Higher Plasma Urate Research Articles

A biosensor based on the biomimetic oxidase Fe3O4@MnO2 for colorimetric determination of uric acid

High plasma urate is closely related to gout, cardiovascular and other diseases. Therefore, monitoring the content of uric acid (UA) in plasma is of great significance for the treatment of gout and the prevention of other related diseases. Herein, a biosensor based on the biomimetic oxidase Fe3O4 nanoparticles (NPs) @MnO2 nanosheets (Fe3O4@MnO2 NS) was constructed for colorimetric determination of UA. MnO2 NS is an efficient biomimetic oxidase, and we found that the intrinsic oxidase activity of MnO2 NS doped with Fe3O4 NPs can be significantly enhanced. The chromogenic substrate TMB can be catalyzed by Fe3O4 @MnO2 NS to generate blue oxidized TMB, and UA can decompose the MnO2 NS to inhibit the color reaction of TMB selectively, thereby realizing the quantitative detection of UA. In addition, the UA biosensor can perform colorimetric analysis of UA level through three methods: naked eye, smartphone and ultraviolet-visible (UV–vis) spectrophotometer. The linear ranges of UV–vis spectrophotometry and colorimetry with smartphone were 1–70 μM and 200–650 μM, respectively, and the limits of detection (LOD) were 0.27 μM and 21 μM. The analysis results of human plasma samples showed that the method had good selectivity and practicability.

Plasma urate and risk of Parkinson's disease: A mendelian randomization study.

Urate is a potent antioxidant, and high plasma urate has been associated with lower incidence of Parkinson's disease (PD) in epidemiological studies. We tested the hypothesis that high concentrations of plasma urate are associated with low incidence of PD. We performed observational and genetic analyses using plasma urate and the urate SLC2A9 rs7442295 and ABCG2 rs2231142 genotype in >102,000 individuals from the CGPS (Copenhagen General Population Study). Information on PD and mortality was from national patient and death registries. Incidences of PD were calculated using Cox regression, Fine and Gray competing-risks regression, and instrumental variable analyses. In total, 398 individuals were diagnosed with PD, of which 285 were incident cases. The multivariable adjusted hazard ratio for PD was 0.56 (95% confidence interval [CI], 0.41-0.77) for the highest versus the lowest tertile of plasma urate (p for trend across 3 groups, 8 × 10-5 ). Each one-allele increase in the combined allele score was associated with 19μmol/l (95% CI, 18.5-19.9) higher plasma urate. In observational analyses, a 50μmol/l higher plasma urate was associated with a hazard ratio of 0.85 (0.77-0.92) for PD; in instrumental variable analyses, 50μmol/l higher plasma urate was associated with an odds ratio of 1.20 (0.85-1.71) for PD. High plasma urate was associated with lower risk of PD in observational analyses; however, in instrumental variable analysis, high plasma urate was not associated with low risk of PD. Thus, our data do not support a causal relationship between high plasma urate and low risk of PD. Ann Neurol 2018;84:178-190.

Plasma urate, lung function and chronic obstructive pulmonary disease: a Mendelian randomisation study in 114 979 individuals from the general population

BackgroundUrate is a strong antioxidant in plasma and may protect against lung function impairment. We tested the hypothesis that high plasma urate is causally associated with better lung function and...

Plasma Urate, Cancer Incidence, and All-Cause Mortality: A Mendelian Randomization Study.

Observationally, high plasma urate is associated with high risk of cancer. We used a Mendelian randomization design to test the hypothesis that high concentrations of plasma urate are associated with high cancer incidence and all-cause mortality observationally and genetically. We performed observational and genetic analyses using plasma urate and the urate solute carrier family 2 member 9 (SLC2A9) rs7442295 genotype in 86210 individuals from the Copenhagen General Population Study. Cancer and mortality end points were from national cancer and death registries. Incidences and risk of cancer and all-cause mortality were calculated using Cox regression, Fine and Gray competing-risks regression, and instrumental variable analyses. During a median follow-up time of 3.9 years for cancer and 4.9 years for all-cause mortality, 3243 individuals received a diagnosis of cancer and 3978 died. Observationally, 50% higher plasma urate was associated with multivariable-adjusted hazard ratios of 1.11 (95% CI, 1.05-1.18) for cancer incidence and 1.07 (1.01-1.13) for all-cause mortality. Each A-allele of the SLC2A9 rs7442295 was associated with 9% higher plasma urate and hazard ratios of 1.07 (1.01-1.14) for cancer incidence and 1.07 (1.02-1.13) for all-cause mortality. In instrumental variable analyses, the odds ratios for a genetically determined 50% higher plasma urate was 1.22 (1.02-1.47) for cancer incidence and 1.49 (1.13-1.93) for all-cause mortality. High plasma urate was both observationally and genetically associated with high cancer incidence and high all-cause mortality, suggesting causal relationships.

