Hyperuricemia is a modifiable risk factor in the treatment of chronic kidney disease (CKD) and recent advances in the biology of uric acid have led to better understanding of its role in CKD. An article recently published in the January issue of the American Journal of Kidney Diseases explores uric acid as a target of therapy in CKD. Corresponding author Dr. Diana Jalal (DJ) from University of Colorado School of Medicine discussed this review with Dr. Sean Kalloo (eAJKD), eAJKD Contributor.

eAJKD: Can you summarize the focus of this review article on uric acid as a target of therapy in CKD?

DJ: In this manuscript, we discuss the potential role of hyperuricemia in the development and progression of kidney disease. We summarize uric acid homeostasis, discuss the experimental data linking uric acid to kidney disease, and review the epidemiologic studies that have examined high uric acid levels as a predictor of incident kidney disease and CKD progression. In addition, we critique the interventional studies that have evaluated uric acid lowering therapies in CKD.

eAJKD: While one can see the logical progression of uric acid crystals causing kidney disease, you mention the “non-crystal” effects of uric acid. Can you elaborate on these effects?

DJ: Hyperuricemia is known to cause gout. In this disease, uric acid crystals form and deposit in the joints leading to an inflammatory arthritis. Similarly, hyperuricosuria may be associated with uric acid crystallization leading to kidney stone formation. In individuals with tumor lysis syndrome, uric acid crystals are noted in association with acute kidney injury (AKI). While the crystal effects of hyperuricemia are well-described and termed “symptomatic hyperuricemia”, the potentially harmful non-crystal effects of uric acid remain controversial. Data from cell culture and animal experiments suggest that even mild hyperuricemia, in the absence of crystal formation, can lead to inflammation, oxidative stress, endothelial dysfunction, hypertension, and kidney disease. Whether these “non-crystal” effects of hyperuricemia warrant therapy with uric acid lowering agents remains unclear.

eAJKD: There appears to be some uncertainty of the role of serum uric acid levels in CKD progression. What could explain the varying findings in the studies mentioned in your manuscript concerning the role/relationship between serum uric acid and CKD incidence/progression?

DJ: Some of the variation in the observational studies can be explained by the age and co-morbidities of the studied groups. Hyperuricemia tends to be a stronger predictor of risk in high-risk groups such as diabetics and individuals with cardiovascular disease. Other factors such as the length of follow-up may contribute to whether or not hyperuricemia associates with incident kidney disease or CKD progression.

eAJKD: In practice we find a variety of approaches to the management of uric acid in CKD. Many nephrologists would treat hyperuricemia aggressively, while others simply observe. This may be due in part to the increased toxicity of the uric acid lowering agents in CKD. What can a clinician take away from your manuscript in terms of uric acid lowering therapies and CKD incidence and progression?

DJ: This variation in practice is likely a reflection of where the field stands at this time. While there is evidence to suggest high uric acid contributes to kidney disease, the clinical studies that evaluated this have many limitations such as the lack of a placebo arm, a small number of participants, and a short duration of follow-up. As such, many clinicians remain appropriately unconvinced of the need to lower uric acid levels in individuals with kidney disease. In this review, we aimed to convey the opportunity to improve outcomes by lowering uric acid levels in patients with kidney disease, and the urgent need for further study. It is important to note, however, that at this time, uric acid lowering therapy cannot be recommended on a routine basis.

To view the article (freely available for a limited time), please visit AJKD.org.