Proceedings of the Fourth Genoa Meeting on Hypertension, Diabetes, and Renal Diseases
Serum Uric Acid: A Risk Factor and a Target for Treatment?
Daniel I. Feig*,
Marilda Mazzali,
Duk-Hee Kang,
Takahiko Nakagawa,
Karen Price,
John Kannelis|| and
Richard J. Johnson
* Department of Pediatrics, Renal Section, Baylor College of Medicine, Houston, Texas; Division of Nephrology, Faculdade de Ciencias Medicas, Univeridade Estadual De Campinas, UNICAMP, Campinas-SP, Brazil; Division of Nephrology, Ewha Women’s University College of Medicine, Ewha Medical Research Center, Seoul, Korea; Division of Nephrology, University of Florida School of Medicine, Gainesville, Florida; and || Departments of Nephrology and Medicine, University of Melbourne, Austin Hospital, Melbourne, Australia
Address correspondence to: Dr. Daniel I. Feig, Department of Pediatrics, Renal Section, MC3-2482, 1102 Bates Street, Houston, TX 77030. Phone: 832-824-3800; Fax: 832-825-3889; E-mail: dfeig{at}bcm.tmc.edu
Serum uric acid was first noted to be associated with increasedBP by Frederick Mohamed in the 1870s. Although the link wasrediscovered periodically over the years, it generally was dismissedas a surrogate marker for decreased renal function that ledto increased uric acid and increased risk for hypertension andcardiovascular (CV) disease. Recently, however, several linesof evidence suggest that increased serum uric acid may be asignificant modifiable risk factor. Increased serum uric acidis associated with increased risk for future hypertension inseveral large longitudinal clinical trials as well as an independentrisk factor for poor CV prognosis. Animal model experimentsdemonstrate that increased serum uric acid causes increasedBP that initially is reversible but becomes irreversible, saltsensitive, and uric acid independent over time. The mechanismsinclude the direct action of uric acid on smooth muscle andvascular endothelial cells. Finally, in adolescents with new-onsetessential hypertension, the prevalence of elevated serum uricacid is >90%, and preliminary clinical trial evidence suggeststhat agents that lower serum uric acid may lower BP in thisselect population. Although the investigations are still preliminary,serum uric acid represents a possible new and intriguing targetfor the reduction of morbidity and mortality associated withhypertension and CV disease.
The concept that uric acid may be involved in hypertension isnot a new one. In fact, in the paper published in 1879 thatoriginally described essential hypertension, Frederick AkbarMohamed noted that many of his subjects came from gouty families.He hypothesized that uric acid might be integral to the developmentof essential hypertension (1). Ten years later, this hypothesisreemerged when Haig (2) proposed low-purine diets as a meansto prevent hypertension and vascular disease. In 1909, the Frenchacademician Henri Huchard noted that renal arteriolosclerosis(the histologic lesion of hypertension) was observed in threegroups: Those with gout, those with lead poisoning, and thosewho have a diet enriched with fatty meat. All of these groupsare associated with hyperuricemia (3).
The association between elevated serum uric acid and hypertensionwas observed and reported repeatedly in the 1950s to 1980s butreceived relatively little sustained attention because of thelack of a mechanistic explanation (4–6). Twenty-five to40% of adult patients with untreated hypertension have hyperuricemia(>6.5 mg/dl), and this number increases dramatically whenserum uric acid in the high-normal range is included (7,8).In certain special cases of hypertension, such as cyclosporine-associatedhypertension and pre-eclampsia, the correlation between elevatedserum uric acid and hypertension is >70% (9). Despite theseobservations, the lack of a causal mechanism led to mild elevationsof serum uric acid being largely ignored in medical practice.Uric acid was removed from routine laboratory panels, such asthe serum metabolism and chemistries-20 (SMAC-20), in the early1980s and is not considered a risk factor for hypertension byeither the American Heart Association (10) or the Joint NationalCommittee on Prevention, Detection, Evaluation and Treatmentof High Blood Pressure (11).
