Author information

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: justin.belcher@yale.edu.

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

Abstract

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.