Serum Uric Acid-Lowering Effects of Combined Glycine and Tryptophan Treatments in Subjects with Mild Hyperuricemia: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study.
ABSTRACT: We determined the serum uric acid-lowering effects of combined daily supplementation of glycine and tryptophan in patients with mild hyperuricemia using a randomized, double-blind, placebo-controlled, crossover clinical trial design. Japanese healthy adult males and females with mild hyperuricemia (fasting serum uric acid of 6.6⁻7.9 mg/dL) ingested a powder mixture containing 3.0 g of glycine and 0.2 g of tryptophan or a placebo powder once daily at bedtime for 6 weeks. Combined supplementation with glycine and tryptophan significantly decreased serum uric acid levels (from 7.1 mg/dL to 6.7 mg/dL, p = 0.004) before and after the trial. Serum uric acid concentrations significantly decreased in the subjects supplemented with the amino acid mixture compared with those in placebo-treated subjects (p = 0.028). In addition, the combination treatment with glycine and tryptophan decreased serum triglyceride levels (from 119 mg/dL to 86 mg/dL, p = 0.002). Increased solubility of uric acid caused by urinary pH were likely contributors to the serum uric acid-lowering effects of the amino acid mixture.
Project description:Hyperuricemia may contribute to endothelial dysfunction in CKD. We evaluated whether lowering serum uric acid levels with allopurinol improves endothelial dysfunction in 80 participants ?18 years of age with stage 3 CKD and asymptomatic hyperuricemia (?7 mg/dl in men and ?6 mg/dl in women) randomized in a double-blinded manner to receive placebo or allopurinol for 12 weeks. Randomization was stratified according to presence or absence of diabetes mellitus. We measured vascular endothelial function by brachial artery flow-mediated dilation. No significant differences existed between groups at baseline; 61% of the participants had diabetes mellitus in both groups. The placebo and the allopurinol groups had baseline serum uric acid levels (SDs) of 8.7 (1.6) mg/dl and 8.3 (1.4) mg/dl, respectively, and baseline flow-mediated dilation values (SDs) of 6.0% (5.0%) and 4.8% (5.0%), respectively. Compared with placebo, allopurinol lowered serum uric acid significantly but did not improve endothelial function. In participants without diabetes mellitus, allopurinol associated with a trend toward improved flow-mediated dilation (+1.4% [3.9%] versus -0.7% [4.1%] with placebo), but this was not statistically significant (P=0.26). Furthermore, we did not detect significant differences between groups in BP or serum levels of markers of inflammation and oxidative stress. In conclusion, allopurinol effectively and safely lowered serum uric acid levels in adults with stage 3 CKD and asymptomatic hyperuricemia but did not improve endothelial function in this sample of patients.
Project description:Rationale & Objective:Hyperuricemia is associated with chronic kidney disease (CKD) progression. We evaluated whether lowering serum uric acid levels improves levels of biomarkers of kidney damage. Study Design:Post hoc analysis of clinical trial participants. Setting & Participants:A double-blind randomized placebo-controlled study designed to lower serum uric acid levels. 80 patients with stage 3 CKD and asymptomatic hyperuricemia were randomly assigned to allopurinol treatment or placebo (300 mg/d) for 12 weeks. Exposure/Predictor:Allopurinol treatment versus placebo. Outcomes & Measures:We evaluated the change from baseline for the following urinary biomarkers of kidney damage: albumin-creatinine ratio (ACR), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), and transforming growth factor ?1 (TGF-?1). Additionally, we evaluated CKD Epidemiology Collaboration (CKD-EPI)-estimated glomerular filtration rate (eGFR) and cystatin C eGFR. Analytical Approach:Generalized linear mixed modeling was used. Results:After 12 weeks, allopurinol (compared to placebo) significantly lowered serum uric acid levels with an estimate of -3.3 mg/dL (95% CI, -4.1 to -2.5 mg/dL; P < 0.001). Estimates for the change for allopurinol versus placebo over time were 1.09 (95% CI, 0.77-1.54) for ACR, 0.77 (95% CI, 0.36-1.63) for NGAL, and 2.36 (95% CI, 0.97-5.70) for TGF-?1. The model did not converge for KIM-1, but Wilcoxon signed rank test showed no significant difference in change from baseline between study groups. There was no significant change observed in CKD-EPI eGFR or cystatin C eGFR. Limitations:Post hoc analysis and short duration of the study. Conclusions:Uric acid-lowering with allopurinol is not associated with improvement in levels of biomarkers of kidney damage in patients with asymptomatic hyperuricemia and stage 3 CKD. Funding:The study was funded by the National Institutes of Health through a career development award, K23DK088833, and the Clinical and Translational Science Award UL1TR002537. Trial Registration:NCT01228903.
