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MicroRNAs (miRNAs) are sequence-specific inhibitors of post-transcriptional gene expression. However, the physiological functions of these non-coding RNAs in renal interstitial mesenchymal cells remain unclear. To conclusively evaluate the role of miRNAs, we generated conditional knockout (cKO) mice with platelet-derived growth factor receptor-β (PDGFR-β)-specific inactivation of the key miRNA pathway gene Dicer. The cKO mice were subjected to unilateral ureteral ligation, and renal interstitial fibrosis was quantitatively evaluated using real-time polymerase chain reaction and immunofluorescence staining. Compared with control mice, cKO mice had exacerbated interstitial fibrosis exhibited by immunofluorescence staining and mRNA expression of PDGFR-β. A microarray analysis showed decreased expressions of miR-9-5p, miR-344g-3p, and miR-7074-3p in cKO mice compared with those in control mice, suggesting an association with the increased expression of PDGFR-β. An analysis of the signaling pathways showed that the major transcriptional changes in cKO mice were related to smooth muscle cell differentiation, regulation of DNA metabolic processes and the actin cytoskeleton, positive regulation of fibroblast proliferation and Ras protein signal transduction, and focal adhesion-PI3K/Akt/mTOR signaling pathways. Depletion of Dicer in mesenchymal cells may downregulate the signaling pathway related to miR-9-5p, miR-344g-3p, and miR-7074-3p, which can lead to the progression of chronic kidney disease. These findings highlight the possibility for future diagnostic or therapeutic developments for renal fibrosis using miR-9-5p, miR-344g-3p, and miR-7074-3p.

DOI： 10.1038/s41598-024-61560-y

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Background: It is well known that kidney injury is vital organ damage in Fabry disease (FD). Renin–angiotensin system (RAS) inhibitors are known to reduce proteinuria in patients with chronic kidney disease (CKD) by dilating the glomerular export arteries and reducing intraglomerular pressure. This improvement in intraglomerular pressure, although lowering the glomerular filtration rate, is thought to prevent renal damage and be renoprotective in the long term. RAS inhibitors may be effective in FD patients with proteinuria to prevent the progression of kidney disease, however, the degree to which they are used in clinical practice is unknown. Methods: The J-CKD-DB-Ex is a comprehensive multicenter database that automatically extracts medical data on CKD patients. J-CKD-DB-Ex contains data on 187,398 patients in five medical centers. FD patients were identified by ICD-10. Clinical data and prescriptions of FD patients between January 1 of 2014, and December 31 of 2020 were used for the analysis. Results: We identified 39 patients with FD from the J-CKD-DB-Ex including those with suspected FD. We confirmed 22 patients as FD. Half of the patients received RAS inhibitors. RAS inhibitors tended to be used in CKD patients with more severe renal impairment. Conclusions: This case series revealed the actual clinical practice of FD patients with CKD. In particular, we found cases in which patients had proteinuria, but were not treated with RAS inhibitors. The database was shown to be useful in assessing the clinical patterns of patients with rare diseases.

DOI： 10.1007/s10157-023-02439-6

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Membranous nephropathy (MN) is a common cause of nephrotic syndrome in middle-aged and older adults. MN etiology is mainly primary or idiopathic; however, it may also be secondary to infections, drugs, neoplasms, and autoimmune diseases. We present the case of a 52-year-old Japanese man with coexisting nephrotic MN and immune thrombocytopenic purpura (ITP). Renal biopsy revealed glomerular basement membrane thickening with immunoglobulin (Ig) G and complement component 3 deposition. Glomerular IgG subclass analysis revealed predominant IgG4 deposition with weak IgG1 and IgG2 deposition. IgG3 and phospholipase A2 receptor deposits were negative. Upper endoscopy revealed no ulcers, but histological examination demonstrated Helicobacter pylori infection in the gastric mucosa with elevated IgG antibodies. After gastric Helicobacter pylori eradication, the nephrotic-range proteinuria and thrombocytopenia of the patient were markedly improved without initiation of immunosuppressive treatment. Therefore, clinicians should consider the possibility of Helicobacter pylori infection in patients with coexisting MN and ITP. Further studies are required to demonstrate the associated pathophysiological aspects.

DOI： 10.1007/s13730-023-00805-7

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Adequate blood pressure (BP) management poses a significant challenge in improving the prognosis of patients undergoing dialysis. We aimed to investigate the relationship between pre-dialysis systolic blood pressure (SBP) and underlying disease in Japanese patients undergoing dialysis, based on prefectural location, and assess the association between pre-dialysis SBP and cardiovascular disease (CVD) mortality rate. We extracted the basic information of 336,182 patients who were undergoing dialysis in 2021 from the Web-based Analysis of Dialysis Data Archives database. Data on average pre-dialysis SBP were analyzed according to sex, prefectural location, and diabetic status, and the CVD mortality rate for each prefecture was calculated. The mean pre-dialysis SBP of the patients (males, 66.3%; mean age, 69.7 ± 12.5 years) was 151.9 ± 24.7 mmHg. Overall, 133,037 patients had underlying diabetic kidney disease (DKD). The patients with DKD were younger, had a shorter dialysis duration, and a higher pre-dialysis SBP than those with non-DKD comorbidities. The prefecture-based mean pre-dialysis SBP values were all higher than 140 mmHg. At the prefectural level, CVD mortality rate was positively correlated with pre-dialysis SBP (r = 0.3127, p = 0.0324) and diastolic blood pressure (r = 0.3378, p = 0.0202) among female patients. At the prefectural level, pre-dialysis SBP is >140 mmHg in Japanese patients undergoing dialysis, especially in those with DKD. The positive association between pre-dialysis SBP and CVD mortality rate suggests that optimal BP management at the prefectural level may reduce CVD mortality rates. [Figure not available: see fulltext.].

DOI： 10.1038/s41440-023-01415-7

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Background: Tonsillectomy with steroid pulse therapy (TSP) and tonsillectomy monotherapy (T) have improved the prognosis of patients with immunoglobulin A nephropathy (IgAN). However, a consensus has not been reached on the best treatment for these patients. This study aimed to compare the efficacies of TSP and T. Methods: Data of patients with IgAN who received TSP or T were retrospectively analyzed. The exclusion criterion was a serum creatinine level > 1.5 mg/dL. The clinical remission and renal survival rates were compared. Results: Patients were divided into groups based on the treatment method: the TSP (n = 82) and T groups (n = 41). No significant differences were observed in patient characteristics, except for the observation period (TSP: 60 months, T: 113 months). The log-rank test revealed that the clinical remission rate was significantly higher in the TSP group than in the T group (p < 0.05). The superiority of TSP was also observed in the urinary protein excretion (> / = or < 1 g/day) of the two subgroups. According to the Cox proportional-hazards model, the treatment method and daily urinary protein extraction were independent factors affecting clinical remission. The 10-year renal survival rates in the TSP and T groups were 100% and 92.5%, respectively. The log-rank test revealed a tendency for a higher renal survival rate in the TSP group than in the T group (p = 0.09). Conclusion: The clinical remission rate was significantly higher with TSP than with T, regardless of urinary protein levels. TSP tended to have a better renal survival rate than T.

DOI： 10.1007/s10157-024-02527-1

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DOI： 10.1007/s10396-024-01480-6

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The effectiveness of ischemic postconditioning (iPoC) in patients with ST-elevation myocardial infarction (STEMI) without ischemic preconditioning has not been determined. Therefore, we investigated the impact of iPoC and its potential mechanism related to heat shock protein 72 (HSP72) induction on myocardial salvage in patients with STEMI without prodromal angina (PA). We retrospectively analyzed data from 102 patients with STEMI with successful reperfusion among 323 consecutive patients with acute coronary syndrome. Among these, 55 patients with iPoC (iPoC(+)) underwent 4 cycles of 60-second inflation and 30-second deflation of the angioplasty balloon. Both the iPoC(+) and iPoC(-) groups were divided into 2 further subgroups: patients with PA (PA(+)) and those without (PA(-)). We analyzed HSP72 levels in neutrophils, which were measured until 48 hours after reperfusion. I-123 β-methyl-piodophenyl-pentadecanoic acid (BMIPP) scintigraphy was performed within a week of reperfusion therapy. In 64% of patients, thallium-201 (TL) scintigraphy was performed 6-8 months after STEMI onset. Using BMIPP and TL, in the PA(-) subgroups, the iPoC(+) group had a significantly greater myocardial salvage ratio than the iPoC(-) group. iPoC was identified as an independent predictor of the myocardial salvage ratio. The HSP72 increase ratio was significantly elevated in the iPoC(+)PA(-) group. Importantly, the myocardial salvage effect in patients without PA was significantly correlated with the HSP72 increase ratio, which was greater in patients with iPoC. These results suggest the potential impact of iPoC via HSP72 induction on myocardial salvage; however, the effects may be limited to patients with STEMI without PA.

DOI： 10.1536/ihj.23-651

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The prevalence of hypertension is high among patients undergoing dialysis. We extracted data of patients undergoing dialysis between 2012 and 2020 with recorded pre-dialysis systolic blood pressure (SBP) using a web-based national database in Japan. Following the 2019 Japanese Society of Hypertension guidelines, we classified SBP and assessed its trends over time based on sex, age, diabetes status, and the anti-hypertensive medication use. Using the 2020 database, we examined 336,759 Japanese patients undergoing dialysis (114,249 female; 222,510 male). The mean age was 69.4 ± 12.5 years, and the mean SBP was 152.3 ± 24.7 mm Hg. The prevalence rate of pre-dialysis hypertension was 70.2%, with 32.5%, 24.5%, and 13.2% of patients having grade I, grade II, and grade III hypertension, respectively. From 2014 to 2020, prevalence rate of pre-dialysis hypertension and absolute values of pre-dialysis SBP were higher in dialysis patients with diabetes than in those without diabetes across all age groups and sexes. Younger patients with diabetes or those on anti-hypertensive medication exhibited an SBP of approximately 160 mm Hg. Cerebrovascular death in patients with diabetes was associated with a higher rate of pre-dialysis hypertension than that in those without diabetes, and there was a significant difference in the prevalence of grade III hypertension between the two groups. In conclusion, the mean pre-dialysis SBP among patients undergoing dialysis remained high, and younger patients with diabetes or those receiving anti-hypertensive medications had poor blood pressure control. Optimal blood pressure management may be necessary to reduce the risk of cardiovascular mortality.

DOI： 10.1111/jch.14736

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AIM: Among patients with Immunoglobulin A (IgA) nephropathy, we aimed to identify trajectory patterns stratified by the magnitude of haematuria and proteinuria using repeated urine dipstick tests, and assess whether the trajectories were associated with kidney events. METHODS: Using a nationwide multicentre chronic kidney disease (CKD) registry, we analysed data from 889 patients with IgA nephropathy (mean age 49.3 years). The primary outcome was a sustained reduction in eGFR of 50% or more from the index date and thereafter. During follow-up (median 49.0 months), we identified four trajectories (low-stable, moderate-decreasing, moderate-stable, and high-stable) in both urine dipstick haematuria and proteinuria measurements, respectively. RESULTS: In haematuria trajectory analyses, compared to the low-stable group, the adjusted hazard ratios (HRs) (95% confidence interval [CI]) for kidney events were 2.59 (95% CI, 1.48-4.51) for the high-stable, 2.31 (95% CI, 1.19-4.50) for the moderate-stable, and 1.43 (95% CI, (0.72-2.82) for the moderate-decreasing groups, respectively. When each proteinuria trajectory group was subcategorized according to haematuria trajectories, the proteinuria group with high-stable and with modest-stable haematuria trajectories had approximately 2-times higher risk for eGFR reduction ≥50% compared to that with low-stable haematuria trajectory. CONCLUSION: Assessments of both haematuria and proteinuria trajectories using urine dipstick could identify high-risk IgA nephropathy patients.

DOI： 10.1111/nep.14250

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The nationwide clinical features of Japanese patients with primary nephrotic syndrome (NS), including minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), or membranous nephropathy (MN), have not yet been reported. We collected the clinical personal records of patients with primary NS between 2015 and 2018 from the national registry organized by the Japanese Ministry of Health, Labour, and Welfare. Overall, the demographics, chronic kidney disease classification based on glomerular filtration rate and albuminuria, and treatment of 6036 patients were collected: 3394 (56.2%) with MCD, 677 (11.2%) with FSGS, 1455 (24.1%) with MN, and 510 (8.5%) with others. MN patients were older than MCD and FSGS patients (67 vs. 42 and 47 years, respectively). Steroid-dependent NS or frequently relapsing NS was found in 70.2%, 40.5%, and 24.6%, whereas steroid-resistant NS was found in 6.4%, 36.0%, and 37.9% of patients in the MCD, FSGS, and MN, respectively. The present oral prednisolone use (mean dose, mg/day) was 87.2% (21.2), 80.9% (20.0), and 77.5% (18.8) of patients in the MCD, FSGS, and MN, respectively. The national registry of clinical personal records of primary NS could provide an informative insight into the characteristics, clinical features, and treatment approaches for patients with primary NS in Japan.

DOI： 10.1038/s41598-023-41909-5

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BACKGROUND: Membranoproliferative glomerulonephritis (MPGN) is a rare glomerular injury that causes nephrotic syndrome and end-stage kidney disease. The nationwide demographics and treatment of Japanese patients with primary MPGN have not yet been reported. METHODS: We collected clinical personal records of patients with primary MPGN between 2015 and 2018 from the national registry organized by the Japanese Ministry of Health, Labour, and Welfare and investigated the characteristics of primary MPGN throughout Japan. RESULTS: Of 258 patients with primary MPGN, 199 and 59 showed nephrotic and non-nephrotic syndrome, respectively. The median age at onset was higher in patients with nephrotic syndrome than in those with non-nephrotic syndrome (45 [24-63] vs. 35 [14-53] years, respectively; P = 0.010). The use of oral prednisolone was significantly higher in patients with nephrotic syndrome than in those with non-nephrotic syndrome (73.9% vs. 59.3%, respectively; P = 0.032). When patients were divided into three age groups: adolescent and young adult group (≤ 39 years; n = 80), middle adult group (40-64 years; n = 111), and older adult group (≥ 65 years; n = 67), the use of oral prednisolone, cyclosporine, and mizoribine was significantly higher in the adolescent and young adult group than in the middle adult group. The mean dosage of oral prednisolone and mizoribine showed no differences among the three age groups. CONCLUSION: The national registry of clinical personal records of primary MPGN could provide an informative insight into the characteristics, clinical features, and treatment approaches for patients with primary MPGN in Japan.

DOI： 10.1007/s10157-023-02387-1

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DOI： 10.1038/s41440-023-01186-1

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DOI： 10.1038/s41440-023-01209-x

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Ischemic preconditioning (IPC) describes a phenomenon wherein brief ischemia of the heart induces a potent cardioprotective mechanism against succeeding ischemic insult. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in prostanoid biosynthesis, is upregulated in the ischemic heart and contributes to IPC. Prostaglandin E2 (PGE2) protects the heart from ischemia–reperfusion (I/R) injury via its receptor subtype EP4. We sought to clarify the role of the PGE2/EP4 system in the late phase of IPC. Mice were subjected to four IPC treatment cycles, consisting of 5 min of occlusion of the left anterior descending coronary artery (LAD). We found that COX-2 mRNA was significantly upregulated in wild-type hearts at 6 h after IPC treatment. Cardiac PGE2 levels at 24 h after IPC treatment were significantly increased in both wild-type mice and mice lacking EP4 (EP4–/–). At 24 h after IPC treatment, I/R injury was induced by 30 min of LAD occlusion followed by 2 h of reperfusion and the cardiac infarct size was determined. The infarct size was significantly reduced by IPC treatment in wild-type mice; a reduction was not observed in EP4–/– mice. AE1-329, an EP4 agonist, significantly reduced infarct size and significantly ameliorated deterioration of cardiac function in wild-type mice subjected to I/R without IPC treatment. Furthermore, AE1-329 significantly enhanced the I/R-induced activation of Akt, a pro-survival kinase. We demonstrated that the PGE2/EP4 system in the heart plays a critical role in the late phase of IPC, partly by augmenting Akt-mediated signaling. These findings clarify the mechanism of IPC and may contribute to the development of therapeutic strategies for ischemic heart disease.

