged hyperglycemia during and after transient Dexa loading accompanied by persistently lower blood GLP-1 level and higher activity of DPP-4. The expression level of Dpp-4 was increased in the mononuclear cells and the promoter region of Dpp-4 was hyperacetylated during and after the transient Dexa treatment. In vitro experiments also indicated development of histone hyperacetylation in the Dpp-4 promoter region during and after Dexa treatment. The upregulation of Dpp-4 in cultured cells was significantly inhibited by a histone acetyltransferase inhibitor. Moreover, the histone hyperacetylation induced by Dexa was reversible by treatment with a sirtuin histone deacetylase activator, nicotinamide mononucleotide. We identified persistent reduction in blood GLP-1 level with hyperglycemia during and after Dexa treatment in mice, associated with histone hyperacetylation of promoter region of Dpp-4. The results unveil a novel mechanism of glucocorticoid-induced hyperglycemia, and suggest therapeutic intervention through epigenetic modification of Dpp-4.

Hypoglycemia is the major symptom of insulinoma. Chronic and recurrent hypoglycemia leads to the disappearance of autonomic symptoms and persistence of non-specific symptoms alone, possibly contributing to the delayed diagnosis of insulinoma and accounting for several undiagnosed cases. We previously reported the usefulness of hemoglobin A1c (HbA1c) and glycated albumin as markers for early insulinoma screening; however, their diagnostic prediction performance and diagnostic performance were not satisfactory. We hypothesized that the product of fasting plasma glucose (FPG) and HbA1c levels (FPG × HbA1c index) is low in insulinoma, and this index may be a useful marker for screening. This cross-sectional multicenter study compared 82 insulinoma patients with 100 age-, sex-, and body mass index-matched controls with normal glucose tolerance based on 75-g oral glucose tolerance test. The FPG × HbA1c index was significantly lower in the insulinoma group than in the control group. Receiver operating curve analysis showed that the optimal cutoff point of the FPG × HbA1c index to diagnose insulinoma was 447.1, and the area under the curves (AUCs) of the FPG × HbA1c index and HbA1c were 0.998 and 0.966, respectively. The AUC of the index was significantly higher than that of HbA1c (p = 0.010). Conversely, no significant difference existed between the AUC of the FPG × HbA1c index and that of the FPG/fasting immunoreactive insulin index. Thus, in apparently healthy population, the product of FPG and HbA1c yields a useful index for insulinoma screening in terms of accuracy and versatility.

There is a critical need for efficient treatment of chronic kidney disease (CKD). Renal fibrosis is a final common pathway to end-stage renal disease independent of the underlying etiology, and connective tissue growth factor (CTGF) is a well-recognized profibrotic factor in fibrosis of various organ systems. Here, we developed a novel peptide vaccine against CTGF to attenuate the development of renal fibrosis. Three inoculations with this CTGF vaccine at 2-week intervals elicited antibodies specifically binding to human full-length CTGF, and the antigen-specific serum IgG antibody titers were maintained for > 30 weeks. The efficacy of the CTGF vaccine on renal fibrosis was evaluated in adenine-induced CKD and unilateral ureteral obstruction (UUO) murine models. In adenine-induced CKD model, immunization with the CTGF vaccine attenuated renal interstitial fibrosis. Vaccinated mice showed low levels of serum creatinine and urea nitrogen and low urine albumin-creatinine ratio compared with vehicle-treated mice. In UUO model, the CTGF vaccination also suppressed the onset of renal fibrosis. In an in vitro study, CTGF vaccine-elicited IgG antibodies efficiently suppressed CTGF-induced- and transforming growth factor-β-induced α-smooth muscle actin expression in kidney fibroblasts. These results demonstrate that the CTGF vaccine is a promising strategy to attenuate the development of renal fibrosis.

