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We analyzed the seasonal variations in the number of renal biopsies and clinical characteristics of primary glomerular disease in Japan using the Japan Renal Biopsy Registry (J-RBR). We retrospectively collected clinical and pathological data of patients with primary glomerular disease who were registered in the J-RBR between 2007 and 2018. Immunoglobulin A nephropathy (IgAN), minimal change nephrotic syndrome (MCNS), membranous nephropathy (MN), and postinfectious acute glomerulonephritis (PIAGN) constituted the four major glomerular disorders included in this study (total, 13,989; IgAN, 9121; MCNS, 2298; MN, 2447; and PIAGN, 123). The number of patients with IgAN or MCNS was higher during summer. However, no overt seasonal variations were observed in patients with MN or PIAGN. Subgroup analyses suggested that in the patients with IgAN, more renal biopsies of severe cases were performed during winter, probably owing to age and blood pressure. Furthermore, more renal biopsies of severe cases were performed during spring and winter in patients with MCNS even after adjusting for the abovementioned host factors. This study suggests that seasonal factors influence the decision to perform renal biopsy as well as the pathogenesis of primary glomerular disease. Thus, our findings may provide important insights regarding the pathophysiology of primary glomerular disease. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Recent studies have suggested a higher incidence of cardiovascular disease (CVD) among patients with chronic kidney disease (CKD) in the USA than in Japan. Hyperphosphatemia, a possible risk for CVD, may explain this difference; however, international differences in phosphate parameters in CKD have not been well elaborated. Methods: By using the baseline data from the USA and the Japanese nation-wide, multicenter, CKD cohort studies; the Chronic Renal Insufficiency Cohort Study (CRIC, N = 3,870) and the Chronic Kidney Disease-Japan Cohort Study (CKD-JAC, N = 2,632), we harmonized the measures and compared clinical parameters regarding phosphate metabolism or serum phosphate, fibroblast growth factor-23 (FGF23), and parathyroid hormone (PTH), in the cross-sectional model. Results: Multivariable linear regression analyses revealed that serum phosphate levels were significantly higher in CRIC across all levels of estimated glomerular filtration rate (eGFR) with the greatest difference being observed at lower levels of eGFR. Serum FGF23 and 25-hydroxy vitamin D (25OHD) levels were higher in CRIC, while PTH levels were higher in CKD-JAC at all levels of eGFR. Adjustments for demographics, 25OHD, medications, dietary intake or urinary excretion of phosphate, PTH, and FGF23 did not eliminate the difference in serum phosphate levels between the cohorts (0.43, 0.46, 0.54, 0.64, and 0.78 mg/dL higher in CRIC within eGFR strata of >50, 41–50, 31–40, 21–30, and ≤20 mL/min/1.73 m2, respectively). These findings were consistent when only Asian CRIC participants (N = 105) were included in the analysis. Conclusion: Serum phosphate levels in CRIC were significantly higher than those of CKD-JAC across all stages of CKD, which may shed light on the international variations in phosphate parameters and thus in cardiovascular risk among CKD patients. The key mechanisms for the substantial differences in phosphate parameters need to be elucidated. [ABSTRACT FROM AUTHOR]

COVID-19 has been prevalent worldwide since 2019. Increasing COVID-19 vaccination coverage is an important measure to combat the disease. An online survey was conducted with university students and personnel who were vaccinated against COVID-19 at a mass vaccination event to examine the factors promoting vaccination among young adults. The online survey was conducted with persons vaccinated at Okayama University from June 5 to September 27, 2021. Although the number of those who had fever >37.5°C increased after the second vaccination compared to the first, the vaccinated persons got more satisfied after the second shot. [ABSTRACT FROM AUTHOR]

Aims/Introduction: We evaluated the efficacy of multifactorial intensive treatment (IT) on renal outcomes in patients with type 2 diabetes and advanced‐stage diabetic kidney disease (DKD). Materials and Methods: The Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) is a multicenter, open‐label, randomized controlled trial with a 5‐year follow‐up period. We randomly assigned 164 patients with advanced‐stage diabetic kidney disease (urinary albumin‐to‐creatinine ratio ≥300 mg/g creatinine, serum creatinine level 1.2–2.5 mg/dL in men and 1.0–2.5 mg/dL in women) to receive either IT or conventional treatment. The primary composite outcome was end‐stage kidney failure, doubling of serum creatinine or death from any cause, which was assessed in the intention‐to‐treat population. Results: The IT tended to reduce the risk of primary end‐points as compared with conventional treatment, but the difference between treatment groups did not reach the statistically significant level (hazard ratio 0.69, 95% confidence interval 0.43–1.11; P = 0.13). Meanwhile, the decrease in serum low‐density lipoprotein cholesterol level and the use of statin were significantly associated with the decrease in primary outcome (hazard ratio 1.14; 95% confidence interval 1.05–1.23, P < 0.001 and hazard ratio 0.53, 95% confidence interval 0.28–0.998, P < 0.05, respectively). The incidence of adverse events was not different between treatment groups. Conclusions: The risk of kidney events tended to decrease by IT, although it was not statistically significant. Lipid control using statin was associated with a lower risk of adverse kidney events. Further follow‐up study might show the effect of IT in patients with advanced diabetic kidney disease. [ABSTRACT FROM AUTHOR]

BACKGROUND Our aims were to assess whether arterial stiffness is associated with a higher risk for kidney dysfunction among persons without chronic kidney disease (CKD). METHODS We analyzed data from the national health checkup system in Japan; for our analyses, we selected records of individuals who completed assessments of cardio-ankle vascular index (CAVI) and kidney function from 2005 to 2016. We excluded participants who had CKD at baseline, defined as the presence of proteinuria or estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2. We compared 2 groups of CAVI measurements—the highest quartile (≧8.1) and the combined lower 3 quartiles (<8.1). We used Cox proportional hazards models to assess associations between these 2 groups and subsequent CKD events, proteinuria, eGFR <60 ml/min/1.73 m2, and rapid eGFR decline (greater than or equal to −3 ml/min/1.73 m2 per year). RESULTS The mean age of the 24,297 included participants was 46.2 years, and 60% were female. Over a mean follow-up of 3.1 years, 1,435 CKD events occurred. In a multivariable analysis, the hazard ratios with 95% confidence intervals (CIs) for the highest vs. combined lower quartiles of CAVI measurements were 1.3 (1.1, 1.5) for CKD events, 1.3 (0.96, 1.62) for proteinuria, 1.4 (1.1, 1.7) for eGFR <60 ml/min/1.73 m2, and the odds ratio with 95% CI was 1.3 (1.1, 1.4) for rapid eGFR decline. CONCLUSIONS Persons with CAVI measurements ≧8.1 had a higher risk for CKD events compared with their counterparts with CAVI measurements <8.1. Greater arterial stiffness among adults without CKD may be associated with kidney dysfunction. [ABSTRACT FROM AUTHOR]

Background: Rapidly progressive glomerulonephritis (RPGN) has been known to have a poor prognosis. Although evidence across adult RPGN cases has accumulated over many years, the number of case series in adolescents and young adults has been limited, requiring further studies. Methods: A total of 1,766 cases from 1989 to 2007 were included in this nationwide questionnaire survey, led by Intractable (former name, Progressive) Renal Diseases Research, Research on intractable disease, from the Ministry of Health, Labour and Welfare of Japan. To elucidate age-related differences in 2-year patient and renal survival rates, the cases were divided into the following four groups: children (0–18 years), young adults (19–39 years), the middle-aged (40–64 years), and the elderly (over 65 years). Results: Of the 1,766 total RPGN cases, antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis comprised 1,128 cases (63.9% of all RPGN cases), showing a tendency to increase with age. Two-year patient survival for RPGN was 93.9% among children, 92.6% in young adults, 83.2% in the middle-aged, and 68.8% in the elderly. The younger group (children plus young adults) showed a clearly higher survival rate compared to the older group (middle-aged plus elderly) (p<0.05). ANCA-associated glomerulonephritis also showed similar age-related results with all RPGN cases. The comparison of renal prognosis showed no statistically significant differences both in RPGN and in ANCA-associated GN. Conclusion: The present study described the age-dependent characteristics of the classification of RPGN, especially focusing on a better prognosis of the younger group in patient survival both in RPGN and in ANCA-associated GN. [ABSTRACT FROM AUTHOR]

