Liver transplantation, presence of a transplanted liver, liver transplant failure and rejection: clinical guidelines

List of Abbreviations

BP – blood pressure;

AIH – autoimmune hepatitis;

ALT – alanine aminotransferase;

ACE – angiotensin-converting enzyme;

AST – aspartate aminotransferase;

aPTT – activated partial thromboplastin time;

HIV – human immunodeficiency virus;

EGV – esophageal varices;

GGT – gamma-glutamyl transferase;

GCs – glucocorticoids;

HPS – hepatopulmonary syndrome;

HCC – hepatocellular carcinoma;

DNA – deoxyribonucleic acid;

GIT – gastrointestinal tract;

BMI – body mass index;

LDH – lactate dehydrogenase;

INR – international normalized ratio;

MRI – magnetic resonance imaging;

CRC LM – colorectal cancer liver metastases;

NAFLD – non-alcoholic fatty liver disease;

NASH – non-alcoholic steatohepatitis;

OLT – orthotopic liver transplantation;

PBC – primary biliary cholangitis;

PPH – portopulmonary hypertension;

PSC – primary sclerosing cholangitis;

PT – prothrombin time;

PCR – polymerase chain reaction;

RNA – ribonucleic acid;

DM – diabetes mellitus;

FFP – fresh frozen plasma;

SCT – spiral computed tomography;

GFR – glomerular filtration rate;

LT – liver transplantation;

ultrasound – ultrasound examination;

CKD – chronic kidney disease;

CHC – chronic viral hepatitis C;

CRF – chronic renal failure;

CVC – central venous catheter;

CMV – cytomegalovirus;

RR – respiratory rate;

HR – heart rate;

ALP – alkaline phosphatase;

ECG – electrocardiogram;

EchoCG – echocardiography;

HBV – hepatitis B virus;

HCV – hepatitis C virus;

HSV – herpes simplex virus;

HZV – varicella-zoster virus;

HLA – (human leukocyte antigen) human leukocyte antigens, major histocompatibility complex;

MELD – Model for End-Stage Liver Disease score;

MRSA – methicillin-resistant Staphylococcus aureus;

RAI – rejection activity index.

Terms and Definitions

Living related donor – a legally competent individual aged 18 years or older who has given consent to provide and/or has provided their organ during their lifetime for the purpose of related transplantation.

Liver transplantation – a surgical procedure in which a liver affected by a pathological process is replaced with a properly functioning graft.

Potential liver transplant recipient – a patient with indications for liver transplantation who has been placed on the waiting list.

Liver transplant recipient – a patient who has undergone liver transplantation.

Liver transplant rejection – a pathological process in which the recipient's immune system recognizes the liver graft as foreign, activating humoral and/or cellular inflammatory response systems, which can lead to severe graft dysfunction.

Deceased (cadaveric) organ donor – an individual declared dead in the prescribed manner (biological death or brain death) who serves as a source of organs (transplantable objects).

1. Brief information on the disease or condition

These clinical guidelines describe medical care technologies, including a series of evaluations for potential liver recipients to determine indications and rule out contraindications for liver transplantation, the procedure for waiting list inclusion, surgical treatment, and postoperative patient rehabilitation. Liver transplantation is the most effective and often the only radical treatment method for patients with end-stage chronic diffuse liver diseases, fulminant hepatic failure, and malignant or benign liver tumors.

These guidelines are intended for surgeons (transplant surgeons), general practitioners, gastroenterologists, and generalists.

1.1 Definition of the disease or condition

Liver transplantation – a medical technology involving a surgical procedure in which a liver affected by a pathological process is replaced with a properly functioning graft.

Liver transplant recipient – a patient who has undergone liver transplantation.

Liver transplant rejection – a pathological process in which the recipient's immune system recognizes the liver graft as foreign, activating humoral and/or cellular inflammatory response systems, which can lead to severe graft dysfunction.

