OVERVIEW
Functional acute kidney injury caused by advanced chronic liver disease or fulminant liver failure with mild pathologic changes
In addition to cirrhosis loss of compensation, the characteristic manifestations include oliguria or anuria, azotemia, etc.
Cirrhosis combined with ascites, acute liver failure, alcoholic hepatitis and other severe liver injury
Including measures such as drug therapy, renal replacement therapy, and surgical treatment
Definition
Hepatorenal syndrome is a group of clinical syndromes characterized by renal insufficiency, endogenous vasoactive substance abnormalities, and altered hemodynamics of the arterial circulation in patients with chronic liver disease presenting with progressive hepatic failure and portal hypertension, which can also occur in patients with acute liver failure [1-2].
Types
Type I hepatorenal syndrome
Also known as rapidly progressive hepatorenal syndrome [3].
The onset of the disease is often preceded by an obvious trigger, with infections being the most common, especially spontaneous bacterial peritonitis.
Blood creatinine doubles in less than two weeks and exceeds 221 μmol/L; creatinine clearance decreases by 50% and is less than 20 ml/min. As renal function deteriorates, patients often develop severe water, electrolyte, and acid-base balance disturbances, such as decreased urine output, and oliguria or anuria in some patients [3].
Type II hepatorenal syndrome
Also known as slowly progressive renal impairment.
There are often no obvious triggers before the onset of the disease, and the patients’ renal function is slowly progressing or relatively stable, with blood creatinine <221 μmol/L, averaging at around 177 μmol/L.
It is often accompanied by intractable ascites and diuretic resistance.
Morbidity
The incidence of hepatorenal syndrome is 18% and 39% at 1 and 5 years of cirrhotic ascites, respectively [4].
With the improvement of the diagnosis and treatment of liver disease, the incidence of this disease has gradually decreased, and the incidence of hepatorenal syndrome at 2 years of having cirrhotic ascites is 7.6%, and the estimated incidence at 5 years is only about 11% [3].
Causes
Causes
Those who clinically develop hepatorenal syndrome tend to have severe underlying liver-related disease, which often occurs in the following conditions.
Advanced chronic liver disease such as decompensated cirrhosis and hepatocellular carcinoma.
Severe viral hepatitis, alcoholic hepatitis, drug-induced hepatitis and ischemic hepatitis leading to fulminant liver failure.
Uncompensated cirrhosis in combination with ascites.
Predisposing factors
Infection
Bacterial infection is a common cause of hepatorenal syndrome, accounting for about 57% of all predisposing factors [3].
The release of inflammatory factors due to bacterial infections can exacerbate the degree of hemodynamic instability, thereby inducing the disease.
A common bacterial infectious disease in clinical practice is spontaneous bacterial peritonitis [3].
Hemorrhage in the digestive tract
For example, rupture and bleeding of esophagogastric fundic varices due to cirrhosis.
Bleeding can exacerbate poor renal perfusion and induce renal failure leading to hepatorenal syndrome.
The anemic state caused by bleeding activates the sympathetic nervous system, which in turn leads to exacerbation of hyperdynamic circulation in cirrhosis and induces hepatorenal syndrome [5].
Massive ascites discharge
Massive ascites discharge without timely protein supplementation leads to decreased circulating blood volume, which in turn leads to inadequate renal perfusion and induces hepatorenal syndrome.
Other triggers
Factors that cause loss of body fluids over a short period of time, including surgery and diarrhea.
Recent use of nephrotoxic drugs, such as aminoglycosides such as gentamicin, nonsteroidal anti-inflammatory drugs such as acetaminophen, and iodine contrast agents, can also induce hepatorenal syndrome.
Pathogenesis
Inadequate renal perfusion
Visceral arteries are highly diastolic and effective circulating volume is reduced, leading to decreased renal perfusion.