Background and objectives: There are very little data available regarding nephrotic syndrome (NS) in elderly (aged ≥65 years) Japanese. The aim of this study was to examine the causes and outcomes of NS in elderly patients who underwent renal biopsies between 2007 and 2010. Design, setting, participants, and measurements: From July 2007 to June 2010, all of the elderly (aged ≥65 years) Japanese primary NS patients who underwent native renal biopsies and were registered in the Japan renal biopsy registry (J-RBR; 438 patients including 226 males and 212 females) were identified. From this cohort, 61 patients [28 males and 33 females including 29, 19, 6, 4, and 3 patients with membranous nephropathy (MN), minimal change nephrotic syndrome (MCNS), focal segmental glomerulosclerosis (FSGS), membranoproliferative glomerulonephritis (MPGN), and other conditions, respectively] were registered from the representative multi-centers over all districts of Japan, and analyzed retrospectively. The treatment outcome was assessed using proteinuria-based criteria; i.e., complete remission (CR) was defined as urinary protein level of <0.3 g/day or g/g Cr, and incomplete remission type I (ICR-I) was defined as urinary protein level of <1.0-0.3 g/day or g/g Cr, and renal dysfunction was defined as a serum creatinine (Cr) level of 1.5 times the baseline level. Results: In this elderly primary NS cohort, MN was the most common histological type of NS (54.8 %), followed by MCNS (19.4 %), FSGS (17.4 %), and MPGN (8.4 %). Of the patients with MN, MCNS, or FSGS, immunosuppressive therapy involving oral prednisolone was performed in 25 MN patients (86.2 %), 18 MCNS patients (94.7 %), and all 6 FSGS patients (100 %). CR was achieved in all 19 (100 %) MCNS patients. In addition, CR and ICR-I were achieved in 16 (55.2 %) and 18 (62.1 %) MN patients and 4 (66.7 %) and 5 (83.3 %) FSGS patients, respectively. There were significant differences in the median time to CR among the MCNS, FSGS, and MN patients (median: 26 vs. 271 vs. 461 days, respectively, p < 0.001), and between the elderly (65-74 years, n = 7) and very elderly (aged ≥75 years, n = 12) MCNS patients (7 vs. 22 days, p = 0.037). Relapse occurred in two (6.9 %) of the MN and nine (47.4 %) of the MCNS patients. Renal dysfunction was observed in five (7.2 %) of the MN patients. Serious complications developed in eight (14.8 %) patients, i.e., two (3.7 %) patients died, four (7.4 %, including three MCNS patients) were hospitalized due to infectious disease, and two (3.7 %) developed malignancies. The initiation of diabetic therapy was necessary in 14 of the 61 patients (23.0 %) with much higher initial steroid dosage. Conclusion: Renal biopsy is a valuable diagnostic tool for elderly Japanese NS patients. In this study, most of elderly primary NS patients respond to immunosuppressive therapy with favorable clinical outcomes. On the other hand, infectious disease is a harmful complication among elderly NS patients, especially those with MCNS. In future, modified clinical guidelines for elderly NS patients should be developed. [ABSTRACT FROM AUTHOR]

Background: This study aimed to describe the epidemiologic characteristics of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) in Japan. Methods: We used the database of the Ministry of Health, Labour and Welfare (MHLW) from 2006 to 2008, and analyzed data from 938 patients (MPA = 697, GPA = 241) who fulfilled the MHLW diagnostic criteria and had registered within a year after onset. Results: The mean ages of the MPA and GPA patients were 69.4 ± 0.4 and 58.4 ± 1.1 years, respectively. Renal (86.9 %), chest (73.7 %), and nervous system (45.2 %) symptoms were common in MPA patients. Ear, nose, and throat (86.7 %), chest (78.0 %), and renal (60.6 %) symptoms were frequently observed in GPA patients. The concomitant use of cyclophosphamide (CY) with corticosteroids was observed in 22.2 % of the MPA patients and 58.5 % of the GPA patients. In multivariate analysis, the concomitant use of CY was associated with a younger age and pulmonary hemorrhage in MPA patients, and the avoidance of CY was associated with nervous system symptoms and rapidly progressive glomerulonephritis in GPA patients. Plasma exchanges were inducted in 5.2 % of the MPA patients and 4.1 % of the GPA patients. The addition of plasma exchange was associated with elevation of the serum creatinine level in patients with both MPA and GPA. Conclusion: A dominance of MPA and a reduced frequency of renal involvement in GPA patients may be significant features of the Japanese population. Clinical practice relating to MPA and GPA in Japan can be characterized as follows: CY is used less commonly, and plasma exchange is employed for patients with deteriorated renal function. [ABSTRACT FROM AUTHOR]

The current therapeutic regimen recommended by the European League against Rheumatism (EULAR) for anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is continuation of initially administered doses of glucocorticoids (GCs) in combination with cyclophosphamide (CYC) for 1 month followed by gradual tapering. Considering the adverse effects of GCs, another tapering regimen of GCs with CYC, which was characterized by tapering GCs weekly, was reported by the British Society of Rheumatology (weekly-reduction regimen). The aim of the present study is to evaluate the safety and efficacy of this weekly-reduction regimen for Japanese AAV patients in comparison with the monthly-reduction regimen recommended by the EULAR. We retrospectively reviewed medical records of adult patients newly diagnosed with AAV during the period from April 2000 to December 2010. The outcome measures were rates of remission, relapse, infection, and GC-induced diabetes mellitus during the first 12 months. Clinical data in the two groups and categorial variables with a possible relation to the outcomes were compared by using the t test and chi-square test, respectively. Twenty-four patients were enrolled in our study. All of the patients achieved remission, and the rates of relapse during the first 12 months were not statistically different between the two groups ( P = 0.16). Patients treated with the weekly-reduction regimen were less liable to have infection ( P = 0.03) and impaired glucose tolerance ( P = 0.017), compared with those treated with the monthly-reduction regimen. A therapeutic strategy using the weekly-reduction regimen of GCs would be effective and would have fewer side effects than the monthly-reduction regimen. [ABSTRACT FROM AUTHOR]

Background: This study was conducted to standardize treatment and determine patient and renal outcome in Japanese anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis/rapidly progressive glomerulonephritis (AAV/RPGN) patients, because the prognosis of AAV/RPGN patients in Japan had been poor compared with that of other countries. Methods: The participants in this retrospective cohort study were 824 ANCA-positive RPGN patients, 705 of whom were only myeloperoxidase (MPO)-ANCA positive. Results: Among the early-years cohort (group A; cases diagnosed between 1988 and 1998), patients frequently died due to opportunistic infection. Therefore, we recommended a reduced dose of prednisolone (oral prednisolone dose <0.8 mg/kg/day) with or without cyclophosphamide for initial treatment of Japanese RPGN patients. After this recommendation, 1-year survival of the patients improved: 75% in group A, 79% in group B (between 1999 and 2002), and 81% in group C (after 2003). During the entire observation period, average serum creatinine level at the start of treatment decreased, and improvement of 1-year renal survival was also found (72% in group A, 83% in group B, and 83% in group C), while the recurrence rate was significantly increased in group C (0.05/patient-year in group A, 0.07/patient-year in group B, and 0.13/patient-year in group C). Conclusions: Oral prednisolone dose <0.8 mg/kg/day with or without cyclophosphamide as an initial treatment could improve patient survival in older Japanese AAV/RPGN patients. However, maintenance treatment avoiding relapse should be established to improve renal outcomes. [ABSTRACT FROM AUTHOR]

Background: Prevalence of chronic kidney disease (CKD) is estimated to be 13.3 million in Japan, but patient characteristics during the predialysis period (CKD stages 3-5) are not well studied. Methods: We established the Chronic Kidney Disease Japan Cohort (CKD-JAC) to study the incidence of cardiovascular disease (CVD), end-stage renal disease (ESRD), and all-cause mortality in predialysis patients treated by nephrologists for 4 years. The inclusion criteria were (1) Japanese and Asian patients living in Japan, (2) age 20-75 years, and (3) estimated glomerular filtration rate (eGFR) 10-59 ml/min/1.73 m. Results: We analyzed 2977 participants for baseline characteristics. Mean eGFR was 28.6 ± 11.8 ml/min/1.73 m, and mean albuminuria was 976 ± 1340 mg/g Cr. In our study, 91.9% of participants had hypertension, but it was well controlled (131/76 mmHg). Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) were used by most participants. Less than 15% of participants had history of ischemic heart disease, and 11.5% had history of stroke. Heart failure and arteriosclerosis obliterans were present in 3.9% and 3.6% of patients, respectively. Indicators of arteriosclerosis, higher pulse wave velocity (PWV), and high pulse pressure were associated with diabetes and particularly with diabetic nephropathy. Patients included due to glomerulonephritis seemed to be at low risk for atherosclerosis and also to show lower levels of hypertension. Conclusions: The difference between causative diseases is associated with different comorbidity and level of arteriosclerosis. Future analysis of the cohort will clarify whether incidence of ESRD and CVD differs among causative diseases. [ABSTRACT FROM AUTHOR]

The continuous increase in the number of people requiring dialysis is a major clinical and socioeconomical issue in Japan and other countries. This study was designed to encourage chronic kidney disease (CKD) patients to consult a physician, enhance cooperation between nephrologists and general practices, and prevent the progression of kidney disease. Subjects comprise CKD patients aged between 40 and 74 years consulting a general physician, and patients in CKD stage 3 with proteinuria and diabetes or hypertension. This trial is a stratified open cluster-randomized study with two intervention groups: group A (weak intervention) and group B (strong intervention). We have recruited 49 local medical associations (clusters) in 15 different prefectures, which were classified into four regions (strata) based on the level of increase rate of dialysis patients. The patients in group A clusters were instructed initially to undergo treatment in accordance with the current CKD treatment guide, whereas patients in group B clusters were not only instructed in the same fashion but also received support from an information technology (IT)-based system designed to help achieve the goals of CKD treatment, consultation support centers, and consultations by dietitians visiting the local general practice offices. We assessed the rates of continued consultation, collaboration between general practitioners and nephrologists, and progression of CKD (as expressed by CKD stage). Through this study, filling the evidence-practice gap by facilitating effective communication and supporting general physicians and nephrologists, we will establish a CKD care system and decrease the number of advanced-stage CKD patients. [ABSTRACT FROM AUTHOR]

