Genetic Basis of the Epidemiological Features and Clinical Significance of Renal Hypouricemia.

A genetic defect in urate transporter 1 (URAT1) is the major cause of renal hypouricemia (RHUC). Although RHUC is detected using a serum uric acid (UA) concentration <2.0 mg/dL, the relationship between the genetic state of URAT1 and serum UA concentration is not clear. Homozygosity and compound heterozygosity with respect to mutant URAT1 alleles are associated with a serum UA concentration of <1.0 mg/dL and are present at a prevalence of ~0.1% in Japan. In heterozygous individuals, the prevalence of a serum UA of 1.1−2.0 mg/dL is much higher in women than in men. The frequency of mutant URAT1 alleles is as high as 3% in the general Japanese population. The expansion of a specific mutant URAT1 allele derived from a single mutant gene that occurred in ancient times is reflected in modern Japan at a high frequency. Similar findings were reported in Roma populations in Europe. These phenomena are thought to reflect the ancient migration history of each ethnic group (founder effects). Exercise-induced acute kidney injury (EI-AKI) is mostly observed in individuals with homozygous/compound heterozygous URAT1 mutation, and laboratory experiments suggested that a high UA load on the renal tubules is a plausible mechanism for EI-AKI.

Effects of Menstrual Cycle Phase on Fluid Regulation during Walking Exercise.

To elucidate the fluid regulation in different menstrual cycle phases during exercise. Sex hormones affect fluid regulation in different ways. Moreover, the renin angiotensin-aldosterone system is activated in the luteal phase in rest. However, there are limited studies on fluid regulation affected by such hormone excretion in the menstrual cycle during exercise, especially during a light walking exercise. A non-invasive method using urine samples to determine menstrual cycle phases was used, and the follicular and luteal phases were successfully confirmed in 10 participants (age, 21 ± 1 years; body mass index, 20.5 ± 2.1 kg/m2). The experimental exercise sessions consisted of 5-min standing and 15-min walking at 2 km/h on 15% slope (approximately 8.3°) on a treadmill. Each participant carried a backpack weighing 5% of her own weight, and performed three sessions of walking exercise. Urine aldosterone excretion was significantly higher in the luteal than in the follicular phase before and after walking (p < 0.05). Urinary excretion of aldosterone was five times higher in the luteal than in the follicular phase before and after walking exercise. Heart rates during walking, after rest, and after recovery were all significantly higher in the luteal than in the follicular phase (p < 0.05). The participants' ratings of perceived exertion during the first and third session of walking in the luteal phase was not higher than that at the follicular phase. The results of our study suggested that increased activity of the renin-angiotensin-aldosterone system in the luteal phase of the menstrual cycle might be further activated during exercise. This may increase the circulatory load, which is reflected as increased heart rate. These results suggested that premenopausal women may better take into account a possibility of an increased circulatory load in the luteal phase even when they perform light exercise.

Clinical practice guideline for renal hypouricemia (1st edition).

Renal hypouricemia (RHUC) is a disease caused by dysfunction of renal urate reabsorption transporters; however, diagnostic guidance and guidelines for RHUC have been lacking, partly due to the low evidence level of studies on RHUC. This review describes a world-first clinical practice guideline (CPG) and its first version in English for this condition. It was developed following the "MINDS Manual for Guideline Development" methodology, which prioritizes evidence-based medicine. It was published in Japanese in 2017 and later translated into English. The primary goal of this CPG is to clarify the criteria for diagnosing RHUC; another aim is to work towards a consensus on clinical decision-making. One of the CPG's unique points is that it contains textbook descriptions at the expert consensus level, in addition to two clinical questions and recommendations derived from a systematic review of the literature. The guidance shown in this CPG makes it easy to diagnose RHUC from simple blood and urine tests. This CPG contains almost all of the clinical foci of RHUC: epidemiology, pathophysiology, diagnostic guidance, clinical examinations, differential diagnosis, and complications, including exercise-induced acute kidney injury and urolithiasis. A CPG summary as well as a clinical algorithm to assist healthcare providers with a quick reference and notes from an athlete for both physicians and patients are included. We hope that this CPG will help healthcare providers and patients to make clinical decisions, and that it will promote further research on RHUC.