The above conditions may stimulate the excitation of the renin-angiotensin-aldosterone system and the sympathetic nervous system, producing vasoconstrictor substances that can act directly on the renal arteries, causing them to constrict and further reducing renal perfusion.
Under the combined effect of reduced renal perfusion and vasoconstrictive substances, the ability of the kidney to excrete sodium and water is significantly reduced, which further aggravates ascites and promotes the development of the disease.
Hemodynamic abnormalities
When hepatic impairment disease occurs, the degradation of vasorelaxant substances such as nitric oxide and prostacyclin is reduced, resulting in a high degree of dilatation of visceral arteries and a decrease in effective circulating volume.
When cirrhosis progresses to an advanced stage, compensatory mechanisms such as the renin-angiotensin-aldosterone system, sympathetic mediators, vasopressin and endothelin fail, myocardial contractility decreases, cardiac output decreases, arterial blood pressure decreases, and renal perfusion decreases, which in turn leads to hepatorenal syndrome.
Inflammatory response
Hepatorenal syndrome may be induced by an infectious inflammatory response due to bacterial infection, as well as by non-infectious inflammatory conditions such as systemic inflammatory response syndrome.
Bacterial infection of mesenteric lymph nodes activates substances such as endothelial nitric oxide synthase, which in turn leads to overproduction of nitric oxide, resulting in diastole of visceral arteries.
Systemic inflammation produces substances such as interleukin-6, which not only stimulates the production of vasodilating substances in the body, causing dilatation of the visceral arteries, but also impairs cellular function through direct action or induces oxidative stress, resulting in damage to the kidneys.
Symptoms
The most typical symptoms of hepatorenal syndrome are oliguria or anuria, azotemia and other renal function impairment, which can be complicated by ascites and electrolyte disorders.
Main Symptoms
Renal function impairment
Oliguria or anuria
Daily urine volume below 400ml is called oliguria.
Daily urine volume below 100ml is called anuria.
Oliguria and anuria are the most typical symptoms of hepatorenal syndrome, and they are also the important reasons for the retention of toxins in the body and the disturbance of water, electrolyte and acid-base balance in hepatorenal syndrome.
Azotemia
The rapid decline in renal function due to hepatorenal syndrome is characterized by a decrease in glomerular filtration rate.
Nitrogen products generated in the body such as creatinine and urea nitrogen are mainly metabolized by the kidneys.
When hepatorenal syndrome occurs, nitrogen products are retained and azotemia occurs.
Electrolyte disorders
Excessive water in the body, metabolic acidosis, elevated blood potassium, lowered blood sodium, and lowered blood calcium may occur as a result of the weakened or diminished function of the kidneys to regulate water and electrolytes in the body.
Severe electrolyte disorders may lead to confusion and fainting.
Primary Hepatic Hypoplasia
Jaundice
Jaundice is characterized by yellowing of the skin, sclera and other mucous membranes.
It may be accompanied by a deepening of the color of the urine.
Bleeding or anemia
Bleeding from mucosal tissues such as the nose and gums, accompanied by skin petechiae, ecchymosis and gastrointestinal bleeding.
Ascites
The mechanism of ascites formation is complex and closely related to hepatic decompensation, portal hypertension and renal failure.
It manifests as abdominal distension, abdominal bulging, large amount of fluid in the abdominal cavity, etc. In severe cases, umbilical hernia, dyspnea, palpitation and other symptoms may occur. Hypovolemic shock may occur in severe cases.
Other symptoms
These include digestive manifestations such as nausea, dyspepsia, and abdominal distension.
Malnutrition manifestations such as wasting, weakness, depression, dry skin or edema.
Consultation
Department of Medicine
Nephrology
If there is oliguria, anuria, or a large increase in ascites (e.g., bloating, abdominal distension), it is recommended to consult the Nephrology Department immediately.
Gastroenterology
If there is yellow staining of the skin, sclera and other mucous membrane tissues, accompanied by nausea, dyspepsia, abdominal distension and other digestive symptoms, it is recommended to consult the Department of Gastroenterology immediately.
