Publications by authors named "Takanari Kitazono"

565 Publications

Regional Disparity of Reperfusion Therapy for Acute Ischemic Stroke in Japan: A Retrospective Analysis of Nationwide Claims Data from 2010 to 2015.

J Am Heart Assoc 2021 Oct 8:e021853. Epub 2021 Oct 8.

Department of Health Care Administration and Management Graduate School of Medical Sciences Kyushu University Fukuoka Japan.

Background We aimed to determine whether a regional disparity exists in usage of reperfusion therapy (intravenous recombinant tissue plasminogen activator [IV rt-PA] and endovascular thrombectomy [EVT]) and post-reperfusion 30-day mortality in patients with acute ischemic stroke, and which regional factors are associated with their usage. Methods and Results We retrospectively investigated 69 948 patients (mean age±SD, 74.9±12.0 years; women, 41.4%) with acute ischemic stroke treated with reperfusion therapy between April 2010 and March 2016 in Japan using nationwide claims data. Regional disparity was evaluated using Gini coefficients for age- and sex-adjusted usage of reperfusion therapy and 30-day post-reperfusion in-hospital death ratio in 47 administrative regions. The association between regional factors and reperfusion therapy usage was evaluated with fixed-effects regression models. During the study period, Gini coefficients showed low inequality (0.11-0.15) for use of IV rt-PA monotherapy and IV rt-PA and/or EVT and extreme inequality (0.49) for EVT usage in 2010, which became moderate inequality (0.25) by 2015. The densities of stroke centers and endovascular specialists, as well as market concentration, were associated with increased usage of reperfusion therapy whereas the proportion of rural residents and delayed ambulance transport were negatively associated with usage. Inequality in the standardized death ratio after EVT was extreme (0.86) in 2010 but became moderate (0.29) by 2015; inequality was low to moderate (0.17-0.23) for IV rt-PA monotherapy and IV rt-PA and/or EVT. Conclusions Scrutinizing existing data sources revealed regional disparity in reperfusion therapy for acute ischemic stroke and its associated regional factors in Japan.
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http://dx.doi.org/10.1161/JAHA.121.021853DOI Listing
October 2021

The Transient Receptor Potential Vanilloid 4 Channel and Cardiovascular Disease Risk Factors.

Front Physiol 2021 20;12:728979. Epub 2021 Sep 20.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Vascular endothelial cells regulate arterial tone through the release of nitric oxide and other diffusible factors such as prostacyclin and endothelium derived hyperpolarizing factors. Alongside these diffusible factors, contact-mediated electrical propagation from endothelial cells to smooth muscle cells myoendothelial gap junctions, termed endothelium-dependent hyperpolarization (EDH), plays a critical role in endothelium-dependent vasodilation in certain vascular beds. A rise in intracellular Ca concentration in endothelial cells is a prerequisite for both the production of diffusible factors and the generation of EDH, and Ca influx through the endothelial transient receptor potential vanilloid 4 (TRPV4) ion channel, a nonselective cation channel of the TRP family, plays a critical role in this process in various vascular beds. Emerging evidence suggests that the dysregulation of endothelial TRPV4 channels underpins endothelial dysfunction associated with cardiovascular disease (CVD) risk factors, including hypertension, obesity, diabetes, and aging. Because endothelial dysfunction is a precursor to CVD, a better understanding of the mechanisms underlying impaired TRPV4 channels could lead to novel therapeutic strategies for CVD prevention. In this mini review, we present the current knowledge of the pathophysiological changes in endothelial TRPV4 channels associated with CVD risk factors, and then explore the underlying mechanisms involved.
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http://dx.doi.org/10.3389/fphys.2021.728979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488390PMC
September 2021

Association between Multimorbidity and Kidney Function among Patients with Non-Dialysis-Dependent CKD.

J Atheroscler Thromb 2021 Oct 2. Epub 2021 Oct 2.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University.

Aim: Individuals with chronic kidney disease (CKD) have a high prevalence of comorbidities, including cardiovascular disease (CVD) and its risk factors. However, epidemiological results to assess the association between multimorbidity and kidney function among the CKD population remains limited.

Methods: We performed a cross-sectional analysis of the association between 23 comorbid conditions and reduced kidney function in 4,476 patients with non-dialysis-dependent CKD enrolled in a multicenter cohort in Japan. Reduced kidney function was defined as an estimated glomerular filtration rate of ≤ 60 mL/min/1.73 m.

Results: The mean age of patients was 67 years (male, 56.0%). The prevalence of hypertension, diabetes mellitus, dyslipidemia, prior CVD, cancer, and bone fracture, which are the major comorbidities, was 83.3%, 28.7%, 45.9%, 23.3%, 12.7%, and 6.3%, respectively. Multivariable-adjusted analyses revealed that age, male sex, hypertension, dyslipidemia, prior CVD, body mass index, urinary protein excretion, and underlying kidney disease were independent factors associated with reduced kidney function. Importantly, the odds ratios (ORs) for reduced kidney function increased linearly as the number of major comorbid conditions increased (OR for 1-2 conditions: 2.22, 95% confidence interval [CI]: 1.65-2.97; OR for 3-4 conditions: 3.04, 95% CI: 2.12-4.37; OR for ≥ 5 conditions: 4.37, 95% CI: 1.75-10.9). The upward trend in OR was more pronounced with cardiovascular comorbidities but not significant with non-cardiovascular comorbidities.

Conclusions: In conclusion, we observed an independent association between cardiovascular comorbidity and its risk factors and reduced kidney function. The results of this study highlight the importance of managing multimorbidity among patients with CKD.
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http://dx.doi.org/10.5551/jat.62900DOI Listing
October 2021

Incidence of end-stage renal disease and risk factors for progression of renal dysfunction in Japanese patients with type 2 diabetes: the Fukuoka Diabetes Registry.

Clin Exp Nephrol 2021 Sep 28. Epub 2021 Sep 28.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.

Background: Epidemiological data regarding diabetic kidney disease are accumulated insufficiently in Japan. We prospectively investigated the incidence of end-stage renal disease (ESRD) and risk factors for progression of renal dysfunction in Japanese patients with type 2 diabetes.

Methods: 4904 participants with type 2 diabetes (mean age 65 years, mean estimated glomerular filtration rate (eGFR) 75 mL/min/1.73 m, proportion of eGFR  < 60 mL/min/1.73 m 21%) were investigated for the progression to ESRD requiring dialysis in multicenter outpatients registry for 5 years. Risk factors for progression of renal dysfunction (≥ 30% decline in eGFR from the baseline and annual eGFR decline rates) were evaluated.