Effective treatment of diabetic kidney disease (DKD) remains a large unmet medical need. Within the disease's complicated pathogenic mechanism, activation of the advanced glycation end products (AGEs)-receptor for AGE (RAGE) axis plays a pivotal role in the development and progression of DKD. To provide a new therapeutic strategy against DKD progression, we developed a vaccine against RAGE. Three rounds of immunization of mice with the RAGE vaccine successfully induced antigen-specific serum IgG antibody titers and elevated antibody titers were sustained for at least 38 weeks. In addition, RAGE vaccination significantly attenuated the increase in urinary albumin excretion in streptozotocin-induced diabetic mice (type 1 diabetes model) and leptin-receptor-deficient db/db mice (type 2 diabetes model). In microscopic analyses, RAGE vaccination suppressed glomerular hypertrophy and mesangial expansion in both diabetic models and significantly reduced glomerular basement membrane thickness in streptozotocin-induced diabetic mice. Results of an in vitro study indicated that the serum IgG antibody elicited by RAGE vaccination suppressed the expression of AGE-induced vascular cell adhesion molecule 1 and intracellular adhesion molecule 1 in endothelial cells. Thus, our newly developed RAGE vaccine attenuated the progression of DKD in mice and is a promising potential therapeutic strategy for patients with DKD.

Hypertension is a global public health issue and the most important preventable cause of cardiovascular diseases. Despite the clinical availability of many antihypertensive drugs, many hypertensive patients have poor medication adherence and blood pressure control due, at least partially, to the asymptomatic and chronic characteristics of hypertension. Immunotherapeutic approaches have the potential to improve medication adherence in hypertension because they induce prolonged therapeutic effects and need a low frequency of administration. The first attempts to reduce blood pressure by using vaccines targeting the renin-angiotensin system were made more than half a century ago; however, at the time, a poor understanding of immunology and the mechanisms of hypertension and a lack of optimal vaccine technologies such as suitable antigen design, proper adjuvants, and effective antigen delivery systems meant that attempts to develop antihypertensive vaccines failed. Recent advances in immunology and vaccinology have provided potential therapeutic immunologic approaches to treat not only infectious diseases but also cancers and other noncommunicable diseases. One important biotechnology that has had a major impact on modern vaccinology is virus-like particle technology, which can efficiently deliver vaccine antigens without the need for artificial adjuvants. A human clinical trial that indicated the effectiveness and safety of a virus-like particle-based antiangiotensin II vaccine marked a turning point in the field of therapeutic antihypertensive vaccines. Here, we review the history of the development of immunotherapies for the treatment of hypertension and discuss the current perspectives in the field.

Sodium benzoate (SB), a known D-amino acid oxidase (DAO) enzyme inhibitor, has an anti-inflammatory effect, although its role in renal damage has not been explored. 2,8-dihydroxyadenine crystal induced chronic kidney disease, in which TNF-α is involved in the pathogenesis, was established by oral adenine administration in C57BL/6JJcl mice (AdCKD) with or without SB to investigate its renal protective effects. SB significantly attenuated AdCKD by decreasing serum creatinine and urea nitrogen levels, and kidney interstitial fibrosis and tubular atrophy scores. The survival of AdCKD mice improved 2.6-fold by SB administration. SB significantly decreased the number of infiltrating macrophages observed in the positive F4/80 immunohistochemistry area and reduced the expression of macrophage markers and inflammatory genes, including TNF-α, in the kidneys of AdCKD. Human THP-1 cells stimulated with either lipopolysaccharide or TNF-α showed increased expression of inflammatory genes, although this was significantly reduced by SB, confirming the anti-inflammatory effects of SB. SB exhibited renal protective effects in AdCKD in DAO enzyme deficient mice, suggesting that anti-inflammatory effect of SB was independent of DAO enzyme activity. Moreover, binding to motif DNA sequence, protein level, and mRNA level of NF-κB RelB were significantly inhibited by SB in AdCKD kidneys and lipopolysaccharide treated THP-1 cells, respectively. We report that anti-inflammatory property of SB is independent of DAO enzymatic activity and is associated with down regulated NF-κB RelB as well as its downstream inflammatory genes such as TNF-α in AdCKD.