Increasing trend of asymptomatic hyperuricemia under treatment with urate-lowering drugs in Japan.

Objectives: To describe recent trends in the prevalence of gout and asymptomatic hyperuricemia regarding urate-lowering treatment (ULT) in Japan. Methods: A database of health insurance claims managed by the Japan Medical Data Center was used to estimate the annual prevalence of gout and asymptomatic hyperuricemia during 2010-2014. ULT was evaluated for status of the two diseases during the same period. The significance of time trends was evaluated by Cochrane-Armitage trend test. Results: The prevalence of physician-diagnosed gout in men aged 20-64 years was 1.54% (95% CI: 1.49%-1.58%) in 2010, with a slight but significant (p < 0.001) annual increase, up to 1.66% (95% CI: 1.62%-1.71%) in 2014. In women, gout prevalence was somewhat constant about 0.09% during 2010-2014. Among male patients with gout, 78% received ULT. The prevalence of male patients with asymptomatic hyperuricemia in the same age range, who received ULT, increased significantly from 1.77% (95% CI: 1.72%-1.81%) to 2.14% (95% CI: 2.09%-2.19%) during 2010-2014 (p < 0.001). Conclusion: Gout prevalence in adult men in Japan has increased significantly in recent years. The prevalence of asymptomatic hyperuricemia under ULT has also increased significantly and was higher than that of gout.

Metabolic Profile as a Potential Modifier of Long-Term Radiation Effects on Peripheral Lymphocyte Subsets in Atomic Bomb Survivors.

Immune system impairments reflected by the composition and function of circulating lymphocytes are still observed in atomic bomb survivors, and metabolic abnormalities including altered blood triglyceride and cholesterol levels have also been detected in such survivors. Based on closely related features of immune and metabolic profiles of individuals, we investigated the hypothesis that long-term effects of radiation exposure on lymphocyte subsets might be modified by metabolic profiles in 3,113 atomic bomb survivors who participated in health examinations at the Radiation Effect Research Foundation, Hiroshima and Nagasaki, in 2000-2002. The lymphocyte subsets analyzed involved T-, B- and NK-cell subsets, and their percentages in the lymphocyte fraction were assessed using flow cytometry. Health examinations included metabolic indicators, body mass index, serum levels of total cholesterol, high-density lipoprotein cholesterol, C-reactive protein and hemoglobin A1c, as well as diabetes and fatty liver diagnoses. Standard regression analyses indicated that several metabolic indicators of obesity/related disease, particularly high-density lipoprotein cholesterol levels, were positively associated with type-1 helper T- and B-cell percentages but were inversely associated with naïve CD4 T and NK cells. A regression analysis adjusted for high-density lipoprotein cholesterol revealed a radiation dose relationship with increasing NK-cell percentage. Additionally, an interaction effect was suggested between radiation dose and C-reactive protein on B-cell percentage with a negative coefficient of the interaction term. Collectively, these findings suggest that radiation exposure and subsequent metabolic profile changes, potentially in relationship to obesity-related inflammation, lead to such long-term alterations in lymphocyte subset composition. Because this study is based on cross-sectional and exploratory analyses, the implications regarding radiation exposure, metabolic profiles and circulating lymphocytes warrant future longitudinal and molecular mechanistic studies.

Recent trends in hyperuricemia and gout in Japan.

The prevalence of hyperuricemia amongst Japanese adult men is now estimated to be nearly 30%. Although it had been increasing continuously until a few years ago, it now seems to have reached a plateau. In women, the prevalence of hyperuricemia is much lower than in men: 1-2% among those aged younger than 50 years and around 3% amongst those aged 50 years or older. A population-based study conducted in 2003 in a small district in Wakayama Prefecture, the age distribution of which was representative of Japan, found that the prevalence of gout was 1.7% in adult men who were older than 30 years. In that study, all 14 of the gouty patients detected were male. The results of research on the prevalence of gout in the same area conducted 30 years ago were about half of the 2003 results, suggesting that the gout prevalence may have increased. Since the number of tablets of urate-lowering drugs sold in Japan has continued to increase, the number of patients with hyperuricemia or gout that are being treated is thought to be increasing. Since hyperuricemia can cause chronic kidney disease and urolithiasis as well as gout, proper management of serum uric acid levels is warranted.