Results: The incidence rates of ESRD and all-cause mortality were 4.1/1000 person-years and 12.3/1000 person-years, respectively, and increased according to stages of chronic kidney disease (eGFR  < 30 mL/min/1.73 m, incidence of ESRD 176.6/1000 person-years, all-cause mortality 57.4/1000 person-years). Incidence of  ≥ 30% decline in eGFR from the baseline was 16.4% at 5 years, and the mean annual decline rate was -1.84 mL/min/1.73 m/year. The progression of renal dysfunction was significantly associated with older age, poor glycemic control, blood pressure, albuminuria, eGFR, previous cardiovascular disease, lifestyle factors (body mass index, reduced intake of dietary fiber, increased intake of sodium, no regular exercise), and depressive symptoms.

Conclusions: This prospective study has emphasized the importance of multifactorial interventions on risk factors to suppress the high incidence of ESRD in Japanese patients with type 2 diabetes.
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http://dx.doi.org/10.1007/s10157-021-02136-2DOI Listing
September 2021

Intraplaque high-intensity signal on time-of-flight magnetic resonance angiography and restenosis after carotid artery stenting.

J Neurosurg 2021 Sep 24:1-6. Epub 2021 Sep 24.

1Department of Neuroendovascular Surgery, Clinical Research Institute, National Hospital Organization Kyushu Medical Center.

Objective: To test the hypothesis that intraplaque hemorrhage is a predictor of restenosis after carotid artery stenting (CAS), the association between intraplaque high-intensity signal (HIS) on time-of-flight MR angiography (TOF-MRA), as a marker of intraplaque hemorrhage, and restenosis after CAS was assessed in the present observational study.

Methods: Consecutive patients who underwent initial CAS for atherosclerotic stenosis in the cervical internal carotid artery in the authors' department were enrolled. Of these, patients without preprocedural cervical TOF-MRA were excluded. Outcome measures were ≥ 50% restenosis, defined as a peak systolic velocity of > 1.3 m/sec; or occlusion and ≥ 70% restenosis, defined as a peak systolic velocity of > 2.1 m/sec; or occlusion on carotid duplex ultrasound.

Results: Of 230 consecutive patients who underwent initial CAS, 22 without preprocedural cervical TOF-MRA were excluded. Of the remaining 208 patients (mean age 73 years; 33 women), 46 had intraplaque HIS. Ultrasound follow-up was not performed in 4 patients. The median follow-up duration was 3.2 years (interquartile range 1.7-5.1 years). During the follow-up period, 102 patients had ≥ 50% restenosis and 36 had ≥ 70% restenosis. Intraplaque HIS was significantly associated with increased risk of ≥ 50% restenosis (adjusted hazard ratio 2.18; 95% CI 1.28-3.68) and ≥ 70% restenosis (adjusted hazard ratio 3.12; 95% CI 1.32-7.52).

Conclusions: Intraplaque HIS on TOF-MRA was associated with increased risk of restenosis after CAS. The present results indicate that intraplaque hemorrhage is a predictor of restenosis after CAS.
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http://dx.doi.org/10.3171/2021.4.JNS21546DOI Listing
September 2021

Gastric microbiota in patients with Helicobacter pylori-negative gastric MALT lymphoma.

Medicine (Baltimore) 2021 Sep;100(38):e27287

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Abstract: To investigate the mucosal microbiota in the stomach of patients with Helicobacter pylori-negative mucosa-associated lymphoid tissue (MALT) lymphoma by means of metagenomic analysis.Although some gastric MALT lymphomas are associated with the presence of H. pylori, other gastric MALT lymphomas occur independently of H. pylori infection. The pathogenesis of H. pylori-negative MALT lymphoma remains unclear.Mucosal biopsy specimens were collected from the gastric body from 33 MALT lymphoma patients with gastric lesions, including both H. pylori-infection naïve patients and posteradication patients, as well as 27 control participants without H. pylori infection or cancer. Subsequently, the samples were subjected to 16S rRNA gene sequencing. Quantitative insights into microbial ecology, linear discriminant analysis effect size, and phylogenetic investigation of communities by reconstruction of unobserved states softwares were used to analyze the participants' microbiota.H. pylori-negative MALT lymphoma patients had significantly lower alpha diversity (P = .04), compared with control participants. Significant differences were evident in the microbial composition (P = .04), as determined by comparison of beta diversity between the 2 groups. Taxonomic composition analysis indicated that the genera Burkholderia and Sphingomonas were significantly more abundant in MALT lymphoma patients, while the genera Prevotella and Veillonella were less abundant. Functional microbiota prediction showed that the predicted gene pathways "replication and repair," "translation," and "nucleotide metabolism" were downregulated in MALT lymphoma patients.H. pylori-negative MALT lymphoma patients exhibited altered gastric mucosal microbial compositions, suggesting that altered microbiota might be involved in the pathogenesis of H. pylori-negative MALT lymphoma.
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http://dx.doi.org/10.1097/MD.0000000000027287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462607PMC
September 2021

A case of Graves' disease presenting with internal ophthalmoplegia during methylmercaptoimidazole treatment.

Endocr J 2021 Sep 18. Epub 2021 Sep 18.

Dept. of Medicine and Clinical Science, Graduate School of Medicine, Kyushu University, Fukuoka 812-8582, Japan.

A 28-year-old Japanese woman positive for TSH receptor antibody and anti-nuclear antibody complained of difficulty seeing nearby objects, severe throbbing retro-orbital pain, diplopia, blepharoptosis and upward gaze palsy when she became hypothyroid during treatment with 30 mg methylmercaptoimidazole for Graves' hyperthyroidism. Brain magnetic resonance imaging revealed slightly swollen bilateral inferior rectus muscles, suggesting the external ophthalmoplegia due to the muscle pathology commonly encountered in Graves' disease. The retro-orbital pain was associated with marked accommodation failure and the pupillary abnormalities. The left and/or right eye showed intermittent, asymmetric and fluctuating mydriasis, being unresponsive to ordinary light but slowly responsive to strong sunlight and slowly responsive in a dark room. During the 5-year period, mydriasis was observed 9 times on both sides, 11 times only on the right side and 4 times only on the left side. Internal ophthalmoplegia with tonic pupils and accommodation failure affecting both the pupillary sphincter muscle and ciliary muscle due to damage to the parasympathetic outflow to these muscles was suggested. Autoimmune mechanism and/or the mechanism underlying channelopathy affecting the ciliary ganglion or short ciliary nerves might be responsible for this fluctuating complication. This very rare panophthalmopathy affecting both external and internal muscles occurred when the patient was suffering from iatrogenic hypothyroidism during the 30 mg methylmercaptimidazole treatment for Graves' disease.
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http://dx.doi.org/10.1507/endocrj.EJ21-0340DOI Listing
September 2021

Autophagy gene regulates albumin transcytosis in renal tubule epithelial cells.