DOI： 10.1007/s00380-022-02219-4

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BACKGROUND: Inconsistencies between the office and out-of-office blood pressure (BP) values (described as white-coat hypertension or masked hypertension) may be attributable in part to differences in the BP monitoring devices used. METHODS: We studied consistency in the classification of BP control (well-controlled BP vs. uncontrolled BP) among office, home, and ambulatory BPs by using a validated "all-in-one"BP monitoring device. In the nationwide, general practitioner-based multicenter HI-JAMP study, 2,322 hypertensive patients treated with antihypertensive drugs underwent office BP measurements and 24-hour ambulatory BP monitoring (ABPM), consecutively followed by 5-day home BP monitoring (HBPM), for a total of seven BP measurement days. RESULTS: Using the thresholds of the JSH2019 and ESC2018 guidelines, the patients with consistent classification of well-controlled status in the office (<140 mmHg) and home systolic BP (SBP) (<135 mmHg) (n=970) also tended to have well-controlled 24-hour SBP (<130 mmHg) (n=808, 83.3%). The patients with the consistent classification of uncontrolled status in office and home SBP (n=579) also tended to have uncontrolled 24-hour SBP (n=444, 80.9%). Among the patients with inconsistent classifications of office and home BP control (n=803), 46.1% had inconsistent ABPM-vs.-HBPM out-of-office BP control status. When the 2017 ACC/AHA thresholds were applied as an alternative, the results were essentially the same. CONCLUSIONS: The combined assessment of the office and home BP is useful in clinical practice. Especially for patients whose office BP classification and home BP classification conflict, the complementary clinical use of both HBPM and ABPM might be recommended.

DOI： 10.1093/ajh/hpac103

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Background: Fabry disease (FD) is an X-linked inherited disease where renal complications are associated with a poor prognosis. However, little is known about the prevalence of Fabry nephropathy (FN) in patients with chronic kidney disease (CKD). We extracted FN data from the Japan Renal Biopsy Registry, analyzed the prevalence of FN, and examined the correlation between clinical characteristics and renal involvement according to sex differences and hemi- and heterozygosity in patients with FD. Methods: A total of 38,351 participants who underwent renal biopsy were retrospectively enrolled, and FN was determined. The clinical characteristics of FD patients were examined based on sex differences. Results: Twenty-nine patients (0.076%) (19 males and 10 females, mean age: 43.7 ± 15.5 years old) were diagnosed with FN. Median estimated urinary protein (UP) and mean eGFR levels were 0.9 [interquartile range (IQR) [0.7–1.6] g/gCr and 67.1 ± 36.8 mL/min/1.73 m2, respectively. Mean systolic blood pressure (SBP) was 126.4 ± 17.1 mmHg and diastolic blood pressure was 76.1 ± 12.6 mmHg. An inverse correlation between eGFR and logarithm UP levels was observed (r2 = 0.23, p = 0.02), SBP was positively associated with logarithm UP (r2 = 0.34, p = 0.004) overall and inversely associated with eGFR (r2 = 0.25, p = 0.007) regardless of sex, and SBP was an independent determinant of proteinuria (p = 0.004) and eGFR (p = 0.007). Conclusions: The prevalence of biopsy-proven FN was 0.076%. Since SBP is associated with eGFR regardless of zygosity, strict SBP control might be necessary to prevent progression to end-stage kidney disease in both male and female patients with FN.

DOI： 10.1007/s10157-022-02287-w

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Public education programs about chronic kidney disease (CKD) are important activities worldwide. The present study investigated the knowledge of CKD in the general population of 58 out of 179 cities or towns in Hokkaido between 1 April and 30 September 2019. A total of 15,012 respondents who underwent specific health checkups at these centers answered the questionnaire. In response to a questionnaire item asking about the respondent’s familiarity with the term “CKD”, only 6% of the respondents answered “know it well” and 13% answered “heard of it”. In contrast, in response to a questionnaire item asking about the respondent’s familiarity with “chronic kidney disease”, 31% answered “know it well” and 33% answered “heard of it”. The leading avenue by which the respondents learned about CKD was television, followed by newspapers, magazines, and a family doctor or nurse. The leading component that the respondents considered essential for the diagnosis of CKD was proteinuria. These results indicated that the knowledge of CKD in Hokkaido prefecture is still inadequate. Many people did not appear to realize that the term “CKD” represents “chronic kidney disease”. Further continuous public education efforts are required to enlighten people about CKD.

DOI： 10.3390/jpm12111837

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BACKGROUND: The life prognosis of elderly patients with myeloperoxidase-anti-neutrophil cytoplasmic antibodies-associated vasculitis (MPO-AAV) has been improved by reducing the corticosteroid or cyclophosphamide dose to avoid opportunistic infection. However, many elderly MPO-AAV patients experience recurrence and renal death. An effective and safer maintenance treatment method is necessary to improve the renal prognosis of MPO-AAV. METHODS: Patients with MPO-AAV who reached complete or incomplete remission after induction therapy were prospectively and randomly divided into mizoribine (MZR; n = 25) and control (n = 28) groups. The primary endpoint was relapse of MPO-AAV. The patients' serum MZR concentration was measured before (C0) and 3 h after taking the MZR. The maximum drug concentration (Cmax) and the serum MZR concentration curves were determined using population pharmacokinetics parameters. We also assessed the relationship between the MZR concentrations and adverse events. The observation period was 12 months. RESULTS: Fifty-eight MPO-AAV patients from 16 hospitals in Japan were enrolled. Ten patients relapsed (MZR group, n = 6; control group, n = 4; a nonsignificant between-group difference). Changes in the serum MZR concentration could be estimated for 22 of the 25 MZR-treated patients: 2 of the 11 patients who reached a Cmax of 3 μg/mL relapsed, whereas 4 of the 11 patients who did not reach this Cmax relapsed. The treatment of one patient with C0 > 1 μg/mL was discontinued due to adverse events. No serious adverse events occurred. CONCLUSION: There was no significant difference in the recurrence rate of MPO-AAV between treatment with versus without MZR.

DOI： 10.1007/s10157-022-02253-6

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BACKGROUND: The prognosis of lupus nephritis (LN) has improved following the introduction of effective immunosuppressive therapy and progress in supportive care. This study examined recent renal and patient prognosis for adults with LN in Japan. METHODS: We conducted a nationwide retrospective cohort study of LN patients who received a renal biopsy between 2007 and 2012 that were registered in the Japan Renal Biopsy Registry. Of 623 registered adults with LN from 25 institutions and their affiliated or community hospitals, 489 were eligible for this study. RESULTS: The median age at renal biopsy was 39 years, and 82.2% of patients were female. Renal biopsies were performed in 348 patients with new-onset LN, 106 with relapse LN, and 35 with refractory LN. The distribution of ISN/RPS 2003 Classes was as follows: I 1.6%; II 5.3%; III (± V) 27.0%; IV (± V) 47.0%; V 18.4%; VI 0.6%. During the median observation period of 63.8 months, 36 patients (7.3%) reached a doubling of serum creatinine or end-stage kidney disease (ESKD), and 28 patients (5.7%) died. The 5 year renal and patient survival rates were 93.9% and 94.7%, respectively. Multivariate analysis revealed body mass index (BMI) and estimated glomerular filtration rate (eGFR) were independent risk factors for a doubling of serum creatinine in ESKD. Age and eGFR were independent risk factors for death. CONCLUSION: Recent prognosis for adults with LN are relatively good in Japan. Risk factors for impaired renal function are BMI and eGFR at renal biopsy, while age and eGFR are risk factors for death.

DOI： 10.1007/s10157-022-02232-x

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DOI： 10.1038/s41440-022-00949-6

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We describe the cases of 47- and 45-year-old sisters who were diagnosed with Fabry disease by genomic analysis. Although the only abnormal finding was the presence of mulberry cells in their urinary sediment, the renal pathological scores, which were evaluated by light and electron microscopy, were unexpectedly very high due to severe accumulation of globotriaosylceramide in the glomerular podocytes and tubular epithelial cells. Nephrologists and laboratory technicians should recognize the importance of screening for mulberry cells during urinalysis as this is a simple, inexpensive, and non-invasive method for early diagnosis, leading to early treatment of Fabry disease.

DOI： 10.1016/j.ymgmr.2022.100874

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BACKGROUND: Recent clinical reports indicate a correlation between new-onset and relapse of nephrotic syndrome (NS) following coronavirus 2019 (COVID-19) vaccination in patients with glomerular diseases. However, there are no reports of a nationwide survey on NS following COVID-19 vaccination in Japan. METHODS: We conducted a web-based survey of council members of the Japanese Society of Nephrology (581 members, 382 facilities) to elucidate the relationship between COVID-19 vaccination and new-onset and relapse of NS. RESULTS: Following COVID-19 vaccination, 27 patients (male: 15, 55.6%) with new-onset (n = 6) and relapse (n = 21) of NS were reported. Of them, 12 (44.4%) patients were diagnosed with minimal change disease at the occurrence of NS. Five patients developed a slight increase in serum creatinine levels; however, none progressed to severe renal dysfunction. CONCLUSION: Our findings clarify the clinical features of new-onset and relapse of NS following COVID-19 vaccination. Although there was no obvious progression to severe renal dysfunction, clinicians and pathologists should be aware that NS is a potential adverse effect of the vaccines.

DOI： 10.1007/s10157-022-02231-y

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DOI： 10.3390/nu14061234

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Background: We previously identified tissue inhibitor of metalloproteinase 1 (TIMP-1) as a biomarker of disease activity that distinguished mildly or highly active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) from remission 6 months after the initiation of remission-induction therapy. In the present study, we investigated whether TIMP-1 is clinically useful as a predictor of relapse and sustained remission in AAV patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) during maintenance therapy. Methods: The relationship between serum TIMP-1 levels and clinical outcomes in AAV patients receiving maintenance therapy was assessed using the follow-up data of a Japanese large-cohort study (the RemIT-JAV-RPGN study) and data collected from AAV patients on maintenance therapy in our hospital (the MAAV-EU study). Results: In the RemIT-JAV RPGN study, serum levels of TIMP-1 were significantly higher in mildly active AAV patients with MPA and GPA 6 months after the initiation of remission-induction therapy than in patients in remission. Regarding maintenance therapy, elevated levels of TIMP-1 in patients in remission were associated with relapse and/or difficulty reducing the glucocorticoid dosage after 6 to 12 months. In the MAAV-EU study, serum levels of TIMP-1 were elevated in relapsed patients 6 months before relapse, earlier than the increase in serum levels of CRP. Analyses of both studies revealed that approximately 30% of patients in remission with a serum TIMP-1 level ≥ 150 ng/mL relapsed after 6 to 12 months, while the majority of patients with a TIMP-1 level < 150 ng/mL sustained remission for at least 12 months. Conclusion: We herein demonstrated that TIMP-1 is more useful as a predictive biomarker of sustained remission than as a predictor of relapse in maintenance therapy for AAV. TIMP-1 levels < 150 ng/mL are important for the long-term maintenance of remission and may be an indicator for the tapering or cessation of treatment.

DOI： 10.1186/s13075-021-02471-5

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OBJECTIVE: Randomized controlled trials have shown kidney-protective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors, and clinical practice databases have suggested that these effects translate to clinical practice. However, long-term efficacy, as well as whether the presence or absence of proteinuria and the rate of estimated glomerular filtration rates (eGFR) decline prior to SGLT2 inhibitor initiation modify treatment efficacy among type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) patients, is unknown. RESEARCH DESIGN AND METHODS: Using the Japan Chronic Kidney Disease Database (J-CKD-DB), a nationwide multicenter CKD registry, we developed propensity scores for SGLT2 inhibitor initiation, with 1:1 matching with patients who were initiated on other glucose-lowering drugs. The primary outcome included rate of eGFR decline, and the secondary outcomes included a composite outcome of 50% eGFR decline or end-stage kidney disease. RESULTS: At baseline, mean age at initiation of the SGLT2 inhibitor (n = 1,033) or other glucose-lowering drug (n = 1,033) was 64.4 years, mean eGFR was 68.1 mL/min per 1.73 m2, and proteinuria was apparent in 578 (28.0%) of included patients. During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs. other drugs 0.75 mL/min/1.73 m2 per year [0.51 to 1.00]). During a mean follow-up of 24 months, 103 composite kidney outcomes occurred: 30 (14 events per 1,000 patient-years) among the SGLT2 inhibitors group and 73 (36 events per 1,000 patient-years) among the other drugs group (hazard ratio 0.40, 95% CI 0.26-0.61). The benefit provided by SGLT2 inhibitors was consistent irrespective of proteinuria and rate of eGFR decline before initiation of SGLT2 inhibitors (P heterogeneity ≥ 0.35). CONCLUSIONS: The benefits of SGLT2 inhibitors on kidney function as observed in clinical trials translate to patients treated in clinical practice with no evidence that the effects are modified by the underlying rate of kidney function decline or the presence of proteinuria.

DOI： 10.2337/dc21-1081

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DOI： 10.1038/s41440-021-00730-1

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Chronic kidney disease (CKD) is one of the most significant risk factors for cardiovascu-lardisese. Malnutrition has been recognized as a significant risk factor for cardiovascular disease in patients with CKD, including those on chronic dialysis. Current studies showed higher all‐cause and cardiovascular mortality rates in patients with CKD and malnutrition. Geriatric nutritional risk index (GNRI), a simple and validated nutritional screening measure for both elderly people and patients on dialysis, is based only on three objective parameters: body weight, height, and serum albumin level. Recently, we demonstrated that the cutoff GNRI for predicting all‐cause and cardiovascular mortality was 96 in patients on hemodialysis. Moreover, together with left ventricular hypertrophy and low estimated glomerular filtration rate, the utility of GNRI as a significant determinant of cardiovascular events was demonstrated in non‐dialysis‐dependent patients with CKD. In the present review, we summarize available evidence regarding the relationship of GNRI with all-cause and cardiovascular mortality in patients with CKD including those on dialysis.

DOI： 10.3390/nu13113688

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Sarcopenia is a pathophysiological malfunction induced by skeletal muscle atrophy. Several studies reported an association between sarcopenia-induced cardiac cachexia and poor prognosis in heart disease. However, due to lack of an established animal models, the underlying mechanism of disturbed cardiac repair accompanied with sarcopenia remains poorly understood. Here, we developed a novel sarcopenia-induced cardiac repair disturbance mouse model induced by tail suspension (TS) after cardiac ischemia and reperfusion (I/R). Importantly, we identified a specific exosomal-microRNA marker, miR-16-5p, in the circulating exosomes of I/R-TS mice. Of note, sarcopenia after I/R disturbed cardiac repair and raised the level of circulating-exosomal-miR-16-5p secreting from both the atrophic limbs and heart of TS mice. Likewise, miR-16-5p mimic plasmid disturbed cardiac repair in I/R mice directly. Additionally, in neonatal rat ventricular myocytes (NRVMs) cultured in vitro under hypoxic conditions in the presence of a miR-16-5p mimic, we observed increased apoptosis through p53 and Caspase3 upregulation, and also clarified that autophagosomes were decreased in NRVMs via SESN1 transcript interference-mediated mTOR activation. In conclusion, we show the pro-apoptotic effect of sarcopenia-derived miR-16-5p, which may be behind the exacerbation of myocardial infarction. Therefore, miR-16-5p can be a novel therapeutic target in the context of cardiac repair disturbances in sarcopenia-cachexia.

DOI： 10.1038/s41598-021-98761-8

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Background: Only a few studies have investigated epidemiological and clinicopathological information regarding pediatric and adolescent and young adult (AYA) patients with renal disease. The purpose of this study was to clarify the differences and relationship of clinicopathological findings between pediatric and AYA patients using the Japan Renal Biopsy Registry (J-RBR). Methods: This cross-sectional study analyzed data from patients registered in the J-RBR between 2007 and 2017. Clinicopathological findings at diagnosis were analyzed for 3,463 pediatric (age < 15 years) and 6,532 AYA (age 15–30 years) patients. Results: Although chronic nephritic syndrome was the most common clinical diagnosis at age > 5 years, nephrotic syndrome was the most frequent diagnosis at age < 4 years. The most common pathological diagnosis as classified by pathogenesis in pediatric patients was primary glomerular disease (except IgA nephropathy), whereas IgA nephropathy was increased in AYA patients. Mesangial proliferative glomerulonephritis was the most common pathological diagnosis as classified by histopathology in both pediatric and AYA patients. Minor glomerular abnormalities were the most frequent histopathologic diagnoses of nephrotic syndrome in childhood, but their frequency decreased with age. Conclusion: To the best of our knowledge, this is the first report of clinicopathological features of pediatric and AYA patients in a large nationwide registry of renal biopsy. There were differences of clinical, pathological and histopathologic findings between pediatric and AYA patients.

