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Is There a Pathogenetic Role for Uric Acid in Hypertension and Cardiovascular and Renal Disease?

Originally publishedhttps://doi.org/10.1161/01.HYP.0000069700.62727.C5Hypertension. 2003;41:1183–1190

Abstract

Hyperuricemia is associated with hypertension, vascular disease, renal disease, and cardiovascular events. In this report, we review the epidemiologic evidence and potential mechanisms for this association. We also summarize experimental studies that demonstrate that uric acid is not inert but may have both beneficial functions (acting as an antioxidant) as well as detrimental actions (to stimulate vascular smooth muscle cell proliferation and induce endothelial dysfunction). A recently developed experimental model of mild hyperuricemia also provides the first provocative evidence that uric acid may have a pathogenic role in the development of hypertension, vascular disease, and renal disease. Thus, it is time to reevaluate the role of uric acid as a risk factor for cardiovascular disease and hypertension and to design human studies to address this controversy.

Uric acid, a product of purine metabolism, is degraded in most mammals by the hepatic enzyme, urate oxidase (uricase), to allantoin, which is freely excreted in the urine. However, during the Miocene epoch (20 to 5 million years ago), 2 parallel but distinct mutations occurred in early hominoids that rendered the uricase gene nonfunctional.1 As a consequence, humans and the great apes have higher uric acid levels (>2 mg/dL) compared with most mammals (<2 mg/dL).

Uric acid levels also vary significantly within humans as the result of factors that increase generation (such as high purine or protein diets, alcohol consumption, conditions with high cell turnover, or enzymatic defects in purine metabolism) or decrease excretion. A reduction in glomerular filtration rate (GFR) increases serum uric acid, although a significant compensatory increase in gastrointestinal excretion occurs.2 Hyperuricemia also may result from increased net tubular absorption. After filtration, uric acid undergoes both reabsorption and secretion in the proximal tubule, and this process is mediated by a urate/anion exchanger and a voltage-sensitive urate channel.3,4 Organic anions such as lactate decrease urate secretion by competing for urate through the organic anion transporter, whereas several substances, including probenacid and benziodarone, have opposite effects.5 Hyperuricemia is usually defined as >6.5 or 7.0 mg/dL in men and >6.0 mg/dL in women.

Hyperuricemia Is Increased in Subjects at Cardiovascular Risk

Serum uric acid is frequently elevated in subjects at cardiovascular risk (Table 1).6–15 Uric acid is higher in men and postmenopausal women because estrogen is uricosuric.8 In subjects with obesity, insulin resistance, and dyslipidemia (“the metabolic syndrome”), hyperuricemia frequently occurs because insulin stimulates sodium and urate reabsorption in the proximal tubule.8 Uric acid is increased in subjects with renal disease as the result of reduction in GFR and renal urate excretion. Diuretics, such as thiazides, increase serum uric acid by stimulating both sodium and urate reabsorption in the proximal tubule. Alcohol intake results in elevated uric acid levels due to increased urate generation (from increased adenine nucleotide turnover) and decreased excretion (due to lactate blocking tubular transport of urate).14,15

TABLE 1. Uric Acid Is Increased in Groups at Cardiovascular Risk

GroupMechanism
GFR indicates glomerular filtration rate.
Postmenopausal women and menEstrogen is uricosuric6
African Americans7Unknown
Renal diseaseDecrease in GFR increases uric acid levels
DiureticsVolume contraction promotes urate reabsorption
Obesity/insulin resistanceInsulin increases sodium reabsorption and is tightly linked to urate reabsorption8
Hypertension9Urate reabsorption increased in setting of increased renal vascular resistance;10 microvascular disease predisposes to tissue ischemia that leads to increased urate generation (from adenosine breakdown) and reduced excretion (due to lactate competing with urate transporter in the proximal tubule);11 some hyperuricemic hypertension may be due to alcohol ingestion12 or lead intoxication13
Alcohol useIncreases urate generation,14 decreases urate excretion15

Uric acid is also commonly associated with hypertension. It is present in 25% of untreated hypertensive subjects, in 50% of subjects taking diuretics, and in >75% of subjects with malignant hypertension.9 The increase in serum uric acid in hypertension may be due to the decrease in renal blood flow that accompanies the hypertensive state, since a low renal blood flow will stimulate urate reabsorption.10 Hypertension also results in microvascular disease, and this can lead to local tissue ischemia.11 In addition to the release of lactate that blocks urate secretion in the proximal tubule, ischemia also results in increased uric acid synthesis.16 With ischemia, ATP is degraded to adenine and xanthine, and there is also increased generation of xanthine oxidase. The increased availability of substrate (xanthine) and enzyme (xanthine oxidase) results in increased uric acid generation as well as oxidant (O2) formation. The finding that ischemia results in an increase in uric acid levels may also account for why uric acid is increased in preeclampsia17 and congestive heart failure.18 Other factors may also contribute to why uric acid is associated with hypertension, including alcohol abuse,12 lead intoxication,13 obesity and insulin resistance,8 and diuretic use.

The observation that an elevated uric acid is associated with subjects at cardiovascular risk may account for why hyperuricemia predicts the development of cardiovascular disease in the general population (Table 2), in subjects with hypertension (Table 3), and in subjects with preexisting cardiovascular disease (Table 4).19–47 Hyperuricemia also predicts stroke in diabetic and nondiabetic subjects48,49 and predicts the development of hypertension50–52 and renal disease in the general population.53 In these studies, uric acid may be simply “marking” subjects at increased cardiovascular and renal risk.54,55 Consistent with this hypothesis, many studies have found that uric acid is not an independent risk factor for cardiovascular disease after controlling for these other risk factors (Tables 2 through 4). Hyperuricemia is therefore considered benign unless associated with gout or kidney stones.56

TABLE 2. Hyperuricemia Predicts Cardiovascular Events: Studies of the General Population

