Masaharu Nagata

Secular Trends in Cardiovascular Disease and Its Risk Factors in Japanese Half-Century Data From the Hisayama Study (1961–2009)

Background— Changes in lifestyle and advances in medical technology during the past half century are likely to have affected the incidence and mortality of cardiovascular disease and the prevalence of its risk factors in Japan. Methods and Results— We established 5 cohorts consisting of residents aged ≥40 years in a Japanese community, in 1961 (n=1618), 1974 (n=2038), 1983 (n=2459), 1993 (n=1983), and 2002 (n=3108), and followed up each cohort for 7 years. The age-adjusted incidence of stroke decreased greatly, by 51% in men and by 43% in women, from the 1960s to the 1970s, but this decreasing trend slowed from the 1970s to the 2000s. Among the stroke subtypes, ischemic stroke in both sexes and intracerebral hemorrhage in men showed a similar pattern. Stroke mortality decreased as a result of the decline in incidence and a significant improvement in survival rate. Although the incidence of acute myocardial infarction did not change in either sex, disease mortality declined slightly in women. From the 1960s to the 2000s, blood pressure control among hypertensive individuals improved significantly and the smoking rate decreased, but the prevalence of glucose intolerance, hypercholesterolemia, and obesity increased steeply. Conclusions— Our findings suggest that in Japanese, the decreasing trends in the incidence of ischemic stroke have recently slowed down, and there has been no clear change in the incidence of acute myocardial infarction, probably because the benefits of hypertension control and smoking cessation have been negated by increasing metabolic risk factors. # Clinical Perspective {#article-title-30}Background— Changes in lifestyle and advances in medical technology during the past half century are likely to have affected the incidence and mortality of cardiovascular disease and the prevalence of its risk factors in Japan. Methods and Results— We established 5 cohorts consisting of residents aged ≥40 years in a Japanese community, in 1961 (n=1618), 1974 (n=2038), 1983 (n=2459), 1993 (n=1983), and 2002 (n=3108), and followed up each cohort for 7 years. The age-adjusted incidence of stroke decreased greatly, by 51% in men and by 43% in women, from the 1960s to the 1970s, but this decreasing trend slowed from the 1970s to the 2000s. Among the stroke subtypes, ischemic stroke in both sexes and intracerebral hemorrhage in men showed a similar pattern. Stroke mortality decreased as a result of the decline in incidence and a significant improvement in survival rate. Although the incidence of acute myocardial infarction did not change in either sex, disease mortality declined slightly in women. From the 1960s to the 2000s, blood pressure control among hypertensive individuals improved significantly and the smoking rate decreased, but the prevalence of glucose intolerance, hypercholesterolemia, and obesity increased steeply. Conclusions— Our findings suggest that in Japanese, the decreasing trends in the incidence of ischemic stroke have recently slowed down, and there has been no clear change in the incidence of acute myocardial infarction, probably because the benefits of hypertension control and smoking cessation have been negated by increasing metabolic risk factors.

Validation Study of Oxford Classification of IgA Nephropathy: The Significance of Extracapillary Proliferation

UNLABELLED BACKGROUND AND OBJECTIVES The Oxford classification of IgA nephropathy (IgAN) includes mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) as prognosticators. The value of extracapillary proliferation (Ex) was not addressed. Because the Oxford classification excludes patients with urinary protein <0.5 g/d and eGFR <30 ml/min per 1.73 m(2) at biopsy, the significance of Ex should be confirmed by validation cohorts that include more rapidly progressive cases. We present such a study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The significance of pathologic features for development end-stage renal failure (ESRF) was examined by multivariate analysis in 702 patients with IgAN. The association of Ex with kidney survival was examined by univariate analysis in 416 patients who met the Oxford criteria and 286 who did not, separately. RESULTS In a multivariate model, S and T were significantly associated with ESRF. With addition of Ex, not S but Ex was significant for ESRF. In univariate analysis, kidney survival was significantly lower in patients with Ex than in those without, in patients who did not meet the Oxford criteria, but such a difference was not found in patients who met it. CONCLUSIONS The prognostic significance of Ex was evident in our cohort. It seems that Ex did not emerge from the Oxford classification as a prognosticator because of exclusion of severe cases (eGFR <30 ml/min per 1.73 m(2)). We suggest that extracapillary proliferation be included in the next version of the Oxford classification of IgAN to widen the scope of the classification.

