Allopurinol reduces left ventricular hypertrophy and endothelial dysfunction in patients with chronic kidney disease

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1 Allopurinol reduces left ventricular hypertrophy and endothelial dysfunction in patients with chronic kidney disease Michelle P Kao, Donald S Ang, Steve Gandy, Chim C Lang, Allan D Struthers Division of Medical Sciences and Dept of Radiology, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK

2 Declaration No conflict of interest

3 CKD and the risk of death, cardiovascular events and hospitalization Go et al. NEJM 2004, 351:

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6 Pathological manifestation of oxidative stress Left ventricular hypertrophy (LVH) Endothelial dysfunction

7 Left Ventricular Hypertrophy in Nondiabetic Predialysis CKD Paoletti et al. AJKD 2005, 46(2): 320-7

8 Impact of left ventricular hypertrophy on survival in end-stage renal disease. Siberberg et al. Kidney Int Aug;36(2):

9 Prognostic significance of serial changes in LV mass in patients with essential hypertension Verdecchia: Circulation, Volume 97(1).January 6/13,

10 How do we regress LVH? Achieving lower than conventional BP levels ACE-inhibitors/ ARB Aldosterone antagonist (4E study) Reduce oxidative stress?

11 Strategies to reduce oxidative stress in cardiovascular disease Carlene et al. Clinical Science (2004) 106, ( )

12 Uric acid and XO

13 Xanthine oxidase inhibitor XOI improve endothelial function in Diabetics (Butler et al 2000), Smokers (Guthikonda et al 2003), CAD patients (Cardillo et al 1997), CHF (Farquharson et al 2002) Never been assessed in CKD patients

14 High-Dose Allopurinol Improves Endothelial Function by Profoundly Reducing Vascular Oxidative Stress and Not by Lowering Uric Acid George J et al. Circulation. 2006;114: Copyright 2006 American Heart Association

15 Summary of evidences so far LVH is highly prevalent in CKD Oxidative stress promotes LVH and endothelial dysfunction Allopurinol is an alternative way to reduce oxidative stress

16 Do Xanthine Oxidase Inhibitors reduce both Left Ventricular Hypertrophy and Vascular Dysfunction in Cardiovascular Patients with Renal Dysfunction? ISRCTN

17 Primary Endpoint: Does Allopurinol reduce left ventricular hypertrophy in cardiovascular patients with renal dysfunction? Cardiac MRI

18 Secondary endpoint: Does Allopurinol reduce endothelial dysfunction in cardiovascular patients with renal dysfunction? Flow-mediated dilatation (FMD)

19 Augmentation Index and Pulse wave velocity Applanation tonometry

20 Methods Randomised, double-blinded, placebo-controlled trial N = 60 (30 patients in each parallel arm) Inclusion criteria: CKD Stage 3 patients Echo LVH (based on the ASE criteria) Allopurinol 100 mg/day increased to allopurinol 300mg/day, versus placebo. Follow-up period: 9 months

21 Results: basic characteristics Allopurinol 300 mg (n=27) Placebo (n=26) P value Gender, Male (%) 16 (59%) 12 (46%) Age, years 70.6 ± ± Body surface area (BSA), g/m ± ± Systolic, SBP 139 ± ± Diastolic, DBP 70 ± 8 75 ± * egfr, ml/min/1.73m2 44 ± ± Uric acid, mmol/l 0.44 ± ± Haemoglobin, g/dl 13.1 ± ± Glucose, mmol/l 6.4 ± ± UPCR, mg/mmol/24hours 490 ± ± Calcium, mmol/l 2.37 ± ± Phosphate, mmol/l 1.17 ± ± PTH, pmol/l 8.39 ± ± Total cholesterol, mmol/l 4.22 ± ± BNP, pg/ml 161 ± ± Cystatin C, ng/ml 1676 ± ± ACE/ARB use (%) 21 (78%) 18 (69%) LV mass index, g/m ± ± FMD, % 5.02 ± ± AIx, % 18.5 ± ± PWV, m/s 7.7 ± ±

22 Reasons for withdrawal Allopurinol (n = 5) Placebo (n = 9) Claustrophobia to MRI. 2 2 Withdrew participation, prior to any investigations/treatment. 0 2 Rash. 2 0 Arthralgia 1 1 Other reasons 0 3 Death (rupture of known abdominal aortic aneurysm) 0 1

23 Allopurinol Placebo P value Change in LVMI at 9 months (g/m2) (± 4.67) (±4.45) 0.036* End Diastolic Volume (ml) (±16.10) (±16.88) 0.084

24 Allopurinol Placebo P value Change in FMD at 6 months (%) Change in FMD at 9 months (%) (±2.95) (±3.06) (±2.84) (±2.84)

25 Allopurinol Placebo P value Change in AIx at 6 months (%) Change in AIx at 9 months (%) (±7.19) (±9.30) (±5.37) (±6.06) 0.048* 0.015* Change in PWV at 9 months (m/s) (±1.13) (±1.28) 0.086

26 Results: correlation with LVMI Change in LVMI Change in FMD R = P = Change in AIx R = P = Change in PWV R = P = 0.038* Change in EDV R = P = 0.048* Change in UPCR R = P =

27 Results - exit characteristics Allopurinol 300 mg (n=27) Placebo (n=26) P value Blood pressure, mmhg Systolic, SBP Diastolic, DBP -6.9 ± ± ± ± egfr, ml/min/1.73m2) +0.2 ± ± Uric acid, mmol/l ± ± 0.06 <0.001* UPCR, mg/mmol/24hours -214 ± ± Cystatin C, ng/ml +71 ± ± Medications change Antihypertensives commenced (%) Antihypertensives stopped (%) 2 (7%) 5 (18%) 5 (19%) 2 (8%) AE/SAE (%) 5 (17%) 5 (19%) 0.258

28 Conclusions Allopurinol can regress LVH in man Allopurinol can improve both endothelial dysfunction and arterial stiffness in patients with CKD Future studies