We previously estimated the prevalence of chronic kidney disease (CKD) stages 3–5 at 19.1 million based on data from the Japanese annual health check program for 2000–2004 using the Modification of Diet in Renal Disease (MDRD) equation multiplied by the coefficient 0.881 for the Japanese population. However, this equation underestimates the GFR, particularly for glomerular filtration rates (GFRs) of over 60 ml/min/1.73 m2. We did not classify the participants as CKD stages 1 and 2 because we did not obtain proteinuria data for all of the participants. We re-estimated the prevalence of CKD by measuring proteinuria using a dipstick test and by calculating the GFR using a new equation that estimates GFR based on data from the Japanese annual health check program in 2005. Data were obtained for 574,024 (male 240,594, female 333,430) participants over 20 years old taken from the general adult population, who were from 11 different prefectures in Japan (Hokkaido, Yamagata, Fukushima, Tochigi, Ibaraki, Tokyo, Kanazawa, Osaka, Fukuoka, Miyazaki and Okinawa) and took part in the annual health check program in 2005. The glomerular filtration rate (GFR) of each participant was computed from the serum creatinine value using a new equation: GFR (ml/min/1.73 m2) = 194 × Age−0.287 × S-Cr−1.094 (if female × 0.739). The CKD population nationwide was calculated using census data from 2005. We also recalculated the prevalence of CKD in Japan assuming that the age composition of the population was same as that in the USA. The prevalence of CKD stages 1, 2, 3, and 4 + 5 were 0.6, 1.7, 10.4 and 0.2% in the study population, which resulted in predictions of 0.6, 1.7, 10.7 and 0.2 million patients, respectively, nationwide. The prevalence of low GFR was significantly higher in the hypertensive and proteinuric populations than it was in the populations without proteinuria or hypertension. The prevalence rate of CKD in Japan was similar to that in the USA when the Japanese general population was age adjusted to the US 2005 population estimate. About 13% of the Japanese adult population—approximately 13.3 million people—were predicted to have CKD in 2005. [ABSTRACT FROM AUTHOR]

The etiology, prevalence, and prognosis of rapidly progressive glomerulonephritis (RPGN) including renal vasculitis vary among races and periods. To improve the prognosis of Japanese RPGN patients, we conducted a nationwide survey of RPGN in the nephrology departments of 351 tertiary hospitals, and found 1772 patients with RPGN (Group A: diagnosed between 1989 and 1998, 884 cases; Group B: diagnosed between 1999 and 2001, 321 cases; and Group C: diagnosed between 2002 and 2007, 567 cases). ANCA subclasses, renal biopsy findings, treatment, outcome and cause of death were recorded. The most frequent primary disease was renal-limited vasculitis (RLV) (42.1%); the second was microscopic polyangiitis (MPA) (19.4%); the third was anti-GBM-associated RPGN (6.1%). MPO-ANCA was positive in 88.1% of RLV patients and 91.8% of MPA patients. The proportion of primary renal diseases of RPGN was constant during those periods. The most frequent cause of death was infectious complications. The serum creatinine at presentation and the initial dose of oral prednisolone decreased significantly in Groups B and C compared to Group A. However, both patient and renal survival rates improved significantly in Groups B and C (survival rate after six months in Group A: 79.2%, Group B: 80.1%, and Group C: 86.1%. Six-month renal survival in Group A: 73.3%, Group B: 81.3%, and Group C: 81.8%). Early diagnosis was the most important factor for improving the prognosis of RPGN patients. To avoid early death due to opportunistic infection in older patients, a milder immunosuppressive treatment such as an initial oral prednisolone dose reduction with or without immunosuppressant is recommended. [ABSTRACT FROM AUTHOR]

Background/Aims: Given the clear benefits of mortality reduction observed for most β-blockers in clinical trials, they are relatively underused in hemodialysis patients. Since the outcomes associated with the use of β-blockers are not fully known, we investigated their effect on mortality among a cohort of hemodialysis patients. Methods: Data were analyzed from the Dialysis Outcomes and Practice Patterns Study phase II for 2,286 randomly selected patients on hemodialysis in Japan. Treatment with β-blockers was the major predictor variable. The main outcome measure was all-cause mortality. Cox regression analysis was used to assess an association between treatment with β-blockers and the risk of death. Results: 247 patients (11.9%) were administered β-blockers and 1,828 patients (88.1%) were not. Whereas patients treated with β-blockers had a higher prevalence of hypertension and coronary heart disease, Kaplan-Meier analysis revealed that all-cause mortality rates were significantly (p < 0.007) decreased in patients treated with β-blockers compared to those without. In multivariable, fully adjusted models, treatment with β-blockers was also independently associated with reduced all-cause mortality (hazard ratio = 0.48; p = 0.02). Conclusion: This study indicated a possible association between the use of β-blockers and reduced risk of mortality in hemodialysis patients. These results should be confirmed in further randomized controlled trials. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The most problematic issue in clinical nephrology worldwide is the relentless and progressive increase in patients with end-stage renal disease (ESRD). Diabetic nephropathy has considerable impact on society in the areas of public health and social economy; many scientists are involved in research for the elucidation of the pathogenesis of diabetic nephropathy and for the prevention and cure of the disease. In contrast, diabetic nephropathy was a neglected or ignored disease in the historical era, and few dedicated physicians recognized the disease process of diabetic nephropathy. In this review, we look back on the history of basic and clinical research on diabetic nephropathy and survey the recent progress of the research, especially focusing on the contribution of Japanese scientists. [ABSTRACT FROM AUTHOR]

The number of patients with end-stage renal disease (ESRD) in Japan has continuously increased in the past three decades. In 2005, 36 063 patients whose average age was 66 years entered a new dialysis program. This large number of ESRD patients could be just the tip of the iceberg of an increasing number of patients with chronic kidney disease (CKD). However, to date, a nationwide epidemiological study has not been conducted yet to survey the CKD population. Data for 527 594 (male, 211 034; female, 316 560) participants were obtained from the general adult population aged over 20 years who received annual health check programs in 2000–2004, from seven different prefectures in Japan: Hokkaido, Fukushima, Ibaraki, Tokyo, Osaka, Fukuoka, and Okinawa prefectures. The glomerular filtration rate (GFR) for each participant was estimated from the serum creatinine values, using the abbreviated Modification of Diet in Renal Disease (MDRD) study equation modified by the Japanese coefficient. The prevalences of CKD stage 3 in the study population, stratified by age groups of 20–29, 30–39, 40–49, 50–59, 60–69, 70–79, and 80–89 years, were 1.4%, 3.6%, 10.8%, 15.9%, 31.8%, 44.0%, and 59.1%, respectively, predicting 19.1 million patients with stage 3 CKD in the Japanese general adult population of 103.2 million in 2004. CKD stage 4 + 5 was predicted in 200 000 patients in the Japanese general adult population. Comorbidity of hypertension, diabetes, and proteinuria increased as the estimated GFR (eGFR) decreased. The prevalence of concurrent CKD was significantly higher in hypertensive and diabetic populations than in the study population overall when CKD was defined as being present with an eGFR of less than 40 ml/min per 1.73 m2 instead of less than 60 ml/min per 1.73 m2. About 20% of the Japanese adult population (i.e., approximately 19 million people) are predicted to have stage 3 to 5 CKD, as defined by a GFR of less than 60 ml/min per 1.73 m2. [ABSTRACT FROM AUTHOR]

