||Shigeru Tanaka, Toshiharu Ninomiya, Ritsuko Katafuchi, Kosuke Masutani, Akihiro Tsuchimoto, Hideko Noguchi, Hideki Hirakata, Kazuhiko Tsuruya, Takanari Kitazono, Development and validation of a prediction rule using the Oxford classification in IgA nephropathy., Clinical journal of the American Society of Nephrology : CJASN, 10.2215/CJN.03480413, 8, 12, 2082-90, 2013.12, BACKGROUND AND OBJECTIVES: The risk assessment for developing ESRD remains limited in patients with IgA nephropathy (IgAN). The aim of this study was to develop and validate a prediction rule for estimating the individual risk of ESRD in patients with IgAN. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 698 patients with IgAN diagnosed by renal biopsy at Kyushu University Hospital (derivation cohort) between 1982 and 2010 were retrospectively followed. The Oxford classification was used to evaluate the pathologic lesions. The risk factors for developing ESRD were evaluated using a Cox proportional hazard model with a stepwise backward elimination method. The prediction rule was verified using data from 702 patients diagnosed at Japanese Red Cross Fukuoka Hospital (validation cohort) between 1979 and 2002. RESULTS: In the derivation cohort, 73 patients developed ESRD during the median 4.7-year follow-up. The final prediction model included proteinuria (hazard ratio [HR], 1.30; 95% confidence interval [95% CI], 1.16 to 1.45, every 1 g/24 hours), estimated GFR (HR, 0.84; 95% CI, 0.74 to 0.96, every 10 ml/min per 1.73 m(2)), mesangial proliferation (HR, 1.85; 95% CI, 1.10 to 3.11), segmental sclerosis (HR, 3.21; 95% CI, 1.37 to 7.51), and interstitial fibrosis/tubular atrophy (T1: HR, 5.30; 95% CI, 2.63 to 10.7; T2: HR, 20.5; 95% CI, 9.05 to 46.5) as independent risk factors for developing ESRD. To create a prediction rule, the score for each variable was weighted by the regression coefficients calculated using the relevant Cox model. The incidence of ESRD increased linearly with increases in the total risk scores (P for trend <0.001). Furthermore, the prediction rule demonstrated good discrimination (c-statistic=0.89) and calibration (Hosmer-Lemeshow test, P=0.78) in the validation cohort. CONCLUSIONS: This study developed and validated a new prediction rule using clinical measures and the Oxford classification for developing ESRD in patients with IgAN..
||Shigeru Tanaka, Toshiharu Ninomiya, Kosuke Masutani, Masaharu Nagata, Akihiro Tsuchimoto, Kazuhiko Tsuruya, Takanari Kitazono, Prognostic impact of serum bilirubin level on long-term renal survival in IgA nephropathy., Clinical and experimental nephrology, 10.1007/s10157-015-1096-0, 19, 6, 1062-70, 2015.12, BACKGROUND: Serum bilirubin has been recognized as a novel endogenous antioxidant. The aim of our study was to evaluate the impact of serum bilirubin on kidney prognosis in IgA nephropathy (IgAN). METHODS: We followed retrospectively 694 patients with IgAN diagnosed by renal biopsy between 1982 and 2010. The risk factors for developing end-stage renal disease (ESRD) were estimated using a Cox proportional hazard model. Predictive performance between models with or without serum bilirubin was evaluated by calculating the net reclassification improvement (NRI) and integrated discrimination improvement (IDI). RESULTS: Seventy-seven patients developed ESRD during the median 4.9 years of follow-up. Estimated glomerular filtration rate, proteinuria and histological severity were inversely related to bilirubin levels. In multivariate analysis, serum bilirubin was an independent risk factor for ESRD (hazard ratio for every 0.1 mg/dL decrease in serum bilirubin, 1.18; 95 % CI, 1.04-1.33). The incidence rate of ESRD decreased linearly with the increases in bilirubin levels (P for trend <0.01). When bilirubin was incorporated into a model with conventional ESRD risk factors, the NRI and IDI were 0.281 (P = 0.02) and 0.019 (P = 0.01), respectively. CONCLUSIONS: We demonstrated that lower bilirubin levels were significantly associated with higher risk of ESRD in IgAN. In addition, bilirubin provided incremental predictive value in the risk assessment for progression of IgAN beyond that provided by standard risk factors..
