Uric Acid in Hypertension and Renal Disease: The Chicken or the Egg?

After uric acid was recognized as the causative factor in gout, increased prevalence of renal disease and hypertension in this patient population caught the attention of the medical community. Thus, it has been proposed that uric acid might have caused these disorders. However, uric acid suffered a long period of ignorance in which it was considered a metabolically inert substance. However, recent years has witnessed a resurrection of interest. Experimental studies showed an association between increased uric acid and renal arteriolar disease and hypertension. These preliminary results were supported with clinical studies. However, controversy regarding the precise pathophysiologic role of uric acid in inducing hypertension and renal disease remains to be elucidated. Despite being limited at this time, a few randomized intervention studies showed that even treatment of asymptomatic hyperuricemia was beneficial in terms of blood pressure regulation and kidney function. In this review, we focus on the pathophysiologic role of uric acid in Received: August 4, 2010 Accepted: September 7, 2010 Published online: November 20, 2010 Mehmet Kanbay, MD Alparslan Mahallesi, Umit sokak No:25/14, Melikgazi Kayseri (Turkey) Tel. +90 505 266 8866, Fax +90 352 223 97 53, E-Mail drkanbay @ yahoo.com © 2010 S. Karger AG, Basel 0253–5068/10/0304–0288$26.00/0 Accessible online at: www.karger.com/bpu D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /2 3/ 20 17 2 :4 5: 26 A M Uric Acid in Hypertension and Renal Disease Blood Purif 2010;30:288–295 289 creased serum uric acid level a primary initiating factor or merely a secondary phenomenon to abnormal/decreased kidney function and hypertension? Second, is uric acid a pathogenetic factor per se or a surrogate marker of disease [3] ? To some extent, these two questions have been settled via experimental, epidemiologic and interventional studies. One of the difficulties of implicating uric acid in the pathogenesis of hypertension and kidney disease is that most of the traditional risk factors are also associated with elevated uric acid. Thus, controlling for confounding factors has been a major concern of past epidemiologic studies. Furthermore, there is a dual role of uric acid both as a proand as an anti-oxidant molecule. This review will primarily focus on the direct effects of uric acid elevation on the development of hypertension and kidney disease. We will briefly discuss the pathophysiology of uric acid-induced hypertension and kidney disease, along with a summary of clinical and epidemiologic studies pointing to a causal role of uric acid in these disease states. Uric Acid Metabolism Uric acid is the end-product of purine nucleotide metabolism in humans. In contrast to many lower vertebrates, humans lack uric acid oxidase (uricase), an enzyme which further catalyses uric acid to allantoin [4] . Some argued that this evolutionary absence of a uricase enzyme enabled humans to cope with increased oxidative stress, considering the antioxidant capabilities of uric acid. However, recent evidence indicating the intracellular pro-oxidative effects of uric acid challenges this putative evolutionary benefit. Humans have higher serum uric acid levels when compared to other mammals due to the lack of uricase [5] . Xanthine oxidoreductase enzyme catalyses the last two steps of uric acid synthesis, which are blocked by allopurinol and febuxostat. Uric acid is primarily excreted via the urine. The balance between dietary intake and endogenous metabolism of purines, and the urinary excretion rate of uric acid determines plasma uric acid levels. Renal handling of uric acid is dependent on a number of urate transporters, including urate transporter 1 (URAT1), organic ion transporters (OAT1 and OAT3) and ATP-dependent urate export transporters (MRP4) [2] . Mechanisms of Uric Acid-Induced Hypertension It is well established that when uric acid is deposited in tissues in the crystalline form, it initiates a proinflammatory state, as seen in gouty arthritis [6] . However, the precise pathogenetic role of soluble uric acid in the serum is somewhat less clear. Moreover, markedly elevated serum uric acid is clearly associated with gouty arthritis and nephrolithiasis, whereas the importance of subtle elevations in uric acid levels still remains to be established. For many years, uric acid was regarded as a metabolically inert substance. However, several lines of evidence have demonstrated that soluble uric acid is a strong antioxidant [7] . Uric acid is a powerful scavenger of single oxygen, peroxyl radicals (RO 2) and hydroxyl radicals ( OH) [4] . Uric acid reacts with peroxynitrite and stabilizes eNOS activity [8] . On the other hand, uric acid cannot scavenge superoxide (O2 – ) and the presence of ascorbic acid in the plasma is required for the antioxidant effect of uric acid [9] . Several compounds exist that may alter uric acid’s ability to scavenge oxygen radicals – for example, bicarbonate substantially inhibits the ability of uric acid to prevent tyrosine nitrosylation, a crucial mechanism of the oxidative damage of proteins in the cell [10] . Despite these well-recognized antioxidative effects, uric acid also behaves as a pro-oxidant and proinflammatory factor. A few points should be emphasized to better understand this apparent paradox. First, uric acid acts differently inside the cells or in the extracellular milieu, where it is present in soluble form. While being a potent antioxidant in extracellular fluid, uric acid exerts prooxidative effects once inside the cell [11–12] . This effect is mediated by a NADPH oxidase-dependent pathway [4] . Second, one isoform of xanthine oxidoreductase – xanthine dehydrogenase – undergoes extensive phenotypic conversion to xanthine oxidase under local ischemic conditions. Unlike xanthine dehydrogenase, xanthine oxidase uses molecular oxygen instead of NAD as an electron acceptor [13] . In addition to interference with free radical production, uric acid has some direct effects on endothelial and smooth muscle cells of the vascular wall, which ultimately lead to endothelial dysfunction [14] . In endothelial cells, uric acid blocks nitric oxide release, inhibits endothelial proliferation and stimulates C-reactive protein production [15] . Several experimental studies also showed that uric acid can activate smooth muscle cells via activation of specific MAP kinases, nuclear transcription factors, stimulation of Cox-2, and various inflammatory mediators such as the tissue renin-angiotensin system D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /2 3/ 20 17 2 :4 5: 26 A M Kanbay /Solak /Dogan /Lanaspa /Covic Blood Purif 2010;30:288–295 290 [11, 16–17] . Recent evidence also suggests that renal arteriolar microvascular disease, which will be discussed below, may contribute to uric acid-mediated hypertension [16] . In a landmark study by Mazzali et al. [18] , pharmacologically induced mild-to-moderate hyperuricemia via oxonic acid administration in rats resulted in the development of hypertension. Conversely, when uric acid elevation was treated with allopurinol or with a uricosuric agent, development of hypertension could be prevented. This study supported the hypothesis of a direct causative role of uric acid in the development of hypertension. Other experimental studies investigating renal hemodynamic changes leading to hypertension documented that hyperuricemic rats had higher systemic and intraglomerular pressure, as well as an increase in renal arteriolar resistance and a decrease in renal blood flow [19, 20] . Clinical Studies Demonstrating a Link between Uric Acid, Effects of High Fructose Diets and