Accurate estimation of the glomerular filtration rate (GFR) is crucial for the detection of chronic kidney disease (CKD). In clinical practice, GFR is estimated from serum creatinine using the Modification of Diet in Renal Disease (MDRD) study equation or the Cockcroft-Gault (CG) equation instead of the time-consuming method of measured clearance for exogenous markers such as inulin. In the present study, the equations originally developed for a Caucasian population were tested in Japanese CKD patients, and modified with the Japanese coefficient determined by the data. The abbreviated MDRD study and CG equations were tested in 248 Japanese CKD patients and compared with measured inulin clearance (Cin) and estimated GFR (eGFR). The Japanese coefficient was determined by minimizing the sum of squared errors between eGFR and Cin. Serum creatinine values of the enzyme method in the present study were calibrated to values of the noncompensated Jaffé method by adding 0.207 mg/dl, because the original MDRD study equation was determined by the data for serum creatinine values measured by the noncompensated Jaffé method. The abbreviated MDRD study equation modified with the Japanese coefficient was validated in another set of 269 CKD patients. There was a significant discrepancy between measured Cin and eGFR by the 1.0 × MDRD or CG equations. The MDRD study equation modified with the Japanese coefficient (0.881 × MDRD) determined for Japanese CKD patients yielded lower mean difference and higher accuracy for GFR estimation. In particular, in Cin 30–59 ml/min per 1.73 m2, the mean difference was significantly smaller with the 0.881 × MDRD equation than that with the 1.0 × MDRD study equation (1.9 vs 7.9 ml/min per 1.73 m2; P < 0.01), and the accuracy was significantly higher, with 60% vs 39% of the points deviating within 15%, and 97% vs 87% of points within 50%, respectively (both P < 0.01). Validation with the different data set showed the correlation between eGFR and Cin was better with the 0.881 × MDRD equation than with the 1.0 × MDRD study equation. In Cin less than 60 ml/min per 1.73 m2, the accuracy was significantly higher, with 85% vs 69% of the points deviating within 50% ( P < 0.01), respectively. The mean difference was also significantly smaller ( P < 0.01). However, GFR values calculated by the 0.881 × MDRD equation were still underestimated in the range of Cin over 60 ml/min per 1.73 m2. Although the Japanese coefficient improves the accuracy of GFR estimation of the original MDRD study equation, a new equation is needed for more accurate estimation of GFR in Japanese patients with CKD stages 3 and 4. [ABSTRACT FROM AUTHOR]

In Japan, the Research Committee on Intractable Vasculitides, supported by the Ministry of Health, Labour and Welfare, has been promoting basic and clinical research on vasculitis since 1972. The present Research Committee on Intractable Vasculitides comprises 4 subcommittees under the direction of a Principal Investigator: Basic and Pathological Research Subcommittee, Clinical Research Subcommittee of Small and Medium-sized Vessel Vasculitis, Clinical Research Subcommittee of Large-sized Vessel Vasculitis, and International Cooperation Research Subcommittee. Since 2008, 9 nationwide clinical studies for vasculitis have been conducted and 8 clinical and basic studies are in progress. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated the prevention of overt diabetic nephropathy using an angiotensin receptor blocker (ARB) in normotensive and hypertensive Japanese patients with type 2 diabetes. The study found that telmisartan decreased the transition rate to overt nephropathy after adjustment for changes in systolic blood pressure (SBP). It also revealed that patients with type 2 diabetes and microalbuminuria receiving telmisartan achieved better renoprotection.

Abstract: The prevalence of end-stage renal disease (ESRD) is uprising in the paralleled with the increase of chronic kidney disease (CKD) patients. Diabetic nephropathy (DN) is the most important underlying disease of CKD and a leading cause of ESRD in Japan. Intensified multifactorial intervention in patients with type 2 diabetes with microalbuminuria slows the progression to nephropathy, and progression of retinopathy and autonomic neuropathy. However, further studies are needed to establish the effect of intensified multifactorial treatment on DN with overt proteinuria. In this trial, doctors and co-medicals collaborate to treat the DN patients to prevent the deterioration of DN by multifactorial intensive therapy. Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT-Japan) is an open, randomized controlled trial to evaluate the efficacy of renal protection of multifactorial intensive therapy in type 2 diabetes patients with overt proteinuria (urinary albumin-to-creatinine ratio ≥300mg/g creatinine). The study has a targeted enrollment of 600 Japanese patients, and divided into two protocols by renal insufficiency (protocol A: serum creatinine: <1.2mg/dl in male and <1.0mg/dl in female, and protocol B: serum creatinine: 1.2–2.5mg/dl in male and 1.0–2.5mg/dl in female). The patients were allocated standard treatment or intensive multifactorial treatment. Intensive treatment was a stepwise implementation of behavior modification, pharmacological therapy targeting hyperglycaemia, hypertension, dyslipidaemia, and proteinuria. The primary outcome is the proteinuria in protocol A and the composite endpoint of time to the first occurrence of doubling of serum creatinine, ESRD (the need for chronic dialysis, or renal transplantation) or death in protocol B. The follow-up period is 5 years and the study ends in 2014. [Copyright &y& Elsevier]

Abstract: Objective: We compared the levels of ventilatory threshold (VT) and exercise habits in subjects with metabolic syndrome with those in age, sex-matched subjects without metabolic syndrome. Methods: We used data of 155 Japanese men (47.1±9.2 years) with metabolic syndrome; the diagnosis was given by the definition and the diagnostic standard for metabolic syndrome in Japan. The influence of metabolic syndrome on oxygen uptake, work rate and heart rate at VT, and exercise habits were evaluated. Results: Oxygen uptake and work rate at VT in subjects with metabolic syndrome were significantly lower than those in subjects without metabolic syndrome even after adjusting for body mass index (BMI). The number of subjects with exercise habits was significantly lower in metabolic syndrome. The subjects with exercise habits were significantly older than that in subjects without exercise habits. Furthermore, oxygen uptake and work rate at VT were significantly higher in subjects with exercise habits than those in subjects without exercise habits. Conclusion: Lower level of VT was characteristic in subjects with metabolic syndrome. Promotion of exercise habits is necessary for preventing and improving metabolic syndrome in Japanese men. [Copyright &y& Elsevier]

Objective: To investigate the link between a reduction in blood pressure (BP) and daily exercise. Design: Cross-sectional and longitudinal clinical intervention study with exercise education. Subjects: 43 overweight Japanese men aged 32–59 years (BMI, 29.0±2.3 kg/m2) at baseline. Among the participants, a randomly selected 23 overweight men (BMI, 28.5±1.7) were further enrolled into the 10 months exercise program. Measurements: BP was measured every week and steps per day were also recorded every day throughout the observation period. Fat distribution was evaluated by visceral fat (V) and subcutaneous fat (S) areas measured with computed tomography (CT) scanning at umbilical level, at before, 5 months and after intervention. Anthropometric parameters were also measured at same point. Aerobic exercise level, muscle strength, flexibility and calorie intake and insulin resistance (HOMA index) were investigated at before and after the study. Results: In a cross sectional analysis, systolic BP (SBP) and diastolic BP (DBP) were significantly correlated with body composition. In a second longitudinal analysis, SBP was significantly reduced at 2 months and DBP was also reduced at 3 months, and almost maintained until the end of the observation period. Increasing daily walking was observed in 3 months and maintained until 10 months. Body composition, aerobic exercise level, muscle strength, flexibility and insulin resistance were significantly improved. There was positive correlation between ΔDBP and Δvisceral fat area (1–5, 5–10, 1–10 months). By stepwise multiple regression analysis, only Δvisceral fat area was independently related to ΔDBP at a significant level (1–10 months: ΔDBP=−0.608+0.105Δvisceral fat area, r2=0.227, P=0.0334). Conclusion: The present study indicated daily exercise lowers BP and visceral fat area is the critical factor for BP change. [Copyright &y& Elsevier]

Objective: To assess the long-term safety and effectiveness of tacrolimus as maintenance therapy in patients with lupus nephritis (LN) receiving treatment in real-world clinical settings in Japan., Methods: An open-label, noncomparative, observational, prospective postmarketing surveillance study was conducted in 1395 patients with LN receiving maintenance treatment with tacrolimus at 278 medical institutions across Japan over a period of 10 years. Tacrolimus continuation rate and cumulative incidence of adverse drug reactions (ADRs), relapse, progression to renal failure, and progression to dialysis were calculated using Kaplan-Meier analysis., Results: Safety data were available for 1355 patients, almost half (49.3%) of whom remained on tacrolimus for the full 10 years of follow-up. A significant reduction in mean (SD) daily oral corticosteroid dose was observed from 16.0 (9.7) mg/day at 4 weeks after initiation of tacrolimus treatment to 7.2 (4.4) mg/day at year 10 ( P < 0.001). The most frequently reported serious ADRs were infections (reported for 131 [9.7%] patients). Except for infections, no marked increase in the incidence of any other ADRs was seen over time, including renal impairment, malignant tumors, and cardiac dysfunction. Renal function was generally well maintained over the 10 years of follow-up. At year 10, cumulative rates of relapse, renal failure, and dialysis were 44.5%, 12.2%, and 4.5%, respectively., Conclusion: Tacrolimus was effective and generally well tolerated as maintenance therapy for LN in a large cohort of patients in Japan followed for 10 years, almost half of whom remained on therapy for the entire duration of follow-up. (ClinicalTrials.gov: NCT01410747)., (Copyright © 2024 by the Journal of Rheumatology.)

