Changes In Serum Uric Acid Research Articles

Mediators of the effect of ertugliflozin on a composite kidney outcome in patients with type 2 diabetes and atherosclerotic cardiovascular disease: analyses from VERTIS CV

Abstract Introduction Sodium–glucose cotransporter 2 (SGLT2) inhibitors have been shown to slow the decline of kidney function in outcome trials, but the biological mediator(s) underlying the therapeutic benefit are not well established. Purpose We performed a post-hoc analysis exploring potential mediators of the effects of the SGLT2 inhibitor ertugliflozin on the VERTIS CV exploratory kidney composite outcome (sustained 40% decrease from baseline in estimated glomerular filtration rate [eGFR], chronic kidney replacement therapy or kidney death). Methods In VERTIS CV, 8246 participants with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease were randomised to placebo, ertugliflozin 5 mg or 15 mg (pooled for analyses, as prospectively planned), and were followed for a mean of 3.5 years. The hazard ratio (HR; 95% confidence interval) for the pre-specified exploratory kidney composite outcome was 0.66 (0.50, 0.88). Cox regression models were used to evaluate covariates that were significantly differentially changed from baseline with ertugliflozin treatment as candidate mediators, with a mediator identified as a covariate when added to an unadjusted model of randomised treatment assignment a) yielded a larger hazard ratio; and b) the mediator retained P<0.05 in the model (eGFR was excluded as a covariate). The percentage of mediation was determined by the proportional increase in the HR between the unadjusted and adjusted models for each post-randomisation period: early (first change from baseline measurement) and average (weighted average of change from baseline from all post-baseline measurements). Each potential mediator was tested individually, so across analyses, mediation % sums to >100%. Results Of 22 covariates significantly changed by ertugliflozin, nine were identified as potential mediators (Table). The covariates with a high percentage of mediation were those related to changes in blood erythrocytes (haemoglobin, haematocrit and red blood cell mass), with average changes in haemoglobin having the highest percentage of mediation (61.8%). Serum uric acid was associated with a mediation of 29.4% and 50.0% for the early and average post-randomisation effect periods, respectively. Early changes in glycated haemoglobin had a large mediation (50%), but the average change during the trial was not significant. Average change in serum albumin had a large mediation (29.4%). Average changes in body weight and systolic blood pressure had percentages of mediation of 41.2% and 14.7%, respectively. Conclusion Multiple factors may be involved in the reduction of the kidney composite outcome observed with ertugliflozin. In the short-term, changes in glycaemia had a high mediation effect. Over the long-term, changes suggestive of haemoconcentration and/or haematopoiesis (natriuresis-related effects), showed the highest percentage of mediation, followed by changes in serum uric acid and body weight (glucosuria-related effects). Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA in collaboration with Pfizer Inc., New York, NY, USA

Effect of changes in serum uric acid on the risk of stroke and its subtypes

Background and aimsThe role of serum uric acid (SUA) in stroke remains controversial and analyses of changes in SUA and stroke are limited. The objective of the study was to investigate the associations of changes in SUA with stroke and its subtypes (ischemic and hemorrhagic stroke). Methods and resultsA total of 51 441 participants (mean age 52.69 ± 11.71 years) without history of myocardial infarction or stroke were enrolled. Participants were divided into four groups based on SUA level changes during 2006 and 2010: stable low, increasing, decreasing, and stable high. SUA score was quantified on a 3-point scale with 1 point awarded for hyperuricemia at either year 2006, 2008 or 2010. Multivariate Cox proportion models were used to calculated hazard ratios (HRs) and their 95% confidence intervals (CIs). During 7.03-year follow up, 1611 stroke (1410 ischemic stroke, 199 hemorrhagic stroke, and 47 subarachnoid hemorrhage) were identified. Participants with stable high SUA had higher risk of hemorrhagic stroke, the HR was 1.93 (95% CI: 1.06–3.51), compared to those with stable low SUA. Furthermore, cumulative high SUA exposure also increased the risk of hemorrhagic stroke, the HR (95%CI) was 2.99 (1.55–5.74), compared with cumulative low SUA exposure. However, no significant evidence indicated changes in SUA was associated with the risk of total and ischemic stroke, the HRs (95% CIs) were 0.98 (0.74–1.29) and 0.88 (0.65–1.19), respectively. ConclusionsStable high SUA was positively associated with the risk of hemorrhagic stroke, but not with total and ischemic stroke risk.

Relationship Between Change in Serum Uric Acid and Ischemic Stroke in Chinese Hypertensive Patients.

