Narrative Review
Uric Acid as a Target of Therapy in CKD

https://doi.org/10.1053/j.ajkd.2012.07.021Get rights and content

The prevalence of chronic kidney disease (CKD) has increased and will continue to increase in the United States and worldwide. This is alarming considering that CKD is an irreversible condition and patients who progress to chronic kidney failure have reduced quality of life and high mortality rates. As such, it is imperative to identify modifiable risk factors to develop strategies to slow CKD progression. One such factor is hyperuricemia. Recent observational studies have associated hyperuricemia with kidney disease. In addition, hyperuricemia is largely prevalent in patients with CKD. Data from experimental studies have shown several potential mechanisms by which hyperuricemia may contribute to the development and progression of CKD. In this article, we offer a critical review of the experimental evidence linking hyperuricemia to CKD, highlight gaps in our knowledge on the topic as it stands today, and review the observational and interventional studies that have examined the potential nephroprotective effect of decreasing uric acid levels in patients with CKD. Although uric acid also may be linked to cardiovascular disease and mortality in patients with CKD, this review focuses only on uric acid as a potential therapeutic target to prevent kidney disease onset and progression.

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.

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