Background:Uric acid (UA) serves as an antioxidant in vascular endothelial cells. UA transporter 1 (URAT1) encoded by SLC22A12 is expressed in the kidney and vessels and its loss of function causes ...hypouricemia. The purpose of this study was to examine whether there is any endothelial dysfunction in patients with hypouricemia.Methods and Results:Twenty-six patients with hypouricemia (<2.5 mg/dl) and 13 healthy control subjects were enrolled. Endothelial function was evaluated using flow-mediated dilation (FMD). mRNA of UA transporters expressed in cultured human umbilical endothelial cells (HUVEC) was detected on RT-PCR. There was a positive correlation between FMD and serum UA in the hypouricemia group. URAT1 loss-of-function mutations were found in the genome of 21 of 26 patients with hypouricemia, and not in the other 5. In the hypouricemia groups, serum UA in homozygous and compound heterozygous patients was significantly lower than in other groups, suggesting that severity of URAT1 dysfunction may influence the severity of hypouricemia. Thirteen of 16 hypouricemia subjects with homozygous and compound heterozygote mutations had SUA <0.8 mg/dl and their FMD was lower than in other groups. HUVEC do not express mRNA of URAT1, suggesting the null role of URAT1 in endothelial function.Conclusions:Depletion of UA due to SLC22A12/URAT1 loss-of-function mutations causes endothelial dysfunction in hypouricemia patients. (Circ J 2015; 79: 1125–1132)
Hypouricemia was reported as a risk factor for exercise-induced acute renal injury (EIAKI) and urinary stones. However, the prevalence of kidney diseases among hypouricemic subjects has not been ...evaluated. This study was conducted to clarify the prevalence of hypouricemia and the association of hypouricemia with kidney diseases by using a large-scale Japanese population data.
This study is a retrospective cross-sectional study at the Center for Preventive Medicine, St. Luke's International Hospital, Tokyo, Japan, and Sanin Rousai Hospital, Yonago, Japan. We analyzed the medical records of 90,143 Japanese subjects at the center in St. Luke's International Hospital, Tokyo, and 4,837 subjects in Sanin Rousai Hospital, Yonago, who underwent annual regular health check-up between January 2004 and June 2010. We defined hypouricemia as serum uric acid level of ≤2.0 mg/dL. We checked the medical history of all the study subjects and compared the rates of complications including urinary stones and kidney diseases among those with or without hypouricemia.
The prevalence of hypouricemia was 0.19% in St. Luke's International Hospital, Tokyo, and 0.58% in Sanin Rousai Hospital, Yonago. The prevalence of hypouricemia in women was larger than that in men both in Tokyo (0.31% vs 0.068%, p<0.001) and in Yonago (1.237% vs 0.318%, p<0.001). Among 172 hypouricemic subjects (30 men), the rates of previous urinary stones and kidney diseases (including nephritis/nephrosis) were 1.2% (3.3% men, 0.7% women) and 2.3% (10% men, 0.7% women), respectively. Hypouricemic men had a 9-fold higher rate of previously having kidney diseases compared to non-hypouricemic men (p<0.001). However, the rates of other diseases including urinary stones were not significantly different between the two groups.
Hypouricemia was associated with a history of kidney disease especially in men.
Background:Ischemia/reperfusion (I/R) injury triggers cardiac dysfunctions via creating reactive oxygen species (ROS). Because xanthine oxidase (XO) is one of the major enzymes that generate ROS, ...inhibition of XO is expected to suppress ROS-induced I/R injury. However, it remains unclear whether XO inhibition really yields cardioprotection during I/R. The protective effects of the XO inhibitors, topiroxostat and allopurinol, on cardiac I/R injury were evaluated.Methods and Results:Using isolated rat hearts, ventricular functions, occurrence of arrhythmias, XO activities and thiobarbituric acid reactive substances (TBARS) productions and myocardial levels of adenine nucleotides before and after I/R, and cardiomyocyte death markers during reperfusion, were evaluated. Topiroxostat prevented left ventricular dysfunctions and facilitated recovery from arrhythmias during I/R. Allopurinol and the antioxidant, N-acetylcysteine (NAC), exhibited similar effects at higher concentrations. Topiroxostat inhibited myocardial XO activities and TBARS productions after I/R. I/R decreased myocardial levels of ATP, ADP and AMP, but increased that of xanthine. While topiroxostat, allopurinol or NAC did not change myocardial levels of ATP, ADP or AMP after I/R, all of the agents decreased the level of xanthine. They also decreased releases of CPK and LDH during reperfusion.Conclusions:Topiroxostat showed protective effects against I/R injury with higher potency than allopurinol or NAC. It dramatically inhibited XO activity and TBARS production, suggesting suppression of ROS generation.