DOI： 10.1007/s10157-021-02077-w

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Objective Fabry disease (FD) is a hereditary lysosomal storage disease that has been highlighted as a possible etiology of stroke at a young age and presents with other various neurological symptoms. Since FD is rare, limited information is currently available on the prevalence of neurological symptoms in Japanese patients with FD. Therefore, we examined the characteristics of neurological symptoms and brain magnetic resonance imaging (MRI) findings in adult Japanese patients with FD. Methods This was a retrospective, single-center study. We reviewed neurological symptoms and brain MRI findings in the medical records of 12 adult Japanese patients with FD diagnosed by a gene analysis of the α-galactosidase gene. Results Ten out of 12 patients with FD presented with the following neurological symptoms: acroparesthesia (n=6), headache (n=5) [migraine (n=4)], hypohidrosis (n=5), and cerebral infarction (n=3). Two and three of the patients with migraine were complicated by ischemic stroke and coronary spastic angina, respectively. Five and 10 patients presented with periventricular hyperintensity and deep white matter hyperintensity, respectively, on brain MRI. Two out of eight patients had cerebral microbleeds. Seven out of 11 patients had a dilated basilar artery diameter on magnetic resonance angiography. There were no patients with the pulvinar hyperintensity sign. Conclusion Patients with FD present with various neurological symptoms. Headache, particularly migraine, might be a major neurological symptom in patients with FD. Since migraine, ischemic stroke, and coronary spastic angina might occur together in FD, caution is needed when administering triptan to FD patients with migraine.

DOI： 10.2169/internalmedicine.6420-20

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Adventitial abnormalities including enhanced vasa vasorum malformation are associated with development and vulnerability of atherosclerotic plaque. However, the mechanisms of vasa vasorum malformation and its role in vascular remodeling have not been fully clarified. We recently reported that Ninjurin-1 (Ninj1) is a crucial adhesion molecule for pericytes to form matured neovessels. The purpose is to examine if Ninj1 regulate adventitial angiogenesis and affects the vascular remodeling of injured vessels using pericyte-specific Ninj1 deletion mouse model. Mouse femoral arteries were injured by insertion of coiled wire. Four weeks after vascular injury, fixed arteries were decolorized. Vascular remodeling, including intimal hyperplasia and adventitial microvessel formation were estimated in three-dimensional view. Vascular fragility, including blood leakiness was estimated by extravasation of FITC-lectin or -dextran from microvessels. Ninj1 expression was increased in pericytes in response to vascular injury. NG2-CreER/Ninj1loxp mice were treated with tamoxifen (Tam) to induce deletion of Ninj1 in pericyte (Ninj1KO). Tam-treated-NG2-CreER or Tam-nontreated NG2-CreER/Ninj1loxp mice were used as controls. Intimal hyperplasia was significantly enhanced in Ninj1KO compared with controls. Vascular leakiness was significantly enhanced in Ninj1KO. In Ninj1KO, the number of infiltrated macrophages in adventitia was increased, along with the expression of inflammatory cytokines. In conclusion, deletion of Ninj1 in pericytes induces the immature vasa vasorum formation of injured vasculature and exacerbates adventitial inflammation and intimal hyperplasia. Thus, Ninj1 contributes to the vasa vasorum maturation in response to vascular injury, and to reduction of vascular remodeling.

DOI： 10.1152/ajpheart.00931.2020

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The reclassification of membranoproliferative glomerulonephritis (MPGN) into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G) based on immunofluorescence findings in kidney biopsies has provided insights into these two distinct diseases. C3G is further classified into dense deposit disease and C3 glomerulonephritis (C3GN) based on electron micrographic findings. Although these diseases have poor outcomes, limited Japanese literature confined to small, single-center cohorts exist on these diseases. We retrospectively analyzed 81 patients with MPGN type I and III from 15 hospitals in the Japan Renal Biopsy Registry to compare demographic, clinical characteristics and treatment outcomes of patients with IC-MPGN to those with C3GN. Of the 81 patients reviewed by immunofluorescence findings in kidney biopsies, 67 patients had IC-MPGN and 14 patients had C3GN. Age at diagnosis and systolic and diastolic pressure were higher and proteinuria and impaired renal function were significantly more prevalent in patients with IC-MPGN than those with C3GN. About 80% of the patients in both groups were treated with immunosuppressive therapy. At last follow-up (median 4.8 years), complete remission rate of proteinuria was significantly higher in patients with C3GN (64.3%) than in those with IC-MPGN (29.9%; P = 0.015). The renal survival rate was lower in patients with IC-MPGN when compared to C3GN (73.1% vs. 100%; log-rank, P = 0.031). Systolic blood pressure and renal function at baseline were independent predictors of progression to end-stage kidney disease. The overall prognosis of patients with C3GN is more favorable than for patients with IC-MPGN.

DOI： 10.1371/journal.pone.0257397

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Background: It is not elucidated that there is treatment-related damage in elderly patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods: Elderly (≥ 75 years of age) patients were enrolled from two nationwide prospective inception cohort studies. The primary outcome was 12-month treatment-related Vasculitis Damage Index (VDI) score. Secondary outcomes included serious infections within 6 months, total VDI score, remission, and relapse. Patient characteristics and outcomes were compared across three different initial glucocorticoid (GC) dose groups: high-dose, prednisolone (PSL) ≥ 0.8 mg/kg/day; medium-dose, 0.6 ≤ PSL < 0.8 mg/kg/day; and low-dose, PSL < 0.6 mg/kg/day. Results: Of the 179 eligible patients, the mean age was 80.0 years; 111 (62%) were female. The mean Birmingham Vasculitis Activity Score was 16.1. Myeloperoxidase-ANCA findings were positive in 168 (94%) patients, while proteinase 3-ANCA findings were positive in 11 (6%). The low-dose group was older and had higher serum creatinine levels than the other groups. There were no statistically significant intergroup differences in remission or relapse, whereas serious infection developed more frequently in the high-dose (29 patients [43%]) than the low-dose (13 patients [22%]) or medium-dose (10 patients [19%]) groups (p = 0.0007). Frequent VDI items at 12 months included hypertension (19%), diabetes (13%), atrophy and weakness (13%), osteoporosis (8%), and cataracts (8%). Logistic regression analysis revealed that GC dose at 12 months (odds ratio, 1.14; 95% confidence interval, 1.00-1.35) was a predictor for diabetes. Conclusion: A reduced initial GC dose with rapid reduction might be required to ensure the safe treatment of elderly AAV patients.

DOI： 10.1186/s13075-020-02341-6

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© 2020 Wiley Periodicals LLC Unattended automated office blood pressure (AOBP) measurement has been endorsed as the preferred in-office measurement modality in recent Canadian and American clinical practice guidelines. However, the difference between AOBP and conventional office blood pressure (CBP) under the environment of a health checkup remains unclear. We aimed to identify the clinical significance of AOBP as compared to CBP under the environment of a health checkup. There were 491 participants (333 females, mean age of 62.5 years) who were at least 20 years old, including 179 participants who were previously diagnosed with hypertension. Mean AOBPs were 131.8 ± 20.9/76.6 ± 11.7 mm Hg, and CBPs were 135.6 ± 21.6/77.3 ± 11.5 mm Hg. There was a difference of 3.9 mm Hg in systolic blood pressure (SBP) and 0.8 mm Hg in diastolic BP between AOBP and CBP. In all participants, SBP and pulse pressure, as well as the white coat effect (WCE), increased with age. The cutoff value used was 140/90 mm Hg for CBP and 135/85 mm Hg for AOBP, and the prevalence of WCE and masked hypertension effect (MHE) was 12.4% and 14.1%, respectively. Even in a health checkup environment of the general population, there was a difference between the AOBP and CBP, and the WCE was observed more strongly in the elderly with a history of hypertension, suggesting that a combination of AOBP with CBP may be useful in detecting WCE and MHE in all clinical scenarios including health checkups, and help solve the “hypertension paradox” not only in Japan but in all over the world.

DOI： 10.1111/jch.14008

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Copyright: © 2020 Sofue et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background The Japan Chronic Kidney Disease Database (J-CKD-DB) is a nationwide clinical database of patients with chronic kidney disease (CKD) based on electronic health records. The objective of this study was to assess the prevalences of hyperuricemia and electrolyte abnormalities in Japanese patients with CKD. Methods In total, 35,508 adult outpatients with estimated glomerular filtration rates of 5–60 ml/min/ 1.73 m2 in seven university hospitals were included this analysis. The proportions of patients with CKD stages G3b, G4, and G5 were 23.5%, 7.6%, and 3.1%, respectively. Results Logistic regression analysis showed that prevalence of hyperuricemia was associated with CKD stages G3b (adjusted odds ratio [95% confidence interval]: 2.12 [1.90–2.37]), G4 (4.57 [3.92–5.32]), and G5 (2.25 [1.80–2.80]). The respective prevalences of hyponatremia, hypercalcemia, hyperphosphatemia, and narrower difference between serum sodium and chloride concentrations were elevated in patients with CKD stages G3b, G4, and G5, compared with those prevalences in patients with CKD stage G3a. The prevalences of hyperkalemia were 8.3% and 11.6% in patients with CKD stages G4 and G5, respectively. In patients with CKD stage G5, the proportions of patients with optimal ranges of serum uric acid, potassium, corrected calcium, and phosphate were 49.6%, 73.5%, 81.9%, and 56.1%, respectively. Conclusions We determined the prevalences of hyperuricemia and electrolyte abnormalities in Japanese patients with CKD using data from a nationwide cohort study.

DOI： 10.1371/journal.pone.0240402

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© 2020 The Author(s) Skeletal muscle has a capacity for muscular regeneration mediated by satellite cells (SCs) and non-SCs. Although it is proposed that non-SCs are attractive therapeutic targets for dystrophies, the biological properties of these cells remain unclear. We have recently identified novel multipotent pericytes (PCs), capillary stem cells (CapSCs) derived from the microvasculature. In the present study, we determined if CapSCs contributed to myogenic regeneration using muscular dystrophy mouse model. CapSCs were isolated as EphA7+NG2+PCs from the subcutaneous adipose tissues of GFP-transgenic mice. Co-culture with C2C12 myoblast cells showed that CapSCs effectively enhanced myogenesis as compared to controls including EphA7− PCs and adipose stromal cells (ASCs). CapSCs transplanted in cardiotoxin-injured gastrocnemius muscles were well differentiated into both muscle fibers and microvessels, as compared to controls. At three weeks after cell-transplantation into the limbs of the mdx/utrn-/-mouse, CapSCs increased the number of GFP+myofibers along with dystrophin expression and the area size of myofibers, and also enhanced the muscular mass and its performance, assessed by treadmill test as compared to controls. In conclusion, CapSCs have potent myogenic regeneration capacity and improved the pathological condition in a muscular dystrophy mouse. Thus, CapSCs are an attractive cellular source in regenerative therapy for muscular dystrophy.

DOI： 10.1016/j.scr.2020.101914

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© 2020 Sofue et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background The Japan Chronic Kidney Disease Database (J-CKD-DB) is a nationwide clinical database of patients with chronic kidney disease (CKD) based on electronic health records. The objective of this study was to assess the prevalence of anemia and the utilization rate of erythropoiesis-stimulating agents (ESAs) in Japanese patients with CKD. Methods In total, 31,082 adult outpatients with estimated glomerular filtration rates of 5–60 ml/min/1.73 m2 in seven university hospitals were included this analysis. The proportions of patients with CKD stages G3b, G4, and G5 were 23.5%, 7.6%, and 3.1%, respectively. Results The mean (standard deviation) hemoglobin level of male patients was 13.6 (1.9) g/dl, which was significantly higher than the mean hemoglobin level of female patients (12.4 (1.6) g/dl). The mean (standard deviation) hemoglobin levels were 11.4 (2.1) g/dl in patients with CKD stage G4 and 11.2 (1.8) g/dl in patients with CKD stage G5. The prevalences of anemia were 40.1% in patients with CKD stage G4 and 60.3% in patients with CKD stage G5. Logistic regression analysis showed that diagnoses of CKD stage G3b (adjusted odds ratio [95% confidence interval]: 2.32 [2.09–2.58]), G4 (5.50 [4.80–6.31]), and G5 (9.75 [8.13–11.7]) were associated with increased prevalence of anemia. The utilization rates of ESAs were 7.9% in patients with CKD stage G4 and 22.4% in patients with CKD stage G5. Conclusions We determined the prevalence of anemia and utilization rate of ESAs in Japanese patients with CKD using data from a nationwide cohort study.

DOI： 10.1371/journal.pone.0236132

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© 2020, The Author(s). The Japan Chronic Kidney Disease (CKD) Database (J-CKD-DB) is a large-scale, nation-wide registry based on electronic health record (EHR) data from participating university hospitals. Using a standardized exchangeable information storage, the J-CKD-DB succeeded to efficiently collect clinical data of CKD patients across hospitals despite their different EHR systems. CKD was defined as dipstick proteinuria ≥1+ and/or estimated glomerular filtration rate <60 mL/min/1.73 m2 base on both out- and inpatient laboratory data. As an initial analysis, we analyzed 39,121 CKD outpatients (median age was 71 years, 54.7% were men, median eGFR was 51.3 mL/min/1.73 m2) and observed that the number of patients with a CKD stage G1, G2, G3a, G3b, G4 and G5 were 1,001 (2.6%), 2,612 (6.7%), 23,333 (59.6%), 8,357 (21.4%), 2,710 (6.9%) and 1,108 (2.8%), respectively. According to the KDIGO risk classification, there were 30.1% and 25.5% of male and female patients with CKD at very high-risk, respectively. As the information from every clinical encounter from those participating hospitals will be continuously updated with an anonymized patient ID, the J-CKD-DB will be a dynamic registry of Japanese CKD patients by expanding and linking with other existing databases and a platform for a number of cross-sectional and prospective analyses to answer important clinical questions in CKD care.

DOI： 10.1038/s41598-020-64123-z

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© 2019 The Authors. Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press The presence of pericytes (PCs) with multipotency and broad distribution along capillary suggests that microvasculature plays a role not only as a duct for blood fluid transport but also as a stem cell niche that contributes to tissue maintenance and regeneration. The lack of an appropriate marker for multipotent PCs still limits our understanding of their pathophysiological roles. We identified the novel marker EphA7 to detect multipotent PCs using microarray analysis of an immortalized PC library. PCs were isolated from microvessels of mouse subcutaneous adipose tissues, then EphA7+ PCs called capillary stem cells (CapSCs) were separated from EphA7− control PCs (ctPCs) using fluorescence-activated cell sorting system. CapSCs had highly multipotency that enabled them to differentiate into mesenchymal and neuronal lineages compared with ctPCs. CapSCs also differentiated into endothelial cells and PCs to form capillary-like structures by themselves. Transplantation of CapSCs into ischemic tissues significantly improved blood flow recovery in hind limb ischemia mouse model due to vascular formation compared with that of ctPCs and adipose stromal cells. These data demonstrate that EphA7 identifies a subpopulation of multipotent PCs that have high angiogenesis and regenerative potency and are an attractive target for regenerative therapies.

DOI： 10.1002/sctm.19-0148

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©2020 Wiley Periodicals LLC Angiotensin receptor blockers (ARBs) plus calcium channel blockers (CCBs) are a widely used combination therapy for hypertensive patients. In order to determine which combination was better as the next-step therapy for standard-dose combination of ARBs and CCBs, a combination with high-dose CCBs or a triple combination with diuretics, the authors conducted a prospective, randomized, open-label trial to determine which of the following combination is better as the next-step treatment: a combination with high-dose CCBs or a triple combination with diuretics. Hypertensive outpatients who did not achieve their target blood pressure (BP) with usual dosages of ARBs and amlodipine 5 mg were randomly assigned to treatment with irbesartan 100 mg/amlodipine 10 mg (Group 1: n = 48) or indapamide 1 mg in addition to ARBs plus amlodipine 5 mg (Group 2: n = 46). The primary end point was changes in the systolic BP (SBP) and diastolic BP (DBP) after the 12-week treatment period, while secondary end points were changes in BP after the 24-week treatment period and laboratory values. At 12 weeks, the SBP/DBP significantly decreased from 152.1/83.4 mm Hg to 131.5/76.1 mm Hg in Group 1 and 153.9/82.1 mm Hg to 132.7/75.9 mm Hg in Group 2. Although both groups produced a similar efficacy in reducing the SBP/DBP (−19.2/-9.2 mm Hg in Group 1 and −21.6/-8.8 mm Hg in Group 2; SBP P =.378, DBP P =.825), high-dose CCBs combined with ARBs controlled hypertension without elevation of serum uric acid. These results will provide new evidence for selecting optimal combination therapies for uncontrolled hypertensive patients.