Background: Limited studies focused on the association between serum uric acid (SUA) change with ischemic stroke, and their results remain controversial. The present study aimed to investigate the relationship between change in SUA with ischemic stroke among hypertensive patients.Method: This was a retrospective cohort study. We recruited adult hypertensive patients who had two consecutive measurements of SUA levels from 2013 to 2014 and reported no history of stroke. Change in SUA was assessed as SUA concentration measured in 2014 minus SUA concentration in 2013. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). The Kaplan–Meier analysis and log-rank test were performed to quantify the difference in cumulative event rate. Additionally, subgroup analysis and interaction tests were conducted to investigate heterogeneity.Results: A total of 4,628 hypertensive patients were included, and 93 cases of ischemic stroke occurred during the mean follow-up time of 3.14 years. Participants were categorized into three groups according to their SUA change tertiles [low (SUA decrease substantially): <-32.6 μmol/L; middle (SUA stable): ≥-32.6 μmol/L, <40.2 μmol/L; high (SUA increase substantially): ≥40.2 μmol/L]. In the fully adjusted model, setting the SUA stable group as reference, participants in the SUA increase substantially group had a significantly elevated risk of ischemic stroke [HR (95% CI), 1.76 (1.01, 3.06), P = 0.0451], but for the SUA decrease substantially group, the hazard effect was insignificant [HR (95% CI), 1.31 (0.75, 2.28), P = 0.3353]. Age played an interactive role in the relationship between SUA change and ischemic stroke. Younger participants (age < 65 years) tended to have a higher risk of ischemic stroke when SUA increase substantially.Conclusion: SUA increase substantially was significantly correlated with an elevated risk of ischemic stroke among patients with hypertension.

Incident hyperuricemia in relation to antihypertensive therapy with the irbesartan/hydrochlorothiazide combination.

We investigated serum uric acid changes and incident hyperuricemia in relation to the achieved blood pressure (BP) after 12 weeks of antihypertensive therapy with the irbesartan/hydrochlorothiazide combination. The study participants were 449 patients who completed the study. Analysis of covariance and multiple logistic regression analyses were performed to calculate the least square mean changes (± standard error) from baseline in serum uric acid and odds ratios (ORs) for incident hyperuricemia according to the achieved levels of BP. Adjusted analyses showed that serum uric acid changes differed according to the achieved SBP/DBP (P = 0.002), with a smaller mean (± standard error) increase in the range of 130-139/<90 mm Hg (n = 132, 19.8 ± 5.7 µmol/L) than that of ≥140/90 (n = 129, 32.4 ± 7.3 µmol/L) or <130/90 mm Hg (n = 188, 39.5 ± 5.1 µmol/L). Adjusted analyses showed similar results for the incident hyperuricemia (n = 95, 24.0%) in those patients with normal serum uric acid at baseline (n = 396). The risk of incident hyperuricemia was lower (OR, 0.45; 95% confidence interval 0.25-0.83; P = 0.04) in patients with an achieved SBP/DBP of 130-139/<90 mm Hg (n = 117, incidence rate, 17.1%) than those with an achieved SBP/DBP of ≥140/90 (n = 118, 31.4%) or <130/90 mm Hg (n = 161, 23.6%). Thiazide-induced changes in serum uric acid or incident hyperuricemia were associated with the achieved SBP/DBP, being lower at the level of 130-139/<90 mm Hg.

Association between baseline and changes in serum uric acid and incident metabolic syndrome: a nation-wide cohort study and updated meta-analysis

BackgroundTo prospectively examine the associations of baseline serum uric acid (SUA) and SUA changes with incident metabolic syndrome (MetS) and update the evidence through a meta-analysis.MethodsOur analyses were based on the China Health and Retirement Longitudinal Study from 2011–2012 to 2015–2016. The exposures were baseline SUA and SUA changes, and the outcome was incident MetS assessed in 2015–2016. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). A meta-analysis was conducted to synthesize evidence from all cohort studies on the same topic.ResultsOf 3779 participants (47.2% men; mean age: 59.5 years) without MetS, 452 participants developed MetS after a follow-up of 4 years. Compared to the lowest quartiles, the adjusted ORs (95% CIs) for MetS were 1.08 (0.77–1.50), 1.32 (0.95–1.82), and 1.55 (1.12–2.16) for three higher quartiles of baseline SUA, and 1.23 (0.89–1.71), 1.39 (1.00–1.93), and 1.89 (1.38–2.58) for three higher quartiles of SUA changes. Each increment of 1 mg/dL of baseline SUA level was associated with 19% higher odds of MetS (adjusted OR 1.19; 95% CI 1.07–1.33). In the meta-analysis of 24 cohort studies among 140,913 participants, the pooled relative risk (95% CI) was 1.32 (1.25–1.40) for the highest versus lowest SUA category, and 1.15 (1.09–1.21) for each 1 mg/dL increase in the SUA level.ConclusionsBoth baseline SUA and longitudinal SUA changes were positively associated with risk of MetS among middle-aged and elderly Chinese, which was supported by findings from a comprehensive meta-analysis across multiple populations. SUA levels might need to be monitored closely for subsequent risk of MetS in clinical practice.

