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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.

SUBMITTER: Oshima S

PROVIDER: S-EPMC6471320 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Serum Uric Acid-Lowering Effects of Combined Glycine and Tryptophan Treatments in Subjects with Mild Hyperuricemia: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study.

Oshima Shunji S Shiiya Sachie S Nakamura Yasunori Y

Nutrients 20190306 3

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 ...[more]

PMID: 30845731

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Project description:Background: Hyperuricemia is very common in patients with chronic kidney disease (CKD); the role of hyperuricemia in the occurrence and progression of kidney disease remains an interesting and unresolved issue for nephrologists, and whether urate-lowering therapy (ULT) is warranted in CKD patients is still in controversy. To summarize and compare the clinical outcomes and adverse events (AEs) of three common ULT drugs, we performed a systematic review and network meta-analysis of randomized clinical trials (RCTs). Method: PubMed, MEDLINE, Clinical Trials.gov, EMBASE, and the Cochrane Central Register of Controlled Trials electronic databases were searched. The network meta-analysis was performed using the "gemtc 0.8-7" and its dependent packages in R software. The primary outcome was the change of renal function and uric acid; creatinine, proteinuria, blood pressure, and adverse events were assessed as the secondary outcomes. Results: 16 RCTs involving 1,943 patients were included in the final network analysis. Febuxostat, allopurinol, and benzbromarone were not found to exert superior effects over placebo upon renoprotective effect. With respect to lowering urate, the three drugs showed to be statistically superior to placebo, while febuxostat could better lower urate than allopurinol (MD: -1.547; 95% CrI: -2.473 to -0.626). It is also indicated that febuxostat was superior to placebo at controlling blood pressure, while no differences were observed when allopurinol and benzbromarone were compared to placebo. These results are stable in subgroup analysis. Conclusion: There is insufficient evidence to support the renoprotective effects of the three urate-lowering agents in CKD patients with hyperuricemia; febuxostat shows a tendency to be superior to allopurinol on lowering the decline of eGFR and increment of proteinturia, but the difference does not reach a statistical significance. Regarding its urate-lowering effect, febuxostat appears to be a satisfactory alternative to allopurinol and benzbromarone, and can control blood pressure better.

Project description:Increased plasma uric acid (hyperuricemia) has been associated with worse outcomes for chronic kidney disease (CKD). But some attempts to control uric acid (UA) in large-cohort clinical trials did not produce clinically meaningful benefits for CKD. Some studies suggest that only hyperuricemia with crystals, but not asymptomatic hyperuricemia promotes the progression of CKD. Salt-sensitivity (SS) in blood pressure is a prevalent trait that is sexually dimorphic and results in kidney damage. But the connection between hyperuricemia and SS hypertension (HTN) is still unclear. Here we tested the connection between the two using both male and female Dahl SS rats, a well-establish model of SS HTN. We hypothesized that mild asymptomatic hyperuricemia is beneficial in controlling the progression of SS HTN. A uricase inhibitor, oxonic acid (2%) (Oxo) was used to induce hyperuricemia and high-salt (HS) (4% NaCl) diet was used to induce SS HTN. After 3 weeks, in response to oxonic acid supplementation, both sexes showed a significant increase of UA in plasma compared to their respective HS-only controls (Males: 0.63 ±0.07 vs. 2.17 ±0.34; Females: 0.78 ±0.15 vs. 2.04 ±0.35 mg/dl, HS vs. HS/oxo). Interestingly, only male HS/oxo rats showed a significant increase in uricosuria (Males: 0.23 ±0.03 vs. 0.45 ±0.06; Femaels: 0.26 ±0.06 vs. 0.26 ±0.001 UA/Cre, HS vs. HS/oxo). Moreover, the mild hyperuricemia was associated with a significant attenuation of the progression and magnitude of the mean arterial pressure in male but not female rats (Males: 157 ±3 vs. 136 ±3; Females: 155 ±6 vs. 154 ±5 mmHg, HS vs. HS/oxo). Xanthine oxidase (XO) is one of the enzymes that produce UA, and its activity has been shown to affect HTN as well. Therefore, we examined the level of XO activity in the plasma after the treatment. While there was no difference in the activity based on the diet within each sex, females had significantly lower levels of XO activity compared to males in each of the diets. To further investigate the beneficial phenotype seen in male rats, we evaluate changes in the progression of renal pathology. The HS/oxo group compared to the HS group had a lower kidney weight/body weight ratio and lower protein cast accumulation, indicating lower kidney damage. Furthermore, the HS/Oxo treated males had less oxidative damage in their tubules than the HS-only males. Bulk-RNA seq done on the male kidneys revealed that attenuated HTN phenotype was associated with an increased expression in Mas1 (MAS receptor), Klk-1 (Kallikrein-1), and Pcsk6 (PCSK6 enzyme) which can all lead to the activation of different vasodilatory pathways. Our study showed that in male but not female Dahl SS rats, asymptomatic mild hyperuricemia accompanied by hyperuricosuria ameliorates the progression of SS HTN and protects kidneys from further damage. Thus, our findings challenge the notion of hyperuricemia being inherently detrimental to health and highlight that this is an oversimplified view of UA’s role in disease.

