Impact of insulin-like growth factor-1 receptor and amphiregulin expression on survival in patients with stage II/III gastric cancer enrolled in the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer.

BACKGROUND: Exploratory biomarker analysis was conducted to identify factors related to the outcomes of patients with stage II/III gastric cancer using data from the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer, which was a randomized controlled study comparing the administration of an orally active combination of tegafur, gimeracil, and oteracil with surgery alone. METHODS: Formalin-fixed paraffin-embedded surgical specimens from 829 patients were retrospectively examined, and 63 genes were analyzed by quantitative real-time RT-PCR after TaqMan assay-based pre-amplification. Gene expression was normalized to the geometric mean of GAPDH, ACTB, and RPLP0 as reference genes, and categorized into low and high values based on the median. The impact of gene expression on survival was analyzed using 5-year survival data. The Benjamini and Hochberg procedure was used to control the false discovery rate. RESULTS: IGF1R and AREG were most strongly correlated with overall survival, which was significantly worse in high IGF1R patients than low IGF1R patients, but better in high AREG patients than low AREG patients. The hazard ratio for death in the analysis of overall survival (S-1 vs. surgery alone) was reduced in the high IGF1R group compared with the low IGF1R group and in the low AREG group compared with the high AREG group. There were no significant interaction effects. CONCLUSION: IGF1R gene expression was associated with poor outcomes after curative resection of stage II/III gastric cancer, whereas AREG gene expression was associated with good outcomes. No significant interaction effect on survival was evident between S-1 treatment and gene expression.

Decreased serum bone specific alkaline phosphatase and increased urinary N-terminal telopeptide of type I collagen as prognostic markers for bone mineral density loss in HIV patients on cART.

OBJECTIVES: Bone mineral density (BMD) loss is a major chronic complication in HIV patients. We performed a prospective study to determine the time course of BMD changes and to find prognostic factors of BMD loss in HIV patients on combination antiretroviral therapy (cART). PATIENTS AND METHODS: Subjects were 54 male Japanese HIV patients who had been on cART ≥1 year with no therapeutic agents for osteoporosis. Patients were observed for ≥1 year (median 3.1 years) and underwent annual BMD analyses using dual energy X-ray absorptiometry. Changes in BMD at lumbar spine and femoral neck were calculated for each person-year of all the patients. Clinical factors were also collected simultaneously with BMD examinations to determine prognostic factors for BMD loss. RESULTS: In total, 173 person-years in 54 patients were observed. One third (19, 35.2%) and slightly over half (30, 55.6%) patients showed BMD decreases at lumbar spine and femoral neck, respectively. However, the median BMD changes at lumbar spine and femoral neck were 0.0% and -0.52% per year, respectively. Monovariant and mixed model analyses determined that decreased serum bone specific alkaline phosphatase (BAP, p = 0.0047) and increased urinary N-terminal telopeptide (uNTx, p = 0.0011) were prognostic factors for BMD loss at lumbar spine and femoral neck, respectively. CONCLUSIONS: BMD at both lumbar spine and femoral neck changed little on average in HIV patients on cART. Decreased serum BAP or increased uNTx may be helpful to predict progressive BMD loss in the following year and to select patients for BMD follow-up or initiation of anti-osteoporosis treatment.

Impact of the Triglycerides to High-Density Lipoprotein Cholesterol Ratio on the Incidence and Progression of CKD: A Longitudinal Study in a Large Japanese Population.