EFFECTS OF FEBUXOSTAT ON CAROTID INTIMA-MEDIA THICKNESS IN ASYMPTOMATIC HYPERURICEMIA: A RANDOMIZED CLINICAL TRIAL (PRIZE)

Objective: Elevated levels of serum uric acid (SUA) increase the risk of gout and may be associated with the risk of cardiometabolic disorders and subsequent cardiovascular disease. Clinical evidence regarding the effects of xanthine oxidase (XO) inhibitors on atherosclerosis is lacking. The purpose of the study was to test whether treatment with febuxostat, a non-purine selective inhibitor of XO, delays carotid intima-media thickness (IMT) progression in patients with asymptomatic hyperuricemia. Design and method: This was an investigator-initiated, multicenter, randomized, controlled, open-label clinical trial undertaken at 48 Japanese sites. A total of 514 adults, who had both asymptomatic hyperuricemia with SUA &gt;7.0 mg/dL and maximum IMT of the common carotid artery (CCA) 1.1 mm or greater at screening, were equally allocated to receive either dose-titrated febuxostat (10–60 mg daily) or non-pharmacological lifestyle modification for hyperuricemia as a control-arm. The primary endpoint was the percentage change from baseline in mean IMT of the CCA at 24 months. Key secondary outcomes included other carotid ultrasonographic parameters, SUA, and adverse events. Results: Compared with the control group, febuxostat had no significant effect on the primary endpoint (1.2% [95% CI, -0.6% to 3.0%] in the febuxostat group vs 1.4% [95% CI, -0.5% to 3.3%] in the control group; between-group difference [febuxostat-control], -0.2% [95% CI, -2.3% to 1.9%]; P = 0.83) and any other carotid ultrasonographic parameters. At 24 months, the between-group difference [febuxostat-control] in the SUA change from baseline was significant (-2.65 mg/dL [95% CI, -2.93 mg/dL to -2.37 mg/dL]; P &lt; 0.001), and gout arthritis occurred only in the control group (4 patients [1.6%]). There were three deaths in the febuxostat group and seven in the control group during follow-up. Conclusions: In Japanese patients with asymptomatic hyperuricemia, 24 months of febuxostat treatment did not delay carotid atherosclerosis progression, compared with non-pharmacological care. These findings do not support the use of febuxostat for delaying carotid atherosclerosis in this population. However, febuxostat treatment was tolerable and did not increase the incidence of cardiovascular and all-cause mortality.

LONGITUDINAL CHANGE IN RENAL DYSFUNCTION BIOMARKERS PREDICT OUTCOME DIFFERENTLY IN HYPERTENSIVE AND NORMOTENSIVE PERSONS FROM THE GENERAL POPULATION. THE TROMSØ STUDY

Objective: Serum uric acid (SUA), urinary albumin-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) are associated with hypertension and adverse cardiovascular (CV) outcome. Little is known about outcome after longitudinal changes in these biomarkers. We aimed to assess the associations between seven years’ change in these renal biomarkers and the incidence of CV disease and mortality in hypertensive and normotensive individuals from the general population. Design and method: We included all participants with measurements of SUA, eGFR and ACR in survey 4 (1994/95) and 5 (2001/02) of the Tromsø Study. Hypertension at baseline (1994/95) was defined as systolic blood pressure (BP) &gt; = 140 mmHg, diastolic BP &gt; = 90 mmHg and/or antihypertensive drug use. We used Cox regression to examine the associations between seven years’ &gt; = 25% increase in SUA and/or ACR, and/or annual eGFR decline of &gt; = 3 mL/min/1.73 m2, and myocardial infarction (MI), ischaemic stroke (IS) and all-cause mortality. Multivariable models adjusted for baseline CV risk factors, changes in systolic BP and body mass index were run separately in hypertensive and normotensive subjects Results: Of the 4663 participants included, 59% had hypertension. At baseline, mean age was 58.3 (9.8) years, eGFR 94 (13) mL/min/1.73 m2, SUA 310 (89) μmol/L and median ACR 0.53 (0.36, 0.87) mg/mmol. Between the 2001/02 visit and 31.12.2013, 479 persons suffered from MI, 394 IS and 1296 died. Increase in ACR &gt; = 25% was associated with MI in normotensive (HR 2.09; 95% CI 1.47, 2.98), but not hypertensive subjects. Change in ACR, SUA or eGFR was not associated with IS. All three variables were associated with all-cause mortality in hypertensive, but not normotensive subjects. However, the association between SUA and death was no longer significant when adjusted for ACR and eGFR change. Conclusions: Increasing ACR was a risk factor for MI in normotensives, whereas increasing ACR and rapid eGFR decline predicted mortality in hypertensive individuals. Change in different biomarkers of kidney dysfunction may reflect different pathophysiological processes. Further research is needed to determine whether change in renal biomarkers may be useful in follow-up of hypertensive and normotensive persons.