StudyLength of Follow-Up, yUnivariate Correlation With EventsIndependent Predictor in Multivariate Analyses
*Subanalysis of men with gout.
‡For all-cause mortality.
†Includes original participants of the Framingham Study who took part in the 13th biennial exam and participants of the Framingham Offspring Study.
Framingham
    19851926YesNo
    19872030YesYes (women)
    19882132*YesYes
    19992217.3Only womenNo
Honolulu Heart (Japanese American men)
    1975232YesYes
    19952420YesYes
    19962521YesYes (in alcohol abstainers)
Chicago Heart Association Detection Project
    1979265YesYes (only women)
    19892711.5Only womenYes (only women)
NHANES I
    19952813.5YesYes (only women)
    20002916.4YesYes
ARIC (Atherosclerosis Risk in Communities Study)
    2000308Only womenNo
British Regional Heart Study (adult males)
    19973116.8YesNo
Social Institute of Finland
    1982325YesNo
Gothenburg
    19883312YesYes
MONICA (Monitoring Trends and Determinants in Cardiovascular Diseases)
    1999348YesYes
CASTEL (Cardiovascular Study in the Elderly)
    1993357YesYes

TABLE 3. Hyperuricemia Predicts Cardiovascular Events: Studies of the Hypertensive Population

StudyLength of Follow-Up, yUnivariate Correlation with EventsIndependent Predictor in Multivariate Analyses
*Patients with isolated systolic hypertension;
†subanalysis of patients on thiazides.
Hypertension Detection Follow-Up Program Cooperative Research Group
    1985365YesYes
    1987375YesOnly women
Work site
    1999386.6YesYes
PIUMA (Progetto Ipertensione Umbria Monitoraggio Ambulatoriale)
    2000394YesYes
European Working Party on High BP in the Elderly
    1991403YesNo
SHEP (Systolic Hypertension in the Elderly Program)*
    2001415YesYes
Syst-China*
    2001423YesYes
Syst-Eur*
    2002432NoNo

TABLE 4. Hyperuricemia Predicts Cardiovascular Events in Patients With Pre-Existing Cardiovascular Disease

StudyUnivariate Correlation With EventsIndependent Predictor in Multivariate Analyses
Coronary Drug Project Research Group, 197644YesNo
French Canadian Study, 197345NoNot done
Atherogene Study, 200246YesYes
The Heart Institute of Spokane, 200247YesYes

Nevertheless, some studies find uric acid predictive for the development of cardiovascular disease, hypertension, and renal disease despite controlling for associated risk factors. This raises the possibility that uric acid may have a pathogenic role in hypertension and cardiovascular disease. Indeed, recently soluble uric acid has been recognized to not be inert but rather to have several biological actions that could either be beneficial or detrimental to humans. We now review these studies and provide an interpretation for how they may relate to human disease.

Uric Acid as an Antioxidant: A Protective Factor in Cardiovascular Disease?

An important observation was that uric acid may function as an antioxidant, and possibly one of the most important antioxidants in plasma.57–59 Urate (the soluble form of uric acid in the blood) can scavenge superoxide, hydroxyl radical, and singlet oxygen and can chelate transition metals.57–59 Peroxynitrite is a particularly toxic product formed by the reaction of superoxide anion with nitric oxide that can injure cells by nitrosylating the tyrosine residues (nitrotyrosine formation) of proteins. Uric acid can also block this reaction.60

Recently, Hink et al61 reported that uric acid may also prevent the degradation of extracellular superoxide dismutase (SOD3), an enzyme critical in maintaining endothelial and vascular function. SOD3 is an extracellular enzyme that catalyzes the reaction of superoxide anion (O2·) to hydrogen peroxide (H2O2). The removal of O2· by SOD3 prevents the reaction and inactivation by O2· of the important endothelial vasodilator, nitric oxide (NO). SOD3, by removing O2·, therefore helps to maintain NO levels and maintain endothelial function.

Normally, SOD3 is inactivated in the presence of H2O2, suggesting a feedback inactivation of the enzyme. However, uric acid blocks SOD inactivation by H2O2 by regenerating SOD3 with the production of a urate radical.61 This latter radical, although potentially a pro-oxidant, has been found to be markedly less reactive than classic oxidants and can be rapidly regenerated back to urate in the presence of ascorbate.62

Ames et al57 hypothesized that the uricase mutation occurred during early hominoid evolution because the antioxidant action of uric may have provided an evolutionary advantage and that this may account for the greater longevity of humans and the great apes compared with most other primates. The increase in serum uric acid in subjects with cardiovascular disease might therefore reflect a compensatory mechanism to counter the oxidative stress that occurs in these conditions.63 However, this does not readily explain why higher uric acid levels in patients with cardiovascular disease are generally associated with worse outcomes (Tables 3 and 4).

Is Uric Acid a Mediator of Hypertension and Renal Disease?

Uric Acid, Endothelial Dysfunction, and Impaired Nitric Oxide Production

Endothelial dysfunction, local oxidant generation, elevated circulating cytokines, and a proinflammatory state are common in patients with cardiovascular disease.18,64 Endothelial dysfunction is often demonstrated by showing an impaired NO release in response to acetylcholine, which results in impaired endothelium-dependent vasodilation. Oxidants may cause endothelial dysfunction by reacting with and removing the NO. The observation that xanthine oxidase generates oxidants and uric acid in settings of tissue ischemia potentially explains why uric acid is associated with endothelial dysfunction and oxidative stress in conditions such as heart failure and diabetes.65–67 Hyperuricemia is also associated with the activation of circulating platelets, which also may reflect endothelial dysfunction.68 Allopurinol, which inhibits xanthine oxidase and hence blocks both uric acid and oxidant formation, can reverse the impaired endothelial NO production in both heart failure and type 2 diabetes.65–67 Allopurinol has also been reported to reduce cardiovascular complications after coronary artery bypass68–70 and in patients with dilated cardiomyopathy.71 Although the beneficial effects correlate with the lowering of uric acid in some of these studies, most authorities have hypothesized that the beneficial effect of allopurinol is to reduce oxidative stress.65–70

Uric acid may contribute to endothelial dysfunction. Waring et al72 have reported that uric acid infusion in healthy humans resulted in impaired acetylcholine-induced vasodilation in the forearm, thereby documenting impaired endothelial NO release. Serum uric acid and serum nitric oxide levels also vary during the day in a reciprocal pattern, suggesting a pattern of physiological regulation.73 Recent studies in experimental animal models have also found that mild hyperuricemia inhibits the nitric oxide system in the kidney (see below).