BACKGROUND: The impact of the triglycerides to high-density lipoprotein cholesterol (TG:HDL-C) ratio on chronic kidney disease (CKD) is unclear. STUDY DESIGN: Longitudinal cohort study. SETTING & PARTICIPANTS: 124,700 participants aged 39 to 74 years in the Japanese Specific Health Check and Guidance System, including 50,392 men, 74,308 women, 102,900 without CKD, and 21,800 with CKD. PREDICTOR: Quartiles of TG:HDL-C ratio. OUTCOMES & MEASUREMENTS: Changes in estimated glomerular filtration rate (eGFR) and urinary protein excretion during the 2-year study period. Incident CKD in participants without CKD, and progression of CKD in participants with CKD. RESULTS: In the entire study population, higher quartile of TG:HDL-C ratio at baseline was significantly associated with greater decline in eGFR and increase in urinary protein excretion during the 2-year study period, even after adjustment for confounding factors. A higher ratio was associated with higher risk of incident CKD in participants without CKD and higher risk of rapid decline in eGFR and increase in urinary protein excretion in participants with CKD. Higher TG:HDL-C ratio was more strongly associated with decline in eGFR (P for interaction = 0.002) and with incident CKD (P for interaction = 0.05) in participants with diabetes than without diabetes. LIMITATIONS: Short observation period and single measurement of all variables. CONCLUSIONS: A higher TG:HDL-C ratio affects the decline in eGFR and incidence and progression of CKD in the Japanese population.

Association between hypouricemia and reduced kidney function: a cross-sectional population-based study in Japan.

BACKGROUND: Hypouricemia, conventionally defined as a serum uric acid level of ≤2 mg/dl, is considered a biochemical disorder with no clinical significance. However, individuals with renal hypouricemia have a high risk of urolithiasis and exercise-induced acute kidney injury, both of which are risk factors for reduced kidney function. METHODS: To test the hypothesis that individuals with hypouricemia would be at a higher risk of reduced kidney function, we conducted a population-based cross-sectional study using data from the Specific Health Checkups and Guidance System in Japan. Logistic analysis was used to examine the relationship between hypouricemia and reduced kidney function, defined as estimated glomerular filtration rate <60 ml/min/1.73 m(2). RESULTS: Among 90,710 men (mean age, 63.8 years) and 136,935 women (63.7 years), 193 (0.2%) and 540 (0.4%) were identified as having hypouricemia, respectively. The prevalence of hypouricemia decreased with age in women (p for trend <0.001), but not in men (p for trend = 0.24). Hypouricemia was associated with reduced kidney function in men (odds ratio, 1.83; 95% confidence interval, 1.23-2.74), but not in women (0.61; 0.43-0.86), relative to the reference category (i.e., serum uric acid levels of 4.1-5.0 mg/dl) after adjusting for age, drinking, smoking, diabetes, hypertension, hypercholesterolemia, obesity, and history of renal failure. Sensitivity analyses stratified by diabetic status yielded similar results. CONCLUSIONS: This study is the first to provide evidence that hypouricemia is associated with reduced kidney function in men. Further research will be needed to determine the long-term prognosis of individuals with hypouricemia.

Impact of the expression of thymidylate synthase and dihydropyrimidine dehydrogenase genes on survival in stage II/III gastric cancer.

BACKGROUND: The efficacy of 5-fluorouracil (5FU)-based therapy, which remains the cornerstone of gastrointestinal cancer treatment, depends upon the expression of enzymes involved in pyrimidine metabolism, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), and orotate phosphoribosyltransferase (OPRT). We analyzed the expression of these genes in patients enrolled in the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) and their possible roles as biomarkers for treatment outcomes. METHODS: Formalin-fixed, paraffin-embedded specimens were available for 829 of a total of 1,059 (78.3 %) patients. TS, DPD, TP, and OPRT expression was measured by RT-PCR in manually microdissected tumor specimens and normalized to the reference gene, ß-actin. The expression level of each gene was categorized as low or high using cutoffs at the 33.3rd, 50th, or 66.7th percentiles. RESULTS: The hazard ratio (HR) for overall survival (OS) after S-1 treatment versus surgery alone was significantly lower in high (>66.7th percentile; HR = 0.370; 95 % CI 0.221-0.619) compared to low (<66.7th percentile; HR = 0.757; 95 % CI 0.563-1.018) TS expression groups (P = 0.015). Similarly, the HR for OS after S-1 therapy versus surgery alone was significantly lower in high (>33.3rd percentile; HR = 0.520, 95 % CI 0.376-0.720) compared to low (<33.3rd percentile; HR = 0.848, 95 % CI 0.563-1.276) DPD expression groups (P = 0.065). There was no interaction between TP or OPRT expression and OS. CONCLUSIONS: This large biomarker study showed that high TS and DPD gene expression in tumors was associated with enhanced benefit from postoperative adjuvant S-1 treatment in gastric cancer. There was no interaction between TP and OPRT expression and S-1 treatment.

