One of the most common causes of dementia is vascular cognitive impairment (VCI), which is strongly associated with chronic hypertension, cerebral microvascular disease, and the development of diffuse lesions of the white matter [6]. One of the key risk factors appears to be disease of the cerebral arterioles, which results in altered cerebral autoregulation that makes the distal cortex vulnerable to changes in blood pressure (BP), thereby increasing the risk to reduced cerebral pressure in the presence of low BP or to elevated cerebral pressure with sudden increases in systemic BP [6].

Hypertension is also associated with microvascular disease of the kidney (arteriolosclerosis), and experimental studies have also shown that its presence also alters renal autoregulation and increases the risk for renal progression (the Herrera hypothesis) [7,8]. Since hypertension is associated with both renal and cerebral arteriolar disease, one might expect the two conditions to be commonly present in the same individual, thus providing a link between CKD and VCI. Indeed, in subjects with type 2 diabetes, the presence of cerebral microvascular disease (as manifested by silent cerebral infarction) is associated with increased risk for progression of renal disease [9].

While these studies implicate hypertension as the cause of arteriolar disease that then predisposes subjects to CKD and VCI, recent studies have suggested that elevated serum uric acid could also act as an etiologic factor [10]. Hyperuricemic rats develop renal microvascular disease involving the afferent arteriole that alters the autoregulatory response and results in glomerular hypertension [11,12]. In the remnant kidney model of CKD, the induction of hyperuricemia does not result in severe preglomerular arteriolar disease, and is associated with accelerated decline in renal function [13]. Importantly, the control of hypertension by thiazides in hyperuricemic rats does not block the development of renal arteriolopathy [14]. Rather, uric acid may directly induce vascular smooth muscle cell proliferation through a mechanism involving the stimulation of platelet-derived growth factor [15,16].

SSME scores ranged between 20 and 30 in all subjects, and showed a normal distribution. When SSME scores were categorized according to quartiles of serum uric acid, a progressive worsening of SSME scores were observed with increasing quartile of serum uric acid suggestive of worsening cognitive dysfunction (fig. ​(fig.1;1; p = 0.019). However, post-hoc analysis demonstrated that there was no linear trend, and only groups 1 and 4 were different with respect to SMMSE scores (p = 0.025).

By univariate analysis, SSMSE scores correlated with age (rho: −0.337, p < 0.0001), serum creatinine (rho: −0.132, p = 0.039), blood urea nitrogen (rho: −0.159, p = 0.012), diastolic BP (rho: +0.125, p = 0.01) and serum uric acid (rho: −0.261, p ≤ 0.0001). A weak but statistically significant relationship between uric acid (logarithmic values) and SMMSE score was observed (fig. ​(fig.2;2; r = 0.297, p < 0.001).

The major new finding is that elevated serum uric acid was independently associated with worse cognitive function in subjects with CKD. Our data are consistent with previous reports – mainly from healthy elderly – suggesting that serum uric acid predicts cognitive decline and white matter lesions are consistent with cerebral ischemia [19,21]. Elevated serum uric acid has also been shown to predict both hypertension and stroke by meta-analyses [25,26]. The observation that elevated uric acid can also induce vascular smooth muscle cell proliferation in vitro [14,15] and induce renal microvascular disease in vivo [12,27] suggests that it may also be able to induce cerebral microvascular disease, which underlies the development of VCI [28].

Of note, there are some contradictory data. Serum uric acid levels tend to be low in subjects with established Alzheimer's dementia or VCI [29,30,31]. Some studies also suggest that elevated uric acid might reduce the risk for progression of dementia in subjects with underlying impaired cognitive function [32]. One study reported that the risk for developing dementia in subjects with a high uric acid is due to the frequent coexistence of hypertension and cardiovascular disease, and in the absence of such associated risk factors, elevated uric acid may actually reduce the risk for dementia [33].

Several potential mechanisms might account for such an apparent paradox. For example, since serum uric acid reflects to some extent the nutritional status, a lower uric acid could reflect a reduction in intake as may be observed in subjects with progressive dementia. In dialysis patients, for example, lower uric acid levels are associated with low serum albumin, a bedridden state, or a history of cerebrovascular accident [34]. A lower serum uric acid may also reflect a reduction in serum antioxidants, which has been postulated to increase the risk for Alzheimer's dementia [29,30,31]. This possibility is based on studies that show that uric acid is a major antioxidant in human plasma and can scavenge numerous oxidants in vitro, including superoxide, hydroxyl radical and peroxynitrite [35,36]. However, when uric acid reacts with peroxynitrite, it will also generate free radicals in the process, including triuretcarbonyl and aminocarbonyl radicals [37]. Furthermore, while uric acid is an antioxidant in the extracellular environment, inside the cell it induces endothelial dysfunction [38], oxidative stress [39,40,41], inflammation [42,43] and stimulation of vasoactive mediators such as thromboxane and angiotensin II [13,39,40]. Thus, it remains possible that uric acid might have both deleterious and beneficial effects on neural function. Nevertheless, our studies suggest that in CKD the presence of elevated uric acid is associated with worse cognitive function. Furthermore, pilot studies suggest that lowering uric acid in subjects with CKD may have beneficial effects on renal function, BP, and inflammation, and in one study it was associated with a marked (70%) reduction in cardiovascular events [44,45,46].

Our study has limitations. First, our study is cross-sectional, and hence cause and effect can not be ascertained. Second, the overall impact of elevated uric acid on cognitive function was relatively weak, even though it was statistically significant. Third, we did not perform computed tomography or MRI in our patients to determine a relationship of uric acid with white matter lesions such as observed in subjects with VCI. Thus, we can not rule out the possibility of subtle/silent cerebral lesions. Fourth, the SMMSE is not the gold standard for the detection of cognitive dysfunction; however, it is easy to administer and provides a global score of cognitive ability that correlates with function in activities of daily living [23].