The mechanism by which uric acid impairs endothelial function is not known. However, whereas uric acid is considered an antioxidant, it is also pro-oxidative under certain conditions, especially when other antioxidants are at a low level.74,75

Uric Acid, Vascular Smooth Muscle Cell Proliferation, and Inflammation

Uric acid also stimulates rat vascular smooth muscle cell proliferation in vitro.76–79 Vascular smooth muscle cells do not express a receptor for uric acid but rather have organic anion transporters that allow urate uptake.80 Once inside the vascular smooth muscle cell, uric acid activates specific mitogen activated protein kinases (Erk1/2) with the de novo induction of cyclooxygenase-2 (COX-2), local thromboxane formation, and with upregulation of platelet-derived growth factor A (PDGF A) and C-chain and PDGF-α receptor mRNA76–79 (Figure). The uric acid-induced cell proliferation can be inhibited by blocking any member of this pathway.76–79

Pathway for uric acid-mediated vascular smooth muscle cell proliferation. Uric acid is posited to enter into vascular smooth muscle cell through an anion exchanger/transporter (OAT), where it alters intracellular redox, activates mitogen activated protein kinases (Erk1/2 and p38), COX-2, and nuclear transcription factors (NFκB and AP-1), leading to synthesis of thromboxane (TXA2), PDGF and PDGF receptors, and MCP-1.

Soluble uric acid also is proinflammatory. Uric acid stimulates synthesis of monocyte chemoattractant protein-1 (MCP-1) in rat vascular smooth muscle cells by activating p38 MAP kinase and the nuclear transcription factors, NF-κB and AP-1.81 MCP-1 is a chemokine that is important in vascular disease and atherosclerosis.82 Soluble uric acid also stimulates human mononuclear cells to produce interleukin-1β, interleukin-6, and tumor necrosis factor (TNF)-α.83 Infusion of uric acid into mice also leads to a marked increase in circulating TNF-α levels.84 Thus, in experimental and in vitro systems, uric acid appears to have the ability to induce inflammatory and vascular mechanisms that may contribute to rather than protect against the development of cardiovascular disease.

Experimental Models: Hypertension in Hyperuricemic Rats

Recently, mild hyperuricemia was developed in rats through the use of a uricase inhibitor (oxonic acid). Unlike previous hyperuricemic models,85,86 this model was associated with no urate crystal deposition in the kidney and relatively preserved renal function.87 A remarkable observation, now documented by two different laboratories, was that systemic hypertension developed in hyperuricemic rats after several weeks.77,78,87,88 The hypertension was associated with increased renin and a decreased neuronal nitric oxide synthase (NOS1) in the juxtaglomerular apparatus.87 The hypertension was prevented by administration of an ACE inhibitor and to a lesser extent by l-arginine (a substrate for nitric oxide), thereby confirming a key role for renin-angiotensin and NOS systems in the blood pressure elevation. The hypertension and changes in renin and NOS1 were also prevented by maintaining uric acid levels in the normal range with allopurinol or benziodarone (a uricosuric).87

Hyperuricemic rats were also shown to have salt sensitivity (that is, a greater increase in blood pressure for the same sodium load compared with normal rats).78 An explanation for the mechanism comes from studies in other experimental models that have shown that salt sensitivity may result from preglomerular vascular disease.89 Experimental models associated with preglomerular vascular disease have renal ischemia, leading to the infiltration of leukocytes into the interstitium that generate local oxidants, altering the balance of local vasoregulatory factors favoring vasoconstriction, and resulting in a reduction in sodium excretion, a shift in pressure natriuresis, and an increase in blood pressure. Elements of this pathway have been demonstrated in a variety of animal models, and the salt sensitivity can be prevented or ameliorated by interrupting this pathway.89

Consistent with this pathway of salt sensitivity, chronically hyperuricemic rats have thickening and hypercellularity of the afferent arteriole of the glomerulus, with inward hypertrophic vascular remodeling, leading to an increase in medial thickness and a reduction in lumen diameter.78 The arteriolopathy occurs independent of blood pressure, although it is dependent on the renin-angiotensin system.77 In concert with the development of preglomerular vascular disease, rats manifest subtle tubulointerstitial inflammation and fibrosis.78 Once these renal changes develop, salt sensitivity can be shown. At this point, the kidney is driving salt sensitivity because correction of the elevated uric acid level is no longer protective.78

Experimental Hyperuricemia and Renal Injury

Renal injury also occurs in hyperuricemic rats, consisting of afferent arteriolopathy, mild tubulointerstitial fibrosis, glomerular hypertrophy, and eventually, glomerulosclerosis and albuminuria.90 Micropuncture studies document that this is associated with an increase in glomerular hydrostatic pressure.88 The renal changes are prevented if serum uric acid is maintained in the normal range with allopurinol. 88,90

Experimental hyperuricemia also accelerated injury in established models of renal disease. Hyperuricemia exacerbates cyclosporine nephropathy in rats, resulting in worse tubulo-interstitial injury and arteriolar hyalinosis with increased renin and a greater loss of macula densa NOS1 and renal NOS3 expression.91 Hyperuricemia also accelerated progression in the remnant kidney model and resulted in higher blood pressure, more proteinuria, worse renal function, and more glomerulosclerosis and tubulo-interstitial fibrosis.79 These rats also had severe vasculopathy, involving the interlobular artery and afferent arteriole with de novo expression of COX-2 in the blood vessels and increased renal renin expression. The renal changes were significantly improved by reducing uric acid levels with allopurinol.

Do the Experimental Studies Provide New Insights?

The observation that hyperuricemic animals have salt sensitivity and increased blood pressure provide an additional mechanism to explain why the uricase mutation occurred in early hominoid evolution. Thus, the uricase mutation may have provided an evolutionary advantage to early hominoids by maintaining blood pressure under the low sodium dietary conditions of that period.78

The observation that experimental hyperuricemia causes hypertension, intrarenal vascular disease, renal disease, and vascular inflammation in rats may also provide the long-sought pathogenic mechanism by which uric acid could cause cardiovascular disease in humans.