Comparison of predictive value for first cardiovascular event between Japanese GFR equation and coefficient-modified CKD-EPI equation.

BACKGROUND: The most superior GFR-estimating equation from the viewpoint of cardiovascular disease (CVD) prediction remains unclear. Thus, we performed cross-sectional comparison between two GFR-estimating equations (Japanese GFR equation and coefficient-modified CKD-EPI equation) and CVD incidence using Japanese nationwide "specific health checkup" data. METHODS: We recruited Japanese residents (241,159 individuals; mean 63 years; male, 38.6 %) who had not experienced CVD event (cardiac disease or stroke, or both). We calculated estimated GFR using two equations, and compared their predictive value for first symptomatic CVD event within 1 year. RESULTS: Of all subjects, the mean GFR estimated by the Japanese GFR equation (JPN-eGFR) modified for Japanese was 75.83 ± 16.18 mL/min/1.73 m(2), and that by the coefficient-modified CKD-EPI equation (mCKDEPI-eGFR) was 76.39 ± 9.61 mL/min/1.73 m(2). Area under the receiver operating characteristics curves (95 % confidence intervals) for predicting CVD event by mCKDEPI-eGFR vs. JPN-eGFR were 0.596 (0.589-0.603) vs. 0.562 (0.554-0.569). Using mCKDEPI-eGFR, the crude odds ratio (OR) for CVD incident in the 4th quartile group was far more than double (OR 2.46, 95 % CI 2.29-2.66) that in the 1st quartile group. Using JPN-eGFR, the crude OR in the 4th quartile group was less than double (OR 1.61, 95 % CI 1.51-1.73) that in the 1st quartile group. However, such superior predictive value of mCKDEPI-eGFR disappeared after adjustment for confounding factors (age, gender, BMI, presence of proteinuria, hypertension, diabetes, dyslipidemia and current smoking). CONCLUSION: GFR estimated by the coefficient-modified CKD-EPI equation was more closely related to CVD incidence than that estimated by the Japanese GFR equation. However, it is possible that low mCKDEPI-eGFR also reflects some cardiovascular risk(s) other than kidney dysfunction.

Significance of estimated glomerular filtration rate in predicting brain or heart attacks in obese and non-obese populations.

BACKGROUND: The Japanese Specific Health Checkup mainly focuses on metabolic syndrome for preventing cardiovascular events. Subjects are stratified by measuring waist circumference, body mass index, blood pressure, triglycerides, and fasting plasma glucose. However, estimated glomerular filtration rate (eGFR) is not considered essential. METHODS: A longitudinal cohort study assessed the association of eGFR with new-onset brain or heart attacks in a large Japanese nationwide Specific Health Checkup database. A total of 109,349 Japanese subjects (mean age 63.2 years, 39.5 % men) were examined for the events 2 years later. The odds ratios were calculated for new events in the total and subgroup populations divided by BMI < or ≥25 kg/m(2), obese and non-obese, respectively. RESULTS: Obese subjects were more often male and had proteinuria (dipstick test ≥1+), lower eGFR, and higher systolic and diastolic BP, fasting plasma glucose, hemoglobin A1c, and triglycerides (TG). Rates of new-onset brain or heart attacks were 3.1 and 4.0 % in the groups of non-obese and obese subjects, respectively. In the total population, eGFR as well as higher BMI (≥25 kg/m(2)), higher BP (high-normal hypertension or greater), higher TG (≥150 mg/dl), and proteinuria were significant risk factors for developing brain or heart attacks. The eGFR was significant in non-obese subjects, but not in the obese. CONCLUSION: As the ultimate aim of 'Specific Health Checkup' is to prevent cardiovascular events, our study suggests that eGFR should be evaluated in non-obese subjects.

U-shaped association between body mass index and proteinuria in a large Japanese general population sample.

