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Allopurinol Benefits Left Ventricular Mass and Endothelial Dysfunction in Chronic Kidney Disease

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Allopurinol Benefits Left Ventricular Mass and Endothelial Dysfunction in Chronic Kidney Disease CLINICAL RESEARCH www.jasn.org Allopurinol Benefits Left Ventricular Mass and Endothelial Dysfunction in Chronic Kidney Disease Michelle P. Kao,* Donald S. Ang,* Stephen J. Gandy,† M. Adnan Nadir,* J. Graeme Houston,† Chim C. Lang,* and Allan D. Struthers* *Division of Medical Sciences and †Department of Radiology, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom ABSTRACT Allopurinol ameliorates endothelial dysfunction and arterial stiffness among patients without chronic kidney disease (CKD), but it is unknown if it has similar effects among patients with CKD. Furthermore, because arterial stiffness increases left ventricular afterload, any allopurinol-induced improvement in arterial compliance might also regress left ventricular hypertrophy (LVH). We conducted a randomized, double-blind, placebo-controlled, parallel-group study in patients with stage 3 CKD and LVH. We randomly assigned 67 subjects to allopurinol at 300 mg/d or placebo for 9 months; 53 patients completed the study. We measured left ventricular mass index (LVMI) with cardiac magnetic resonance imaging (MRI), assessed endothelial function by flow-mediated dilation (FMD) of the brachial artery, and evaluated central arterial stiffness by pulse-wave analysis. Allopurinol significantly reduced LVH (P ϭ 0.036), improved endothelial function (P ϭ 0.009), and improved the central augmentation index (P ϭ 0.015). This study demonstrates that allopurinol can regress left ventricular mass and improve endothe- lial function among patients with CKD. Because LVH and endothelial dysfunction associate with prog- nosis, these results call for further trials to examine whether allopurinol reduces cardiovascular events in patients with CKD and LVH. J Am Soc Nephrol 22: 1382–1389, 2011. doi: 10.1681/ASN.2010111185 Patients with chronic kidney disease (CKD) have might imply fewer atherothrombotic events in approximately 20 times the mortality risk of the the future. general population, and they mainly die from car- However, another major adverse cardiovascular diovascular-related deaths.1 However treatments consequence of CKD is left ventricular hypertrophy that reduce cardiovascular events in non-CKD pa- (LVH). LVH is highly prevalent in CKD8,9 and is a tients do not always do so in CKD; for example, well known independent predictor of cardiovascu- statins alone do not always reduce cardiovascular lar mortality. Indeed after age, LVH is claimed to be events in severe CKD.2–4 This implies that one can- the strongest independent predictor of cardiovas- not necessarily extrapolate clinical trial results from cular events, cardiovascular death, and total mor- non-CKD patients to CKD patients and that highly novel approaches might be required to reduce car- diovascular events in CKD patients. Received November 19, 2010. Accepted March 10, 2011. In non-CKD patients, allopurinol has consis- Published online ahead of print. Publication date available at tently been found to improve endothelial/vascu- www.jasn.org. lar function and arterial wave reflection.5–7 How- Correspondence: Dr. Michelle Kao, Centre for Cardiovascular and Lung Biology, Division of Medical Sciences, Ninewells Hos- ever, no data exist as to whether it does the same pital and Medical School, Dundee DD1 9SY, United Kingdom. in CKD patients. Our first aim was therefore to Phone: ϩ44[0-1382-496440; Fax: ϩ44-0-1382-644972; e-mail: see if allopurinol improved endothelial/vascular [email protected] function in CKD patients because such an effect Copyright © 2011 by the American Society of Nephrology 1382 ISSN : 1046-6673/2207-1382 J Am Soc Nephrol 22: 1382–1389, 2011 www.jasn.org CLINICAL RESEARCH tality.10 Conversely, LVH regression has Table 1. Baseline characteristics been shown to deliver prognostic benefit Allopurinol at P (26 ؍ Characteristic Placebo (n (27 ؍ independent of BP changes.11,12 Therefore, 300 mg (n novel ways to regress LVH independent of Gender BP could be a promising way to reduce car- Male (%) 16 (59%) 12 (46%) 0.139 diovascular events/mortality in CKD. Allo- Age, years 70.6 Ϯ 6.9 73.7 Ϯ 5.3 0.070 purinol could be such a novel therapy Body surface area, g/m2 1.90 Ϯ 0.17 1.91 Ϯ 0.23 0.954 against LVH. Blood pressure, mmHg In fact, there are two good reasons to SBP 139 Ϯ 14 145 Ϯ 18 0.164 a think that allopurinol might reduce LVH. DBP 70 Ϯ 875Ϯ 8 0.036 The first reason