Objectives: Chronic kidney disease (CKD) is a significant public health problem. An advanced, or innovative, CKD care system of clinical practice collaboration among general physicians (GPs), nephrologists, and other healthcare workers achieved behavior modification in patients with Stage 3 CKD in the Frontier of Renal Outcome Modifications in Japan (FROM-J) study. This behavior modification intervention consisted of educational sessions on nutrition and lifestyle, as well as encouragement of patients' regular visits. The intervention contributed to slowing CKD progression. This study aimed to evaluate the cost-effectiveness of the widespread diffusion of the behavior modification intervention proven effective by the FROM-J study., Methods: A cost-effectiveness analysis was carried out to compare the behavior modification intervention with the current practice recommended by the latest CKD clinical guidelines for GPs. A Markov model with a societal perspective under Japan's health system was constructed. We assumed that the behavior modification intervention proven effective by the FROM-J study would be initiated by GPs for targeted patient cohorts-patients aged 40-74 years with Stage 3 CKD-as a part of the innovative CKD care system., Results: The incremental cost-effectiveness ratio for the behavior modification intervention compared with current guideline-based practice was calculated as 145,593 Japanese yen (¥; $1,324 United States dollars [$]) per quality-adjusted life year (QALY)., Conclusions: Using the suggested value of social willingness to pay for a one-QALY gain in Japan of ¥5 million (US$45,455) as the threshold to judge cost-effectiveness, the behavior modification intervention is cost-effective. Our results suggest that diffusing the behavior modification intervention proven effective by the FROM-J study could be justifiable as an efficient use of finite healthcare resources. GPs could be encouraged to initiate this intervention by revising the National Health Insurance fee schedule and strengthening clinical guidelines regarding behavior modification interventions., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

A novel patient cluster in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) may be identified in Japan. We performed multiple correspondence and cluster analysis regarding 427 clinically diagnosed AAV patients excluding eosinophilic granulomatosis with polyangiitis. Model 1 included the ANCA phenotype, items of the Birmingham Vasculitis Activity Score, and interstitial lung disease; model 2 included serum creatinine (s-Cr) and C-reactive protein (CRP) levels with model 1 components. In seven clusters determined in model 1, the ANCA-negative (n = 8) and proteinase 3-ANCA-positive (n = 41) groups emerged as two distinct clusters. The other five myeloperoxidase-ANCA-positive clusters were characterized by ear, nose, and throat (ENT) (n = 47); cutaneous (n = 36); renal (n = 256), non-renal (n = 33); and both ENT and cutaneous symptoms (n = 6). Four clusters in model 2 were characterized by myeloperoxidase-ANCA negativity (n = 42), without s-Cr elevation (< 1.3 mg/dL) (n = 157), s-Cr elevation (≥ 1.3 mg/dL) with high CRP (> 10 mg/dL) (n = 71), or s-Cr elevation (≥ 1.3 mg/dL) without high CRP (≤ 10 mg/dL) (n = 157). Overall, renal, and relapse-free survival rates were significantly different across the four clusters in model 2. ENT, cutaneous, and renal symptoms may be useful in characterization of Japanese AAV patients with myeloperoxidase-ANCA. The combination of s-Cr and CRP levels may be predictive of prognosis.

Background: Effective prognostic markers are needed for antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study evaluated the clinical associations of serum vascular endothelial growth factor-A (sVEGF-A) and sVEGF-A 165 b (an antiangiogenic isoform of VEGF-A) concentrations with time to remission of AAV in a nationwide Japanese prospective follow-up cohort., Methods: We collected samples from patients with AAV who were enrolled in the nationwide Japanese cohort study (RemIT-JAV-RPGN). We measured sVEGF-A and sVEGF-A 165 b concentrations using enzyme-linked immunosorbent assays in 57 serum samples collected 6 months before and after initiation of AAV treatment. Patients were classified based on AAV disease subtypes: microscopic polyangiitis, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis (EGPA)., Results: Results revealed significant reductions in sVEGF-A and sVEGF-A 165 b concentrations in patients with microscopic polyangiitis and EGPA, respectively. However, despite the comparable concentrations of sVEGF-A and sVEGF-A 165 b during the 6 months of treatment in granulomatosis with polyangiitis patients, correlation analysis revealed that the differences in log 2 -transformed concentrations of sVEGF-A and sVEGF-A 165 b were inversely correlated with time to remission in granulomatosis with polyangiitis patients., Conclusion: These results suggest that sVEGF-A and -A 165 b can serve as potential markers of time to remission in patients with granulomatosis with polyangiitis.

Objective: To assess the long-term safety and effectiveness of tacrolimus for treating lupus nephritis (LN) in the real-world clinical setting., Methods: This is an ongoing, open-label, noncomparative, observational, postmarketing surveillance study conducted across 275 sites in Japan. Registered patients with LN were followed for 10 years. Here we report data relating to 5 years of tacrolimus maintenance therapy at the interim data cutoff in August 2016., Results: Of 1395 registered patients, 1355 received tacrolimus maintenance therapy for LN and provided safety data. The most common serious adverse drug reactions (ADR) included pneumonia (1.1%), herpes zoster (1.0%), cellulitis (1.0%), and diabetes mellitus (1.0%). ADR occurred mainly within the first 28 weeks of tacrolimus treatment, and no marked increase was observed during the follow-up period. Subgroup analyses suggested that risk factors for commonly observed ADR associated with tacrolimus included inpatient management, LN disease severity, increasing age, abnormal renal or hepatic function, and comorbid or previous disease. The cumulative rate of progression to renal failure (based on the attending physician's assessment) was 0.8% at Year 1 and 6.6% at Year 5. Cumulative relapse rates were 7.8% and 30.6%, respectively. Urine protein:creatinine ratio, serum anti-dsDNA antibody levels, complement C3 levels, and steroid-sparing effects were all significantly improved from 4 weeks after tacrolimus treatment initiation ( P < 0.001) and were sustained over 5 years., Conclusion: Long-term tacrolimus maintenance treatment over 5 years in the real-world clinical setting was well tolerated and effective in a large population of patients with LN (www.ClinicalTrials.gov: NCT01410747).

Background: Interstitial lung disease (ILD) is a severe complication with poor prognosis in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Prevalence of AAV-associated ILD (AAV-ILD) in Japan is considerably higher than that in Europe. Recently, we reported that a MUC5B variant rs35705950, the strongest susceptibility variant to idiopathic pulmonary fibrosis (IPF), was strikingly increased in AAV-ILD patients but not in AAV patients without ILD; however, due to the low allele frequency in the Japanese population, the MUC5B variant alone cannot account for the high prevalence of AAV-ILD in Japan. In this study, we examined whether other IPF susceptibility alleles in TERT and DSP genes are associated with susceptibility to AAV subsets and AAV-ILD., Methods: Five hundred and forty-four Japanese patients with AAV and 5558 controls were analyzed. Among the AAV patients, 432 were positive for myeloperoxidase (MPO)-ANCA (MPO-AAV). A total of 176 MPO-AAV patients were positive and 216 were negative for ILD based on CT or high-resolution CT. Genotypes of TERT and DSP variants were determined by TaqMan SNP Genotyping Assay, and their association was tested by chi-square test., Results: When the frequencies of the IPF risk alleles TERT rs2736100A and DSP rs2076295G were compared between AAV subsets and healthy controls, both alleles were significantly increased in microscopic polyangiitis (MPA) (TERT P = 2.3 × 10 -4 , P c  = 0.0023, odds ratio [OR] 1.38; DSP P = 6.9 × 10 -4 , P c  = 0.0069, OR 1.32) and MPO-AAV (TERT P = 1.5 × 10 -4 , P c  = 0.0015, OR 1.33; DSP P = 0.0011, P c  = 0.011, OR 1.26). On the other hand, no significant association was detected when the allele frequencies were compared between MPO-AAV patients with and without ILD., Conclusions: Unexpectedly, TERT and DSP IPF risk alleles were found to be associated with MPA and MPO-AAV, regardless of the presence of ILD. These findings suggest that TERT and DSP may be novel susceptibility genes to MPA/MPO-AAV and also that some susceptibility genes may be shared between IPF and MPA/MPO-AAV.