The risk factors for intradialytic systolic blood pressure decline remain poorly understood. We aimed to identify clinical and laboratory predictors of the intradialytic systolic blood pressure decline, considering its seasonal variation. In a retrospective cohort of 47,219 hemodialysis sessions of 307 patients undergoing hemodialysis over one year in three dialysis clinics, the seasonal variation and the predictors of intradialytic systolic blood pressure decline (predialysis systolic blood pressure--nadir intradialytic systolic blood pressure) were assessed using cosinor analysis and linear mixed models adjusted for baseline or monthly hemodialysis-related variables, respectively. The intradialytic systolic blood pressure decline was greatest and least in the winter and summer, respectively, showing a clear seasonal pattern. In both models adjusted for baseline and monthly hemodialysis-related parameters, calcium channel blocker use was associated with a smaller decline (-4.58 [95% confidence interval (CI), -5.84 to -3.33], P < 0.001; -3.66 [95% CI, -5.69 to -1.64], P < 0.001) and α blocker use, with a greater decline (3.25 [95% CI, 1.53-4.97], P < 0.001; 3.57 [95% CI, 1.08-6.06], P = 0.005). Baseline and monthly serum phosphorus levels were positively correlated with the decline (1.55 [95% CI, 0.30-2.80], P = 0.02; 0.59 [95% CI, 0.16-1.00], P = 0.007), and baseline and monthly normalized protein catabolic rates were inversely correlated (respectively, -22.41 [95% CI, -33.53 to -11.28], P < 0.001; 9.65 [95% CI, 4.60-14.70], P < 0.001). In conclusion, calcium channel blocker use, α blocker avoidance, and serum phosphorus-lowering therapy may attenuate the intradialytic systolic blood pressure decline and should be investigated in prospective trials.

Predialysis systolic blood pressure (SBP) in patients on hemodialysis (HD) consistently followed a seasonal pattern, reaching a peak in winter and nadir in summer, similar to blood pressure in the general population. However, the relationship between seasonal variations in predialysis SBP and clinical outcomes is still under-investigated in Japanese patients on HD. This retrospective cohort study included 307 Japanese patients undergoing HD for >1 year in three dialysis clinics and evaluated the association between the standard deviation (SD) of predialysis 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) with 2.5 years follow-up. The SD of predialysis SBP was 8.2 (6.4-10.9) mmHg. In the model fully adjusted for the SD of predialysis SBP, predialysis SBP, age, sex, HD vintage, Charlson comorbidity index, ultrafiltration rate, renin-angiotensin system inhibitors, corrected calcium, phosphorus, human atrial natriuretic peptide, C-reactive protein, albumin, hemoglobin, body mass index, normalized protein catabolism rate, and intradialytic SBP decline, Cox regression analyses showed that a higher SD of predialysis SBP (per 10 mmHg) was significantly associated with increased MACE risk (hazard ratio [HR], 1.89; 95% confidence interval [95% CI], 1.07-3.36) and all-cause hospitalization (HR, 1.57; 95% CI, 1.07-2.30). Therefore, greater seasonal variations in predialysis SBP were associated with worse clinical outcomes, including MACEs and all-cause hospitalization. Whether interventions to reduce seasonal variations in predialysis SBP will improve the prognosis of Japanese patients on HD must be investigated further.

AIM: Patients play a crucial role in preventing peritoneal dialysis (PD)-related events, including peritonitis and fluid overload, as PD procedures are mainly carried out at home. We asked patients to submit a PD self-assessment sheet at each outpatient visit in our daily clinical practice and evaluated its usefulness for outcomes in patients initiating PD. METHODS: This retrospective cohort study included patients who underwent PD catheter insertion between January 2008 and October 2018. The submission rate of a PD self-assessment sheet was calculated from medical records until PD cessation or study completion (October 2020). The association between the submission rate and technique survival was analysed. RESULTS: Among the 105 recruited patients (78 men, 60.4 ± 12.2 years), 44 discontinued PD and transferred to haemodialysis during the study period. The follow-up was 52.3 (28.7-79.3) months, and the median submission rate was 78%. The log-rank test showed that technique survival was significantly better in patients with a submission rate ≥ 78% than those with a submission rate <78% (p = .006). The submission rate remained significantly associated with less technique failure (hazard ratio 0.88 per 10%, p = .002) by the Cox regression analysis adjusted for age, sex, Charlson comorbidity index, estimated glomerular filtration rate and geriatric nutritional risk index. CONCLUSION: The submission rate of a PD self-assessment sheet is useful as a predictor of technique survival in patients initiating PD. Instruction that increases submission may improve technique survival in PD patients.