Background Approximately 70% of urate is excreted by the kidney. Renal excretion is governed by reabsorption and secretion in the proximal convoluted tubule. However, there is little direct evidence that renal uric acid secretion occurs in humans, and it is unknown if higher renal uric acid reabsorption or low renal uric acid secretion contributes to the low fractional excretion of uric acid (FEUA) observed in patients with gout.
Objectives The objectives of the study were to test the hypothesis that uric acid secretion occurs in humans, to distinguish uric acid secretion from incomplete reabsorption, and to determine if insufficient secretion and/or enhanced reabsorption are responsible for low FEUA.
Methods Patients with gout in a Phase II study were treated once daily with 40 and 80 mg of febuxostat (FBX), with each treatment lasting 1 week. FBX is a xanthine oxidase inhibitor that reduces uric acid production and lowers serum uric acid (sUA). sUA and FEUA were measured at baseline and at the end of each treatment. sUA (X-axis) and FEUA (Y-axis) were plotted to evaluate the kinetics of renal uric acid handling (Figure).
Results Forty-five male patients with gout, with a mean (SD) age of 49±9.3 years and BMI of 32±3.9 kg/m2, participated in this study. As has been observed in previous publications, decreasing sUA led to a decrease in FEUA. However, this effect reached a plateau at low sUA levels for those who had low (<3.5%) baseline FEUA; the FEUA did not decrease further when the FBX dosage was increased from 40 mg to 80 mg (Figure). The FEUA response to decreasing sUA reaches a plateau at an FEUA of ∼ 2.5%. In contrast, the curve for fractional excretion of glucose reaches zero at lower plasma glucose levels.1 Since a prominent difference in renal handling of uric acid and glucose is that glucose is not secreted while uric acid is believed to be secreted, we suggest that the plateauing of the FEUA curve at the lower sUA range is due to renal uric acid secretion. Preliminary modeling of transporter kinetics also suggests that the observed relationship between sUA and FEUA requires secretion. In addition, the sUA level at which the FEUA begins to rise (equivalent to the renal glucose threshold) is higher for those whose baseline FEUA was low, and this observation is consistent with the hypothesis that patients with gout with low FEUA have higher reabsorption capacity. To determine the ultimate contribution of secretion to low FEUA, sUA will need to be lowered even further.
Conclusions We provide direct evidence for renal uric acid secretion occurring in humans. This method can also be used to determine the relative importance of candidate renal secretory transporters in the secretion of uric acid. Higher reabsorption capacity appears to contribute to low baseline FEUA.
DeFronzo RA, et al. Diabetes Care. 2013;36:3169–3176.
Acknowledgement Research sponsored by Ardea Biosciences/AstraZeneca. Editorial support was provided by PAREXEL and funded by AstraZeneca.
Disclosure of Interest S. Liu Employee of: Ardea Biosciences, Inc., D. Hyndman Employee of: Ardea Biosciences, Inc., J. Miner Employee of: Ardea Biosciences, Inc.