Project description:Association between vitamin D and uric acid is complex and might be bidirectional. Our study aimed to determine the bidirectional association between vitamin D and uric acid in adults. Using MEDLINE via PubMed and Scopus, we systematically searched for observational or interventional studies in adults, which assessed the association between serum vitamin D and serum uric acid, extracted the data, and conducted analysis by direct and network meta-analysis. The present review included 32 studies, of which 21 had vitamin D as outcome and 11 had uric acid as outcome. Meta-analysis showed a significant pooled beta coefficient of serum uric acid level on serum 25(OH)D level from 3 studies of 0.512 (95% confidence interval: 0.199, 0.825) and a significant pooled odds ratio between vitamin D deficiency and hyperuricemia of 1.496 (1.141, 1.963). The pooled mean difference of serum 25(OH)D between groups with hyperuricemia and normouricemia was non-significant at 0.138 (-0.430, 0.707) ng/ml, and the pooled mean difference of serum uric acid between categories of 25(OH)D were also non-significant at 0.072 (-0.153, 0.298) mg/dl between deficiency and normal, 0.038 (-0.216, 0.292) mg/dl between insufficiency and normal, and 0.034 (-0.216, 0.283) mg/dl between deficiency and insufficiency. In conclusion, increasing serum uric acid might be associated with increasing 25(OH)D level, while vitamin D deficiency is associated with hyperuricemia. These reverse relationships should be further evaluated in a longitudinal study.
Project description:Hyperuricemia is associated with hypertension, with elevated serum uric acid levels postulated to have a causal role in the development of hypertension. Consequently, serum uric acid reduction may help lower blood pressure (BP). A Phase 2, double-blind, placebo-controlled trial was conducted to assess the potential BP-lowering effects of the xanthine oxidase inhibitor febuxostat in subjects with hypertension and hyperuricemia (serum uric acid ?0.42 mmol/L [?7.0 mg/dL]).Subjects (n=121) were randomized 1:1 to febuxostat 80 mg once daily or to placebo. The primary end point was change from baseline to Week 6 in 24-hour mean ambulatory systolic BP (SBP). Additional end points included the following: change from baseline to Week 3 in 24-hour mean SBP and changes from baseline to Weeks 3 and 6 in 24-hour mean ambulatory diastolic BP, serum uric acid, mean daytime and nighttime ambulatory SBP/diastolic BP, and clinic SBP/diastolic BP. For the overall study population, there were no significant differences between febuxostat and placebo for changes from baseline to Weeks 3 or 6 in ambulatory, daytime or nighttime, or clinic SBP or diastolic BP. However, in a preplanned subgroup analysis, there was a significant decrease in SBP from baseline to Week 6 in subjects with normal renal function (estimated glomerular filtration rate ?90 mL/min) treated with febuxostat versus placebo; least squares mean difference, -6.7; 95% confidence interval -13.3 to -0.0; P=0.049.This study suggests that febuxostat may lower BP in hyperuricemic patients with hypertension and normal renal function; further studies should be conducted to confirm this finding.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01496469.
