Terlipressin in Combined Hepatorenal Syndrome in Patients With Signs of Chronic Renal Disease

Liver cirrhosis is a major cause of global health burden, accounting for 31 million disability adjusted life years and 1 million deaths worldwide in 2010. In the natural history of liver disease, there are two clearly distinct clinical phases. During the compensated phase, patients remain asymptomatic or oligosymptomatic. Although these patients may exhibit signs of cirrhosis, such as varices, spider naevi, or abnormalities in blood tests, they do not experience overt symptoms of the disease. The median survival rate for these patients is approximately 15 years 2. During the course of liver cirrhosis, patients may develop ascites, variceal bleeding or hepatic encephalopathy, which marks the transition to the decompensated phase of the disease. Thus, decompensation is associated with a significant reduction in survival, with a median of approximately 2 years, and ascites is the most frequent decompensating event. Clinically significant portal hypertension, as determined by the hepatic venous pressure gradient, is a main driver for the development of decompensation. In the decompensated phase, one can differentiate between patients who have a sole event as a decompensating event (typically ascites or variceal bleeding) and those who develop more than one decompensating event (further decompensation). These patients are at risk of dying due to their liver disease.

Hepatorenal syndrome refers to a "functional" renal dysfunction that occurs in patients with cirrhosis and ascites due to reduced renal perfusion secondary to hemodynamic alterations in the arterial circulation and activation of endogenous vasoactive system. Traditionally, one distinguished between hepatorenal syndrome type 1, which was a rapidly progressive renal failure (increase of serum creatinine (SCr) to greater than 2.5 mg/dL within two weeks) or hepatorenal syndrome type 2, which has a less rapid course, with a progressive increase of SCr to greater than 1.5 mg/dL. Typically, hepatorenal syndrome type 1 takes place in the context of an acute event, whereas hepatorenal syndrome type 2 takes place in end-stage refractory ascites.

In 2015, the International Club of Ascites (ICA) adopted a new classification of renal dysfunction in cirrhosis.

The decision was motivated by increasing evidence suggesting that serum creatinine could underestimate the real renal function in cirrhosis due to muscle wasting, increased tubular secretion of creatinine, increased volume of distribution potentially diluting creatinine and interference with bilirubin. Furthermore, the use of thresholds does not allow the flexibility that is required to confront a dynamic situation like hepatorenal syndrome type 1. To address these concerns, the ICA proposed to adopt criteria from The Kidney Disease: Improving Global Out-comes (KDIGO) guidelines, which define AKI as any of the following: 1) increase in SCr by ≥ 0.3 mg/dl (≥ 26.5 µmol/L) within 48 h; or 2) increase in SCr to ≥ 1.5x baseline, which is known or presumed to have occurred within the prior 7 days; or 3) urine volume < 0.5 ml/kg/h for 6 h. In the specific context of cirrhosis, the ICA proposed a modification by using only the first three KDIGO criteria, given the fact that urine output frequently does not properly reflect the renal function as patients with cirrhosis often are oliguric due to avid sodium retention or have a falsely high urine output due to the use of diuretics. Furthermore, ICA proposed that if a baseline value within the previous 7 days is unavailable, a SCr within the last 3 months before admission can be used.

According to the relative increase in creatinine, various stages of AKI can be identified. Noticeably, AKI can occur even when renal function remains within the given normal range. Within AKI Stage I, a differentiation can be made between individuals who achieve a peak over SCr ≥ 1.5 mg/dL (Stage Ib) and those who achieve a peak below this threshold (Stage Ia), the latter of which may have a similar survival as those without AKI and in whom the AKI is more frequently reversible.

AKI occurs in approximately 20 % of hospitalized patients with cirrhosis and is associated with higher mortality in patients with cirrhosis admitted to regular wards. Approximately 2/3 of AKI are due to renal hypoperfusion, which in turn can be divided into prerenal AKI (responsive to the administration of volume overload) or hepatorenal-AKI (HRS-AKI) (unresponsive to the administration of volume overload. HRS type 1 (now included in HRS-AKI) has a high mortality of almost 100 % when left untreated and is frequently part of multiorgan failure (acute on chronic liver failure). Among the etiologies of AKI in cirrhosis, hepatorenal AKI has the worst prognosis.

The diagnosis of HRS-AKI is based on ruling out other causes of AKI, mainly hypovolemia, ongoing infection, nephrotoxic medications, and intrinsic renal disease. Nevertheless, with the increasing incidence of MASLD (metabolic dysfunction associated steatotic liver disease) patients frequently have associated metabolic conditions (such as diabetes or arterial hypertension) which can lead to chronic renal injury and chronic kidney disease independent of liver cirrhosis and portal hypertension.

It's crucial to note that patients showing signs of parenchymal kidney disease at baseline cannot be classified as having HRS according to the current definition, but in occasion may have an AKI which follows the same pathophysiology as HRS (HRS-AKI-like syndrome).

Nevertheless, patients with HRS-AKI-like syndrome are regularly treated with vasoactive therapy, although this would be considered as off-label use in case of terlipressin.

Importantly, data regarding outcomes of this therapy in patients who do not fulfill the strict definition of hepatorenal syndrome are not available and are urgently needed.

The aim of the present study is to evaluate the treatment response to vasoactive therapy in patients who do not fulfill the criteria of hepatorenal syndrome due to the presence of signs of intrinsic nephropathy, but otherwise have a high suspicion of HRS-AKI (HRS-AKI-like syndrome). It is expected, that physicians considered the presence of a HRS-AKI-like syndrome as the dominating cause of AKI and a high proportion of patients were treated with terlipressin and albumin according to clinical practice. The secondary aims include the evaluation of 3-month, 6-month and 12-month survival rate, the improvement of renal function at different time-points (partial- or complete-response), the in-hospital mortality and duration of hospital stay as well as the need of renal replacement therapy, the need of LT during follow-up and the development of cirrhosis complications and acute-on-chronic liver failure.

Inclusion criteria

• Patients with cirrhosis confirmed by histology or liver stiffness or with unequivocal signs in ultrasound, endoscopy and/or blood tests hospitalized between 1st of January 2018 and 31st of December 2022.
• Evidence of ascites due to portal hypertension
• Clinical suspicion of HRS-AKI or HRS-AKI-like syndrome (in case of previously diagnosed CKD)
• Pre-existing data on kidney function (SCr and eGFR) minimum 3 months prior to admission in a stable situation
• Dip stick urine test results (screening for proteinuria and hematuria) before initiation of AKI-treatment
• Vasoactive treatment for the management of HRS-AKI, as defined by the administration of terlipressin or noradrenalin plus albumin
• Age ≥ 18 years old

Exclusion criteria

• Uncontrolled shock
• Patients with cardiac cirrhosis as defined by the development of cirrhosis in a patient with chronic heart failure due to a primary cardiac disease (ischemic cardiomyopathy, hypertensive cardiomyopathy, etc.)
• Patients with hepatocellular carcinoma BCLC C or D
• Patients receiving renal replacement therapy at baseline