||Shigeru Tanaka, Toshiharu Ninomiya, Ritsuko Katafuchi, Kosuke Masutani, Masaharu Nagata, Akihiro Tsuchimoto, Hideki Hirakata, Takanari Kitazono, Kazuhiko Tsuruya, The effect of renin-angiotensin system blockade on the incidence of end-stage renal disease in IgA nephropathy., Clinical and experimental nephrology, 20, 5, 689-698, 2016.10, BACKGROUND: The impact of renin-angiotensin system blockade (RASB) on the incidence of end-stage renal disease (ESRD) remains unclear in IgA nephropathy (IgAN). METHODS: This study assessed associations between RASB treatment and the incidence of ESRD in IgAN using propensity score approaches. We retrospectively analyzed 1273 patients with IgAN biopsied between 1979 and 2010. Propensity scores were calculated using logistic regression. Associations between RASB and ESRD were examined using a Cox regression model adjusted by inverse probability of treatment weighted, regression, stratification and matching. RESULTS: During follow-up (median 5.1 years), 130 patients developed ESRD. With Cox regression adjusted by inverse probability of treatment weighted, RASB use was significantly associated with a lower risk of ESRD (hazard ratio 0.58; 95 % confidence interval 0.42-0.80). Significant associations were observed for other propensity score-based approaches. In stratified analysis, a beneficial association between RASB and ESRD was observed in patients ≥35 years, with hypertension, reduced estimated glomerular filtration rate (<60 mL/min/1.73 m2), mesangial proliferation and segmental glomerulosclerosis (P for interaction <0.05), and tended to be greater in patients with proteinuria (≥1.0 g/24 h), extracapillary proliferation and receiving methylprednisolone pulse therapy (P for interaction <0.10). CONCLUSION: Treatment with RASB was associated with a lower incidence of ESRD in the real-world practice of IgAN..
||Shigeru Tanaka, Toshiharu Ninomiya, Masatomo Taniguchi, Kiichiro Fujisaki, Masanori Tokumoto, Hideki Hirakata, Hiroaki Ooboshi, Takanari Kitazono, Kazuhiko Tsuruya, Comparison of oral versus intravenous vitamin D receptor activator in reducing infection-related mortality in hemodialysis patients: the Q-Cohort Study., Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 10.1093/ndt/gfw205, 31, 7, 1152-60, 2016.07, BACKGROUND: Hemodialysis patients who receive vitamin D receptor activator (VDRA) reportedly have better survival after infection than those who do not. However, the optimal route of its administration for minimizing death from infection remains unclear. METHODS: This prospective cohort study aimed to compare the effectiveness of oral versus intravenous VDRA regarding infection-related mortality in 3372 hemodialysis patients. Eligible subjects were divided into the following three groups by route of administration of VDRA: oral (n = 1868), intravenous (n = 492) and not administered (n = 1012). The effect of VDRA on infection-related mortality was examined using a Cox regression model with propensity score-based adjustments. RESULTS: During follow-up (median, 4.0 years), 118 study patients died of infection. There was a significantly lower incidence of death from infection in subjects who received intravenous VDRA than in those who did not receive VDRA; however, oral VDRA did not significantly reduce the risk of mortality from infection compared with those who did not receive VDRA [hazard ratio (HR) for intravenous VDRA, 0.16; 95% confidence interval (CI), 0.10-0.25, and HR for oral VDRA, 0.78; 95% CI, 0.60-1.01]. Direct comparison between the oral and intravenous VDRA groups showed that the intravenous group had significantly better survival than the oral group (HR, 0.39; 95% CI, 0.27-0.62). CONCLUSIONS: Treatment with intravenous VDRA more effectively reduces the incidence of mortality from infection than oral VDRA in hemodialysis patients..