Whether or not extremely low levels of serum uric acid (SUA) in xanthinuria are associated with impairment of the endothelial function and exercise-induced acute kidney injury (EIAKI) is unclear. A ...59-year-old woman without EIAKI or urolithiasis had undetectable levels of UA in serum and urine and elevated levels of hypoxanthine and xanthine in urine. A genetic analysis revealed homozygous mutations in the XDH gene c.1585 C>T (p. Gln529*). Flow-mediated dilation was within the normal range. This is the first report of a case with extremely low levels of SUA, xanthinuria with novel mutations of xanthine dehydrogenase (XDH) and a normal endothelial function.
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.
Objective Both renal hypouricemia (RHU) and gout are associated with renal dysfunction and urolithiasis. The difference in renal complications associated with RHU and gout, however, has not been ...studied. We characterized the urate metabolism and complications of patients with RHU and compared them with patients with gout. Methods Eighteen patients with RHU who had a serum uric acid (SUA) level <2 mg/dL (10 men and 8 women), 44 patients with gout (44 men) and 16 normouricemic patients (4 men and 12 women) were included. The blood and urinary biochemical data were evaluated. A genetic analysis of uric acid transporter 1 (URAT1) was also conducted in 15 cases with RHU. Results The SUA level of RHU was 0.9±0.5/mg/dL, and the Uur/Ucr and Cur/Ccr were 0.56±0.14% and 45.7±18.0%, respectively. A genetic analysis of URAT1 in 15 RHU patients showed that 13 harbored a URAT1 gene mutation, whereas 2 harbored the wild-type gene. The SUA level was significantly lower in RHU patients (n=11) than in either gout patients (n=44) or normouricemic patients (n=16). This reduction was accompanied by the elevation of Cua/Ccr. Urinary beta 2-microglobulin levels were higher in RHU patients than in gout or normouricemia patients. Cua/Ccr correlated with normalized urinary beta 2-microglobulin levels. The prevalence of urolithiasis was 18.2% in RHU cases and 6.8% in gout cases. A homozygous URAT1 mutation was associated with urolithiasis. Conclusion Besides urolithiasis, RHU can be associated with tubular dysfunction, such as elevated urinary beta 2-microglobulin levels.
The prevalence of patients with hyperuricemia or gout is increasing worldwide. Hyperuricemia and gout are primarily attributed to genetic factors, along with lifestyle factors like consuming a ...purine-rich diet, alcohol and/or fructose intake, and physical activity. While numerous studies have reported various comorbidities linked to hyperuricemia or gout, the range of these associations is extensive. This review article focuses on the relationship between uric acid and thirteen specific domains: transporters, genetic factors, diet, lifestyle, gout, diabetes mellitus, metabolic syndrome, atherosclerosis, hypertension, kidney diseases, cardiovascular diseases, neurological diseases, and malignancies. The present article provides a comprehensive review of recent developments in these areas, compiled by experts from the Young Committee of the Japanese Society of Gout and Uric and Nucleic Acids. The consolidated summary serves to enhance the global comprehension of uric acid-related matters.