Mild Hyperuricemia in the Rat, an Animal Model for Essential Hypertension
The study of mild hyperuricemia required an animal model beforethe lack of any mechanistic detail that had plagued the hypothesisover 100 yr could be addressed. The biggest challenge comesfrom the presence of the enzyme urate oxidase in all mammalsexcept humans and the great apes. Consequently, normal serumuric acid levels in potential mammalian systems are in the 0.5-to 1.5-mg/dl range (humans typically have 3.5 to 7.0 mg/dl),and additional uric acid administered in the diet or intravenouslyis metabolized rapidly to allantoin without altering serum levels.The obvious solution would be a uricase knockout animal; however,such mice develop uric acid nephropathy and die of renal failurebefore 3 mo of age, limiting their utility for the study ofchronic elevations of uric acid.
In the late 1990s, Johnson and colleagues (12) developed a modelusing a pharmacologic inhibitor of urate oxidase, oxonic acid,that allows the study of sustained mild hyperuricemia. Whenfed 2% oxonic acid in their standard diet, Sprague-Dawley ratshave an increase of mean serum uric acid concentrations from0.5 to 1.4 g/dl to 1.7 to 3.0 mg/dl (12). During a 7-wk treatmentperiod, systolic BP increases an average of 22 mmHg. The increasein BP can be prevented entirely by the co-administration ofthe xanthine oxidase inhibitor allopurinol or by the uricosuricagent benziodarone, indicating that the rise in uric acid isthe cause of the increased BP. In fact, the increase in BP islinearly related to the rise in uric acid (r = 0.77). It isimportant to note that the change in BP is seen maximally whenthe rats are maintained on a low-salt diet and that there areno changes in renal function or measurable health parametersof the rats. After 7 wk on a low-salt diet and oxonic acid,if the oxonic acid is removed, then the serum uric acid fallsto normal as does the BP over 3 wk; however, if formally hyperuricemicrats then are switched to a high-salt diet, then they becomehypertensive (13). In short, mild hyperuricemia leads to anirreversible salt-sensitive hypertension over time.
Histologic evaluation of the renal tissue of the hyperuricemic,hypertensive rats reveals an expansion of the vascular smoothmuscle and narrowing of the lumina of the afferent arterioles.This lesion, arteriolosclerosis, is the pathognomonic lesionassociated with essential hypertension in humans. It is interestingthat the development of arteriolosclerosis can be preventedusing allopurinol to control uric acid levels; however, hydrochlorothiazide,which normalizes BP without lowering serum uric acid, does notprevent the development of arteriolosclerosis, indicating thaturic acid, not hypertension, is the causative stimulus (14,15).
Several studies have elucidated the mechanisms by which increasedserum uric acid leads to hypertension in the rat model. Directstaining of renal tissue for renin reveals that hyperuricemiacauses an average of 62% of juxtaglomerular apparatuses to stainpositive for renin, in comparison with <40% of controls (P< 0.05) (14). Histologic evaluation also reveals a dramaticincrease in renal parenchymal infiltration with macrophage,suggesting that hyperuricemia confers a proinflammatory stateon the kidneys of effected rats. Analysis of the serum of treatedand control rats also reveals a 50% fall in total plasma nitratesduring mild hyperuricemia (16,17). Taken together, these experimentalresults indicate that mild hyperuricemia induces renal inflammation,activation of the renin-angiotensin system, and downregulationof nitric oxide production, all of which are potentially importantpathways that lead to uric acid–mediated hypertension.