Is there evidence that uric acid causes hypertension in humans? Epidemiological studies show a continuous relation of serum uric acid with blood pressure that is stronger in younger subjects with some dampening over time,19,20,92 which is consistent with the experimental studies that demonstrate that once sufficient renal injury occurs that animals develop salt-sensitive hypertension regardless of the uric acid levels.78 Hyperuricemia is also an independent risk factor for predicting the development of hypertension (Table 5).51,52 To date, no studies have examined whether lowering uric acid will reduce blood pressure in hypertensive humans, but it should be noted that the above studies suggest that lowering uric acid would be more effective at preventing rather than treating hypertension, for once the intrarenal vascular disease develops, the hypertension would then be expected to be driven by the kidney. Hyperuricemia also correlates with plasma renin activity,93,94 and renal renin expression is also increased in hyperuricemic rats.87

TABLE 5. Hyperuricemia Predicts the Development of Hypertension

*Shown to independently predict the development of hypertension.
Israeli Ischemic Heart Study, 197250
Kaiser Permanente Medical Care Program, 199051*
Olivetti Heart Study, 199452*

Does uric acid cause renal disease in humans? Patients with gout frequently have renal dysfunction (25% to 40% of cases), with histologic injury in the majority.95 The renal lesion consists of variable degrees of arteriolosclerosis, glomerulosclerosis, and interstitial fibrosis, often with focal deposition of urate crystals in the outer medulla.95 Many authorities have ascribed the renal lesion to coexistent hypertension or aging-associated renal disease.96 However, this type of analysis cannot account for all of the renal injury observed.97

Recently, an elevated uric acid has been reported to predict the development of renal insufficiency in individuals with normal renal function.55 Uric acid is an independent predictor for progression in IgA nephropathy.98,99 Hyperuricemia also correlates with the development of renal dysfunction in type II diabetes100 and independently predicts progression in renal transplant patients on cyclosporine (Al-Uzri AY, Prather JC, Norman DJ, Gloconda S, and de Mattos AM. Hyperuricemia as a risk factor for renal allograft loss, American Transplant Congress, 2002, abstract). In contrast, it remains unclear if uric acid is a risk factor for progression in subjects with established renal disease. Although experimental studies suggest uric acid may act as a risk factor for progression,79 in the MDRD study, uric acid was not found to be a risk factor.101 Furthermore, whereas some studies report an improvement in renal function with the lowering of uric acid in gouty subjects,102,103 others have not been able to confirm these findings.104

How about the role of uric acid in mediating the systemic inflammatory response and endothelial dysfunction in humans? As discussed earlier, uric acid infusion into humans causes endothelial dysfunction,72 and allopurinol improves endothelial dysfunction in subjects with congestive heart failure or diabetes.65–67 Uric acid also stimulates the production of cytokines from leukocytes and chemokines from vascular smooth muscle cells. This suggests a potential role for uric acid or for xanthine oxidase in mediating the systemic inflammatory response that is linked to cardiovascular events.

Finally, these studies may provide insights into why uric acid is not always found to be an independent risk factor for cardiovascular events. Thus, if uric acid caused cardiovascular disease as a consequence of causing hypertension or renal disease, then it would not be expected to be independent of these latter variables when evaluated as risk factors for cardiovascular events. Furthermore, in the SHEP trial, in which diuretics were shown to reduce cardiovascular mortality rates in the elderly, a recent subanalysis showed that the cardioprotection was lost in those treated patients in whom uric acid levels increased.41 It is therefore of interest that many studies that failed to show uric acid to be an independent risk factor for cardiovascular events found that the association of uric acid with cardiovascular events was attenuated by either the presence of hypertension or the use of diuretics.22,30,31,34,44

Another reason why uric acid may not always be an independent risk factor for cardiovascular events could be that the beneficial antioxidant actions of uric acid may partially counter its potential detrimental effects. It is of interest that almost all studies examining the relation of uric acid levels with cardiovascular events show a J-shaped curve with the nadir of risk being in the second quartile.20–25,28,29,39,43,44 Although speculative, it is possible that the increased risk for the lowest quartile reflects the decreased plasma antioxidant activity, whereas the increased risk at higher levels reflects the role of uric acid in inducing vascular disease and hypertension.

In conclusion, recent evidence supports a role for uric acid as a true cardiovascular risk factor, particularly for the development of hypertension and renal disease. Studies need to be performed in humans to prove or disprove this possibility before lowering uric acid is routinely recommended. Given that hyperuricemia causes preglomerular vascular disease in rats, one might posit that it may be easier to show a role for uric acid in hypertension by designing preventive trials as opposed to treatment trials. However, it is possible that treating hyperuricemia may be effective in lowering blood pressure when the hyperuricemia has not been present for a long period (such as in children with hypertension and in patients given short-term treatment with cyclosporine or diuretics) or when subjects are given a low salt diet (which would remove the renal injury-dependent mechanism).

This study was supported by National Institutes of Health grants HL-68607, DK-52121, and 1P50DK-064233-01. Dr Mazzali is supported by a postdoctoral grant from FAPESP-Fundação de Amparo a Pesquisa do Estado de S. Paulo, Brazil.

Footnotes

Correspondence to Richard J. Johnson, Baylor College of Medicine, Division of Nephrology, SM-1273, 6550 Fannin St, Houston, TX 77030. E-mail

