Hepatorenal syndrome (HRS) is a form of acute kidney injury (AKI) 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 that result in pooling blood in the splanchnic system and a corresponding reduction in effective circulating volume. Compensatory activation of the sympathetic nervous system and the 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. There are no approved treatments for HRS in the United States, but multiple countries, including much of Europe, use terlipressin, a synthetic vasopressin analogue, as a first-line therapy. CONFIRM (A Multi-Center, Randomized, Placebo Controlled, Double-Blind Study to Confirm Efficacy and Safety of Terlipressin in Subjects With Hepatorenal Syndrome Type 1), the third randomized trial based in North America evaluating terlipressin, met its primary end point of showing greater rates of HRS reversal in the terlipressin arm. However, due to concerns about the 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). 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.

肝肾综合征 (HRS) 是一种发生在晚期肝硬化患者中的急性肾损伤 (AKI)，与显着的发病率和死亡率相关。HRS 的病理生理学始于门静脉压力增加，导致血管舒张物质释放，导致内脏系统中的血液汇集，有效循环量相应减少。交感神经系统和肾素-血管紧张素-醛固酮系统的代偿性激活和精氨酸加压素的释放有助于保护平均动脉压，但代价是肾血管系统严重收缩，导致 AKI 进行性发展，通常是暴发性形式。美国没有批准的 HRS 治疗方法，但包括欧洲大部分地区在内的多个国家使用特利加压素，一种合成的加压素类似物，作为一线治疗。CONFIRM（一项多中心、随机、安慰剂对照、双盲研究，以确认特利加压素对 1 型肝肾综合征患者的疗效和安全性）是北美第三个评估特利加压素的随机试验，其主要终点是显示特利加压素组的 HRS 逆转率更高。然而，由于担心呼吸系统不良事件的发生率明显增加以及缺乏死亡率益处的证据，特利加压素未获得美国食品和药物管理局 (FDA) 的批准。我们探讨了特利加压素在美国的监管批准历史，检查了 CONFIRM 的结果和他们提出的担忧，并考虑了特利加压素在这一持续未满足需求的关键临床领域中的未来作用。