Influence of chronic kidney disease on hospitalization, chronic dialysis, and mortality in Japanese men: a longitudinal analysis.

BACKGROUND: Little is known concerning the risk of hospitalization and the risk of death before receiving dialysis by the stage of chronic kidney disease (CKD) in Japan. METHODS: The subjects comprised a total of 13,911 Japanese men (mean age 49.2 ± 9.9 years). Based on the results of a health checkup performed in 2006, they were divided into 5 groups according to their estimated glomerular filtration rate (GFR) levels and dialysis status: GFR ≥60, 45-59, 30-44, <30 mL/min/1.73 m2, and undergoing dialysis. From 2006 through to 2013, we investigated their hospitalization, dialysis initiation, and cause-specific death. The adjusted hazard ratios (HRs) for each end point were calculated compared with the GFR ≥60 mL/min/1.73 m2 group using a Cox proportional hazard model. RESULTS: A lower GFR was independently associated with higher risks of overall hospitalization, dialysis initiation, and all-cause death. In particular, the HRs for long-term hospitalization (≥1 month a year), dialysis, and cardiovascular disease (CVD) death markedly increased along with a decreased GFR. The rate ratios of dialysis to all-cause death (calculated based on the incidences of dialysis and death per 1000 person-years) were 0.03 (0.11 vs. 3.19), 0.08 (0.29 vs. 3.62), 0.51 (12.5 vs. 24.7), and 4.50 (179.8 vs. 40.0) for GFR ≥60, 45-59, 30-44, and <30 mL/min/1.73 m2, respectively. CONCLUSION: In Japanese men, although the risk of CVD death before dialysis initiation can never be ignored, CKD patients aged <60 years with a GFR of <30 mL/min/1.73 m2 are more likely to undergo dialysis prior to death.

Risk of chronic kidney disease in non-obese individuals with clustering of metabolic factors: a longitudinal study.

OBJECTIVE: The impact of the clustering of metabolic factors on chronic kidney disease (CKD) in non-obese individuals remains unclear. METHODS: We conducted a follow-up study of 23,894 Japanese adults (age, 18-69 years) who continuously received annual health examinations between 2000 and 2011. Obesity, high blood pressure, high triglycerides, low high-density lipoprotein (HDL) cholesterol and high fasting blood sugar were defined as metabolic factors, and CKD was defined as renal dysfunction (estimated glomerular filtration rate: <60 mL/min/1.73 m(2)) or proteinuria (dipstick test: ≥1+). The association between the clustering of metabolic factors and CKD was assessed based on the presence or absence of obesity using a Cox proportional hazard model. RESULTS: Of 2,867 subjects with ≥3 metabolic factors, 650 (22.7%) were non-obese. These individuals were older and had higher metabolic risks than their obese counterparts at baseline. Among the entire cohort of 23,894 subjects, 1,764 developed renal dysfunction and 904 developed proteinuria during an average follow-up period of 7.8 years. The cumulative incidence of renal dysfunction was higher (22.1% vs. 16.1%), whereas that of proteinuria was lower (10.5% vs. 14.4%), among the non-obese subjects with ≥3 metabolic factors than the obese subjects with ≥3 metabolic factors after 11 years. The adjusted relative risk (RR) (95% confidence interval) of renal dysfunction was 1.54 (1.34-1.77) and 1.67 (1.35-2.07) for the obese and non-obese subjects with ≥3 metabolic factors, respectively. CONCLUSION: Non-obese subjects with ≥3 metabolic factors, who are missed based on the essential criterion of obesity for metabolic syndrome, may have an equal or slightly higher risk of renal dysfunction than obese subjects with ≥3 metabolic factors.

Increased frequencies of micronucleated reticulocytes and T-cell receptor mutation in Aldh2 knockout mice exposed to acetaldehyde.

Aldehyde dehydrogenase-2 (ALDH2) metabolizes acetaldehyde produced from ethanol into acetate and plays a major role in the oxidation of acetaldehyde in vivo. About half of all Japanese people have inactive ALDH2. We generated homozygous Aldh2 null (Aldh2-/-) mice by gene targeting knockout as a model of ALDH2-deficient humans. To investigate the mutagenicity of acetaldehyde, a micronucleus assay and a T-cell receptor (TCR) gene mutation assay were performed in Aldh2-/- mice and wild-type (Aldh2 +/+) mice exposed to acetaldehyde. The mice were continuously exposed to 125 and 500 ppm of acetaldehyde vapor for 2 weeks. Another group was orally administered 100 mg/kg once a day for 2 weeks continuously. The mice were killed after 2 weeks of exposure to acetaldehyde, and the frequency of micronucleated reticulocytes was measured by flow cytometry. We also observed the incidence of TCR gene mutations in T-lymphocytes by measuring the variant CD3(-CD4+) expression by flow cytometry. The frequency of micronucleated reticulocytes induced by acetaldehyde was significantly increased in Aldh2 -/- mice, but not in Aldh2 +/+ mice. TCR mutant frequency was also associated with acetaldehyde exposure in Aldh2-/ - mice, especially after oral administration; however, it was not associated with acetaldehyde exposure in Aldh2 +/+ mice. In conclusion, Aldh2 -/- mice showed high sensitivity in the micronuclei and TCR mutation assays compared with Aldh2 +/+ mice after exposure to acetaldehyde.