DOI： 10.1111/jch.13977

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© 2019, The Author(s). Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional protein that controls the cellular response to oxidative stress and possesses DNA-repair functions. It has important roles in the progression and outcomes of various diseases; however, its function and therapeutic prospects with respect to kidney injury are unknown. To study this, we activated APE1 during kidney injury by constructing an expression vector (pCAG-APE1), using an EGFP expression plasmid (pCAG-EGFP) as a control. We performed unilateral ureteral obstruction (UUO) as a model of tubulointerstitial fibrosis on ICR mice before each vector was administrated via retrograde renal vein injection. In this model, pCAG-APE1 injection did not produce any adverse effects and significantly reduced histological end points including fibrosis, inflammation, tubular injury, and oxidative stress, as compared to those parameters after pCAG-EGFP injection. qPCR analysis showed significantly lower expression of Casp3 and inflammation-related genes in pCAG-APE1-injected animals compared to those in pCAG-EGFP-injected UUO kidneys. RNA-Seq analyses showed that the major transcriptional changes in pCAG-APE1-injected UUO kidneys were related to immune system processes, metabolic processes, catalytic activity, and apoptosis, leading to normal kidney repair. Therefore, APE1 suppressed renal fibrosis, not only via antioxidant and DNA-repair functions, but also partly by modulating the immune system through multiple pathways including Il6, Tnf, and chemokine families. Thus, therapeutic APE1 modulation might be beneficial for the treatment of renal diseases.

DOI： 10.1038/s41598-019-44241-z

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© 2019 National Kidney Foundation, Inc. Myeloproliferative neoplasms (MPNs) are associated with somatic mutations of genes including JAK2, CALR, or MPL in hematopoietic stem cells. Various glomerular lesions are known to be involved in MPN-related glomerulopathy, including mesangial hypercellularity, segmental sclerosis, features of chronic thrombotic microangiopathy, and intracapillary hematopoietic cell infiltration. Renal extramedullary hematopoiesis (EMH) is uncommon, but it is reported to occur in the setting of MPN; however, to our knowledge, there have been no reports of renal EMH with pathologically verified mutations. We report the case of a 65-year-old woman with MPN who had a CALR mutation and developed nephrotic syndrome. Kidney biopsy showed the typical findings of MPN-related glomerulopathy. CALR mutation–specific immunostaining of the kidney revealed immunopositive cells in the EMH lesion of the interstitium, indicating that renal EMH was caused by CALR-mutated cells. Based on these findings, we diagnosed nephrotic syndrome caused by MPN-related glomerulopathy. After initiation of steroid therapy, the patient's proteinuria gradually decreased and she achieved an incomplete remission. Additionally, the patient was prescribed the JAK inhibitor ruxolitinib and maintained incomplete remission. There is no established treatment for MPN-related glomerulopathy; therefore, further studies are needed to elucidate its pathophysiology.

DOI： 10.1053/j.ajkd.2019.05.016

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© 2019 Elsevier Inc. Ninjurin 1 (Ninj1) is identified as a peripheral nerve injury-induced protein. However, the role of Ninj1 in nerve regeneration is unclear. Schwann cells (SCs) and microvasculature are critical for peripheral nerve regeneration. SCs precursors and microvascular pericytes (PCs), which are nerve/glial antigen 2 (NG2)-positive cells are observed in peripheral nervous system. In this study, we investigated the role of Ninj1 in peripheral nerve regeneration using NG2+cell-specific inducible deletion of Ninj1 mouse model. The number of NG2+cells, which were associated with and without microvessels was increased after sciatic nerve crush injury. There was a significant increase in the expression of Ninj1 and EphA7 in the injured nerve tissue. This increase was mostly observed in NG2+cells. Genetic tracing of NG2+cells was performed using tamoxifen (Tam) treatment on NG2CreERT:R26R-tdTomato mice. The sciatic nerve was injured following the Tam-treatment, then tdTomato-expressing SCs were mostly observed in regenerated SCs at 21 days after nerve injury. Ninj1 gene knockout (Ninj1 KO) in NG2+cells was induced using NG2CreERT:Ninj1loxp mice. Tam-treated-NG2CreERT or Tam-nontreated NG2CreERT:Ninj1loxp mice were used as controls. Following Tam-treatment, the sciatic nerve in each group was injured. Ninj1KO significantly attenuated the expression of the myelin binding protein (MBP) as well as the number of myelinated axons. The expression of MBP in cultured SCs was significantly reduced by SiRNA-mediated Ninj1 knockdown (KD). Ninj1KD also attenuated the differentiation of SCs by isolated EphA7+multipotent PCs. The current data indicate that Ninj1 plays a vital role in peripheral nerve regeneration. This is observed particularly in the myelination process of NG2+cells including SCs precursors and multipotent PCs.

DOI： 10.1016/j.bbrc.2019.09.007

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© 2019, The Author(s), under exclusive licence to The Japan Society of Human Genetics. Anderson–Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by abnormalities in the α-galactosidase (Gal) A gene (GLA; MIM:300644). The reduced activity of the lysosomal enzyme, α-galactosidase A (α-Gal A) leads to classic early manifestations and vascular disease of the heart, kidneys, and brain. As a high-risk screening for symptomatic AFD using an enzymatic assay on dried blood spot samples, we enrolled 2325 individuals (803 females and 1522 males; median age: 66 years) with cardiac, renal, or neurological manifestations that met at least one of the following criteria: (a) family history of early-onset cardiovascular diseases; (b) typical classic manifestations, such as acroparesthesias, clustered angiokeratoma, cornea verticillata, and hypo-anhidrosis; (c) proteinuria; (d) receiving dialysis; (e) left ventricular hypertrophy on electrocardiography or echocardiography; or (f) history of stroke. Ninety-two patients displayed low α-Gal A activity. Four males and two females had different pathogenic GLA mutations (0.26%) including a novel mutation c.908-928del21. Four males (0.17%) harbored the GLA c.196G>C (p.E66Q) variant. This simple screening protocol using dried blood spot samples is useful for early diagnosis of AFD in high-risk and underdiagnosed patients suffering from various cardiac, renal, or neurological manifestations.

DOI： 10.1038/s10038-019-0633-1

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© 2018, Japanese Society of Nephrology. Background: The prognostic value of the EUVAS-proposed histopathological classification of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis has been evaluated throughout the world. Here, we performed a Japanese nationwide biopsy survey to assess the association between this histopathological classification and renal prognosis after 2-year follow-up in ANCA-associated glomerulonephritis. Methods: We collected 67 renal biopsy materials of the 321 entries in the RemIT-JAV-RPGN cohort study, and assessed their histologies. Based on the EUVAS-proposed histopathological classification and some histological parameters, we statistically evaluated renal survival and the comparison of renal function for 2 years. Results: Based on the histopathological classification, the largest number of biopsy samples belonged to the Focal class, followed by the Mixed, Crescentic, and Sclerotic classes (n = 30, 19, 10, 8, respectively). Although the number of events might be too low (four patients with renal death) to make this conclusion, the Focal and Mixed classes had higher renal-survival rates compared to the others in the renal-survival curve. Comparing renal function among all classes, the estimated glomerular filtration rate (eGFR) throughout 2-year follow-up period was significantly higher in the Focal class compared to the other 3 classes. The eGFR-values in the Crescentic, Mixed, and Sclerotic classes increased with time. Based on both combined results, the Focal class could be the best prognosis. Conclusion: This histopathological classification was valuable for both the stratification of renal function and the estimation of partial renal survival during 2-year follow-up in ANCA-associated glomerulonephritis.

DOI： 10.1007/s10157-018-1656-1

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© 2019, Japanese Circulation Society. Background: Although we and others have reported cases of patients with Anderson-Fabry disease (AFD) complicated by coronary spastic angina (CSA), the prevalence of CSA in these patients remains unknown. Methods and Results: We performed the acetylcholine-induced provocation test, according to the Japanese guidelines for the diagnosis and treatment of patients with CSA, in 9 consecutive patients having 5 independent AFD pedigrees. Coronary spasms were provoked in conjunction with symptoms and ECG ischemic changes in 8 of 9 (89%) patients with AFD. Conclusions: We found an unexpectedly high prevalence of CSA in patients with AFD.

DOI： 10.1253/circj.CJ-18-0734

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© 2019, Springer Science+Business Media, LLC, part of Springer Nature. Purpose of Review: To estimate the impact of the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for high blood pressure (BP) on the next hypertension guidelines in Asia. Recent Findings: The 2017 ACC/AHA guidelines for high BP in adults changed the diagnostic threshold and the management goal of BP from 140/90 to 130/80 mmHg. Another characteristic of the new guideline is its focus on a practical approach for the effective management of hypertension by using home and ambulatory BP monitoring; this point is also recommended in the 2014 Japanese Society of Hypertension Guidelines for the Management of Hypertension. Summary: In Japan, the guidelines for hypertension management are currently under revision and will be released in the spring of 2019. The core concept of the 2019 Japanese Society of Hypertension Guidelines for the Management of Hypertension, i.e., early and tight BP control over 24 h, will contribute to target-organ protection and cardiovascular disease prevention for Asians.

DOI： 10.1007/s11906-019-0906-2

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© 2019 The Japanese Society of Internal Medicine. Hypertensive emergency, which occurs even in young adults, induces systemic organ damage and results in a poor prognosis. We herein report the case of a 27-year-old man who developed alveolar hemorrhaging with hypertensive emergency. He presented with bloody sputum, renal failure, and extremely high blood pressure (200/128 mmHg). Chest computed tomography revealed diffuse bilateral alveolar infiltrates suggestive of diffuse alveolar hemorrhaging. After intensive therapy with anti-hypertensive drugs, the alveolar hemorrhaging disappeared. Renal impairment was partially reversed. Therefore, we conclude that hypertensive emergency should be considered as a possible cause of hemoptysis, even in young adults.

DOI： 10.2169/internalmedicine.0920-18

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Objective: To evaluate clinical links between levels of myeloperoxidase (MPO)–antineutrophil cytoplasmic antibody (ANCA) and relapse in patients with ANCA-associated vasculitis (AAV) using a data set from 2 nationwide prospective cohort studies. Methods: From the cohort studies, MPO-ANCA–positive patients who achieved remission during the 6 months after remission induction therapy were enrolled. We measured MPO-ANCA levels at months 0, 3, 6, 12, 18, 24, and at the time of relapse. The primary outcome measure was relapse. A nested case–control analysis and multivariable analysis were performed to investigate the relationship between ANCA reappearance and relapse. Results: Of 271 patients, 183 were classified as having microscopic polyangiitis, 34 as having granulomatosis with polyangiitis, 15 as having eosinophilic granulomatosis with polyangiitis, and 39 were unclassifiable. The median age was 73 years, and 165 (61%) were female. In 195 patients (72%), MPO-ANCA levels decreased to normal levels within 6 months after commencement of treatment, and MPO-ANCA reappeared in 73 of 181 patients (40%) with complete follow-up data. Reappearance of MPO-ANCA was more frequent in patients with relapse than in 75 age- and sex-matched control patients without relapse (odds ratio 26.2 [95% confidence interval 8.2–101], P < 0.0001) after adjustment for confounding factors. Conclusion: Reappearance of MPO-ANCA could be a clinically useful biomarker for predicting relapse in patients with MPO-ANCA–positive AAV in remission. This suggests that routine MPO-ANCA monitoring should be implemented in this patient population.

DOI： 10.1002/art.40538

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ltd  

© 2018 Japanese College of Cardiology Spontaneous coronary artery dissection (SCAD) is defined as a spontaneous separation of the coronary artery wall that is not iatrogenic or related to trauma and usually affects young women. We describe a 65-year-old woman who presented with SCAD extending from the left main trunk involving the left anterior descending artery and the left circumflex artery, and coronary artery bypass graft surgery was performed to treat the dissection. Coronary angiography performed 3 months later, showed complete angiographic healing. A conservative management strategy is known to be associated with spontaneous angiographic healing in patients with SCAD who are hemodynamically stable. Healthcare providers should consider SCAD among the differential diagnoses in patients presenting with acute coronary syndrome, particularly in women. Further studies are needed to establish an optimal management strategy for SCAD. <Learning objective: Spontaneous coronary artery dissection (SCAD) might be a cause of acute coronary syndrome not only in younger but also in older women. Even if the area of the dissection is broad, healing can be expected in future. Therefore, it is important to select between conservative and invasive therapy such as percutaneous coronary intervention or coronary artery bypass graft including selection of graft, i.e. saphenous vein graft and radial arteries, and internal mammalian arteries.>

DOI： 10.1016/j.jccase.2018.05.006

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

© 2017, The Author(s). Background: The incidence and age distribution of membranoproliferative glomerulonephritis (MPGN) vary throughout the world by race and ethnicity. We sought to evaluate the clinical features, pathogenesis, and age distribution of MPGN among a large nationwide data from the Japan Renal Biopsy Registry (J-RBR). Methods: A cross-sectional survey of 593 patients with MPGN (types I and III) registered in the J-RBR between 2007 and 2015 was conducted. Clinical parameters, and laboratory findings at diagnosis were compared between children (< 20 years), adults (20–64 years), and elderly patients (≥ 65 years). Results: The median age of the patients was 59.0 years and mean proteinuria was 3.7 g/day. The rate of nephrotic syndrome was significantly higher in adults (40.4%) and elderly patients (54.0%) than in children (14.9%), whereas the rate of chronic glomerulonephritis was significantly higher in children (66.2%) than in adults (34.4%) and elderly patients (31.2%). According to the CGA risk classification, high-risk (red zone) cases accounted for 3.4% of children, 52.5% of adults and 84.1% of elderly patients with MPGN. As for pathogenesis, primary MPGN was most frequent (56.0%). Lupus nephritis was the most common disease among adult patients with secondary MPGN, whereas infectious disease was more common in elderly patients. Multiple regression analysis revealed that high systolic blood pressure and high proteinuria were independent factors associated with decreased estimated glomerular filtration rate (eGFR) in adults and elderly patients with MPGN. Conclusions: In Japan, adults and elderly patients with MPGN had a lower eGFR and severer proteinuria than children.

DOI： 10.1007/s10157-017-1513-7

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Language：English   Publisher：Nature Publishing Group  

DOI： 10.1038/s41440-018-0055-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W.B. Saunders  

© 2018 National Stroke Association Background: Although the impact of malnutrition in patients with acute stroke has been reported, its significance after rehabilitation is not well understood. The geriatric nutritional risk index (GNRI) is a simple and well-established nutritional screening tool that predicts poor prognosis in elderly patients and in those with a high risk of cardiovascular events. We investigated the associations between GNRI and all-cause mortality, cardiovascular events, and infectious diseases in patients with stroke after rehabilitation. Methods: This study included 138 patients aged 80 years or below who were discharged between 2010 and 2013 in a single center, and followed up for more than 1 year. Malnutrition was defined as a GNRI of 96 or lower. Results: The mean age was 63.9 ± 11.0 years, the mean GNRI at discharge was 98.8 ± 6.5, and the mean total functional independence measure (FIM) score at discharge was 91.8 ± 25.8. Among the patients, 37 (27%) had malnutrition. During the follow-up period, all-cause mortality, cardiovascular events, and infectious diseases were recorded in 11 (8%), 21 (15%), and 20 (15%) patients, respectively. Kaplan–Meier curves showed a significantly higher incidence of each outcome in patients with a GNRI of 96 or lower. In the Cox proportional analysis, GNRI was an independent determinant of all-cause mortality (hazard ratio [HR],.71; 95% confidence interval [CI],.61-.83), cardiovascular events (HR,.87; 95% CI,.80-.95), and infectious diseases (HR,.80; 95% CI,.74-.87) after adjusting for age, gender, and total FIM score. Conclusions: Malnutrition has a negative impact on prognosis in patients with stroke even after rehabilitation.

DOI： 10.1016/j.jstrokecerebrovasdis.2017.10.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

© 2018 The Japanese Society of Internal Medicine. Pazopanib has been reported to induce proteinuria; however, no pathological findings have been reported. We herein report the case of a 31-year-old man with rhabdomyosarcoma treated with pazopanib who developed nephrotic syndrome. A renal biopsy revealed endothelial injury with podocyte changes. Based on the biopsy findings, we diagnosed the patient with nephrotic syndrome caused by pazopanib. Following the discontinuation of pazopanib, the patient’s proteinuria gradually decreased without any specific treatment. We should be careful when encountering drug-induced proteinuria in patients taking pazopanib.