BACKGROUND: There is little data on the association between body mass index (BMI) and proteinuria. METHODS: This was a cross-sectional cohort study assessing the association between BMI and proteinuria in a large Japanese population. Using a nationwide health check-up database of 212,251 Japanese aged >20 years with no pre-existing cardiovascular diseases (185,183 men, median age 66 years; 127,068 women, median age 65 years), we examined the association between BMI and proteinuria (≥ 1+ on dipstick). RESULTS: Subjects were divided into 11 subgroups by BMI grading in 1 kg/m(2) intervals from 18.5-27.5 kg/m(2). A BMI of approximately 22 ± 0.5 kg/m(2) was considered optimal for Japanese; therefore, this subgroup was set as a reference when logistic analysis was applied. Age, waist circumference, height, weight, smoking and drinking habits, use of medications such as antihypertensive, antidiabetic, or antihyperlipidemic, as well as proteinuria, estimated glomerular filtration rate (eGFR), chemistry data, and blood pressure levels were significantly different between subgroups in both genders. The odds ratio for proteinuria showed a U-shape in men and women, even after adjustment for significant covariates such as age, waist circumference, systolic blood pressure, eGFR, fasting plasma glucose, triglyceride, low-density lipoprotein, antihypertensive use, antidiabetic use, antihyperlipidemic use, and lifestyle factors (smoking and drinking). Gender differences were also prominent--a BMI <20.4 kg/m(2) was significantly associated with proteinuria in men compared to a BMI <18.4 kg/m(2) in women. On the other hand, a BMI ≥ 25.5 kg/m(2) was also significantly associated with proteinuria in men compared to a BMI ≥ 22.5 kg/m(2) in women. CONCLUSIONS: We found that BMI levels were associated with proteinuria in a U-shaped manner and showed marked gender differences. Health guidance should not only focus on higher BMI subjects, but also on thin subjects, in terms of the prevention of chronic kidney disease.

An association between serum γ-glutamyltransferase and proteinuria in drinkers and non-drinkers: a Japanese nationwide cross-sectional survey.

BACKGROUND: The association between alcohol consumption and chronic kidney disease (CKD), characterized by reduced glomerular filtration rate and proteinuria, is controversial. Recent studies suggest that serum γ-glutamyltransferase (GGT) level, a conventional marker of excessive alcohol consumption, predicts the CKD incidence. Little information is available on the difference in the clinical impact of alcohol consumption and GGT on proteinuria. METHODS: The present cross-sectional survey included 332,296 Japanese people aged ≥40 years in 2008. To examine the associations of GGT and alcohol consumption with proteinuria, 134,600 men and 197,696 women were classified into 20 categories based on GGT quartiles and alcohol consumption categories, and their prevalence rate ratios (PRR) of proteinuria defined as ≥1+ of dipstick urinary protein were calculated after adjusting for clinically relevant factors. RESULTS: Prevalence of proteinuria was 7.5 and 3.7 % in men and women, respectively. In both gender an association between alcohol consumption and proteinuria was in a J-shaped fashion with the lowest PRR of mild drinkers with ≤19 g/day of ethanol consumption, whereas an association between serum GGT level and proteinuria was linear. Compared with rare drinkers in the lowest GGT quartile, the subjects in higher GGT quartiles had a higher probability of proteinuria, irrespective of alcohol consumption. An optimal cutoff level of serum GGT was 43.6 and 23.2 IU/L in men and women, respectively. CONCLUSIONS: The subjects with higher serum GGT level had a higher probability of proteinuria, regardless of alcohol consumption, suggesting that GGT has a clinically greater impact on CKD than alcohol consumption.

Effect of glomerular filtration rate and proteinuria on medical cost among screened subjects.