Trends in the prevalence of chronic kidney disease and its risk factors in a general Japanese population: The Hisayama Study

BACKGROUND Chronic kidney disease (CKD) is increasingly recognized as a leading public health issue. However, there are limited data assessing secular trends in the prevalence of CKD in general Asian communities. METHODS We performed three repeated cross-sectional surveys of residents aged >or=40 years in 1974 [2118 subjects (participation rate, 81.2%)], 1988 [2741 subjects (80.9%)] and 2002 [3297 subjects (77.6%)] in a Japanese community. We compared the prevalence of CKD [one or both of proteinuria and estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2)] and potential risk factors among the three surveys. RESULTS The prevalence of CKD increased significantly with time in men (13.8% [95% confidence interval (95% CI), 11.4-16.2%] in 1974, 15.9% [95% CI, 13.6-18.2%] in 1988 and 22.1% [95% CI, 19.6-24.6%] in 2002; P for trend < 0.001), but not in women (14.3% [95% CI, 12.2-16.4%], 12.6% [95% CI, 10.9-14.3%] and 15.3% [95% CI, 13.4-17.2%]; P for trend = 0.97). The frequencies of individuals with CKD Stages 3-5 (eGFR < 60 mL/min/1.73 m(2)) increased over the three decades in both sexes. Despite the widespread use of antihypertensive agents, the proportions of individuals with CKD who reached blood pressure of <130/80 mmHg were only 27.0% in men and 47.5% in women. The frequency of metabolic disorders including diabetes, hypercholesterolaemia and obesity increased over the three decades in both sexes. CONCLUSIONS The prevalence of CKD increased significantly in men, but not in women over the last three decades in a general Japanese population. Our findings support the requirement for a comprehensive treatment for hypertension and metabolic disorders to reduce the burden of CKD.

Association between ratio of serum eicosapentaenoic acid to arachidonic acid and risk of cardiovascular disease: The Hisayama Study

OBJECTIVE We examined the association between the ratio of serum eicosapentaenoic acid to arachidonic acid (EPA/AA) or the docosahexaenoic acid (DHA)/AA and the development of cardiovascular disease in a general Japanese population. METHODS A total of 3103 community-dwelling Japanese individuals aged ≥40 years were followed up for an average of 5.1 years. Serum EPA/AA ratios were categorized into quartiles. The risk estimates were computed using a Cox proportional hazards model. RESULTS During the follow-up period, 127 subjects experienced cardiovascular events. Age- and sex-adjusted incidence rates of cardiovascular disease increased with lower serum EPA/AA ratios in individuals with high-sensitivity C-reactive protein (HS-CRP) of ≥1.0 mg/L (p for trend = 0.006), whereas no clear association was observed in those with HS-CRP of <1.0 mg/L (p for trend = 0.27). The multivariable-adjusted risk of cardiovascular disease increased significantly, by 1.52 times (95% confidence interval 1.12-2.04) per 0.20 decrement in serum EPA/AA ratio in subjects with HS-CRP of ≥1.0 mg/L. A lower serum EPA/AA ratio was significantly associated with an increased risk of coronary heart disease, but there was no evidence of an association with stroke. The magnitude of the influence of the serum EPA/AA ratio on the cardiovascular risk increased significantly with elevating HS-CRP levels taken as a continuous variable (p for heterogeneity = 0.007). However, no such association was observed for DHA/AA ratio. CONCLUSION Our findings suggest that a lower serum EPA/AA ratio is associated with a greater risk of cardiovascular disease, especially coronary heart disease, among subjects with higher HS-CRP levels in the general Japanese population.

White-Coat and Masked Hypertension Are Associated With Carotid Atherosclerosis in a General Population: The Hisayama Study

