Aspectos metabólicos y complicaciones de la hiperuricemia

  • Florencia Aranguren División Diabetología, Hospital de Clínicas José de San Martín, Buenos Aires
  • Mabel Elisa Morales Fresenius Medical Care, Buenos Aires
  • Luciana González Paganti Servicio de Nefrología, Hospital Militar Central Dr. Cosme Argerich, Buenos Aires
  • Silvia Russomando Sección Nefrología, Hospital General de Agudos Gral. Manuel Belgrano, Buenos Aires
  • Martín Salazar Hospital Interzonal General de Agudos General José de San Martín, La Plata, Buenos Aires
  • Mercedes A. Traversa División Diabetología, Hospital de Clínicas José de San Martín, Buenos Aires
  • Elisa Elena Del Valle Instituto de Diagnóstico e Investigaciones Metabólicas, Buenos Aires
  • Alfredo Wassermann Comité de Hipertensión, Sección Nefrología, Hospital Municipal Prof. Dr. Bernardo A. Houssay, Buenos Aires
  • Alicia Ester Elbert Centro de Enfermedades Renales e Hipertensión Arterial, Buenos Aires

Resumen

El resultado de observaciones epidemiológicas inicia en la actualidad una reevaluación del ácido úrico en diferentes enfermedades metabólicas, enfermedad cardiovascular y renal. El rol de la hiperuricemia como factor de riesgo cardiovascular independiente es difícil de evaluar aún en análisis de modelos multivariados, dado que existen resultados inconclusos e inconsistentes en la mayoría de los estudios. Esta dificultad se observa por la fuerte asociación del ácido úrico con otros factores clásicos de riesgo cardiovascular que no permiten diferenciar el riesgo. Durante muchos años se lo consideró una sustancia biológicamente inerte, pero posteriormente se encontró que tiene muchas propiedades biológicas que podrían ser beneficiosas o perjudiciales para los seres humanos. Existen en la actualidad una controversia sobre si su rol es protector por tener propiedades anti-oxidante o lesivo por sus propiedades pro-oxidantes en la placa arterioesclerótica y en tejido adiposo lo que podría determinar que no solo se trate de un marcador de riesgo, sino que conforme un factor causal en las enfermedades metabólicas como la diabetes mellitus, el síndrome metabólico, las enfermedades cardiovasculares y/o renales. En esta revisión hemos actualizado estos conceptos de manera de intentar esclarecer dicho rol, para en un futuro se pueda instituir normas, que actualmente no están establecidas, para decidir si se debe tratar la hiperuricemia, en qué casos, con que niveles de corte y cuáles serían sus objetivos terapéuticos en cada circunstancia.

Citas

Filiopoulos V, Hadjiyannakos D, Vlassopoulos D. New insights into uric acid effects on the progression and prognosis of chronic kidney disease. Ren Fail. 2012;34(4):510-20.

Gustafsson D, Unwin R. The pathophysiology of hyperuricaemia and its possible relationship to cardiovascular disease, morbidity and mortality. BMC Nephrol. 2013; 14:164.

Watanabe S, Kang DH, Feng L, Nakagawa T, Kanellis J, Lan H, et al. Uric acid, hominoide volution, and the pathogenesis of salt-sensitivity. Hypertension. 2002;40(3): 355-60.

Johnson RJ, Titte S, Cade JR, Rideout BA, Oliver WJ. Uric acid, evolution and primitive cultures. Semin Nephrol. 2005; 25(1):3-8.

Nieto FJ, Iribarren C, Gross MD, Comstock GW, Cutler RG. Uric acid and serum antioxidant capacity: a reaction to atherosclerosis? Atherosclerosis. 2000;148(1):131-9.

Kellogg EW 3rd, Fridovich I. Liposome oxidation and erythrocyte lysis by enzymically generated superoxide and hydrogen peroxide. J Biol Chem. 1977;252(19):6721-8.

Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides antioxidant defense in humans against oxidant- and radical-causing aging and cancer: a hypothesis. Proc Natl Acad Sci U S A. 1981;78(11):6858-62.

Vásquez-Vivar J, Santos AM, Junqueira VB, Augusto O. Peroxynitrite-mediated formation of free radicals in human plasma: EPR detection of ascorbyl, albumin-thiyl and uric acid-derived free radicals. Biochem J 1996;314(Pt 3):869-76.

Kim KM, Henderson GN, Ouyang X, Frye RF, Sautin YY, Feig DI, et al. A sensitive and specific liquid chromatography-tandem mass spectrometry method for the determination of intracellular and extracellular uric acid. J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Jul 15;877(22):2032-8.