Association between uric acid lowering and renal function progression: a longitudinal study.

BackgroundThis study aimed to explore the association between uric acid lowering and renal function.Materials and MethodsWe conducted a population-based cohort study with 1,534 subjects for 4 years from 2012 to 2016. The population was divided into four groups according to the interquartile range of changes in serum uric acid with quartile 1 representing lower quarter. Renal function decline was defined as eGFR decreased more than 10% from baseline in 2016. Renal function improvement was defined as eGFR increased more than 10% from baseline in 2016. Cox regression analysis was used to calculate the hazard ratio (HR) and 95% confidence interval (CI).ResultsIn the adjusted Cox regression models, compared to quartile 4, quartile 1 (HR = 0.64, 95% CI [0.49–0.85]), quartile 2 (HR = 0.65, 95% CI [0.50–0.84]) and quartile 3 (HR = 0.75, 95% CI [0.58–0.96]) have reduced risk of renal function decline. An increasing hazard ratio of renal function improvement was shown in quartile 1 (HR = 2.27, 95% CI [1.45–3.57]) and quartile 2 (HR = 1.78, 95% CI [1.17–2.69]) compared with quartile 4.ConclusionsUric acid lowering is associated with changes in renal function. The management of serum uric acid should receive attention in clinical practice and is supposed to be part of the treatment of chronic kidney disease.

Baseline and change in serum uric acid predict the progression from prehypertension to hypertension: a prospective cohort study.

Evidence is lacking about the role of serum uric acid (SUA) in the progression from prehypertension to hypertension. Herein, we aimed to investigate the association of both baseline and dynamic change in SUA with the risk of hypertension developing from prehypertension. The study enrolled 11,488 participants with prehypertension during 2006-2010 from the Kailuan study. Change in SUA was assessed as % change of SUA from 2006 (baseline) to 2010. Participants were categorized into four groups by quartiles of baseline and change in SUA, separately. Multivariable logistic regressions were used to calculation the odds ratio (OR) and 95% confidence interval (CI). During a median follow-up of 7.06 years, 2716 (23.64%) participants developed hypertension from prehypertension. In the multivariable-adjusted model, the OR for hypertension comparing participants in the highest versus the lowest quartile of baseline SUA were 1.18 (95% CI, 1.02-1.36). Increased SUA over time was also associated with elevated risk of hypertension (OR in the highest quartile was 1.41 [95% CI, 1.23-1.62] versus the lowest quartile), especially in those with baseline SUA ≥ median (OR, 1.48; 95% CI, 1.21-1.81). Moreover, the addition of SUA to a conventional risk model had an incremental effect on the predictive value for hypertension (integrated discrimination improvement 0.30%, P < 0.0001; category-free net reclassification improvement 12.36%, P < 0.0001). Both high initial SUA and increased SUA over time can independently predict the progression from prehypertension to hypertension. Strategies aiming at controlling SUA level in prehypertensive subjects may impede the onset of hypertension.

Vitamin D supplementation is associated with serum uric acid concentration in patients with prediabetes and hyperuricemia

AimsVitamin D deficiency is associated with a number of noncommunicable conditions. We conducted a randomised controlled trial to determine the effect of vitamin D supplementation on serum uric acid concentration in patients with prediabetes, in whom hyperuricaemia is common. MethodsSeventy-one volunteers (35–80 years), with impaired fasting glucose and/or impaired glucose tolerance were randomised to three groups, vitamin D3, vitamin D2 and control, and followed for 12 months. ResultsAfter 12 weeks, vitamin D supplementation was associated with a reduction in serum uric acid concentration in participants with baseline uric acid concentration > 6 mg/dL, but no significant change was observed in controls. We then assessed the dose–response relationship between vitamin D supplementation and the change in serum uric acid concentration and found that the change in serum total 25-hydroxyvitamin D did not correlate with the change in serum uric acid that occurred during vitamin D supplementation. The factors associated with larger reductions in serum uric acid were a higher baseline serum uric acid and a larger increase in serum 1,25-dihydroxyvitamin D. ConclusionsVitamin D supplementation lowers serum uric acid in prediabetic patients with hyperuricaemia, and supplementation might be considered to help alleviate hyperuricaemia in these patients.

