In their Clinical review article(1) Gutiérrez-Macías et al. state that ”....high urate concentrations do not seem to cause cardiovascular disease, as was previously thought.” However, recent evidence support the contrary conclusion—that hyperuricemia directly contributes to cardiovascular or renal disease.
Although hyperuricemia is associated with a number of cardiovascular or renal risk factors, a substantial body of epidemiological evidence suggests that serum uric acid is an important, independent risk factor for cardiovascular and renal disease. (2-4) This is consistent with findings that endogenous uric acid concentrations correlate with endothelial dysfunction(5) and that exogenous uric acid causes endothelial dysfunction when infused into the human brachial artery.(6) In addition, hyperuricemia is also associated with deleterious effects on oxidative metabolism, platelet adhesiveness, hemorheology, and aggregation.
Most importantly, rats with mild experimentally-induced hyperuricemia develop intrarenal vascular disease with increased renin expression, systemic and glomerular hypertension, and renal injury in the absence of intrarenal crystal deposition. (7,8) Although these effects could be blocked by enalapril and losartan, losartan's effect could be mediated in part by its known uricosuric action, because uric acid levels tended to be lower in the losartan-treated rats.
Interestingly, recent study showed that one third of cardiovascular benefit of losartan- versus atenolol-based therapy on the primary composite endpoint (death, myocardial infarction, or stroke) may be related to differences in achieved serum uric acid levels.(9) These study findings contribute to mounting evidence that lowering uric acid can improve renal function in patients with either minimal or moderate renal disease.(10,11) Of importance, early treatment with allopurinol may slow or prevent the progression of kidney disease also in patients with hyperuricemia and renal impairment but without gout.(12,13)
Allopurinol has also been reported to reduce cardiovascular complications after coronary artery bypass (14) and in patients with dilated cardiomyopathy.(15) Moreover, long term high dose allopurinol was associated with a better mortality than long term low dose in patients with congestive heart failure(CHF).(16) Consistent with these findings, allopurinol improves peripheral vasodilator capacity and blood flow both locally and systemically in hyperuricemic CHF patients.(17)
Taken together, the data mentioned above obviously raise the possibility that treatment-induced decrease in serum uric acid may indeed attenuate the risk of cardiovascular and renal complications. These assumption has prompted initiation of a randomized, double-blind, placebo -controlled clinical trial (OxyPurinol Therapy for CHF) initiated in 2003.(18) It should be noted, however, that some of the beneficial effects of allopurinol may also be related to inhibition of xanthine oxidase, which is one of the main producers of superoxide anions, which are well known to inactivate endogenous nitric oxide.
1. Gutierrez-Macias A, Lizarralde-Palacios E, Martinez-Odriozola P, Miguel-De la Villa F. Fatal allopurinol hypersensitivity syndrome after treatment of asymptomatic hyperuricaemia. BMJ 2005;331:623-624.
2. Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S, et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 2003;41:1183-1190.
3. Wang JG, Staessen JA, Fagard RH, Birkenhager WH, Gong L, Liu L. Prognostic significance of serum creatinine and uric acid in older Chinese patients with isolated systolic hypertension. Hypertension 2001;37:1069–1074.
4. Gerhardt U, Grobe Huttman M, Hohage H. Influence of hyperglycemia and hyperuricemia on long-term transplant survival in kidney transplant patients. Clin Transplantation1999;13:375–379.
5. Britten MB, Elsner M, Walter DH, Schachinger V. Elevated uric acid levels in hypercholesterolaemia are associated with coronary endothelial dysfunction [abstract]. Circulation 1999;100(Suppl):I–6.
6. Waring WS, Webb DJ, Maxwell SRJ. Effect of local hyperuricaemia on endothelial function in the human forearm vascular bed. Br J Clin Pharmacol 2000;49:511P.
7. Wu X, Wakamiya M, Vaishnav S, Geske R, Montgomery C Jr, Jones P, Bradley A, Caskey CT: Hyperuricemia and urate nephropathy in urate oxidase -deficient mice. Proc Natl Acad Sci U S A 1994;91:742-746.
8. Mazzali, M, Hughes J, Kim YG, Jefferson J, Kang DH, Gordon KL, et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension 2001;38:1101-1106.
9. Hoieggen A, Alderman MH, Kjeldsen SE, Julius S, Devereux RB, De Faire U, et al. LIFE Study Group. The impact of serum uric acid on cardiovascular outcomes in the LIFE study. Kidney Int 2004;65:1041-1049.
10. Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, Herrero-Beites A, Garcia -Erauskin G, Ruiz-Lucca E. Efficacy of allopurinol and benzbromarone for the control of hyperuricemia: a pathogenic approach to the treatment of primary chronic gout. Ann Rheum Dis 1998;57:545–549.
11. Perez-Ruiz F, Calabozo M, Fernandez-Lopez MJ, Herrero-Beites A, Ruiz-Lucea E, Garcia-Erasukin G, et al. Treatment of chronic gout in patients with renal function impairment: an open, randomized actively controlled study. J Clin Rheumatol 1999;5:49–55.
12. Neal DA, Tom BD, Gimson AE, Gibbs P, Alexander GJ. Hyperuricemia, gout, and renal function after liver transplantation. Transplantation 2001;72:1689-1691.
13. Fairbanks LD, Cameron JS, Venkat-Raman G, Rigden SP, Rees L, Van'T Hoff W, et al. Early treatment with allopurinol in familial juvenile hyerpuricaemic nephropathy (FJHN) ameliorates the long-term progression of renal disease. QJM 2002;95:597-607
14. Johnson WD, Kayser KL, Brenowitz JB, Saedi SF. A randomized controlled trial of allopurinol in coronary bypass surgery. Am Heart J 1991;121:20–24.
15. Cappola TP, Kass DA, Nelson GS, Berger RD, Rosas GO, Kobeissi ZA, et al. Allopurinol improves myocardial efficiency in patients with idiopathic dilated cardiomyopathy. Circulation 2001;104: 2407–2411.
16. Struthers AD, Donnan PT, Lindsay P, McNaughton D, Broomhall J, MacDonald TM. Effect of allopurinol on mortality and hospitalisations in chronic heart failure: a retrospective cohort study. Heart 2002;87:229- 234.
17. Doehner W, Anker SD. Xanthine oxidase inhibition for chronic heart failure: is allopurinol the next therapeutic advance in heart failure? Heart 2005;91:707-709.
18. Hare JM, Johnson RJ. Uric acid predicts clinical outcomes in heart failure: insights regarding the role of xanthine oxidase and uric acid in disease pathophysiology. Circulation 2003;107:1951-1953
About the author:
Dr. Michal R. Pijak is a consultant in rheumatology, allergy and clinical immunology at the University Hospital in Bratislava, Slovakia.
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