Background: Risk stratification for elderly patients with acute decompensated heart failure (ADHF) may help clinicians to select the appropriate therapy and raise the quality of care. Methods and ...Results: The present study enrolled 349 patients aged over 65 years who were hospitalized with ADHF from January 2004 to October 2008. Five independent prognostic factors were identified by multivariate logistic regression analysis, and each factor was assigned a number of points proportional to its regression coefficient: prior heart failure hospitalization (2points), sodium ≤138 mmol/L (2points), BUN ≥35 mg/dl (2points), albumin ≤3.2 g/dl (3points), and BNP ≥980 pg/ml (2points); in particular, hypoalbuminemia was identified as the strongest prognostic factor. The patients were stratified into 3 groups: low risk (0-4points), moderate risk (5-7points), and high risk (8-11points). The respective in-hospital mortality rates were 1.6%, 15.8%, and 42.1% (P<0.05). Conclusions: In addition to known prognostic factors, hypoalbuminemia may provide important information for elderly patients with ADHF. A simple risk score may help to stratify the risk of in-hospital mortality and contribute to better clinical management of these elderly patients. (Circ J 2009; 73: 2276-2281)
Adipose stem cells (ASCs) are a source of regenerative cells available for autologous transplantation to hearts. We compared protective actions of ASC sheets on rat myocardial infarction (MI) in ...comparison with those of skeletal myoblast cell sheets. Their effects on infarcted hearts were evaluated by biological, histochemical as well as physiological analyses. ASC sheets secreted higher concentrations of angiogenic factors (HGF, VEGF, and bFGF; P < 0.05) under normoxic and hypoxic conditions than those of myoblast cell sheets, associated with reduction of cell apoptosis (P < 0.05). Like myoblast cell sheets, ASC sheets improved cardiac function (P < 0.05) and decreased the plasma level of ANP (P < 0.05) in MI hearts. ASC sheets restored cardiac remodeling characterized by fibrosis, cardiac hypertrophy and impaired angiogenesis (P < 0.05), which was associated with increases in angiogenic factors (P < 0.05). In isolated perfused rat hearts, ASC sheets improved both systolic and diastolic functions, which was comparable to cardiac functions of myoblast cell sheets, while both cell sheets failed to restore cardiac contractile response to either isoproterenol, pimobendan or dibutyryl cAMP. These results indicated that ASC sheets improved cardiac function and remodeling of MI hearts mediated by their paracrine action and this improvement was comparable to those by myoblast cell sheets.
Cell sheets using myoblasts have been developed for the treatment of heart failure after myocardial infarction (MI) bridging to heart transplantation. Stem cells are supposed to be better than ...myoblasts as a source of cells, since they possess a potential to proliferate and differentiate into cardiomyocytes, and also have capacity to secrete angiogenic factors. Adipose-derived stem cells (ASCs) obtained from fat tissues are expected to be a new cell source for ASC sheet therapies. Administration of angiotensin II receptor blockers (ARBs) is a standard therapy for heart failure after MI. However, it is not known whether ARBs affect the cell sheet therapy. This study aimed to examine ameliorating effects of ASC sheets on heart failure and remodeling after MI, and how pretreatment with ARBs prior to the creation of MI and ASC sheet transplantation modifies the effects of ASC sheets.
ASCs were isolated from fat tissues of wild-type rats, and ASC sheets were engineered on temperature-responsive dishes. In in vitro studies using cultured cells, mRNA levels of vascular endothelial growth factor (VEGF) in ASCs were determined by RT-PCR in the presence of angiotensin II and/or an ARB, irbesartan, under normoxia and hypoxia; mRNA and protein levels of angiotensin II receptor type 1a (AT1aR), type 1b (AT1bR) and type 2 (AT2R) were also determined by RT-PCR and western blotting. In in vivo studies using a rat MI model, effects of transplanted ASC sheets and/or irbesartan on cardiac functions and remodeling after MI were evaluated by echocardiography, histological analysis and molecular biological techniques.
In the in vitro studies, ASCs expressed higher levels of VEGF mRNA under hypoxia. They also expressed mRNA and protein of AT1aR but not AT1bR or AT2R. Under normoxia, angiotensin II increased the level of VEGF mRNA in ASCs, which was abolished by irbesartan. Under hypoxia, irbesartan reduced the level of VEGF mRNA in ASCs regardless of whether angiotensin II was present or not. In the in vivo studies, ASC sheets improved cardiac functions after MI, leading to decreased interstitial fibrosis and increased capillary density in border zones. These effects of ASC sheets were abolished by oral administration of irbesartan before MI and their transplantation.
ASC sheets ameliorated cardiac dysfunctions and remodeling after MI via increasing VEGF expression, which was abolished by pretreatment with irbesartan before the creation of MI and transplantation.
•ASC sheets ameliorated cardiac dysfunctions and remodeling after MI in rats.•ASC sheets could protect hearts after MI through activation of AT1aR.•Pretreatment with an ARB, irbesartan, abolished ameliorating effects of ASC sheets.•We need to pay attention to the attenuating effect of ARBs on cell sheet therapy.
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