Recent in vitro studies also have elucidated the possible mechanismof uric acid–mediated arteriolosclerosis. Primary humanvascular smooth muscle cells (HVSMC) are induced to proliferateby addition of uric acid to the growth medium in a dose-dependentmanner (18). The human smooth muscle cells express the urate-transportchannel URAT1 as evidenced by both Northern and Western analyses.Consistent with this observation, cultured HVSMC rapidly takeup 14C-urate, and blockade of this uptake by probenecid attenuatesthe uric acid–mediated induction of proliferation in adose-dependent manner (19). Signaling studies have revealedfurther the possible mechanism by which urate uptake leads toHVSMC proliferation (13,18,20). This pathway is summarized inFigure 1.
Figure 1. The effect of uric acid on vascular smooth muscle cells (VSMC). Uric acid is taken up through the probenecid-sensitive urate-transport channel URAT1. This leads mitogen-activated protein kinase activation and extracellular signal–regulated kinase 1 and 2 (Erk 1/2) phosphorylation. In turn, transcription factors NF-B and AP1 are activated leading to increased cyclo-oxygenase-2 (COX-2) expression and activity. The COX-2 product Thromboxane A2 mediates increased expression and elaboration of platelet derived growth factor (PDGF) and monocyte chemoattractant protein-1 (MCP-1), which induce VSMC proliferation and macrophage infiltration, respectively (13,18–20).
The Rat Revisited: Uric Acid and Progressive Renal Injury
Uric acid–mediated arteriolopathy and interstitial inflammationsuggest mechanisms that would exacerbate or potentiate progressiverenal functional decline after injury, also known as renal progression.Our collaborative groups have investigated the effect of uricacid on multiple mechanisms of progressive renal injury. Tworepresentative systems are the remnant kidney model and themodel of cyclosporine nephropathy. In the remnant kidney model,rats undergo unilateral nephrectomy and ligation of two of thethree main branch renal arteries on the contralateral side.Hyperuricemic remnant kidney rats (caused by addition of 2%oxonic acid to their diets) had higher BP, greater proteinuria,and higher serum creatinine. Their histology revealed a 50%increase in glomerulosclerosis and a 30% increase in interstitialfibrosis compared with rats with remnant kidneys alone (21,22).Similar results were seen in the rat model of cyclosporine nephropathy.Addition of oxonic acid to cyclosporine treatment led to higheruric acid levels, more severe arteriolar hyalinosis, macrophageinfiltration, and tubulointerstitial damage compared with ratsthat were treated with cyclosporine alone (23). Furthermore,treatment of cyclosporine-exposed rats with allopurinol improvesGFR (23), and in human liver transplant patients who were receivingcyclosporine, treatment with allopurinol resulted in improvedrenal function (24).
In the same period during which reports of animal models ofmild hyperuricemia have been published, five new studies thatreported that serum uric acid predicts the development of hypertensionappeared in the literature. This is a significant departurefrom previous decades, in which there was considerable skepticismover a potential association between uric acid in high BP. Before1990, only Khan et al. (25) had reported that an increased serumuric acid is an independent risk factor for hypertension; however,it had been noted that 25 to 40% of adults with hypertensionhave serum uric acid >6.5 mg/dl and >60% have a serumuric acid >5.5 mg/dl (7,8) and that there was a linear relationshipbetween serum uric acid and systolic BP in both white and blackpatients (26). Three reports that indicated that serum uricacid is an independent risk factor for hypertension were publishedin the 1990s (27–29), and five more were published inthe past 4 yr (30–34), including two in the first monthof 2005 (Table 1). The recent evaluation of a subset of theFramingham Heart Study found that serum uric acid level wasan independent predictor of hypertension and BP progressionover as little as 4 yr.
