Uric Acid in Hypertension and Renal Disease: The Chicken or the EggKanbay M.a · Solak Y.b · Dogan E.c · Lanaspa M.A.d · Covic A.e
aDepartment of Medicine, Division of Nephrology, Gulhane School of Medicine, Ankara, bDepartment of Medicine, Division of Nephrology, Selcuk University, Meram School of Medicine, Konya, and cDepartment of Medicine, Division of Nephrology, Sutcu Imam University School of Medicine, Kahramanmaras, Turkey; dDivision of Renal Diseases and Hypertension, University of Colorado-Denver, Denver, Colo., USA; eNephrology Clinic, Dialysis and Renal Transplant Center, ‘C.I. Parhon’ University Hospital, ‘Gr. T. Popa’ University of Medicine and Pharmacy, Iasi, Romania
Mehmet Kanbay, MD
Alparslan Mahallesi, Umit sokak
Tel. +90 505 266 8866, Fax +90 352 223 97 53, E-Mail firstname.lastname@example.org
Do you have an account?
After uric acid was recognized as the causative factor in gout, increased prevalence of renal disease and hypertension in this patient population caught the attention of the medical community. Thus, it has been proposed that uric acid might have caused these disorders. However, uric acid suffered a long period of ignorance in which it was considered a metabolically inert substance. However, recent years has witnessed a resurrection of interest. Experimental studies showed an association between increased uric acid and renal arteriolar disease and hypertension. These preliminary results were supported with clinical studies. However, controversy regarding the precise pathophysiologic role of uric acid in inducing hypertension and renal disease remains to be elucidated. Despite being limited at this time, a few randomized intervention studies showed that even treatment of asymptomatic hyperuricemia was beneficial in terms of blood pressure regulation and kidney function. In this review, we focus on the pathophysiologic role of uric acid in the development and progression of renal disease and hypertension. We also discuss recent clinical evidence suggesting a causal role of uric acid in these disease states.
© 2010 S. Karger AG, Basel
- Nakagawa T, Kang DH, Feig D, et al: Unearthing uric acid: an ancient factor with recently found significance in renal and cardiovascular disease. Kidney Int 2006;69:1722–1725.
- Kutzing MK, Firestein BL: Altered uric acid levels and disease states. J Pharmacol Exp Ther 2008;324:1–7.
- Feig DI, Kang DH, Johnson RJ: Uric acid and cardiovascular risk. N Engl J Med 2008;359:1811–1821.
- Sautin YY, Johnson RJ: Uric acid: the oxidant-antioxidant paradox. Nucleosides Nucleotides Nucleic Acids 2008;27:608–619.
- Johnson RJ, Kang DH, Feig D, et al: Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 2003;41:1183–1190.
- Sanchez-Lozada LG, Nakagawa T, Kang DH, et al: Hormonal and cytokine effects of uric acid. Curr Opin Nephrol Hypertens 2006;15:30–33.
- Ames BN, Cathcart R, Schwiers E, Hochstein P: Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci USA 1981;78:6858–6862.
- Kuzkaya N, Weissmann N, Harrison DG, Dikalov S: Interactions of peroxynitrite with uric acid in the presence of ascorbate and thiols: implications for uncoupling endothelial nitric oxide synthase. Biochem Pharmacol 2005;70:343–354.
- Frei B, Stocker R, Ames BN: Antioxidant defenses and lipid peroxidation in human blood plasma. Proc Natl Acad Sci USA 1988;85:9748–9752.
- Whiteman M, Ketsawatsakul U, Halliwell B: A reassessment of the peroxynitrite scavenging activity of uric acid. Ann NY Acad Sci 2002;962:242–259.
- Corry DB, Eslami P, Yamamoto K, Nyby MD, Makino H, Tuck ML: Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin-angiotensin system. J Hypertens 2008;26:269–275.
- Sautin YY, Nakagawa T, Zharikov S, Johnson RJ: Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. Am J Physiol Cell Physiol 2007;293:C584–C596.
- Glantzounis GK, Tsimoyiannis EC, Kappas AM, Galaris DA: Uric acid and oxidative stress. Curr Pharm Des 2005;11:4145–4151.
- Mazzali M, Kanellis J, Han L, Feng L, Xia YY, Chen Q, et al: Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism. Am J Physiol Renal Physiol 2002;282:F991–F997.
- Khosla UM, Zharikov S, Finch JL, et al: Hyperuricemia induces endothelial dysfunction. Kidney Int 2005;67:1739–1742.
- Watanabe S, Kang DH, Feng L, et al: Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity. Hypertension 2002;40:355–360.
- Kang DH, Nakagawa T, Feng L, et al: A role for uric acid in the progression of renal disease. J Am Soc Nephrol 2002;13:2888–2897.
- 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;38:1101–1106.
- Sanchez-Lozada LG, Tapia E, Santamaria J, et al: Mild hyperuricemia induces vasoconstriction and maintains glomerular hypertension in normal and remnant kidney rats. Kidney Int 2005;67:237–247.
