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The effects of urate lowering therapy on inflammation, endothelial function, and blood pressure (SURPHER) study design and rationale.

ABSTRACT: The association between hyperuricemia and hypertension is controversial. Animal models, epidemiological data, and small clinical trials have favored a causative role for hyperuricemia in hypertension but more studies are necessary to elucidate putative mechanisms, population susceptibility, and potential for urate-lowering therapies (ULT) to decrease blood pressure (BP).To describe the background and design of the Serum Urate Reduction to Prevent Hypertension (SURPHER) study.SURPHER is a single center, double-blinded, crossover trial in which participants are randomly assigned to allopurinol (300mg) or placebo. Enrollment focused on adults 18-40years old with baseline systolic blood pressure?120 and <160mmHg or diastolic blood pressure?80 and <100mmHg, and serum urate ?5.0mg/dL or ?4.0mg/dL for men or women, respectively. SURPHER recruitment targets participants without chronic kidney disease (estimated glomerular filtration rate>60mL/min/1.73m2), and without prior diagnosis of gout or use of ULT to treat gout. The primary outcome is change from baseline in blood pressure assessed by 24hour ambulatory blood pressure monitoring and mechanistic outcomes include changes in endothelial function as measured by flow-mediated dilation, as well as C-reactive protein levels.Since June 16, 2014 until present, SURPHER is recruiting participants in the city of Birmingham, Alabama.The study aims to enroll otherwise healthy young adults for a pharmacological intervention study with multiple study-related procedures. Challenges related to recruitment are anticipated and multiple strategies for increasing recruitment and retention are planned if necessary.

SUBMITTER: Saddekni MB

PROVIDER: S-EPMC5261071 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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The effects of urate lowering therapy on inflammation, endothelial function, and blood pressure (SURPHER) study design and rationale.

Saddekni Michael B MB Saag Kenneth G KG Dudenbostel Tanja T Oparil Suzanne S Calhoun David A DA Sattui Sebastian E SE Feig Daniel I DI Muntner Paul P Redden David T DT Foster Phillip J PJ Rahn Elizabeth J EJ Biggers Stephanie R SR Li Peng P Gaffo Angelo L AL

Contemporary clinical trials 20160830

<h4>Background</h4>The association between hyperuricemia and hypertension is controversial. Animal models, epidemiological data, and small clinical trials have favored a causative role for hyperuricemia in hypertension but more studies are necessary to elucidate putative mechanisms, population susceptibility, and potential for urate-lowering therapies (ULT) to decrease blood pressure (BP).<h4>Purpose</h4>To describe the background and design of the Serum Urate Reduction to Prevent Hypertension ( ...[more]

PMID: 27587282

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Project description:BackgroundPrevious studies have noted significant variation in serum urate (sUA) levels, and it is unknown how this influences the accuracy of hyperuricemia classification based on single data points. Despite this known variability, hyperuricemic patients are often used as a control group in gout studies. Our objective was to determine the accuracy of hyperuricemia classifications based on single data points versus multiple data points given the degree of variability observed with serial measurements of sUA.MethodsData was analyzed from a cross-over clinical trial of urate-lowering therapy in young adults without a gout diagnosis. In the control phase, sUA levels used for this analysis were collected at 2-4 week intervals. Mean coefficient of variation for sUA was determined, as were rates of conversion between normouricemia (sUA ≤6.8 mg/dL) and hyperuricemia (sUA > 6.8 mg/dL).ResultsMean study participant (n = 85) age was 27.8 ± 7.0 years, with 39% female participants and 41% African-American participants. Mean sUA coefficient of variation was 8.5% ± 4.9% (1 to 23%). There was no significant difference in variation between men and women, or between participants initially normouricemic and those who were initially hyperuricemic. Among those initially normouricemic (n = 72), 21% converted to hyperuricemia during at least one subsequent measurement. The subgroup with initial sUA < 6.0 (n = 54) was much less likely to have future values in the range of hyperuricemia compared to the group with screening sUA values between 6.0-6.8 (n = 18) (7% vs 39%, p = 0.0037). Of the participants initially hyperuricemic (n = 13), 46% were later normouricemic during at least one measurement.ConclusionSingle sUA measurements were unreliable in hyperuricemia classification due to spontaneous variation. Knowing this, if a single measurement must be used in classification, it is worth noting that those with an sUA of < 6.0 mg/dL were less likely to demonstrate future hyperuricemic measurements and this could be considered a safer threshold to rule out intermittent hyperuricemia based on a single measurement point.Trial registrationData from parent study ClinicalTrials.gov Identifier: NCT02038179 .