||Shigeru Tanaka, Toshiharu Ninomiya, Kiichiro Fujisaki, Hisako Yoshida, Masaharu Nagata, Kosuke Masutani, Masanori Tokumoto, Koji Mitsuiki, Hideki Hirakata, Satoru Fujimi, Yutaka Kiyohara, Takanari Kitazono, Kazuhiko Tsuruya, The Fukuoka Kidney disease Registry (FKR) Study: design and methods., Clinical and experimental nephrology, 10.1007/s10157-016-1294-4, 21, 3, 465-473, 2017.06, BACKGROUND: Chronic kidney disease (CKD) is an established independent risk factor for progression to end-stage renal disease (ESRD) and incidence of cardiovascular disease (CVD). The onset and progression of CKD are associated with both genetic predisposition and various lifestyle-related factors, but little is known about the influence of genetic-environmental interactions on the incidence of ESRD or CVD in patients with CKD. METHODS: The Fukuoka Kidney disease Registry (FKR) Study is designed as one of the largest prospective, multicenter, observational cohort studies in non-dialysis dependent CKD patients. The FKR Study aims to enroll approximately 5000 individuals at multiple clinical centers and follow them for up to at least 5 years. At baseline, subjects enrolled in the FKR Study will fill out extensive lifestyle-related questionnaires. Further, their health status and treatments will be monitored annually through a research network of nephrology centers. Blood and urine samples, including DNA/RNA, will be collected at the time of enrolment and every 5-years follow-up. CONCLUSIONS: The FKR Study will provide many insights into the onset and progression of CKD, which will suggest hypothesis-driven interventional clinical trials aimed at reducing the burden of CKD. The features of the FKR Study may also facilitate innovative research to identify and validate novel risk factors, including genetic susceptibility and biomarkers, using biomaterials by high-throughput omics technologies..
||Shigeru Tanaka, Toshiharu Ninomiya, Masatomo Taniguchi, Masanori Tokumoto, Kosuke Masutani, Hiroaki Ooboshi, Takanari Kitazono, Kazuhiko Tsuruya, Impact of blood urea nitrogen to creatinine ratio on mortality and morbidity in hemodialysis patients: The Q-Cohort Study., Scientific reports, 10.1038/s41598-017-14205-2, 7, 1, 14901-14901, 2017.11, The association between blood urea nitrogen to creatinine ratio (UCR) and survival is uncertain in hemodialysis patients. We examined the influence of UCR on mortality and morbidity in hemodialysis patients. A total of 3,401 hemodialysis patients were prospectively followed for 4 years. The association between UCR with overall survival was analyzed using a Cox regression model. During a 4-year follow-up period, 545 patients died from any cause and 582 experienced MACE, 392 with coronary heart disease (CHD), 114 with infection-related death, 77 with hemorrhagic stroke, 141 with ischemic stroke, and 107 with cancer death. Every 1 increase in UCR level was significantly associated with an increased risk for all-cause mortality (hazard ratio [HR] 1.07; 95% confidence interval [CI] 1.03-1.12), CHD (HR 1.08; 95% CI 1.02-1.14), and infection-related death (HR 1.11; 95% CI 1.02-1.21). There was no evidence of a significant association between UCR and death from cancer, and incidence of stroke. A high UCR was significantly associated with an increased risk for all-cause mortality, infection-related death and incidence of CHD in hemodialysis patients..
||Shigeru Tanaka, Toshiharu Ninomiya, Ritsuko Katafuchi, Kosuke Masutani, Akihiro Tsuchimoto, Masanori Tokumoto, Hideki Hirakata, Hiroaki Ooboshi, Takanari Kitazono, Kazuhiko Tsuruya, Secular trends in the incidence of end-stage renal disease and its risk factors in Japanese patients with immunoglobulin A nephropathy., Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 10.1093/ndt/gfx223, 33, 6, 963-971, 2018.06, Background: There are limited data on secular trends in the incidence of end-stage renal disease (ESRD) and frequencies of its risk factors or treatment modalities in patients with immunoglobulin A nephropathy (IgAN). Methods: This study divided 1255 patients with IgAN into three groups according to the timing of renal biopsy: 1979-89 (n = 232), 1990-99 (n = 574) and 2000-10 (n = 449). The age-adjusted incidence rates, incidence rate ratios and 95% confidence intervals (CIs) for ESRD were calculated by the person-year method and compared using Poisson regression analysis. Results: A total of 63 patients (5.0%) developed ESRD. The age-adjusted incidence of ESRD decreased significantly over time, i.e. 11.5 per 1000 person-years (95% CI 5.4-24.6) in 1979-89, 6.5 per 1000 person-years (95% CI 1.0-25.2) in 1990-99 and 4.2 per 1000 person-years (95% CI 1.0-17.7) in 2000-10. The proportions of patients with preserved renal function and acute-stage inflammatory histologic changes (i.e. endocapillary hypercellularity and extracapillary proliferation) at the timing of biopsy increased over time, as did the rates of prescriptions of renin-angiotensin system blockers and corticosteroids (all P for trend <0.05). The effect of acute inflammatory histologic lesions on renal prognosis was drastically reduced over time. Conclusions: These findings suggest that early diagnosis in the acute inflammatory phase and subsequent aggressive treatment may have contributed to the significant downward trend in the incidence of ESRD in patients with IgAN over three decades..