References

  • 1 Wu X, Muzny DM, Lee CC, Caskey CT. Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol. 1992; 34: 78–84.CrossrefMedlineGoogle Scholar
  • 2 Vaziri ND, Freel RK, Hatch M. Effect of chronic experimental renal insufficiency on urate metabolism. J Am Soc Nephrol. 1995; 6: 1313–1317.CrossrefMedlineGoogle Scholar
  • 3 Leal-Pinto E, Cohen BE, Abramson RG. Functional analysis and molecular modeling of a cloned urate transporter/channel. J Membr Biol. 1999; 169: 13–27.CrossrefMedlineGoogle Scholar
  • 4 Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, Cha SH, Hosoyamada M, Takeda M, Sekine T, Igarashi T, Matsuo H, Kikuchi Y, Oda T, Ichida K, Hosoya T, Shimokata K, Niwa T, Kanai Y, Endou H. Molecular identification of a renal urate-anion exchanger that regulates blood urate levels. Nature. 2002; 417: 447–452.CrossrefMedlineGoogle Scholar
  • 5 Roch-Ramel F, Guisan B, Diezi J. Effects of uricosuric and antiuricosuric agents on urate transport in human brush-border membrane vesicles. J Pharmacol Exp Ther. 1997; 280: 839–845.MedlineGoogle Scholar
  • 6 Nicholls A, Snaith ML, Scott JT. Effect of oestrogen therapy on plasma and urinary urate levels. BMJ. 1973; 1: 449–451.CrossrefMedlineGoogle Scholar
  • 7 Hochberg MC, Thomas J, Thomas DJ, Mead L, Levine DM, Klag MJ. Racial differences in the incidence of gout. Arthritis Rheum. 1995; 38: 628–632.CrossrefMedlineGoogle Scholar
  • 8 Galvan AQ, Natali A, Baldi S, Frascerra S, Sanna G, Ciociaro D, Ferrannini E. Effect of insulin on uric acid excretion in humans. Am J Physiol. 1995; 268: E1–E5.CrossrefMedlineGoogle Scholar
  • 9 Cannon PJ, Stason WB, Demartini FE, Sommers SC, Laragh JH. Hyperuricemia in primary and renal hypertension. N Engl J Med. 1966; 275: 457–464.CrossrefMedlineGoogle Scholar
  • 10 Messerli FH, Frohlich ED, Dreslinski GR, Suarez DH, Aristimuno GG. Serum uric acid in essential hypertension: an indicator of renal vascular involvement. Arch Intern Med. 1980; 93: 817–821.Google Scholar
  • 11 Puig JG, Ruilope LM. Uric acid as a cardiovascular risk factor in arterial hypertension. J Hypertens. 1999; 17: 869–872.CrossrefMedlineGoogle Scholar
  • 12 Ramsay LE. Hyperuricemia in hypertension: role of alcohol. BMJ. 1979; 1: 653–654.CrossrefMedlineGoogle Scholar
  • 13 Sánchez-Fructuoso AI, Torralbo A, Arroyo M, Luque M, Ruilope LM, Santos JL, Cruceyra A, Barrientos A. Occult lead intoxication as a cause of hypertension and renal failure. Nephrol Dial Transplant. 1996; 11: 1775–1780.CrossrefMedlineGoogle Scholar
  • 14 Faller J, Fox IH. Ethanol-induced hyperuricemia. evidence for increased urate production by activation of adenine nucleotide turnover. N Engl J Med. 1982; 307: 1598–1602.CrossrefMedlineGoogle Scholar
  • 15 Lieber CS, Jones DP, Losowsky MS, Davidson CS. Interrelation of uric acid and ethanol metabolism in man. J Clin Invest. 1962; 41: 1863–1870.CrossrefMedlineGoogle Scholar
  • 16 Friedl HP, Till GO, Trentz O, Ward PA. Role of oxygen radicals in tourniquet related ischemia reperfusion injury of human patients. Klin Wochenschr. 1991; 69: 1109–1112.CrossrefMedlineGoogle Scholar
  • 17 Many A, Hubel CQA, Roberts JM. Hyperuricemia and xanthine oxidase in preeclampsia, revisited. Am J Obstet Gynecol. 1996; 174: 288–291.CrossrefMedlineGoogle Scholar
  • 18 Leyva F, Anker S, Swan JW, Godsland IF, Wingrove CS, Chua TP, Stevenson JC, Coats AJ. Serum uric acid as an index of impaired oxidative metabolism in chronic heart failure. Eur Heart J. 1997; 8: 858–865.Google Scholar
  • 19 Brand FN, McGee DL, Kannel WB, Stokes J, Castelli W. Hyperuricemia as a risk factor of coronary heart disease: the Framingham study. Am J Epidemiol. 1985; 121: 11–18.CrossrefMedlineGoogle Scholar
  • 20 Kannel WB. Metabolic risk factors for coronary heart disease in women: perspective from the Framingham Study. Am Heart J. 1987; 114: 413–419.CrossrefMedlineGoogle Scholar
  • 21 Abbott RD, Brand FN, Kannel WB, Castelli WP. Gout and coronary heart disease: the Framingham study. J Clin Epidemiol. 1988; 41: 237–42.CrossrefMedlineGoogle Scholar
  • 22 Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk of cardiovascular disease and mortality: the Framingham Heart Study. Ann Intern Med. 1999; 31: 7–13.CrossrefGoogle Scholar
  • 23 Kagen A, Gordon T, Rhoads GG, Schiffman JC. Some factors related to coronary heart disease incidence in Honolulu Japanese men: the Honolulu Heart Study. Int J Epidemiol. 1975; 4: 271–279.CrossrefMedlineGoogle Scholar
  • 24 Goldberg RJ, Burchfiel CM, Benfante R, Chiu D, Reed DM, Yano K. Lifestyle and biologic factors associated with atherosclerotic disease in middle-aged men. Arch Intern Med. 1995; 155: 686–694.CrossrefMedlineGoogle Scholar
  • 25 Iribarren C, Sharp DS, Curb JD, Yano K. High uric acid: a metabolic marker of coronary heart disease among alcohol abstainers? J Clin Epidemiol. 1996; 49: 673–678.CrossrefMedlineGoogle Scholar
  • 26 Persky VW, Dyer AR, Idris-Soven E, Stamler J, Shekelle RB, Schoenberger JA, Berkson DM, Lindberg HA. Uric acid: a risk factor for coronary heart disease? Circulation. 1979; 59: 969–977.CrossrefMedlineGoogle Scholar
  • 27 Levine W, Dyer AR, Shekelle RB, Schoenberger JA, Stamler J. Serum uric acid and 11.5-year mortality of middle-aged women: findings of the Chicago Heart Association Detection Project in Industry. J Clin Epidemiol. 1989; 42: 257–267.CrossrefMedlineGoogle Scholar
