Hepatorenal syndrome is one of the serious complications of end-stage liver disease, and even though there are many comprehensive medical treatments, the efficacy is inaccurate and the death rate is extremely high once it occurs. In the prevention and treatment of hepatorenal syndrome, any factors that impair liver and kidney function should be detected, corrected or avoided in time; blood volume deficiency caused by emesis, bleeding or any other factors that can reduce effective blood volume must also be corrected rapidly; drugs that may be harmful to systemic hemodynamics and renal function should be avoided as much as possible or should be carefully weighed when necessary; most patients with severe liver disease have circulatory Most patients with severe liver disease have circulatory insufficiency, and repeated supplementation with albumin preparations or fresh plasma is an effective option to correct this insufficiency. Because the etiology of HRS is complex and the pathogenesis is not fully understood, the treatment lacks direction. The most effective treatment for HRS is living liver transplantation or combined liver/kidney transplantation, but its clinical application is limited by the high cost and limited source of donors. Most patients with liver failure and cirrhotic decompensation die within one month of clinical diagnosis. Therefore, active treatment of the primary disease, elimination of predisposing factors, and improvement of renal function are still the focus of treatment to delay the disease and prolong the survival of patients, and to strive for liver transplantation. Yi Jianhua, Department of Infection, Wuhan Union Hospital The treatment of HRS includes preventive or basic treatment of HRS, pharmacological treatment and non-pharmacological treatment. Among them, pharmacological treatment is mainly the application of vasoactive drugs will be discussed by Professor Xu Xiaoyuan in a separate article, and this article focuses on the prevention and non-pharmacological treatment of HRS.
I. Prevention of hepatorenal syndrome
Early identification and timely and effective treatment of bacterial infections can help to reduce and stop the release of inflammatory factors, prevent hemodynamic disturbances and prevent the occurrence of HRS in patients with liver failure and cirrhosis.
Studies have found that predisposing factors for HRS include infection in 48%, gastrointestinal bleeding in 33%, and excessive laparotomy fluid release in 27%. The most frequent complicating or secondary infections in patients with severe liver disease, including liver failure and cirrhotic decompensation, are abdominal (spontaneous bacterial peritonitis, SBP) and pulmonary infections, and bacterial infections can occur in 50% of patients with esophagogastric fundic variceal bleeding in cirrhosis. The pathogens of infection are predominantly gram-negative bacteria (about 60-80%), and antibiotic prophylaxis improves survival by about 10-30%. Patients with cirrhosis with a history of SBP have a 68% chance of reinfection within 1 year, especially those with ascites protein below 10 g/L, prothrombin activity below 45%, and severe hepatic impairment are more likely to relapse, which will lead to renal failure in 33% of patients. Therefore, prophylactic antibiotics should be considered more in patients with liver failure and cirrhotic decompensation, especially those with a history of esophagogastric fundic variceal bleeding and SBP; and early identification of concurrent or secondary bacterial infections and timely and reasonable anti-infective treatment in patients with liver failure and cirrhotic decompensation can effectively prevent the occurrence of HRS. Although antibiotics can fight infection, they can also lead to the release of endotoxin from gram-negative bacilli due to bacterial lysis, causing deterioration of the disease. Therefore, the selection of antibiotics with good bactericidal effect and low endotoxin release and nephrotoxicity is the issue that needs attention.
As for the prevention of SBP, AASLD recommends the prophylactic application of quinolone antibiotics for cirrhosis combined with the following conditions.
① ascites protein less than 10g/L.
②Persons with a previous history of SBP.
③ Those with ruptured esophagogastric fundic variceal bleeding.
2, prevention and control of bleeding at various sites liver failure and cirrhosis decompensated patients have coagulation mechanism disorders, and because some patients often receive a variety of invasive operations, prone to multi-site bleeding; at the same time, the body is in a state of stress, prone to gastrointestinal bleeding. Insufficient blood volume after hemorrhage can cause the fragile balance of the patient’s circulatory system to be disrupted, thus triggering the occurrence of HRS. Therefore, prevention of bleeding due to invasive operations and spontaneous bleeding from multiple sites, especially upper gastrointestinal bleeding, is the key to preventing HRS. The routine application of acid suppressants including H2 receptor antagonists or proton pump inhibitors to inhibit gastric acid secretion in patients with liver failure and cirrhosis, and the infusion of coagulation substances including platelets and cold precipitation before invasive operations to prevent bleeding are the key points to prevent and control bleeding.