The variation of serum uric acid levels among patients with myocardial infarction treated with ticagrelor and the association between serum uric acid and platelet reactivity

Objectives: To compare the impact of ticagrelor or clopidogrel on serum uric acid levels among patients with ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PCI) and further evaluate the effects of variation of serum uric acid levels on platelet reactivity. Methods: STEMI patients who admitted to Fuwai Hospital from April 2017 to January 2020, and underwent primary PCI and discharged alive with aspirin and ticagrelor or clopidogrel were included in this study. Patients were divided into ticagrelor group and clopidogrel group. The baseline clinical data were collected. Serum uric acid and creatinine levels at baseline and 30 days post-PCI were measured. Light transmittance aggregometry was used to assess maximum aggregation rate induced by adenosine diphosphate and arachidonic acid. The changes of serum uric acid and creatinine were compared between the two groups. Multivariate logistic regression was performed to evaluate independent related factors for rise in the uric acid levels, and the effect of variation of serum uric acid level on platelet reactivity was analyzed. Results: A total of 967 patients were included, the age was (59.4±12.1) years, and 163 case were female. There were 550 cases in ticagrelor group (56.9%) and 417 cases in clopidogrel group (43.1%). Baseline serum uric acid and creatinine levels were similar between the 2 groups. At 30 days, the serum uric acid level [(347.2±96.5) mmol/L vs. (341.2±105.3) mmol/L, P=0.009] and absolute [46.4 (-2.4, 88.1) mmol/L vs. 25.0 (-21.9, 73.0) mmol/L, P=0.001] and percentage [13.2 (-0.01, 29.0) % vs. 7.9 (-5.7, 25.0) %, P=0.007] increase in the serum uric acid levels were significantly higher in ticagrelor group than in clopidogrel group. The level of serum creatinine at 30 days was significantly lower in ticagrelor group than in clopidogrel group [(89.7±21.3) μmol/L vs. (94.4±43.9) μmol/L, P<0.05], whereas there were no differences in absolute [8.0 (-1.4, 16.6) μmol/L vs. 7.8 (-2.0, 16.6) μmol/L] and percentage [10.5 (-1.7%, 22.6%) vs. 9.8 (-2.4%, 22.1%)] change in the serum creatinine between the 2 groups (all P>0.05). Logistic regression analysis showed that, after adjusting for confounding factors, ticagrelor therapy was an independent related factor of serum uric acid elevation (OR=1.582, 95% CI:1.023-2.447, P=0.039). The variation of the serum uric acid levels did not affect platelet aggregation and the percentage of high platelet reactivity in both groups. Conclusions: Ticagrelor use is related to a significant increase in the serum uric acid levels at 30 days post-PCI in this patient cohort. The variations in the uric acid levels do not increase the percentage of high platelet reactivity in STEMI patients treated with ticagrelor or clopidogrel.

Changes in serum uric acid and the risk of cardiovascular disease and all-cause mortality in the general population

Background and aimLongitudinal evidence on change in serum (SUA) with risk of cardiovascular disease (CVD) and all-cause mortality is limited, as many prior studies focused on baseline SUA. Further, the optimal threshold range of SUA change is unclear. Methods and resultsA total of 63,127 participants without history of CVD were enrolled. Change in SUA was determined by the difference of SUA levels between 2006 and 2010, which divided by baseline SUA was percent change in SUA. Multivariable Cox proportional hazards models were used to calculated the hazard ratios (HRs) and 95% confidence intervals (CIs). Our analysis also included restricted cubic spline model and three-piecewise Cox proportion hazards model to address the non-linearity between percent change in SUA and outcomes. During a median follow-up of 7.04 years, 3341 CVD and 3238 deaths occurred. We did not observed a significant association between changes in SUA and CVD. However, changes in SUA at extreme were associated with higher risk of all-cause mortality, the HRs (95% CIs) were 1.15 (1.02–1.29) and 1.20 (1.06–1.35) in the first and fifth quintile group, compared with the third quintile group. We further found a U-shaped association between percent change in SUA and all-cause mortality, and the optimal range was within 20%. ConclusionsChanges in SUA at extreme were risk factors for all-cause mortality, but not for CVD in the general population. The findings are relevant for role of SUA in the management of CVD risk and may contribute to improve identification of patients at higher risk.

