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      Allopurinol Is an Independent Determinant of Improved Arterial Stiffness in Chronic Kidney Disease: A Cross-Sectional Study

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          Abstract

          Background

          Arterial stiffness is increased in patients with CKD and is a powerful predictor of cardiovascular morbidity and mortality. Use of the xanthine oxidase inhibitor allopurinol has been shown to improve endothelial function, reduce left ventricular hypertrophy and possibly improve cardiovascular outcome. We explored the relationship between use of allopurinol and arterial stiffness in patients with chronic kidney disease (CKD).

          Methods

          Cross-sectional observational study of 422 patients with CKD with evidence of, or at high risk of, renal disease progression. Arterial stiffness was determined by carotid-femoral pulse wave velocity (PWV).

          Results

          The mean age was 63±16 years, median estimated glomerular filtration rate was 25 (interquartile range: 19–31) ml/min/1.73 m 2 and mean PWV was 10.2±2.4 m/s. Seventy-seven patients (18%) were receiving regular allopurinol, 61% at a dose of 100 mg/day (range: 50–400 mg/day). Patients receiving allopurinol had significantly lower peripheral pulse pressure, central pulse pressure, central systolic blood pressure, serum uric acid level tissue advanced glycation end product levels but comparable high-sensitivity C-reactive protein levels. Use of allopurinol was associated with lower PWV. After adjusting for age, gender, ethnicity, tissue advanced glycation end product level, peripheral pulse pressure, smoking pack years, presence of diabetes mellitus and use of angiotensin converting enzyme inhibitor or angiotensin II receptor blocker, the use of allopurinol remained a significant independent determinant of PWV (mean difference: −0.63 m/s; 95% CI, −0.09 to −1.17 m/s, p = 0.02).

          Conclusion

          In patients with CKD, use of allopurinol is independently associated with lower arterial stiffness. This study provides further justification for a large definitive randomised controlled trial examining the therapeutic potential of allopurinol to reduce cardiovascular risk in people with CKD.

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          Most cited references39

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          Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study.

          B Culleton, M Larson, W Kannel … (1999)
          Hyperuricemia is associated with risk for cardiovascular disease and death. However, the role of uric acid independent of established risk factors is uncertain. To examine the relation of serum uric acid level to incident coronary heart disease, death from cardiovascular disease, and death from all causes. Community-based, prospective observational study. Framingham, Massachusetts. 6763 Framingham Heart Study participants (mean age, 47 years). Serum uricacid level at baseline (1971 to 1976); event rates per 1000 person-years by sex-specific uric acid quintile. During 117,376 person-years of follow-up, 617 coronary heart disease events, 429 cardiovascular disease deaths, and 1460 deaths from all causes occurred. In men, after adjustment for age, elevated serum uric acid level was not associated with increased risk for an adverse outcome. In women, after adjustment for age, uric acid level was predictive of coronary heart disease (P = 0.002), death from cardiovascular disease (P = 0.009), and death from all causes (P = 0.03). After additional adjustment for cardiovascular disease risk factors, uric acid level was no longer associated with coronary heart disease, death from cardiovascular disease, or death from all causes. In a stepwise Cox model, diuretic use was identified as the covariate responsible for rendering serum uric acid a statistically nonsignificant predictor of outcomes. These findings indicate that uric acid does not have a causal role in the development of coronary heart disease, death from cardiovascular disease, or death from all causes. Any apparent association with these outcomes is probably due to the association of uric acid level with other risk factors.
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            Effect of allopurinol in chronic kidney disease progression and cardiovascular risk.

            Marian Goicoechea, Soledad García de Vinuesa, Ursula Verdalles … (2010)
            Hyperuricemia is associated with hypertension, inflammation, renal disease progression, and cardiovascular disease. However, no data are available regarding the effect of allopurinol in patients with chronic kidney disease. We conducted a prospective, randomized trial of 113 patients with estimated GFR (eGFR) <60 ml/min. Patients were randomly assigned to treatment with allopurinol 100 mg/d (n = 57) or to continue the usual therapy (n = 56). Clinical, biochemical, and inflammatory parameters were measured at baseline and at 6, 12, and 24 months of treatment. The objectives of study were: (1) renal disease progression; (2) cardiovascular events; and (3) hospitalizations of any causes. Serum uric acid and C-reactive protein levels were significantly decreased in subjects treated with allopurinol. In the control group, eGFR decreased 3.3 +/- 1.2 ml/min per 1.73 m(2), and in the allopurinol group, eGFR increased 1.3 +/- 1.3 ml/min per 1.73 m(2) after 24 months. Allopurinol treatment slowed down renal disease progression independently of age, gender, diabetes, C-reactive protein, albuminuria, and renin-angiotensin system blockers use. After a mean follow-up time of 23.4 +/- 7.8 months, 22 patients suffered a cardiovascular event. Diabetes mellitus, previous coronary heart disease, and C-reactive protein levels increased cardiovascular risk. Allopurinol treatment reduces risk of cardiovascular events in 71% compared with standard therapy. Allopurinol decreases C-reactive protein and slows down the progression of renal disease in patients with chronic kidney disease. In addition, allopurinol reduces cardiovascular and hospitalization risk in these subjects.
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              The influence of heart rate on augmentation index and central arterial pressure in humans.