Am J Physiol Renal Physiol 2021 Nov 20;321(5):F572-F586. Epub 2021 Sep 20.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Receptor-mediated albumin transport in proximal tubule epithelial cells (PTECs) is important to control proteinuria. Autophagy is an evolutionarily conserved degradation pathway, and its role in intracellular trafficking through interactions with the endocytic pathway has recently been highlighted. Here, we determined whether autophagy regulates albumin transcytosis in PTECs and suppresses albumin-induced cytotoxicity using human proximal tubule (HK-2) cells. The neonatal Fc receptor (FcRn), a receptor for albumin transcytosis, is partially colocalized with autophagosomes. Recycling of FcRn was attenuated, and FcRn accumulated in autophagy-related 7 () knockdown HK-2 cells. Colocalization of FcRn with RAB7-positive late endosomes and RAB11-positive recycling endosomes was reduced in knockdown cells, which decreased recycling of FcRn to the plasma membrane. In or autophagy-related 5 () knockdown cells and or knockout mouse embryonic fibroblasts, albumin transcytosis was significantly reduced and intracellular albumin accumulation was increased. Finally, the release of kidney injury molecule-1, a marker of tubule injury, from or knockdown cells was increased in response to excess albumin. In conclusion, suppression of autophagy in tubules impairs FcRn transport, thereby inhibiting albumin transcytosis. The resulting accumulation of albumin induces cytotoxicity in tubules. Albumin transport in proximal tubule epithelial cells (PTECs) is important to control proteinuria. The neonatal Fc receptor (FcRn), a receptor for albumin transcytosis, is partially colocalized with autophagosomes. Recycling of FcRn to the plasma membrane was decreased in autophagy-related 7 () knockdown cells. In addition, albumin transcytosis was decreased in or autophagy-related 5 () knockdown PTECs. Finally, release of kidney injury molecule-1 from or knockdown cells was increased in response to excess albumin.
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http://dx.doi.org/10.1152/ajprenal.00172.2021DOI Listing
November 2021

A case of peritoneal dialysis-related peritonitis caused by dialysate leakage with successful treatment by intravenous and intraperitoneal antibiotic therapy.

CEN Case Rep 2021 Sep 12. Epub 2021 Sep 12.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.

Dialysate leakage is one of the causes of peritoneal dialysis (PD)-related peritonitis. The rate of catheter removal in PD-related peritonitis caused by dialysate leakage (PDPDL) is high, and the correct treatment is unclear. We experienced a case of PDPDL that was treated with intravenous and intraperitoneal antibiotic therapy. A 44-year-old Japanese man had high glucose discharge from the exit site after 14 days of initiating PD, and he had a fever and cloudy effluent with a high white cell count. We diagnosed him with PDPDL and began to administer vancomycin and ceftazidime intraperitoneally. However, the peritonitis could not be ameliorated. A culture examination showed Staphylococcus aureus from the effluent of peritoneal cavity and exit site cultures. We began intraperitoneal cefazolin administration according to a drug susceptibility test, but the effluent cell count remained high. As we added intravenous cefazolin administration, his symptoms and cloudy effluent improved, and the effluent cell count normalized. He has not developed any recurrence of dialysate leakage or peritonitis. Our findings suggest that PD-related peritonitis accompanied by other infectious sites, such as PDPDL, should be treated with additional intravenous antibiotic therapy to taking effect on the infectious sites except for peritoneum and to keep plasma concentration of antibiotics sufficient especially in cases with preserved residual kidney function.
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http://dx.doi.org/10.1007/s13730-021-00644-4DOI Listing
September 2021

Day-by-Day Blood Pressure Variability in the Subacute Stage of Ischemic Stroke and Long-Term Recurrence.

Stroke 2021 Sep 9:STROKEAHA120033751. Epub 2021 Sep 9.

Center for Cohort Studies, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. (M.K., J.H., T.K.).

Background And Purpose: This study aimed to determine whether variability of day-by-day blood pressure (BP) during the subacute stage of acute ischemic stroke is predictive of long-term stroke recurrence.

Methods: We analyzed 7665 patients (mean±SD age: 72.9±13.1 years; women: 42.4%) hospitalized for first-ever ischemic stroke in 7 stroke centers in Fukuoka, Japan, from June 2007 to November 2018. BP was measured daily during the subacute stage (4-10 days after onset). Its mean and coefficient of variation (CV) values were calculated and divided into 4 groups according to the quartiles of these BP parameters. Patients were prospectively followed up for recurrent stroke or all-cause death. The cumulative event rate was calculated with the Kaplan-Meier method. We estimated the hazard ratios and 95% confidence intervals of the events of interest after adjusting for potential confounders and mean BP values using Cox proportional hazards models. The Fine-Gray model was also used to account for the competing risk of death.

Results: With a mean (±SD) follow-up duration of 3.9±3.2 years, the rates of recurrent stroke and all-cause death were 3.9 and 9.9 per 100 patient-years, respectively. The cumulative event rates of recurrent stroke and all-cause death increased with increasing CVs of systolic BP and diastolic BP. The systolic BP CV was significantly associated with an increased risk of recurrent stroke after adjusting for multiple confounders and mean BP (hazard ratio [95% CI] for fourth quartile versus first quartile, 1.26 [1.05-1.50]); the risk of recurrent stroke also increased with an increasing systolic BP CV for nonfatal strokes (1.26 [1.05-1.51]) and when death was regarded as a competing risk (1.21 [1.02-1.45]). Similar associations were observed for the diastolic BP CV.

Conclusions: Day-by-day variability of BP during the subacute stage of acute ischemic stroke was associated with an increased long-term risk of recurrent stroke.
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http://dx.doi.org/10.1161/STROKEAHA.120.033751DOI Listing
September 2021

Association between the urinary sodium-to-potassium ratio and renal outcomes in patients with chronic kidney disease: a prospective cohort study.

