Plasma Xanthine Oxidase Activity Is Predictive of Cardiovascular Disease in Patients with Chronic Kidney Disease, Independently of Uric Acid Levels

Abstract

Background: Chronic kidney disease (CKD) is associated with increased cardiovascular morbidity and mortality. Oxidative stress seems to play a pivotal role in this process, and purine metabolism may be involved in CKD-related oxidative stress. Xanthine oxidase (XO) is an enzyme involved in purine metabolism and is also responsible for the production of reactive oxygen species. Methods: This prospective study aimed to analyze the relation between plasma dosages of molecules involved in redox balance, purine metabolism and cardiovascular events in patients with non-diabetic CKD stages 3-5 or on chronic hemodialysis (HD). CKD (n = 51) and HD (n = 50) patients were compared to matched healthy controls (n = 38) and followed-up for 3 years. Results: Both CKD and HD patients had decreased plasma levels of antioxidants (selenium, zinc, vitamin C). HD patients had decreased levels of the antioxidant enzyme superoxide dismutase and increased levels of oxidation products (ischemia-modified albumin, malondialdehyde [MDA]). The following substrates and enzymes involved in purine metabolism were increased in the HD cohort: adenosine, adenosine deaminase and the pro-oxidant XO. XO activity was negatively correlated with super oxide dismutase and positively with MDA. Interestingly, XO activity was an independent predictor of cardiovascular events in CKD and HD patients, regardless of uric acid levels. Uric acid was not predictive of events. Conclusion: This highlights a possible role of XO itself in CKD-related cardiovascular disease (CVD) and raises the hypothesis that beneficial effects observed with XO inhibitors on CVD in CKD may also be due to the reduction of oxidative stress.

The Relationship between Xanthine Oxidoreductase and Xanthine Oxidase Activities in Plasma and Kidney Dysfunction

“…This result is in line with the report by Otaki et al, in which eGFR of "low XOR" group (53 ± 25 mL/min/1.73 m2) was significantly lower than that of "normal XOR" group (68 ± 26 mL/min/1.73 m2) [21]. On the other hand, Gondouin et al reported the "increase" of XOR activity in accordance with renal dysfunction [31]. To measure XOR activity, Gondouin et al used the "classical method", in which XOR activity is measured as urate level after administration of xanthine to the specimen.…”

Allopurinol therapy improves vascular endothelial function in subjects at risk for cardiovascular diseases: a meta‐analysis of randomized controlled trials

“…47 In fact, a recent study of patients with CKD demonstrated that plasma xanthine oxidase activity is predictive of CVDs independently of UA levels. 48 Taken together, these results suggested that allopurinol may confer benefits to reduce the risk factors for cardiovascular disease independent of its UA-lowering effect.…”

“…Indeed, a previous study in a cohort of hypertensive nephropathy patients with impaired kidney function indicated that the use of allopurinol appears to be beneficial in preventing cardiovascular morbidity and all‐cause mortality without a significant influence on serum UA, suggesting that the benefits of allopurinol may be independent of its UA‐lowering effect . In fact, a recent study of patients with CKD demonstrated that plasma xanthine oxidase activity is predictive of CVDs independently of UA levels . Taken together, these results suggested that allopurinol may confer benefits to reduce the risk factors for cardiovascular disease independent of its UA‐lowering effect.…”

Is Serum Uric Acid Independently Associated With Left Ventricular Mass Index, Ejection Fraction, and B-Type Natriuretic Peptide Among Female and Male Cardiac Patients?

“…32) However, in these two studies, increased risk in subjects with low and high SUA was shown (J-shaped); therefore, the pattern differed from our observation (inverse J-shaped). Considering that an inverse J-shaped association was present only in female patients, it may suggest that not SUA per se, but other related factors, such as xanthine oxidase activity, 33) might explain the observed link between SUA and LVH. This possibility needs to be examined in future studies.…”