Introduction: The speed of declining kidney function differs among patients with diabetic nephropathy. This study was undertaken to clarify clinical and pathological features that affect the speed of declining kidney function in patients with diabetic nephropathy., Research Design and Methods: This study was design as multicenter retrospective study. The subjects (377 patients with diabetic nephropathy diagnosed by kidney biopsy at 13 centers in Japan) were classified into three groups based on the estimated glomerular filtration rate (eGFR) declining speed. The eGFR increasing group, the control group, and the eGFR declining group were divided at 0 and 5 mL/min/1.73 m 2 /year, respectively. Characteristics of clinicopathological findings of declining kidney function were evaluated., Results: The mean observation period of this study was 6.9 years. The control group, the eGFR increasing group, and the eGFR declining group included 81, 66, and 230 patients, respectively. The incidences of composite kidney events represented by 100 persons/year were 25.8 in the eGFR declining group and 2.0 in the eGFR increasing group. After adjustment for age, sex, systolic blood pressure, hemoglobin, and urinary albumin levels, three clinicopathological findings (urinary albumin levels, presence of nodular lesion, and mesangiolysis) were risk factors for inclusion in the eGFR declining group (the ORs were 1.49, 2.18, and 2.08, respectively). In contrast, the presence of subendothelial space widening and polar vasculosis were characteristic findings for inclusion in the eGFR increasing group (the ORs were 0.53 and 0.41, respectively)., Conclusions: As well as urinary albumin elevation, nodular lesion and mesangiolysis were characteristic pathological features of patients with fast declining kidney function., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In the trial known as COPE (Combination Therapy of Hypertension to Prevent Cardiovascular Events), three benidipine (a Calcium Channel Blocker; CCB) regimens were compared. Hypertensive Japanese outpatients aged 40-85 years (n=3,293) who did not achieve the target blood pressure of <140/90 mmHg with benidipine 4 mg/day were treated with the diuretic thiazide (n=1,094) or a β-blocker (n=1,089) or an additional Angiotensin Receptor Blocker (ARB; n=1,110). A significantly higher incidence of hard cardiovascular composite endpoints and of fatal or non-fatal strokes was observed in the benidipine-β-blocker group compared to the benidipine-thiazide group., Objective and Methods: We further evaluated the treatment effects of the three benidipine-based regimens on vascular and renal events in a sub-analysis of the COPE patients., Results: A total of 10 vascular events (0.8 per 1,000 person-years) including one aortic dissection (0.1 per 1,000 person-years) and nine cases of peripheral artery disease (0.8 per 1,000 person-years) were documented, as was a total of seven renal events (0.6 per 1,000 person-years). No significant differences in vascular and renal events were revealed among the three treatment groups: vascular events, p=0.92; renal events, p=0.16, log-rank test., Conclusion: Blood pressure-lowering therapy with benidipine combined with an ARB, β-blocker, or thiazide was similarly effective in the prevention of vascular and renal events in hypertensive outpatients, although there are not enough events to compare the difference in the three treatment groups., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Genome-wide association studies of systemic lupus erythematosus (SLE) in Chinese and Korean populations demonstrated strong association of single nucleotide polymorphisms (SNPs) located in the GTF2I-NCF1 region, rs73366469 (GTF2I), rs117026326 (GTF2I), rs80346167(GTF2IRD1) and rs201802880 (NCF1). This region has also been associated with susceptibility to Sjögren syndrome and rheumatoid arthritis; however, association studies with systemic sclerosis (SSc) and ANCA-associated vasculitis (AAV) have not been reported. Here we made an attempt to confirm their associations with SLE in the Japanese population, to find the primarily associated SNP, and to investigate whether these SNPs are also associated with susceptibility to SSc and AAV. By genotyping these four SNPs on 842 SLE, 467 SSc, 477 AAV patients and 934 healthy controls, striking association was confirmed in Japanese SLE. In addition, these SNPs were significantly associated with susceptibility to SSc, but not with AAV. Conditional logistic regression analysis revealed that the association of NCF1 rs201802880, a missense SNP encoding p.Arg90His, can account for the association of other SNPs by linkage disequilibrium. These results suggested that GTF2I-NCF1 region is associated with susceptibility to multiple autoimmune rheumatic diseases but not with AAV, and the primarily associated variant may be the missense SNP in NCF1.

Background: Chronic kidney disease is a known risk factor for end-stage renal and cardiovascular diseases. However, data are limited on the causes of hospitalization in patients with chronic kidney disease of maintenance period. This study aimed to aggregate hospitalization data of CKD patients and to determine the high-risk population. In addition, we compared CKD population to general population., Methods: We conducted a post hoc analysis of the chronic kidney disease-Japan cohort study, a multicenter prospective cohort study of 2966 patients with chronic kidney disease with a median 3.9 years of follow-up. We examined the hospitalization reasons and analyzed the risk factors., Results: We found 2897 all-cause hospitalization events (252.3 events/1000 person-years), a hospitalization incidence 17.1-fold higher than that in an age- and sex-matched cohort from the general Japanese population. Kidney, eye and adnexa, and heart-related hospital admissions were the most common. All-cause hospitalization increased with chronic kidney disease stage and with the presence of diabetes. Patients with diabetes at enrollment had 345.7 hospitalization events/1000 person-years, which is considerably higher than 196.8 events/1000 person-years for those without diabetes. Survival analysis, using hospitalization as an event, showed earlier all-cause hospitalization with the progression of chronic kidney disease stage and diabetes. Cardiovascular disease hospitalizations were more strongly influenced by diabetes than chronic kidney disease stage., Conclusions: Patients with chronic kidney disease and diabetes are highly vulnerable to hospitalization for a variety of diseases. These descriptive data can be valuable in predicting the prognosis of patients with chronic kidney disease.

Background: Greater variability in estimated glomerular filtration rate (eGFR) is associated with mortality in patients with chronic kidney disease (CKD). However, the association between eGFR variability and cardiovascular (CV) mortality and/or end-stage kidney disease (ESKD) in the CKD population is not very clear. This study aimed to clarify whether such an association exists., Methods: We analyzed a final cohort of 2869 eligible Asian patients with CKD. Patients were stratified into three groups according to eGFR variability during the first year and were followed-up for a median of 3.15 years. Primary CV composite endpoints were hospitalization or death due to CV events, and renal composite endpoints were doubling of serum creatinine levels or ESKD. Multivariate Cox hazard models adjusted for classical risk factors and eGFR slope were used to examine the CV and renal risk associated with eGFR variability., Results: CV endpoints were observed in 14 (2.89%), 25 (5.69%), and 41 (10.79%) patients and renal endpoints were observed in 165 (27.6%), 235 (39.0%), and 298 patients (50.9%) in the lowest, intermediate, and highest tertiles of eGFR variability, respectively. Patients in the highest tertile were at a significantly higher risk for CV events (hazard ratio 1.90; 95% confidence interval 1.03-3.71) than those in the lowest tertile. However, there was no association between eGFR variability and renal endpoints., Conclusions: Variability in eGFR can predict CV outcomes among patients with CKD.

Objective: Clinicopathological characteristics, renal prognosis, and mortality in patients with type 2 diabetes and reduced renal function without overt proteinuria are scarce., Research Design and Methods: We retrospectively assessed 526 patients with type 2 diabetes and reduced renal function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m 2 ), who underwent clinical renal biopsy and had follow-up data, from Japan's nationwide multicenter renal biopsy registry. For comparative analyses, we derived one-to-two cohorts of those without proteinuria versus those with proteinuria using propensity score-matching methods addressing the imbalances of age, sex, diabetes duration, and baseline eGFR. The primary end point was progression of chronic kidney disease (CKD) defined as new-onset end-stage renal disease, decrease of eGFR by ≥50%, or doubling of serum creatinine. The secondary end point was all-cause mortality., Results: Eighty-two patients with nonproteinuria (urine albumin-to-creatinine ratio [UACR] <300 mg/g) had lower systolic blood pressure and less severe pathological lesions compared with 164 propensity score-matched patients with proteinuria (UACR ≥300 mg/g). After a median follow-up of 1.9 years (interquartile range 0.9-5.0 years) from the date of renal biopsy, the 5-year CKD progression-free survival was 86.6% (95% CI 72.5-93.8) for the nonproteinuric group and 30.3% (95% CI 22.4-38.6) for the proteinuric group (log-rank test P < 0.001). The lower renal risk was consistent across all subgroup analyses. The all-cause mortality was also lower in the nonproteinuric group (log-rank test P = 0.005)., Conclusions: Patients with nonproteinuric diabetic kidney disease had better-controlled blood pressure and fewer typical morphological changes and were at lower risk of CKD progression and all-cause mortality., (© 2019 by the American Diabetes Association.)

Background: Although left ventricular hypertrophy (LVH) has been established as a predictor of cardiovascular events in chronic kidney disease (CKD), the relationship between the prevalence of LVH and CKD stage during the pre-dialysis period has not been fully examined., Methods: We measured left ventricular mass index (LVMI) in a cross-sectional cohort of participants in the Chronic Kidney Disease Japan Cohort (CKD-JAC) study to identify factors that are associated with increased LVMI in patients with stage 3-5 CKD., Results: We analyzed the baseline characteristics in 1088 participants (male 63.8%, female 36.2%). Diabetes mellitus was the underlying disease in 41.7% of the patients, and mean age was 61.8 ± 11.1 years. LVH was detected in 23.4% of the patients at baseline. By multivariate logistic analysis, independent risk factors for LVH were past history of cardiovascular disease [odds ratio (OR) 2.364; 95% confidence interval ([CI) 1.463-3.822; P = 0.0004], body mass index (OR 1.108; 95% CI 1.046-1.173; P = 0.0005), systolic blood pressure (OR 1.173; 95% CI 1.005-1.369; P = 0.0433), urinary albumin (OR 1.425; 95% CI 1.028-1.974; P = 0.0333), and serum total cholesterol level (OR 0.994; 95% CI 0.989-0.999; P = 0.0174)., Conclusion: The cross-sectional baseline data from the CKD-JAC study shed light on the association between LVH and risk factors in patients with decreased renal function. Further longitudinal analyses of the CKD-JAC cohort are needed to evaluate the prognostic value of LVH in CKD patients.