BACKGROUND: Chronic kidney disease is a predictor of end-stage renal disease (ESRD) and cardiovascular disease (CVD). Therefore, the medical expenses are higher with the decrease in glomerular filtration rate (GFR). However, few studies have examined the medical expenses according to the baseline GFR. METHODS: We investigated the relationship between GFR at health checks and medical expenses, combining the registries of both the health checks and report of medical expenses (receipts). The health checks were done from April 2008 to March 2009, and the eligible subjects were covered by the Okinawa Branch of the Japan Health Insurance Association. All reports of medical expenses were reviewed from April 2008 to March 2010 (24 months). RESULTS: A total of 74,354 subjects, 38.2 % females with the mean age of 48.1 years, were examined according to whether they had visited medical facilities during the study period. The total number of receipts was 773,276. The average receipt point, 1 point = 10 Yen, was 686,410 (eGFR < 15), 56,408 (eGFR 15-29), 47,263 (eGFR 30-44), 24,372 (45-59), 16,018 (eGFR 60-74), 13,893 (eGFR 75-89), 13,990 (eGFR 90-104), 14,717 (eGFR 105-119), and 19,139 (eGFR 120 and over), respectively. The relationship between eGFR and medical expense was U-shaped, and the expense was lowest at eGFR 75-89. CONCLUSION: We demonstrate that the medical expenses increase as eGFR decreases. Subjects with higher eGFR, 120 and over, seemed to have higher medical expenses.

Three epochs on estimating the parameter values of thermodynamic Sharpe-Schoolfield-Ikemoto (SSI) model describing the relation of temperature and insect development rate.

The SSI model describes the relationship between temperature and development rate of insect based on the laws of thermodynamics. The greatest feature of the SSI model curve is that it defines the "Intrinsic optimum temperature for the development of ectotherms". However, this model has 8 parameters, it was extremely difficult to estimate the values of these parameters from experimental data. This is because the curve fitting of experimental data yields multiple curves depending on the initial conditions. In the first epoch of estimating parameter values, the difficulties were overcome by clarifying the model and applying all the knowledge gained about the model, but it took several days to determine the model. In the second epoch, the OptimSSI-program, which incorporates a basic optimization function, was developed, making it possible to obtain parameter values instantaneously after inputting experimental data. Although this program mostly runs automatically on a PC, a manual calculation remains to be carried outs so that the obtained model curves do not deviate from Arrhenius' law. Afterward, a new program was suggested. This new program called DEoptim.sqrt not only incorporates an optimization function available on the internet but also was completely different from OptimSSI-P in terms of the design concept. Users had hoped that this new program would be start of the third epoch; however, when we examined the output values, there were serious problems, and we were back in the state before the first epoch. After all, OptimSSI-P of the second epoch was decided to be more reliable.

Association between prehypertension and chronic kidney disease in the Japanese general population.

The increased prevalence of chronic kidney disease (CKD) is a consequence of the accumulation of risk factors, one of which is hypertension. Here we assessed the prevalence of CKD according to blood pressure among 232,025 patients in a Japanese nationwide database with a focus on the prevalence and risk factors of CKD in prehypertension. Patients were stratified by blood pressure and included 75,474 with optimal blood pressure (less than 120/80 mm Hg); 59,194 with prehypertension and a normal blood pressure (120-129/80-84 mm Hg) or 46,547 patients with high-normal blood pressure (130-139/85-89 mm Hg); and 50,810 with hypertension (over 140/90 mm Hg without anti-hypertensive drugs). CKD was defined as an estimated glomerular filtration rate of stage 3 or lower or having proteinuria greater than 1+ by a dipstick method. The prevalence of CKD among patients with optimal blood pressure, prehypertension having normal or high-normal blood pressure, and hypertension was 13.9, 15.6, 18.1, and 20.7% in men, and 10.9, 11.6, 12.9, and 15.0% in women, with a significant difference between genders at each strata of blood pressure. In men, but not in women, whose blood pressure was high-normal, the CKD risk was significantly greater (odds ratio 1.11) than those with optimal blood pressure. Obesity (body mass index over 25) was significantly associated with an increased risk of CKD in both men and women (odds ratio 1.43 and 1.26, respectively), and there was an additive effect of obesity and pre-hypertension on CKD risk in men compared with men with optimal blood pressure. Thus, the prevalence of CKD increased with the severity of blood pressure. Prehypertension with high-normal blood pressure, particularly in conjunction with obesity, was found to be an independent risk factor of CKD in men.