DOI： 10.2169/internalmedicine.9576-17

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© 2018 The Authors. Objective-Angiogenesis, entire step from endothelial cells (ECs) sprouts to vascular maturation, is a critical response to ischemia. To form functional mature vessels, interactions between ECs and pericytes are essential. Ninj1 (ninjurin1) is an adhesion molecule that contributes to the pathogenesis of neuroinflammation. We recently demonstrated that Ninj1 is expressed in pericytes during angiogenesis. However, the role of Ninj1 in angiogenesis under pathophysiological ischemic conditions has not yet been elucidated. Approach and Results-Ninj1 was detected in microvessels, and its expression was enhanced in ischemic tissues after mouse hindlimb ischemia. Knockdown of Ninj1 was performed by injection of biodegradable microspheres releasing Ninj1-small interfering RNA into muscle tissues. Alternatively, pericyte-specific Ninj1 knockout was induced by tamoxifen treatment of NG2-CreERT/Ninj1-flox mice. Ninj1 knockdown/knockout reduced the formation of blood-circulating functional vessels among total CD31+ microvessels within ischemic tissues and subsequently attenuated color Doppler-assessed blood flow recovery. Ninj1 overexpression enhanced expression of Anpt (angiopoietin) 1, whereas Ninj1 knockdown enhanced the endogenous Anpt1 antagonist, Anpt2 expression in pericytes and inhibited the association of pericytes with ECs and subsequent formation of capillary-like structure, that is, EC tube surrounded with pericytes in 3-dimensional gel culture. Conclusions-Our data demonstrate that Ninj1 is involved in the formation of functional matured vessels through the association between pericytes and ECs, resulting in blood flow recovery from ischemia. These findings further the current our understanding of vascular maturation and may support the development of therapeutics for ischemic diseases. Visual Overview-An online visual overview is available for this article.

DOI： 10.1161/ATVBAHA.118.311375

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© 2017 The Authors Loss of the microvascular (MV) network results in tissue ischemia, loss of tissue function, and is a hallmark of chronic diseases. The incorporation of a functional vascular network with that of the host remains a challenge to utilizing engineered tissues in clinically relevant therapies. We showed that vascular-bed-specific endothelial cells (ECs) exhibit differing angiogenic capacities, with kidney microvascular endothelial cells (MVECs) being the most deficient, and sought to explore the underlying mechanism. Constitutive activation of the phosphatase PTEN in kidney MVECs resulted in impaired PI3K/AKT activity in response to vascular endothelial growth factor (VEGF). Suppression of PTEN in vivo resulted in microvascular regeneration, but was insufficient to improve tissue function. Promoter analysis of the differentially regulated genes in KMVECs suggests that the transcription factor FOXO1 is highly active and RNAseq analysis revealed that hyperactive FOXO1 inhibits VEGF-Notch-dependent tip-cell formation by direct and indirect inhibition of DLL4 expression in response to VEGF. Inhibition of FOXO1 enhanced angiogenesis in human bio-engineered capillaries, and resulted in microvascular regeneration and improved function in mouse models of injury-repair.

DOI： 10.1016/j.biomaterials.2017.07.010

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Background: Targeted proteomics, which involves quantitative analysis of targeted proteins using selected reaction monitoring (SRM) mass spectrometry, has emerged as a new methodology for discovery of clinical biomarkers. In this study, we used targeted serum proteomics to identify circulating biomarkers for prediction of disease activity and organ involvement in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods: A large-scale SRM assay targeting 135 biomarker candidates was established using a triple-quadrupole mass spectrometer coupled with nanoflow liquid chromatography. Target proteins in serum samples from patients in the active and remission (6 months after treatment) stages were quantified using the established assays. Identified marker candidates were further validated by enzyme-linked immunosorbent assay using serum samples (n = 169) collected in a large-cohort Japanese study (the RemIT-JAV-RPGN study). Results: Our proteomic analysis identified the following proteins as biomarkers for discriminating patients with highly active AAV from those in remission or healthy control subjects: tenascin C (TNC), C-reactive protein (CRP), tissue inhibitor of metalloproteinase 1 (TIMP1), leucine-rich alpha-2-glycoprotein 1, S100A8/A9, CD93, matrix metalloproteinase 9, and transketolase (TKT). Of these, TIMP1 was the best-performing marker of disease activity, allowing distinction between mildly active AAV and remission. Moreover, in contrast to CRP, serum levels of TIMP1 in patients with active AAV were significantly higher than those in patients with infectious diseases. The serum levels of TKT and CD93 were higher in patients with renal involvement than in those without, and they predicted kidney outcome. The level of circulating TNC was elevated significantly in patients with lung infiltration. AAV severity was associated with markers reflecting organ involvement (TKT, CD93, and TNC) rather than inflammation. The eight markers and myeloperoxidase (MPO)-ANCA were clustered into three groups: MPO-ANCA, renal involvement (TKT and CD93), and inflammation (the other six markers). Conclusions: We have identified promising biomarkers of disease activity, disease severity, and organ involvement in AAV with a targeted proteomics approach using serum samples obtained from a large-cohort Japanese study. Especially, our analysis demonstrated the effectiveness of TIMP1 as a marker of AAV activity. In addition, we identified TKT and CD93 as novel markers for evaluation of renal involvement and kidney outcome in AAV.

DOI： 10.1186/s13075-017-1429-3

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DOI： 10.1038/hr.2017.51

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

© 2015 Japan College of Rheumatology. Microscopic polyangiitis (MPA) is a systemic vasculitis associated with antineutrophil cytoplasmic antibodies, and it involves multiple organs, including the kidneys and lungs. We report on the case of a 72-year-old woman with MPA who developed hemocholecyst in addition to alveolar hemorrhage and rapidly progressive glomerulonephritis. Although her renal function was not salvaged, the alveolar hemorrhage and hemocholecyst were treated conservatively. Clinicians should consider the possibility of hemocholecyst in patients with MPA complaining of abdominal pain.

DOI： 10.3109/14397595.2015.1016138

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© 2016, Springer Japan. The pro-arrhythmic triggers in Brugada and early repolarization syndromes (BrS, ERS) have not been analyzed systematically except for case reports. We clinically investigated the circumstances which precede/predispose to arrhythmic events in these syndromes during long-term follow-up. A detailed history from the patients/witnesses was taken to investigate the antecedent events in the last few hours that preceded syncope/ventricular fibrillation (VF); medical records, ECG and blood test from the emergency room (ER) were reviewed. 19 patients that fulfilled the investigation criteria were followed up for 71 ± 49 months (34–190 months). Prior to the event (syncope/VF), the patients were partaking different activities in the following decreasing order; drinking alcoholic beverage, having meal, and getting up from sleep, exercise. 3 patients reported mental/physical stress prior to the event and 2 patients developed VF several days after starting oral steroid for treatment of bronchial asthma. In the ER, elevated J-wave amplitude (0.27 ± 0.15 mV) was found with 58 % of the patients having hypokalemia. After electrolyte correction and cessation of steroids, the following day plasma K+ (4.2 ± 0.3 mEq/L, P < 0.001) was significantly increased and J-wave amplitude (0.13 ± 0.1 mV, P < 0.001) was remarkably reduced. Three patients were kept on oral spironolactone/potassium supplements. During follow-up for 71 ± 49 (34–190) months, among 4 patients with VF recurrence, one patient developed VF after taking oral steroid. In ERS and BrS, hypokalemia and corticosteroid therapy add substantial pro-arrhythmic effects, but potentially treatable. Stopping steroid therapy and avoiding hypokalemia had excellent long-term outcome.

DOI： 10.1007/s00380-016-0828-8

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Copyright © 2016 by the American Society of Nephrology. The identification of the cellular origins of myofibroblasts has led to the discovery of novel pathways that potentially drive myofibroblast perpetuation in disease. Here, we further investigated the role of innate immune signaling pathways in this process. In mice, renal injury-induced activation of pericytes, which are myofibroblast precursors attached to endothelial cells, led to upregulated expression of TNF receptor superfamily member 12a, also known as fibroblast growth factor-inducible 14 (Fn14), by these cells. In live rat kidney slices, administration of the Fn14 ligand, TNF-related weak inducer of apoptosis (TWEAK), promoted pericyte-dependent vasoconstriction followed by pericyte detachment from capillaries. In vitro, administration of TWEAK activated and differentiated pericytes into cytokine-producing myofibroblasts, and further activated established myofibroblasts in a manner requiring canonical and noncanonicalNF-kB signaling pathways. Deficiency of Fn14 protected mouse kidneys from fibrogenesis, inflammation, and associated vascular instability after in vivo injury, and was associated with loss of NF-kB signaling. In a genetic model of spontaneous CKD, therapeutic delivery of anti-TWEAK blocking antibodies attenuated disease progression, preserved organ function, and increased survival. These results identify theTWEAK-Fn14 signaling pathway as an important factor in myofibroblast perpetuation, fibrogenesis, and chronic disease progression.

DOI： 10.1681/ASN.2015111227

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© 2016 The Japanese Society of Hypertension. All rights reserved. Although malnutrition indicates an unfavorable prognosis in some clinical settings, the synergistic impact of nutritional state, renal dysfunction and left ventricular hypertrophy (LVH) on cardiovascular events is unknown. Among 338 patients aged 40-80 years who underwent echocardiographic evaluation between 2003 and 2005, 161 patients who were followed for >7 years were recruited. Malnutrition was defined as a geriatric nutritional risk index (GNRI) of ≤96. The mean patient age was 63.5±9.2 years; the mean estimated glomerular filtration rate (eGFR) was 72.9±18.7 ml min -1 per 1.73 m 2; the mean LV mass index was 114±33 g m - 2; and the mean GNRI was 100.4±6.0. Among the patients, 25% (n=40) had an eGFR of <60 ml min -1 per 1.73 m 2, 29% (n=46) exhibited chronic kidney disease (CKD) and 37% (n=59) had LVH. During the follow-up period (median: 96 months), cardiovascular events were observed in 15 patients (9%). Kaplan-Meier curves showed a significantly higher incidence of cardiovascular events in patients with an eGFR of <60 ml min -1 per 1.73 m 2 (log-rank P=0.007), a GNRI of ≤96 (P=0.003) or LVH (P=0.010). In a Cox regression analysis, eGFR, LVH and GNRI were independent determinants of cardiovascular event incidence after adjusting for age, gender and the presence of hypertension and diabetes. Furthermore, the combination of LVH and lower GNRI was significantly associated with a higher rate of cardiovascular events not only in all patients but also in patients with CKD. In conclusion, malnutrition, low eGFR and LVH were independent determinants of cardiovascular event incidence; they synergistically increased rates of these events in the long term. The evaluation and management of LVH progression and the improvement of nutritional status are critical for preventing cardiovascular complications even in non-dialysis patients.

DOI： 10.1038/hr.2016.47

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DOI： 10.1038/hr.2016.55

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Language：English   Publisher：AMER PHYSIOLOGICAL SOC  

MicroRNAs (miRs), a class of small noncoding RNAs that act as post-transcriptional regulators of gene expression, have attracted increasing attention as critical regulators of organogenesis, cancer, and disease. Interest has been spurred by development of a novel class of synthetic RNA oligonucleotides with excellent drug-like properties that hybridize to a specific miR, preventing its action. In kidney disease, a small number of miRs are dysregulated. These overlap with regulated miRs in nephrogenesis and kidney cancers. Several dysregulated miRs have been identified in fibrotic diseases of other organs, representing a "fibrotic signature," and some of these fibrotic miRs contribute remarkably to the pathogenesis of kidney disease. Chronic kidney disease, affecting similar to 10% of the population, leads to kidney failure, with few treatment options. Here, we will explore the pathological mechanism of miR-21, whose pre-eminent role in amplifying kidney disease and fibrosis by suppressing mitochondrial biogenesis and function is established. Evolving roles for miR-214, -199, -200, -155, -29, -223, and -126 in kidney disease will be discussed, and we will demonstrate how studying functions of distinct miRs has led to new mechanistic insights for kidney disease progression. Finally, the utility of anti-miR oligonucleotides as potential novel therapeutics to treat chronic disease will be highlighted.

DOI： 10.1152/ajprenal.00523.2015

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© 2016 American Society for Clinical Investigation. All rights reserved. Pentraxin-2 (PTX-2), also known as serum amyloid P component (SAP/APCS), is a constitutive, antiinflammatory, innate immune plasma protein whose circulating level is decreased in chronic human fibrotic diseases. Here we show that recombinant human PTX-2 (rhPTX-2) retards progression of chronic kidney disease in Col4a3 mutant mice with Alport syndrome, reducing blood markers of kidney failure, enhancing lifespan by 20%, and improving histological signs of disease. Exogenously delivered rhPTX-2 was detected in macrophages but also in tubular epithelial cells, where it counteracted macrophage activation and was cytoprotective for the epithelium. Computational analysis of genes regulated by rhPTX-2 identified the transcriptional regulator c-Jun along with its activator protein–1 (AP-1) binding partners as a central target for the function of rhPTX-2. Accordingly, PTX-2 attenuates c-Jun and AP-1 activity, and reduces expression of AP-1–dependent inflammatory genes in both monocytes and epithelium. Our studies therefore identify rhPTX-2 as a potential therapy for chronic fibrotic disease of the kidney and an important inhibitor of pathological c-Jun signaling in this setting.

DOI： 10.1172/jci.insight.87446

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

© 2015 The Japanese Society of Internal Medicine. Fabry disease can cause various neurological manifestations. We describe the case of a Japanese woman with Fabry disease who presented with ischemic stroke, aseptic meningitis, and psychiatric symptoms. The patient had a mutation in intron 4 of her a-galactosidase A gene, which was not detected in her family. This case suggests that Fabry disease should be considered in young patients who exhibit central nervous system symptoms such as ischemic stroke, even if there is no family history of the condition. The episodes of aseptic meningitis and stroke experienced by our patient suggest that persistent inflammation might be the mechanism underlying Fabry disease.

DOI： 10.2169/internalmedicine.54.4719

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© 2015 International Society of Nephrology. MicroRNAs, activated by the enzyme Dicer1, control post-transcriptional gene expression. Dicer1 has important roles in the epithelium during nephrogenesis, but its function in stromal cells during kidney development is unknown. To study this, we inactivated Dicer1 in renal stromal cells. This resulted in hypoplastic kidneys, abnormal differentiation of the nephron tubule and vasculature, and perinatal mortality. In mutant kidneys, genes involved in stromal cell migration and activation were suppressed as were those involved in epithelial and endothelial differentiation and maturation. Consistently, polarity of the proximal tubule was incorrect, distal tubule differentiation was diminished, and elongation of Henle's loop attenuated resulting in lack of inner medulla and papilla in stroma-specific Dicer1 mutants. Glomerular maturation and capillary loop formation were abnormal, whereas peritubular capillaries, with enhanced branching and increased diameter, formed later. In Dicer1-null renal stromal cells, expression of factors associated with migration, proliferation, and morphogenic functions including α-smooth muscle actin, integrin-α8, -β1, and the WNT pathway transcriptional regulator LEF1 were reduced. Dicer1 mutation in stroma led to loss of expression of distinct microRNAs. Of these, miR-214, -199a-5p, and -199a-3p regulate stromal cell functions ex vivo, including WNT pathway activation, migration, and proliferation. Thus, Dicer1 activity in the renal stromal compartment regulates critical stromal cell functions that, in turn, regulate differentiation of the nephron and vasculature during nephrogenesis.

DOI： 10.1038/ki.2014.406

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© 2015 The Japanese Society of Internal Medicine. Minimal change nephrotic syndrome (MCNS) is a common form of nephrotic syndrome (NS). We herein present the case of a 57-year-old woman with advanced lung adenocarcinoma treated with the tyrosine kinase inhibitor (TKI) gefitinib who developed NS. A renal biopsy revealed minor glomerular abnormalities, and the patient’s symptoms improved exclusively with the discontinuation of gefitinib. Therefore, we diagnosed her with MCNS associated with gefitinib treatment. A few months later, however, she developed recurrent lung tumors. Following the challenging initiation of the TKI erlotinib, she achieved remission without proteinuria. We thus conclude that erlotinib is a potential treatment option in patients with NS associated with gefitinib therapy.