Effects of bariatric surgery on serum uric acid in people with obesity with or without hyperuricaemia and gout: a retrospective analysis

Weight reduction may reduce serum uric acid (SUA). This study aimed to examine the changes of SUA before and after bariatric surgery in patients with obesity with or without hyperuricaemia and gout. This is a retrospective analysis of 147 routinely collected data on hospital patients with obesity who underwent bariatric surgery. The body weight and SUA were measured at baseline and after surgery at 1-7 days, 1, 3, 6 and 12 months. The mean (95% CI) weight reduction of 147 patients was 30.7 (28.7, 32.7) kg 1 year after surgery (P < 0.001). SUA decreased rapidly from 419.0 (400.1, 437.8) µmol/l at baseline to 308.4 (289.6, 327.2) µmol/l at 1-7 days, flared up to 444.8 (423.9, 465.6) µmol/l at 1 month, then decreased again to 383.8 (361.5, 406.1) µmol/l at 3 months, 348.9 (326.3, 371.5) µmol/l at 6 months and 327.9 (305.3, 350.5) µmol/l at 12 months (P < 0.001). Similar trends but more rapid reductions were observed in 55 hyperuricaemia patients and 25 gout patients. All 25 gout patients had an elevated SUA above the therapeutic target (≥360µmmol/l) at baseline, but in 10 patients it was reduced below this target at 12 months. The mean reduction (95% CI) of SUA in all patients and gout patients was 84.3 (63.1-105.4) and 163.6 (103.9, 223.3) µmmol/l, respectively. Bariatric surgery significantly reduces body weight and SUA for obese patients with hyperuricaemia and gout. Gout may be considered as an indicator for this surgical treatment in people with severe obesity.

Alteration of normal level of serum urate may contribute to decrease in estimated glomerular filtration rate decline in healthy Japanese men

Introduction Serum uric acid (SUA) levels have a linear relationship with the estimated glomerular filtration rate (eGFR). It is unclear whether further changes, subsequent to normal level of SUA can attenuate eGFR decline in a healthy population, so we aimed to determine the normal level of SUA that can contribute to preventing kidney dysfunction. Methods In this retrospective cohort study from Japan, annual health checkup data from 2009 to 2014 was collected. After propensity score matching (1:1), data from 2,634 individuals with basal SUA ≤7.0 mg/dL (normal; mean age, 39 y; mean eGFR, 80.8 mL/min/1.73 m2) and 1,642 individuals with basal SUA >7.0 mg/dL (elevated; mean age, 42 y; mean eGFR, 75.0 mL/min/1.73 m2) were collected to determine the relationship between followed-up SUA level and the rate of change in eGFR. Results In individuals with normal level SUA at baseline, the elevation of SUA (>7.0 mg/dL) accelerated eGFR decline compared to those with normal SUA levels at 5-year follow-up (−4.1 ± 9.6% vs −9.9 ± 9.0%, p < .0001). Digression of SUA level (≤7.0 mg/dL) reduced eGFR decline compared with persistent SUA level over 7.0 mg/dL (−1.5 ± 11.5% vs −7.0 ± 10.1, p < .0001). In multiple linear regression analysis, there was strong association between the rate of change in SUA and eGFR in individuals with basal SUA ≤7.0 and >7.0 mg/dL (standardized coefficient; −0.3348, p < .001 and −.2523, p < .001, respectively). Conclusion Subsequent to normal level of SUA (under 7.0 mg/dL) may contribute to a decrease in eGFR decline in apparently healthy men.

Losartan and Eprosartan Induce a Similar Effect on the Acute Rise in Serum Uric Acid Concentration after an Oral Fructose Load in Patients with Metabolic Syndrome.

Introduction Excessive intake of fructose increases serum uric acid concentration. Hyperuricemia induces a negative effect on atherosclerosis and inflammation. Hyperuricemia is common in patients with arterial hypertension. Several antihypertensive drugs including diuretics increase serum uric acid concentration. In contrast, the angiotensin II receptor antagonist (ARB) losartan was found to lower serum uric acid though it may increase renal excretion while other ARBs showed mostly a neutral effect. In this study, effects of two AT1 receptor antagonists losartan and eprosartan on serum uric acid changes induced by oral fructose load were directly compared. Methods The randomized, crossover, head-to-head comparative study comprised 16 ambulatory patients (mean age 64.5 ± 9.8 years). The patients fulfilled AHA/NHLBI 2005 criteria of metabolic syndrome. A daily single morning dose of each study drug (50 mg of losartan or 600 mg of eprosartan) was given during two 3-month periods in a random order separated by 2-week washout time. The oral fructose tolerance test (OFTT) was performed at baseline and after each two 3-onth treatment periods. Before and during OFTT, urine excretion of uric acid and creatinine was assessed in the first morning portion of urine. Blood samples for the measurement of serum uric acid and lipids were taken at baseline and 30, 60, and 120 minutes after oral intake of 75 g of fructose. Results After 3-month treatment with eprosartan and losartan, both systolic and diastolic blood pressure decreased significantly and to a similar extent. After the treatment, serum uric acid and its baseline and postfructose urine excretion were unchanged. No significant changes of plasma lipids before and after OFTT were observed throughout the study. Conclusions The study showed that in patients with hypertension and metabolic syndrome, both losartan and eprosartan have a neutral effect on fasting and postfructose load serum uric acid concentration and its urinary excretion. This trial is registered with NCT04954560.