Glycohemoglobin not as predictive as fasting glucose as a measure of prediabetes in predicting proteinuria.

BACKGROUND: There is little data on the assessment of prediabetes with proteinuria. METHODS: This is a cross-sectional cohort study assessing prediabetes with proteinuria in a large Japanese population. Using a nationwide health checkup database of 228 778 Japanese aged ≥20 years (median 66 years; 39.3% were men; none had pre-existing cardiovascular disease), we examined the association between prediabetes and proteinuria (≥1+ on dipstick) separately in prediabetes subjects diagnosed with the new hemoglobin A1c (HbA1c) criterion only (PD-A1c), the impaired fasting plasma glucose only (PD-IFG) and fulfilling both criteria (PD-Both). RESULTS: According to the American Diabetes Association's (ADA's) criterion of 5.7-6.4% HbA1c and/or 100-125 mg/dL fasting plasma glucose, 43.8% of the subjects were judged as having prediabetes. Prediabetes subjects were divided into subclasses of PD-A1c (53.7%), PD-IFG (21.7%) and PD-Both (24.5%), respectively. Therefore, 21.7% of prediabetes subjects were missed using the new HbA1c criterion only. Compared with subjects with normal glucose tolerance (as a reference), the odds ratio (OR) [95% confidence interval (95% CI)] for the increased risk of proteinuria (≥1+) in diabetes itself was 2.191 (2.081-2.307) and in whole prediabetes was 1.093 (1.046-1.142); when prediabetes was subdivided, the OR for proteinuria in PD-IFG was 1.217 (1.140-1.300) and that in PD-Both was 1.249 (1.174-1.329), but that in PD-A1c was not significant, even after adjustment for significant covariates, such as age, sex, body mass index, systolic blood pressure, antihypertensive medication, eGFR, lifestyle and lipid profile. CONCLUSIONS: Prediabetes is a significant risk factor for proteinuria compared with completely normal glucose level, and subjects with prediabetes defined using IFG are at significantly higher risk for proteinuria than those defined by HbA1c only.

Risk factor profiles based on estimated glomerular filtration rate and dipstick proteinuria among participants of the Specific Health Check and Guidance System in Japan 2008.

BACKGROUND: Estimated glomerular filtration rate (eGFR) and albuminuria (proteinuria) are both important determinants of the risk of cardiovascular disease (CVD), end-stage renal disease (ESRD), and mortality. Few studies, however, have examined the risk factor profiles based on eGFR and proteinuria among the general population. METHODS: Data of the newly developed nationwide screening program of the Specific Health Check-up and Guidance System (Tokutei-Kensin) initiated in 2008 were used in this study. The aim of this screening, targeting people 40-74 years of age, was to detect those with metabolic syndrome and to offer those services regarding lifestyle modifications that will lead to the reduction of diabetes mellitus (DM) and DM-related ESRD. Individual records of 580,000 participants in 69 cities and towns and 3 union cohorts throughout Japan were anonymously provided and included in the present study. RESULTS: Details of 332,174 participants (57.3% of the total) with both serum creatinine and dipstick urine test data were analyzed. Mean (SD) age was 63.6 (8.3) years and 40.6% were men. The mean (SD) eGFR was 75.0 (16.2) ml/min/1.73 m(2) and 5.4% had proteinuria. The prevalence of chronic kidney disease (CKD) stage 3, 4, and 5 was 14.2%, 0.2%, and 0.07%, respectively. The prevalence of DM, hypertension, and history of stroke and heart disease was correlated with the combination of eGFR and degree of proteinuria. CONCLUSION: The findings of the present study indicate that CKD and risk factors for CVD are quite common among middle-aged Japanese. CKD classification based on eGFR and proteinuria may be useful for predicting CVD, mortality rate, and ESRD in the Japanese population.

Weight gain after 20 years of age is associated with prevalence of chronic kidney disease.