              I Wilkinson, H MacCallum, L. Flint … (2000)
              Arterial stiffness is an important determinant of cardiovascular risk. Augmentation index (AIx) is a measure of systemic arterial stiffness derived from the ascending aortic pressure waveform. The aim of the present study was to assess the effect of heart rate on AIx. We elected to use cardiac pacing rather than chronotropic drugs to minimize confounding effects on the systemic circulation and myocardial contractility. Twenty-two subjects (13 male) with a mean age of 63 years and permanent cardiac pacemakers in situ were studied. Pulse wave analysis was used to determine central arterial pressure waveforms, non-invasively, during incremental pacing (from 60 to 110 beats min-1), from which AIx and central blood pressure were calculated. Peripheral blood pressure was recorded non-invasively from the brachial artery. There was a significant, inverse, linear relationship between AIx and heart rate (r = -0.76; P < 0.001). For a 10 beats min-1 increment, AIx fell by around 4 %. Ejection duration and heart rate were also inversely related (r = -0. 51; P < 0.001). Peripheral systolic, diastolic and mean arterial pressure increased significantly during incremental pacing. Although central diastolic pressure increased significantly with pacing, central systolic pressure did not. There was a significant increase in the ratio of peripheral to central pulse pressure (P < 0.001), which was accounted for by the observed change in central pressure augmentation. These results demonstrate an inverse, linear relationship between AIx and heart rate. This is likely to be due to alterations in the timing of the reflected pressure wave, produced by changes in the absolute duration of systole. Consideration of wave reflection and aortic pressure augmentation may explain the lack of rise in central systolic pressure during incremental pacing despite an increase in peripheral pressure.
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                Author and article information

                Contributors
                Jose Vina: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2014
                Publication date (Electronic): 14 March 2014
                Volume: 9
                Issue: 3
                Electronic Location Identifier: e91961
                Affiliations
                [1 ]Department of Renal Medicine, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
                [2 ]School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom
                University of Valencia, Spain
                Author notes

                Competing Interests: The authors have read the journal's policy and have the following conflicts: PC has received an honorarium for a lecture and research funding for investigator led studies from the Binding Site. CJF has received lecture fees and advisory board fees from Genzyme Corp. The other authors have declared no competing interests exist. This does not alter their adherence to PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: SJS MD CJF PC. Performed the experiments: KPN SJS MDJ PY RA MD. Analyzed the data: KPN CJF PC. Wrote the paper: KPN CJF PC.

                Article
                Publisher ID: PONE-D-13-45650
                DOI: 10.1371/journal.pone.0091961
                PMC ID: 3954864
                PubMed ID: 24632580
                SO-VID: 360ce5a6-672b-42c9-b147-4cd04675efee
                Copyright statement: Copyright @ 2014
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 25 October 2013
                Date accepted : 17 February 2014
                Page count
                Pages: 8
                Funding
                The study is supported by JABBS foundation (Birmingham, United Kingdom) (URL: http://opencharities.org/charities/1128402), University Hospital Birmingham Charities (URL: http://qehb.org/) and the British Renal Society (URL: http://www.britishrenal.org/). CJF is supported through a National Institute for Health Research Fellowship (URL: http://www.nihrtcc.nhs.uk/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Cardiovascular Anatomy
                Subject: Medicine and Health Sciences
                Subject: Cardiology
                Subject: Cardiovascular Pharmacology
                Subject: Clinical Medicine
                Subject: Hematology
                Subject: Hemodynamics
                Subject: Nephrology
                Subject: Chronic Kidney Disease
                Subject: Vascular Medicine
                Subject: Blood Pressure
                Subject: Hypertension
                Subject: Aortic Diseases
                Subject: Research and Analysis Methods
                Subject: Research Design
                Subject: Clinical Research Design
                Subject: Cross-Sectional Studies
                Subject: Observational Studies

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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