Ferrucci L, Corsi A, Lauretani F, Bandinelli S, Bartali B, Taub DD, et al. The origins of age-related proin-flammatory state. Blood. 2005; 105(6):2294-9.

Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature. 2003; 425(6957):516-21.

Price KL, Sautin YY, Long DA, Zhang L, Miyazaki H, Mu W, et al. Human vascular smooth muscle cells express a urate transporter. J Am Soc Nephrol. 2006;17(7):1791-5.

Nakagawa T, Kang DH, Feig D, Sanchez-Lozada LG, Srinivas TR, Sautin Y, et al. Unearthing uric acid: an ancient factor with recently found significance in renal and cardiovascular disease. Kidney Int. 2006;69(10):1722-5.

Wright AF, Rudan I, Hastie ND, Campbell H. A ‘complexity’ of urate transporters. Kidney Int. 2010;78(5):446-52.

Bobulescu IA, Moe OW. Renal transport of uric acid: evolving concepts and uncertainties. Adv Chronic Kidney Dis. 2012;19(6):358-71.

Anzai N, Endou H. Urate transporters: an evolving field. Semin Nephrol. 2011;31(5):400-9.

Grassi D, Ferri L, Desideri G, Di Giosia P, Cheli P, Del Pinto R, et al. Chronic hyperuricemia, uric acid deposit and cardiovascular risk. Curr Pharm Des. 2013;19(13):2432-8.

De Oliveira EP, Burini RC. High plasma uric acid concentration: causes and consequences. Diabetol Metab Syndr. 2012;4:12.

Rho YH, Zhu Y, Choi HK. The epidemiology of uric acid and fructose. Semin Nephrol. 2011;31(5):410-9.

Stiburkova B, Bleyer AJ. Changes in serum urate and urate excretion with age. Adv Chronic Kidney Dis. 2012 Nov;19(6):372-6.

Rho YH, Zhu Y, Choi HK. The epidemiology of uric acid and fructose. Semin Nephrol. 2011;31(5):410-9.

Fox IH, Kelley WN. Studies on the mechanism of fructose-induced hyperuricemia in man. Metabolism. 1972;21(8):713-21.

Hwang IS, Ho H, Hoffman BB, Reaven GM. Fructose-induced insulin resistance and hypertension in rats. Hypertension. 1987;10(5):512-6.

Johnson RJ, Segal MS, Sautin Y, Nakagawa T, Feig DI, Kang DH, et al. Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr. 2007;86(4):899-906.

Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, et al. A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol. 2006;290(3):F625-31.

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(3):R730-7.

Bremer AA, Mietus-Snyder M, Lustig RH. Toward a unifying hypothesis of metabolic syndrome. Pediatrics. 2012;129(3):557-70.

Salazar MR, Espeche WG, March CE, Marillet AG, Balbín E, Dulbecco CA, et al. Optimal uric acid threshold to identify insulin resistance in healthy women. Metab Syndr Relat Disord. 2012;10(1):39-46.

Forman JP, Choi H, Curhan GC. Uric acid and insulin sensitivity and risk of incident hypertension. Arch Intern Med. 2009;169(2):155-62.

Bobridge KS, Haines GL, Mori TA, Beilin LJ, Oddy WH, Sherriff J, et al. Dietary fructose in relation to blood pressure and serum uric acid in adolescent boys and girls. J Hum Hypertens. 2013;27(4):217-24.

Perez-Pozo SE, Schold J, Nakagawa T, Sánchez-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(3):454-61.

Nielsen SJ, Popkin BM. Changes in beverage intake between 1977 and 2001. Am J Prev Med. 2004;27(3):205-10.

Johnson RJ, Sánchez-Lozada LG, Mazzali M, Feig DI, Kanbay M, Sautin YY. What are the key arguments against uric acid as a true risk factor for hypertension? Hypertension. 2013;61(5):948-51.

Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension. 2001;38(5):1101-6.

Sundström J, Sullivan L, D’Agostino RB, Levy D, Kannel WB, Vasan RS. Relations of serum uric acid to longitudinal blood pressure tracking and hypertension incidence. Hypertension. 2005;45(1):28-33.

Mellen PB, Bleyer AJ, Erlinger TP, Evans GW, Nieto FJ, Wagenknecht LE, et al. Serum uric acid predicts incident hypertension in a biethnic cohort: the atherosclerosis risk in communities study. Hypertension. 2006;48(6):1037-42.