||Shigeru Tanaka, Toshiharu Ninomiya, Hiroto Hiyamuta, Masatomo Taniguchi, Masanori Tokumoto, Kosuke Masutani, Hiroaki Ooboshi, Toshiaki Nakano, Kazuhiko Tsuruya, Takanari Kitazono, Apparent Treatment-Resistant Hypertension and Cardiovascular Risk in Hemodialysis Patients: Ten-Year Outcomes of the Q-Cohort Study., Scientific reports, 10.1038/s41598-018-37961-1, 9, 1, 1043-1043, 2019.01, There has been limited data discussing the relationship between apparent treatment-resistant hypertension (ATRH) and cardiovascular disease risk in patients receiving maintenance hemodialysis. We analyzed data for 2999 hypertensive patients on maintenance hemodialysis. ATRH was defined as uncontrolled blood pressure despite the use of three or more classes of antihypertensive medications, or four or more classes of antihypertensive medications regardless of blood pressure level. We examined the relationships between ATRH and cardiovascular events using a Cox proportional hazards model. The proportion of participants with ATRH was 18.0% (539/2999). During follow-up (median: 106.6 months, interquartile range: 51.3-121.8 months), 931 patients experienced cardiovascular events including coronary heart disease (n = 424), hemorrhagic stroke (n = 158), ischemic stroke (n = 344), and peripheral arterial disease (n = 242). Compared with the non-ATRH group, the ATRH group showed a significant increased risk of developing cardiovascular disease (hazard ratio [HR]: 1.27; 95% confidence interval [CI]: 1.08-1.49), coronary heart disease (HR: 1.28; 95% CI: 1.01-1.62), ischemic stroke (HR: 1.31; 95% CI: 1.01-1.69), and peripheral arterial disease (HR: 1.42; 95% CI: 1.06-1.91) even after adjusting for potential confounders. This study demonstrated that ATRH was significantly associated with increased cardiovascular risk in hemodialysis patients..
||Shigeru Tanaka, Toshiaki Nakano, Masanori Tokumoto, Kosuke Masutani, Akihiro Tsuchimoto, Hiroaki Ooboshi, Takanari Kitazono, Estimated plasma osmolarity and risk of end-stage kidney disease in patients with IgA nephropathy., Clinical and experimental nephrology, 10.1007/s10157-020-01919-3, 24, 10, 910-918, 2020.10, BACKGROUND: Several experimental studies have indicated that increased plasma osmolarity caused by recurrent dehydration is involved in kidney injury via a mechanism, mediated by vasopressin secretion and activation of the aldose reductase pathway. Epidemiologic evidence linking increased plasma osmolarity and the onset of end-stage kidney disease (ESKD), in patients with primary glomerulonephritis, is lacking. METHODS: We retrospectively examined 663 patients with IgA nephropathy (IgAN) diagnosed by kidney biopsy and evaluated the association between estimated plasma osmolarity and ESKD prevalence, using a Cox proportional hazards model. RESULTS: During follow-up (median 80.4 months; interquartile range 22.2-120.1), 73 patients developed ESKD. In a baseline survey, plasma osmolarity was correlated negatively with the mean value of the estimated glomerular filtration rate, but correlated positively with the mean value of urinary protein excretion, systolic blood pressure, and pathologic severity of extracapillary proliferation, in addition to tissue fibrosis and sclerosis. The incidence rate of ESKD increased linearly with increase in plasma osmolarity (P < 0.05 for trend). In multivariate analyses, plasma osmolarity was an independent risk factor for ESKD (hazard ratio for each increment of 5 mOsm/kg in plasma osmolarity 1.56; 95% confidence interval 1.18-2.07) even after adjustment for potential confounders. CONCLUSIONS: Increased plasma osmolarity was associated significantly with an increased risk of ESKD in patients with IgAN. Maintenance of plasma osmolarity by appropriate control of the balance between salt and water may contribute to kidney protection..