Hypertens Res 2021 Sep 3. Epub 2021 Sep 3.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

A higher urinary sodium-to-potassium (UNa/K) ratio has been reported to be associated with high blood pressure and subsequent cardiovascular events. However, the association between the UNa/K ratio and renal outcomes remains uncertain. We prospectively investigated the association between the UNa/K ratio and renal outcomes in patients with chronic kidney disease (CKD). We enrolled 716 patients with CKD, and 24-h urinary sodium and potassium excretion were measured. Patients were divided into UNa/K ratio tertiles (T1-T3). Endpoints were defined as a composite of doubling of serum creatinine (SCr), end-stage kidney disease (ESKD), or death and a composite of doubling of SCr or ESKD (added as an alternative outcome). We investigated the association between the UNa/K ratio and renal outcomes using a Cox proportional hazards model. During a median follow-up of 2.3 years, doubling of SCr, ESKD, or death and doubling of SCr or ESKD occurred in 332 and 293 patients, respectively. After adjustment for covariates including potentially confounding variables such as plasma renin activity, plasma aldosterone concentration, and B-type natriuretic peptide, the hazard ratios (HRs) (95% confidence intervals [CIs]) for the composite of doubling of SCr, ESKD, or death for T2 and T3 were 1.44 (1.06-1.96) and 1.59 (1.14-2.21), respectively, compared with T1. Additionally, compared with T1, the highest tertile (T3) of the UNa/K ratio was associated with a composite of doubling of SCr or ESKD (HR 1.55, 95% CI 1.09-2.20). A higher UNa/K ratio was independently associated with poor renal outcomes in patients with CKD.
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http://dx.doi.org/10.1038/s41440-021-00741-yDOI Listing
September 2021

Association of the nutritional risk index for Japanese hemodialysis patients with long-term mortality: The Q-Cohort Study.

Clin Exp Nephrol 2021 Aug 17. Epub 2021 Aug 17.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 8128582, Japan.

Background: Protein-energy wasting (PEW) is a risk factor for mortality in patients undergoing hemodialysis. Recently, a nutritional risk index for Japanese hemodialysis patients (NRI-JH) has been proposed as a surrogate index of PEW. However, no study has determined the association of the NRI-JH with long-term mortality in patients undergoing hemodialysis. Furthermore, the validity of the NRI-JH has not been confirmed.

Methods: In total, 3046 patients undergoing hemodialysis and registered in the Q-Cohort Study were followed up for 10 years. The NRI-JH was calculated on the basis of body mass index and serum levels of albumin, total cholesterol, and creatinine. The patients were divided into four groups according to the NRI-JH scores: 0-3 (G1, n = 1343), 4-7 (G2, n = 1136), 8-10 (G3, n = 321), and 11-13 (G4, n = 246). We examined the association between the NRI-JH and the 4-year and 10-year risks of all-cause, cardiovascular, and infection-related deaths using the Cox proportional hazards model.

Results: During the follow-up period, 647 patients died during the first 4 years, and 1503 patients died within 10 years. The 4-year prognosis was analyzed and compared with the lowest NRI-JH score group. Multivariable-adjusted hazard ratios (95% confidence intervals) for all-cause death were 1.93 (1.57-2.38), 2.68 (2.05-3.50), and 3.16 (2.40-4.16) in the G2, G3, and G4 groups, respectively. Similarly, a higher NRI-JH score was associated with an increased risk of cardiovascular and infection-related deaths.

Conclusion: A higher NRI-JH score was associated with an increased risk of long-term mortality in patients undergoing maintenance hemodialysis.

Trial Registration: The study protocol was registered in the University Hospital Medical Information Network (UMIN) clinical trial registry (UMIN ID: 000000556).
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http://dx.doi.org/10.1007/s10157-021-02124-6DOI Listing
August 2021

Impact of Physician Volume and Specialty on In-Hospital Mortality of Ischemic and Hemorrhagic Stroke.

Circ J 2021 Sep 13;85(10):1876-1884. Epub 2021 Aug 13.

National Cerebral and Cardiovascular Center.

Background: The degree of association between mortality and case volume/physician volume is well known for many surgical procedures and medical conditions. However, the link between physician volume and death rate in patients hospitalized for stroke remains unclear. This study analyzed the correlation between in-hospital stroke mortality and physician volume per hospital, considering board certification status.Methods and Results:For this retrospective registry-based cohort study, data were obtained from the Japanese nationwide registry on patients hospitalized for ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH) between 2010 and 2016. The number of stroke care physicians and relevant board-certified physicians was also obtained. Odd ratios (ORs) of 30-day in-hospital mortality were estimated after adjusting for institutional and patient differences using generalized mixed logistic regression. From 295,150 (ischemic stroke), 98,657 (ICH), and 36,174 (SAH) patients, 30-day in-hospital mortality rates were 4.4%, 16.0%, and 26.6%, respectively. There was a correlation between case volume and physician volume. A higher number of stroke care physicians was associated with a reduction in 30-day mortality after adjusting for stroke case volume and comorbidities for all stroke types (all P for trend<0.05).

Conclusions: An increased number of stroke care physicians was associated with reduced in-hospital mortality for all types of stroke. The volume threshold of board-certified physicians depends on the specialty and stroke type.
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http://dx.doi.org/10.1253/circj.CJ-20-1214DOI Listing
September 2021

Angiotensin II promotes primary tumor growth and metastasis formation of murine TNBC 4T1 cells through the fibroblasts around cancer cells.

Eur J Pharmacol 2021 Oct 8;909:174415. Epub 2021 Aug 8.

Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address:

Angiotensin II (Ang II) reportedly facilitates primary tumor growth and distal hematogenous metastasis formation in various murine intravenous metastasis models. However, it is unclear whether Ang II accelerates the initial processes of metastasis formation that begins in primary tumors surrounded by tumor microenvironment. We examined the effects of Ang II on primary tumors and lung metastasis lesions using a murine spontaneous metastasis model, in which triple negative breast cancer 4T1 cells constitutively expressing luciferase (4T1-Luc cells) were injected into the mammary fat pad of BALB/c mice. Subcutaneous injection of Ang II significantly accelerated primary tumor growth and lung metastasis formation. Ang II increased the protein expression levels of c-Myc, cyclin D1, fibronectin, vimentin, αSMA and Snail, and the treatment with the Ang II type 1 receptor blocker valsartan significantly suppressed the Ang II-induced increases of fibronectin and vimentin. Valsartan also significantly reduced lung metastatic lesions. However, Ang II did not have significant effects on 4T1-Luc cells including the proliferation, migration, invasion, or the expressions of proteins related to cell proliferation and epithelial-to-mesenchymal transition. In contrast, when 4T1-Luc cells were co-cultured with dermal fibroblasts, Ang II significantly accelerated cell migration and increased the expressions of fibronectin, vimentin, αSMA and Snail in 4T1-Luc cells. And moreover, Ang II significantly increased the mRNA expression of IL-6 in fibroblasts co-cultured with 4T1-Luc cells. These results suggested that Ang II accelerates surrounding fibroblasts by soluble factors such as IL-6 to promote epithelial-to-mesenchymal transition, which result in the initiation of cancer metastasis.
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http://dx.doi.org/10.1016/j.ejphar.2021.174415DOI Listing
October 2021

Clinical epidemiological analysis of cohort studies investigating the pathogenesis of kidney disease.

