We thank Drs. Knowles and Reaven for their insightful letter (1), which meaningfully adds to the debate regarding uric acid as a biomarker of risk of or causal factor for cardiovascular disease. Here are a few additional observations to add to this discussion.
The existing body of scientific literature suggests that uric acid is not causal in the pathogenesis of diabetes. This is evident not only in Mendelian randomization studies (2) but also in how uric acid is generated in the body. Uric acid is a product of glucose metabolism via the pentose phosphate shunt pathway. As a result, factors that contribute to the pathogenesis of diabetes also contribute to elevations in uric acid, such as excess intracellular glucose (3) or dietary choices that increase glycolysis (4). Despite this, the epidemiologic literature has shown uric acid to be a strong marker of the risk of diabetes. Uric acid concentration is typically elevated before diabetes is diagnosed, sometimes even before elevations in serum glucose levels are observed (5–7). Our study further demonstrated that despite being elevated before a diabetes diagnosis, uric acid concentrations decline in persons with diabetes over time independently of serum measures of kidney function, insulin, or glucose (8).
The role of uric acid as a causal factor in the pathogenesis of cardiovascular disease is more controversial. As pointed out by Knowles and Reaven, Mendelian randomization studies provide evidence that uric acid is not a cause of elevated blood pressure, elevated fasting glucose levels, chronic kidney disease, or coronary heart disease (9). However, there is substantial evidence from animal models that hyperuricemia may increase blood pressure (10) and contribute to chronic kidney disease in the form of crystal deposition (11), renin-angiotensin interference (12), or glomerular injury (13). Furthermore, several randomized, controlled trials of urate-lowering therapy demonstrated that reductions in uric acid may lower blood pressure (14–16) and even improve kidney function (16–19). Given these contradictory data, whether uric acid reduction has direct effects on cardiovascular risk remains unknown.
Our study highlights the challenge of studying individual components of complex metabolic states with constituents that evolve and interact over time. Unlike environmental or infectious agents, which may be individually sufficient and necessary to cause disease (20), biomarkers are rarely aberrant without influencing multiple other biomarkers and organs. With better understanding of these interactions, future studies will be able to account for the complex relationship of diabetes and uric acid in analytic models and/or in the selection of their study populations.
Acknowledgments
Conflict of interest: none declared.
References
- 1.Knowles JW, Reaven G. RE: “Temporal relationship between uric acid concentration and risk of diabetes in a community-based study population” [letter] Am J Epidemiol. 2014 doi: 10.1093/aje/kwu055. 179(9):1147–1148. [DOI] [PubMed] [Google Scholar]
- 2.Pfister R, Barnes D, Luben R, et al. No evidence for a causal link between uric acid and type 2 diabetes: a Mendelian randomisation approach. Diabetologia. 2011;54(10):2561–2569. doi: 10.1007/s00125-011-2235-0. [DOI] [PubMed] [Google Scholar]
- 3.Howell RR. The interrelationship of glycogen storage disease and gout. Arthritis Rheum. 1965;8(5):780–785. doi: 10.1002/art.1780080441. [DOI] [PubMed] [Google Scholar]
- 4.Stirpe F, Della Corte E, Bonetti E, et al. Fructose-induced hyperuricaemia. Lancet. 1970;2(7686):1310–1311. doi: 10.1016/s0140-6736(70)92269-5. [DOI] [PubMed] [Google Scholar]
- 5.Kodama S, Saito K, Yachi Y, et al. Association between serum uric acid and development of type 2 diabetes. Diabetes Care. 2009;32(9):1737–1742. doi: 10.2337/dc09-0288. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Bhole V, Choi JWJ, Kim SW, et al. Serum uric acid levels and the risk of type 2 diabetes: a prospective study. Am J Med. 2010;123(10):957–961. doi: 10.1016/j.amjmed.2010.03.027. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Herman JB, Goldbourt U. Uric acid and diabetes: observations in a population study. Lancet. 1982;2(8292):240–243. doi: 10.1016/s0140-6736(82)90324-5. [DOI] [PubMed] [Google Scholar]
- 8.Juraschek SP, McAdams-Demarco M, Miller ER, et al. Temporal relationship between uric acid concentration and risk of diabetes in a community-based study population. Am J Epidemiol. 2014;179(6):684–691. doi: 10.1093/aje/kwt320. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Yang Q, Köttgen A, Dehghan A, et al. Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. Circ Cardiovasc Genet. 2010;3(6):523–530. doi: 10.1161/CIRCGENETICS.109.934455. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Mazzali M, Hughes J, Kim YG, et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension. 2001;38(5):1101–1106. doi: 10.1161/hy1101.092839. [DOI] [PubMed] [Google Scholar]
- 11.Gonick HC, Rubini ME, Gleason IO, et al. The renal lesion in gout. Ann Intern Med. 1965;62:667–674. doi: 10.7326/0003-4819-62-4-667. [DOI] [PubMed] [Google Scholar]
- 12.Mazzali M, Kanellis J, Han L, et al. Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism. Am J Physiol Renal Physiol. 2002;282(6):F991–F997. doi: 10.1152/ajprenal.00283.2001. [DOI] [PubMed] [Google Scholar]
- 13.Nakagawa T, Mazzali M, Kang DH, et al. Hyperuricemia causes glomerular hypertrophy in the rat. Am J Nephrol. 2003;23(1):2–7. doi: 10.1159/000066303. [DOI] [PubMed] [Google Scholar]
- 14.Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA. 2008;300(8):924–932. doi: 10.1001/jama.300.8.924. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Assadi F. Allopurinol enhances the blood pressure lowering effect of enalapril in children with hyperuricemic essential hypertension. J Nephrol. 2014;27(1):51–56. doi: 10.1007/s40620-013-0009-0. [DOI] [PubMed] [Google Scholar]
- 16.Siu Y-P, Leung K-T, Tong MK-H, et al. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis. 2006;47(1):51–59. doi: 10.1053/j.ajkd.2005.10.006. [DOI] [PubMed] [Google Scholar]
- 17.Goicoechea M, de Vinuesa SG, Verdalles U, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol. 2010;5(8):1388–1393. doi: 10.2215/CJN.01580210. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Momeni A, Shahidi S, Seirafian S, et al. Effect of allopurinol in decreasing proteinuria in type 2 diabetic patients. Iran J Kidney Dis. 2010;4(2):128–132. [PubMed] [Google Scholar]
- 19.Gibson T, Rodgers V, Potter C, et al. Allopurinol treatment and its effect on renal function in gout: a controlled study. Ann Rheum Dis. 1982;41(1):59–65. doi: 10.1136/ard.41.1.59. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Parascandola M, Weed DL. Causation in epidemiology. J Epidemiol Community Health. 2001;55(12):905–912. doi: 10.1136/jech.55.12.905. [DOI] [PMC free article] [PubMed] [Google Scholar]