3, avoid the application of nephrotoxic drugs aminoglycosides, polymyxins, non-steroidal anti-inflammatory drugs, contrast agents, etc. can lead to abnormal renal function, these drugs can inhibit prostaglandin synthesis, causing hyperalgesia and impaired water and sodium excretion in patients with cirrhosis, and should be used with caution in clinical practice.
4, avoid simply a large number of ascites release for a large number of ascites or intractable ascites patients, need a large number of ascites release should be based on the amount of ascites release intravenous supplementation of human albumin, each release of 1 liter of ascites then intravenous infusion of 8 grams of human albumin for expansion.
5, expand blood volume, maintain water-electrolyte balance liver failure and cirrhosis decompensated patients with reduced peripheral vascular resistance, effective blood volume, potential hypovolemic shock may occur. Clinically, it is common for patients to experience syncope due to postural hypotension, when renal vascular perfusion pressure has been severely reduced, which, together with electrolyte disturbances and other factors, can easily induce HRS.
Insufficient effective blood volume may be the initiating factor of HRS. Studies have shown that although there is excessive peripheral circulatory retention in HRS, there is insufficient effective arterial blood volume. renal blood flow, glomerular filtration rate, urine volume, creatinine clearance and urinary sodium content are significantly increased in patients with HRS after volume expansion with fresh plasma transfusion. Although volume expansion therapy may improve renal function, there is a risk of pulmonary edema and increased dilutional hyponatremia if urine volume does not increase, which in turn decreases plasma osmolality and affects renal blood flow, thus further aggravating HRS. volume expansion therapy does not fundamentally address changes in systemic circulation and renal hemodynamics, but can be used as a basic treatment for HRS and in combination with other therapeutic measures in combination.
Non-pharmacological treatment of hepatorenal syndrome
Blood purification therapy can replenish coagulation factors, remove toxins, stabilize the internal environment and create conditions for liver regeneration in a short period of time, while prolonging the waiting time for liver transplantation. The main hemodialysis treatments are hemodialysis, hemofiltration, continuous renal replacement therapy (CRRT), and molecular adsorption recirculation system (MARS).
Hemopurification therapy should be considered when HRS patients have serum creatinine >300 μmol/L, arterial blood gas analysis pH <7. 20 or severe fluid volume overload and hyperkalemia, pulmonary edema, and uncorrectable acidosis. Due to the presence of serious adverse effects such as hypotension or shock, gastrointestinal bleeding, DIC, imbalance syndrome, and uncertain efficacy, conventional hemodialysis is not recommended for the treatment of HRS. some studies suggest that CRRT may have some efficacy for HRS; and MARS system transitional therapy can be selectively used for some patients with acute liver failure or chronic liver disease complicated by HRS awaiting liver transplantation, with relatively efficacy and The relative efficacy and safety are better. However, further clinical studies are needed to confirm which hemodialysis modality is best. It is important to note that hemodialysis is only indicated for those patients with HRS who are likely to recover liver function or have the opportunity to await liver transplantation or combined liver and kidney transplantation.
CRRT is a series of blood purification methods for slow, continuous removal of water and solutes, including continuous hemofiltration and continuous hemodialysis, all of which have the effect of removing toxins from the blood, excess water from the body, and maintaining water-electrolyte and acid-base balance. Compared with conventional hemodialysis, CRRT applied to patients with liver failure not only has better hemodynamic stability and gradually corrects hyponatremia, but also has less fluctuation of patients’ intracranial pressure; more importantly, CRRT treatment can remove inflammatory cytokines such as TNF-α and IL-6, which cause the progression of HRS and aggravation of liver injury. Nevertheless, CRRT treatment does not improve the survival rate of HRS patients.
MARS is a modified hemodialysis system in which an albumin-containing dialysate is circulated and perfused to selectively remove excess water, water-soluble toxins, and non-water-soluble toxins bound to plasma proteins including bilirubin, bile acids, nitric oxide, and inflammatory cytokines such as TNF-α, IL-6, and IL-10 through activated carbon and anion-exchange resin, while stabilizing blood flow kinetics, reduce intracranial pressure, and have a role in reducing the inflammatory response, promoting hepatocyte regeneration, improving renal circulation and blocking the progression of HRS. A randomized controlled clinical trial demonstrated that MARS treatment of type I HRS patients not only improved clinical and biochemical parameters, but also prolonged survival by about 20 days. Even so, the overall survival rate for HRS patients was low, with a 7-day survival rate of 37% and a 30-day survival rate of only 25%. In contrast, in another uncontrolled study of MARS in patients with type I HRS, improvement in urine output, mean arterial pressure, stage of hepatic encephalopathy and Child-Pugh score was found, with five patients surviving longer than 12 months and only one patient requiring liver transplantation after 18 months of treatment. Thus, MARS is considered as an adjuvant treatment for patients with liver failure combined with type I HRS in combination with vasoactive drugs and human albumin. However, to date, MARS has only been used as a transitional treatment awaiting liver transplantation and has not been applied to clinical treatment outside of clinical trials, and its efficacy has yet to be further evaluated.