Perlstein TS, Gumieniak O, Williams GH, Sparrow D, Vokonas PS, Gaziano M, et al. Uric acid and the development of hypertension: the normative aging study. Hypertension. 2006;48(6):1031-6.

Feig DI. The role of uric acid in the pathogenesis of hypertension in the young. J Clin Hypertens (Greenwich). 2012;14(6):346-52.

Loeffler LF, Navas-Acien A, Brady TM, Miller ER 3rd, Fadrowski JJ. Uric acid level and elevated blood pressure in US adolescents: National Health and Nutrition Examination Survey, 1999-2006. Hypertension. 2012;59(4):811-7.

Alper AB Jr, Chen W, Yau L, Srinivasan SR, Berenson GS, Hamm LL. Childhood uric acid predicts adult blood pressure: the Bogalusa Heart Study. Hypertension. 2005;45(1):34-8.

Feig DI, Johnson RJ. Hyperuricemia in childhood primary hypertension. Hypertension. 2003;42(3):247-52.

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):924-32.

Soletsky B, Feig DI. Uric acid reduction rectifies prehypertension in obese adolescents. Hypertension. 2012;60(5):1148-56.

Song K, Wang Y, Wang G, Zhang Q, Jiao H, Huang G, et al. Does decreasing serum uric acid level prevent hypertension? A nested RCT in cohort study: rationale, methods, and baseline characteristics of study cohort. BMC Public Health. 2013;13:1069.

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(6):1183-90.

Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, et al. Hyperuricemia induces endothelial dysfunction. Kidney Int. 2005;67(5):1739-42.

Kanellis J, Watanabe S, Li JH, Kang DH, Li P, Nakagawa T, 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(6):1287-93.

Quiñones Galvan A, Natali A, Baldi S, Frascerra S, Sanna G, Ciociaro D, et al. Effect of insulin on uric acid excretion in humans. Am J Physiol. 1995;268(1Pt 1):E1-5.

Nakagawa T, Tuttle KR, Short RA, Johnson RJ. Hypothesis: fructose-induced hyperuricemia as a causal mechanism for the epidemic of the metabolic syndrome. Nat Clin Pract Nephrol. 2005;1(2):80-6.

Carnethon MR, Fortmann SP, Palaniappan L, Duncan BB, Schmidt MI, Chambless LE. Risk factors for progression to incident hyperinsulinemia: the Atherosclerosis Risk in Communities Study, 1987-1998. Am J Epidemiol. 2003;158(11):1058-67.

Masuo K, Kawaguchi H, Mikami H, Ogihara T, Tuck ML. Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation. Hypertension. 2003;42(4):474-80.

Nakanishi N, Okamoto M, Yoshida H, Matsuo Y, Suzuki K, Tatara K. Serum uric acid and risk for development of hypertension and impaired fasting glucose or Type II diabetes in Japanese male office workers. Eur J Epidemiol. 2003;18(6):523-30.

Dehghan A, van Hoek M, Sijbrands EJ, Hofman A, Witteman JC. High serum uric acid as a novel risk factor for type 2 diabetes. Diabetes Care. 2008;31(2):361-2.

Chien KL, Chen MF, Hsu HC, Chang WT, Su TC, Lee YT, et al. Plasma uric acid and the risk of type 2 diabetes in a Chinese community. Clin Chem. 2008;54(2):310-6.

Choi HK, Ford ES. Prevalence of the metabolic syndrome in individuals with hyperuricemia. Am J Med. 2007;120(5):442-7.

Kylin E. Studien über das Hypertonie-Hyperglykämie-Hyperurikämie Syndrom. Zentralblatt für Innere Medizin. 1923;44:105-2.

Engelhardt HT, Wagner EL. Gout, diabetes mellitus and obesity, a poorly appreciated syndrome. South Med J. 1950;43(1):51-3.

Mikkelsen WM. The possible association of hyperuricemia and/or gout with diabetes mellitus. Arthritis Rheum. 1965;8(5):853-64.

Medalie JH, Papier CM, Goldbourt U, Herman JB. Major factors in the development of diabetes mellitus in 10,000 men. Arch Intern Med. 1975;135(6):811-7.

Niskanen L, Laaksonen DE, Lindström J, Eriksson JG, Keinänen-Kiukaanniemi S, Ilanne-Parikka P, et al. Serum uric acid as a harbinger of metabolic outcome in subjects with impaired glucose tolerance: the Finnish Diabetes Prevention Study. Diabetes Care. 2006;29(3):709-11.

Kramer CK, von Mühlen D, Jassal SK, Barrett-Connor E. Serum uric acid levels improve prediction of incident type 2 diabetes in individuals with impaired fasting glucose: the Rancho Bernardo Study. Diabetes Care. 2009;32(7):1272-3.