Lymphocyte subset characterization associated with persistent hepatitis C virus infection and subsequent progression of liver fibrosis.

This study aims to deepen the understanding of lymphocyte phenotypes related to the course of hepatitis C virus (HCV) infection and progression of liver fibrosis in a cohort of atomic bomb survivors. The study subjects comprise 3 groups: 162 HCV persistently infected, 145 spontaneously cleared, and 3,511 uninfected individuals. We observed increased percentages of peripheral blood T(H)1 and total CD8 T cells and decreased percentages of natural killer (NK) cells in the HCV persistence group compared with the other 2 groups after adjustment for age, gender, and radiation exposure dose. Subsequently, we determined that increased T(H)1 cell percentages in the HCV persistence group were significantly associated with an accelerated time-course reduction in platelet counts-accelerated progression of liver fibrosis-whereas T(C)1 and NK cell percentages were inversely associated with progression. This study suggests that T(H)1 immunity is enhanced by persistent HCV infection and that percentages of peripheral T(H)1, T(C)1, and NK cells may help predict progression of liver fibrosis.

Urine alkalization facilitates uric acid excretion.

BACKGROUND: Increase in the incidence of hyperuricemia associated with gout as well as hypertension, renal diseases and cardiovascular diseases has been a public health concern. We examined the possibility of facilitated excretion of uric acid by change in urine pH by managing food materials. METHODS: Within the framework of the Japanese government's health promotion program, we made recipes which consist of protein-rich and less vegetable-fruit food materials for H+-load (acid diet) and others composed of less protein but vegetable-fruit rich food materials (alkali diet). Healthy female students were enrolled in this consecutive 5-day study for each test. From whole-day collected urine, total volume, pH, organic acid, creatinine, uric acid and all cations (Na+,K+,Ca(2+),Mg(2+),NH4+) and anions (Cl⁻,SO4(2-),PO4⁻) necessary for the estimation of acid-base balance were measured. RESULTS: Urine pH reached a steady state 3 days after switching from ordinary daily diets to specified regimens. The amount of acid generated ([SO4(2-)] +organic acid-gut alkai) were linearly related with those of the excretion of acid (titratable acidity+ [NH4+] - [HCO3⁻]), indicating that H+ in urine is generated by the metabolic degradation of food materials. Uric acid and excreted urine pH retained a linear relationship, where uric acid excretion increased from 302 mg/day at pH 5.9 to 413 mg/day at pH 6.5, despite the fact that the alkali diet contained a smaller purine load than the acid diet. CONCLUSION: We conclude that alkalization of urine by eating nutritionally well-designed food is effective for removing uric acid from the body.

Combining effects of polymorphism of tumor necrosis factor alpha 5'-flanking region and HLA-DRB1 on radiological progression in patients with rheumatoid arthritis.

We examined whether polymorphisms upstream of the TNF-alpha gene (TNFA) were associated with the radiological progression of rheumatoid arthritis (RA). One hundred and twenty-three patients with early RA (disease duration <1 year) were enrolled in a prospective follow-up study. The laboratory findings (ESR, CRP, and RF) were evaluated every 2 months for 2 years. Radiological progression in hands/wrists and feet was evaluated every 6 months for 2 years using Larsen's score. HLA-DRB1 genotype was determined by PCR-RFLP method. The genotypes for -1031, -863, and -857 single-nucleotide polymorphisms in the upstream 5'-flanking region of TNFA were determined by a PCR-preferential homoduplex formation assay in patients with RA and 265 healthy controls. Four TNFA alleles (U01, U02, U03, and U04) were identified. The frequency of individuals with U02 was significantly higher in patients than in controls (P = 0.0025). Radiographs of hands/wrists/feet were available for 72 patients after 1 year and for 73 patients after 2 years. When the HLA-DRB1 genotype was analyzed simultaneously, patients possessing U02 without an HLA-DRB1 shared epitope (SE) (U02+SE-) showed the lowest progression of Larsen's score (12 months). There was no difference in the level of ESR, CRP, or RF at the first visit among U02+SE+, U02+SE-, U02-SE+, and U02-SE- groups. The combination of the polymorphism of the TNFA upstream promoter region and HLA-DRB1 allele was associated with radiological progression in the early stage of RA.