Age category: adults, children;

Gender: any;

Stage: end-stage (decompensated liver cirrhosis, CTP class B-C, MELD/PELD score > 15) (Appendix G3);

Complications: liver graft failure and rejection;

Type of medical care: high-tech medical care, compulsory medical insurance;

Care settings: outpatient, inpatient;

Form of medical care delivery: elective, urgent, emergency.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Indications for liver transplantation include liver diseases leading to acute or chronic liver failure, clinically significant portal hypertension; metabolic diseases caused by abnormal hepatocyte function; focal liver lesions, as well as irreversible graft dysfunction.

End-stage chronic diffuse liver diseases:

✔ autoimmune;

✔ viral;

✔ toxic (including alcoholic etiology); K70.3 and others.

Predominantly cholestatic disorders

✔ primary biliary cholangitis; K74.3;

✔ primary sclerosing cholangitis;

✔ secondary biliary cirrhosis; K74.4;

✔ Caroli disease;

✔ biliary atresia; Q44.2;

✔ non-syndromic biliary hypoplasia;

✔ ductopenia (incl. Alagille syndrome);

✔ progressive familial intrahepatic cholestasis types I–III (incl. Byler disease and syndrome), etc.

Vascular disorders leading to impaired liver function and/or portal hypertension syndrome:

✔ Budd-Chiari syndrome;

✔ veno-occlusive disease.

Metabolic disorders due to congenital hepatocyte developmental defects:

diseases clinically manifesting as severe liver damage:

✔ Wilson's disease;

✔ alpha-1 antitrypsin deficiency;

✔ idiopathic hemochromatosis;

✔ hereditary tyrosinemia;

✔ cystic fibrosis;

✔ protoporphyria;

✔ galactosemia;

✔ glycogen storage disease types 1 and 4; E74.0;

✔ Gaucher disease type 1;

✔ Crigler-Najjar syndrome type I. E80.5.

Diseases in which the genetic defect causing abnormal liver cell function does not affect the structure and function of the liver itself, but leads to various disorders in other organs and systems:

✔ primary hyperoxaluria type 1;

✔ protein C deficiency;

✔ urea cycle disorders;

✔ familial hypercholesterolemia;

✔ hemophilia A and B, etc.

Acute liver failure:

✔ acute viral hepatitis;

✔ acute autoimmune hepatitis;

✔ fulminant Wilson's disease;

✔ fulminant course of Budd-Chiari syndrome;

✔ toxic etiology (e.g., halothane inhalation anesthesia, paracetamol overdose, mushroom poisoning, etc.).

Focal liver lesions:

malignant: C22.0

✔ hepatocellular carcinoma;

✔ cholangiocarcinoma;

✔ hepatoblastoma, etc.

benign: D13.4

✔ hepatocellular adenoma;

✔ infantile hemangioendothelioma;

✔ cystadenoma, etc.;

✔ parasitic (alveococcosis);

✔ secondary focal (metastatic) liver lesions (metastases of neuroendocrine tumors, colorectal cancer).

Liver retransplantation:

✔ primary graft non-function;

✔ hepatic artery thrombosis;

✔ graft cirrhosis (resulting from recurrence of the primary disease or de novo development);

✔ secondary biliary cirrhosis (incl. ischemic cholangiopathy);

✔ chronic rejection.

1.3 Epidemiology of the Disease or Condition

The ever-increasing number of performed procedures each year (over 30,000 globally per year) testifies to the success of this treatment method for patients with end-stage liver disease. The need for liver transplantation is at least 20 per 1,000,000 population annually. According to the 16th report of the Russian Transplantology Society Registry in 2024 [1], a total of 894 liver transplantations were performed in the Russian Federation; compared to 2023, the number of liver transplantations increased by 65 operations, or 7.8% (2023: 829). Liver transplantation was performed in 38 centers. After liver transplantation, recipient survival is 85%–90% at one year, 70%–75% at five years, 60% at ten years, and 40% at twenty years. The best prognosis is observed in patients with cholestatic diseases. In malignant liver tumors, the five-year patient survival rate is 50%–70%, depending on the tumor type and stage.

1.4 Features of Coding the Disease or Condition

Liver transplantation is a treatment method for end-stage various liver diseases.

To designate the presence of a transplanted liver in the absence of any signs of its dysfunction—clinical, laboratory, instrumental, or morphological—the code Z94.4 (presence of transplanted liver) is used.