DOI： 10.2169/internalmedicine.54.3661

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© 2014 International Society for Apheresis. Metabolic syndrome confers an increased risk of cardiovascular disease (CVD) in the general population. The relationship between adiponectins, and clinical outcomes in patients undergoing hemodialysis remains controversial. We investigated whether adiponectins, biomarkers of inflammation, nutrition status and clinical features predict the mortality of patients undergoing hemodialysis for 6 years. We measured baseline plasma total and high-molecular-weight (HMW) adiponectins, tumor necrosis factor (TNF)-α, serum high sensitivity C-reactive protein (hsCRP), and clinical characteristics including visceral fat area (VFA) and the Geriatric Nutritional Risk Index (GNRI) in 133 patients undergoing chronic hemodialysis. Forty-one of the 133 patients died during follow-up. The deceased patients were significantly older, had more prior CVD and diabetes, higher TNF-α and hsCRP levels but lower GNRI. VFA, and total and HMW adiponectin did not significantly differ between the two groups. TNF-α and hsCRP levels and GNRI score were significant for predicting all-cause and cardiovascular mortality in receiver operating curve analyses. When stratified by a GNRI score of 96, Cox proportional hazards analyses identified TNF-α as a significant predictor of all-cause mortality (hazard ratio [HR] 1.23; P=0.038) and hsCRP as a significant predictor of all-cause and cardiovascular mortality (HR, 2.32, P=0.003; HR 2.30, P=0.012, respectively) after adjusting for age, sex, diabetes mellitus, and prior CVD, only in malnourished patients. These results demonstrate that malnutrition and the inflammatory markers TNF-α and hsCRP, but not metabolic markers, including VFA and adiponectins have a significant impact on 6-year all-cause and cardiovascular mortality in Japanese patients undergoing hemodialysis. Therapeutic Apheresis and Dialysis.

DOI： 10.1111/1744-9987.12190

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL INVESTIGATION INC  

MicroRNA-21 (miR-21) contributes to the pathogenesis of fibrogenic diseases in multiple organs, including the kidneys, potentially by silencing metabolic pathways that are critical for cellular ATP generation, ROS production, and inflammatory signaling. Here, we developed highly specific oligonucleotides that distribute to the kidney and inhibit miR-21 function when administered subcutaneously and evaluated the therapeutic potential of these anti-miR-21 oligonucleotides in chronic kidney disease. In a murine model of Alport nephropathy, miR-21 silencing did not produce any adverse effects and resulted in substantially milder kidney disease, with minimal albuminuria and dysfunction, compared with vehicle-treated mice. miR-21 silencing dramatically improved survival of Alport mice and reduced histological end points, including glomerulosclerosis, interstitial fibrosis, tubular injury, and inflammation. Anti-miR-21 enhanced PPARα/retinoid X receptor (PPARα/RXR) activity and downstream signaling pathways in glomerular, tubular, and interstitial cells. Moreover, miR-21 silencing enhanced mitochondrial function, which reduced mitochondrial ROS production and thus preserved tubular functions. Inhibition of miR-21 was protective against TGF-β-induced fibrogenesis and inflammation in glomerular and interstitial cells, likely as the result of enhanced PPARα/RXR activity and improved mitochondrial function. Together, these results demonstrate that inhibition of miR-21 represents a potential therapeutic strategy for chronic kidney diseases including Alport nephropathy.

DOI： 10.1172/JCI75852

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© 2013, The Author(s). Renovascular hypertension is an important cause of secondary hypertension. We present the case of a 61-year-old man with renovascular hypertension caused by chronic total occlusion of the left renal artery resulting in an atrophic kidney. Although renography indicated almost no residual function of the left kidney, renal vein sampling showed a significant increase of renin secretion in the left kidney. The endocrine function of the left kidney was believed to be preserved; thus, we performed percutaneous transluminal renal angioplasty with stent placement. After the procedure, the patient’s blood pressure decreased gradually to within the normal range without adverse events. The laboratory data on endocrine function and the renography findings drastically improved. Percutaneous transluminal renal angioplasty is a promising therapeutic procedure for renovascular hypertension with an atrophic kidney.

DOI： 10.1007/s00380-013-0457-4

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©2014 Izawa et al. Background: Angiotensin II (AII) plays a central role in vascular remodeling via oxidative stress. However, the interaction between AII and reduced glutathione (GSH) redox status in cardiovascular remodeling remains unknown.Methods: In vivo: The cuff-induced vascular injury model was applied to Sprague Dawley rats. Then we administered saline or a GSH inhibitor, buthionine sulfoximine (BSO, 30 mmol/L in drinking water) for a week, subsequently administered 4 more weeks by osmotic pump with saline or AII (200 ng/kg/minute) to the rats. In vitro: Incorporation of bromodeoxyuridine (BrdU) was measured to determine DNA synthesis in cultured rat vascular smooth muscle cells (VSMCs).Results: BSO reduced whole blood GSH levels. Systolic blood pressure was increased up to 215±4 mmHg by AII at 4 weeks (p〈0.01), which was not affected by BSO. Superoxide production in vascular wall was increased by AII and BSO alone, and was markedly enhanced by AII+BSO. The left ventricular weight to body weight ratio was significantly increased in AII and AII+BSO as compared to controls (2.52±0.08, 2.50±0.09 and 2.10±0.07 mg/g respectively, p〈0.05). Surprisingly, the cotreatment of BSO totally abolished these morphological changes. Although the vascular circumferential wall stress was well compensated in AII, significantly increased in AII +BSO. The anti-single-stranded DNA staining revealed increasing apoptotic cells in the neointima of injured arteries in BSO groups. BrdU incorporation in cultured VSMCs with AII was increased dosedependently. Furthermore it was totally abolished by BSO and was reversed by GSH monoethyl ester.Conclusions: We demonstrated that a vast oxidative stress in impaired GSH redox system totally abolished AII-induced vascular, not cardiac remodeling via enhancement of apoptosis in the neointima and suppression of cell growth in the media. The drastic suppression of remodeling may result in fragile vasculature intolerable to mechanical stress by AII.

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Objective: The aim of the present study was to compare the cardiovascular effects of olmesartan, an angiotensin II receptor blocker, combined with a calcium channel blocker (CCB) or a diuretic, in a prospective, randomized, openlabel, blinded endpoint trial. Methods: Japanese hypertensive patients aged at least 65 to less than 85 years with SBP at least 140mmHg and/or DBP at least 90mmHg with antihypertensive treatment, or SBP at least 160mmHg and/or DBP at least 100mmHg without antihypertensive treatment were randomized to receive olmesartan with either a dihydropyridine CCB or a low-dose diuretic. If SBP and/or DBP remained at least 140 and/or at least 90mmHg, the other antihypertensive drug was added. The primary endpoint was a composite of fatal and nonfatal cardiovascular events. The median follow-up time was 3.3 years. Results: Blood pressure decreased similarly in both groups. The primary endpoint occurred in 116/2568 patients (4.5%) in the olmesartan plus CCB group and in 135/2573 patients (5.3%) in the olmesartan plus diuretic group [hazard ratio 0.83, 95% confidence interval (CI) 0.65- 1.07, P=0.16]. Rates of all-cause death and cardiovascular deaths were similar. Among patients aged at least 75 years, the incidence of stroke tended to be lower in the olmesartan plus CCB group than in the olmesartan plus diuretic group (hazard ratio 0.63, 95% CI 0.38-1.02, P=0.059, interaction P=0.019). Fewer patients in the olmesartan plus CCB group (8.2%, 211/2568) than in the olmesartan plus diuretic group (9.8%, 253/2573; P=0.046) experienced serious adverse events. Conclusion: Despite no significant difference in cardiovascular events, the different safety profiles suggest that the combination of olmesartan and CCB may be preferable to that of olmesartan and diuretic.

DOI： 10.1097/HJH.0000000000000281

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© 2013, Springer Science+Business Media New York. Fibrosis of the kidney glomerulus and interstitium are characteristic features of almost all chronic kidney diseases. Fibrosis is tightly associated with destruction of capillaries, inflammation, and epithelial injury which progresses to loss of nephrons, and replacement of kidney parenchyma with scar tissue. Understanding the origins and nature of the cells known as myofibroblasts that make scar tissue is central to development of new therapeutics for kidney disease. Whereas many cell lineages in the body have become defined by well-established markers, myofibroblasts have been much harder to identify with certainty. Recent insights from genetic fate mapping and the use of dynamic reporting of cells that make fibrillar collagen in mice have identified with greater clarity the major population of myofibroblasts and their precursors in the kidney. This review will explore the nature of these cells in health and disease of the kidney to understand their central role in the pathogenesis of kidney disease.

DOI： 10.1007/s40139-013-0025-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

QT Dynamics in Early Repolarization Syndrome Introduction Almost all current investigations on early repolarization syndrome (ERS) have focused on the J-wave characteristics and ST-segment configuration; however, few have reported on ventricular repolarization indexes in ERS. Methods and Results A total of 145 subjects were enrolled: 10 ERS patients, 45 uneventful ER pattern (ERP) subjects, and 90 healthy controls without J waves or ST-segment elevation. Ambulatory ECG-derived parameters (QT, QTc(B), QTc(F), T peak-Tend(Tpe), and QT/RR slope) were measured and statistically compared. Among the groups, there was no significant difference in the average QT and QTc(B); however, ERS patients had the shortest QTc(F) and longest Tpe (QTc(F): 396.2 ± 19 vs 410.4 ± 20 vs 419.2 ± 19 milliseconds, P = 0.036, Tpe: 84.9 ± 12 vs 70.4 ± 11 vs 66.9 ± 15 milliseconds, P < 0.001, for the ERS, ERP, and control groups, respectively). Importantly, the 24-hour QT/RR slope was significantly smaller in the ERS than ERP and control groups (QT/RR: 0.105 ± 0.01 vs 0.154 ± 0.02 vs 0.161 ± 0.03, respectively; P < 0.001). When analyzing the diurnal and nocturnal QT/RR slopes, ERS patients had small diurnal and nocturnal QT/RR slopes while the ERP and control groups had large diurnal and small nocturnal QT/RR slopes (diurnal QT/RR: 0. 077 ± 0.01 vs 0.132 ± 0.03 vs 0.143 ± 0.03, P < 0.001; nocturnal QT/RR: 0.093 ± 0.02 vs 0.129 ± 0.03 vs 0.130 ± 0.04, P = 0.02 in the ERS, ERP, and control groups, respectively). Conclusion ERS patients had a continuously depressed diurnal and nocturnal adaptation of the QT interval to the heart rate. Such abnormal repolarization dynamics might provide a substrate for reentry and be an important element for developing ventricular fibrillation in the ERS cohort. © 2012 Wiley Periodicals, Inc.

DOI： 10.1111/jce.12074

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Sarcoidosis is a multisystem disease related to helper T cell responses. We recently experienced the case of a 57-year-old woman with sarcoidosis complicated by crescentic glomerulonephritis with low levels of myeloperoxidase-antineutrophil cytoplasmic antibody. We herein describe the details of her clinical course and discuss the effectiveness of mizoribine, which has an immunosuppressive effect equivalent to that of mycophenolate mofetil, not only for urinalysis abnormalities but also for hilar lymph node enlargement. © 2012 Japan College of Rheumatology.

DOI： 10.1007/s10165-012-0614-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CIRCULATION SOC  

Background: Prostacyclin (PGI2) enhances angiogenesis, especially in cooperation with bone marrow (BM)-derived endothelial progenitor cells (EPCs). However, the mechanisms of PGI2 in EPC-mediated angiogenesis in vivo remain unclear. The purpose of this study was to clarify the role of PGI2 in EPC-mediated angiogenesis using BM-specific IP deletion mice. Methods and Results: Hind limb ischemia (HLI) was induced in wild-type (WT) mice transplanted with IP-deleted BM (WT/BM(IP-/-). Recovery of blood flow (RBF) in WT/BM(IP-/-) was impaired for 28 days after HLI, whereas RBF in IP-/-/BM(WT) was attenuated for up to 7 days compared with WT/BM(WT). The impaired RBF in WT/BM(IP-/-) was completely recovered by intramuscular injection of WT EPCs but not IP-/- EPCs. The impaired effects of IP-/- EPCs were in accordance with reduced formation of capillary and arterioles in ischemic muscle. An ex vivo aortic ring assay revealed that microvessel formation was enhanced by accumulation/adhesion of EPCs to perivascular sites as pericytes. IP-/-EPCs, in which expression of integrins was decreased, had impaired production of angiogenic cytokines, adhesion to neovessels and their angiogenic effects. The small-interfering RNA (siRNA)-mediated knockdown of integrin β1 in WT EPCs attenuated adhesion to microvessels and their in vivo and in vitro angiogenic effects. Conclusions: PGI2 may induce persistent angiogenic effects in HLI through adhesion of EPCs to perivascular sites of neovessels via integrins in addition to paracrine effects.

DOI： 10.1253/circj.CJ-12-0897

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Background and objectives: Data regarding renal disease in the elderly (age ≥65 years old) and very elderly (age ≥80 years old) Japanese are extremely limited. The aim of this study was to examine the causes of renal disease and their clinical presentations in elderly patients who underwent renal biopsy. Design, setting, participants, and measurements: From July 2007 to November 2011, all of the elderly native renal biopsy patients who had been registered in the Japan Renal Biopsy Registry (J-RBR; 2802 including 1596 males and 1206 females) were identified. Their data were compared with a control group of 7416 patients who ranged in age from 20 to 64 years old and were registered on the J-RBR over the same period. In addition, the clinical and pathological classifications of 276 very elderly patients were also analyzed. Results: The indications for biopsy were nephrotic syndrome (NS) in 36.2 and 50.7 % of the elderly and the very elderly patients, chronic nephritic syndrome in 31.8 and 17.4 %, and acute kidney injury including rapidly progressive glomerulonephritis in 18.6 and 22.5 %, respectively. Primary glomerular disease was the most frequent diagnosis, followed by MPO-ANCA-positive nephritis, IgA nephropathy (IgAN), and diabetic nephropathy. In primary GN including IgAN, membranous nephropathy (MN) was the most frequent histological type, followed by IgAN and minor glomerular abnormalities. A comparison with the control group showed that MN, MPO-ANCA-positive nephritis, and amyloid nephropathy were more common in the elderly (P < 0.001), and IgAN was less common (P < 0.001). As for nephrotic syndrome in the elderly, MN was the most common histological type, followed by minimal change NS, diabetic nephropathy, amyloid nephropathy, and focal segmental glomerulosclerosis. There was a significant discrepancy between the urinary protein/creatinine ratio and daily proteinuria after the 7th decade of life. Conclusions: Renal biopsy is a valuable diagnostic tool, even in elderly and very elderly Japanese patients. In the future, modified clinical guidelines for elderly renal disease should be developed. © 2012 Japanese Society of Nephrology.

DOI： 10.1007/s10157-012-0673-8

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Inflammatory responses in the kidney lead to tubulointerstitial fibrosis, a common feature of chronic kidney diseases. Here we examined the role of prostaglandin E2 (PGE2) in the development of tubulointerstitial fibrosis. In the kidneys of wild-type mice, unilateral ureteral obstruction leads to progressive tubulointerstitial fibrosis with macrophage infiltration and myofibroblast proliferation. This was accompanied by an upregulation of COX-2 and PGE2 receptor subtype EP4 mRNAs. In the kidneys of EP4 gene knockout mice, however, obstruction-induced histological alterations were significantly augmented. In contrast, an EP4-specific agonist significantly attenuated these alterations in the kidneys of wild-type mice. The mRNAs for macrophage chemokines and profibrotic growth factors were upregulated in the kidneys of wild-type mice after ureteral obstruction. This was significantly augmented in the kidneys of EP4-knockout mice and suppressed by the EP4 agonist but only in the kidneys of wild-type mice. Notably, COX-2 and MCP-1 proteins, as well as EP4 mRNA, were localized in renal tubular epithelial cells after ureteral obstruction. In cultured renal fibroblasts, another EP4-specific agonist significantly inhibited PDGF-induced proliferation and profibrotic connective tissue growth factor production. Hence, an endogenous PGE2-EP4 system in the tubular epithelium limits the development of tubulointerstitial fibrosis by suppressing inflammatory responses. © 2012 International Society of Nephrology.

DOI： 10.1038/ki.2012.115

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Fetuin-A and osteoprotegerin (OPG) are arterial calcification regulators, which are related to cardiovascular survival in hemodialysis patients. We hypothesized that a balance of these calcification regulators might mediate the progression of left ventricular (LV) diastolic dysfunction in hemodialysis patients. We recruited 63 hemodialysis patients and measured their serum fetuin-A, OPG, arterial stiffness, aortic calcification and echocardiographic parameters, including the transmitral early diastolic velocity/tissue Doppler mitral annular early diastolic velocity ratio (E/E′), and analyzed the relationships between these variables. Fetuin-A levels were significantly and negatively correlated with the ankle-brachial pulse wave velocity (baPWV), aortic calcification score (AOCS), left atrial volume index (LAVI), LV mass index (LVMI) and E/E′. OPG levels and the ratio of OPG to fetuin-A levels were significantly and positively correlated with the baPWV, AOCS, LAVI and E/E′. A stepwise multiple regression analysis revealed that E/E′ was independently correlated with fetuin-A levels (β=-0.334, P=0.02), OPG levels (β0.367, P=0.01) and the ratio of OPG to fetuin-A (β0.295, P=0.04). Categorizing the patients according to their serum fetuin-A and OPG levels revealed that patients with low fetuin-A and high OPG levels had the highest LAVI, LVMI and E/E′ values after adjusting for potential confounders. Serum fetuin-A levels negatively reflected, whereas OPG levels and the ratio of OPG to fetuin-A positively reflected an increase in vascular and ventricular stiffness, leading to the aggravation of diastolic dysfunction. Therefore, based on our results, the balance of the tissue calcification regulators fetuin-A and OPG could mediate the progression of LV diastolic dysfunction in hemodialysis patients. © 2012 The Japanese Society of Hypertension All rights reserved.

