Narrative ReviewUric Acid as a Target of Therapy in CKD
Section snippets
Uric Acid Homeostasis
Uric acid is an end product of purine metabolism that is produced mainly by the liver and intestines, but also by other peripheral tissues, such as muscles, the endothelium, and the kidneys. Under normal conditions, two-thirds of the uric acid produced is eliminated in the urine and one-third is removed by the biliary tree. Although uric acid occurs predominantly as a urate anion under physiologic pH, more uric acid than urate is present in urine (pH 5-6).11 In the kidney, urate is filtered
A Plausible Role for Uric Acid in Kidney Disease
Traditionally, hyperuricemia associated with hyperuricosuria has been postulated to cause kidney disease by depositing intraluminal crystal in the collecting duct of the nephron in a manner reminiscent of gouty arthropathy.16, 17 Individuals with increased serum uric acid levels secondary to high dietary purine intake also may have lower than normal urinary pH, favoring even more uric acid in urine than urate. Considering that uric acid is less soluble than urate, this milieu would favor uric
Uric Acid as a Predictor of Human Kidney Disease
In the last 2 decades, a large number of observational studies have examined the potential link between increased serum uric acid levels and CKD.34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57 These studies (summarized in Table 1) have shown conflicted results in some instances. For example, an analysis of the Cardiovascular Health Study (CHS),45 which involved 5,808 participants with 5 years of follow-up, showed no significant association between
Uric Acid and Xanthine Oxidase
As indicated, a major challenge in understanding the potential role of uric acid in CKD is that it is a product of xanthine oxidase in conjunction with reactive oxidative species. Xanthine oxidoreductase exists in 2 forms, xanthine dehydrogenase and xanthine oxidase. When grouped together, the dehydrogenase and oxidase forms catalyze the final step in purine metabolism by converting hypoxanthine to xanthine and xanthine to urate/uric acid. Xanthine oxidoreductase has an important role in
Treatment of Hyperuricemia in CKD
In general, xanthine oxidase inhibitors such as allopurinol or febuxostat are the preferred agents to decrease uric acid levels due to their effectiveness in both overproducers and undersecretors of uric acid. Allopurinol is metabolized by xanthine oxidase to oxypurinol, and both substrates act to inhibit xanthine oxidase.65 Patients with CKD may be at increased risk of toxicity with allopurinol (eg, rash, gastrointestinal intolerance, leukopenia, and severe hypersensitivity reaction) because
Hyperuricemia in Kidney Transplantation
Hyperuricemia is common in patients after kidney transplantation.85 Although increased uric acid levels in this setting may represent decreased transplant function, hyperuricemia has been reported even in patients with intact transplant function.81 Several factors contribute to hyperuricemia after transplantation, such as cyclosporine therapy, use of diuretics, and the high prevalence of metabolic syndrome and diabetes in kidney transplant recipients.86 Although hyperuricemia contributes to
Conclusions
Hyperuricemia is common in CKD. Experimental evidence suggests that uric acid itself may harm patients with CKD by contributing to increased inflammation and CKD progression. Although controversial, these observations are supported by many large prospective observational studies that show increased serum uric acid levels that predict the development and progression of CKD in various populations. Interventional studies, although sparse, suggest that decreasing uric acid levels in hyperuricemic
Acknowledgements
Support: This review was supported by the following grants: 1K23DK088833, 1R01 DK081473-01A1, and 1R01DK078112-01A2, as well as ISN Fellowship.
Financial Disclosure: The authors declare that they have no relevant financial interests.
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Originally published online October 11, 2012.