is that left ventricular after- Causes of CKD load is the main determinant of left ventric- glomerulonephritis 4 5 diabetic nephropathy 5 1 ular mass; hence, treatments that reduce vascular/hypertension 11 12 left ventricular afterload by improving ar- chronic pyelonephritis 0 2 terial compliance and arterial wave reflec- others 2 1 tion might also reduce LVH (even if they do unknown 5 7 not reduce BP itself). Thus, if allopurinol Estimated GFR, ml/min per 1.73 m2 44 Ϯ 11 46 Ϯ 9 0.427 does improve endothelial function and/or Uric acid, mmol/L 0.44 Ϯ 0.09 0.42 Ϯ 0.08 0.575 arterial wave reflection in CKD, then in Hemoglobin, g/dl 13.1 Ϯ 1.1 13.4 Ϯ 1.5 0.375 theory it might also regress LVH. The sec- Glucose, mmol/L 6.4 Ϯ 3.5 5.3 Ϯ 0.8 0.121 ond reason for thinking this might be the UPCR, mg/mmol 49.0 Ϯ 115.5 26.1 Ϯ 30.5 0.333 Ϯ Ϯ case is that allopurinol does indeed regress Calcium, mmol/L 2.37 0.10 2.35 0.84 0.526 Ϯ Ϯ LVH in two different animal models.13,14 Phosphate, mmol/L 1.17 0.15 1.11 0.18 0.218 Parathyroid hormone, pmol/L 8.39 Ϯ 4.63 8.33 Ϯ 5.17 0.961 Therefore, in this study our main aim Total cholesterol, mmol/L 4.22 Ϯ 0.81 4.45 Ϯ 1.13 0.393 was to see if allopurinol, a xanthine oxidase BNP, pg/ml 161 Ϯ 250 171 Ϯ 236 0.884 (XO) inhibitor, is able to regress left ven- Cystatin C, ng/ml 1676 Ϯ 558 1508 Ϯ 406 0.216 tricular mass because no human data exist Oxidized LDL 30.85 Ϯ 8.67 31.26 Ϯ 9.03 0.867 yet for any population that show that allo- Smoking status purinol can reduce LVH. Our other aim nonsmoker 16 15 0.118 was to see if allopurinol reduces endothelial active 4 3 dysfunction in patients with CKD. ex-smoker 7 7 ACEI/ARB (%) 21 (78%) 18 (69%) 0.192 Diuretics (%) 12 (44%) 12 (46%) 0.215 RESULTS Calcium channel blocker (%) 13 (48%) 17 (65%) 0.101 Beta-blocker (%) 13 (48%) 12 (46%) 0.214 Statin 21 (78%) 20 (77%) 0.255 A total of 67 Caucasian patients who met LVMI, g/m2 (MRI) 61.6 Ϯ 13.7 62.1 Ϯ 15.4 0.900 the criteria were included for the study, and EDV, ml 124.9 Ϯ 30.1 119.8 Ϯ 34.4 0.564 53 (allopurinol, n ϭ 27; placebo, n ϭ 26) FMD, % 5.02 Ϯ 1.91 4.93 Ϯ 2.50 0.885 completed the study. There were no signif- AIx, % 18.5 Ϯ 10.2 17.2 Ϯ 6.3 0.585 icant differences between both groups with PWV, m/s 7.7 Ϯ 1.3 8.2 Ϯ 1.2 0.194 respect to demographic or baseline charac- ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker. a teristics, apart from the diastolic BP (DBP). P Ͻ 0.05. Mean left ventricular mass, estimated GFR, and uric acid level were also similar at baseline. Patient dispo- Ϫ1.42 Ϯ 4.67 g/m2 compared with the placebo at ϩ1.28 Ϯ 4.45 sition is summarized in Table 1. g/m2 [P ϭ 0.036], Figure 2). After correction for demographic Fourteen patients withdrew during the course of the study factors that should most influence LVMI changes (age, systolic for various reasons as set out in Figure 1. The three patients BP [SBP], DBP, and baseline LVMI), the result was little al- who withdrew because of rash and arthralgia on allopurinol tered and remained significant (P ϭ 0.030). The end-diastolic developed these symptoms when the dose was increased to 300 volume (EDV) also showed a corresponding fall in volume in mg once per day. Apart from these three subjects, the withdraw- the allopurinol group, although it did not reach statistical sig- als were unrelated to the therapy and had more to do with the nificance, whereby EDV change was Ϫ9.64 Ϯ 16.10 ml with study demands, such as MRI (claustrophobia), the lengthy na- allopurinol compared with placebo at Ϫ1.65 Ϯ 16.88 ml (P ϭ ture of the trial, and the complex end point measurements. 0.084). End-systolic volume and ejection fraction (EF) did not Treatment with allopurinol resulted in a decrease in left change with treatment of allopurinol. ventricular mass index (LVMI) (⌬LVMI in active group Baseline flow-mediated dilation (FMD) was found to be J Am Soc Nephrol 22: 1382–1389, 2011 Allopurinol and CV Effects in CKD 1383 CLINICAL RESEARCH www.jasn.org There was no difference in response to glyc- eryl trinitrate between both treatment arms (Table 2). These results imply that allopuri- nol’s vascular effect was endothelial depen- dent and not endothelial independent to any extent. Similarly, treatment with allopurinol also improved the augmentation index (AIx), with a marked difference seen at month 9 (Table 2 and Figure 4). AIx wors- ened significantly at month 6 in the placebo group, and this effect was negated by allo- purinol. As for pulse wave velocity (PWV), although no difference was noted at month 6, a trend toward improvement on allo- purinol was seen at month 9 (Table 2).
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