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Uric Acid Lowering and Biomarkers of Kidney Damage in CKD Stage 3: A Post Hoc Analysis of a Randomized Clinical Trial.

ABSTRACT: 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.

SUBMITTER: Perrenoud L

PROVIDER: S-EPMC7487946 | biostudies-literature | 2020 Mar-Apr

REPOSITORIES: biostudies-literature

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Uric Acid Lowering and Biomarkers of Kidney Damage in CKD Stage 3: A Post Hoc Analysis of a Randomized Clinical Trial.

Perrenoud Loni L Kruse Nicholas T NT Andrews Emily E You Zhiying Z Chonchol Michel M Wu Chaorong C Ten Eyck Patrick P Zepeda-Orozco Diana D Jalal Diana D

Kidney medicine 20200226 2

<h4>Rationale & objective</h4>Hyperuricemia is associated with chronic kidney disease (CKD) progression. We evaluated whether lowering serum uric acid levels improves levels of biomarkers of kidney damage.<h4>Study design</h4>Post hoc analysis of clinical trial participants.<h4>Setting & participants</h4>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 tre ...[more]

PMID: 32964203

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Project description:BACKGROUND:Serum uric acid concentrations increase in chronic kidney disease (CKD) and may lead to tubular injury, endothelial dysfunction, oxidative stress, and intrarenal inflammation. Whether uric acid concentrations are associated with kidney failure and death in CKD is unknown. STUDY DESIGN:Prospective observational cohort study. SETTINGS & PARTICIPANTS:3,885 individuals with CKD stages 2 to 4 enrolled in the Chronic Renal Insufficiency Cohort (CRIC) between June 2003 and September 2008 and followed up through March 2013. PREDICTOR:Baseline uric acid concentrations. OUTCOMES:Kidney failure (initiation of dialysis therapy or transplantation) and all-cause mortality. RESULTS:During a median follow-up of 7.9 years, 885 participants progressed to kidney failure and 789 participants died. After adjustment for demographic, cardiovascular, and kidney-specific covariates, higher uric acid concentrations were independently associated with risk for kidney failure in participants with estimated glomerular filtration rates (eGFRs) ? 45mL/min/1.73m2 (adjusted HR per 1-standard deviation greater baseline uric acid, 1.40; 95% CI, 1.12-1.75), but not in those with eGFRs<30mL/min/1.73m2. There was a nominally higher HR in participants with eGFRs of 30 to 44mL/min/1.73m2 (adjusted HR, 1.13; 95% CI, 0.99-1.29), but this did not reach statistical significance. The relationship between uric acid concentration and all-cause mortality was J-shaped (P=0.007). LIMITATIONS:Potential residual confounding through unavailable confounders; lack of follow-up measurements to adjust for changes in uric acid concentrations over time. CONCLUSIONS:Uric acid concentration is an independent risk factor for kidney failure in earlier stages of CKD and has a J-shaped relationship with all-cause mortality in CKD. Adequately powered randomized placebo-controlled trials in CKD are needed to test whether urate lowering may prove to be an effective approach to prevent complications and progression of CKD.

Project description:AIMS:To determine the effects of glucagon-like peptide (GLP)-1 receptor agonists (RA) on uric acid (UA) levels and kidney UA clearance. MATERIAL AND METHODS:This study involved post-hoc analyses of 4 controlled clinical trials, which assessed actions of GLP-1RA administration on kidney physiology. The immediate effects of GLP-1RA exenatide infusion vs placebo were determined in 9 healthy overweight men (Study-A) and in 52 overweight T2DM patients (Study-B). The effects of 12 weeks of long-acting GLP-1RA liraglutide vs placebo in 36 overweight T2DM patients (Study-C) and of 8 weeks of short-acting GLP-1RA lixisenatide vs once-daily titrated insulin glulisine in 35 overweight T2DM patients (Study-D) were also examined. Plasma UA, fractional (inulin-corrected) and absolute urinary excretion of UA (UEUA ) and sodium (UENa ), and urine pH were determined. RESULTS:Median baseline plasma UA level was 5.39 to 6.33 mg/dL across all studies (17%-22% of subjects were hyperuricaemic). In Study-A, exenatide infusion slightly increased plasma UA (+0.07 ± 0.02 mg/dL, P = .04), and raised absolute-UEUA (+1.58 ± 0.65 mg/min/1.73 m2 , P = .02), but did not affect fractional UEUA compared to placebo. Fractional UEUA and absolute UEUA correlated with increases in urine pH (r:0.86, P = .003 and r:0.92, P < .001, respectively). Fractional UEUA correlated with increased fractional UENa (r:0.76, P = .02). In Study-B, exenatide infusion did not affect plasma UA, but increased fractional UEUA (+0.76 ± 0.38%, P = .049) and absolute UEUA (+0.75 ± 0.27 mg/min/1.73 m2 , P = .007), compared to placebo. In regression analyses, both parameters were explained by changes in urine pH and, in part, by changes in UENa . In Study-C, liraglutide treatment did not affect plasma UA, UEUA, UENa or urine pH, compared to placebo. In Study-D, lixisenatide treatment increased UENa and urine pH from baseline, but did not affect plasma UA or UEUA . CONCLUSION:Immediate exenatide infusion increases UEUA in overweight healthy men and in T2DM patients, probably by inhibiting Na+ /H+ -exchanger type-3 in the renal proximal tubule. Prolonged treatment with a long-acting or short-acting GLP-1RA does not affect plasma UA or UEUA in T2DM patients with normal plasma UA levels and at relatively low cardiovascular risk. Our results suggest that the cardio-renal benefits of GLP-1RA are not mediated through changes in UA.

Dataset Information

Uric Acid Lowering and Biomarkers of Kidney Damage in CKD Stage 3: A Post Hoc Analysis of a Randomized Clinical Trial.

Publications

Uric Acid Lowering and Biomarkers of Kidney Damage in CKD Stage 3: A Post Hoc Analysis of a Randomized Clinical Trial.

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