Clin Exp Nephrol 2021 Aug 10. Epub 2021 Aug 10.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

In recent years, large cohort studies of patients with chronic kidney disease (CKD) have been established all over the world. These studies have attempted to analyze the pathogenesis of CKD using a large body of published evidence. The design of cohort studies is characterized by the measurement of the exposure prior to the occurrence of the outcome, which has the advantage of clarifying the temporal relationship between predictors and outcomes and estimating the strength of the causal relationship between predictors and multiple outcomes. Recent advances in biostatistical analysis methods, such as propensity scores and risk prediction models, are facilitating causal inference using higher quality evidence with greater precision in observational studies. In this review, we will discuss clinical epidemiological research of kidney disease based on the analysis of observational cohort data sets, with a focus on our previous studies.
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http://dx.doi.org/10.1007/s10157-021-02121-9DOI Listing
August 2021

Ustekinumab Improves Active Crohn's Disease by Suppressing the T Helper 17 Pathway.

Digestion 2021 Jul 22:1-10. Epub 2021 Jul 22.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Ustekinumab (UST), an antibody targeting the p40 subunit of interleukin (IL)-12 and IL-23, is effective in treating Crohn's disease (CD). To clarify the mechanism of UST, we investigated T-cell differentiation in CD patients treated with UST.

Methods: Twenty-seven patients with active CD were enrolled in this study. Seventeen patients were treated with UST, and 10 patients were treated with anti-tumor necrosis factor (TNF)-alpha therapy. The changes in the proportions of T-cell subsets after these therapies were analyzed by flow cytometry. Comprehensive gene expression changes in the colonic mucosa were also evaluated.

Results: The frequency of T helper (Th) 17 cells was significantly decreased in the peripheral blood of patients with active CD after UST therapy. Anti-TNF therapy had a minimal effect on Th17 cells but increased the proportion of regulatory T cells. Enrichment analysis showed the expression of genes involved in the Th17 differentiation pathway was downregulated in the colonic mucosa after UST but not anti-TNF therapy. There were no common differentially expressed genes between CD patients treated with UST and anti-TNF therapy, suggesting a clear difference in their mechanism of action.

Conclusion: In patients with active CD, UST therapy suppressed Th17 cell differentiation both in the peripheral blood and colonic tissues.
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http://dx.doi.org/10.1159/000518103DOI Listing
July 2021

Association of blood pressure after peritoneal dialysis initiation with the decline rate of residual kidney function in newly-initiated peritoneal dialysis patients.

PLoS One 2021 8;16(7):e0254169. Epub 2021 Jul 8.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Lower blood pressure (BP) levels are linked to a slower decline of kidney function in patients with chronic kidney disease (CKD) without kidney replacement therapy. However, there are limited data on this relation in peritoneal dialysis (PD) patients. Here we evaluated the association of BP levels with the decline of residual kidney function (RKF) in a retrospective cohort study.

Methods: We enrolled 228 patients whose PD was initiated between 1998 and 2014. RKF was measured as the average of creatinine and urea clearance in 24-hr urine collections. We calculated the annual decline rate of RKF by determining the regression line for individual patients. RKF is thought to decline exponentially, and thus we also calculated the annual decline rate of logarithmic scale of RKF (log RKF). We categorized the patients' BP levels at 3 months after PD initiation (BP3M) into four groups (Optimal, Normal & High normal, Grade 1 hypertension, Grade 2 & 3 hypertension) according to the 2018 European Society of Cardiology and European Society of Hypertension Guidelines for the management of arterial hypertension.

Results: The unadjusted, age- and sex-adjusted, and multivariable-adjusted decline rate of RKF and log RKF decreased significantly with higher BP3M levels (P for trend <0.01). Compared to those of the Optimal group, the multivariable-adjusted odds ratios (95% confidence interval) for the faster side of the median decline rate of RKF and log RKF were 4.04 (1.24-13.2) and 5.50 (1.58-19.2) in the Grade 2 and 3 hypertension group, respectively (p<0.05).

Conclusions: Higher BP levels after PD initiation are associated with a faster decline in RKF among PD patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254169PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266121PMC
July 2021

Roles of Sodium-Glucose Cotransporter 2 of Mesangial Cells in Diabetic Kidney Disease.

J Endocr Soc 2021 Aug 7;5(8):bvab083. Epub 2021 May 7.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 8128582, Japan.

We have been studying the presence of sodium-glucose cotransporter 2 (SGLT2) in mesangial cells and pericytes since 1992. Recent large placebo-controlled studies of SGLT2 inhibitors in patients with type 2 diabetes mellitus have reported desirable effects of the inhibitors on the diabetic kidney and the diabetic heart. Most studies have indicated that these effects of SGLT2 inhibitors could be mediated by the tubuloglomerular feedback system. However, a recent study about urine sodium excretion in the presence of an SGLT2 inhibitor did not show any increases in urine sodium excretion. A very small dose of an SGLT2 inhibitor did not inhibit SGLT2 at the S1 segment of proximal tubules. Moreover, SGLT2 inhibition protects against progression in chronic kidney disease with and without type 2 diabetes. In these circumstances, the tubuloglomerular feedback hypothesis involves several theoretical concerns that must be clarified. The presence of SGLT2 in mesangial cells seems to be very important for diabetic nephropathy. We now propose a novel mechanism by which the desirable effects of SGLT2 inhibitors on diabetic nephropathy are derived from the direct effect on SGLT2 expressed in mesangial cells.
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http://dx.doi.org/10.1210/jendso/bvab083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237847PMC
August 2021

Constipation and diabetic kidney disease: The Fukuoka Diabetes Registry.

Clin Exp Nephrol 2021 Nov 26;25(11):1247-1254. Epub 2021 Jun 26.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.

Background: Constipation was shown to be associated with higher risk of end-stage kidney disease or incident chronic kidney disease, although evidence in diabetic patients is lacking. The objective of the present study was to examine the association between constipation and diabetic kidney disease (DKD).

Methods: In total, 4826 Japanese outpatients with type 2 diabetes were classified according to presence or absence of constipation (defecation frequency < 3 times/week and/or taking laxative medication). DKD was defined as presence of decreased estimated glomerular filtration rate (eGFR < 60 ml/min/1.73 m), and/or albuminuria (urinary albumin-to-creatinine ratio ≥ 30 mg/g). Odds ratios for the presence of DKD were computed by a logistic regression model.