Stronger Uricosuric Effects of the Novel Selective URAT1 Inhibitor UR-1102 Lowered Plasma Urate in Tufted Capuchin Monkeys to a Greater Extent than Benzbromarone.

Urate-lowering therapy is indispensable for the treatment of gout, but available drugs do not control serum urate levels tightly enough. Although the uricosurics benzbromarone and probenecid inhibit a urate reabsorption transporter known as renal urate transporter 1 (URAT1) and thus lower serum urate levels, they also inhibit other transporters responsible for secretion of urate into urine, which suggests that inhibiting URAT1 selectively would lower serum urate more effectively. We identified a novel potent and selective URAT1 inhibitor, UR-1102, and compared its efficacy with benzbromarone in vitro and in vivo. In human embryonic kidney (HEK)293 cells overexpressing URAT1, organic anion transporter 1 (OAT1), and OAT3, benzbromarone inhibited all transporters similarly, whereas UR-1102 inhibited URAT1 comparably to benzbromarone but inhibited OAT1 and OAT3 quite modestly. UR-1102 at 3-30 mg/kg or benzbromarone at 3-100 mg/kg was administered orally once a day for 3 consecutive days to tufted capuchin monkeys, whose low uricase activity causes a high plasma urate level. When compared with the same dosage of benzbromarone, UR-1102 showed a better pharmacokinetic profile, increased the fractional excretion of urinary uric acid, and reduced plasma uric acid more effectively. Moreover, the maximum efficacy of UR-1102 was twice that of benzbromarone, suggesting that selective inhibition of URAT1 is effective. Additionally UR-1102 showed lower in vitro potential for mechanisms causing the hepatotoxicity induced by benzbromarone. These results indicate that UR-1102 achieves strong uricosuric effects by selectively inhibiting URAT1 over OAT1 and OAT3 in monkeys, and could be a novel therapeutic option for patients with gout or hyperuricemia.

Understanding the dose–response relationship of allopurinol: predicting the optimal dosage

The aim of the study was to identify and quantify factors that control the plasma concentrations of urate during allopurinol treatment and to predict optimal doses of allopurinol. Plasma concentrations of urate and creatinine (112 samples, 46 patients) before and during treatment with various doses of allopurinol (50-600 mg daily) were monitored. Non-linear and multiple linear regression equations were used to examine the relationships between allopurinol dose (D), creatinine clearance (CLcr) and plasma concentrations of urate before (UP) and during treatment with allopurinol (UT). Plasma concentrations of urate achieved during allopurinol therapy were dependent on the daily dose of allopurinol and the plasma concentration of urate pre-treatment. The non-linear equation: UT = (1 - D/(ID50 + D)) × (UP - UR) + UR , fitted the data well (r(2) = 0.74, P < 0.0001). The parameters and their best fit values were: daily dose of allopurinol reducing the inhibitable plasma urate by 50% (ID50 = 226 mg, 95% CI 167, 303 mg), apparent resistant plasma urate (UR = 0.20 mmol l(-1), 95 % CI 0.14, 0.25 mmol l(-1)). Incorporation of CLcr did not significantly improve the fit (P = 0.09). A high baseline plasma urate concentration requires a high dose of allopurinol to reduce plasma urate below recommended concentrations. This dose is dependent on only the pre-treatment plasma urate concentration and is not influenced by CLcr .

Short communication: genetic variations of SLC2A9 in relation to Parkinson’s disease

BackgroundEpidemiological studies showed that higher plasma urate was associated with lower risk for Parkinson’s disease (PD) and slower disease progression. Recent genome-wide association studies (GWAS) consistently showed that several single nucleotide polymorphisms (SNPs) in the solute carrier family 2 member 9 gene (SLC2A9 ) were associated with plasma urate concentration and the risk of gout.MethodsWe conducted a case–control study to examine twelve tag SNPs of the SLC2A9 gene in relation to PD among 788 cases and 911 controls of European ancestry. Odds ratios (OR) and 95% confidence intervals (CI) were derived from logistic regression models, adjusting for age, sex, smoking and caffeine consumption.ResultsThese SNPs were all in linkage disequilibrium (R2 > 0.7). None of them were associated with PD risk. Among women, however, there was a suggestion that the presence of the minor allele of one SNP (rs7442295) was related to a small increase in PD risk [OR (95% CI) = 1.48 (1.01-2.16)].ConclusionThis study provides little support for genetic variations of SLC2A9 and PD risk.