2. Transjugular intrahepatic portosystemic shunt Transjugular intrahepatic portosystemic shunt (TIPS) is an intrahepatic stent inserted through the jugular vein connecting the portal vein and the hepatic vein, which can reduce portal pressure, increase renal perfusion and improve renal function, and is suitable for HRS patients with Child-Pugh score <12 and good general condition.
Studies have confirmed that renal function improves and survival is prolonged in HRS patients after TIPS treatment, and can be used in HRS patients for whom other treatments are ineffective. Patients with type I HRS treated with TIPS showed significant improvement in glomerular filtration rate and renal plasma flow at 30 days postoperatively and prolonged survival in patients who could not receive liver transplantation. Further TIPS treatment in patients with type I HRS was clinically more effective after improvement in renal function with drug therapy. In a prospective study, 86% of patients with type I HRS showed improvement in renal function 1 month after TIPS treatment, with increased urine output, significant reduction in serum creatinine, and simultaneous improvement in glomerular filtration rate and renal plasma flow, with a 30-day survival rate of 71%. Another prospective, non-randomized study evaluated the long-term survival of patients with type I and type II HRS treated with TIPS and found that the survival rates at 3, 6, 12, and 18 months after TIPS were 81%, 71%, 48%, and 35%, respectively.
Although TIPS treatment of HRS patients may improve renal function, increase plasma creatinine clearance and prolong survival, the current study excludes patients with severe hepatic encephalopathy, bilirubin >85 μmol/L or Child-Pugh score >12. Therefore, the application of TIPS to patients with liver failure combined with HRS needs further study, and TIPS can induce portal-body shunt encephalopathy, concomitant embolism and restenosis, which limits its clinical application.
3, liver transplantation or combined liver and kidney transplantation is currently believed that in the early stages of HRS, renal failure is a functional lesion, and renal function can be reversed with the improvement of liver function. While the key to successful treatment of HRS is the recovery and reversal of the underlying liver disease, most liver failure or chronic end-stage liver disease is irreversible. Thus, liver transplantation or combined liver and kidney transplantation is currently recognized as the most effective means of treating HRS. Patients with liver failure combined with type I HRS have a poor prognosis, with an average survival of 2-4 weeks; after liver transplantation, the survival rate of patients is significantly improved. One study showed that the 5-year survival rate after liver transplantation in patients with HRS was 60%, while the 5-year survival rate after liver transplantation in patients without combined HRS was 68%. In a recent retrospective study, 32 liver transplant patients with preoperative combined type I HRS had 1-month and 1-year survival rates of 71.9% and 65.6%, respectively, and patients with low MELD scores and no hyponatremia had better outcomes for liver transplantation.
Whether liver failure combined with HRS is an indication for combined liver and kidney transplantation is debated. However, the US Organ Sharing Network database shows that HRS is present in 38% of combined liver and kidney transplant patients. a retrospective controlled study showed that 98 patients who underwent combined liver and kidney transplantation (including 22 patients with HRS) compared with 88 patients with HRS who underwent liver transplantation only had survival rates of 72% and 66%, respectively, with no statistically significant difference; patients who required postoperative renal replacement therapy were 55% and 89%, respectively, and the mean duration of need for renal replacement therapy was 2. 5 days and 9 days, respectively. However, there is a lack of information on clinical studies comparing liver transplantation alone or combined liver-kidney transplantation in patients with liver failure combined with HRS.
Although liver transplantation or combined liver-kidney transplantation is currently recognized as the most effective treatment for HRS, unfortunately, the rapid progression of HRS patients, especially type I HRS patients who die before transplantation, coupled with the current difficulties in donor sourcing and the high cost of surgery, limit its clinical application.
In conclusion, the most effective treatment for HRS is still liver transplantation or combined liver and kidney transplantation, but it is especially important to prolong the survival of HRS patients waiting for liver transplantation or combined liver and kidney transplantation because of the short survival time of HRS patients and the difficulty and high cost of donor.