Rationale & Objective: Epidemiologic and clinical studies have suggested that urate-lowering therapy may slow the progression of chronic kidney disease (CKD). However, definitive evidence is lacking., Study Design: Randomized, double-blind, placebo-controlled trial., Setting & Participants: 467 patients with stage 3 CKD and asymptomatic hyperuricemia at 55 medical institutions in Japan., Intervention: Participants were randomly assigned in a 1:1 ratio to receive febuxostat or placebo for 108 weeks., Outcomes: The primary end point was the slope (in mL/min/1.73m 2 per year) of estimated glomerular filtration rate (eGFR). Secondary end points included changes in eGFRs and serum uric acid levels at 24, 48, 72, and 108 weeks of follow-up and the event of doubling of serum creatinine level or initiation of dialysis therapy., Results: Of 443 patients who were randomly assigned, 219 and 222 assigned to febuxostat and placebo, respectively, were included in the analysis. There was no significant difference in mean eGFR slope between the febuxostat (0.23±5.26mL/min/1.73m 2 per year) and placebo (-0.47±4.48mL/min/1.73m 2 per year) groups (difference, 0.70; 95% CI, -0.21 to 1.62; P=0.1). Subgroup analysis demonstrated a significant benefit from febuxostat in patients without proteinuria (P=0.005) and for whom serum creatinine concentration was lower than the median (P=0.009). The incidence of gouty arthritis was significantly lower (P=0.007) in the febuxostat group (0.91%) than in the placebo group (5.86%). Adverse events specific to febuxostat were not observed., Limitations: GFR was estimated rather than measured, and patients with stages 4 and 5 CKD were excluded., Conclusions: Compared to placebo, febuxostat did not mitigate the decline in kidney function among patients with stage 3 CKD and asymptomatic hyperuricemia., Funding: Funded by Teijin Pharma Limited., Trial Registration: Registered at the UMIN (University Hospital Medical Information Network) Clinical Trials Registry with study number UMIN000008343., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The practice patterns of exercise restrictions for patients with chronic kidney disease have not been adequately evaluated yet; thus, we examined them using a cross-sectional design and explored the factors related with those restrictions., Methods: The Chronic Kidney Disease Japan Cohort study was a multicentre cohort study of Japanese patients (age 20-75 years) living in Japan. We used the information in the questionnaire on the restriction of physical activities offered by physicians to the patients during enrolment. We initially considered and used the following data as the clinical factors that the physician used for decision making on the directions of restriction of physical activities: age, sex, cause of chronic kidney disease (CKD), comorbid diseases, body mass index (BMI), systolic blood pressure, estimated glomerular filtration rate (eGFR) and urine albumin. The logistic regression model was used to explore the factors and estimate their adjusted odds ratio with regard to physician's direction of restriction of physical activities., Results: Physician's direction of exercise restrictions was implemented in 9.9% of the participants. In 17 facilities, the proportion of physician's direction of exercise restriction ranged from 2.9 to 17.8%. The logistic regression analysis showed that the proportion of the factors such as younger age, cardiovascular disease, congestive heart failure and lower eGFR was higher in patients with physician's direction of exercise restrictions., Conclusions: The findings from this study suggested the factors related with prescribing exercise restrictions. Further studies examining which patients with CKD need direction of exercise restrictions are needed.

Objective: The aim was to elucidate the prognosis and risk factors associated with relapse during longterm remission maintenance therapy for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)., Methods: Patients with newly diagnosed AAV (n = 156) were registered in the Remission Induction Therapy in Japanese patients with ANCA-associated Vasculitides (RemIT-JAV) study, and among them, 83 patients who achieved remission were enrolled and followed up for 24 additional months in our nationwide, prospective cohort study (Co-RemIT-JAV; registration number UMIN 000006373). Patterns of maintenance therapy, effectiveness, and safety were evaluated from months 25 to 48 after the RemIT-JAV. The primary outcome measure was the rate of relapse. Secondary outcome measures included overall and renal survival, risk factors associated with relapse, and incidence rates of serious infections., Results: The patients comprised 35 men and 48 women aged 65.3 ± 12.6 years. Between months 25 and 48, the survival rate was 95% (79/83). Causes of death included 1 thyroid cancer, 1 infection, and 2 unknown reasons. Four patients had developed endstage renal disease (ESRD) by Month 24; 1 developed ESRD beyond Month 25. The relapse rate was 24% (20/83) from months 25 to 48. Multivariable analysis revealed that oral prednisolone ≤ 2.5 mg/day at Month 24 was a significant risk factor for relapse between months 25 and 48 (HR = 3.1, 95% CI 1.1-8.5)., Conclusion: One-quarter of patients with AAV relapsed during maintenance therapy, and relapse was associated with the dose of oral prednisolone 24 months after the initiation of remission induction therapy in Japan.

ETS proto-oncogene 1, transcription factor (ETS1) is involved in various immune responses. Genome-wide association studies on systemic lupus erythematosus in Chinese populations identified the association of ETS1 polymorphism in 3' untranslated region, rs1128334A, which was associated with lower ETS1 expression. In view of substantial sharing of susceptibility genes across multiple autoimmune diseases, we examined whether ETS1 is associated with a rare autoimmune rheumatic disease, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Association of rs1128334 was tested in 466 Japanese patients with AAV and 1099 healthy controls by logistic regression analysis under the additive model. AAV patients were classified into 285 microscopic polyangiitis (MPA), 92 granulomatosis with polyangiitis (GPA), 56 eosinophilic GPA, and 33 unclassifiable AAV, according to the European Medicines Agency (EMEA) algorithm. Among the patients, 376 were positive for MPO-ANCA and 62 for PR3-ANCA. When the patients were classified according to the EMEA classification, rs1128334A allele was significantly increased in GPA (P = 0.0060, P c  = 0.030, odds ratio (OR), 1.54; 95% confidence interval (CI), 1.13-2.10). With respect to the ANCA specificity, significant association was observed in PR3-ANCA positive AAV (P = 0.0042, P c  = 0.021, OR, 1.72; 95% CI, 1.19-2.49). In conclusion, ETS1 polymorphism was suggested to be associated with GPA and PR3-ANCA positive AAV in a Japanese population.

Background: Chronic kidney disease (CKD) eventually progresses to end-stage renal disease (ESRD). However, risk factors associated with CKD progression have not been well characterized in Japanese patients with CKD who are less affected with coronary disease than Westerners., Methods: A large-scale, multicenter, prospective, cohort study was conducted in patients with CKD and under nephrology care, who met the eligibility criteria [Japanese; age 20-75 years; and estimated glomerular filtration rate (eGFR): 10-59 mL/min/1.73 m 2 ]. The primary endpoint was a composite of time to a 50 % decline in eGFR from baseline or time to the initiation of renal replacement therapy (RRT). The secondary endpoints were the rate of decline in eGFR from baseline, time to a 50 % decline in eGFR from baseline, time to the initiation of RRT, and time to doubling of serum creatinine (Cre) concentration., Results: 2966 patients (female, 38.9 %; age, 60. 3 ± 11.6 years) were enrolled. The incidence of the primary endpoint increased significantly (P < 0.0001) in concert with CKD stage at baseline. The multivariate Cox proportional hazards models revealed that elevated systolic blood pressure (SBP) [hazard ratio (HR) 1.203, 95 % confidence interval (CI) 1.099-1.318)] and increased albumin-to-creatinine ratio (UACR ≥ 1000 mg/g Cre; HR: 4.523; 95 % CI 3.098-6.604) at baseline were significantly associated (P < 0.0001, respectively) with the primary endpoint., Conclusions: Elevated SBP and increased UACR were risk factors that were significantly associated with CKD progression to ESRD in Japanese patients under nephrology care. UMIN clinical trial registry number: UMIN000020038.

Background: Acute kidney injury (AKI) is frequently observed in critically ill patients in the intensive care unit (ICU) and is associated with increased mortality. Prostanoids regulate numerous biological functions, including hemodynamics and renal tubular transport. We herein investigated the ability of urinary prostanoid metabolites to predict the onset of AKI in critically ill adult patients., Methods: The current study was conducted as a prospective observational study. Urine of patients admitted to the ICU at Okayama University Hospital was collected and the urinary levels of prostaglandin E2 (PGE2), PGI2 metabolite (2,3-dinor-6-OXO-PGF1α), thromboxane A2 (TXA2) metabolite (11-dehydro-TXB2) were determined., Results: Of the 93 patients, 24 developed AKI (AKIN criteria). Surgical intervention (93, 75 %) was the leading cause of ICU admission. Overall, the ratio of the level of serum Cr on Day 1 after ICU admission to that observed at baseline positively correlated with the urinary 2,3-dinor-6-OXO-PGF1α/Cr (r = 0.57, p < 0.0001) and 11-dehydro-TXB2/Cr (r = 0.47, p < 0.0001) ratios. In 16 cases of de novo AKI, the urinary 2,3-dinor-6-OXO-PGF1α/Cr and 11-dehydro-TXB2/Cr values were significantly elevated compared with that observed in the non-AKI group, whereas the urinary PGE2/Cr values were not. The urinary 2,3-dinor-6-OXO-PGF1α/Cr ratio exhibited the best diagnostic and predictive performance among the prostanoid metabolites according to the receiver operating characteristic (ROC) analysis [ROC-area under the curve (AUC): 0.75]., Conclusions: Taken together, these results demonstrate that the urinary 2,3-dinor-6-OXO-PGF1α/Cr and 11-dehydro-TXB2/Cr ratios are associated with the subsequent onset of AKI and poor outcomes in adult heterogeneous ICU patients.