Results: Compared with participants without constipation, the age- and sex-adjusted odds ratio for presence of DKD was 1.58 (95% confidence interval 1.38-1.82) for those with constipation. This association persisted following adjustment for potential confounding factors. Decreased defecation frequency and laxative use were also significantly associated with higher prevalence of DKD. Overall, these findings were identical even when decreased eGFR and albuminuria were separately analyzed.

Conclusions: Constipation was associated with higher likelihood of DKD in patients with diabetes, suggesting the importance of clinical assessment of constipation to identify patients at high risk of progression of kidney disease.
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http://dx.doi.org/10.1007/s10157-021-02105-9DOI Listing
November 2021

Risk of Rebleeding in Patients with Small Bowel Vascular Lesions.

Intern Med 2021 Jun 12. Epub 2021 Jun 12.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Japan.

Background With recent advances in endoscopic modalities, small bowel vascular lesions (SBVLs) are often now detected in patients with gastrointestinal bleeding. Given the high invasiveness of endoscopic treatment, it is important to select patients at high risk for bleeding. Aim To assess the risk of rebleeding in patients with SBVLs as a systemic disease rather than a gastrointestinal disease in relation to their general health. Methods We retrospectively analyzed the clinical data of 55 patients with SBVLs among patients with obscure gastrointestinal bleeding. The possible association between the clinical findings and the updated Charlson comorbidity index with rebleeding was evaluated. Results Gastrointestinal rebleeding occurred in 20 patients (36.4%) during the follow-up period. The presence of multiple comorbidities as indicated by an updated Charlson comorbidity index of ≥4 was a risk factor for rebleeding (hazard ratio, 3.64; P = 0.004). Other risk factors were arteriosclerosis of the superior mesenteric artery and multiple SBVLs. Endoscopic hemostasis and the discontinuation of antithrombotic medications were not significantly associated with rebleeding. Patients with a high updated Charlson comorbidity index had a high risk of death of causes other than gastrointestinal rebleeding. Conclusions Gastrointestinal rebleeding is not a rare condition among patients with SBVLs. Patients with poor general health may therefore have a higher risk of rebleeding.
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http://dx.doi.org/10.2169/internalmedicine.6341-20DOI Listing
June 2021

Real-world safety and effectiveness of rivaroxaban using Japan-specific dosage during long-term follow-up in patients with atrial fibrillation: XAPASS.

PLoS One 2021 11;16(6):e0251325. Epub 2021 Jun 11.

Medical Affairs and Pharmacovigilance, Bayer Yakuhin, Ltd., Osaka, Japan.

Background: The Xarelto Post-Authorization Safety and Effectiveness Study in Japanese Patients with Atrial Fibrillation (XAPASS) was designed to investigate safety and effectiveness during long-term follow-up of rivaroxaban treatment, using reduced doses compared with other global regions, in Japanese patients with non-valvular atrial fibrillation in real-world clinical practice.

Methods: In this prospective, open-label, single-arm, observational study, 11,308 patients with non-valvular atrial fibrillation newly prescribed rivaroxaban (15/10 mg once daily) at 1416 sites across Japan were enrolled and followed for a mean of 2.5 years.

Results: In total, 10,664 and 10,628 patients were included in the safety and effectiveness analyses, respectively. In the safety population, mean (standard deviation) age was 73.1 (9.8) years and Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, previous Stroke/TIA (2 points) (CHADS2) score was 2.2 (1.3). Incidences (95% confidence intervals) of any and major bleeding were 3.77 (3.53-4.01) and 1.16 (1.03-1.29) events per 100 patient-years, respectively. Age ≥75 years, creatinine clearance <50 mL/min, diabetes mellitus, and vascular disease were independently associated with incidence of major bleeding. The primary composite effectiveness outcome of stroke, non-central nervous system systemic embolism, and myocardial infarction occurred at an incidence (95% confidence interval) of 1.32 (1.18-1.46) events per 100 patient-years. Age ≥75 years, hypertension, prior ischemic stroke/transient ischemic attack, and concomitant use of antiplatelets were independently associated with incidence of the composite outcome of stroke, non-central nervous system systemic embolism, and myocardial infarction.

Conclusion: In the XAPASS, a large-scale study involving a broad range of patients with non-valvular atrial fibrillation newly prescribed rivaroxaban using Japan-specific dosage in real-world clinical practice, no unexpected safety or effectiveness concerns were detected during up to 5 years of follow-up.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251325PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195353PMC
June 2021

Efficacy of thromboelastography in the management of anticoagulation for veno-venous extracorporeal membrane oxygenation in a coronavirus disease 2019 patient: A case report.

Medicine (Baltimore) 2021 Jun;100(23):e26313

Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.

Rationale: In coronavirus disease 2019 (COVID-19) patients with acute respiratory distress syndrome refractory to optimal conventional management, we should consider the indication for veno-venous extracorporeal membrane oxygenation (V-V ECMO). Growing evidence indicates that COVID-19 frequently causes coagulopathy, presenting as hypercoagulation and incidental thrombosis. For these reasons, a multifactorial approach with several anticoagulant markers should be considered in the management of anticoagulation using heparin in COVID-19 patients on V-V ECMO.

Patient Concerns: A 48-year-old man was infected with COVID-19 with a worsening condition manifesting as acute respiratory distress syndrome.

Diagnoses: He was refractory to conventional therapy, thus we decided to introduce V-V ECMO. We used heparin as an anticoagulant therapy for V-V ECMO and adjusted the doses of heparin by careful monitoring of the activated clotting time (ACT) and activated partial thromboplastin time (APTT) to avoid both hemorrhagic and thrombotic complications. We controlled the doses of heparin in the therapeutic ranges of ACT and APTT, but clinical hemorrhaging and profound elevation of coagulant marker became apparent.

Interventions: Using thromboelastography (TEG; Haemonetics) in addition to ACT and APTT, we were able to clearly detect not only sufficient coagulability of COVID19 on V-V ECMO (citrated rapid thromboelastography-R 0.5 min, angle 75.5°, MA 64.0 mm, citrated functional fibrinogen-MA 20.7 mm) but also an excessive effect of heparin (citrated kaolin -R 42.7 min, citrated kaolin with heparinase 11.7 min).

Outcomes: Given the TEG findings indicating an excessive heparin effect, the early withdrawal of ECMO was considered. After an evaluation of the patient's respiratory capacity, withdrawal from V-V ECMO was achieved and then anticoagulation was stopped. The hemorrhagic complications and elevated thrombotic marker levels dramatically decreased.