Dehghan A, van Hoek M, Sijbrands EJ, Hofman A, Witteman JC. High serum uric acid as a novel risk factor for type 2 diabetes. Diabetes Care. 2008;31(2):361-2.

Ogbera AO, Azenabor AO. Hyperuricaemia and the metabolic syndrome in type 2 DM. Diabetol Metab Syndr. 2010;2:24.

Herman JB, Goldbourt U. Uric acid and diabetes: observations in a population study. Lancet. 1982;2(8292):240-3.

Katsiki N, Papanas N, Fonseca VA, Maltezos E, Mikhailidis DP. Uric acid and diabetes: Is there a link? Curr Pharm Des. 2013;19(27):4930-7.

Boner G, Rieselbach RE. The effect of glucose upon reabsorptive transport of urate by the kidney. Adv Exp Med Biol. 1974;41:781-7.

Modan M, Halkin H, Karasik A, Lusky A. Elevated serum uric acid--a facet of hyperinsulinaemia. Diabetologia. 1987;30(9):713-8.

Chou P, Lin KC, Lin HY, Tsai ST. Gender differences in the relationships of serum uric acid with fasting serum insulin and plasma glucose in patients without diabetes. J Rheumatol. 2001;28(3):571-6.

Cook S, Hugli O, Egli M, Vollenweider P, Burcelin R, Nicod P, et al. Clustering of cardiovascular risk factors mimicking the human metabolic syndrome X in eNOS null mice. Swiss Med Wkly. 2003;133(25-26):360-3.

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(2):C584-96.

Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004;114(12):1752-61.

Lanaspa MA, Ishimoto T, Cicerchi C, Tamura Y, Roncal-Jimenez CA, Chen W, et al. Endogenous fructose production and fructokinase activation mediate renal injury in diabetic nephropathy. J Am Soc Nephrol. 2014;25(11):2526-38.

Nakayama T, Kosugi T, Gersch M, Connor T, Sanchez-Lozada LG, Lanaspa MA, et al. Dietary fructose causes tubulointerstitial injury in the normal rat kidney. Am J Physiol Renal Physiol. 2010;298(3):F712-20.

Ferretti JL, Sarano H, González A, Dotta A, Boccio C, Premoli JJ, et al. Prevalencia de trastornos metabólicos en 500 pacientes urolitiásicos del litoral argentino. Arch Esp Urol. 1988;41(6):434-40.

Parks JH, Worcester EM, O’Connor RC, Coe FL. Urine stone risk factors in nephrolithiasis patients with and without bowel disease. Kidney Int. 2003;63(1):255-65.

Daudon M, Traxer O, Conort P, Lacour B, Jungers P. Type 2 diabetes increases the risk for uric acid stones. J Am Soc Nephrol. 2006;17(7):2026-33.

Ekeruo WO, Tan YH, Young MD, Dahm P, Maloney ME, Mathias BJ, et al. Metabolic risk factors and the impact of medical therapy on the management of nephrolithiasis in obese patients. J Urol. 2004;172(1):159-63.

Abate N, Chandalia M, Cabo-Chan AV Jr, Moe OW, Sakhaee K. The metabolic syndrome and uric acid nephrolithiasis: novel features of renal manifestation of insulin resistance. Kidney Int. 2004;65(2):386-92.

Kamel KS, Cheema-Dhadli S, Shafiee MA, Davids MR, Halperin ML. Recurrent uric acid stones. QJM. 2005;98(1):57-68.

Chobanian MC, Hammerman MR. Insulin stimulates ammoniagenesis in canine renal proximal tubular segments. Am J Physiol. 1987;253(6 Pt 2):F1171-7.

Gesek FA, Schoolwerth AC. Insulin increases Na(+)-H+ exchange activity in proximal tubules from normotensive and hypertensive rats. Am J Physiol. 1991;260(5 Pt 2):F695-703.

Pak CY. Renal stone disease: pathogenesis, prevention, and treatment. Boston: Academic Publishers, 1997, p. 105-7.

Maalouf NM, Sakhaee K, Parks JH, Coe FL, Adams-Huet B, Pak CY. Association of urinary pH with body weight in nephrolithiasis. Kidney Int. 2004;65(4):1422-5.

Cameron MA, Maalouf NM, Adams-Huet B, Moe OW, Sakhaee K. Urine composition in type 2 diabetes: predisposition to uric acid nephrolithiasis. J Am Soc Nephrol. 2006;17(5):1422-8.