  • 28 Freedman DS, Williamson DF, Gunter EW, Byers T. Relation of serum uric acid to mortality and ischemic heart disease. Am J Epidemiol. 1995; 141: 637–644.CrossrefMedlineGoogle Scholar
  • 29 Fang J, Alderman MH. Serum uric acid and cardiovascular mortality: the NHANES I epidemiologic follow-up study, 1971–1992. JAMA. 2000; 283: 2404–2410.CrossrefMedlineGoogle Scholar
  • 30 Moriarity JT, Folsom AR, Iribarren C, Nieto FJ, Rosamond WE. Serum uric acid and risk of coronary heart disease: atherosclerosis risk in communities (ARIC) Study. Ann Epidemiol. 2000; 10: 136–143.CrossrefMedlineGoogle Scholar
  • 31 Wannamethee SG, Shaper AG, Whincup PH. Serum urate and the risk of major coronary heart disease events. Heart. 1997; 78: 147–153.CrossrefMedlineGoogle Scholar
  • 32 Reunanen A, Takkunen H, Knekt P, Aromaa A. Hyperuricemia as a risk factor for cardiovascular mortality. Acta Med Scand. 1982; 668: 49–59.Google Scholar
  • 33 Bengtsson C, Lapidus L, Stendahle C, Waldenstrom J. Hyperuricemia and risk of cardiovascular disease and overall death: a 12-year follow-up of participants in the population study of women in Gothenburg, Sweden. Acta Med Scand. 1988; 224: 549–555.CrossrefMedlineGoogle Scholar
  • 34 Liese AD, Hense H-W, Löwel H, Döring A, Tietze M, Keil U. Association of serum uric acid with all-cause and cardiovascular disease mortality and incident myocardial infarction in the MONICA Augsburg Cohort. Epidemiology. 1999; 10: 391–397.CrossrefMedlineGoogle Scholar
  • 35 Casiglia E, Spolaore P, Ginocchio G, Colangeli G, Di Menza G, Marchioro M, Mazza A, Ambrosio GB. Predictors of mortality in very old subjects aged 80 years or over. Eur J Epidemiol. 1993; 9: 577–586.CrossrefMedlineGoogle Scholar
  • 36 Hypertension Detection, and Follow-up Program Cooperative Research Group. Mortality findings for stepped-care and referred-care participants in the Hypertension Detection and Follow-up Program, stratified by other risk factors. Prev Med. 1985; 14: 312–335.CrossrefMedlineGoogle Scholar
  • 37 Langford HG, Blaufox MD, Borhani NO, Curb JD, Molteni A, Schneider KA, Pressel S. Is thiazide-produced uric acid elevation harmful? Analysis of data from the Hypertension Detection and Follow-up Program. Arch Intern Med. 1987; 147: 645–649.CrossrefMedlineGoogle Scholar
  • 38 Alderman MH, Cohen H, Madhavean S, Kivlighn S. Serum uric acid and cardiovascular events in successfully treated hypertensive patients. Hypertension. 1999; 34: 144–150.CrossrefMedlineGoogle Scholar
  • 39 Verdecchia P, Schilllaci G, Reboldi GP, Santeusanio F, Porcellati C, Brunetti P. Relation between serum uric acid and risk of cardiovascular disease in essential hypertension: the PIUMA Study. Hypertension. 2000; 36: 1072–1078.CrossrefMedlineGoogle Scholar
  • 40 Staessen J. The determinants and prognostic significance of serum uric acid in elderly patients of the European Working Party on High Blood Pressure in the Elderly trial. Am J Med. 1991; 90: 50S–53S.MedlineGoogle Scholar
  • 41 Franse LV, Pahor M, Di Bari M, Shorr RI, Wan JY, Somes GW, Applegate WB. Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program. J Hypertens. 2000; 18: 1149–1154.CrossrefMedlineGoogle Scholar
  • 42 Wang J-G, Staessen JA, Fagard RH, Birkenhäger 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.CrossrefMedlineGoogle Scholar
  • 43 De Leeuw PW, Thijs L, Birkenhäger WH, Voyaki SM, Efstratopoulos AD, Fagard RH, Leonetti G, Nachev C, Petrie JC, Rodicio JL, Rosenfeld JJ, Sarti C, Staessen JA. Prognostic significance of renal function in elderly patients with isolated systolic hypertension: results from the Syst-Eur Trial. J Am Soc Nephrol. 2002; 13: 2213–2222.CrossrefMedlineGoogle Scholar
  • 44 Coronary Drug Project Research Group. Serum uric acid: its association with other risk factors and with mortality in coronary heart disease. J Chron Dis. 1976; 29: 557–569.CrossrefMedlineGoogle Scholar
  • 45 Allard C, Goulet C. Serum uric acid: not a discriminator of coronary heart disease in men and women. Can Med Assoc J. 1973; 109: 986–988.MedlineGoogle Scholar
  • 46 Bickel C, Rupprecht HJ, Blankenberg S, Rippin G, Hafner G, Daunhauer A, Hofmann KP, Meyer J. Serum uric acid as an independent predictor of mortality in patients with angiographically proven coronary artery disease. Am J Cardiol. 2002; 89: 12–17.MedlineGoogle Scholar
  • 47 Tuttle KR, Johnson RJ, Short RA. Microalbuminuria and serum uric acid levels as predictors of cardiovascular events over 5 years. J Am Soc Nephrol. 2002; 13: 442A.Abstract.Google Scholar
  • 48 Lehto S, Niskanen L, Rönnemaa T, Laakso M. Serum uric acid is a strong predictor of stroke in patients with non-insulin-dependent diabetes mellitus. Stroke. 1998; 29: 635–639.CrossrefMedlineGoogle Scholar
  • 49 Mazza A, Pessina AC, Pavei A, Scarpa R, Tikhonoff V, Casiglia E. Predictors of stroke mortality in elderly people from the general population. Eur J Epidemiol. 2001; 17: 1097–1104.CrossrefMedlineGoogle Scholar
  • 50 Kahn HA, Medalie JH, Neufeld HN, Riss E, Goldbourt U. The incidence of hypertension and associated factors: the Israeli ischemic heart disease study. Am Heart J. 1972; 84: 171–182.CrossrefMedlineGoogle Scholar
