Hepatorenal syndrome (HRS) is a serious condition associated with loss of kidney function among patients with cirrhosis of the liver. Constricted and narrowed blood vessels accompany liver failure, which reduces the blood flow kidneys receive. With the body unable to produce sufficient urine, waste products high in nitrogen build up in a process known as azotemia. Untreated, this can result in death.
Approximately 10 percent of those in the hospital for liver failure develop the disease. In addition, HRS occurs occasionally among those who develop fulminant hepatitis, associated with alcoholism, and accompanies symptoms such as ascites (fluid collecting in abdominal spaces) and portal hypertension.
HRS has traditionally been categorized as either Type 1 or Type 2, with the former associated with more rapid onset. Related to gastrointestinal hemorrhage, bacterial infection, or excessive response to diuretics, it causes rapid liver and renal (kidney) failure. By contrast, the slower-to-progress Type 2 HRS is usually spontaneous and occurs in tandem with refractory ascites.
In recent years, HRS subtypes, based on the presence of chronic kidney injury (CKI) or acute kidney injury (AKI), have evolved as the primary classification system, with Type 1 HRS now known as HRS-AKI. A defining trait of Stage 1 AKI is a 50 percent increase in serum creatinine from a stable baseline reading within three months (or a 0.3 mg/dL spike within 48 hours). Stage 2 and 3 AKI represent a doubling and tripling of serum creatinine levels, respectively.
When renal insufficiency appears or worsens in patients with decompensated cirrhosis, physicians often work to rule out alternative causes and discontinue the use of diuretics while exploring avenues such as drugs or liver transplants.
One unique aspect of HRS is that the kidneys’ histological appearance (structure of cells and tissue) is normal. This means that the kidneys often return to regular functioning after liver transplantation. For researchers, this makes it a pathophysiological disorder that enables them to understand better how vasodilator and vasoconstrictor blood flow systems operate within the kidneys.
With this at the forefront, researchers are actively exploring how various drugs may be able to reverse HRS-AKI in patients. One promising pathway centers on the synthetic vasopressin analog terlipressin, which functions as a systemic vasoconstrictor through vascular vasopressin V1 receptors. Vasoconstrictors help increase mean arterial pressure and have been employed in combatting systemic vasodilation, one of the primary mechanisms associated with HRS.
A phase 3 study from 2016 to 2019 involved an assessment of the efficacy and safety of terlipressin, intravenously administered in tandem with albumin. Undertaken at 60 investigational sites spanning North America, the study encompassed 300 patients with HRS-AKI who received either a placebo or a terlipressin regimen for up to two weeks. The results were encouraging, with 32 percent of patients within the terlipressin group achieving verified HRS reversal, as opposed to 17 percent within the placebo group.
This led to FDA approval of terlipressin, already in use in Europe, for the United States. It joins liver transplant evaluation and the standard treatments octreotide, midodrine, and albumin as an approved treatment for hepatorenal syndrome. That said, cardiopulmonary complications that often accompany terlipressin mean that physicians may be reluctant to recommend the drug’s routine use and instead administer it on a case-by-case basis.
