Uric acid and inflammation

Uric acid and highly sensitive C reactive protein (hsCRP) each now share a respected inclusion as two of the novel risk markers – risk factors associated with the metabolic syndrome. It is not surprising that these two markers of risk track together within the MS. If there is increased apoptosis and necrosis of vascular cells and inflammatory cells in accelerated – vulnerable atherosclerotic plaques as noted in the above section then one would expect to see an increase in the metabolic breakdown products of RNA and DNA with arginine and guanine to its end product of uric acid. Serum uric acid elevation may indeed be a sensitive marker for underlying vascular inflammation and remodeling within the arterial vessel wall and capillary interstitium.

Is it possible that serum uric acid levels could be as similarly predictive as hsCRP since it is a sensitive marker for underlying inflammation and remodeling within the arterial vessel wall and the myocardium [57].

Should the measurement of serum uric acid be part of the national cholesterol educational program adult treatment panel III and future IV (NCEP ATPIII or the future NCEP ATPIV) clinical guidelines (especially in certain ethnic groups such as females and in the African Americans)?

Uric acid is known to induce the nuclear transcription factor (NF-kappaB) and monocyte chemoattractant protein-1 (MCP-1) [58]. Regarding TNF alpha it has been shown that serum uric acid levels significantly correlate with TNF alpha concentrations in congestive heart failure and as a result Olexa P et al. conclude that serum uric acid may reflect the severity of systolic dysfunction and the activation of an inflammatory reaction in patients with congestive heart failure [59]. Additionally, uric acid also stimulates human mononuclear cells to produce interleukin-1 beta, IL-6, and TNF alpha [11].

Tamakoshi K et al. have shown a statistically significant positive correlation between CRP and body mass index (BMI), total cholesterol, triglycerides, LDL-cholesterol (ldl-C), fasting glucose, fasting insulin, uric acid, systolic blood pressure, and diastolic blood pressure and a significant negative correlation of CRP with HDL-cholesterol (HDL-C)in a study of 3692 Japanese men aged 34–69 years of age. They conclude that there are a variety of components of the MS, which are associated with elevated CRP levels in a systemic low-grade inflammatory state [60].

CRP and IL-6 are important confounders in the relationship between serum uric acid and overall mortality in elderly persons, thus when evaluating this association the potential confounding effect of underlying inflammation and other risk factors should be considered [61].


Uric acid and chronic renal disease

Hyperuricemia can be the consequence of increased uric acid production or decreased excretion. Any cause for decreased glomerular filtration, tubular excretion or increased reabsorption would result in an elevated serum uric acid. Increased serum uric acid has been found to predict the development of renal insufficiency in individuals with normal renal function [11]. In T2DM hyperuricemia seems to be associated with MS and with early onset or increased progression to overt nephropathy, whereas hypouricemia was associated with hyperfiltration, and a later onset or decreased progression to overt nephropathy [62]. An elevated serum uric acid could be advantageous information for the clinician when examining the global picture of T2DM in order to detect those patients who might gain from more aggressive global risk reduction to delay or prevent the transition to overt nephropathy. Elevated serum uric acid contributes to endothelial dysfunction and increased oxidative stress within the glomerulus and the tubulo-interstitium with associated increased remodeling fibrosis of the kidney and as noted earlier in this discussion to be pro-atherosclerotic and proinflammatory. This would have a direct effect on the vascular supply affecting macrovessels, particularly the afferent arterioles. The glomeruli would be affected also through the effect of uric acid on the glomerular endothelium with endothelial dysfunction due to oxidative – redox stress and result in glomerular remodeling. Serum uric acid's effect on hypertension would have an additional affect on the glomeruli and the tubulo-interstitium with remodeling changes and progressive deterioration of renal function. Increased ischemia – ischemia reperfusion would activate the xanthine oxidase mechanism and contribute to an increased production of ROS through H2O2 generation and oxidative stress within the renal architecture with resultant increased remodeling. Hyperuricemia could increase the potential for urate crystal formation and in addition to elevated levels of soluble uric acid could induce inflammatory and remodeling changes within the medullary tubulo-interstitium.

A recent publication by Hsu SP et al. revealed a J-shaped curve association with serum uric acid levels and all-cause mortality in hemodialysis patients [63]. They were able to demonstrate that decreased serum albumin, underlying diabetic nephropathy, and those in the lowest and highest quintiles of serum uric acid had higher all-cause mortality. It is interesting to note that almost all of the large trials with serum uric acid and cardiovascular events have demonstrated this same J shaped curve regarding all-cause mortality with the nadir of risk occurring in the second quartile [11].

Johnson RJ et al. have speculated that the increased risk for the lowest quartile reflects a decreased antioxidant activity, while the increased risk at higher levels reflects the role of uric acid in inducing vascular disease and hypertension through the mechanism of the previously discussed antioxidant prooxidant urate redox shuttle. This would suggest that treatment with xanthine oxidase inhibitors (allopurinol) should strive to bring levels to the 3–4 mg/dl range and not go lower [11].