Curr Hypertens Rep DOI 10.

1007/s11906-013-0391-y

HOT TOPIC

Uric Acid, Hypertension, and Cardiovascular and Renal Complications

Carmine Zoccali & Francesca Mallamaci

# Springer Science+Business Media New York 2013

Abstract Over the last decade, the biologic interference of uric acid with the cardiovascular (CV) system and the kidney has been intensively investigated, and several experimental studies in animal models and in vitro documented that hyperuricemia may trigger hypertension and incite endothelial dysfunction, vascular damage and renal disease. A substantial proportion of epidemiological studies are compatible with the hypothesis that hyperuricemia may be noxious to the CV system and the kidney as well. However, there are still no well-powered trials testing whether uric acidlowering interventions may reduce BP or attenuate the risk for adverse CV and renal outcomes. Evidence still remains largely insufficient to recommend changes in the current policy of not prescribing uric acidlowering drugs to individuals with asymptomatic hyperuricemia. Keywords Uric acid . Hypertension . Chronic kidney disease . CKD . End-stage renal disease . ESRD . Cardiovascular risk . Endothelial dysfunction . Inflammation . Atherosclerosis . Arteriolosclerosis . Nephrosclerosis
C. Zoccali : F. Mallamaci CNR National Research Council (Italy) Clinical Epidemiology and Physiopathology of Renal Disease and Hypertension Unit and Nephrology, Hypertension and Renal Transplantation unit, Ospedali Riuniti, Reggio Calabria 89124, Italy F. Mallamaci e-mail: francesca.mallamaci@libero.it C. Zoccali : F. Mallamaci Renal and Transplantation Unit Ospedali Riuniti, Reggio Calabria 89124, Italy C. Zoccali (*) Nefrologia e CNR, Ospedali Riuniti, Reggio Calabria 89124, Italy e-mail: carmine.zoccali@tin.it

Introduction Uric acid is perhaps one of the first factors to be suspected as a possible cause of hypertension. Mahomed, a prominent nineteenth century British physician, hypothesized that hypertension could be incited by circulating toxins damaging the heart and kidneys via an increase in blood pressure. Among several factors, he singled out uric acid as a main causative factor of high BP and documented hypertension with sphymograph tracings in a patient with gout (quoted by Feig DI [1]). After this seminal observation, interest on uric acid as a noxious factor for the cardiovascular (CV) system waxed and waned. In the nineties it was prevailing view that uric acid is a mere surrogate of other, more important, risk factors such diabetes, overweight and obesity and renal disease [2]. The main reason why the role of uric acid was dismissed as a pro-hypertensive factor and as a CV risk factor rested on the fact that there was no plausible biological hypothesis to explain its prohypertensive effect, and that the association between uric acid and blood pressure and CV complications registered in observational studies is confounded by diabetes and other major risk factors. Over the last two decades, groundbreaking experimental work in animal and in vitro models and epidemiological studies have given new impetus to research on the health risks of uric acid. Herein we will review (1) experimental studies showing that hyperuricemia disturbs endothelial function and integrity and incites arterial damage, (2) epidemiological studies looking at the association between uric acid and hypertension. Additionally, in this section we will expand upon the relationship between hyperuricemia and CV renal disease and (3) clinical trials testing the effect of uric acidlowering interventions on major clinical end-points including hypertension, the risk of CV complications and progressive chronic kidney disease (CKD).