Emergency Medicine
If there are symptoms such as confusion, fainting, or shock, it is recommended to call 120 for emergency treatment or to be taken to the Emergency Department immediately.
Preparation for medical treatment
Preparation for medical consultation: registration, preparation of information, common problems
Tips for seeking medical treatment
Record the development and characteristics of your condition before seeking medical treatment so that you can give your doctor more reference.
Avoid self-medication to avoid covering up the condition.
Record the frequency of urination and the volume of urine each time you urinate in the last few days.
Preparation Checklist
Symptom list
It needs to focus on the time of symptom onset, special manifestations, etc.
Is there any situation that the urine volume is less than 100ml or 400ml per day? How long has it been occurring?
What is the color of the urine? Is there any difficulty in urination?
Do you feel bloated recently? Is there any sudden increase in the size of the abdomen?
Is there any combination of nausea, dyspepsia, abdominal distension, fatigue, mental depression, etc.?
Has there been abnormal bleeding or deepening of the skin or mucous membranes recently?
Is there any abnormal skin edema? How long has it been present?
List of medical history
Is there any past history of cirrhosis, severe hepatitis, etc.?
Any recent infectious diseases such as peritonitis?
Any recent use of nephrotoxic medications such as aminoglycosides such as gentamicin, NSAIDs such as acetaminophen, iodine contrast, etc.?
Checklist
Test results in the last six months, which can be brought to the doctor’s office
Laboratory tests: routine blood test, urine test, blood biochemistry (including liver and kidney function, electrolytes, C-reactive protein, etc.)
Imaging examination: ultrasound examination, CT examination.
Medication list
Medication used in the last 3 months, such as medication or package, can be carried to the doctor
Vasopressin analog: terlipressin.
Alpha-adrenergic agonists: norepinephrine, midodrine.
Growth inhibitor analogs: octreotide, etc.
Plasma albumin.
Diagnosis
Diagnosis is based on
Medical history
History of cirrhosis, severe hepatitis, etc.
Presence of history of infectious diseases such as peritonitis.
Recent use of nephrotoxic drugs such as aminoglycosides such as gentamicin, nonsteroidal anti-inflammatory drugs such as acetaminophen, and iodine contrast agents.
Clinical manifestations
Symptoms.
Progressive or sudden decrease in urine output, manifested as oliguria or anuria.
Jaundice symptoms such as yellow staining or abnormal deepening of the color of the skin and sclera and other mucous membrane tissues.
Abnormal bleeding or petechiae or ecchymosis of mucosal tissues such as nasal cavity and gums, etc. Symptoms of liver function impairment.
Symptoms of ascites such as abdominal distension, abdominal distension, and large amount of fluid in the abdominal cavity.
Physical signs
Full abdominal distension, positive abdominal mobile turbidities, umbilicus may be protruding.
Yellowish coloration of the skin and sclera.
Laboratory Tests
Blood tests
The main tests are hemoglobin and white blood cell counts.
If there is an increase in the level of white blood cells, it suggests the presence of infection; if there is a decrease in hemoglobin, it suggests the presence of anemia, which can guide the treatment of the disease.
Urinalysis
Urine tests are used to assess the presence or absence of hematuria, proteinuria, and abnormalities in urine specific gravity and sodium.
Hepatorenal syndrome usually does not have proteinuria, no trace hematuria and other signs of organic kidney damage, if the presence of hematuria, proteinuria, urine specific gravity and sodium abnormalities, it will help in the differential diagnosis of the disease.
Blood biochemistry
It mainly includes liver and kidney function, electrolytes and C-reactive protein.
The main purpose is to check whether the patient’s liver function and kidney function are impaired and the degree of impairment, and to determine whether there are electrolyte disorders and inflammation.
The presence of elevated or decreased aminotransferases, bilirubin, albumin and other indicators suggests the presence of liver function damage.