Maalouf NM, Cameron MA, Moe OW, Adams-Huet B, Sakhaee K. Low urine pH: a novel feature of the metabolic syndrome. Clin J Am Soc Nephrol. 2007;2(5):883-8.

Zerwekh JE, Holt K, Pak CY. Natural urinary macromolecular inhibitors: attenuation of inhibitory activity by urate salts. Kidney Int. 1983;23(6):838-41.

Breckenridge A. Hypertension and hyperuricaemia. Lancet. 1966;1(7427):15-8.

Cannon PJ, Stason WB, Demartini FE, Sommers SC, Laragh JH. Hyperuricemia in primary and renal hypertension. N Engl J Med. 1966;275(9):457-64.

Alderman MH. Uric acid and cardiovascular risk. Curr Opin Pharmacol. 2002;2(2):126-30.

Puig JG, Ruilope LM. Uric acid as a cardiovascular risk factor in arterial hypertension. J Hypertens. 1999;17(7):869-72.

Tykarski A. Evaluation of renal handling of uric acid in essential hypertension: hyperuricemia related to decreased urate secretion. Nephron. 1991;59(3):364-8.

García Puig J, Mateos Antón F, López Jiménez M, Conthe Gutiérrez P. Renal handling of uric acid in gout: impaired tubular transport of urate not dependent on serum urate levels. Metabolism. 1986;35(12):1147-53.

Ruilope LM, Lahera V, Rodicio JL, Carlos Romero J. Are renal hemodynamics a key factor in the development and maintenance of arterial hypertension in humans? Hypertension. 1994 Jan;23(1):3-9.

Johnson RJ, Herrera-Acosta J, Schreiner GF, Rodriguez-Iturbe B. Subtle acquired renal injury as a mechanism of salt-sensitive hypertension. N Engl J Med. 2002;346(12):913-23.

Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, Cha SH, et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature. 2002;417(6887):447-52.

Messerli FH, Frohlich ED, Dreslinski GR, Suarez DH, Aristimuno GG. Serum uric acid in essential hypertension: an indicator of renal vascular involvement. Ann Intern Med. 1980;93(6):817-21.

Cappuccio FP, Strazzullo P, Farinaro E, Trevisan M. Uric acid metabolism and tubular sodium handling. Results from a population-based study. JAMA. 1993;270(3):354-9.

Reaven GM, Lithell H, Landsberg L. Hypertension and associated metabolic abnormalities: the role of insulin resistance and the sympathoadrenal system. N Engl J Med. 1996;334(6):374-81.

Rathmann W, Funkhouser E, Dyer AR, Roseman JM. Relations of hyperuricemia with the various components of the insulin resistance syndrome in young black and white adults: the CARDIA study. Coronary Artery Risk Development in Young Adults. Ann Epidemiol. 1998;8(4):250-61.

Kekäläinen P, Sarlund H, Laakso M. Long-term association of cardiovascular risk factors with impaired insulin secretion and insulin resistance. Metabolism. 2000;49(10):1247-54.

Quiñones-Galvan A, Ferrannini E. Renal effects of insulin in man. J Nephrol. 1997;10(4):188-91.

Tsunoda S, Kamide K, Minami J, Kawano Y. Decreases in serum uric acid by amelioration of insulin resistance in overweight hypertensive patients: effect of a low-energy diet and an insulin-sensitizing agent. Am J Hypertens. 2002;15(8):697-701.

Maxwell AJ, Bruinsma KA. Uric acid is closely linked to vascular nitric oxide activity. Evidence for mechanism of association with cardiovascular disease. J Am Coll Cardiol 2001; 38: 1850–8.

Gibson TJ. Hypertension, its treatment, hyperuricaemia and gout. Curr Opin Rheumatol. 2013;25(2):217-22.

Lin CS, Lee WL, Hung YJ, Lee DY, Chen KF, Chi WC, et al. Prevalence of hyperuricemia and its association with antihypertensive treatment in hypertensive patients in Taiwan. Int J Cardiol. 2012;156(1):41-6.

Publicado
2017-04-22
Cómo citar
1.
Aranguren F, Morales ME, González Paganti L, Russomando S, Salazar M, Traversa MA, Del Valle EE, Wassermann A, Elbert AE. Aspectos metabólicos y complicaciones de la hiperuricemia. Rev Nefrol Dial Traspl. [Internet]. 22 de abril de 2017 [citado 19 de marzo de 2024];35(3):140-52. Disponible en: http://www.revistarenal.org.ar/index.php/rndt/article/view/33
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