Dose–response relationship between distinct serum uric acid trajectories and metabolic syndrome risk: A 5-year prospective cohort study

Background and aimsAlthough high serum uric acid (SUA) at baseline has been linked to increased risk for metabolic syndrome (MetS), the association of longitudinal SUA changes with MetS risk is unclear. We aimed to examine the effect of distinct SUA trajectories on new-onset MetS risk by sex in a Chinese cohort. Methods and resultsA total of 2364 women and 2770 men who were free of MetS in 2013 were enrolled in this study and followed up to 2018. Group-based trajectory modeling was applied to identify SUA trajectories. Cox proportional hazards model was used to evaluate the association between SUA trajectory and new-onset MetS. The dose–response relationship between SUA trajectories and MetS risk was examined by treating trajectory groups as a continuous variable. During a median follow-up of 48.0 months, 311 (13.16%) women and 950 (34.30%) men developed MetS. SUA trajectories (2013–2018) were defined as four distinct patterns in both women and men: “low”, “moderate”, “moderate-high”, and “high”. Compared with “low” SUA trajectory, the adjusted hazard ratio for incident MetS among participants with “moderate”, “moderate-high” and “high” trajectory was in a dose–response manner: 1.75 (95% CI: 1.08–2.82), 1.94 (95% CI: 1.20–3.14), and 3.05 (95% CI: 1.81–5.13), respectively, for women; 1.20 (95% CI: 0.97–1.49), 1.48 (95% CI: 1.19–1.85), and 1.66 (95% CI: 1.25–2.21), respectively, for men. ConclusionsElevated SUA trajectories are associated with increased risk for new-onset MetS in women and men. Monitoring SUA trajectories may assist in identifying subpopulations at higher risk for MetS.

Inulin supplementation ameliorates hyperuricemia and modulates gut microbiota in Uox-knockout mice

PurposeInulin is a type of fermentable dietary fiber, which is non-digestible, and can improve metabolic function by modulating intestinal microbiota. This study aimed to evaluate the role of inulin in hyperuricemia and microbial composition of the gut microbiota in a mouse model of hyperuricemia established through knockout of Uox (urate oxidase) gene.MethodsKO (Uox-knockout) and WT (wild-type) mice were given inulin or saline by gavage for 7 weeks. The effect of inulin to combat hyperuricemia was determined by assessing the changes in serum UA (uric acid) levels, inflammatory parameters, epithelial barrier integrity, fecal microbiota alterations, and SCFA (short-chain fatty acid) concentrations in KO mice.ResultsInulin supplementation can effectively alleviate hyperuricemia, increase the expressions of ABCG2 in intestine, and downregulate expression and activity of hepatic XOD (xanthine oxidase) in KO mice. It was revealed that the levels of inflammatory cytokines and the LPS (lipopolysaccharide) were remarkably higher in the KO group than those in the WT group, indicating systemic inflammation of hyperuricemic mice, but inulin treatment ameliorated inflammation in KO mice. Besides, inulin treatment repaired the intestinal epithelial barrier as evidenced by increased levels of intestinal TJ (tight junction) proteins [ZO-1 (zonula occludens-1) and occluding] in KO mice. Moreover, serum levels of uremic toxins, including IS (indoxyl sulfate) and PCS (p-cresol sulfate), were reduced in inulin-treated KO mice. Further investigation unveiled that inulin supplementation enhanced microbial diversity and raised the relative abundance of beneficial bacteria, involving SCFAs-producing bacteria (e.g., Akkermansia and Ruminococcus). Additionally, inulin treatment increased the production of gut microbiota-derived SCFAs (acetate, propionate and butyrate concentrations) in KO mice, which was positively correlated with the effectiveness of hyperuricemia relief.ConclusionsOur findings showed that inulin may be a promising therapeutic candidate for the treatment of hyperuricemia. Moreover, alleviation of hyperuricemia by inulin supplementation was, at least, partially conciliated by modulation of gut microbiota and its metabolites.

Elevated Serum Uric Acid is Associated with Rapid Decline in Kidney Function: A 10-Year Follow-Up Study.