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Experimental Evidence in Animal and In Vitro Models That Uric Acid Affects Endothelial Function and Integrity and That High Uric May Incite Arterial Damage Arteriolosclerosis is a hallmark of high blood pressure. When present in the renal vasculature, such a lesion appears to be critical for the very generation and maintenance of hypertension [3]. Arteriolosclerosis in the kidney extends from interlobular arteries to afferent arterioles. Intimal thickening, vascular fibrosis and smooth muscle hyperplasia are widespread across this reno-vascular territory. These alterations have long been considered just as a mere consequence of hypertension. According to this view, microvascular disease develops in rats exposed to high-salt diet and DOCA [4], while in vitro high pressure is a strong stimulus for endothelial [5] and vascular smooth muscle cells proliferation [6]. In the kidney, afferent arteriole vasoconstriction serves to protect the kidney from systemic hypertension. Microvascular lesions typical of arteriosclerosis are evident in the remnant kidney model, i.e., an established model of CKD. On the other hand, arteriolosclerosis can be triggered independently of hypertension in experimental animals. Angiotensin II induces a microvascular disease indistinguishable from arteriolosclerosis [7], as it induces nitric oxide (NO) antagonism [8]. Of note, fructose, a main ingredient of a western-style diet which increases serum uric acid, is an established trigger of the same alteration [9]. The plasma concentration of uric acid in the general population has a wide range which extends from 1 mg/dl to 12 mg/dl [10]. Uric acid per se is an anti-oxidant responsible for the 60 % of the total antioxidant capacity in humans and therefore high uric levels have been interpreted as a potential counter-regulatory, protective response to oxidant stress in CV diseases [11]. Hyperuricemia is an established, modifiable risk factor for gout or kidney stones, but the clinical evidence-base that it is also causally implicated in hypertension and cardiovascular disease is still insufficient. Therefore, current guidelines do not recommend treatment of asymptomatic hyperuricemia. Notwithstanding that the quality of clinical studies produced so far is still inadequate to promote uric acid to the first league of cardiovascular risk factors, the biological implication of hyperuricemia in vascular and kidney disease is impressive. Basic science studies convincingly documented that uric acid can directly promote vascular smooth muscle cell proliferation, stimulate the synthesis of inflammatory and vasoconstrictive substances and enhance the production of reactive oxygen species [1215]. Uric acid inhibits basal and vascular endothelial growth factor (VEGF)induced nitric oxide production in bovine aortic endothelial cells [16]. Oxonic acid, an inhibitor of the enzyme which degrades uric acid (uricase), causes mild hyperuricemia in rats and the occurrence of this alteration goes in parallel with a rise in blood pressure, renal vasoconstriction and arteriolosclerosis

[17], a phenomenon attributed to increased local synthesis of angiotensin II and reduced endothelial NO generation and oxidative stress (reviewed by Johnson R et al. [18]). Uric acid in the kidney suppresses 1- hydroxylation of vitamin D, a key metabolic step in 1,25-(OH)2 vitamin D synthesis [19], a fundamental factor for the regulation of mineral metabolism and a well know modulator of the renin-angiotensin system [20]. This phenomenon is of relevance in patients with CKD because the administration of allopurinol over 1 week causes a 25 % increase in serum 1,25-(OH)2 vitamin D [21]. Since this active form of vitamin D affects endothelial function, impaired synthesis of this sterol could be a relevant mechanism whereby hyperuricemia engenders vascular disease. Whether the angiotensin IIdependent noxious effects of uric acid at arteriolar levels in vivo are independent of hypertension remains uncertain. Prevention of hypertension in hyperuricemic rats with hydrochlorothiazide [22] does not to protect these animals from microvascular disease, while both renal arteriolopathy and hypertension are prevented by enalapril and losartan. However, this study was criticized because it was based on a sub-optimal method of measurement of BP (tail-cuff BP). In rats with angiotensin IIinduced hypertension in which BP is kept at normal levels in one kidney and left to raise in the contralateral kidney, the normotensive kidney displays trivial vascular lesions notwithstanding it is exposed to the same concentration of angiotensin II of the contralateral hypertensive kidney [23]. Thus it remains uncertain whether angiotensin II (the purported mediator of uric acid arteriolopathy) may cause microvascular disease independently of hypertension. Uric acid directly impairs NO generation in endothelial cells in vitro [24]. In animals with mild hyperuricemia induced by uricase inhibition, serum nitrate (a biomarker which broadly reflects NO synthesis) is reduced and such an effect is completely reversed by allopurinol [24]. In contrast, shortterm infusion of uric acid in normal subjects does not modify the forearm blood flow response to acetylcholine, sodium nitroprusside, and L-NG-monomethylarginine [25] which would be against the hypothesis that uric acid impairs endothelial function in humans. The acute and the chronic response to hyperuricemia may not coincide. In a large cross-sectional study in uncomplicated, untreated subjects with essential hypertension uric acid was inversely related with the hemodynamic response to acetyl-choline in the forearm [26]. Endothelial dysfunction in essential hypertensives is associated with mild to moderate CKD [27] and therefore such an association may at least in part be the expression of renal insufficiency. Furthermore, the uric acidendothelial function relationship in essential hypertensives may result from the confounding effect of components of metabolic syndrome. However, the link between high uric acid and endothelial dysfunction was largely independent of the GFR and components of the metabolic syndrome [26]. Inflammation is an additional