  • 51 Selby JV, Friedman GD, Quesenberry CP. Precursors of essential hypertension: pulmonary function, heart rate, uric acid, serum cholesterol, and other serum chemistries. Am J Epidemiol. 1990; 131: 1017–1027.CrossrefMedlineGoogle Scholar
  • 52 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. 1994; 8: 677–681.MedlineGoogle Scholar
  • 53 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.CrossrefMedlineGoogle Scholar
  • 54 Vaccarino V, Krunholz HM. Risk factors for cardiovascular disease: one down, many more to evaluate. Ann Intern Med. 1999; 131: 62–63.CrossrefMedlineGoogle Scholar
  • 55 Beck L. Requiem for gouty nephropathy. Kidney Int. 1986; 30: 280–287.CrossrefMedlineGoogle Scholar
  • 56 Duffy WB, Sennekjian HO, Knight TF, Weinman EJ. Management of asymptomatic hyperuricemia. JAMA. 1981; 246: 2215–2216.CrossrefMedlineGoogle Scholar
  • 57 Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-causing aging and cancer: a hypothesis. Proc Natl Acad Sci U S A. 1981; 78: 6853–6862.Google Scholar
  • 58 Davies KJ, Sevanian A, Muakkassah-Kelly SF, Hochstein P. Uric acid-iron ion complexes: a new aspect of the anti-oxidant functions of uric acid. Biochem J. 1986; 235: 747–754.CrossrefMedlineGoogle Scholar
  • 59 Simie MG, Jovanovic SV. Antioxidation mechanisms of uric acid. J Am Chem Soc. 1989; 111: 5778–5782.CrossrefGoogle Scholar
  • 60 Squadrito GL, Cueto R, Splenser AE, Valavanidis A, Zhang H, Uppu RM, Pryor WA. Reaction of uric acid with peroxynitrite and implications for the mechanism of neuroprotection by uric acid. Arch Biochem Biophys. 2000; 376: 333–337.CrossrefMedlineGoogle Scholar
  • 61 Hink HU, Santanam N, Dikalov S, McCann L, Nguyen AD, Parthasarathy S, Harrison DG, Fukai T. Peroxidase properties of extracellular superoxide dismutase: role of uric acid in modulating in vivo activity. Arterioscler Thromb Vasc Biol. 2002; 22: 1402–1408.LinkGoogle Scholar
  • 62 Maples KR, Mason RP. Free radical metabolite of uric acid. J Biol Chem. 1988; 263: 1709–1712.CrossrefMedlineGoogle Scholar
  • 63 Nieto FJ, Iribarren C, Gross MD, Comstock GW, Cutler RG. Uric acid and serum antioxidant capacity: a reaction to atherosclerosis? Atherosclerosis. 2000; 148: 131–139.CrossrefMedlineGoogle Scholar
  • 64 Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997; 336: 973–979.CrossrefMedlineGoogle Scholar
  • 65 Farquharson CA, Butler R, Hill A, Belch JJ, Struthers AD. Allopurinol improves endothelial dysfunction in chronic heart failure. Circulation. 2002; 106: 221–226.LinkGoogle Scholar
  • 66 Doehner W, Schoene N, Rauchhaus M, Leyva-Leon F, Pavitt DV, Reaveley DA, Schuler G, Coats AJS. Anker SD, Hambrecht R. Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure. Circulation. 2002; 105: 2619–2624.LinkGoogle Scholar
  • 67 Butler R, Morris AD, Belch JJF, Hill A, Struthers AD. Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Hypertension. 2000; 35: 746–751.CrossrefMedlineGoogle Scholar
  • 68 Mustard JF, Murphy EA, Ogryzlo MA. Smythe HA. Blood coagulation and platelet economy in subjects with primary gout. Can Med Assoc J. 1963; 89: 1207–1211.MedlineGoogle Scholar
  • 69 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.CrossrefMedlineGoogle Scholar
  • 70 Tabayashi K, Suzuki Y, Nagamine S, Ito Y, Sekino Y, Mohri H. A clinical trial of allopurinol (Zyloric) for myocardial protection. J Thorac Cardiovasc Surg. 1991; 101: 713–718.CrossrefMedlineGoogle Scholar
  • 71 Cappola TP, Kass DA, Nelson GS, Berger RD, Rosas GO, Kobeissi ZA, Marban E, Hare JM. Allopurinol improves myocardial efficiency in patients with idiopathic dilated cardiomyopathy. Circulation. 2001; 104: 2407–2411.CrossrefMedlineGoogle Scholar
  • 72 Waring WS, Webb DJ, Maxwell SRJ. Effect of local hyperuricemia on endothelial function in the human forearm vascular bed. Br J Clin Pharmacol. 2000; 49: 511.Google Scholar
  • 73 Kanabrocki EL, Third JL, Ryan MD, Nemchausky BA, Shirazi P, Scheving LE, McCormick JB, Hermida RC, Bremner WF, Hoppensteadt DA, Fareed J, Olwin JH. Circadian relationship of serum uric acid and nitric oxide. JAMA. 2000; 283: 2240–2241.CrossrefMedlineGoogle Scholar
  • 74 Santos CXC, Anjos EI, Augusto O. Uric acid oxidation by peroxynitrite: multiple reactions, free radical formation, and amplification of lipid oxidation. Arch Biochem Biophys. 1999; 372: 285–294.CrossrefMedlineGoogle Scholar
  • 75 Abuja PM. Ascorbate prevents prooxidant effects of urate in oxidation of human low density lipoprotein. FEBS Lett. 1999; 446: 305–308.CrossrefMedlineGoogle Scholar
  • 76 Rao GN, Corson MA, Berk BC. Uric acid stimulates vascular smooth muscle cell proliferation by increasing platelet derived growth factor A-chain expression. J Biol Chem. 1991; 266: 8604–8608.CrossrefMedlineGoogle Scholar
  • 77 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 arteriolopathy in rats by a blood pressure-independent mechanism. Am J Physiol Renal Physiol. 2002; 282: F991–F997.CrossrefMedlineGoogle Scholar
  • 78 Watanabe S, Kang DH, Feng L, Nakagawa T, Kanellis J, Lan H, Mazzali M, Johnson RJ. Uric acid, hominoid evolution, and the pathogenesis salt-sensitivity. Hypertension. 2002; 40: 355–360.LinkGoogle Scholar
