MINERAL METABOLISM: Edited by Aline Martin and Tamara IsakovaUric acid stone disease: lessons from recent human physiologic studiesTran, Triet Vincent M.a; Maalouf, Naim M.a,bAuthor Information aCharles and Jane Pak Center for Mineral Metabolism and Clinical Research bDepartment of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA Correspondence to Naim M. Maalouf, MD, 5323 Harry Hines Boulevard, Dallas, TX 75390-8885, USA. Tel: +1 214 648 9640; fax: +1 214 648 2526; e-mail: Naim.Maalouf@UTSouthwestern.edu Current Opinion in Nephrology and Hypertension: July 2020 - Volume 29 - Issue 4 - p 407-413 doi: 10.1097/MNH.0000000000000610 Buy Metrics Abstract Purpose of review An overly acidic urine resulting in supersaturation of urine with respect to uric acid is the major mechanism responsible for uric acid nephrolithiasis. The present review summarizes findings from recent human physiologic studies examining the pathophysiology and reversibility of low urine pH in uric acid stone formers. Recent findings Epidemiologic and metabolic studies have confirmed an increase in the prevalence of uric acid nephrolithiasis and reported its association with several features of the metabolic syndrome including dyslipidemia, hyperglycemia, hepatic steatosis, and greater visceral adiposity. Physiologic studies in uric acid stone formers have identified diet-independent excessive net acid excretion and concomitant reduction in urinary buffering from impaired renal ammoniagenesis as the two causes underlying the greater aciduria. Administration of the insulin sensitizer pioglitazone to uric acid stone formers reduced the acid load presented to the kidney and enhanced ammoniagenesis and ammonium excretion, resulting in significantly higher urine pH. Summary Recent human physiologic studies have identified greater acid excretion and reduced urinary buffering by ammonia as two culprits of aciduria in uric acid nephrolithiasis that can be reversed by pioglitazone, raising new questions regarding the origin of the aciduria and opening the door to pathophysiology-based treatment of uric acid stones. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.