Combining effects of polymorphism of tumor necrosis factor α 5'-flanking region and HLA-DRB1 on radiological progression in patients with rheumatoid arthritis.

We examined whether polymorphisms upstream of the TNF-α gene (TNFA) were associated with the radiological progression of rheumatoid arthritis (RA). One hundred and twenty-three patients with early RA (disease duration <1 year) were enrolled in a prospective follow-up study. The laboratory findings (ESR, CRP, and RF) were evaluated every 2 months for 2 years. Radiological progression in hands/wrists and feet was evaluated every 6 months for 2 years using Larsen's score. HLA-DRB1 genotype was determined by PCR-RFLP method. The genotypes for -1031, -863, and -857 single-nucleotide polymorphisms in the upstream 5'-flanking region of TNFA were determined by a PCR-preferential homoduplex formation assay in patients with RA and 265 healthy controls. Four TNFA alleles (U01, U02, U03, and U04) were identified. The frequency of individuals with U02 was significantly higher in patients than in controls (P = 0.0025). Radiographs of hands/wrists/feet were available for 72 patients after 1 year and for 73 patients after 2 years. When the HLA-DRB1 genotype was analyzed simultaneously, patients possessing U02 without an HLA-DRB1 shared epitope (SE) (U02+SE-) showed the lowest progression of Larsen's score (12 months). There was no difference in the level of ESR, CRP, or RF at the first visit among U02+SE+, U02+SE-, U02-SE+, and U02-SE- groups. The combination of the polymorphism of the TNFA upstream promoter region and HLA-DRB1 allele was associated with radiological progression in the early stage of RA.

[Epidemiology of hyperuricemia and gout in Japan].

It has been reported that the prevalence of hyperuricemia in Japan is 20-25% in adult male population and has been increasing at least until a few years ago. Although epidemiological data for the prevalence of gout in Japan is limited, a recent study conducted in a local area of Wakayama prefecture reported a prevalence of 1.1% in men. Japanese national census data revealed that the number of individuals visiting hospitals with a self-diagnosis of gout has been increasing. The census data also showed that the proportion of individuals with obesity(BMI > or = 25) has been increasing in male population, probably due to decreasing physical exercise. This epidemic of obesity may be one cause for a recent increase in hyperuricemic individuals in Japan.

Associations between HLA-DRB1, RANK, RANKL, OPG, and IL-17 genotypes and disease severity phenotypes in Japanese patients with early rheumatoid arthritis.

We examined associations between human leukocyte antigen DRB1 (HLA-DRB1) shared epitope (SE), receptor activator of nuclear factor-kappaB (RANK), RANK ligand (RANKL), osteoprotegerin (OPG), and interleukin 17 (IL-17) genotypes with age of disease onset and radiographic progression in Japanese patients with early rheumatoid arthritis (RA). HLA-DRB1 genotypes were evaluated in 123 patients with early RA (98 female, 25 male) within 1 year of symptom onset. In 72 patients, radiographic progression over a 2-year period was evaluated using Larsen's methods, and genotypes of three polymorphic sites in RANK, five sites in RANKL, two sites in OPG, and three sites in IL-17 were determined by direct polymerase chain reaction sequencing. Possession of an SE allele was significantly associated with earlier disease onset in females (median 46.9 vs 51.9 years in SE- patients; P = 0.04). Single nucleotide polymorphisms (SNPs) in RANKL (rs2277438, P = 0.028) and IL-17 (rs3804513, P = 0.049) were significantly associated with radiographic progression at 2 years. RANKL-G-, SE- patients (n = 12) had significantly less joint damage than did RANKL-G+, SE- patients (n = 11; P = 0.0038), RANKL-G-, SE+ patients (n = 21; P = 0.0018) and RANKL-G+, SE+ patients (n = 28; P = 0.0024). In Japanese RA patients, HLA-DRB1 SE alleles are associated with disease onset at an earlier age, as has been observed in Caucasian RA patients. In addition, SNPs in RANKL and IL-17 may be associated with radiographic progression in Japanese patients with early RA.

[Absolute risk for fracture and WHO guideline. Epidemiology of rheumatoid arthritis].