Decrease in glomerular filtration rate, manifested by abnormal creatinine, urea nitrogen and other indicators, suggesting that there is damage to renal function.
The appearance of C-reactive protein elevation, can suggest the existence of inflammatory reaction, the existence of infection may be.
The presence of electrolytes such as blood sodium <125mmol/L abnormalities, suggesting hyponatremia, can assist in the diagnosis of hepatorenal syndrome.
Imaging
Ultrasound
It can assess the ascites stasis and the volume of ascites, as well as check for the presence of organic lesions in the liver, kidneys, and other organs.
If a large amount of fluid is found in the abdominal cavity, as well as abnormal liver morphology and density. The kidneys usually do not have obvious organic lesions, both of which help in the diagnosis of the disease.
CT examination
It can clarify the presence of organic kidney damage and evaluate the condition of cirrhosis and other diseases.
If abnormal liver morphology and density are present, the kidneys usually do not have obvious organic lesions, which may help in the diagnosis of the disease.
Diagnostic criteria
The current reference value is the 2015 diagnostic criteria for hepatorenal syndrome developed and revised by the International Ascites Club (ICA).
Diagnosis of cirrhosis and ascites.
Diagnosis of acute kidney injury according to the ICA-AKI criteria, i.e., a rise in blood creatinine (Scr) of ≥26.5 μmo/L (0.3 mg/dl) within 48 hours or a rise in Scr of ≥1.5 times the baseline within a known or presumed period of 7 d [6].
Discontinuation of diuretics and infusion of albumin 1 g/(kg-d) for volume expansion for 2 consecutive days is ineffective.
No shock.
No current or recent use of nephrotoxic drugs, such as nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics, and iodine contrast agents.
No signs of organic renal damage, e.g., no proteinuria (<500 mg/d), no microhematuria (urine erythrocytes <50/high magnification view), and normal renal ultrasonography.
Differential diagnosis
Chronic glomerulonephritis
Common point: Both may have persistent abnormal blood creatinine levels, and both have a slow decline in renal function.
Differences: Chronic glomerulonephritis usually does not show persistent ascites, jaundice and other signs of liver function impairment. Renal puncture biopsy of hepatorenal syndrome does not show obvious signs of renal tissue damage.
Acute tubular necrosis
Common point: Both may show oliguria, anuria, azotemia, and a significant decrease in glomerular filtration rate.
Differences: Acute tubular necrosis has higher urinary sodium level and lower blood or urine osmolality; hepatorenal syndrome has lower urinary sodium level and higher blood or urine osmolality. And hepatorenal syndrome is ineffective after volume expansion therapy.
Treatment
Treatment principle: The main treatment is for liver disease and its complications. Treatment includes drug therapy, renal replacement therapy, liver transplantation and other surgical treatments.
Treatment purpose: to improve liver function and prevent further deterioration of renal failure.
General treatment
Take bed rest and give low protein, high calorie and easily digestible diet.
Closely monitor blood pressure and urine output, and maintain fluid balance.
Monitor the changes of liver and kidney function, and the status of cirrhosis complications.
Avoid excessive fluid intake to prevent fluid overload and dilutional hyponatremia.
Remove triggers and discontinue nephrotoxic drugs.
Drug therapy
The combination of vasoconstrictor drugs (including the vasopressin analog terlipressin, the α-adrenergic agonists norepinephrine and midodrine, and the growth inhibitor analog octreotide, etc.) and albumin dilation is a commonly used therapeutic agent for hepatorenal syndrome [7].
Vasopressin analogs
The commonly used drug is terlipressin.
It can selectively act on type 1 vasopressin receptors in the endothelium of visceral blood vessels and attenuate visceral vasodilation. It is often used in combination with albumin and is the first-line treatment for type I hepatorenal syndrome.