Treating gout with pegloticase, a PEGylated urate oxidase, provides insight into the importance of uric acid as an antioxidant in vivo

A high plasma urate concentration (PUA), related to loss of urate oxidase in evolution, is postulated to protect humans from oxidative injury. This hypothesis has broad clinical relevance, but support rests largely on in vitro data and epidemiologic associations. Pegloticase therapy generates H(2)O(2) while depleting urate, offering an in vivo test of the antioxidant hypothesis. We show that erythrocytes can efficiently eliminate H(2)O(2) derived from urate oxidation to prevent cell injury in vitro; during therapy, disulfide-linked peroxiredoxin 2 dimer did not accumulate in red blood cells, indicating that their peroxidase capacity was not exceeded. To assess oxidative stress, we monitored F2-Isoprostanes (F2-IsoPs) and protein carbonyls (PC), products of arachidonic acid and protein oxidation, in plasma of 26 refractory gout patients receiving up to five infusions of pegloticase at 3-wk intervals. At baseline, PUA was markedly elevated in all patients, and plasma F2-IsoP concentration was elevated in most. Pegloticase infusion rapidly lowered mean PUA to < or = 1 mg/dL in all patients, and PUA remained low in 16 of 21 patients who completed treatment. F2-IsoP levels did not correlate with PUA and did not increase during 15 wk of sustained urate depletion. There also was no significant change in the levels of plasma PC. Because refractory gout is associated with high oxidative stress in spite of high PUA, and profoundly depleting uric acid did not increase lipid or protein oxidation, we conclude that urate is not a major factor controlling oxidative stress in vivo.

Plasma Urate and Progression of Mild Cognitive Impairment

Background: Impaired antioxidant defenses are implicated in neurodegenerative disease. The plasma levels of urate, a water-soluble antioxidant, are reduced in Alzheimer’s disease (AD). Objective: We aimed to test the hypotheses that high plasma urate at baseline is associated with: (1) a reduced rate of conversion from mild cognitive impairment (MCI) to AD and (2) a lower rate of cognitive decline in MCI. Methods: Plasma urate was obtained at baseline from 747 participants in a 3-year, randomized, double-blind, placebo-controlled study of donepezil, vitamin E or placebo for delaying the progression of MCI to AD.The association between baseline urate and conversion from MCI to AD was examined by Cox proportional hazards regression. The relationship between baseline urate and cognitive change on the cognitive subscale of the Alzheimer’s Disease Assessment Scale was evaluated by longitudinal analysis. Results: Baseline plasma urate was not associated with the rate of conversion of MCI to AD. In the placebo arm, high plasma urate was related to a slower rate of cognitive decline over 3 years, although this was not reproduced in the other treatment arms. Conclusion: While plasma urate levels did not predict the progression of MCI to AD, high urate may be associated with a reduced rate of cognitive decline in MCI patients not treated with donepezil or vitamin E. The results support the investigation of biomarkers of antioxidant status as risk factors for cognitive decline in MCI.

Avian renal proximal tubule epithelium urate secretion is mediated by Mrp4

Birds are uricotelic and, like humans, maintain high plasma urate concentrations (approximately 300 microM). The majority of their urate waste, as in humans, is eliminated by renal proximal tubular secretion; however, the mechanism of urate transport across the brush-border membrane of the intact proximal tubule epithelium during secretion is uncertain. The dominance of secretory urate transport in the bird provides a convenient model for examining this process. The present study shows that short hairpin RNA interference (shRNAi) effectively knocked down gene expression of multidrug resistance protein 4 (Mrp4; 25% of control) in primary monolayer cultures of isolated chicken proximal tubule epithelial cells (cPTCs). Control and Mrp4-shRNAi-treated cPTCs were mounted in Ussing chambers and unidirectional transepithelial fluxes of urate were measured. To detect nonspecific effects, transepithelial electrical resistance (TER) and sodium-dependent glucose transport (Iglu) were monitored throughout experiments. Knocking down Mrp4 expression resulted in a reduction of transepithelial urate secretion to 35% of control with no effects on TER or Iglu. Although electrical gradient-driven urate transport in isolated brush-border membrane vesicles was confirmed, potassium-induced depolarization of the plasma membrane in intact cPTCs failed to inhibit active transepithelial urate secretion. However, electrical gradient-dependent vesicular urate transport was inhibited by the MRP4 inhibitor MK-571 also known to inhibit active transepithelial urate transport by cPTCs. Based on these data, direct measure of active transepithelial urate secretion in functional avian proximal tubule epithelium indicates that Mrp4 is the dominant apical membrane exit pathway from cell to lumen.