Project description:The objective of the study was to evaluate the effect of lesinurad, a selective uric acid uptake inhibitor, alone and in combination with the xanthine oxidase inhibitor allopurinol, on serum uric acid and urinary urate excretion in patients with gout and hyperuricemia. A phase 1b, multicenter, open-label, multiple-dose study was carried out in patients with gout with serum uric acid ?8 mg/dL following washout of urate-lowering therapy. Patients were treated with allopurinol 300 mg/day alone in week 1; lesinurad 400 or 600 mg/day was added in week 2, followed by lesinurad 400 or 600 mg/day alone in week 3. Serum uric acid and urine uric acid were evaluated each week. Safety was assessed throughout the study. Lesinurad 400 or 600 mg/day added to allopurinol 300 mg/day reduced serum uric acid by 60% and 72%, respectively, versus allopurinol alone (37%) or lesinurad 400 mg/day (44%) or 600 mg/day (47%) alone. A 100% response rate of serum uric acid <6 mg/dL was achieved by all combinations (serum uric acid <5 mg/dL by 50%-90%). Mean 24-hour urate excretion compared with baseline was -35% with allopurinol, +36% and +56.5% with lesinurad 400 mg/day and 600 mg/day, respectively, and -11.6% and -7.1% with the respective combination therapies. Treatments were well tolerated. In this phase 1 trial, lesinurad added to allopurinol resulted in greater serum uric acid reduction than did allopurinol or lesinurad monotherapy.
Project description:Background:Hyperuricemia is associated with the development and progression of chronic kidney disease (CKD) as well as cardiovascular diseases. However, there is no consistent recommendation regarding the treatment of asymptomatic hyperuricemia (AHU) in CKD patients. Here, we surveyed Korean physicians' perceptions regarding the diagnosis and management of AHU in CKD patients. Methods:Questionnaires on the management of AHU in CKD patients were emailed to regular members registered with the Korean Society of Nephrology. Results:A total of 158 members answered the questionnaire. Among the respondents, 49.4%/41.1% were considered hyperuricemic in male CKD patients whereas 36.7%/20.9% were considered hyperuricemic in female CKD patients when defined by serum uric acid level over 7.0/8.0 mg/dL, respectively. A total of 80.4% reported treating AHU in CKD patients. The most important reasons to treat AHU in CKD patients were renal function preservation followed by cerebro-cardiac protection. Majority of respondents (59.5%) thought that uric acid-lowering agents (ULAs) were the most effective method for controlling serum uric acid levels. Approximately 80% chose febuxostat as the preferred medication. A total of 32.3% and 31.0%, respectively, initiated ULA treatment if the serum uric acid level was more than 8.0 or 9.0 mg/dL, respectively. In addition, 39.2% and 30.4% answered that target serum uric acid levels of less than 6.0 or 7.0 mg/dL, respectively, were appropriate. The two major hurdles to prescribing ULAs were concerns of adverse reactions and the existing lack of evidence (i.e., the absence of Korean guidelines). Conclusion:Most Korean physicians treat AHU in CKD patients to prevent CKD progression and cerebro-cardiovascular complications.
Project description:It is thought that hyperuricemia might lower the risk of mortality among hemodialysis patients, unlike in the general population, but the evidence is controversial. The aim of the current study was to evaluate the impact of serum uric acid level on the long-term clinical outcomes of hemodialysis patients in Korea.Retrospective analysis was performed on data from the End-Stage Renal Disease Registry of the Korean Society of Nephrology. This included data for 7,333 patients (mean age, 61 ± 14 years; 61% male) who received hemodialysis from January 2001 through April 2015. Initial laboratory data were used in the analysis.The mean serum uric acid level in this study was 7.1 ± 1.7 mg/dL. Body mass index, normalized protein catabolic rate, albumin, and cholesterol were positively correlated with serum uric acid level after controlling for age and sex. After controlling for demographic data, comorbidities, and residual renal function, a higher uric acid level was independently associated with a significantly lower all-cause mortality (hazard ratio [HR], 0.90 per 1 mg/dL increase in uric acid level; 95% confidence interval [CI], 0.83-0.97; P = 0.008), but not cardiovascular mortality (HR, 0.90; 95% CI, 0.80-1.01; P = 0.078). Comparing uric acid levels in the highest and lowest quintiles, the HR for all-cause mortality was 0.65 (95% CI, 0.42-0.99; P = 0.046).Hyperuricemia was strongly associated with a lower risk of all-cause mortality, but there seems to be no significant association between serum uric acid level and cardiovascular mortality among Korean hemodialysis patients with end-stage renal disease.