  • 79 Kang D, Nakagawa T, Feng L, Truong L, Harris RC, Johnson RJ. A role for uric acid in renal progression. J Am Soc Nephrol. 2002; 13: 2888–2897.CrossrefMedlineGoogle Scholar
  • 80 Han L, Kanellis J, Li P, Feng L, Nakagawa T, Kooyer S, Watanabe S, Ohashi R, Kahm AM, Johnson RJ. The evidence for a functional organic anion transporter in vascular smooth muscle cells. Presented at: American Society of Nephrology 35th Annual Meeting and Scientific Exposition. October 30–November 4, 2002; Philadelphia, Pa. In: Program and Abstracts;13:329A. Abstract.Google Scholar
  • 81 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 MCP-1 production in vascular smooth muscle cells via MAPK and COX-2. Hypertension. 2003; 41: 1287–1293.LinkGoogle Scholar
  • 82 Gu L, Okada Y, Clinton SK, Gerard C, Sukhova GK, Libby P, Rollins BJ. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell. 1998; 2: 275–281.CrossrefMedlineGoogle Scholar
  • 83 Kang DH, Seoh Y, Yoon K-I. A possible link between hyperuricemia and systemic inflammatory reaction as a mechanism of endothelial dysfunction in chronic renal failure. Presented at: American Society of Nephrology 35th Annual Meeting and Scientific Exposition. October 30–November 4, 2002; Philadelphia, Pa. In: Program and Abstracts;13:466A. Abstract.Google Scholar
  • 84 Netea MG, Kullberg BJ, Block WL, Netea RT, van der Meer JW. The role of hyperuricemia in the increased cytokine production after lipopolysaccharide challenge in neutropenic mice. Blood. 1997; 89: 577–582.CrossrefMedlineGoogle Scholar
  • 85 Stavric B, Johnson WJ, Grice HC. Uric acid nephropathy: an experimental model. Proc Soc Exp Biol Med. 1969; 130: 512–516.CrossrefMedlineGoogle Scholar
  • 86 Bradley A, Caskey CT. Hyperuricemia and urate nephropathy in urate oxidase deficient mice. Proc Natl Acad Sci U S A. 1994; 91: 742–746.CrossrefMedlineGoogle Scholar
  • 87 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. 2001; 38: 1101–1106.CrossrefMedlineGoogle Scholar
  • 88 Sanchez-Lozada LG, Tapia E, Avila-Casado C, Soto V, Franco M, Santamaria J, Nakagawa T, Rodriguez-Iturbe B, Johnson RJ, Herrera-Acosta J. Mild hyperuricemia induces glomerular hypertension in normal rats. Am J Physiol Renal Physiol. 2002; 283: F1105–F1110.CrossrefMedlineGoogle Scholar
  • 89 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: 913–923.CrossrefMedlineGoogle Scholar
  • 90 Nakagawa T, Mazzali M, Kang DH, Kanellis J, Watanabe S, Sanchez-Lozada LG, Rodriguez-Iturbe B, Herrera-Acosta J, Johnson RJ. Hyperuricemia causes glomerular hypertrophy in the rat. Am J Nephrol. 2003; 23: 2–7.CrossrefMedlineGoogle Scholar
  • 91 Mazzali M, Kim YG, Suga S, Gordon KL, Kang DH, Jefferson JA, Hughes J, Kivlighn SD, Lan HY, Johnson RJ. Hyperuricemia exacerbates chronic cyclosporine nephropathy. Transplantation. 2001; 71: 900–905.CrossrefMedlineGoogle Scholar
  • 92 Klein RN. Serum uric acid: its relationship to coronary heart disease risk factors and cardiovascular disease: Evans County, Georgia. Arch Intern Med. 1973; 132: 401–410.CrossrefMedlineGoogle Scholar
  • 93 Saito I, Saruta T, Kondo K, Nakamura R, Oguro T, Yamagami K, Ozawa Y, Kato E. Serum uric acid and the renin-angiotensin system in hypertension. J Am Geriatr Soc. 1978; 26: 241–247.CrossrefMedlineGoogle Scholar
  • 94 Gruskin AB. The adolescent with essential hypertension. Am J Kidney Dis. 1985; 6: 86–90.CrossrefMedlineGoogle Scholar
  • 95 Talbott JH, Terplan KL. The Kidney in gout. Medicine. 1960; 39: 405–467.MedlineGoogle Scholar
  • 96 Beck L. Requiem for gouty nephropathy. Kidney Int. 1986; 30: 280–287.CrossrefMedlineGoogle Scholar
  • 97 Johnson RJ, Kivlighn SD, Kim Y-G, Suga S, Fogo A. Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease, and renal disease. Am J Kidney Dis. 1999; 33: 225–234.CrossrefMedlineGoogle Scholar
  • 98 Syrjänen J, Mustonen J, Pasternak A. Hypertriglyceridemia and hyperuricemia are risk factors for progression of IgA nephropathy. Nephrol Dial Transplant. 2000; 15: 34–42.CrossrefGoogle Scholar
  • 99 Ohno I, Hosoya T, Gomi H, Ichida K, Okabe H, Hikita M. Serum uric acid and renal prognosis in IgA nephropathy. Nephron. 2001; 87: 333–339.CrossrefMedlineGoogle Scholar
  • 100 Bo S, Cavallo-Perin P, Gentile L, Repetti E, Pagano G. Hypouricemia and hyperuricemia in type 2 diabetes: two different phenotypes. Eur J Clin Invest. 2001; 31: 318–321.CrossrefMedlineGoogle Scholar
  • 101 Hunsicker LG, Adler S, Caggiula A, England BK, Greene T, Kusek JW, Rogers NL, Teschan PE. Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study. Kidney Int. 1997; 51: 1908–1919.CrossrefMedlineGoogle Scholar
  • 102 Briney WG, Ogden D, Bartholomew B, Smyth CJ. The influence of allopurinol on renal function in gout. Arthritis Rheum. 1975; 18: 877–881.CrossrefMedlineGoogle Scholar
  • 103 Perez-Ruiz F, Calabozo M, Herrero-Beites AM, Garcia-Erauskin G, Pijoan JI. Improvement of renal function in patients with chronic gout after proper control of hyperuricemia and gouty bouts. Nephron. 2000; 86: 287–291.CrossrefMedlineGoogle Scholar
  • 104 Rosenfeld JB. Effect of allopurinol administration on serial GFR in normotensive and hypertensive hyperuricemic subjects. Adv Exp Med Biol. 1974; 41B: 581–596.Google Scholar

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