In adolescents, the association between elevated serum uricacid and the onset of essential hypertension is even more striking.The Moscow Children’s Hypertension Study found hyperuricemia(>8.0 mg/dl) in 9.5% of children with normal BP, 49% of childrenwith borderline hypertension, and 73% of children with moderateand severe hypertension (35). The Hungarian Children’sHealth Study followed all 17,624 children who were born in Budapestin 1964 for 13 yr and found that significant risk factors forthe development of hypertension were elevated heart rate, earlysexual maturity, and hyperuricemia (36). These two studies donot separate the hypertensive children by underlying diagnosis,so the relationship between serum uric acid and hypertensionmay be skewed by ascertainment bias. In a small study, Gruskin(37) compared adolescents (13 to 18 yr of age) who had essentialhypertension with age-matched healthy control subjects who hadnormal BP. The hypertensive children had both elevated serumuric acid (mean >6.5 mg/dl) and higher peripheral renin activity.In a racially mixed population of patients who were referredfor the evaluation of hypertension, Feig and Johnson observedthat the mean serum uric acid level (± SD) in controlsubjects and children with white coat hypertension were nearlyidentical (3.6 ± 0.8 and 3.6 ± 0.7 mg/dl, respectively;P = 0.80) but slightly higher in secondary hypertension (4.3± 1.4 mg/dl; P = 0.008) and significantly elevated inchildren with primary hypertension (6.7 ± 1.3 mg/dl;P = 0.000004) (38). There was a tight, linear correlation betweenthe serum uric acid levels and the systolic and diastolic BPin patients who were referred for evaluation of hypertension(r = 0.8 for systolic BP and r = 0.6 for diastolic BP) (38).Among patients who were referred for evaluation of hypertension,a serum uric acid >5.5 mg/dl had an 89% positive predictivevalue for essential hypertension, whereas a serum uric acidlevel <5.0 had a negative predictive value for essentialhypertension of 96% (38).
Results from a very small, unblinded pilot study in childrensuggested that uric acid may contribute directly to the onsetof hypertension in some humans. Five children, aged 14 to 17yr of age, with newly diagnosed and as yet untreated essentialhypertension were treated for 1 mo with allopurinol as a solitarypharmacologic agent. All five children had a decrease in BPby both casual and ambulatory monitoring, and four of the fivewere normotensive at the end of 1 mo. All five also had a reboundin their BP after discontinuation of the therapy (39). Becausethis study was very small and not blinded, a great deal of careshould be taken in interpreting or generalizing the results;however, they are intriguing. A blinded, randomized, placebo-controlled,crossover trial is under way and nearing completion and shouldshed greater light on the utility of uric acid–loweringregimens in the management of new-onset hypertension in children.
The results from both animal and human studies strongly implicateuric acid as a factor in the onset of essential hypertensionin some individuals and as a potential contributor to the progressionof renal injury. The animal model data also present a mechanismby which uric acid leads to the renal pathologic changes, afferentarteriolosclerosis, of essential hypertension. If the arteriolosclerosisis irreversible and later hypertension becomes uric acid independent,then this would both explain why xanthine oxidase inhibitorsand uricosurics have not previously been noted to be usefulantihypertensive agents and suggest their potential utilityas first-line drugs for primary prevention of essential hypertensionin selected populations. It is important, however, to interpretthe results judiciously. We do not as yet have conclusive humanclinical trial data to prove the utility of uric acid–loweringregimens as antihypertensive agents, hypertension preventionagents, or agents to attenuate progressive renal injury. Untiland unless clinical trial data demonstrate these actions, theuse of allopurinol or uricosuric agents for all asymptomatichyperuricemic patients is not yet warranted. As the clinicaltrials are under way, the recommendations regarding the useclinical use of uric acid–lowering regimens may be modifiedin the near future.
Acknowledgments
This work was supported by NIH grants DK064587, DK071223, andRR17665 (D.I.F.).
Mohamed FA: On chronic Bright’s disease, and its essential symptoms.
Lancet 1
: 399
–401, 1879
Haig A: On uric acid and arterial tension.
BMJ 1
: 288
–291, 1889
Huchard H: Arteriolosclerosis: Including its cardiac form.
JAMA 53
: 1129
–1132, 1909
Gertler MM, Garn SM, Levine SA: Serum uric acid in relation to age and physique in health and in coronary heart disease.