PurposeThe long-term impact of changes in serum uric acid (SUA) concentration on the estimated glomerular filtration rate (eGFR) among the general population remains unclear. We investigated the longitudinal associations between changes in SUA and eGFR over 10 years in 1222 participants with baseline eGFR ≥60 mL/min/1.73 m2.MethodsThis was a 10-year retrospective cohort study conducted from 2007 to 2017. Rapid eGFR decline (defined as the highest quartile of change in eGFR between 2007 and 2017) and new-onset kidney disease (defined as an eGFR <60 mL/min/1.73 m2 at a 10-year follow-up) were examined using multiple logistic regression analysis, adjusted for sex, age, body mass index, systolic blood pressure, SUA, fasting plasma glucose, serum total cholesterol, and triglyceride at baseline.ResultsSUA was inversely correlated with eGFR, and the slopes of the SUA-eGFR regression lines were consistently steeper in females than males. A significant inverse correlation was also observed between 10-year changes in SUA and eGFR in both sexes. Multivariate analysis showed that every 1 mg/dL increase in SUA from baseline was associated with higher risk of rapid eGFR decline and new-onset kidney disease (OR 1.25; 95% CI 1.14–1.33 and OR 1.40; 95% CI 1.26–1.49, respectively). Furthermore, the subjects in the highest SUA quartile (>6.0 mg/dL) had a 2.45 times higher risk of rapid eGFR decline (95% CI 1.51–3.42) compared to those in the lowest SUA quartile (<3.9 mg/dL).ConclusionElevated baseline SUA is an independent risk factor for rapid eGFR decline and new-onset kidney disease in the general population.

Serum uric acid, influence of sacubitril-valsartan, and cardiovascular outcomes in heart failure with preserved ejection fraction: PARAGON-HF.

This study aimed to determine the prognostic value of serum uric acid (SUA) on outcomes in heart failure (HF) with preserved ejection fraction (HFpEF), and whether sacubitril-valsartan reduces SUA and use of SUA-related therapies. We analysed 4795 participants from the Prospective Comparison of ARNI [angiotensin receptor-neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF) trial. We related baseline hyperuricaemia (using age and gender adjusted assay definitions) to the primary outcome [cardiovascular (CV) death and total HF hospitalizations]. We assessed the associations between changes in SUA and Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) and other cardiac biomarkers from baseline to 4 months. We simultaneously adjusted for baseline and time-updated SUA to determine whether lowering SUA was associated with clinical benefit. The mean (± standard deviation) age of patients was 73 ± 8 years and 52% were women. After multivariable adjustment, hyperuricaemia was associated with increased risk for the primary outcome [rate ratio 1.61, 95% confidence interval (CI) 1.37-1.90]. The treatment effect of sacubitril-valsartan for the primary endpoint was not significantly modified by hyperuricaemia (P-value for interaction=0.14). Sacubitril-valsartan reduced SUA by 0.38 mg/dL (95% CI 0.31-0.45) compared with valsartan at 4months, with greater effect in those with elevated SUA vs. normal SUA (-0.51 mg/dL vs. -0.32 mg/dL) (P-value for interaction=0.031). Sacubitril-valsartan reduced the odds of initiating SUA-related treatments by 32% during follow-up (P< 0.001). After multivariable adjustment, change in SUA was inversely associated with change in KCCQ-OSS and directly associated with high-sensitivity troponin T (P< 0.05). Time-updated SUA was a stronger predictor of adverse outcomes than baseline SUA. Serum uric acid independently predicted adverse outcomes in HFpEF. Sacubitril-valsartan reduced SUA and the initiation of related therapy compared with valsartan. Reductions in SUA were associated with improved outcomes.

Evolution of isolated systolic hypertension with normal central blood pressure in adolescents\u2014prospective study

BackgroundThe clinical significance of isolated systolic hypertension with normal central blood pressure known as spurious hypertension (sHT) in adolescents and its evolution over time is not known.MethodsThe aim of this study was to analyze changes in office, ambulatory blood pressure (ABPM), central systolic blood pressure (cSBP), hemodynamic parameters, and target organ damage (TOD) over a 1-year follow-up in a group of non-obese children with sHT.ResultsOf 294 patients referred for primary hypertension, 138 patients (31 girls; 22%) had hypertension confirmed by ABPM. 48/138 (35%) patients (7 girls; 15%) were diagnosed with sHT (elevated office and ambulatory systolic BP, but normal cSBP); 43 of them (6 girls; 14%) were followed for 12 ± 3 months during non-pharmacological therapy. At baseline 7 (16%) patients had borderline values of cIMT or LVMi indicating mild TOD. After 12 months, 10/43 (3 girls; 23%) patients developed sustained HT (elevated office, ambulatory BP and cSBP), 11/43 (1 girl; 26%) maintained sHT, and 22/43 (2 girls; 51%) evolved to white coat hypertension or normotension. The cSBP values increased in 27 patients (4 girls; 63%), but the group average remained in the normal range. Prevalence of TOD did not change during observation. The multivariate regression analysis showed that the only predictor of cSBP change over time was a change in serum uric acid level.ConclusionsIn conclusion, after 1 year of non-pharmacological treatment, 23% of adolescents with sHT developed sustained hypertension, with the main predictor of cSBP change being the change in serum uric acid.