If signs of functional impairment or structural changes in the liver graft are detected (see section 1.5.1), code T86.4 (liver transplant failure and rejection) must be used.

1.5 Classification of the disease or condition

Due to the many different aspects of liver transplantation, several classifications are used. Regarding the liver transplantation procedure itself, the following classification can be applied (Table 1).

Table 1. Classification of liver transplantation

1.6 Clinical presentation of the disease or condition

Liver transplantation is a treatment method for a large number of liver diseases leading to the irreversible loss of its functions; therefore, the clinical presentation is diverse and depends on the disease that necessitated liver transplantation.

In patients after liver transplantation with normal liver function (should be coded as Z94.4), there is a complete restoration of liver function and an absence of any symptoms.

The presence of a transplanted liver is detected during anamnesis collection, when the fact of the patient's liver transplantation surgery is established, by the results of a physical examination revealing a postoperative scar, typically in the right flank region. Laboratory diagnostics show no deviations from reference values when the function of the transplanted liver is normal. Instrumental diagnostic methods (comprehensive abdominal ultrasound, abdominal computed tomography, abdominal magnetic resonance imaging) visualize the liver graft in the abdominal cavity.

When transplanted liver dysfunction develops, various symptoms and syndromes may manifest, caused both directly by the etiological cause of the disease and by general nonspecific symptoms of liver damage. Patients most frequently complain of weakness, fever, and pruritus. With the progression of graft dysfunction, abdominal distension, ascites, edema, jaundice, sleep inversion, and confusion are observed.

Transplanted liver dysfunction can be caused by the following factors:

● Vascular-origin graft dysfunction (graft artery thrombosis/stenosis, hepatic vein thrombosis/stenosis, portal vein thrombosis/stenosis, inferior vena cava stenosis, splenic artery steal syndrome, etc.).

Symptoms are nonspecific and depend on the severity and duration of the vascular lesion: weakness, abdominal distension; laboratory findings include increased transaminase activity, development of coagulopathy, and hyperbilirubinemia at advanced stages, etc. Some patients may lack any symptoms. The main diagnostic methods are comprehensive abdominal ultrasound with duplex scanning of the hepatobiliary vessels, abdominal computed tomography with intravenous bolus contrast enhancement, as well as interventional radiological studies (portal venography, inferior vena cava venography), which visualize a blood supply defect in the affected vessel.

● Biliary-origin graft dysfunction (anastomotic and non-anastomotic strictures of the common bile duct, acute and chronic recurrent cholangitis, secondary biliary cirrhosis, etc.).

The leading syndromes in the development of biliary complications are cholestatic syndrome (pruritus, jaundice, dark urine, light-colored stool, bitter taste in the mouth, nausea, vomiting), febrile-intoxication syndrome (fever, often above 38^oC-39^oC, weakness, headache, chills, decreased appetite), and febrile seizures may develop. Characteristic laboratory markers include increased activity of cholestatic enzymes (GGT, ALP, total, direct, and indirect bilirubin), increased acute-phase markers (leukocytosis, neutrophilia, left shift of the leukocyte formula, elevated levels of C-reactive protein, presepsin, procalcitonin test) in the development of acute/exacerbation of chronic cholangitis. Instrumental diagnostics (comprehensive abdominal ultrasound, magnetic resonance cholangiopancreatography, retrograde cholangiopancreatography) reveal choledochal strictures in the anastomotic area/other areas, dilation of the distal intrahepatic bile ducts, and graft abscesses.

● Graft dysfunction as an outcome of viral hepatitis (viral hepatitis A, B, C, D, CMV).

Nonspecific symptoms are observed: unexplained weakness, increased fatigue, hepatomegaly, heaviness, and pain in the right upper quadrant. Laboratory and instrumental examinations reveal increased liver enzyme activity, diffuse parenchymal changes, and detection of the etiological viral agent in the blood.

● Transplanted liver rejection (acute and chronic, cellular and humoral rejection reactions).

The clinical presentation is diverse, varying from complete absence of symptoms to the development of signs of severe hepatocellular insufficiency in advanced stages. Due to the special clinical significance and specificity of this complication exclusively for liver transplant recipients, the absence of a characteristic clinical presentation, and a multi-step diagnostic algorithm, transplanted liver rejection will be described in detail in chapter 2.5.