- Sanchez-Lozada LG, Tapia E, Avila-Casado C, et al: Mild hyperuricemia induces glomerular hypertension in normal rats. Am J Physiol Renal Physiol 2002;283:F1105–F1110.
- Mellen PB, Bleyer AJ, Erlinger TP, et al: Serum uric acid predicts incident hypertension in a biethnic cohort: the atherosclerosis risk in community studies. Hypertension 2006;48:1037–1042.
- Nagahama K, Inoue T, Iseki K, et al: Hyperuricemia as a predictor of hypertension in a screened cohort in Okinawa, Japan. Hypertens Res 2004;27:835–841.
- Selby JV, Friedman GD, Quesenberry CP Jr: Precursors of essential hypertension: pulmonary function, heart rate, uric acid, serum cholesterol, and other serum chemistries. Am J Epidemiol 1990;131:1017–1027.
- Taniguchi Y, Hayashi T, Tsumura K, Endo G, Fujii S, Okada K: Serum uric acid and the risk for hypertension and type 2 diabetes in Japanese men: the Osaka Health Survey. J Hypertens 2001;19:1209–1215.
- Feig DI, Johnson RJ: Hyperuricemia in childhood primary hypertension. Hypertension 2003;42:247–252.
- Feig DI, Soletsky B, Johnson RJ: Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA 2008;300:924–932.
- Kanbay M, Ozkara A, Selcoki Y, et al: Effect of treatment of hyperuricemia with allopurinol on blood pressure, creatinine clearence, and proteinuria in patients with normal renal functions. Int Urol Nephrol 2007;39:1227–1233.
- Hu QH, Wang C, Li JM, Zhang DM, Kong LD: Allopurinol, rutin, and quercetin attenuate hyperuricemia and renal dysfunction in rats induced by fructose intake: renal organic ion transporter involvement. Am J Physiol Renal Physiol 2009;297:F1080–F1091.
- Tran LT, Yuen VG, McNeill JH: The fructose-fed rat: a review on the mechanisms of fructose-induced insulin resistance and hypertension. Mol Cell Biochem 2009;332:145–159.
- Brown CM, Dulloo AG, Yepuri G, Montani JP: Fructose ingestion acutely elevates blood pressure in healthy young humans. Am J Physiol Regul Integr Comp Physiol 2008;294:R730–R737.
- Jalal DI, Smits G, Johnson RJ, Chonchol M: Increased fructose associates with elevated blood pressure. J Am Soc Nephrol 2010;21:1543–1549.
- Nguyen S, Choi HK, Lustig RH, Hsu CY: Sugar-sweetened beverages, serum uric acid, and blood pressure in adolescents. J Pediatr 2009;154:807–813.
- Forman JP, Choi H, Curhan GC: Fructose and vitamin C intake do not influence risk for developing hypertension. J Am Soc Nephrol 2009;20:863–871.
- Dhingra R, Sullivan L, Jacques PF, et al: Soft drink consumption and risk of developing cardiometabolic risk factors and the metabolic syndrome in middle-aged adults in the community. Circulation 2007;116:480–488.
- Perez-Pozo SE, Schold J, Nakagawa T, Sanchez-Lozada LG, Johnson RJ, Lillo JL: Excessive fructose intake induces the features of metabolic syndrome in healthy adult men: role of uric acid in the hypertensive response. Int J Obes (Lond) 2010;34:454–461.
- Feig DI: Uric acid: a novel mediator and marker of risk in chronic kidney disease? Curr Opin Nephrol Hypertens 2009;18:526–530.
- Wu X, Wakamiya M, Vaishnav S, et al: Hyperuricemia and urate nephropathy in urate oxidase-deficient mice. Proc Natl Acad Sci USA 1994;91:742–746.
- Nakagawa T, Mazzali M, Kang DH, et al: Hyperuricemia causes glomerular hypertrophy in the rat. Am J Nephrol 2003;23:2–7.
- Mazzali M, Kim YG, Suga S, et al: Hyperuricemia exacerbates chronic cyclosporine nephropathy. Transplantation 2001;71:900–905.
- Sanchez-Lozada LG, Tapia E, Soto V, et al: Effect of febuxostat on the progression of renal disease in 5/6 nephrectomy rats with and without hyperuricemia. Nephron Physiol 2008;108:p69–p78.
- Sanchez-Lozada LG, Tapia E, Soto V, et al: Treatment with the xanthine oxidase inhibitor febuxostat lowers uric acid and alleviates systemic and glomerular hypertension in experimental hyperuricaemia. Nephrol Dial Transplant 2008;23:1179–1185.
- Kanellis J, Watanabe S, Li JH, et al: Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension 2003;41:1287–1293.
Cirillo P, Sato W, Reungjui S, et al: Uric acid, the metabolic syndrome, and renal disease. J Am Soc Nephrol 2006;17(suppl 3):S165–S168.
- Facchini F, Chen YD, Hollenbeck CB, Reaven GM: Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. JAMA 1991;266:3008–3011.
- Calabro P, Yeh ET: Intra-abdominal adiposity, inflammation, and cardiovascular risk: new insight into global cardiometabolic risk. Curr Hypertens Rep 2008;10:32–38.
