Much Ado About Something: The Clinical Pattern of Tolvaptan-Associated Liver Injury in Participants With ADPKD

although loss of kidney function over time is inevitable. The quest for a treatment to slow down the loss of kidney function and progression to kidney failure has spanned decades. Three large phase 3 clinical trials—TEMPO 3:4 (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 Trial), TEMPO 4:4, and REPRISE (Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD)—showed that tolvaptan decreased rate of kidney growth and kidney function loss. Its use for ADPKD was approved by the European Renal Association (ERA) in 2016 and US Food and Drug Administration (FDA) in 2018. However, the risk of tolvaptaninduced hepatic injury remains a major concern. In this issue of AJKD, Alpers et al conducted a retrospective study of tolvaptan safety data from clinical trials to address this concern. They analyzed data from more than 2,900 tolvaptan-treated study participants, including more than 2,300 with ≥18 months of drug exposure. The intervention in all clinical trials was twice-daily dosing of tolvaptan. The main outcome was an elevation above the upper limit of normal (ULN) of ≥3× (in alanine aminotransferase [ALT] or aspartate aminotransferase [AST] level) or of ≥2× (in total bilirubin level). In TEMPO 3:4, there were 2 patients who experienced concurrent elevations in levels of ALT/AST and bilirubin. No one had persistent liver dysfunction. During the TEMPO 3:4 study period, 1.2% of the participants needed to discontinue the trial owing to liver injury. Later, Endo et al published a case report of a patient with tolvaptan-induced acute liver failure requiring liver transplantation, which proved that clinicians’ concerns were relevant. In the REPRISE trial, ALT elevations >3× ULN were more frequently seen in the tolvaptan arm compared to the placebo arm, but no participant in REPRISE had a concomitant increase in total bilirubin. The analysis by Alpers et al showed that liver enzyme abnormalities were more common in the first 18 months of tolvaptan use, and liver enzyme levels improved or returned to normal after stopping tolvaptan. To date, our understanding of tolvaptan-associated drug-induced liver injury (DILI) is that this can occur in