● Recurrence of the underlying disease (recurrence of viral hepatitis, autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, etc.).

The clinical presentation is pathognomonic for the disease that led to the need for liver transplantation and recurs after it.

2. Diagnostics, medical indications and contraindications for diagnostic methods

2.1 Complaints and Anamnesis

Comment: when considering the possibility of liver transplantation for alcoholic cirrhosis, it is necessary to verify the patient's sustained abstinence [14]. Assistance from a specialist qualified in the management of patients with alcohol dependence is indicated. Abstinence is associated with both the recompensation of liver function in patients with decompensated alcoholic cirrhosis and a lower risk of alcohol relapse after liver transplantation. Inclusion on the waitlist is carried out only after a period of conscious abstinence of at least 6 months [14, 15].

Comment: the Milan criteria are criteria for selecting HCC patients for liver transplantation, demonstrating a 5-year survival rate > 70 %.

They include:

a single HCC nodule < 5 cm or

up to 3 nodules, each < 3 cm,

absence of macroscopic vascular invasion,

absence of metastases [220].

• In case liver transplantation is performed for HCC within the University of California San Francisco criteria (UCSF criteria), it is recommended to perform down-stage therapy to reduce tumor size and extent [18, 24, 27].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comment: University of California San Francisco criteria (UCSF criteria):

a single HCC nodule < 6.5 cm or

up to 3 nodules, each < 4.5 cm, with a total sum < 8 cm,

absence of macroscopic vascular invasion,

absence of metastases [18].

Adherence to broader UCSF criteria with careful patient selection and tumor down-stage therapy allows achieving comparable survival rates [18].

Comment: Traditionally, metastatic liver disease has been a contraindication to liver transplantation (LT); however, currently, LT is considered feasible for metastases of neuroendocrine tumors or colorectal cancer. With careful recipient selection, a 5-year survival rate of up to 60% can be achieved [19, 20]. Given the shortage of donor organs, this issue must be addressed collegially on an individual basis [24].

Intrahepatic cholangiocarcinoma has historically been a contraindication to LT due to the high risk of recurrence. The outcomes of such transplants are inferior to corresponding oncological treatment [24, 25]. However, in the absence of extrahepatic spread and in the presence of liver cirrhosis precluding liver resection, LT for hilar cholangiocarcinoma in a highly selected group of patients provides a 5-year survival rate of up to 60% [26].

2.2 Physical Examination

Comment: the initial surgical consultation (examination) includes the evaluation of the surgical management strategy (especially important in “surgically complex” patients: with massive portal vein thrombosis, multiple prior abdominal surgeries, etc.). In addition, it is necessary to assess the presence of comorbidities that may negatively affect postoperative wound healing (obesity, cachexia).

Comment: Liver transplantation is classified as a high-risk or extremely high-risk surgical procedure. Furthermore, lifelong immunosuppressive therapy is prescribed postoperatively to prevent rejection. These factors can exacerbate comorbid conditions and pathological states, which in turn may lead to life-threatening complications. To prevent the aforementioned risks, a thorough pre-transplant evaluation of the recipient is required to rule out comorbidities, and if present, to provide adequate therapy in accordance with current clinical guidelines.

Comment: in cases of unexplained liver disease, additional evaluation should be performed to establish a diagnosis. This is important both during the liver transplant waiting list period, if the patient requires etiotropic/pathogenetic therapy to slow disease progression (e.g., ursodeoxycholic acid** for cholestatic liver diseases, copper-chelating therapy for Wilson's disease), and in the postoperative period, since the prescribed immunosuppression regimen may depend on the underlying disease (e.g., prolonged glucocorticoid use post-transplant in patients with autoimmune liver diseases).

Comments: Dental examination is of great importance for detecting oral infections and sanitizing infection foci prior to transplantation and the initiation of immunosuppressive therapy.

Comments: due to the exacerbation of chronic infectious diseases and the increased risk of malignancies associated with long-term immunosuppressive therapy, regular follow-up by an obstetrician-gynecologist is extremely important, including laboratory and instrumental evaluations in accordance with current clinical guidelines.