Ann Intern Med 34
: 1421
–1431, 1951[Medline]
Curtis JJ, Luke RG, Jones P, Diethelm AG: Hypertension in cyclosporine-treated renal transplant recipients is sodium dependent.
Am J Med 85
: 134
–138, 1988[Medline]
Pearson T, Blair S, Daniels S, Eckel RH, Fair JM, Fortmann SP, Franklin BA, Goldstein LB, Greenland P, Grundy SM, Hong Y, Miller NH, Lauer RM, Ockene IS, Sacco RL, Sallis JF Jr, Smith SC Jr, Stone NJ, Taubert KA: AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update: Consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases. American Heart Association Science Advisory and Coordinating Committee.
Circulation 106
: 388
–391, 2002[Free Full Text]
Chobanian A, Bakris G, Black H, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure.
JAMA 289
: 2560
–2572, 2003[Abstract/Free Full Text]
Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, Lan HY, Kivlighn S, Johnson RJ: Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism.
Hypertension 38
: 1101
–1106, 2001[Abstract/Free Full Text]
Watanabe S, Kang DH, Feng L, Nakagawa T, Kanellis J, Lan H, Mazzali M, Johnson RJ: Uric acid hominoid evolution and the pathogenesis of salt-sensitivity.
Hypertension 40
: 355
–360, 2002[Abstract/Free Full Text]
Mazzali M, Kanellis J, Han L, Feng L, Xia YY, Chen Q, Kang DH, Gordon KL, Watanabe S, Nakagawa T, Lan HY, Johnson RJ: Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism.
Am J Physiol Renal Physiol 282
: F991
–F997, 2002[Abstract/Free Full Text]
Johnson RJ, Rodriguez-Iturbe B, Schreiner GF, Herrera-Acosta J: Hypertension: A microvascular and tubulointerstitial disease.
J Hypertens 20[Suppl 3]
: S1
–S7, 2002
Kang DH, Nakagawa T, Feng L, Johnson RJ: Nitric oxide modulates vascular disease in the remnant kidney model.
Am J Pathol 161
: 239
–248, 2002[Abstract/Free Full Text]
Finch J, Mu W, Parra G, Nakagawa T, Johnson RJ: Hyperuricemia induces endothelial dysfunction in rats [Abstract].
J Am Soc Nephrol 14
: 143A
, 2003
Kang DH, Nakagawa T, Feng L, Watanabe S, Han L, Mazzali M, Truong L, Harris R, Johnson RJ: A role for uric acid in the progression of renal disease.
J Am Soc Nephrol 13
: 2888
–2897, 2002[Abstract/Free Full Text]
Price K, Mu W, Raines E, Nakagawa T, Johnson RJ: Expression of a urate transporter in human vascular smooth muscle cells [Abstract].
J Am Soc Nephrol 14
: 145A
, 2003
Kanellis J, Watanabe S, Li JH, Kang DH, Li P, Nakagawa T, Wamsley A, Sheikh-Hamad D, Lan HY, Feng L, Johnson RJ: Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2.
Hypertension 41
: 1287
–1293, 2003[Abstract/Free Full Text]
Kang DH, Joly AH, Oh SW, Hugo C, Kerjaschki D, Gordon KL, Mazzali M, Jefferson JA, Hughes J, Madsen KM, Schreiner GF, Johnson RJ: Impaired angiogenesis in the remnant kidney model: I. Potential role of vascular endothelial growth factor and thrombospondin-1.
J Am Soc Nephrol 12
: 1434
–1447, 2001[Abstract/Free Full Text]
Kang DH, Hughes J, Mazzali M, Schreiner GF, Johnson RJ: Impaired angiogenesis in the remnant kidney model: II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function.
J Am Soc Nephrol 12
: 1448
–1457, 2001[Abstract/Free Full Text]
Kang DH, Kim YG, Andoh TF, Gordon KL, Suga S, Mazzali M, Jefferson JA, Hughes J, Bennett W, Schreiner GF, Johnson RJ: Post-cyclosporine-mediated hypertension and nephropathy: Amelioration by vascular endothelial growth factor.
