Hyperuricemia in Chronic Kidney Disease: a role yet to be explained

Abstract

Hyperuricemia is commonly found in the general population, with a prevalence of about 20 to 25% in adult men and slightly lower prevalence in pre-menopausal women. In both genders, incidence increases with age 1. The prevalence of chronic kidney disease (CKD) has been increasing in the past few years, with its morbidity and mortality not only related to the end-stage renal disease (ESRD), but also with cardiovascular disease. As such, every effort must be made to slow its progression. Emerging evidence suggests that the relationship between hyperuricemia and CKD is more than just a marker of renal dysfunction, playing a much more important role in its pathogenesis and progression, and cardiovascular morbidity-mortality as well. If that association proves to be true, the next question would be when to treat hyperuricemia, and which drugs should be used. Allopurinol has been used for a long time, but febuxostat has been showing growing evidence not only regarding the control of hyperuricemia, but also on slowing CKD progression. In this review, we will try to answer those questions, while describing the most recent evidence on hyperuricemia as a risk factor for CKD and its management in those patients. BIOLOGICAL BASES Uric Acid Homeostasis Uric acid (UA) is a compound endogenously produced by the purine metabolism. These purines, generated in the liver (either from dietary or from endogenous synthesis), are first metabolized into guanine and hypoxanthine, and then into xanthine, which is oxidized into UA by xanthine oxidase 2. Although the reason is not entirely understood, contrary to other mammals, hominids have lost the enzyme uricase, responsible for converting UA into a more soluble molecule 3,4. As such, UA is excreted unmetabolized, mainly by the kidney (about twothirds), and about one-third through the intestinal tract 5,6. Several genes encoding membrane transporters responsible for UA excretion have been identified, such as Abcg2 (ATP-binding cassette subfamily G membrane 2) in the enterocytes and proximal renal tubular epithelium; and others associated with UA reabsorption in the renal tubule, such as URAT1 (urate anion exchanger 1) and GLUT9 (glucose transporter type 9) 7. Physiological Functions UA has two main functions in the human body. The first is related to its role in the elimination of nitrogenous compounds, such as ammonia and urea. The second is derived from its potent antioxidant activity, which is so important that more than half of normal human's free-radical scavenging capacity in the serum is related to UA 8,9. This ability is of great importance to the microvascular endothelium, where UA prevents oxidative inactivation of endothelial enzymes, maintaining its ability to mediate vascular dilation in situations of oxidative stress 10. Apart from its beneficial biological effects, higher levels of UA have been linked to a higher risk of cardiovascular disease, with several studies describing it as an independent risk predictor of cardiovascular mortality 10,11. This duality has been named ...

Association of uric acid and uric acid to creatinine ratio with chronic kidney disease in hypertensive patients

“…Recent studies have shown that soluble SUA exhibits a behavioral duality acting as pro-oxidant within the cell and antioxidant in the extracellular environment [ 3 , 4 ]. The remnant of circulating SUA accounts for more than half of the antioxidant potential of human blood [ 5 ]. However, when it is inside the cells, it exhibits a pro-oxidant behavior [ 6 ].…”

“…In patients with CKD, the level of SUA may be increased due to decreased excretion capacity of the kidneys [ 7 ]. On the other hand, some studies suggest that hyperuricemia causes renal injury by vasoconstriction mediated by endothelium dysfunction, activation of the renin-angiotensin system and epithelial changes in renal tubular cells [ 5 , 11 ]. SUA may also be associated with the development of CKD through some factors, such as organ toxicity and worsening of risk factors for CKD, such as arterial hypertension (AH) [ 5 , 12 ].…”

A systematic review and meta-analysis of the association between uric acid levels and chronic kidney disease

“…UA is the final product of purine catabolism from exogenous sources, through diet, and endogenous, by cell degradation 10 . The remnant of circulating UA accounts for more than half of the antioxidant potential of human blood 11 . However, when it is inside the cells, it exhibits a pro-oxidant behavior, stimulating the production of free radicals and pro-inflammatory cytokines, reducing the bioavailability of vasodilator substances and increasing vasoconstrictor substances such as angiotensin, which lead to oxidative stress, chronic inflammation and endothelial dysfunction, the tripod of the pathogenesis and progression of CKD 12 , 13 .…”

Association of serum uric acid with albuminuria in type 2 diabetic patients with comorbid obesity and/or essential arterial hypertension

“…There are several mechanisms by which high levels of uric acid increases the risk for CKD development and progression [31,32]: direct toxicity to the kidney; exacerbation of other risk factors for kidney disease, such as hypertension; or by being a marker of the severity of other risk factors, including those attributable to or associated with DM and the metabolic syndrome. In a study in rats, hyperuricemia increased systemic blood pressure, proteinuria, renal dysfunction, progressive renal scarring and induced vascular disease via a cyclooxygenase-2-dependent pathway [33].…”

“…At the same time despite the vast evidence of an association between hyperuricemia and CKD, there are still conflicting results in clinical studies, with several unanswered questions regarding the role of uric acid as a casual, compensatory or coincidental phenomenon in these patients [32].…”