Allopurinol Regresses Left Ventricular Hypertrophy in Chronic Kidney Disease

From Medscape Medical News
Allopurinol Regresses Left Ventricular Hypertrophy in Chronic Kidney Disease

Daniel M. Keller, PhD

July 6, 2010 (Munich, Germany) — In a randomized placebo-controlled trial reported here at the XLVII European Renal Association-European Dialysis and Transplant Association Congress, patients with stage 3 chronic kidney disease (CKD) taking high-dose allopurinol experienced regression of left ventricular hypertrophy (LVH) and had an improvement in endothelial function.

Allopurinol is an inhibitor of xanthine oxidase and acts as an antioxidant by preventing the formation of free radicals from the action of the enzyme, noted clinical research fellow Michelle Kao, MBChB, from the University of Dundee in the United Kingdom, said during her presentation of the study findings.

Dr. Kao pointed out that patients with even mild to moderate kidney disease are at greatly elevated risk for cardiac morbidity and mortality, even beyond the traditional risk factors accounted for in the Framingham risk score. "Increasingly, people are beginning to appreciate that oxidative stress plays a major part in this poor overall outcome in patients with advanced renal disease," she said. She told the audience here that studies have indicated that oxidative stress manifests as LVH and endothelial dysfunction.

LVH is common in patients with CKD and is a strong risk factor for cardiovascular disease. One study has shown that the prevalence of LVH in nondiabetic predialysis populations is 51% among patients with stage 1 to 2 CKD and 78% among those with stages 3 to 5 CKD, compared with less than 10% for control subjects (Am J Kidney Dis. 2005;46:320-327).

Another study comparing the highest and lowest quintiles of the left ventricular mass (LVM) index and adjustment for comorbidities found that LVH conferred an independent risk of 2.9 for all-cause mortality and of 2.7 for cardiac mortality (Kidney Int. 1989;36:286-290).

LVM is a strong predictor of cardiovascular events in patients with essential hypertension, and regression of LVH has been shown to greatly increase event-free survival (P = .002) (Circulation. 1998;97:48-54).

Dr. Kao explained that LVH is such a strong cardiac risk factor because it is arrhythmogenic and reduces coronary perfusion reserve, leading to diastolic heart failure, and leading to left atrial dilatation, a precursor of atrial fibrillation and embolic stroke. She said blood pressure reduction correlates well with LVM regression.

Oxidative Stress Stems From Multiple Causes

One source of oxidative stress is the purine degradation pathway, where xanthine oxidase converts hypoxanthine to xanthine, with the release of free radical byproducts in the form of 2 superoxide anions and 2 hydrogen peroxides. Inhibiting the action of xanthine oxidase should block the generation of these free radicals, Dr. Kao said. She reported that xanthine oxidase inhibition has been shown to improve endothelial function in diabetics, smokers, hypercholesterolemic patients, and those with congestive heart failure, but it has never been tested in patients with CKD.

She therefore investigated the effect of high-dose allopurinol on endothelial function and LVH in patients with CKD. Cardiac magnetic resonance imaging was used to measure cardiac mass at baseline and at 9 months. Endothelial function was determined using ultrasound measurement of flow-mediated dilatation (FMD) of the brachial artery after release of artery occlusion with a cuff. The degree of reactive dilatation is an indication of arterial stiffness.

In this randomized double-blind placebo controlled trial, CKD stage 3 patients were randomized to an allopurinol group (n = 27) or a placebo group (n = 26). LVH was determined with echocardiography.

The allopurinol group received 100 mg/day for 2 weeks, which was increased to 300 mg/day if it was well tolerated and there were no adverse effects on kidney function. All baseline characteristics were similar between the 2 groups, except that the allopurinol group had a slightly lower diastolic blood pressure (70 ± 8 vs 75 ± 8 mm Hg; P = .036). Importantly, LVM was well matched, and most patients were already taking an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker.

During her presentation, Dr. Kao told the audience that they "found that those patients on allopurinol had a regression of the LV mass after 9 months [–1.42 ± 4.67 g/m2], compared with progression for those patients in the placebo group [+1.28 ± 4.45 g/m2; P = .036]. We also found a trend toward improvement in the end-diastolic volume for patients on allopurinol."

Endothelial function, as indicated by FMD, improved for the allopurinol group (mean change, +1.26% ± 3.06%), compared with the placebo group (–1.05% ± 2.84%; P = .009). There were positive correlations between the LVM index and changes in the FMD (P = .008), pulse-wave velocity (P = .038), end-diastolic volume (P = .048), and the urinary protein-to-creatinine ratio (P = .0004).

"This suggests to us that perhaps some of these beneficial effects seen on the LV mass index were due to an improvement in the vascular compliance and the LV afterload," she said.

There were no differences between the 2 groups in terms of blood pressure, renal function, or the prevalence of adverse events or serious adverse events (5 in each group). Serum uric acid levels were lower in the allopurinol group (P < .001) but did not correlate with the changes seen in LVM index.

"We found for the first time that allopurinol can regress LVH in man. We also found that allopurinol can improve both endothelial dysfunction and arterial stiffness in patients with CKD," Dr. Kao concluded. She said that whether these effects translate into improvements in hard clinical end points is yet to be tested. She has blood samples to test for markers of oxidative stress to confirm whether the changes seen correlate with the level of oxidative stress.

David Harris, MD, professor of medicine at the University of Sydney in Australia, who was not involved with the study, said that this study has implications for changing clinical practice "because it's the first trial that's shown a reduction in left ventricular mass with allopurinol, [and] I think that's a very important outcome." He said the findings will have to be confirmed in a larger number of patients given the limited sample size in Dr. Kao's study.

"A major predictor of mortality in our patients with kidney disease is left ventricular mass, so if you can get a drug that reduces that then I think it's a very positive outcome," Dr. Harris said. He was cautious about extrapolating the results to other antioxidants, because previous trials have shown very mixed results, citing vitamin E as an example.

However, Dr. Kao told Medscape Medical News that other antioxidants that are specifically inhibitors of xanthine oxidase might offer protection from oxidative stress and thereby reduce LVH. Febuxostat has already shown positive beneficial effects in an animal model of LVH, she said.

The study was funded by the British Heart Foundation. The University of Dundee has submitted a patent application on the use of xanthine oxidase inhibitors to treat anginal chest pain. The study authors have disclosed no relevant financial relationships. Dr. Harris reports has disclosed no relevant financial relationships.

XLVII European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Congress. Presented June 27, 2010.

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