Project description:Background: Effective xanthine oxidoreductase inhibition (XOI) urate-lowering treatment (ULT) to target significantly reduces gout flare burden and synovitis between 1-2 years therapy, without clearing all monosodium urate crystal deposits. Paradoxically, treat to target ULT is associated with increased flare activity for at least 1 year in duration on average, before gout flare burden decreases. Since XOI has anti-inflammatory effects, we tested for biomarkers of sustained, effective ULT that alters gouty inflammation. Methods: We characterized the proteome of febuxostat-treated murine bone marrow macrophages. Blood samples (baseline and 48 weeks ULT) were analyzed by unbiased proteomics in febuxostat and allopurinol ULT responders from two, independent, racially and ethnically distinct comparative effectiveness trial cohorts (n=19, n=30). STRING-db and multivariate analyses supplemented determinations of significantly altered proteins via Wilcoxon matched pairs signed rank testing. Results: The proteome of cultured IL-1b-stimulated macrophages revealed febuxostat-induced anti-inflammatory changes, including for classical and alternative pathway complement activation pathways. At 48 weeks ULT, with altered purine metabolism confirmed by serum metabolomics, serum urate dropped >30%, to normal (<6.8 mg/dL) in all the studied patients. Overall, flares declined from baseline. Treated gout patient sera and peripheral blood mononuclear cells (PBMCs) showed significantly altered proteins (p<0.05) in clustering and proteome networks. CRP was not a useful therapy response biomarker. By comparison, significant serum proteome changes included decreased complement C8 heterotrimer C8A and C8G chains essential for C5b-9 membrane attack complex assembly and function; increase in the NLRP3 inflammasome activation promoter vimentin; increased urate crystal phagocytosis inhibitor sCD44; increased gouty inflammation pro-resolving mediator TGFB1; decreased phagocyte-recruiting chemokine PPBP/CXCL7, and increased monocyte/macrophage-expressed keratin-related proteins (KRT9,14,16) further validated by PBMC proteomics. STRING-db analyses of significantly altered serum proteins from both cohorts revealed a tight interactome network including central mediators of gouty inflammation (eg, IL-1B, CXCL8, IL6, C5). Conclusions: Rewiring of inflammation mediators in a tight serum protein interactome was a biomarker of sustained XOI-based ULT that effectively reduced serum urate and gout flares. Monitoring of the serum and PBMC proteome, including for changes in the complement pathway could help determine onset and targets of anti-inflammatory changes in response to effective, sustained XOI-based ULT. Trial Registration: ClinicalTrials.gov Identifier: NCT02579096.

Project description:BackgroundGout is a painful chronic disease which disrupts work and family life and can lead to chronic joint damage. Pacific people in Aotearoa/New Zealand experience significant inequities, with over three times the gout prevalence of the non-Pacific non-Māori populations. Pacific people receive less regular urate-lowering drugs to prevent gout flare-ups, and have nine times the hospitalisation from gout compared with non-Pacific non-Māori people. Rates for Indigenous Māori lie between Pacific and non-Pacific non-Māori. A long-established Collective comprising community members from the Pacific People's Health Advisory Group, clinical staff from the Pacific Practice-Based Research Network, and University of Auckland researchers have identified that improving Pacific urate-lowering therapy use as the research question of prime importance for improved health outcomes of Pacific people in South Auckland. Building on the existing knowledge, this study aims to develop, implement and evaluate a novel innovative intervention to improve the uptake of urate-lowering therapy by Pacific patients with gout.MethodsThree-phase mixed methods co-design study using the Fa'afaletui research framework following the STROBE statement. Phase1 is observational times series of prevalence of patients with gout, proportion with urate blood-level monitoring and use of urate-lowering medication over past 5 years. In Phase 2 the Collective will workshop new interventions to address previous uptake barriers, using culturally-appropriate Talanga communications with results synthesised in line with Kakala principles. The designed intervention will be implemented and process and outcome evaluations conducted. Finally, an implementation framework will be produced to facilitate further roll-out.DiscussionThe study aims to enhance health and reduce inequities for Pacific people, contribute to creation of Pacific health knowledge and translation of research findings into Pacific health gains. Potential longer-term impact is a gout-management pathway for use throughout Aotearoa/New Zealand. Māori have similar issues with high gout prevalence and low urate-lowering therapy use hence the intervention is likely to translate to Māori healthcare. The project will contribute to Pacific research capacity and capability-building as well as general upskilling of community and practice members involved in the co-design processes.Trial registrationThe Australian New Zealand Clinical Trial Registry is in process, request number 38206, 1-09-2021.