Lessons: TEG monitoring might be a useful option for managing anticoagulation in COVID-19 patients on V-V ECMO frequently showing a hypercoagulative state and requiring massive doses of heparin, to reduce both hemorrhagic and thrombotic complications.
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http://dx.doi.org/10.1097/MD.0000000000026313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202565PMC
June 2021

Serum Alkaline Phosphatase Levels and Increased Risk of Brain Hemorrhage in Hemodialysis Patients: The Q-Cohort Study.

J Atheroscler Thromb 2021 Jun 10. Epub 2021 Jun 10.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University.

Aim: Elevated serum alkaline phosphatase (ALP) levels have been associated with increased risks of all-cause and cardiovascular mortality in patients receiving hemodialysis. However, little is known about the impact of serum ALP levels on the development of stroke, such as brain hemorrhage and infarction.

Methods: A total of 3,497 patients receiving maintenance hemodialysis registered in the multicenter observational Q-Cohort Study were analyzed. The primary outcomes were the incidences of brain hemorrhage and infarction. The covariate of interest was serum ALP levels. Patients were divided into tertiles based on their serum ALP levels (U/L) at baseline (T1, <69.3; T2, 69.3-98.4; T3, >98.4). The risks of brain hemorrhage, brain infarction, and composite stroke were estimated using Cox proportional hazards models and competing risk models with all-cause death as a competing risk.

Results: A total of 89 patients developed brain hemorrhage and 195 patients developed brain infarction during the 4-year follow-up period. The risk of brain hemorrhage in the highest tertile (T3) was significantly higher than that in the lowest tertile (T1) (multivariable-adjusted hazard ratio [95% confidence interval], 1.93 [1.12-3.35], subdistribution hazard ratio, 1.91 [1.10-3.30]). However, there was no significant association between serum ALP levels and the risk of brain infarction or composite stroke.

Conclusions: Higher serum ALP levels are associated with an increased risk of brain hemorrhage, but not brain infarction, in patients receiving maintenance hemodialysis. High serum ALP level is thus an important risk factor for brain hemorrhage in hemodialysis patients.
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http://dx.doi.org/10.5551/jat.62885DOI Listing
June 2021

Causes of death in patients undergoing maintenance hemodialysis in Japan: 10-year outcomes of the Q-Cohort Study.

Clin Exp Nephrol 2021 Oct 7;25(10):1121-1130. Epub 2021 Jun 7.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 8128582, Japan.

Background: Although the mortality rate in patients on hemodialysis remains extremely high, detailed information on causes of death over long-term periods is limited. The aim of this study was to clarify the underlying causes of death in patients undergoing maintenance hemodialysis in Japan.

Methods: This was a 10-year, multicenter, observational study of 3528 outpatients undergoing maintenance hemodialysis in Japan. Clinical outcomes were analyzed and causes of death were classified into six broad categories including cardiovascular diseases, infectious diseases, malignant neoplasms, cachexia, trauma/accidents, and other diseases, and more detailed subcategories.

Results: During the 10-year follow-up period, 1748 (49.5%) patients died. The most frequent causes of death were cardiovascular diseases (36.1%), followed by infectious diseases (25.8%) and malignant neoplasms (13.5%). In a detailed classification, sudden death, pulmonary infection, and lung cancer were the most common causes of death in cardiovascular diseases, infectious diseases, and malignant neoplasms, respectively.

Conclusion: Our study determined details on causes of death in Japanese hemodialysis patients during the 10-year follow-up period. Cardiovascular disease, especially sudden death is noticeable cause of death among patients on hemodialysis.
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http://dx.doi.org/10.1007/s10157-021-02089-6DOI Listing
October 2021

Development of a risk prediction model for incident hypertension in Japanese individuals: the Hisayama Study.

Hypertens Res 2021 Sep 31;44(9):1221-1229. Epub 2021 May 31.

Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

The identification of individuals at high risk of developing hypertension can be of great value to improve the efficiency of primary prevention strategies for hypertension. The objective of this study was to develop a risk prediction model for incident hypertension based on prospective longitudinal data from a general Japanese population. A total of 982 subjects aged 40-59 years without hypertension at baseline were followed up for 10 years (2002-12) for the incidence of hypertension. Hypertension was defined as systolic blood pressure (SBP) ≥ 140 mmHg, diastolic blood pressure (DBP) ≥ 90 mmHg, or the use of antihypertensive agents. The risk prediction model was developed using a Cox proportional hazards model. A simple risk scoring system was also established based on the developed model. During the follow-up period (median 10 years, interquartile range 5-10 years), 302 subjects (120 men and 182 women) developed new-onset hypertension. The risk prediction model for hypertension consisted of age, sex, SBP, DBP, use of glucose-lowering agents, body mass index (BMI), parental history of hypertension, moderate-to-high alcohol intake, and the interaction between age and BMI. The developed model demonstrated good discrimination (Harrell's C statistic=0.812 [95% confidence interval, 0.791-0.834]; optimism-corrected C statistic based on 200 bootstrap samples=0.804) and calibration (Greenwood-Nam-D'Agostino χ statistic=12.2). This risk prediction model is a useful guide for estimating an individual's absolute risk for hypertension and could facilitate the management of Japanese individuals at high risk of developing hypertension in the future.
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http://dx.doi.org/10.1038/s41440-021-00673-7DOI Listing
September 2021

β-Cell Function and Clinical Outcome in Nondiabetic Patients With Acute Ischemic Stroke.

Stroke 2021 Aug 14;52(8):2621-2628. Epub 2021 May 14.

Department of Medicine and Clinical Science (T. Kiyohara, R.M., J.H., K.N., Y.W., T. Kitazono, T.A.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

[Figure: see text].
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http://dx.doi.org/10.1161/STROKEAHA.120.031392DOI Listing
August 2021

N-Terminal Pro-B-Type Natriuretic Peptide and Incident CKD.

Kidney Int Rep 2021 Apr 16;6(4):976-985. Epub 2021 Jan 16.

Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Introduction: Serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels have been associated with the progression of kidney impairment among patients with chronic kidney disease (CKD), but only a few studies have investigated the association between serum NT-proBNP levels and incident CKD in general populations.

Methods: A total of 2486 Japanese community-dwelling residents ≥40 years of age without CKD at baseline were followed up by repeated annual health examinations for 10 years. Participants were divided into 4 groups according to serum NT-proBNP levels. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m or the presence of proteinuria. Cox proportional hazards models were used to estimate hazard ratios (HRs) for risk of CKD. Linear mixed models were used to compare changes in eGFR.