Japan has been assumed to be a country with a low prevalence of rheumatoid arthritis (RA) . However, when comparing the RA prevalence among different countries in the middle age or in the older ages, in which RA predominantly occurs, RA prevalence of Japan is somewhat lower than that of United Kingdom, Finland, and United States, but is similar to that of Norway, France, and Greece. Several reports showed that RA incidence has been decreasing recently. This indicates that non-genetic factors are related to the occurrence of RA and that such factors have been decreasing with time.

Low-positive antibody titer against Helicobacter pylori cytotoxin-associated gene A (CagA) may predict future gastric cancer better than simple seropositivity against H. pylori CagA or against H. pylori.

BACKGROUND: To investigate the IgG antibody titer against Helicobacter pylori CagA as a risk factor for future noncardia gastric cancer. METHODS: A nested case-control study was done in the longitudinal cohort of atomic bomb survivors using stored sera before diagnosis (mean, 2.3 years). Enrolled were 299 cancer cases and 3 controls per case selected from cohort members matched on age, gender, city, and time and type of serum storage and countermatched on radiation dose. RESULTS: H. pylori IgG seropositive with CagA IgG low titer was the strongest risk factor for noncardia gastric cancer [relative risk (RR), 3.9; 95% confidence interval (95% CI), 2.1-7.0; P < 0.001], especially for intestinal-type tumor (RR, 9.9, 95% CI, 3.5-27.4; P < 0.001), compared with other risk factors, H. pylori IgG seropositive with CagA IgG negative (RR, 2.2; 95% CI, 1.3-3.9; P = 0.0052), H. pylori IgG seropositive with CagA IgG high titer (RR, 2.0; 95% CI, 1.3-3.2; P = 0.0022), chronic atrophic gastritis (RR, 2.4; 95% CI, 1.8-3.3; P < 0.001), current smoking (RR, 2.3; 95% CI, 1.4-3.5; P < 0.001), or radiation dose (RR, 2.1; 95% CI, 1.2-3.1; P = 0.00193). Current smoking showed significantly higher risk for diffuse-type than intestinal-type tumors (P = 0.0372). Radiation risk was significant only for nonsmokers, all noncardia, and diffuse-type gastric cancers. CONCLUSIONS: A low CagA IgG titer is a useful biomarker to identify a high-risk group and it also provides a clue to understanding host-pathogen interaction.

Feasibility of freeze-dried sera for serological and molecular biological detection of hepatitis B and C viruses.

We compared hepatitis B virus (HBV) surface antigen, anti-hepatitis C virus (HCV) antibody, and HCV RNA quantification in frozen and freeze-dried serum samples to assess the usefulness of freeze-dried sera for detection of HBV and HCV. The results indicated that freeze-dried sera as well as frozen sera can be useful for serological and molecular biological analyses of HBV and HCV.

Levels of antibodies to microorganisms implicated in atherosclerosis and of C-reactive protein among atomic bomb survivors.

Although it has been suggested that cardiovascular disease incidence is increased among atomic bomb survivors, the existence of a causal relationship between radiation exposure and atherosclerosis is unclear. Microbial infections, including those caused by Chlamydia pneumoniae, Helicobacter pylori and cytomegalovirus, have recently been implicated in atherosclerosis. Since immune function is somewhat impaired among atomic bomb survivors, their immune defense against such infections might be diminished. To investigate this possibility, we measured antibody levels to the above microorganisms in the sera of survivors. We found that the levels of IgG and IgA antibodies to Chlamydia pneumoniae decreased significantly with radiation dose, whereas the levels of IgG antibodies to Helicobacter pylori or cytomegalovirus remained unchanged. The inflammation marker C-reactive protein was significantly and positively associated with level of antibodies to Chlamydia pneumoniae only in heavily exposed (>or=1000 mGy) survivors. These results may suggest that among atomic bomb survivors, immune response to Chlamydia pneumoniae is diminished and chronic inflammatory reactions related to Chlamydia pneumoniae infection are present.

Individual variation of somatic gene mutability in relation to cancer susceptibility: prospective study on erythrocyte glycophorin a gene mutations of atomic bomb survivors.