Comments: when considering transplantation for alcoholic cirrhosis, it is necessary to verify sustained abstinence [14]. Inclusion on the waiting list for liver transplantation can only be performed after a conscious abstinence period of at least 6 months [14, 15].

2.3 Laboratory Diagnostics

Comment: Patients with liver cirrhosis have an increased risk of developing infections that can lead to multiorgan failure and death [57]. Screening for latent infections is necessary to treat potentially fatal infectious complications prior to transplantation and to prevent exacerbations in the post-transplant period while receiving immunosuppressive therapy.

Detection of cytomegalovirus or Epstein-Barr virus in the blood is not a contraindication to liver transplantation; however, it requires monitoring after liver transplantation due to the high risk of complications associated with these viruses [58].

Comment: The presence of donor-specific antibodies is associated with a higher incidence and severity of acute and chronic antibody-mediated rejection. Alloantibodies are associated with more severe histological damage—graft fibrosis, disease recurrence, etc. However, the correlation mechanism between the appearance of donor-specific antibodies, liver damage, and liver transplantation outcomes is not fully understood [56].

2.4 Instrumental Diagnostics

Comments: The objectives of the ultrasound examination are: 1) to rule out pathology of other abdominal organs (e.g., pancreas); 2) to perform Doppler sonography of the hepatic vessels (portal vein, hepatic veins); 3) to detect additional liver lesions (due to the increased risk of HCC in patients with liver cirrhosis) [167].

Comment: Patients with liver cirrhosis are often compromised by concomitant cardiovascular pathology. An electrocardiogram and echocardiography must be performed on all patients evaluated as candidates for liver transplantation. In the presence of risk factors or age over 50 years, exercise ECG and coronary angiography, followed by endovascular treatment in the presence of hemodynamically significant coronary stenoses, are indicated to detect asymptomatic coronary artery disease [34, 37].

Comment: Portal vein thrombosis is not an absolute contraindication to transplantation. However, extensive thrombosis (Yerdel grade 3–4) significantly complicates the procedure due to the inability to restore adequate afferent blood flow. Liver transplantation in extensive portal vein thrombosis is preferably performed in high-volume transplant centers.

Knowledge of the recipient's vascular anatomy is critical for the upcoming liver transplantation. An important evaluation point is the search for pre-existing portosystemic shunts that require ligation. Isolated portal vein thrombosis is an indication for anticoagulant therapy.

Comment: With thorough evaluation, HPS is detected in 10–17% of patients with liver cirrhosis. The functional basis of HPS is intrapulmonary vasodilation, which leads to arterial hypoxemia and, consequently, a potential need for oxygen therapy. Liver transplantation most frequently leads to the closure of intrapulmonary shunts and is the only possible treatment for HPS. The presence of HPS can be detected using the alveolar-arterial oxygen gradient or contrast echocardiography [39]. Since the severity of HPS does not correlate with the severity of liver disease, HPS itself serves as an indication for liver transplantation. Adequate assessment of HPS severity is extremely crucial, as it determines the postoperative prognosis. Patients with PaO₂ < 50 mmHg refractory to 100% oxygen inhalation have an extremely high risk of irreversible postoperative pulmonary dysfunction with high mortality [40]. It must also be taken into account that the resolution of HPS after transplantation may take several months [41].

Comment: PoPH is detected in 2–8% of patients suffering from liver cirrhosis. The suspected cause of PoPH development is an imbalance between endogenous vasodilators and vasoconstrictors in the setting of compromised liver function [42]. The presence of PoPH can be suspected when mPAP rises above 30 mmHg on transthoracic Echo-CG in the absence of pulmonary pathology. If PoPH is suspected, cardiac catheterization is advisable to confirm the diagnosis. The presence of PoPH significantly increases perioperative mortality risks and requires careful anesthetic risk assessment [43, 44, 45].