Project description:OBJECTIVES:Despite the growing pieces of evidence linking hyperuricemia with metabolic syndrome and cardiovascular disease, the relationship between dyslipidemia and serum uric acid has not yet been established. This study aimed to investigate the association between individual components of dyslipidemia and serum uric acid by using the nationally representative Korea National Health and Nutrition Examination Survey 2016-2017. METHODS:A total of 8,722 participants (age ? 19 years) without missing values were analyzed for this study. Serum uric acid levels according to the presence of individual dyslipidemia components were calculated using multivariable-adjusted general linear models (GLM). Odds ratios of individual dyslipidemia components to hyperuricemia were calculated using unadjusted and multivariable-adjusted logistic regression analysis. RESULTS:A total of 1,061 participants were identified as having hyperuricemia, with a prevalence of 12.2%. Multivariable-adjusted GLM demonstrated a significant trend between individual dyslipidemia components and serum uric acid levels (P < 0.05). A positive association between the numbers of dyslipidemia components and the increments of serum uric acid levels was also observed (P < 0.001). In multivariable-adjusted logistic regression analysis, odds ratios (OR) and 95% confidence interval (CI) of all dyslipidemia components to hyperuricemia were shown to be statistically significant (P < 0.05). When further adjusted for the combined components themselves, each 10 mg/dL increments of total cholesterol (OR 1.053; 95% CI 1.028-1.079), triglycerides (OR 1.017; 95% CI 1.009-1.026) and HDL-C (OR 0.804; 95% CI 0.729-0.887), retained significant correlation with hyperuricemia. CONCLUSION:Our study demonstrated that the dyslipidemia components of serum total cholesterol, triglycerides and LDL-C levels are positively associated with serum uric acid levels, whereas serum HDL-C levels are inversely related. Further complementary studies regarding other lipid parameters are needed to confirm the accurate association between dyslipidemia and serum uric acid levels.
Project description:Hyperuricemia is associated with all-cause and cardiovascular mortality. However, the threshold value of serum uric acid levels for increased risk of mortality has not been determined. This large-scale cohort study used a nationwide database of 500,511 Japanese subjects (40-74 years) who participated in the annual health checkup and were followed up for 7 years. The association of serum uric acid levels at baseline with cardiovascular and all-cause mortality was examined. The Cox proportional hazard model analysis with adjustment for possible confounders revealed that the all-cause and cardiovascular mortality showed a J-shaped association with serum uric acid levels at baseline in both men and women. A significant increase in the hazard ratio for all-cause mortality was noted with serum uric acid levels ? 7?mg/dL in men and ? 5?mg/dL in women. A similar trend was observed for cardiovascular mortality. This study disclosed that even a slight increase in serum uric acid levels was an independent risk factor for all-cause and cardiovascular mortality in both men and women in a community-based population. Moreover, the threshold values of uric acid for mortality might be different for men and women.
Project description:Hyperuricemia is defined as serum uric acid level of more than 7 mg/dL and blood levels of uric acid are causally associated with gout, as implicated by evidence from randomized clinical trials using urate lowering therapies. Uric acid as a cardiovascular risk factor often accompanies metabolic syndrome, hypertension, diabetes, dyslipidemia, chronic renal disease, and obesity. Despite the association of hyperuricemia with cardiovascular risk factors, it has remained controversial as to whether uric acid is an independent predictor of cardiovascular disease. To settle this issue, and in the absence of large randomized controlled trials, Mendelian randomization analysis in which the exposure is defined based on the presence or absence of a specific allele that influences a risk factor of interest have tried to shed light on this.