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potential pathway to CV damage by uric acid [28] and uric acid was indeed directly associated with serum C reactive protein (CRP) in essential hypertensives [26]. Yet the uric acidendothelial function link in the same study remained highly significant also after adjustment for CRP, an observation indicating that inflammation-independent pathways play a role in the putative effect of uric acid on endothelial function. Figure 1 depicts the link between uric acid hypertension and microvascular disease in the kidney. As discussed, basic science and clinical studies indicate that coexistence of hypertension, high angiotensin II and low NO availability represents the risk factors combination which mediates the noxious effects of uric acid on the endothelium and the arterial system.

Epidemiological Evidence That Uric Acid Predicts Hypertension and Hypertension-Related Complications (CV and Renal Disease) Uric Acid and Hypertension Several observational studies have shown that high uric acid predicts the incidence rate of hypertension in population based studies. Young conscripts in the top uric acid tertile manifested a doubling in the risk of incident hypertension over a 5-years follow-up in the Israel ischemic heart study [29]. This association emerged also in African Americans in the Coronary Artery Risk Development In Young Adults (CARDIA) cohort
Fig. 1 In the kidney hyperuricemia triggers high angiotensin II levels and decreases nitric oxide synthesis which cause an afferent arteriolopathy (first arrow ) with intimal hyperplasia, muscular hypertrophy and jalinosis as well as interstitial inflammation (second arrow ) which eventuates in fibrosis. On the other hand, the same process in the vascular system results in endothelial dysfunction, inflammation and atherosclerosis. Hypertension secondary to microvascular renal disease amplifies arterial damage and concur with atherosclerosis in producing a high risk for cardiovascular complications

[30] and in other cohort studies in Asians and Asian Americans [3135]. The excess risk for hypertension by uric acid materializes early in life being evident in children and adolescents both in Europe [36, 37] and in the USA [38]. Studies in older individuals appear less consistent [2, 3941]. Intriguingly, the association between uric acid and CV risk in adult patients becomes much weaker in multivariate analyses including blood pressure [2, 42]. This phenomenon is compatible with the hypothesis that CV complications by hyperuricemia are mediated via raised BP. Two longitudinal studies in Japan coherently confirmed that uric acid predicts a moderate increase in the risk for incident hypertension in young adults [34] or in 3560-year-old adult men [31]. Similarly, in children and young adults in the Bogalusa Heart Study [43], relatively higher uric acid levels within the normal range predicted a risk excess for incident hypertension. In the Framingham Heart Study uric acid was an independent predictor of the incidence of hypertension [44]. Collectively, the association between uric acid and incident hypertension is robust across various races and ethnicities and across young and middle age populations. However, such an association appears to be weak or absent in elderly individuals. Uric Acid and CV Disease The association of uric acid with CV disease and the implication of hyperuricemia for CV diseases was elegantly discussed in a review by Feig [45]. Hyperuricemia associates with