DOI： 10.1038/hr.2011.201

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Large infarcts are associated with a terminal QRS-distortion in ST-elevation myocardial infarction (STEMI) patients. Late gadolinium enhancement (LGE) on the cardiac MRI (CMR) can depict an infarct distribution. However, less is known about the relationship between the LGE findings and QRS-distortion on admission, including the best ECGlead location to reveal the QRS-distortion (DIS-lead) in STEMI patients. Fifty STEMI patients successfully treated with percutaneous coronary intervention were classified into two groups according to whether the QRS-distortion was positive (+) or negative (-). The LGE on a recent CMR was classified into 12 left ventricular segments (Basal-Middle-Apical × Anterior-Septal-Inferior-Lateral). The coincidences between the segmental LGE scores and DIS-lead were investigated. All patients were divided into 23 QRS-distortion (+) and 27 QRS-distortion (-) groups. The total LGE score was significantly greater in the QRS-distortion (+) group (14.7 ± 6.8 versus 9.6 ± 6.2, P < 0.01). The highest LGE score in 96% of QRS-distortion (+) patients was 4, and a score 4 segment indicated a good selection of the DIS-lead (86.4%). QRSdistortion in the ECG on admission represents severe transmural infarction in the LGE using CMR, which represents large infarcts in STEMI patients.

DOI： 10.1536/ihj.53.270

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Objective Patients with chronic kidney disease (CKD) are at a high risk for cardiovascular diseases including stroke. However, the characteristics of the stroke subtypes in patients with CKD remain to be determined. Methods We investigated the associations between stroke subtypes and estimated glomerular filtration rate (eGFR), and traditional risk factors in 451 (males, 239; mean age, 71.1 y) acute stroke patients at our hospital between 2006 and 2010. Results The stroke subtype was cardiogenic cerebral embolism in 129 (29%), cerebral hemorrhage in 104 (23%), unclassified cerebral infarction in 65 (14%), lacunar infarction in 65 (14%), subarachnoid hemorrhage in 41 (9%), atherothrombosis in 30 (7%), and transient ischemic attacks in 17 (4%). Among the 451 patients, 134 (30%) had CKD with eGFR <60 mL/min/1.73 m2. Compared with a group without CKD, mean age (75.9 vs. 69.0 years, p<0.05), the prevalence of atrial fibrillation (AF) (44% vs. 21%, p<0.01) and a history of cardiovascular disease (37% vs. 19%, p<0.01) were significantly higher in that with CKD. A comparison of stroke subtypes revealed a significantly higher incidence of cardiogenic cerebral embolism (36% vs. 26%, p<0.05) in the group with, than without CKD. Conclusion We showed the prevalence of CKD in about 30% of acute stroke patients, and those patients were older, had a significantly higher prevalence of AF and a higher rate of cardiogenic cerebral embolism compared with patients without CKD. Thus, strict control of blood pressure and management of AF should be important to prevent stroke among patients with CKD. © 2012 The Japanese Society of Internal Medicine.

DOI： 10.2169/internalmedicine.51.7185

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Objective Tonsillectomy and steroid-pulse (TSP) therapy have been proposed as a curative treatment for immunoglobulin A nephropathy (IgAN) in Japan. However, we sometimes encounter patients who reject steroid-pulse therapy because of concerns about the side effects of corticosteroids. Here, we examined the efficacy of TSP therapy and tonsillectomy alone for IgAN with urinary abnormalities. Methods Data on 40 IgAN patients diagnosed by renal biopsies, who presented glomerular hematuria and proteinuria at baseline and underwent bilateral palatine tonsillectomy, were analyzed retrospectively. Twenty of them underwent TSP therapy (TSP group), and 20 underwent tonsillectomy alone (T group). We examined associations between therapies, changes in urinary findings and renal function, and subsequent clinical remission (CR), defined as negative proteinuria and urinary erythrocytes of less than 5/high-power field. Results TSP group showed a significant decrease in proteinuria and hematuria earlier than T group. The rates of CR were significantly higher in TSP group compared with T group on the final observation period (75% vs. 45%, p<0.05). There was a significant difference between CR group and non-CR group only in the rate of receiving TSP therapy. Conclusion TSP therapy significantly increased the probability of CR compared with tonsillectomy alone in IgAN patients with urinary abnormalities. © 2012 The Japanese Society of Internal Medicine.

DOI： 10.2169/internalmedicine.51.7238

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Kawasaki disease (KD) is a mucocutaneous lymph node syndrome with important cardiovascular complications which usually afflicts young children. We describe a 16-year-old woman who developed transient heart failure during the acute phase of incomplete KD. The diagnosis was based on the development of coronary aneurysms during heart failure and 2 criteria of the disease. Incomplete KD is a cause, albeit rare, of myocardial dysfunction in human adolescents. Healthcare providers should therefore be aware of the possibility of incomplete KD in patients with heart failure during the course of an acute febrile illness associated with mucocutaneous changes. © 2012 The Japanese Society of Internal Medicine.

DOI： 10.2169/internalmedicine.51.7413

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Microalbuminuria is a recognized risk factor and predictor for cardiovascular events in patients with hypertension. We analyzed changes in hypotensive effect, urinary albumin excretion (UAE) and estimated glomerular filtration rate (eGFR) in subjects with hypertension and microalbuminuria as a subanalysis of the results of the Nifedipine and Candesartan Combination (NICE-Combi) Study. A total of 86 subjects with essential hypertension with microalbuminuria (UAE <300 mg g -1 creatinine) were randomly assigned in a double-blind manner to a combination therapy group (standard-dose candesartan at 8 mg per day plus controlled-release (CR) nifedipine 20 mg per day) (n=42) or an up-titrated monotherapy group (candesartan 12 mg per day) (n=44) for 8 weeks of continuous treatment after initially receiving standard-dose candesartan (8 mg per day) monotherapy for 8 weeks (initial treatment). After 8weeks, blood pressure (BP) was significantly reduced in both groups compared with at the end of initial treatment. UAE also showed a significant decrease in the combination therapy group, while there was no significant change of eGFR in either group. A significant positive correlation was seen between BP reduction and UAE after 8 weeks of double-blind treatment in both groups, whereas no significant association was found between ΔUAE and ΔeGFR in either group. These findings show that combination therapy with standard-dose candesartan and nifedipine CR is more effective than up-titrated candesartan monotherapy for reducing BP and improving UAE while maintaining eGFR, and strongly suggest that the combination of an angiotensin II receptor blocker and long-acting calcium channel blocker is beneficial in patients with hypertension and microalbuminuria. © 2011 The Japanese Society of Hypertension All rights reserved.

DOI： 10.1038/hr.2011.101

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Fabry disease is an X-linked lysosomal storage disorder caused by mutations of the α-galactosidase A gene (GLA), and the disease is a relatively prevalent cause of left ventricular hypertrophy mimicking idiopathic hypertrophic cardio-myopathy. We assessed clinically 5 patients of a three-generation family and also searched for GLA mutations in 10 family members. The proband had left ventricular hypertrophy with localized thinning in the basal posterior wall and late gadolinium enhancement (LGE) in the near-circumferential wall in cardiovascular magnetic resonance images and her sister had vasospastic angina pectoris without organic stenosis of the coronary arteries. LGE notably appeared in parallel with decreased α-galactosidase A activity and increased NT-pro BNP in our patients. We detected a new GLA missense mutation (G195V) in exon 4, resulting in a glycine-to-valine substitution. Of the 10 family members, 5 family members each were positive and negative for this mutation. These new data extend our clinical and molecular knowledge of GLA gene mutations and confirm that a novel missense mutation in the GLA gene is important not only for a precise diagnosis of heterozygous status, but also for confirming relatives who are negative for this mutation.

DOI： 10.1536/ihj.52.308

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DOI： 10.1016/j.ijcard.2010.12.057

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Although metabolic syndrome confers an increased risk of cardiovascular disease in the general population, little is known about the alteration of abdominal adiposity and its association with adipocytokines in hemodialysis patients. We investigated the plasma high-molecular-weight (HMW) adiponectin level and its relationship to visceral fat area (VFA) and various markers of atherosclerosis in hemodialysis patients. In a cross-sectional study, conventional cardiovascular risk factors, plasma total and HMW adiponectin, the number of components of the metabolic syndrome and, using computed tomography, the distribution of abdominal adiposity were assessed in 144 hemodialysis patients (90 men and 54 women; mean age, 60.7 years) and 30 age- and sex-matched patients with chronic kidney disease (CKD). Plasma HMW adiponectin levels in hemodialysis patients were significantly higher than those in patients with CKD, negatively associated with VFA and serum triglycerides and positively associated with plasma total adiponectin, as well as the HMW-to-total adiponectin ratio in men and women (all P0.05) in a simple regression analysis. In a multiple regression analysis, VFA was a significant determinant of HMW adiponectin in hemodialysis patients. Furthermore, after adjustment for classical risk factors, HMW adiponectin levels were significantly higher in patients undergoing treatment with renin-angiotensin system inhibitors or calcium channel blockers compared with patients not undergoing such treatment. This study shows that plasma HMW adiponectin levels were negatively associated with VFA and positively associated with treatment with blockade of the renin-angiotensin system and of the calcium channel. Therefore, these drugs might be effective for improving adipocytokine-related metabolic abnormalities in hemodialysis patients. © 2011 The Japanese Society of Hypertension All rights reserved.

DOI： 10.1038/hr.2010.282

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We describe a case of advanced atrioventricular (AV) block, in which treatment with cilostazol was effective in recovering the AV conduction. The patient was referred to our hospital for close examination of the advanced AV block and permanent pacemaker implantation. Although the patient had experienced thirddegree AV block with occasional AV synchrony for more than two days, the AV conduction completely recovered after treatment with oral cilostazol at 200 mg/day. Here we discuss the possible mechanism of the improvement in the AV conduction by cilostazol. © 2011 The Japanese Society of Internal Medicine.

DOI： 10.2169/internalmedicine.50.5228

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Systemic capillary leak syndrome (SCLS) is a life-threatening disorder which presents with periodic episodes of hypovolemic shock, due to plasma leakage to the extra-vascular space reflected by accompanying hypoalbuminemia, hemoconcentration and edema often with associated monoclonal gammopathy. We describe a 28-year-old woman with SCLS who required aggressive fluid resuscitation and was successfully treated with corticosteroid, terbutaline, and theophylline. At exacerbation, the levels of serum granulocyte colony-stimulating factor (G-CSF) were increased. Thus, G-CSF might play an important role and can be a useful biomarker for the severity of attacks in SCLS. © 2011, The Japanese Society of Internal Medicine. All rights reserved.

DOI： 10.2169/internalmedicine.50.4857

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Language：Japanese   Publisher：(一社)日本脈管学会  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objective-Endothelial progenitor cells (EPCs) play an important role in the self-healing of a vascular injury by participating in the reendothelialization that limits vascular remodeling. We evaluated whether prostaglandin I2 plays a role in the regulation of the function of EPCs to limit vascular remodeling. Methods and Results-EPCs (LincKitFlk-1 cells) were isolated from the bone marrow (BM) of wild-type (WT) mice or mice lacking the prostaglandin I2 receptor IP (IP mice). Reverse transcription-polymerase chain reaction analysis showed that EPCs among BM cells specifically express IP. The cellular properties of EPCs, adhesion, migration, and proliferation on fibronectin were significantly attenuated in IP-deficient EPCs compared with WT EPCs. In contrast, IP agonists facilitated these functions in WT EPCs, but not in IP-deficient EPCs. The specific deletion of IP in BM cells, which was performed by transplanting BM cells of IP mice to WT mice, accelerated wire injury-mediated neointimal hyperplasia in the femoral artery. Notably, transfused WT EPCs, but not IP-deficient EPCs, were recruited to the injured vessels, participated in reendothelialization, and efficiently rescued the accelerated vascular remodeling. Conclusion-These findings clearly indicate that the prostaglandin I2-IP system is essential for EPCs to accomplish their function and plays a critical role in the regulation of vascular remodeling. © 2010 American Heart Association, Inc.

DOI： 10.1161/ATVBAHA.109.193730

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In December 2007, a woman was involved in a traffic accident. At first, her vital signs were normal, but electrocardiogram showed ST-segment elevation in the inferior leads. She was diagnosed as a blunt chest trauma-induced myocardial infarction. Her right coronary angiography showed total occlusion. She underwent an emergency coronary artery bypass surgery; 64-multi-detector-row computed tomography (64-MDCT) demonstrated an intravascular protruding lesion, which suggested subintimal hematoma. One month later, repeat coronary angiogram showed spontaneous recanalization, and 64-MDCT showed no discontinuous vessel wall. Coronary artery occlusion secondary to blunt chest trauma is rare, and it's even rarer to have spontaneous recanalization. © 2010 The Japanese Society of Internal Medicine.

DOI： 10.2169/internalmedicine.49.4286

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Inflammation and pulse wave velocity (PWV) are a potential risk factor and marker, respectively, for atherosclerosis in the primary prevention setting. Atherosclerosis is now generally accepted to be an inflammatory disorder of the arterial wall, and the high-sensitivity C-reactive protein (hs-CRP) level has been reported to be a strong predictor of cardiovascular events. High-sensitivity-CRP is associated with two factors related to inflammation: (1) the local production of CRP by atheromatous tissue or coronary artery smooth muscle cells and (2) adipose tissue as a potent source of inflammatory cytokines. Based on studies in North America and Europe, hs-CRP has been established as a cardiovascular risk factor and a cut-off value has been recommended. However, Japanese have lower hs-CRP values than their Western counterparts, partly because Japanese have a lower body mass index (BMI), which correlates positively to hs-CRP, and partly because lifestyle and genetic factors can affect hs-CRP values. Therefore, a cut-off value needs to be established by cohort studies for the Japanese population. Carotid-femoral PWV is most commonly measured by applanation tonometry, particularly in Europe, but this method is critically dependent upon the accurate placing of transducers over the arteries and is both time-consuming and complex. A novel device has been recently developed in Japan that measures brachial-ankle PWV (baPWV) using a volume-rendering method. Brachian-ankle PWV is a suitable screening method because of its technical simplicity and shorter measurement time. It is associated not only with conventional cardiovascular risk factors but also with new risk factors, such as inflammation, -glutamyltransferase, chronic kidney disease, and psychosocial factors. However, a suitable cut-off value has yet to be established. © 2009 The Japanese Society for Hygiene.

DOI： 10.1007/s12199-009-0080-2

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We describe a case of Brugada syndrome, in which recurrent syncope with convulsive seizures was induced after antidepressant treatment. The patient had been treated with five kinds of psychotropic drugs. The twelve-lead ECG after the syncope exhibited an RSR'-pattern in the precordial leads, however, a coved type ST-segment elevation was induced by a pilsicainide test. Although ventricular fibrillation was not induced in the electrophysiologic study, an ICD implantation was considered as the recommended therapy since Brugada syndrome unmasked by antidepressants could not be ruled out. The possible contribution of antidepressants to Brugada type ST-segment changes is discussed. © 2009 The Japanese Society of Internal Medicine.