Project description:BACKGROUND:Hyperuricemia is an independent risk factor in chronic kidney disease (CKD). Allopurinol and febuxostat are prescription medicines used to treat hyperuricemia but suffer side-effects. Earlier clinical study has shown that an aqueous extract of Terminalia bellerica (TBE), significantly reduced uric acid levels with no serious adverse effects in hyperuricemic subjects. The objective of this study is to determine the efficacy and tolerability of TB in reducing uric acid and creatinine levels in CKD subjects. METHODS:59-subjects were randomized to three groups-40?mg-once-daily febuxostat, 500?mg-twice-daily and 1000?mg-twice-daily of TBE. Serum uric acid, creatinine levels and estimated-glometular-filtration-rate were measured at baseline, 4, 8, 12, 16, 20, 24-weeks. Biomarkers of oxidative-stress, endothelial function, systemic inflammation, and platelet-aggregation were evaluated at baseline, 4, 8, 12, 24-weeks. Adverse drug reactions were recorded. Statistical analysis evaluated using GraphPadPrism4. RESULTS:55-subjects completed 24-week study. Starting at 4-weeks, all treatment groups showed a significant decrease in serum uric acid levels from baseline (p???0.0001). At 24-weeks, febuxostat, T.bellerica 500?mg-twice-daily, and T.bellerica 1000?mg-twice-daily doses decreased mean-percentage serum uric acid by 63.70?±?4.62, 19.84?±?6.43 and 33.88%?±?4.95% respectively (p???0.0001). Significant decrease in serum creatinine with all the groups starting at 16-weeks was seen (p???0.005-p???0.0001). At 24-weeks, the mean-percentage change in creatinine levels was 23.71?±?12.50, 11.70?±?9.0, and 24.42?±?8.14, respectively with febuxostat, T.bellerica 500?mg-twice-daily and T.bellerica 1000?mg-twice-daily. Statistically significant (p???0.05) increase in estimated glomerular filtration rate-(eGFR) was seen at 20 (p ??0.05) and 24-weeks (p???0.01) for both febuxostat vs T.bellerica 500?mg-twice-daily and T.bellerica 1000?mg-twice-daily vs T.bellerica 500?mg-twice-daily. There was no statistically significant difference between febuxostat and T.bellerica 1000?mg-twice-daily, with an increase of eGFR of 41.38 and 40.39?ml/min/1.73m2 respectively, with the inference that T.bellerica at 1000?mg-twice-daily dose is as good as febuxostat 40?mg-once-daily. Positive improvements were made by all the groups in endothelial function and the related biomarkers and high-sensitivity C-reactive protein. None of the products showed effect on platelet aggregation. CONCLUSION:In this 24-week study Febuxostat 40?mg, T. bellerica 500?mg-twice-daily and 1000?mg-twice-daily, significantly decreased the serum uric acid and creatinine levels, increased eGFR in CKD subjects. T. bellerica 500?mg-twice-daily and 1000?mg-twice-daily were one-third and more than half as effective at 24-weeks, respectively. T. bellerica extract may be considered a natural alternative for reducing serum uric acid levels. TRIAL REGISTRATION:This study was registered with the Clinical Trials Registry - India (CTRI) with the registration number: CTRI/2019/11/022093 [Registered on: 21/11/2019] Trial Registered Retrospectively.

Dataset Information

Serum Uric Acid-Lowering Effects of Combined Glycine and Tryptophan Treatments in Subjects with Mild Hyperuricemia: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study.

Publications

Serum Uric Acid-Lowering Effects of Combined Glycine and Tryptophan Treatments in Subjects with Mild Hyperuricemia: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study.

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