A pilot study on subacute ethanol treatment of ALDH2 KO mice.

Aldh (aldehyde dehydrogenase ) 2 knockout (KO) mice have been generated in our laboratory. We evaluated the effects of subacute ethanol treatment on the survival rate, expression of Aldh1, Aldh2, Cytochrome P450 (Cyp) 1A1, Cyp2e1 and Cyp4b1 in wild (Aldh2+/+) mice (C57BL/6) and Aldh2 knock out (Aldh2-/-) mice. Physiological saline (0.3 mL/day) was administered to 4 Aldh2+/+ and 4 Aldh2-/- mice for 8 days as a control. Forty percent ethanol (0.3 mL/day; ethanol 2 g/kg/day) was then administered to 5 Aldh2+/+ and 9 Aldh2-/- mice for 8 days. Three mice of the ethanol administered Aldh2+/+ group and eight mice of the ethanol administered Aldh2-/- group died during the 8 days. The weights of mice were decreased by ethanol exposure to 85% and 74% in Aldh2+/+ and Aldh2-/- group, respectively. The survival rates of the ethanol administered Aldh2+/+ and Aldh2-/- group were 40 and 11%. Liver and pancreas disorder was revealed in the ethanol administered Aldh2+/+ and Aldh2-/- group in the results of serum chemical examination, immunohistochemical staining and western blot analysis. Cyp2e1 is more inducible to ethanol toxicity in Aldh2-/- mice compared with Aldh2+/+ mice when ethanol is administered according to the results of quantitative PCR.

HBV- and HCV- infected workers in the Japanese workplace.

Around three million Japanese are persistently infected with HBV or HCV. Though most of them work in various industries, little is known about the actual conditions in their workplaces. To clarify the workplace conditions of workers with hepatitis, three kinds of questionnaire surveys, answered by occupational health physicians and workers with hepatitis, were carried out. The rates of workers recognized as workers with hepatitis B or C by occupational health physicians were 0.82% and 0.48% of 130,092 workers, respectively. About 30% of workers with hepatitis were engaged in "hazardous work". The percentage of workers engaged in various types of hazardous work among workers with hepatitis was nearly the same as that among all Japanese workers. About 30% of occupational health physicians witnessed exacerbation of hepatitis in the workers at their workplaces, and 22% of workers with hepatitis experienced exacerbation of hepatitis. The rate of workers with hepatitis who had experienced exacerbation was not significantly different between workers with and without hazardous work. Workers with hepatitis have strong concerns about the relationship between work and exacerbation. As causes of exacerbation, occupational health physicians cited "unknown", "drinking" and "quit treatment" while workers with hepatitis answered "work-related causes", besides "unknown" and "drinking."

Urinary 8-hydoxydeoxyguanosine (8-OHdG) and plasma malondialdehyde (MDA) levels in Aldh2 knock-out mice under acetaldehyde exposure.

To clarify the carcinogenicity of acetaldehyde when associated with ALDH (aldehyde dehydrogenase) 2 polymorphism, Aldh2 knock-out (Aldh2-/-) mice and their wild type (Aldh2+/+) mice were exposed to two different concentrations of acetaldehyde (125 ppm and 500 ppm) for two weeks. Aldh2-/- mice, which have the same genetic background as C57BL/6J (wild mice) except for the Aldh2 gene, were used as models of humans who lack ALDH2 activity. Urinary 8-hydroxydeoxyguanosine (8-OHdG) and plasma malondialdehyde (MDA) levels were measured as indicators of oxidative DNA damage and lipid peroxidation, respectively. At 125 ppm acetaldehyde exposure for 12 d, urinary 8-OHdG levels in Aldh2+/+ mice did not increase. However, urinary 8-OHdG levels in Aldh2-/- mice were slightly increased by the end of the exposure. On the other hand, plasma MDA levels did not increase in either Aldh2-/- orAldh2+/+ mice. At 500 ppm, urinary 8-OHdG levels in both Aldh2-/- and Aldh2+/+ mice significantly increased after 6 and 12 d, but there was no genetic difference. On the other hand, plasma MDA levels in Aldh2+/+ and Aldh2-/- mice did not increase at either 125 ppm or 500 ppm after two weeks of exposure. In conclusion, it is suspected that DNA was damaged by acetaldehyde inhalation, and that susceptibility to acetaldehyde varies according to Aldh2 genotype.

Evidence-based prevention (EBP): A review of cytochrome P450 expression in the bronchial epithelium and new approach to lung cancer prevention.