Background and Purpose— On the basis of combined measurements of clinic blood pressure (CBP) and home blood pressure (HBP), blood pressure status can be divided into normotension, white-coat hypertension (WCHT), masked hypertension (MHT), and sustained hypertension (SHT). Despite the clear impact of MHT and SHT on clinical and subclinical arterial disease, uncertainty about the influence of WCHT remains. The objective of this study was to investigate the associations of WCHT, MHT, and SHT with carotid atherosclerosis in a general population. Methods— This is a cross-sectional survey of 2915 community-dwelling Japanese aged ≥40 years. Normotension was defined as CBP<140/90 and HBP<135/85 mm Hg; WCHT, CBP≥140/90 and HBP<135/85 mm Hg; MHT, CBP<140/90 and HBP≥135/85 mm Hg; and SHT, CBP≥140/90 and HBP≥135/85 mm Hg. Mean intima-media thickness of carotid arteries was measured using a computer-automated system, and carotid stenosis was defined as diameter stenosis ≥30%. Results— There were 1374 subjects (47.1%) with normotension, 200 (6.9%) with WCHT, 639 (21.9%) with MHT, and 702 (24.1%) with SHT. The geometric average of mean intima-media thickness was significantly higher among subjects with WCHT (0.73 mm), MHT (0.77 mm), and SHT (0.77 mm) than those with normotension (0.67 mm; all P<0.001 versus normotension). Compared with normotension, all types of hypertension were also associated with increased likelihood of carotid stenosis (age- and sex-adjusted odds ratio, 2.36 [95% confidence interval, 1.27–4.37] for WCHT, 1.95 [1.25–3.03] for MHT, and 3.02 [2.01–4.54] for SHT). These associations remained significant even after adjustment for other cardiovascular risk factors. Conclusions— WCHT, as well as MHT, and SHT were associated with carotid atherosclerosis in a general Japanese population.

Association of the triglycerides to high-density lipoprotein cholesterol ratio with the risk of chronic kidney disease: Analysis in a large Japanese population

OBJECTIVES To investigate the relationship between triglycerides to high-density lipoprotein cholesterol ratio (TG/HDL-C) and chronic kidney disease (CKD). METHODS We used data from 216,007 Japanese adults who participated in a nationwide health checkup program. Men (n = 88,516) and women (n = 127,491) were grouped into quartiles based on their TG/HDL-C levels (<1.26, 1.26-1.98, 1.99-3.18, and >3.18 in men; <0.96, 0.96-1.44, 1.45-2.22, and >2.22 in women). We cross-sectionally assessed the association of TG/HDL-C levels with CKD [defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m(2) (low eGFR) and/or proteinuria (defined as urinary protein ≥ 1+ on dipstick testing)], low eGFR, and proteinuria. RESULTS The prevalence of CKD, low eGFR, and proteinuria increased significantly with elevating quartiles of TG/HDL-C in both genders (all P for trend <0.001). Participants in the highest quartile of TG/HDL-C had a significantly greater risk of CKD than those in the lowest quartile after adjustment for the relevant confounding factors (odds ratio: 1.57, 95% confidence interval: 1.49-1.65 in men; 1.41, 1.34-1.48 in women, respectively). Furthermore, there were significant associations with low eGFR and proteinuria. In stratified analysis, the risk of CKD increased linearly with greater TG/HDL-C levels in participants with and without hypertension, diabetes, and obesity. Moreover, higher TG/HDL-C levels were relevant for CKD, especially in participants with hypertension and diabetes (P for interaction <0.001, respectively). CONCLUSIONS An elevated TG/HDL-C is associated with the risk of CKD in the Japanese population.

Nine-Year Incidence and Risk Factors for Retinal Vein Occlusion in a General Japanese Population: The Hisayama Study

PURPOSE To estimate the long-term cumulative incidence and risk factors for retinal vein occlusion (RVO) in a population-based cohort study of Japanese. METHODS In 1998, a total of 1775 individuals aged 40 years or older underwent a baseline eye examination. Of those, 1369 subjects (77.1%) took part in the follow-up eye examination in 2007 and were enrolled in the present study. Each participant underwent a comprehensive examination. The diagnosis of RVO, including branch (BRVO) and central RVO (CRVO), was determined by grading color fundus photographs. Logistic regression analysis was performed to determine risk factors for RVO. RESULTS The 9-year cumulative incidence of RVO was 3.0% (2.7% for BRVO and 0.3% for CRVO). The age-specific cumulative incidence of RVO significantly increased with age (P for trend = 0.03). After adjusting for age and sex, higher diastolic blood pressure and chronic kidney disease (CKD) were significantly associated with RVO. In multivariate analysis, higher diastolic blood pressure (per 10 mm Hg) (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.14 to 2.01) and CKD (OR, 2.23; 95% CI, 1.02 to 4.89) remained independently significant risk factors for RVO. In stratified analysis, the risk of RVO was higher in subjects with CKD than that in subjects without CKD in both the nonhypertension and the hypertension groups. CONCLUSIONS These findings suggest that the incidence of RVO is higher in Japanese than that in other Asians and Caucasians, and that higher blood pressure and CKD are independent risk factors for RVO in the Japanese.