Introduction: This study aims to elucidate the prognosis and the effectiveness of current treatments for Japanese patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA)., Methods: Patients with newly diagnosed MPA and GPA were enrolled in a nationwide, prospective, inception cohort study from 22 tertiary Japanese institutions, and treatment patterns and responses were evaluated for 24 months. Primary outcome measures were rates of remission (Birmingham Vasculitis Activity Score, 0) and remission with low-dose glucocorticoids (GC) (prednisolone ≤ 10 mg) (GC remission)., Results: Of 156 enrolled patients, 78 MPA patients and 33 GPA patients were included. Concomitant cyclophosphamide (CY) was used in 24 MPA (31 %) and 20 GPA (60 %) patients during the initial 3 weeks of treatment. After 6 months, remission was achieved in 66 MPA (85 %) and 29 GPA (87 %) patients, while GC remission was obtained in only 31 MPA (40 %) and 13 GPA (39 %) patients. During the 24-month period, 14 MPA patients and 2 GPA patients died; end stage renal disease (ESRD) was noted in 13 MPA patients but no GPA patients. Patients with severe disease, according to the European Vasculitis Study Group (EUVAS) classification, showed poorer ESRD-free and overall survival rates than those with generalized disease (p < 0.0001). There were no differences in relapse-free survival rates between GPA and MPA, among EUVAS-defined disease severity categories, and between anti-neutrophil cytoplasmic antibody subspecialties., Conclusions: The majority of Japanese patients with MPA and GPA received treatment with high-dose GC and limited CY use, and showed high remission and relapse-free survival rates but low GC remission rates in clinical practice., Trial Registration: University Hospital Medical Information Network Clinical Trials Registry UMIN000001648 . Registered 28 February 2009.

Background: We reported that both serum albumin (Alb) and glycated albumin (GA) levels influenced the performance of the Japanese GFR equation based on serum creatinine. In the present study, we studied the effects of both markers on the estimated GFR by Japanese GFR equation based on serum cystatin C (Eq-cys)., Methods: 715 Japanese subjects were included. GFR was measured by inulin renal clearance (Cin). Correlations between estimated GFR by Eq-cys (eGFRcys) and Cin were evaluated in subjects stratified by GA (GA-1: GA ≤ 16.3 % and GA-2: GA ≥ 16.4 %) and Alb levels (Alb-1: Alb ≤ 3.5 g/dl and Alb-2: Alb ≥ 3.6 g/dl)., Results: Correlation coefficients between eGFRcys and Cin were 0.863, 0.919, 0.948 and 0.974 in GA-1, GA-2, Alb-1 and Alb-2, respectively. Slopes (95 % confidential interval) of the regression lines with zero intercepts were 1.014 (0.993-1.035), 0.989 (0.944-1.033), 1.019 (0.970-1.068) and 1.011 (0.990-1.031), respectively. The slopes were not significantly different from 1.0, suggesting that Eq-cys performed well in subjects at wide spectrum of GA and Alb levels. Single regression analysis of GA on eGFRcys/GFR was not significant in total subjects and subjects with GA > 12.4 %. Single regression analysis of Alb on eGFRcys/GFR was significant in total subjects, but the correlation coefficient was very low (r = 0.08, p = 0.03). Multiple regression analysis showed that Alb and GA were not significantly associated with eGFRcys/Cin in subjects with GA > 12.4 %. These results suggested that both parameters were not important factors affecting the performance of Eq-cys., Conclusion: Performance of Eq-cys was well irrespective of GA and Alb levels. Both parameters were not important factors affecting the estimated GFR by Eq-cys.

Background: Recently, Tsuda et al. reported that high HbA1C or high glycated albumin (GA) level is a major factor in overestimation of GFR by Japanese GFR equation based on serum creatinine (Eq-cr). They developed a modified equation of Eq-cr (M-Eq-cr) using GA or HbA1c. Therefore, effect of GA levels on the estimated GFR (eGFR) by Eq-cr was evaluated in Japanese subjects. We validated the accuracy of the modified equation using GA by Tsuda et al. (M-Eq-cr) and new equations that we developed in the present study., Methods: Seven hundred and fifteen Japanese subjects were included. GFR was measured by inulin renal clearance (Cin). The subjects were divided into two groups by upper limit of the GA reference range (GA-1: GA < 16.3 % and GA-2: GA > 16.4 %). Factors affecting the ratio of eGFR to Cin (eGFR/Cin) were evaluated using multivariate analysis. New equations based on creatinine and albumin (Eq-cr-alb) and based on creatinine, albumin and GA were developed from development dataset (382 subjects). Performances of the equations were validated in validation dataset (333 subjects)., Results: Correlation coefficients between eGFR by Eq-cr and Cin were 0.839 and 0.914 in GA-1 and GA-2, respectively. Slopes (95 % confidential interval) of the regression lines with zero intercepts were 1.013 (0.991 to 1.036) and 0.997 (0.951 to 1.043), respectively. Both slopes were not significantly different from 1.0. Biases were -2.3 ± 19.0 and 0.2 ± 11.7 ml/min/1.73 m(2), respectively. Accuracy (p30; percentage of subjects within 30 % of Cin) (95 % CI) were 78 % (75, 81) and 71 % (62, 78), respectively. There was no significant difference in bias and accuracy between the two groups, indicating a reasonable accuracy of Eq-cr in GA-1 and GA-2. Multiple regression analysis showed that lower serum albumin and higher GA were associated with higher eGFR/Cin. Albumin was a more potent factor affecting eGFR/Cin than GA. M-Eq-cr significantly underestimated GFR and had significantly larger bias compared with Eq-cr in subjects with GA > 20 %, suggesting that the modification of Eq-cr using GA by Tsuda et al. was too much compensation in our subjects. Precisions of Eq-cr-alb were significantly better compared with Eq-cr., Conclusion: Eq-cr has a reasonable accuracy in GA-1 and GA-2. Lower serum albumin and higher GA were significantly associated with higher eGFR/Cin. The former was a more potent factor affecting eGFR/Cin. Eq-cr-alb showed better performance compared with Eq-cr. M-Eq-cr using GA showed too much compensation and did not improve the accuracy of the equation in our subjects.

Background: Physician-scientists play key roles in biomedical research across the globe, yet prior studies have found that it is increasingly difficult to recruit and retain physician-scientists in research careers. Access to quality research mentorship may help to ameliorate this problem in the U.S., but there is virtually no information on mentoring in academic medicine in Japan. We conducted a survey to determine the availability and quality of mentoring relationships for trainee physician-scientists in Japan., Methods: We surveyed 1700 physician-scientists in post-graduate research training programs in 6 academic medical centers in Japan about mentorship characteristics, mentee perceptions of the mentoring relationship, and attitudes about career development., Results: A total of 683 potential physician-scientist mentees completed the survey. Most reported that they had a departmental mentor (91%) with whom they met at least once a month; 48% reported that they were very satisfied with the mentoring available to them. Mentoring pairs were usually initiated by the mentor (85% of the time); respondents identified translational research skills (55%) and grant writing (50%) as unmet needs. Mentoring concerning long-term career planning was significantly associated with the intention to pursue research careers, however this was also identified by some mentees as an unmet need (35% desired assistance; 15% reported receiving it)., Conclusions: More emphasis and formal training in career mentorship may help to support Japanese physician-scientist mentees to develop a sense of self-efficacy to pursue and stay in research careers.

Background: The number of patients suffering from diabetic nephropathy resulting in end-stage kidney disease is increasing worldwide. In clinical settings, there are limited data regarding the impact of the urinary albumin-to-creatinine ratio (UACR) and reduced estimated glomerular filtration rate (eGFR) on renal and cardiovascular outcomes and all-cause mortality., Methods: We performed a historical cohort study of 4328 Japanese participants with type 2 diabetes from 10 centers. Risks for renal events (requirement for dialysis or transplantation, or half reduction in eGFR), cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke), and all-cause mortality were assessed according to UACR and eGFR levels., Results: During follow-up (median 7.0 years, interquartile range 3.0-8.0 years), 419 renal events, 605 cardiovascular events and 236 deaths occurred. The UACR levels increased the risk and the adjusted hazard ratios for these three events. In addition to the effects of UACR levels, eGFR stages significantly increased the adjusted hazard ratios for renal events and all-cause mortality, especially in patients with macroalbuminuria. Diabetic nephropathy score, based on the prognostic factors, well predicted incidence rates per 1000 patient/year for each event., Conclusions: Increased UACR levels were closely related to the increase in risks for renal, cardiovascular events and all-cause mortality in Japanese patients with type 2 diabetes, whereas the association between high levels of UACR and reduced eGFR was a strong predictor for renal events.