BACKGROUND: Weight gain after maturity is a risk factor for diabetes, coronary heart disease, and stroke, even in individuals with a normal body mass index; however, there is little information about the influence of weight gain after maturity on chronic kidney disease (CKD). Therefore, we examined the association between weight gain after 20 years of age and the prevalence of CKD. METHODS: A cross-sectional study was performed on 28,151 women and 21,110 men aged between 40 and 59 years who participated in the specific health check and guidance system of Japan in 2008. We compared prevalence of CKD between participants with and without weight gain of at least 10 kg after 20 years of age. Multivariate logistic regression models and stratified analyses were used to adjust for possible confounding factors. RESULTS: The prevalence of CKD among participants with weight gain was significantly higher than among those without weight gain both in women (11.8 vs 8.3%, p < 0.0001) and in men (12.2 vs 9.2%, p < 0.0001). After adjustment for age, smoking, regular exercise, alcohol intake, history of kidney disease, hypertension, diabetes, and hypercholesterolemia, the odds ratio (95% confidence interval) for CKD was 1.24 (1.14-1.36) in women and 1.15 (1.05-1.26) in men with weight gain of at least 10 kg after the age of 20 years. Even in participants without metabolic syndrome, weight gain was independently associated with CKD in both genders. CONCLUSIONS: Weight gain after 20 years of age is associated with CKD among Japanese, even those without metabolic syndrome.

Vitamin D insufficiency defined by serum 25-hydroxyvitamin D and parathyroid hormone before and after oral vitamin D3 load in Japanese subjects.

Vitamin D insufficiency is a risk for both skeletal and nonskeletal health. However, some ambiguity remains about threshold serum 25(OH)D for vitamin D insufficiency. To determine the threshold serum 25(OH)D to maintain normal calcium availability without elevation in serum parathyroid hormone (PTH) among Japanese subjects with various calcium intakes, we conducted a multicenter prospective open-labeled study. We recruited 107 ambulatory subjects without disorders affecting vitamin D metabolism to whom oral vitamin D3 800 IU/day for 4 weeks or 1,200 IU/day for 8 weeks was given. Serum 25(OH)D, PTH, calcium, phosphate, and magnesium were measured before and after vitamin D3 supplementation. Calcium intake was assessed by questionnaires. When all the data were combined, serum 25(OH)D was negatively correlated with PTH. The cubic spline curve between serum 25(OH)D and PTH indicated PTH reached its plateau between 35 and 40 pg/ml at 25(OH)D between 25 and 30 ng/ml. Vitamin D3 supplementation increased serum 25(OH)D and decreased PTH. Change in PTH correlated positively with baseline serum 25(OH)D. From the regression analyses, baseline serum 25(OH)D above 28 ng/ml corresponded to the threshold level without reduction in PTH after vitamin D3 supplementation. In multivariate regression analyses, age but not calcium intake was a significant determinant of PTH. We concluded that a serum 25(OH)D level of 28 ng/ml was identified as a threshold for vitamin D insufficiency necessary to stabilize PTH to optimal levels.

Significance of past history of renal failure for the detection of high-risk individuals for cardiovascular and end-stage renal disease: analysis of data from a nationwide health checkup.

BACKGROUND: Clinical information regarding risk factors may be helpful in the detection of various diseases. This cross-sectional study examined the characteristics of subjects with past history of renal failure, and assessed whether this information would be useful for the efficient detection of high-risk individuals for chronic kidney disease (CKD) and cardiovascular disease (CVD) at health checkup. METHODS: This study utilized data from a nationwide health checkup, "The Specific Health Check and Guidance in Japan," and data for 250,130 adult subjects were analyzed. Subjects with self-reported history of renal failure and receiving dialysis therapy were defined as having a history of renal failure. RESULTS: Among total participants, there were 1,400 (0.6%) with a history of renal failure. The prevalence of a history of renal failure was higher in subjects with CKD than in those without CKD (1.5 vs. 0.3%, P < 0.001) and increased with progression of the stage of CKD (0.9-43.5%). Subjects with a history of renal failure had a reduced estimated glomerular filtration rate (44.6 ± 20.3 ml/min/1.73 m(2)) and a higher prevalence of CKD (50.5%) and CVD (31.9%), compared with subjects with hypertension, diabetes or metabolic syndrome. Multivariate logistic regression analysis showed an independent association between a history of CVD and renal failure (odds ratio 3.68, 95% confidence interval 3.26-4.15), after adjustment for confounding factors. CONCLUSIONS: A history of renal failure was strongly associated with advanced CKD and CVD. Information regarding history of renal failure could be utilized to efficiently detect high-risk individuals at health checkup.