It has previously been reported that hemizygous mutant fraction (Mf) at the glycophorin A (GPA) locus in erythrocytes increased with radiation dose in heterozygotes among Hiroshima and Nagasaki atomic bomb survivors. In the present study, we analyzed the relationship between GPA Mf and cancer risk using newly developed cancers among previously cancer-free subjects whose GPA Mf had been measured between 1988 and 1996. Among 1,723 survivors (1,117 in Hiroshima and 606 in Nagasaki), we identified 186 subjects who developed a first cancer by the end of 2000. We compared the radiation dose responses of GPA Mf between cancer and cancer-free groups using a linear-quadratic model fit by multiple regression analysis in combination with age, sex, and city. The slope of the GPA Mf dose-response curve was significantly higher in the cancer group than in the cancer-free group among Hiroshima subjects. Moreover, no significant difference of GPA Mf between cancer and cancer-free groups was found in unexposed controls in the two cities. The same conclusions were obtained using a linear dose-response model and by further analysis using Cox regression of cancer incidence. These findings suggest that there might be interindividual variation in mutability of somatic genes and that Hiroshima survivors who have higher mutability in response to radiation exposure would be expected to have a higher probability of suffering radiation-related cancer.

Serum uric acid concentration as a risk factor for cardiovascular mortality: a longterm cohort study of atomic bomb survivors.

OBJECTIVE: To elucidate the association of serum uric acid concentration with cardiovascular mortality risk. METHODS: Serum uric acid level measured from 1966 through 1970 in 10,615 Japanese individuals from a cohort of atomic bomb survivors was analyzed for association with subsequent cardiovascular and all-cause mortality until 1999 using the Cox proportional hazard model. RESULTS: During an average followup of 24.9 years, 5225 deaths occurred, of which 1984 were ascribed to cardiovascular disease. In men, after adjustment for age, elevated serum uric acid level was associated with both cardiovascular and all-cause mortality. After additional adjustment for potential cardiovascular disease risk factors including body mass index, smoking status, alcohol consumption, systolic blood pressure, cholesterol level, and histories of hypertension, diabetes and cardiovascular disease, elevated serum uric acid level in men was associated with all-cause mortality but not with cardiovascular mortality. In women, even after these adjustments, elevated serum uric acid level was significantly associated with cardiovascular and all-cause mortality. CONCLUSION: Increased serum uric acid level is a significant and independent risk factor for cardiovascular mortality in women and for all-cause mortality in both men and women.

Immunogenetic features in 120 Japanese patients with idiopathic inflammatory myopathy.

OBJECTIVE: To examine the role of HLA-DRB1 and tumor necrosis factor (TNF) promoter genotypes in the development and the autoantibody profiles of idiopathic inflammatory myopathy (IIM) in Japanese patients. METHODS: HLA-DRB1 and TNF promoter genotypes were determined, and serum antinuclear autoantibodies were identified in 120 adult Japanese patients with IIM [72 with dermatomyositis (DM), 30 with polymyositis (PM), 18 with myositis overlapping with other collagen vascular diseases], as well as in 265 controls. RESULTS: Forty-two patients (35%) were positive for myositis-specific autoantibodies (MSA), including 37 (31%) for anti-aminoacyl-tRNA synthetase (ARS) autoantibodies. Allele carrier frequency of HLA-DRB1*0803 was increased in the patients with IIM [p = 0.02, corrected p (pc) NS, 23% vs 14%, odds ratio (OR) = 1.9 (95% confidence interval, CI = 1.1-3.2)], with PM [p = 0.006, pc NS, 33%, OR 3.1 (95% CI 1.3-7.1)], and with anti-ARS autoantibodies [27%, p = 0.04, OR 2.3 (95% CI 1.0-5.1)] compared with controls. DRB1*0405 was increased in patients with anti-ARS autoantibodies compared with controls [41% vs 25%, p = 0.04, pc NS, OR 2.1 (95% CI 1.0-4.3)]. TNF promoter genotype was associated with the presence of interstitial lung disease (ILD). The carriage of a TNF-a haplotype formed by -1031C, -863A, and -857C was increased in the patients with ILD versus those without ILD [33% vs 18%, p = 0.05, pc NS, OR 2.3 (95% CI 0.94-5.5)]. CONCLUSION: HLA-DRB1 alleles were associated with development of IIM and MSA in a Japanese population.