Hepatorenal syndrome is a complication of cirrhosis, with high morbidity and mortality. Nevertheless, the underlying mechanism involving how kidney injury aggravates the progression of cirrhosis remains unclear. This study aims to explore the role of the TLR4 signaling pathway in mediating liver and kidney injuries in HRS mice induced by unilateral ureteral obstruction (UUO) and/or bile duct ligation (BDL). Two weeks after UUO, there were no obvious pathological changes in mouse liver and the unligated side of kidney. Nevertheless, impaired liver and kidney functions, inflammatory response and fibrosis were examined in mice after two weeks of BDL. Compared with those of other groups, mice in the BDL&UUO group presented severer liver and kidney injuries, higher levels of inflammatory factors, and faster deposition of collagens, suggesting that kidney injuries accelerated the aggravation of HRS. Correlation analysis identified a positive correlation between expression levels of inflammatory factors and fibrotic levels. Meanwhile, TLR4 and its ligand MyD88 were upregulated during the process of liver and kidney injuries in HRS mice. Further animal experiments in transgenic TLR4-/- mice or in those treated with TAK242, a small molecule inhibitor of TLR4, showed that blocking the TLR4 signaling pathway significantly improved survival quality and survival rate in HRS mice by alleviating liver fibrosis and kidney injury. It is concluded that kidney dysfunction plays an important role in the aggravation of cirrhosis, which may be attributed to the TLR4 signaling pathway. Targeting TLR4 could be a promising therapeutic strategy for protecting both liver and kidneys in patients.

Rationale: Sacubitril/valsartan (Entresto) is the first drug approved for the treatment of symptomatic chronic heart failure with reduced ejection fraction in adult patients. There have been no reports of hepatotoxicity secondary to sacubitril/valsartan administration. Here, we report the first case of severe liver injury caused by sacubitril/valsartan. Patient concerns: A 90-year-old female patient taking sacubitril/valsartan was admitted due to chronic heart failure. Subsequently, the patient developed serious liver injury with increased hepatic transaminases. Diagnosis: Drug-induced liver injury, sacubitril/valsartan-related. No liver injury caused by other reasons was observed after thorough examination. After the withdrawal of sacubitril/valsartan, the liver function of the patient gradually returned to normal. Interventions: We chose general liver protection methods to improve her hepatic function, including magnesium isoglycyrrhizinate at 100 mg daily and polyene phosphatidylcholine capsules at 456 mg 3 times daily. We consulted with a hepatologist to discuss the best plan for her treatment. The last, we stopped sacubitril/valsartan. Outcomes: After the withdrawal of sacubitril/valsartan, the liver function of the patient gradually returned to normal. Lessons: Sacubitril/valsartan-induced liver injury is very rare. Clinicians should pay particular attention to the possibility of hepatotoxicity during sacubitril/valsartan treatment.