TOP2A, GGH, and PECAM1 are associated with hematogenous, lymph node, and peritoneal recurrence in stage II/III gastric cancer patients enrolled in the ACTS-GC study.

BACKGROUND: To identify factors related to relapse sites, we carried out an exploratory biomarker analysis of data from the Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer study, which is a randomized, controlled trial comparing postoperative adjuvant S-1 therapy with surgery alone in 1,059 patients with stage II/III gastric cancer. PATIENTS AND METHODS: Surgical specimens from 829 patients were retrospectively examined, and 63 genes involved in a variety of biological processes were analyzed by quantitative real-time PCR. Gene expression normalized to reference genes was categorized as lower or higher than the median, and association with relapse sites was analyzed based on 5-year relapse-free survival. RESULTS: Hematogenous, lymph node, and peritoneal recurrence developed in 72, 105, and 138 of the 829 patients, respectively; hazard ratios were 0.79 (95% confidential interval: 0.54-1.16), 0.51 (0.31-0.82), and 0.60 (0.42-0.84), respectively. Expression of platelet/endothelial cell adhesion molecule 1 (PECAM1) and topoisomerase II alpha (TOP2A) was strongly correlated with hematogenous recurrence and peritoneal recurrence, respectively (false discovery rate = 7.7×10-5 and 0.002, respectively). Gamma-glutamyl hydrolase (GGH) expression was moderately correlated with lymph node recurrence (false discovery rate = 0.34). Relapse-free survival was worse in patients expressing high levels of PECAM1 (hazard ratio = 2.37, 1.65-3.41), TOP2A (hazard ratio = 2.35, 1.55-3.57), or GGH (hazard ratio = 1.87, 1.13-3.08), respectively. A multivariate analysis revealed that these were stronger independent risk factors than tumor histological type. CONCLUSION: In patients with stage II/III gastric cancer, TOP2A, GGH, and PECAM1 levels in primary tumors are linked to high risk of hematogenous, lymph node, and peritoneal recurrence, respectively.

Association between Overall Lifestyle Changes and the Incidence of Proteinuria: A Population-based, Cohort Study.

Objective This study aimed to examine the association between the changes in an overall healthy lifestyle, as quantified by the number of unhealthy lifestyle factors and obesity status, and the incidence of proteinuria in the general Japanese population. Methods A retrospective cohort study was conducted among 99,404 (men, 36.9%) participants aged from 40-74 years of age who underwent two health check-ups with a 1-year interval in Japan between 2008 and 2009. Any participants with chronic kidney disease at baseline were excluded. The smoking status, body mass index, physical activity, alcohol consumption, and healthy eating habits were combined into a simple overall healthy lifestyle score ranging from 0 to 5. The changes in overall healthy lifestyle scores from baseline (range, -5 to +5) and the incidence of proteinuria, defined by a dipstick urinalysis (score ≥1+), were assessed at the second check-up. A logistic regression analysis was used to examine the association between the changes in overall healthy lifestyle scores and the incidence of proteinuria. Results After one year of follow-up, 3.9% of men and 2.4% of women developed proteinuria. Each increase (or decrease) in the changes in overall healthy lifestyle scores was associated with a reduced (or increased) risk of proteinuria in both men (odds ratio (OR) 0.87; 95% confidence interval (CI), 0.81-0.94) and women (OR 0.87; 95%CI, 0.80-0.94) after adjusting for age, baseline lifestyle scores, hypertension, diabetes mellitus, and hypercholesterolemia. Stratified analyses based on age, the presence or absence of hypertension, or diabetes mellitus revealed similar results. Conclusion Overall lifestyle changes, even within a year, were found to influence the incidence of proteinuria.