Plasma Urate and Risk of Parkinson's Disease

Oxidative stress contributes to dopaminergic neuron degeneration in Parkinson's disease. Urate, a potent antioxidant, could be neuroprotective. To determine whether higher plasma concentrations of urate predict a reduced risk of Parkinson's disease, the authors conducted a nested case-control study among participants in the Health Professionals Follow-up Study, a cohort comprising over 18,000 men who provided blood samples in 1993-1995. Eighty-four incident cases of Parkinson's disease were diagnosed through 2000, and each was randomly matched to two controls by year of birth, race, and time of blood collection. Rate ratios of Parkinson's disease according to quartile of uricemia were estimated by use of conditional logistic regression. The mean urate concentration was 5.7 mg/dl among cases and 6.1 mg/dl among controls (p = 0.01). After adjustment for age, smoking, and caffeine, the rate ratio of Parkinson's disease for the highest quartile of uricemia compared with the lowest was 0.43 (95% confidence interval: 0.18, 1.02; p(trend) = 0.017). This association was stronger in analyses excluding cases diagnosed within 4 years (median) from blood collection (rate ratio = 0.17, 95% confidence interval: 0.04, 0.69; p(trend) = 0.010). These results suggest that high plasma urate concentrations may decrease the risk of Parkinson's disease, and they raise the possibility that interventions to increase plasma urate may reduce the risk and delay the progression of Parkinson's disease.

URATE HOMEOSTASIS IN POLYCYSTIC KIDNEY DISEASE: COMPARISON WITH CHRONIC GLOMERULONEPHRITIC KIDNEY

Autosomal dominant polycystic kidney disease (ADPKD) might affect urate homeostasis and clearance. Renal tubular urate transport was studied by means of probenecid (PB) and pyrazinamide (PZA) tests in individuals with ADPKD and normal renal function as well as various degrees of renal failure (49 patients). Comparisons were made between polycystic and chronic glomerulonephritic kidney (CGNK), as well as with controls (men with normal renal function). Patients with ADPKD and normal renal function showed plasma urate levels within normal range and normal renal urate handling. In contrast higher plasma urate levels comparing to controls were found in patients with CGNK and normal renal function. During the evolution of renal failure ADPKD patients showed lower urate plasma levels and higher renal clearance as well as, fractional urate excretion, comparing to CGNK patients with the same degree of renal failure. In conclusion patients with ADPKD and normal renal function have normal urate handling and plasma urate levels within normal range. With increasing severity of disease and during evolution of renal failure CGNK patients showed higher urate plasma levels and lower clearances comparing to ADPKD patients. When renal disease becomes more advanced there was no difference in renal urate handling between ADPKD and CGNK patients.

Avian Nephritis Virus Infection of Chicks: Virology, Pathology, and Serology

Avian nephritis virus (ANV), G-4260 strain, was inoculated orally into 1-day-old specific-pathogen-free chicks of the line 15I for virological, pathological, and serological study of the ANV infection of chicks. The virus titer and incidence of appearance of fluorescent antigens in the kidneys were highest at 4 days postinoculation (PI) and decreased gradually. The degeneration of proximal tubules was the principal pathological change in kidneys of chicks at 4 days PI, and interstitial nephritis was the principal pathological change in kidneys of chicks from 6 to 14 days PI. Moreover, gouty nodules were apparent in the kidneys of more than half of the chicks at 10 days PI. The plasma urate value of infected chicks was clearly higher than that of control chicks, reaching a maximum at 10 days PI, then gradually decreasing. The serum antibody was detected from 4 days PI and increased gradually. The chicks affected with visceral urate deposits or urate deposits in the digitated joints showed high plasma urate values (more than 100 mg/dl).