- Kim JA, Montagnani M, Koh KK, Quon MJ: Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation 2006;113:1888–1904.
- Nakayama T, Kosugi T, Gersch M, et al: Dietary fructose causes tubulointerstitial injury in the normal rat kidney. Am J Physiol Renal Physiol 2010;298:F712–720.
- Gersch MS, Mu W, Cirillo P, et al: Fructose, but not dextrose, accelerates the progression of chronic kidney disease. Am J Physiol Renal Physiol 2007;293:F1256–F1261.
- Glushakova O, Kosugi T, Roncal C, et al: Fructose induces the inflammatory molecule ICAM-1 in endothelial cells. J Am Soc Nephrol 2008;19:1712–1720.
- Hunsicker LG, Adler S, Caggiula A, et al: Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study. Kidney Int 1997;51:1908–1919.
- Iseki K, Oshiro S, Tozawa M, Iseki C, Ikemiya Y, Takishita S: Significance of hyperuricemia on the early detection of renal failure in a cohort of screened subjects. Hypertens Res 2001;24:691–697.
- Domrongkitchaiporn S, Sritara P, Kitiyakara C, et al: Risk factors for development of decreased kidney function in a southeast Asian population: a 12-year cohort study. J Am Soc Nephrol 2005;16:791–799.
See LC, Kuo CF, Chuang FH, et al: Hyperuricemia and metabolic syndrome: associations with chronic kidney disease. Clin Rheumatol 2010 Apr 22 [Epub ahead of print].
- Chang HY, Tung CW, Lee PH, et al: Hyperuricemia as an independent risk factor of chronic kidney disease in middle-aged and elderly population. Am J Med Sci 2010;339:509–515.
- Obermayr RP, Temml C, Gutjahr G, Knechtelsdorfer M, Oberbauer R, Klauser-Braun R: Elevated uric acid increases the risk for kidney disease. J Am Soc Nephrol 2008;19:2407–2413.
- Tomita M, Mizuno S, Yamanaka H, et al: Does hyperuricemia affect mortality? A prospective cohort study of Japanese male workers. J Epidemiol 2000;10:403–409.
- Sturm G, Kollerits B, Neyer U, Ritz E, Kronenberg F: Uric acid as a risk factor for progression of non-diabetic chronic kidney disease? The Mild to Moderate Kidney Disease (MMKD) Study. Exp Gerontol 2008;43:347–352.
- Madero M, Sarnak MJ, Wang X, et al: Uric acid and long-term outcomes in CKD. Am J Kidney Dis 2009;53:796–803.
- Myllymaki J, Honkanen T, Syrjanen J, et al: Uric acid correlates with the severity of histopathological parameters in IgA nephropathy. Nephrol Dial Transplant 2005;20:89–95.
- Syrjanen J, Mustonen J, Pasternack A: Hypertriglyceridaemia and hyperuricaemia are risk factors for progression of IgA nephropathy. Nephrol Dial Transplant 2000;15:34–42.
- Park JT, Kim DK, Chang TI, et al: Uric acid is associated with the rate of residual renal function decline in peritoneal dialysis patients. Nephrol Dial Transplant 2009;24:3520–3525.
- Jalal DI, Rivard CJ, Johnson RJ, et al: Serum uric acid levels predict the development of albuminuria over 6 years in patients with type 1 diabetes: findings from the Coronary Artery Calcification in Type 1 Diabetes study. Nephrol Dial Transplant 2010;25:1865–1869.
- Meier-Kriesche HU, Schold JD, Vanrenterghem Y, Halloran PF, Ekberg H: Uric acid levels have no significant effect on renal function in adult renal transplant recipients: evidence from the symphony study. Clin J Am Soc Nephrol 2009;4:1655–1660.
- Haririan A, Nogueira JM, Zandi-Nejad K, et al: The independent association between serum uric acid and graft outcomes after kidney transplantation. Transplantation 2010;89:573–579.
- Bandukwala F, Huang M, Zaltzman JS, Nash MM, Prasad GV: Association of uric acid with inflammation, progressive renal allograft dysfunction and post-transplant cardiovascular risk. Am J Cardiol 2009;103:867–871.
- Akgul A, Bilgic A, Ibis A, Ozdemir FN, Arat Z, Haberal M: Is uric acid a predictive factor for graft dysfunction in renal transplant recipients? Transplant Proc 2007;39:1023–1026.
- Siu YP, Leung KT, Tong MK, Kwan TH: Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis 2006;47:51–59.
- Talaat KM, el-Sheikh AR: The effect of mild hyperuricemia on urinary transforming growth factor beta and the progression of chronic kidney disease. Am J Nephrol 2007;27:435–440.
- Chao J, Terkeltaub: A critical reappraisal of allopurinol dosing, safety, and efficacy for hyperuricemia in gout. Curr Rheumatol Rep 2009;11:135–140.
- Halevy S, Ghislain PD, Mockenhaupt M, et al: Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J Am Acad Dermatol 2008;58:25–32.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.