Uric Acid Physiology
Uric acid is the sole end-product of purine metabolism in humans. Very little uric acid is actually ingested, but dietary nucleic acids contain variable amounts of purine molecules. Thus, restriction of dietary purines has long been a component of gout management. However, the majority of uric acid in the human body is generated in the liver. There, de-novo purine synthesis ultimately leads to hypoxanthine, which is then metabolized to uric acid by xanthine oxidase. Xanthine oxidase is therapeutically inhibited by allopurinol and febuxostat to provide the most prevalent means of controlling hyperuricemia at this time.
Uric acid in the plasma is filtered freely in the kidney, and net tubular reabsorption is reported as 90% or more of the filtrate. In a survey of 72 normal Spanish adults, Perez-Ruiz et al. found the mean serum urate to be 5.0 mg/dl, the glomerular filtration rate (by creatinine clearance) to be 111 ml/min and the 24-h urinary excretion of uric acid to be 594 ± 143 mg/day/1.73 m. If we assume that these individuals had the normal approximately 1200 mg of urate in their bodies, this means that every urate ion in the body is filtered and reabsorbed approximately seven times in the course of every day. The actual number will be higher, as an additional amount of urate is thought to be filtered, reabsorbed and secreted by a complex system of tubular transporters before it reaches the renal collecting system. If the fractional reabsorption decreases only slightly, the serum urate will fall as additional urate escapes reabsorption. However, if there is a rise in the fraction reabsorbed, that person will become hyperuricemic.
Approximately two-thirds of the total uric acid excretion from the body is performed by the kidney, whereas one-third is secreted into the small intestine wherein it undergoes lysis by resident gut bacteria. There is a considerable variation in these fractions among individuals. In those with chronic renal disease, the gastrointestinal tract becomes the principal uric acid disposal pathway.
Hyperuricemia results from qualitatively inefficient excretion of uric acid, with or without quantitative overproduction. Such an apparent double defect was found in a brief meta-analysis of published clearance data in 1979 and has more recently been documented in a large gouty cohort followed by Perez-Ruiz et al.. Urate homeostasis depends on the interplay of renal reabsorption and secretion, as well as excretion through the intestine. Given the complexity of these interactions, it has long seemed logical to pursue simple reabsorptive inhibition as a therapeutic option in treating the problem of hyperuricemia. Even a modest decrease of reabsorption during each pass through the kidneys should significantly increase urate clearance and render hyperuricemic patients normouricemic.