1 INTRODUCTION

Hepatorenal syndrome (HRS) is the most severe complication of end-stage liver disease (ESLD), determining a 30-day mortality of approximately 90%.^{1, 2} The circulatory dysfunction of the cirrhotic patient with ascites determines chronic renal hypoperfusion,³ which might lead to a functional acute kidney injury (AKI). HRS is classified in two types: Type 1, rapidly progressive; and Type 2, slowly progressive. HRS type 1 determines an important worsening of the prognosis of ESLD.^{2, 4}

Since the diagnosis of HRS is one of exclusion, it is used as a set of diagnostic criteria. The first set of diagnostic criteria was published by the International Ascites Club in 1994⁵ and updated in 2007.⁶ In 2015, these criteria were updated to include the concept of AKI.⁷ Nevertheless, such modification was not superior to the previously used cut-off point of a serum creatinine above 1.5 mg/dL for predicting in-hospital mortality.⁸

HRS can be treated pharmacologically, generally with a combination of human albumin and vasopressor drugs.⁴ The two most commonly used are norepinephrine ^{9, 10} and terlipressin.^11-14 Midrodine and octreotide might be used as well, although this combination is inferior to terlipressin.¹⁵ Such treatments are costly—norepinephrine requires monitoring in an intensive care unit and terlipressin is an expensive drug (although it can used in the infirmary). Nevertheless, the total cost of terlipressin treatment has been shown to be lower than that of norepinephrine in a meta-analysis.¹⁶

Even though pharmacological treatments might reverse HRS in some patients, it does not seem to impact overall mortality in the long term, but only in the short term. Liver transplantation (LT) is the only definitive treatment for HRS and these patients should promptly be evaluated for LT.^{17, 18}

The purpose of this study is to analyse and compare the accuracy commonly used liver-specific scores (Child-Turcotte-Pugh, Model for End-Stage Liver Disease, Model for End-Stage Liver Disease-Sodium, Chronic Liver-Failure - Sequential Organ Failure Assessment and CLIF-consortium Acute-on-Chronic Liver Failure) in the prognostication of mortality for HRS patients.

2 METHODS

3 RESULTS

Medical record analysis retrieved 177 hospital admissions of patients who received terlipressin. Of these, 46 admissions were diagnosed as HRS type 1 and included in the study (Figure 1). Other patients had a diagnosis of acute oesophageal variceal haemorrhage. Demographic, clinical and laboratorial data are described in Table 1 for the study population. Mean age was 58 years and 80% were male. The most common cause of cirrhosis was alcohol abuse (76%).

All-cause mortality for 30-day, 90-day and 365-day was 67.3%, 71.7% and 82.6%, respectively. ACLF grade 1 was present in 25 patients, grade 2 in 12 and grade 3 in 8. All-cause mortality for 30-day, 90-day and 365-day was 60%, 68% and 83.3% for ACLF grade 1 patients, 66.6%, 66.6% and 83.3% for ACLF grade 2 patients and 87.5%, 87.5% and 87.5% for ACLF grade 3 patients, respectively (Figure 1). HRS was reversed in 10 patients with the association of terlipressin and human albumin (21.7%).

Child-Turcotte-Pugh was able to predict mortality in 30-, 90- and 365-day, with AUROC of 0.76, 0.75 and 0.72, respectively (Table 2). CLIF-SOFA, CLIF-C ACLF, MELD and MELD-Na were inferior to CTP, with lower AUROC (Figure 2).

Values of CTP above 12 were able to predict higher mortality for all patients, with sensitivity of 38%, 36% and 30% and specificity of 100%, 100% and 100% for 30-, 90- and 365-day mortality, respectively (P < 0.05,Table 3). CTP score had the higher AUROC for 30-, 90- and 365-day mortality (Figure 3).

4 DISCUSSION

HRS type 1 is generally considered an end-of-life event for cirrhotic patients. Even though treatment has got better in the last 20 years, this has not greatly improved the survival.⁴ The present study has sought to demonstrate that the use of liver-specific scores might be useful for prognostication of HRS.

ACLF has been introduced as a concept in order to create a much needed step between decompensated cirrhosis (DC) and death. It was generally regarded as a multi-organ failure associated with a trigger, although it lacked diagnostic criteria.^28-34 Such definitive diagnostic criteria for diagnosis of ACLF have been introduced by the CANONIC study in 2013. It was developed the CLIF-SOFA score and the utility in the prognostication of ACLF was validated.²⁶ As HRS defines kidney failure, its presence already defines a patient as having ACLF.

