1Department of Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, CT, USA and Section of Nephrology, VA-Connecticut Healthcare System, West Haven, CT, USA. Electronic address: email@example.com.
2Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
3Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
4Department of Medicine, University of Arkansas for Medical Sciences, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
5Department of Transplantation, Mayo Clinic, Jacksonville, FL, USA.
6Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA.
7Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI, USA.
8Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
9Section of Digestive Diseases, VA-Connecticut Healthcare System, West Haven, CT, USA.
10Department of Nephrology, Ochsner Health System, Baton Rouge, LA, USA.
11Division of Nephrology, Department of Medicine, Beth Israel Deaconess and Harvard Medical School, Boston, MA, USA; Division of Nephrology, UT Southwestern, Dallas, TX.
12Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts
Hepatorenal syndrome (HRS) is a form of acute kidney injury occurring in patients with advanced cirrhosis and is associated with significant morbidity and mortality. The pathophysiology underlying HRS begins with increasing portal pressures leading to the release of vasodilatory substances which result in pooling blood in the splanchnic system and a corresponding reduction in effective circulating volume. Compensatory activation of the sympathetic nervous system, renin-angiotensin-aldosterone system and release of arginine vasopressin serve to defend mean arterial pressure but at the cost of severe constriction of the renal vasculature, leading to a progressive, often fulminant form of AKI. While there are no approved treatments for HRS in the United States, multiple countries, including much of Europe, utilize terlipressin, a synthetic vasopressin analogue, as first-line therapy. The recently published CONFIRM trial, the third randomized trial based in North America evaluating terlipressin, met its primary endpoint, showing greater rates of HRS reversal in the terlipressin arm. However, due to concerns about apparent increased rates of respiratory adverse events and a lack of evidence for mortality benefit, terlipressin was not approved by the Food and Drug Administration (FDA). In this Perspective, we explore the history of regulatory approval for terlipressin in the United States, examine the results from CONFIRM and the concerns they raised and consider the future role of terlipressin in this critical clinical area of continued unmet need.