The number of fatalities in Japan attributable to lung cancer exceeded 50000 in 2001. It is socially desirable that various markers, which can be utilized for the prevention of lung cancer, be established. We believe that smoking or exposure to carcinogens in air induces mutations in bronchial and alveolar epithelia, leading to the development of lung cancer. It would be useful to have markers of individual differences in susceptibility to chemical carcinogen-induced lung cancer 1) to identify genetic polymorphisms of enzymes metabolizing chemical carcinogens and 2) to investigate the expression of enzymes metabolizing chemical carcinogens. In this paper, we review CYP expression in the bronchial epithelium. CYP1, CYP2 and CYP3 are expressed in the bronchial epithelium. We also show the relationship between the genetic polymorphisms of cytochrome P450 (CYP) and a person's susceptibility to chemical carcinogen-induced lung cancer. We demonstrate the relationship between cigarette consumption and the CYP expression profile in the bronchial epithelium. To maintain and promote public health, we must apply evidence, such as CYP polymorphisms and CYP profiles to disease prevention and also to aggressively advance evidence-based prevention (EBP) of lung cancer.

Paired acute inhalation test reveals that acetaldehyde toxicity is higher in aldehyde dehydrogenase 2 knockout mice than in wild-type mice.

Aldehyde dehydrogenase 2 (ALDH2) is an important enzyme that oxidizes acetaldehyde. Approximately 45% of Chinese and Japanese individuals have the inactive ALDH2 genotypes (ALDH2*2/*2 and ALDH2*1/*2); acute inhalation toxicity of acetaldehyde has not been evaluated in these populations. We compared the toxicity between wild-type (Aldh2+/+) and Aldh2-inactive transgenic (Aldh2-/-) mice by using the paired acute inhalation test modified from the acute toxic class method (OECD TG433). Blood acetaldehyde level was measured 4 hr after the inhalation. A pair of Aldh2+/+ and Aldh2-/- mice was put into a chamber and was exposed to 5000 ppm of acetaldehyde. At the start of the inhalation, the mice exhibited hypoactivity and closing of the eyes. Subsequently, symptoms such as crouching, bradypnea, and piloerection were observed. Flushing was observed only in the Aldh2+/+ mice. Symptoms such as tears, straggling gait, prone position, pale skin, abnormal deep respiration, dyspnea, and one case of death were observed only in the Aldh2-/- mice. The symptoms did not change 1 hr after inhalation in the Aldh2+/+ mice. In contrast, in the Aldh2-/- mice, the symptoms became more severe until the end of the inhalation. The blood acetaldehyde level in the Aldh2-/- mice was approximately twice that in the Aldh2+/+ mice 4 hr after inhalation. The Aldh2-/- mice evidently showed more severe toxicity as compared with the Aldh2+/+ mice due to acute inhalation of acetaldehyde at a concentration of 5000 ppm. Acetaldehyde toxicity in Aldh2+/+ and Aldh2-/- mice was estimated and classified one class different. Based on this study, acetaldehyde inhalations were inferred to pose a higher risk to ALDH2-inactive human individuals.

Tissue-distribution of aldehyde dehydrogenase 2 and effects of the ALDH2 gene-disruption on the expression of enzymes involved in alcohol metabolism.

In alcohol metabolism, acetaldehyde, a highly reactive intermediate that may cause cellular and DNA damages, is converted to acetate by mitochondrial aldehyde dehydrogenase ALDH2. Although the majority of ingested alcohol is eliminated in the liver, the first-pass metabolism of ethanol in the upper digestive tract is also important for prevention and management of ethanol-related gastrointestinal diseases. However, the tissue-distribution of Aldh2 in mice has been poorly investigated. In this study, therefore, we investigated the tissue-distribution of Aldh2 as well as Aldh1, Cyp1a1, Cyp2e1, and Cyp4b1 in wild type and Aldh2-null mice by immuno-histochemical analysis. The human liver and esophageal tissues were also examined. In mice, the Aldh2 protein was detected in the liver, lung, heart, kidney, testis, esophagus, stomach, colon, and pancreas, suggesting that the tissue-distribution of Aldh2 in mice is similar to that in humans. Therefore, Aldh2-null mice may be useful model animals for the investigation of alcohol metabolism and related diseases. Compared with the wild type, the expression level of Cyp2e1 was increased in the liver from Aldh2-null mice based on Western blot analysis, whereas the levels of Aldh1, Cyp1a1, and Cyp4b1 were indistinguishable. This observation suggests that a metabolite(s) of Aldh2 might down-regulate the expression of Cyp2e1 gene.

Expression of cytochrome P450 in tumor tissues and its association with cancer development.

CYPs (cytochrome P450s) catalyze the conversion of numerous numbers of xenobiotics including carcinogens and drugs. CYPs can be involved in metabolic pathways of activation of procarcinogens and/or inactivation of carcinogens during the tumorigenic processes. Recently, increasing number of cancer tissues as well as normal tissues have been found to express a variety of CYPs. The local expression of CYPs in tumors appears to be very important for the management of cancers since CYPs expressed in tumors may be involved in activation and/or inactivation of anticancer drugs. The expression of CYPs in tumors may also convert endogenous substrates to metabolites that facilitate cancer development. In this review, we summarize the association of CYP expression in cancer tissues with carcinogenesis and cancer treatment.