This study, which included only patients with type 1 HRS, found a 30-day mortality of 67.3%, quite higher than 33.9% described in the CANONIC study ²⁶ and 39% described in other Brazilian studies.^35-37 Such finding is to be expected; it is well described that patients with ACLF associated with AKI have higher mortality.³⁸

The total cost of HRS treatment is extremely high—either the cost of the drug (terlipressin) or the cost of intensive care (norepinephrine). Therefore, a better understanding of the prognostication of HRS is paramount to better allocate treatment. Evidence-based protocols are might be helpful as well,³⁹ since compliance to adequate use of human albumin is rather low in a few studies.^{40, 41} Besides, the use of evidence-based protocols for diagnosing and treating HRS might improve prognosis.³⁹

Although terlipressin costs significantly more than norepinephrine, the final cost of norepinephrine has been shown to be higher than terlipressin ^{16, 42} as its use requires monitoring in an intensive care unit. Even where terlipressin is not available, such as the United States, the cost of the treatment of HRS is a major concern.^{43, 44} In the end, only LT can be considered as a definitive treatment for HRS, which actually increases survival in the long term and reduces the need for renal replacement therapy (RRT,17).

The most commonly used liver-specific score in the inpatient and outpatient setting for cirrhotic patients is surely the CTP, which has been used in the past even to allocate organs for LT. Its capacity for predicting adverse outcomes has been well studied for patients admitted to the intensive care unit ⁴⁵ or even HRS patients.⁴⁶ In the present study, CTP has been shown to be superior to MELD, MELD-Na, CLIF-SOFA or CLIF-ACLF for predicting 30-, 90- and 365-day mortality for HRS patients.

Since a couple of weeks is the median survival for HRS without therapy, all cirrhotic patients with AKI should be considered for LT, using RRT as a temporary approach until an organ is available.^{47, 48} AKI, and therefore, HRS generally are caused by a precipitating clinical event, such as bacterial infection, variceal bleeding, vasodilators (such as angiotensin-converting enzyme inhibitors) and large-volume paracentesis without albumin administration.^49-54 Diuretics should be stopped and nonselective beta-blockers should be used with extreme caution ⁵⁵; hypotension should be avoided as it might impair prognosis.^{56, 57}

MELD and MELD-Na scores are currently used to allocate organs for LT and are useful tools to predict 90-day mortality for ESLD, even for HRS patients.⁵⁸ In the present study, CTP was superior to MELD and MELD-Na for the prognostication of HRS.

A meta-analysis has been studied and the capacity of prognostication of intensive care scores and liver-specific scores was compared, with the latter proving to be superior into predicting long-term mortality.⁴⁵ Such scores, as the MELD and CLIF-SOFA, have also been shown to prognosticate recovery of renal function.⁵⁹ If RRT is needed, an intermittent high flux albumin dialysis with continuous venovenous haemodialysis has been shown to be more effective than regular haemodialysis.⁶⁰

Some studies have shown CLIF-SOFA to be superior to other liver-specific scores in prognostication for cirrhotic patients.^61-63 This has been demonstrated for alcoholic cirrhosis,⁶⁴ alcoholic hepatitis,⁶² for extra-hepatic insults ^{36, 65} and for spontaneous bacterial peritonitis.⁶⁶ Although, CLIF-SOFA score was not accurate for prognostication of HRS in the present study.

The most important limitation of the present study is the small sample size. This was caused by the fact that HRS is not a very common complication of cirrhosis. Besides, the present study was developed in a single centre. Studies regarding HRS are generally multi-centric, which helps gather more patients and more data.

5 CONCLUSION

In conclusion, CTP score was superior to other liver-specific scores for predicting mortality in a cohort of cirrhotic patients admitted due to HRS in a tertiary hospital. The authors suggest that, taking into account the high mortality and cost of HRS treatment, the use of liver-specific scores for prognostication of HRS could help to better allocate resources in tertiary hospitals. Although the studies are larger, preferentially multi-centric, are required to further validate the use of liver-specific scores in this context.

ACKNOWLEDGEMENT

Declaration of personal interests: None.

AUTHORSHIP

Guarantor of the article: Prof. MSc. Jonathan Soldera.

Funding: None.

Conflict on Interest: None regarding the subject of the article.

Authors contributions: Terres AZ - Design, data collection, writing and review. Balbinot RS - Data collection, writing and review. Muscope ALF - Data collection, writing and review. Longen ML - Data collection, writing and review. Schena B- Data collection, writing and review. Cini BT - Data collection, writing and review. Rost Jr GL - Data collection, writing and review. Balensiefer JIL - Data collection, writing and review. Eberhardt LZ - Data collection, writing and review. Balbinot RA - Design, writing and review. Balbinot SS - Design, writing and review. Soldera J – Design, statistical analysis, translation, writing and review.