Project description:Background: High blood pressure (BP), particularly systolic BP (SBP), is the major modifiable risk factor for cardiovascular diseases and related disorders of aging. SBP increases markedly with aging in women such that the prevalence of above-normal SBP (i.e., ≥120 mmHg) in postmenopausal women exceeds rates in age-matched men. This increase in SBP is associated with vascular endothelial dysfunction, mediated by excessive reactive oxygen species-induced oxidative stress and consequent reductions in nitric oxide bioavailability. Moderate-intensity aerobic exercise is a recommended lifestyle strategy for reducing SBP. However, adherence to aerobic exercise guidelines among postmenopausal women is low (<30%) and aerobic exercise does not consistently enhance endothelial function in estrogen-deficient postmenopausal women. High-resistance inspiratory muscle strength training (IMST) is a time-efficient, adherable lifestyle intervention that involves inhaling against resistance through a handheld device (30 breaths/day). Here, we present the protocol for a randomized controlled trial investigating the efficacy of 3 months of high-resistance IMST compared to guideline-based, "standard-of-care" aerobic exercise training for decreasing SBP and improving endothelial function in estrogen-deficient postmenopausal women with above-normal SBP (120-159 mmHg) at baseline (ClinicalTrials.gov Identifier: NCT05000515). Methods: A randomized, single-blind, parallel-group design clinical trial will be conducted in 72 (36/group) estrogen-deficient postmenopausal women with above-normal SBP. Participants will complete baseline testing and then be randomized to either 3 months of high-resistance IMST (30 breaths/day, 6 days/week, 75% maximal inspiratory pressure) or moderate-intensity aerobic exercise training (brisk walking 25 min/day, 6 days/week, 40-60% heart rate reserve). Outcome measures will be assessed after 3 months of either intervention. Following end-intervention testing, participants will abstain from their assigned intervention for 6 weeks, after which BP and endothelial function will be assessed to evaluate the potential persistent effects of the intervention on the primary and secondary outcomes. Discussion: This study is designed to compare the effectiveness of time-efficient, high-resistance IMST to guideline-based aerobic exercise training for lowering SBP and improving endothelial function, and interrogating potential mechanisms of action, in estrogen-deficient postmenopausal women. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT05000515.

Project description:BackgroundHigher serum urate levels are associated with an increased risk of diabetic kidney disease. Lowering of the serum urate level with allopurinol may slow the decrease in the glomerular filtration rate (GFR) in persons with type 1 diabetes and early-to-moderate diabetic kidney disease.MethodsIn a double-blind trial, we randomly assigned participants with type 1 diabetes, a serum urate level of at least 4.5 mg per deciliter, an estimated GFR of 40.0 to 99.9 ml per minute per 1.73 m2 of body-surface area, and evidence of diabetic kidney disease to receive allopurinol or placebo. The primary outcome was the baseline-adjusted GFR, as measured with iohexol, after 3 years plus a 2-month washout period. Secondary outcomes included the decrease in the iohexol-based GFR per year and the urinary albumin excretion rate after washout. Safety was also assessed.ResultsA total of 267 patients were assigned to receive allopurinol and 263 to receive placebo. The mean age was 51.1 years, the mean duration of diabetes 34.6 years, and the mean glycated hemoglobin level 8.2%. The mean baseline iohexol-based GFR was 68.7 ml per minute per 1.73 m2 in the allopurinol group and 67.3 ml per minute per 1.73 m2 in the placebo group. During the intervention period, the mean serum urate level decreased from 6.1 to 3.9 mg per deciliter with allopurinol and remained at 6.1 mg per deciliter with placebo. After washout, the between-group difference in the mean iohexol-based GFR was 0.001 ml per minute per 1.73 m2 (95% confidence interval [CI], -1.9 to 1.9; P?=?0.99). The mean decrease in the iohexol-based GFR was -3.0 ml per minute per 1.73 m2 per year with allopurinol and -2.5 ml per minute per 1.73 m2 per year with placebo (between-group difference, -0.6 ml per minute per 1.73 m2 per year; 95% CI, -1.5 to 0.4). The mean urinary albumin excretion rate after washout was 40% (95% CI, 0 to 80) higher with allopurinol than with placebo. The frequency of serious adverse events was similar in the two groups.ConclusionsWe found no evidence of clinically meaningful benefits of serum urate reduction with allopurinol on kidney outcomes among patients with type 1 diabetes and early-to-moderate diabetic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171.).

Dataset Information

The effects of urate lowering therapy on inflammation, endothelial function, and blood pressure (SURPHER) study design and rationale.

Publications

The effects of urate lowering therapy on inflammation, endothelial function, and blood pressure (SURPHER) study design and rationale.

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