Terlipressin can improve renal function in 60% of patients, nearly 50% of patients relapse after stopping the drug, and retreatment is still effective. The drug is only effective in patients with mildly reduced renal function and blood bilirubin <171 μmol/L. Currently, the drug is only used in patients awaiting liver transplantation.
Note that adverse reactions such as abdominal pain, diarrhea, myocardial ischemia, cardiac rhythm disturbances, and skin pallor may occur with use [8]. The drug is contraindicated in women who are allergic to the drug and during pregnancy. In the process of using the drug, it is necessary to pay attention to monitoring changes in blood pressure, serum electrolytes and other indicators.
Alpha-adrenergic agonists
Commonly used drugs include norepinephrine, Midodrine and other drugs.
These drugs are mainly hypertensive drugs, which can improve poor renal perfusion, and can be used as alternative drugs when vasopressin analogs cannot be used.
Alpha-adrenergic agonists need to be combined with octreotide and plasma albumin to obtain good results.
Caution should be exercised in the presence of hypoxia, hypertension, atherosclerosis, hyperthyroidism, and occlusive vasculitis. It should be used with caution in women during pregnancy.
Growth inhibitor analogs
Commonly used drugs include octreotide and other drugs.
These drugs inhibit glucagon, thereby inhibiting glucagon induced dilation of visceral arteries and increasing vasoconstriction.
Note that when used in the treatment of type I hepatorenal syndrome, this drug needs to be combined with midodrine and plasma albumin.
Plasma Albumin
Plasma albumin infusion increases plasma colloid osmolality, increases blood volume, elevates blood pressure, and improves renal perfusion insufficiency. Symptoms of ascites can also be improved to some extent after albumin infusion.
In the treatment of type I hepatorenal syndrome, the therapeutic efficacy of plasma albumin infusion alone is not as good as that of combined treatment with the above vasoconstrictor drugs, so nowadays plasma albumin is usually not infused alone, and is often used in combination.
Because plasma albumin has hypertonic effect, the dosage of this kind of drug must be strictly controlled to avoid complications such as dehydration, congestive heart failure and pulmonary edema.
Renal replacement therapy
Renal replacement therapy is appropriate only for patients awaiting liver transplantation and for those in whom recovery of liver function is estimated to be possible.
It is indicated for severe electrolyte disorders, hyperkalemia, volume overload leading to cardiac insufficiency, severe metabolic acidosis and severe symptoms of uremia [6].
The commonly used treatment is continuous renal replacement therapy (CRRT).
Note that patients with severe liver failure often have bleeding tendency or hemorrhage, so the choice of anticoagulant must be careful when doing CRRT, and low molecular heparin anticoagulation or heparin-free blood purification is required when necessary.
Surgery
Surgical method
Transjugular intrahepatic portosystemic shunt.
Liver transplantation.
Purpose of surgery
Transjugular intrahepatic portosystemic shunt to improve renal function in patients with hepatorenal syndrome, and at the same time to achieve the purpose of controlling ascites and reducing portal pressure.
Liver transplantation to radically improve hepatic failure, thereby correcting renal perfusion insufficiency and avoiding further deterioration of the condition.
Indications
Transjugular intrahepatic portosystemic shunt is indicated in cases of hepatorenal syndrome or combined gastrointestinal bleeding with a high risk, such as when pharmacological intervention is ineffective and there is no relevant contraindication to surgery.
Liver transplantation is the treatment of choice for hepatorenal syndrome. Type I hepatorenal syndrome has a high short-term morbidity and mortality rate and should be prioritized in the liver transplantation program.
Contraindications
Serious impairment of liver function, cardiac function, etc., and inability to tolerate surgery.
Systemic sepsis or severe abdominal infection.
Hemodynamic instability or severe coagulation abnormalities.
Precautions
The specific choice of operation should be determined by the clinician according to the condition of the patient, do not refuse the treatment because of resistance to the operation.
Prognosis
Cure
The prognosis of type I hepatorenal syndrome is very poor, and the average survival period is only 2 weeks if left untreated [9].
