Regulation of uric acid excretion by the kidney

It has been known for many years that the kidney plays a major role in uric acid homeostasis, as more than 70% of urate excretion is renal. Furthermore, hyperuricemia in gout is most commonly the result of relative urate underexcretion, as the kidney has enormous capacity for urate reabsorption. A clear understanding of the mechanisms of renal handling of urate has been hampered by the differences between humans and animal models. The power of human genetics and genome-wide association studies has now provided new insight into the molecular mechanisms of urate transport by identifying the transporters that have critical roles in urate transport. This review surveys the new evidence for a molecular model of urate transport in the renal proximal tubule and uses these data to refute the popular four-component model for urate transport that has long been in vogue. It also discusses data that help us understand the relation of diuretics to hyperuricemia, losartan-induced uricosuria, variations in uric acid levels in hyperglycemia, and the effects of dairy diets on serum urate levels. In the end, several of these clinical findings are explained, and the remaining gaps in our knowledge will become evident.