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peripheral atherosclerosis as well as with carotid and coronary atherosclerosis. Increased uric acid is directly related with the incidence of stroke, dementia and pregnancyrelated hypertensive disorders [2, 42, 4650]. The relationship of uric acid with CV complications is remarkably strong in women and in patients at high risk for cardiac and arterial complications [51]. However consistent, these observational studies do not provide conclusive evidence about the nature of the link between uric acid and CV disease. In the absence (see below) of wellpowered clinical trials, the causal implication of uric acid in CV disease in humans still remains questionable. Uric Acid and Chronic Kidney Disease An inverse relationship between high serum uric acid levels and the GFR has been reported in a large number of crosssectional analyses in population-based studies and in studies in patients with CV diseases. As commented above, nonexperimental studies are inherently inadequate to establish causality in that hyperuricemia may be both a trigger and a consequence of CKD. Longitudinal studies are a better methodological approach for the study of the uric acidCKD association than cross-sectional studies. Iseki et al. were the first to link uric acid with the risk of developing end-stage kidney disease in a community study in Japan involving about 50,000 subjects with a 9-year follow-up [52]. At least five studies associated high uric acid levels and the incident risk of CKD or the incident risk of GFR decline over time. In the Coronary Artery Calcification in type I Diabetes (CACTI) study in subjects with normal albumin excretion rate at baseline, a 1-mg/dl increase in uric acid predicted a 80 % risk excess of developing microalbuminuria over a 6-year follow-up [53]. Similarly, in patients with type 1 diabetes and high-normal albuminuria or frank microalbuminuria, the eGFR decline went along with serum uric acid levels being 36 % in patients with baseline serum uric acid >6 mg/dl and just 9 % in those with levels <3 mg/dl [54]. In a combined analysis of the Atherosclerosis Risk in Communities and the CV Health Study, including over 13,000 individuals with normal renal function at baseline, a 1-mg/dl increase in uric acid predicted a modest (7 %) excess risk for incident CKD which was independent of other factors [55]. Observations in these American cohorts were confirmed in a community-based study in Vienna where mild hyperuricemia (7.08.9 mg/dl) was independently associated with a 26 % risk excess for incident CKD over a median follow up of 7 years [56]. Of note, multivariate analyses in this study showed that BP was the variable that determined the highest attenuation of the risk for CKD by uric acid, an observation compatible with the hypothesis that the effect of uric acid on the kidney is in large part mediated via raised BP. In a recent study that enrolled 900 healthy normotensive blood donors with normal GFR who were followed up for 5 years, uric acid at baseline predicted the decline of the eGFR over time [57].

In contrast to the positive association of uric acid with incident CKD in cohort studies in individuals without CKD at baseline, studies in patients with established CKD produced disparate results. Uric acid associated with mortality in the Modification of Diet in Renal Disease Study (MDRD) but not with CKD progression [58]. In a Chinese study including about 3,000 stage 35 CKD patients, uric acid predicted allcause death and CV events, as well as the risk for end-stage kidney disease (ESKD) or a fast CKD progression in unadjusted analyses, but the risk for faster CKD progression was no longer significant in appropriately adjusted analyses. Similar findings were reported in the Mild to Moderate Kidney Disease study [59]. On the other hand, high uric acid predicted CKD progression in two studies in patients with IgA nephropathy [60, 61] and earlier onset of hypertension and the risk for ESKD in patients with adult polycystic kidney disease [62]. The inherent variability of uric acid levels over time may explain the inability of observational studies to capture the link between uric acid and CKD. Uric acid levels in CKD depend on several factors which are not stable over time in this population, including hydration status and use of diuretics, allopurinol and other drugs, acidbase status and GFR loss. Therefore, prevailing uric acid levels may not reflect the true uric acid burden in CKD. The concentration of uric acid in plasma has an important genetic control and the strongest genetic marker of uric acid levels is the intronic SNP rs734553 of GLUT9 urate transporter [63]. Because genes are randomly transmitted at mating (Mendelian randomization), polymorphisms in the GLUT9 urate transporter gene may represent an instrumental variable to further explore the link between uric acid and renal outcomes in cohort studies [64]. In this regard, it is interesting to note that the rs734553 polymorphism in the GLUT9 gene but not serum uric acid levels predicted progression towards kidney failure in a sizable cohort of CKD patients [65]. Findings in this genetic epidemiology study are compatible with a causative role of uric acid and further highlight the urgent need of clinical trials aimed at testing the hypothesis that lowering uric acid levels may slow the progression of CKD.