The improvement of renal survival with steroid pulse therapy in IgA nephropathy

Background. The benefits of steroid therapy in immunoglobulin A nephropathy (IgAN) have not been established. Methods. The effect of steroids on kidney survival was retrospectively investigated in 702 patients with IgAN by multivariate analyses. Results. There were 295 men and 407 women. The median follow-up period was 62 months. One hundred and ninety-four patients were treated with oral steroids (oral steroid group). Thirty-four patients were treated with methylprednisolone (mPSL) pulse therapy (pulse steroid group) followed by oral prednisolone (PSL). In 474 patients, no steroid was used (no steroid group). The urinary protein-creatinine ratio and histological grade were significantly different among treatment groups and were highest in the pulse steroid group followed by the oral steroid group and lowest in the no steroid patients. Serum creatinine was significantly higher in the pulse steroid group than in other two groups. Eighty-five patients developed end-stage renal failure (ESRF) requiring haemodialysis. In multivariate analysis, steroid pulse therapy significantly decreased the risk of ESRF while oral steroid treatment did not improve renal survival in this cohort. Conclusion. We found that pulse steroid therapy improved kidney survivals in IgAN. Since the clinical findings and histological grade were the most severe in patients treated with mPSL pulse therapy, such therapy may prevent progression of IgAN.

Fibroblast growth factor 23 is associated with carotid artery calcification in chronic kidney disease patients not undergoing dialysis: a cross-sectional study

BackgroundFibroblast growth factor 23 (FGF23) is an important hormone in the regulation of phosphate metabolism. It is unclear whether FGF23 is associated with carotid artery calcification (CAAC) in predialysis patients. The present study aimed to clarify the relationship between FGF23 and CAAC in patients with chronic kidney disease (CKD) who were not on dialysis.MethodsOne-hundred ninety-five predialysis CKD patients were enrolled in this cross-sectional study. CAAC was assessed using multidetector computed tomography, and the prevalence of CAAC was examined. Intact FGF23 was measured in each patient. The risk factors for CAAC were evaluated using a logistic regression model.ResultsWe found CAAC in 66% of the patients. The prevalence of CAAC significantly increased across CKD stages: it was 37% in CKD stages 1–2, 58% in stage 3; 75% in stage 4, and 77% in stage 5 (p < 0.01). In multivariate analysis, smoking, diabetes mellitus and log FGF23 were each identified as risk factors for CAAC. The study population was divided in quartiles of FGF23 levels. Compared with the lowest FGF23 quartile, each subsequent quartile had a progressively higher odds ratio (OR) for CAAC, adjusted for confounders (ORs [95% confidence interval] of 2.34 [0.78 to 7.31], 5.28 [1.56 to 19.5], and 13.6 [2.92 to 74.6] for the second, third, and fourth quartiles, respectively.ConclusionsThe prevalence of CAAC is increased with the decline in the kidney function. FGF23 is independently related to CAAC in patients with CKD who are not on dialysis.

Prediction of Cardiovascular Disease Mortality by Proteinuria and Reduced Kidney Function: Pooled Analysis of 39,000 Individuals From 7 Cohort Studies in Japan

There are limited studies addressing whether proteinuria and estimated glomerular filtration rate (eGFR) are independently associated with cardiovascular disease in Asia. Using data from 7 prospective cohorts recruited between 1980 and 1994 in Japan, we assessed the influence of proteinuria (≥1+ on dipstick) and reduced eGFR on the risk of cardiovascular disease mortality in 39,405 participants (40-89 years) without kidney failure. During a 10.1-year follow-up, 1,927 subjects died from cardiovascular disease. Proteinuria was associated with a 1.75-fold (95% confidence interval (CI): 1.44, 2.11) increased risk of cardiovascular disease mortality after adjustment for potential confounding factors. Additionally, the multivariate-adjusted hazard ratio of cardiovascular disease mortality increased linearly with lower eGFR levels (P(trend) < 0.001): Subjects with eGFR of <45 mL/minute/1.73 m² had a 2.22-fold (95% CI: 1.60, 3.07) greater risk of cardiovascular disease mortality than those with eGFR of ≥90 mL/minute/1.73 m². Subjects with both proteinuria and eGFR of <45 mL/minute/1.73 m² had a 4.05-fold (95% CI: 2.55, 6.43) higher risk of cardiovascular disease mortality compared with those with neither of these risk factors. There was no evidence of interaction in the relationship between proteinuria and lower eGFR (P(interaction) = 0.77). The present results suggest that proteinuria and lower eGFR are independent risk factors for cardiovascular disease mortality in the Japanese population.