Am J Physiol Renal Physiol 280
: F727
–F736, 2001[Abstract/Free Full Text]
Neal D, Tom B, Gimson A, Gibbs P, Alexander GJ: Hyperuricemia, gout and renal function after liver transplantation.
Transplantation 72
: 1689
–1691, 2001[CrossRef][Medline]
Kahn HA, Medalie JH, Neufeld HN, Riss E, Goldbourt U: The incidence of hypertension and associated factors: The Israel ischemic heart study.
Am Heart J 84
: 171
–182, 1972[CrossRef][Medline]
Klein R, Klein BE, Cornoni JC, Maready J, Cassel JC, Tyroler HA: Serum uric acid. Its relationship to coronary heart disease risk factors and cardiovascular disease, Evans County, Georgia.
Arch Intern Med 132
: 401
–410, 1973[CrossRef][Medline]
Jossa F, Farinaro E, Panico S, Krogh V, Celentano E, Galasso R, Mancini M, Trevisan M: Serum uric acid and hypertension: The Olivetti heart study.
J Hum Hypertens 8
: 677
–681, 1994[Medline]
Hunt SC, Stephenson SH, Hopkins PN, Williams RR: Predictors of an increased risk of future hypertension in Utah. A screening analysis.
Hypertension 17
: 969
–976, 1991[Abstract/Free Full Text]
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 131
: 1017
–1027, 1990[Abstract/Free Full Text]
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 19
: 1209
–1215, 2001[CrossRef][Medline]
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 42
: 474
–480, 2003[Abstract/Free Full Text]
Nakanishi N, Okamato M, Yoshida H, Matsuo Y, Suzuki K, Tatara K: Serum uric acid and the risk for development of hypertension and impaired fasting glucose or type II diabetes in Japanese male office workers.
Eur J Epidemiol 18
: 523
–530, 2003[CrossRef][Medline]
Sundstrom J, Sullivan L, D’Agostino R, Levy D, Kannel WB, Vasan RS: Relations of serum uric acid to longitudinal blood pressure tracking and hypertension incidence in the Framingham Heart Study.
Hypertension 45
: 28
–33, 2005[Abstract/Free Full Text]
Rovda Iu I, Kazakova LM, Plaksina EA: [Parameters of uric acid metabolism in healthy children and in patients with arterial hypertension].
Pediatriia 19
–22, 1990
Torok E, Gyarfas I, Csukas M: Factors associated with stable high blood pressure in adolescents.
J Hypertens Suppl 3
: S389
–S390, 1985[Medline]
Gruskin AB: The adolescent with essential hypertension.
Am J Kidney Dis 6
: 86
–90, 1985[Medline]
Feig DI, Johnson RJ: Hyperuricemia in childhood primary hypertension.
Hypertension 42
: 247
–252, 2003[Abstract/Free Full Text]
Feig DI, Nakagawa T, Karumanchi SA, Oliver WJ, Kang DH, Finch J, Johnson RJ: Hypothesis: Uric acid, nephron number and the pathogenesis of essential hypertension.
Kidney Int 66
: 281
–287, 2004[CrossRef][Medline]
Nagahama K, Inoue T, Iseki K, Touma T, Kinjo K, Ohya Y, Takashito S: Hyperuricemia as a predictor of hypertension in a screened cohort in Okinawa, Japan.
Hypertens Res 27
: 835
–841, 2004[CrossRef][Medline]
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Abstract
History of Uric Acid...
B and AP1 are activated leading to increased cyclo-oxygenase-2 (COX-2) expression and activity. The COX-2 product Thromboxane A2 mediates increased expression and elaboration of platelet derived growth factor (PDGF) and monocyte chemoattractant protein-1 (MCP-1), which induce VSMC proliferation and macrophage infiltration, respectively (