DOI： 10.2169/internalmedicine.48.2370

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We describe a case of Brugada syndrome, in which a coved type ST-segment elevation was enhanced by antihistamines and antiallergenic drugs. The patient had been treated with four kinds of antihistamines and antiallergenic drugs. The twelve-lead ECG exhibited a coved type ST-segment elevation in leads V1 and V2, and their enhancement was induced by pilsicainide. After discontinuing those drugs, the ST segment elevation in leads V1 and V2 became reduced. An ICD implantation was selected for the therapy since ventricular fibrillation was induced. Our report discusses the possible contribution of antihistamines and antiallergenic drugs to the Brugada type ST-segment changes. © 2009 The Japanese Society of Internal Medicine.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE  

Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease, and thus is a major worldwide public health problem. Recently, an estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease equation for Japanese patients was proposed by the Japanese Society of Nephrology. However, the role of eGFR in the assessment of atherosclerosis is not well understood in Japanese patients. We analyzed the relationship between eGFR and severity of arterial stiffness using brachial-ankle pulse wave velocity (baPWV) in 647 adult Japanese patients. baPWV correlated significantly and positively with age, hypertension, diabetes, prior cardiovascular disease, blood pressure, pulse pressure and heart rate, and negatively with eGFR (r=-0.405, p<0.0001). A multiple regression analysis revealed that baPWV correlated independently with eGFR. Furthermore, there was a stepwise increase in baPWV, corresponding to advances in CKD through stages 1 to 5. When CKD stage 3 was divided at eGFR 45 mL/min/1.73 m2, the baPWV of stage 3b (eGFR 30 to 44) was significantly higher than that of stage 3a (eGFR 45 to 59) independent of traditional risk factors, suggesting that an eGFR of 45 mL/min/1.73 m2 may be a critical cut off value to predict arterial stiffness in CKD. In conclusion, the newly proposed eGFR is significantly associated with arterial stiffness, independent of traditional risk factors for cardiovascular disease.

DOI： 10.1291/hypres.31.193

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Background: The production of reactive oxygen species (ROS) has been suggested to play an important role in the progression of chronic kidney disease (CKD). An oral adsorbent, AST-120, removes uremic toxins such as indoxyl sulfate (IS) and delays the progression of CKD, but the effect on ROS production is unknown. The present study aimed to determine whether AST-120 reduces oxidative stress in uremic rat kidneys using markers of ROS production such as acrolein and 8-hydroxy-2′-deoxyguanosine (8-OHdG). Methods: Daily administration of AST-120 was started 6 weeks after 5/6 nephrectomy and continued for 18 weeks. The changes in metabolic data, serum and urine IS levels, urinary excretion of markers of oxidative stress, and renal histological findings were investigated in uremic rats with or without AST-120 treatment. Results: In parallel with the increase in serum and urine IS, the serum creatinine, urinary protein and acrolein levels started to increase at 6 weeks, but urinary 8-OHdG remained unchanged and significantly increased at 18 weeks in uremic rats. AST-120 markedly and significantly attenuated increases in uremic toxins and oxidative stress levels as well as the histological changes in glomerular sclerosis, interstitial fibrosis, and the tubular staining of 8-OHdG. Conclusion: AST-120 suppressed the progression of CKD, at least in part, via attenuation of oxidative stress induced by uremic toxin. Copyright © 2006 S. Karger AG.

DOI： 10.1159/000096423

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Language：Japanese   Publisher：(株)先端医学社  

プロスタノイドは,プロスタグランジン(PG)とトロンボキサン(TX)よりなる,一群の生理活性物質である.一方,レニンは腎血管性高血圧症の病態形成および塩類欠乏状態における体液保持機構として中心的な役割を果たしている.また,外来性に投与されたプロスタノイドのレニン分泌促進作用の報告はあるが,腎血管性高血圧症および塩類欠乏状態でのレニン分泌調節におけるプロスタノイドの役割は不明である.そこで,本研究は,各プロスタノイド受容体を欠損するマウスを用い,プロスタノイドのレニン分泌を介した腎血管性高血圧症の病態形成における役割の解明を目指した.その結果,PGI2は,腎血管性高血圧症および塩類欠乏状態の病態形成に重要な役割を果たすことが明らかとなった.また,その作用機構として,PGI2がレニンmRNAの発現を上昇させ,レニン分泌を促進することが解明された(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL INVESTIGATION INC  

Persistent reduction of renal perfusion pressure induces renovascular hypertension by activating the reninangiotensin-aldosterone system; however, the sensing mechanism remains elusive. Here we investigated the role of PGI 2 in renovascular hypertension in vivo, employing mice lacking the PGI2 receptor (LP-/- mice). In WT mice with a two-kidney, one-clip model of renovascular hypertension, the BP was significantly elevated. The increase in BP in IP-/- mice, however, was significantly lower than that in WT mice. Similarly, the increases in plasma renin activity, renal renin mRNA, and plasma aldosterone in response to renal artery stenosis were all significantly lower in IP-/- mice than in WT mice. All these parameters were measured in mice lacking the four PGE2 receptor subtypes individually, and we found that these mice had similar responses to WT mice. PGI2 is produced by COX-2 and a selective inhibitor of this enzyme, SC-58125, also significantly reduced the increases in plasma renin activity and renin mRNA expression in WT mice with renal artery stenosis, but these effects were absent in IP-/- mice. When the renin-angiotensin-aldosterone system was activated by salt depletion, SC-58125 blunted the response in WT mice but not in IP-/- mice. These results indicate that PGI2 derived from COX-2 plays a critical role in regulating the release of renin and consequently renovascular hypertension in vivo.

DOI： 10.1172/JCI21382

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Language：Japanese   Publisher：(一社)日本動脈硬化学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Severe pulmonary hypertension is one of the fetal complications in various connective tissue diseases. We report a case of severe pulmonary hypertension associated with primary Sjögren's syndrome. In a lung biopsy specimen, there were findings of intimal and medial hypertrophy with narrowing vessel lumina and plexiform lesions. Moreover, deposits of immunoglobulin M, immunoglobulin A and complement protein C1q were found in the pulmonary arterial walls. Although pulmonary hypertension was refractory to oral prostacyclin, steroid therapy improved the clinical and hemodynamic conditions. In the present case, the immunological etiology may be related to the mechanisms of pulmonary hypertension associated with Sjögren's syndrome.

DOI： 10.2169/internalmedicine.42.1248

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER VERLAG  

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant, slowly progressive cerebellar ataxia without multisystem involvement. We report a 57-year-old woman with genetically confirmed SCA6 who showed clinical features of olivopontocerebellar atrophy. Conventional T2-weighted and FLAIR MRI demonstrated high signal in the middle cerebellar peduncles, in addition to mild atrophy of the pons and cerebellum.

DOI： 10.1007/s002340050791

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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Language：Japanese   Publisher：(一社)日本循環器学会  

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Language：Japanese   Publisher：(一社)日本移植学会  

重症サルコペニアを有する40代女性に対し生体腎移植を行った。20代に急性骨髄性白血病に対する臍帯血移植、30代に造血障害に対する骨髄移植と免疫抑制剤シクロスポリン内服開始、40代にシクロスポリン腎症による慢性腎不全の診断で腹膜透析導入となった。体重33.1kg、BMI 12.8kg/平方mで、筋力・筋肉量・歩行能力・運動耐容能の低下による身体機能・日常生活機能・活力などの身体的QOLへの影響を認めたため、腎移植前1ヵ月前から移植後2ヵ月までリハビリテーション(リハ)治療を行った。その結果、退院時は移植前と比較して下肢筋力・歩行速度・6分間歩行距離は向上した。以上より、腎移植前後の長期のリハ治療は、移植後の身体機能および身体的QOLが改善することが示唆された。

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J00083&link_issn=&doc_id=20240522480010&doc_link_id=10.11386%2Fjst.58.4_399&url=https%3A%2F%2Fdoi.org%2F10.11386%2Fjst.58.4_399&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：English   Publisher：(一社)日本循環器学会  

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Language：Japanese   Publisher：(株)東京医学社  

＜文献概要＞はじめに 膜性増殖性糸球体腎炎(membranoprolifera-tive glomerulonephritis:MPGN)は,病理組織学的に,主として糸球体毛細血管基底膜の二重化を伴う糸球体係蹄壁の肥厚(membrano-)と係蹄内の細胞増殖(proliferative)を特徴とする病理組織像を呈する糸球体腎炎の総称である。つまり,病理像での疾患分類であり腎組織障害パターンの1つである。本稿では,MPGNの診断と治療について概説する。

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00714&link_issn=&doc_id=20231225110013&doc_link_id=10.24479%2Fkd.0000000995&url=https%3A%2F%2Fdoi.org%2F10.24479%2Fkd.0000000995&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：血管外科症例検討会  

包括的高度慢性下肢虚血(CLTI)治療は、血行再建術による虚血の改善を主軸に、複数の補助治療によって虚血の改善、創傷治癒促進や疼痛の緩和で構成される。LDLアフェレシスは補助治療の一つのオプションとして、難治性高コレステロール血症を有する外科治療が困難な解剖学的複雑性をもつ跛行以上の下肢閉塞性動脈疾患(LEAD)患者がその適応となっている。LDLアフェレシスは全血から血球成分を分離して血漿内の浮遊粒子であるLDLコレステロールを除去することで、血液の粘稠度(レオロジー)を改善させる吸着治療法である。2021年3月に保険収載された閉塞性動脈硬化症用吸着式血液浄化用浄化器(レオカーナ)は、全血直接灌流型カラムにより血漿分離器が不要なことから高コレステロール血症を併発しない症例に適応となり、Fontaine分類IV度のLEAD患者を対象に、LDLコレステロールとフィブリノーゲン吸着による血液レオロジー改善を通じて末梢血液循環の改善と潰瘍治癒促進を図る新しい補助治療である。(著者抄録)

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Language：Japanese   Publisher：(一社)日本老年医学会  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(一社)日本腎臓病薬物療法学会  

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Language：Japanese   Publisher：(一社)日本老年医学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：English   Publisher：(一社)日本循環器学会  

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Language：Japanese   Publisher：(株)ライフ・サイエンス  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(一社)日本アフェレシス学会  

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Language：Japanese   Publisher：(一社)日本移植学会  

免疫抑制剤tacrolimusの効果指標であるトラフ値が低値であったにもかかわらず、生検した移植腎の病理所見からtacrolimusの腎毒性が疑われ、トラフ値と病理所見が相反した原因として、肥満サルコペニアおよびcytochrome P450(CYP)3A5*1 alleleの影響が示唆された症例(30代男性)について報告した。本症例のような肥満サルコペニアが疑われる症例では、CYP3A5遺伝子多型の評価に加え、体組成測定を行うことで、tacrolimusのトラフ値が上がらない場合には増量を繰り返すよりも代替の免疫抑制剤であるeverolimusの追加等を行うことで、腎毒性を呈することなく移植後の拒絶予防ができると考えられた。

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00083&link_issn=&doc_id=20221017280005&doc_link_id=%2Fcl8isoke%2F2022%2F005702%2F005%2F0177-0182%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcl8isoke%2F2022%2F005702%2F005%2F0177-0182%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00083&link_issn=&doc_id=20221028010596&doc_link_id=%2Fcl8isoke%2F2022%2Ft057s1%2F109%2F0403-0403%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcl8isoke%2F2022%2Ft057s1%2F109%2F0403-0403%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本糖尿病合併症学会  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：応用薬理研究会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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マイクロRNAは20〜25塩基長のごく小さな一本鎖RNAであり、遺伝子発現を負に制御するという重要な機能が明らかになってきた。腎臓の線維化は慢性腎臓病の終末像であり、腎臓の線維化制御なくして、慢性腎臓病の予後の改善は期待できない。本稿では、ミトコンドリアの生合成と機能を抑制することによって線維化と腎臓病の進展抑制が確立されているmiR-21の病理学的メカニズムを概説し、慢性腎臓病を治療するための新規治療薬としての抗マイクロRNAオリゴヌクレオチドの臨床応用の可能性について述べる。(著者抄録)

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Language：Japanese   Publisher：(株)ライフメディコム  

高齢者は、無症候性の臓器障害を複数有することが少なくない。慢性腎臓病(chronic kidney disease:CKD)や脳血管障害などの臓器障害合併高血圧症の高齢者における薬物治療の開始基準は、年齢による降圧目標よりも高値の血圧値を降圧薬開始基準とする。降圧目標もまず年齢による降圧目標達成を目指し、忍容性があれば過度の降圧に注意してより低い値を目指すことが推奨される。ただし、75歳以上で収縮期血圧140〜149mmHgや自力での外来通院不能な患者(フレイル、認知症など)の降圧薬開始は個別に判断する。また、降圧目標や降圧スピードの設定において個別に判断すべき病態や、降圧薬の選択において把握しておくべき病態の有無を事前にスクリーニングすることが重要である。特に、冠動脈疾患を有する高齢者における、拡張期血圧の過度の低下は冠動脈イベントリスクを上昇させる可能性があるので注意する。臓器予備能が低い高齢者では、脱水、摂食量低下、生活環境変化などに伴い減薬や薬剤中止が必要な場合があり、事前の服薬指導を行うことも重要である。(著者抄録)

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一般的に血圧は夏に低くなり冬に高くなる季節変動を示し、これには年齢、性別、肥満度などさまざまな因子が影響することがわかっている。降圧薬治療がおこなわれている患者において、著明な血圧の季節変動により夏に起立性低血圧の症状が認められるような場合には、降圧薬を減じることが考慮されるが、これに関しては介入試験などの成績はなく、適切なガイドラインは示されていない。血圧の季節変動は脳卒中・心臓疾患の季節変動と一致しており、血圧の季節変動の把握と適切な対処は高血圧の個別化治療の質を向上させ、循環器疾患の抑制を図るうえできわめて重要なポイントと考えられる。(著者抄録)

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Language：Japanese   Publisher：(株)日本臨床社  

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Other Link： http://search.jamas.or.jp/link/ui/2017181764

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS  

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© 2016 the American Physiological Society. MicroRNAs (miRs), a class of small noncoding RNAs that act as post-transcriptional regulators of gene expression, have attracted increasing attention as critical regulators of organogenesis, cancer, and disease. Interest has been spurred by development of a novel class of synthetic RNA oligonucleotides with excellent drug-like properties that hybridize to a specific miR, preventing its action. In kidney disease, a small number of miRs are dysregulated. These overlap with regulated miRs in nephrogenesis and kidney cancers. Several dysregulated miRs have been identified in fibrotic diseases of other organs, representing a “fibrotic signature,” and some of these fibrotic miRs contribute remarkably to the pathogenesis of kidney disease. Chronic kidney disease, affecting ∼10% of the population, leads to kidney failure, with few treatment options. Here, we will explore the pathological mechanism of miR-21, whose pre-eminent role in amplifying kidney disease and fibrosis by suppressing mitochondrial biogenesis and function is established. Evolving roles for miR-214, -199, -200, -155, -29, -223, and -126 in kidney disease will be discussed, and we will demonstrate how studying functions of distinct miRs has led to new mechanistic insights for kidney disease progression. Finally, the utility of anti-miR oligonucleotides as potential novel therapeutics to treat chronic disease will be highlighted.

DOI： 10.1152/ajprenal.00523.2015

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：Japanese   Publisher：東京医学社  

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Other Link： http://search.jamas.or.jp/link/ui/2011190091

Language：Japanese  

雑誌掲載版虚血性腎症は早期発見・早期治療により可逆性を期待できる疾患である。スクリーニング検査は血漿レニン活性の測定である。片側性狭窄ではレニン高値になるが、両側性では正常から低値になる場合がある。超音波腎血流ドプラ検査は形態的、機能的診断法として大変有用である。各検査の長所・短所を理解したうえで、高リスク患者には非侵襲的なスクリーニング検査を進めていくことが重要である。

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Other Link： http://search.jamas.or.jp/link/ui/2011148024

Language：English   Publisher：JAPAN SOC INTERNAL MEDICINE  

DOI： 10.2169/internalmedicine.50.5960

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS  

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Language：Japanese   Publisher：日本腎臓学会  

CiNii Books

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Language：Japanese  

出版社版

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Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：医学書院  

Scopus

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Language：Japanese   Publisher：日本心臓病学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：Japanese   Publisher：診断と治療社  

CiNii Books

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Language：Japanese  

雑誌掲載版Ca拮抗薬は禁忌となる病態がきわめて少なく、確実な降圧効果を期待できることから、現在わが国で最も頻用される降圧薬である。Ca拮抗薬の積極的適応として脳血管疾患後、狭心症、心筋梗塞後、左室肥大、糖尿病、高齢者があげられる。24時間にわたる厳格な降圧が求められる現代にあって、Ca拮抗薬は第一選択薬としてのみならず、ほかの幅広い降圧薬との併用が可能であり、Ca拮抗薬を含めた併用療法は今後の降圧治療の主体をなすものと考えられる。

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Language：Japanese   Publisher：大道学館出版部  

CiNii Books

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Language：Japanese   Publisher：大道学館出版部  

雑誌掲載版

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Publisher：大道学館出版部  

雑誌掲載版

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Publisher：社団法人日本循環器学会  

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Language：Japanese  

CiNii Books

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Publisher：社団法人日本循環器学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：English   Publisher：(一社)日本腎臓学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：English   Publisher：(一社)日本循環器学会  

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Language：English   Publisher：(一社)日本循環器学会  

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Language：Japanese   Publisher：(公社)日本薬理学会  

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Language：English   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese  

CiNii Books

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Publisher：社団法人日本循環器学会  

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