Clinical Trial Testing the Effect of Uric Acid-Lowering Interventions on Major Clinical End-Points Including Hypertension, the Risk of CV Complications and Progressive Chronic Kidney Disease (CKD) We discussed that the epidemiologic association between uric acid and hypertension was coherently observed in children, adolescents and young adults but not in the elderly. Therefore, clinical trials in children and in young populations are of particular relevance. In a case series of five adolescents with essential hypertension treated with allopurinol for 1 month, a

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coherent decline in office BP and 24-h ambulatory blood pressure was registered. In this uncontrolled study, four out five participants became normotensive [65]. In a randomized, placebo-controlled clinical trial with allopurinol in 30 hypertensive adolescents, 67 % subjects on allopurinol achieved normotension while the corresponding figure in the placebo arm was just 3 % [66]. If confirmed in larger trials and in other populations, these findings have enormous potential for CV and renal disease prevention. If uric acid engenders a renal microvascular disease which triggers salt sensitivity and hypertension, early treatment of mild hyperuricemia may avert hypertension and the CV and renal sequels of hypertension in a substantial proportion of the general population. In line with pilot studies with allopurinol in adolescents, small clinical trials in CKD patients [6769] suggest a benefit of uric acid lowering interventions on renal disease progression but the lack of large scale clinical trials testing the effect of these interventions on major clinical end-points, like progression to kidney failure, leaves unresolved whether uric acid is causally implicated in CKD progression. As to CV disease, there are still no trials testing the effect of uric acid lowering on CV events. It was claimed that the uricosuric effect of Losartan may at least in part explain the reduction in CV events by this drug [70]. However, cardiovascular protection by Losartan is not superior to that by other angiotensin receptor blockers devoid of uricosuric effect. Confirming previous observations in CKD patients [71], a very recent study [72] in patients with left ventricular hypertrophy (LVH) and ischemic heart disease documented that high-dose allopurinol regresses LVH and improves endothelial function in these patients but does not modify 24-h ambulatory BP. The effect of allopurinol on LV mass in this study was quantitatively modest but of the same order of that registered in hypertensive patients with LVH in the LIFE study [73]. However small, this effect may not be of trivial importance because in the LIFE study Losartan produced a 13 % reduction in death and CV events. While the recent trial in patients with LVH [72] and the previous one in CKD [71] indicate that allopurinol might favorably impact upon the high CV risk of patients with CKD or with LVH and cardiac ischemia, these studies cannot be taken as evidence that the reduction of serum uric acid is the mechanism underlying the benefit by allopurinol in these patients. Blocking xanthineoxidase has effects well beyond uric acid lowering, because this enzyme is a key player in oxidative stress modulation in health and disease states as well.

changes in the policy of not prescribing uric acidlowering drugs to individuals with asymptomatic hyperuricemia. Allopurinol is a drug which may have serious adverse effects. The issue of safer uric acid lowering drugs remains an unmet clinical need. Availability of these drugs actually represents a critical issue for advancing knowledge on the relevance of raised uric acid in hypertension and in CV disease in the clinical arena.

Compliance with Ethics Guidelines Conflict of Interest Carmine Zoccali and Francesca Mallamaci declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

References Papers of particular interest, recently published, have been highlighted as: Of importance Of major importance
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Conclusion The hypothesis that uric acid is a hypertension trigger and a risk factor for CV and renal disease still remains to be proven. Evidence accumulated so far is insufficient to recommend

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