Results: During the follow-up period, 800 participants developed CKD. The multivariable-adjusted HRs (95% confidence intervals [CIs]) for developing CKD were 1.00 (reference), 1.32 (1.11-1.57), 1.40 (1.10-1.78), and 1.94 (1.38-2.73) for serum NT-proBNP levels of <55, 55-124, 125-299, and ≥300 pg/ml, respectively ( for trend <0.001). The decline of eGFR during the follow-up was significantly more rapid among participants with higher serum NT-proBNP levels ( for trend <0.001). Adding serum NT-proBNP to the model composed of known risk factors for CKD improved the predictive ability for developing CKD.

Conclusions: Higher serum NT-proBNP levels were associated with greater risks of developing CKD and greater decline in eGFR. Serum NT-proBNP could be a useful biomarker for assessing the future risk of CKD in a general Japanese population.
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http://dx.doi.org/10.1016/j.ekir.2021.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071624PMC
April 2021

Comparison of the contributions of impaired beta cell function and insulin resistance to the development of type 2 diabetes in a Japanese community: the Hisayama Study.

Diabetologia 2021 Aug 28;64(8):1775-1784. Epub 2021 Apr 28.

Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Aims/hypothesis: Our aim was to compare the contributions of impaired beta cell function (IBF) and insulin resistance with the development of type 2 diabetes in a Japanese community.

Methods: A total of 2094 residents aged 40-79 years without diabetes underwent a health examination including a 75 g OGTT in 2007. Participants were divided into four groups according to the presence or absence of IBF (insulinogenic index/HOMA-IR ≤28.5) and insulin resistance (HOMA-IR ≥1.61) and were followed up for 7 years (2007-2014). Cox's proportional hazards model was used to estimate HRs and 95% CIs for type 2 diabetes. The population attributable fractions (PAFs) due to IBF, insulin resistance, and their combination were calculated.

Results: At baseline, the prevalence of isolated IBF, isolated insulin resistance, and both IBF and insulin resistance were 5.4%, 24.1% and 9.5%, respectively. During the follow-up period, 272 participants developed type 2 diabetes. The multivariable-adjusted HRs (95% CI) and PAFs (95% CI) for type 2 diabetes were 6.3 (4.3, 9.2) and 13.3% (8.7, 17.7) in the participants with isolated IBF, 1.9 (1.3, 2.7) and 10.5% (4.0, 16.6) in those with isolated insulin resistance, and 8.0 (5.7, 11.4) and 29.3% (23.0, 35.1) in those with both IBF and insulin resistance, respectively, compared with the participants without either.

Conclusions/interpretation: The present study suggests that the combination of IBF and insulin resistance makes the main contribution to the development of type 2 diabetes in Japanese communities.
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http://dx.doi.org/10.1007/s00125-021-05459-7DOI Listing
August 2021

Associations Between Surrogates of Skeletal Muscle Mass and History of Bone Fracture in Patients with Chronic Kidney Disease: The Fukuoka Kidney disease Registry (FKR) Study.

Calcif Tissue Int 2021 Oct 27;109(4):393-404. Epub 2021 Apr 27.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Patients with chronic kidney disease (CKD) are at increased risks of both sarcopenia and fragility fractures. However, information on the association between skeletal muscle mass (SMM) and the risk of bone fractures in patients with CKD is lacking. We performed a cross-sectional analysis of 4146 patients with CKD using the baseline dataset of the Fukuoka Kidney disease Registry Study, as a multicenter, prospective cohort study of pre-dialysis CKD patients. The main measure was estimated SMM (eSMM) calculated using an equation validated by bioelectrical impedance analysis with two independent datasets of 100 and 81 CKD patients. The main outcome was historical bone fractures. The associations between sex-specific quartiles (Q1-Q4) of eSMM and fracture history were assessed by logistic regression analyses. The prevalence of a history of fractures increased and eSMM decreased with progressive CKD stages. Among the 4146 patients, 249 had prior bone fractures, including 111 patients in Q1 (lowest quartile), 65 in Q2, 46 in Q3, and 27 in Q4 (highest quartile). A multivariable-adjusted model revealed that patients in Q1 had a significantly higher odds ratio (95% confidence interval) for bone fracture history than those in Q4 (reference): Q1, 2.77 (1.32-5.80); Q2, 1.95 (1.05-3.65); and Q3, 1.57 (0.90-2.75) (P-value for trend < 0.001). Similar associations were obtained when other skeletal muscle surrogates were applied: serum creatinine to serum cystatin C and daily urinary creatinine excretion. These results suggest that a lower eSMM is associated with an increased prevalence of historical bone fractures in pre-dialysis CKD patients.
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http://dx.doi.org/10.1007/s00223-021-00851-2DOI Listing
October 2021

Prevalence of bone fracture and its association with severe hypoglycemia in Japanese patients with type 1 diabetes.

BMJ Open Diabetes Res Care 2021 04;9(1)

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Introduction: Type 1 diabetes (T1D) is associated with higher fracture risk. However, few studies have investigated the relationship between severe hypoglycemia and fracture risk in patients with T1D, and the results are controversial. Besides, none has investigated the risk factors for fracture in Asian patients with T1D. The aim of the present study was to investigate the prevalence of bone fracture and its relationship between severe hypoglycemia and other risk factors in Japanese patients with T1D.

Research Design And Methods: The single-center cross-sectional study enrolled 388 Japanese patients with T1D (mean age, 45.2 years; women, 60.4%; mean duration of diabetes, 16.6 years) between October 2019 and April 2020. The occurrence and circumstances of any fracture after the diagnosis of T1D were identified using a self-administered questionnaire. The main outcomes were any anatomic site of fracture and fall-related fracture. Severe hypoglycemia was defined as an episode of hypoglycemia that required the assistance of others to achieve recovery.

Results: A total of 92 fractures occurred in 64 patients, and 59 fractures (64%) were fall-related. Only one participant experienced fracture within the 10 years following their diagnosis of diabetes. In logistic regression analysis, the multivariate-adjusted ORs (95% CIs) of a history of severe hypoglycemia were 2.11 (1.11 to 4.09) for any fracture and 1.91 (0.93 to 4.02) for fall-related fracture. Fourteen of 18 participants with multiple episodes of any type of fracture had a history of severe hypoglycemia (p<0.001 vs no fracture).

Conclusions: We have shown that a history of severe hypoglycemia is significantly associated with a higher risk of bone fracture in Japanese patients with T1D.
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http://dx.doi.org/10.1136/bmjdrc-2020-002099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070870PMC
April 2021
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