Introduction End-stage liver disease (ESLD) refers to the terminal stage of liver disease caused by various types of chronic liver damage. It is characterized by severely impaired liver function and hepatic decompensation. ESLD can present as acute decompensation of liver cirrhosis (ADC), acute-on-chronic liver failure (ACLF), chronic liver failure (CLF), and advanced hepatocellular carcinoma (HCC). ESLD is frequently accompanied by various complications and life-threatening clinical issues, including infection (such as pneumonia or spontaneous bacterial peritonitis), hepatic encephalopathy (HE), hepatorenal syndrome (HRS), and esophageal varices with bleeding.[1] Herein, we briefly review the significant achievements in the management of multiple complications in ESLD, particularly in bacterial or fungal infections, acute kidney injury (AKI), HE, stem cell treatment, and blood purification. Predictive model of ESLD prognosis Previous studies have shown that complications in ESLD are associated with increased mortality. Meticulous prevention and treatment of complications can significantly improve the prognosis of patients with ESLD. In as early as 2012, we discovered that the number of complications was an independent predictor of the prognosis of hepatitis B virus-induced ACLF (HBV-ACLF), leading us to establish the Tongji Prognostic Predictive Model (TPPM).[2] Total bilirubin (TBIL), international normalized ratio (INR), HBV DNA, and the number of complications were adopted in the TPPM score. The TPPM score is calculated using the following formula: TPPM score = 1/(1 + e−logit(p)), logit(p) = 0.0031 × [TBIL (μmol/L)] + 0.9519 × INR + 2.2580 × constant for complications (0 if without or with one complication; 1 if with two or more complications) + 0.114 × [lg HBV DNA(copies/mL)] − 5.012. The TPPM showed superior prognostic ability in patients with HBV-ACLF compared to existing models. The predictive ability of TPPM has been validated in an international multi-center cohort from the Asia Pacific region[3] that was actively recommended by Sarin et al.[4] for the prognosis of HBV-ACLF. Bacterial infection in ESLD During ESLD development, infections can induce or aggravate liver decompensation, resulting in high mortality rates. Bacterial infection is one of the most common complications of disease progression. A working procedure is needed for the appropriate diagnosis and management of ESLD complicated with infections; the Chinese Society of Infectious Diseases and the Chinese Medical Association compiled up-to-date principles and working procedures for clinicians to manage ESLD patients complicated with infections, based on scientific knowledge and the rich experiences of Chinese colleagues.[5] In the recent years, few models have been established to predict the prognosis of ESLD. Pocad et al. reported that white blood cell count, blood urea nitrogen, mean arterial pressure, and the Child-Pugh score were independent risk factors for mortality in cirrhotic patients with complicated spontaneous bacterial peritonitis (SBP). The Area Under Curve (AUC) that predicted the in-hospital death of patients was 0.85.[6] We found that age, serum TBIL, INR, lactate dehydrogenase (LDH), and soluble interleukin 2 receptor (sIL-2R) were predictors of 30-day mortality in patients with HBV-ACLF combined with bacterial infection. Based on these results, we first established a visual nomogram model for HBV-ACLF. Early diagnosis and timely alleviation of bacterial infection in ESLD significantly improved the short-term survival of patients. The GIC model (G, serum globulin; I, interleukin 6 [IL-6]; C, C-reactive protein [CRP]) was established and validated for the prediction of bacterial infection development.[7] Furthermore, it was reported that the diagnostic model constructed using CRP, procalcitonin (PCT), IL-6, and interleukin 10 (IL-10) showed good discrimination, calibration, and clinical practicability in the diagnosis of bacterial infections in HBV-ACLF, which could assist clinicians in the diagnosis of bacterial infections especially for SBP and pneumonia.[7] ESLD patients with MELD scores greater than 30 showed a high risk of SBP development during proton pump inhibitor (PPI) treatment.[8] HE in ESLD HE is another complication that frequently occurs in ESLDs aside from infection. Timely recognition and intervention of HE could significantly improve the survival of patients with ESLD. Currently, there is no precise indicator for identifying mild hepatic encephalopathy (MHE), and several studies are being carried out for the early recognition of MHE. A study recently revealed that feature extraction from node disjointness with the support vector machine classifier has an accuracy of 88.71% in the discrimination of MHE from no HE by a multi-layer modular algorithm machine learning model.[9] AKI in ESLD AKI or HRS is a common complication in patients with ACLF or ADC and is associated with poor outcomes. A randomized controlled study reported that treatment with terlipressin showed higher renal injury alleviation in patients with cirrhosis combined with HRS-1than those with placebo treatment.[10] Consistently, our study revealed that AKI in ACLF patients was associated with structural kidney injury and poor response to terlipressin treatment.[11] Other treatments for complications of ESLD Recent clinical studies have demonstrated that treatment with mesenchymal stromal cells (MSCs) in patients with ACLF significantly increased the short-term survival rate compared to treatment without MSCs.[12] We demonstrated that small-volume plasma perfusion combined with plasma exchange treatment significantly reduced the mortality of patients with HBV-ACLF by reverse organ failure and ameliorated the development of new organ failures and complications.[13] Perspectives In the last few decades, remarkable achievements have been made from clinical viewpoints in the field of ESLD. However, effective management of complications in ESLD remains a significant clinical challenge and an unmet medical need. A comprehensive understanding of the physiopathology of various complications in ESLD would aid not only in optimizing current treatment strategies but also in facilitating the identification of novel diagnostic biomarkers and treatment targets. Additionally, large randomized control trials must be conducted to validate potential treatment strategies, such as the use of immune regulators, stem cell treatments, and hepatocyte regeneration modulators. Conflicts of Interest None. Editor note: Tao Chen and Qin Ning are the editors of Infectious Diseases & Immunity. The article was subject to the journal's standard procedures, with peer review handled independently by these editors and their research groups.