The prognosis of type II hepatorenal syndrome is better than that of type I, and the average survival period can reach 4-6 months. However, type II hepatorenal syndrome can be converted to type I if there is a combination of factors such as infection, and the prognosis becomes worse [1].
A 5-year survival rate of 60% has been reported in patients with hepatorenal syndrome who underwent liver transplantation, compared with 0% in those who did not [1].
Daily
Daily management
Dietary management
For combined malnutrition, a daily energy intake of 30-35 kcal per kg body weight is recommended [10].
Intake of 1.2 to 1.5 g of protein per kg of body weight per day is preferred to vegetable protein [10]. However, it is important to note that oral protein intake may be reduced or restricted for short periods of time, as appropriate, in cases of concurrent severe hepatic encephalopathy.
Avoid prolonged starvation, small and frequent meals, four to six meals per day are recommended.
When hepatorenal syndrome occurs, attention should be paid to restricting water intake.
Alcohol consumption is absolutely prohibited and fatty foods are not recommended.
Life management
Prohibit smoking, pay attention to rest and avoid exertion.
Infection is an important causative factor of the disease, pay attention to keep warm in daily life, avoid colds and other respiratory infections; pay attention to clean diet, avoid gastrointestinal infectious diseases.
Psychological support
Hepatorenal syndrome patients are often combined with underlying liver disease, and are prone to low mood, anxiety, depression and other manifestations, family members can enhance the accompaniment, and at the same time, psychological intervention can be given when necessary.
For patients who are afraid of treatment, health education on the disease can be enhanced to alleviate resistance and improve treatment compliance.
Follow-up
Regular follow-up examinations are needed to monitor the changes of various indicators, to make judgment on the control of the disease, to clarify whether the disease is deteriorating or not, and if deterioration occurs, timely intervention can be carried out.
Patients with hepatorenal syndrome are recommended to have regular follow-up every 1 to 3 months. If oliguria, anuria, or sudden increase of ascites occurs, timely consultation is recommended.
Blood routine, urine routine, liver and kidney function, electrolytes, C-reactive protein, renal ultrasound and other checkups may be needed during the review.
Prevention
Prevention of hepatorenal syndrome is extremely important in patients with liver failure because of its treacherous condition, poor therapeutic efficacy and prognosis. Hepatorenal syndrome is often triggered by a number of causative factors, and avoidance of these causative factors is the main focus of prevention of hepatorenal syndrome.
Active prevention of infection
Pay attention to keep warm in daily life, appropriate physical exercise, pay attention to clean diet, avoid cold, gastroenteritis and other infectious diseases.
Patients with cirrhotic ascites should actively prevent abdominal infections and actively combat spontaneous bacterial peritonitis.
Reasonable ascites discharge treatment
Excessive and large amount of ascites without replenishing albumin to expand the volume may reduce the effective circulating volume and induce hepatorenal syndrome, so it is necessary to reasonably carry out ascites treatment.
Cirrhotic patients with ascites who have lowered blood sodium can be put on a sodium-restricted diet while using diuretics cautiously.
For those whose blood sodium is basically normal, sodium-restricted diet can be used first to avoid renal function injury caused by hyponatremia.
Actively control gastrointestinal bleeding
Portal hypertension in liver cirrhosis often leads to esophagogastric fundus varices, which can lead to severe hemorrhage and induce hepatorenal syndrome, and should be actively prevented.
When hemorrhage occurs, it is necessary to stop bleeding as soon as possible, and under doctor’s guidance, intravenous transfusion of blood products to maintain blood volume and correct anemia, and antibacterial drugs (norfloxacin, etc.) are given to prevent the occurrence of spontaneous bacterial peritonitis.
Avoid nephrotoxic drugs
Avoid taking nephrotoxic drugs, such as aminoglycosides like gentamicin, NSAIDs like acetaminophen, iodine contrast, etc.