2.5 Other Procedures

Comment: renal failure is an unfavorable prognostic factor after liver transplantation [46, 48]. Hepatorenal syndrome (HRS), which is usually a reversible cause of renal failure, must be differentiated from other causes such as sepsis, hypovolemia, and intrinsic renal disease. Patients with end-stage liver disease and an estimated GFR of less than 30 mL/min, or the presence of HRS, requiring renal replacement therapy for more than 8–12 weeks, as well as patients with glomerulosclerosis greater than 30% (according to biopsy data), may be considered candidates for simultaneous liver and kidney transplantation [47, 49].

Comment: liver cirrhosis frequently leads to malnutrition, which is detected in 70% of patients with end-stage liver disease [50]. Wasting worsens outcomes after liver transplantation. Patients with a BMI of less than 18.5 mg/m² are at high risk of postoperative mortality [51]. Assessing the severity of malnutrition in patients with liver cirrhosis can often be very challenging. The use of standard clinical (BMI) and laboratory tests (prealbumin) does not reflect the actual clinical picture in cases of severe liver failure. Psoas muscle thickness on CT scans correlates with the severity of sarcopenia, and its reduction is associated with a worse prognosis after liver transplantation [52]. The presence of obesity also worsens outcomes after liver transplantation. Patients with a BMI greater than 40 have significantly worse outcomes compared to normal-weight patients [52, 53]. Obese patients have a higher risk of developing post-transplant diabetes mellitus [53].

Comment: osteoporosis is common in patients with liver cirrhosis and is most closely associated with cholestatic liver diseases [54]. Absorptiometry is indicated to assess the risk of pathological fractures and determine the need for therapy adjustment. Additional risk factors for osteoporosis in patients with liver cirrhosis include female gender, low BMI, and smoking [55].

Assessment of oncological status

Comment: a history of malignancy is not a contraindication to liver transplantation. Depending on the type and stage of the tumor, a 5-year relapse-free interval after treatment is currently considered sufficient to perform transplantation [27]. It is necessary to assess the risk of disease recurrence at 1, 5, and 10 years post-treatment in cooperation with an oncologist. An acceptable recurrence rate for waitlisting is less than 10%. The currently accepted 5-year interval may vary depending on the tumor type and extent.

Cancer screening as part of the pre-transplant evaluation should be performed based on the recipient's age, gender, alcohol consumption, and smoking status. Colorectal cancer screening is mandatory for candidates older than 50 years. Screening for malignancies of the respiratory tract, upper gastrointestinal tract, and urinary bladder is mandatory in patients with a history of alcohol abuse and smoking. Regular follow-up (examination and consultation) by an obstetrician-gynecologist (including mammography and cervical smear cytology) is mandatory for female recipients. A urologist consultation is required for male recipients.

Presence of HIV infection

Comment: the presence of HIV infection was long considered a contraindication to liver transplantation due to an extremely poor prognosis. The advent of active systemic antiviral drugs (J05) has changed the prognosis for such patients. In the presence of HBV or HCV coinfection with HIV, a significant number of patients may develop liver cirrhosis over the course of their lives [67].

2.5.1 Placement of patients on the waiting list and determination of the urgency for liver transplantation

Comment: see Appendix G1.

Comment: see Appendix G2. Priority on the liver transplantation waiting list was initially determined by waiting time and the severity of liver disease. The Child-Turcotte-Pugh (CTP) score and the MELD score, introduced later, are currently used universally to determine waiting list priority [70]. The MELD score was originally developed to determine short-term survival in patients who underwent TIPS after gastrointestinal bleeding. Subsequently, MELD has been widely adopted as a tool to determine 3-month mortality in patients with end-stage liver disease [71]. For patients with a MELD score of 14, the expected 1-year survival is lower than that following liver transplantation [72, 73]. Accordingly, a MELD threshold of 15 points is considered the criterion for placement on the waiting list in most centers. The MELD score does not reflect the impact on prognosis of complications of liver cirrhosis such as refractory ascites, recurrent gastrointestinal bleeding, or persistent encephalopathy. To adjust for these deviations, as well as to adjust MELD scores in waiting list patients without liver cirrhosis (a list of conditions is provided in Table 2), various MELD score adjustment systems exist, determined by local transplant center guidelines [74, 75].

Table 2. List of diseases in liver transplant waiting list patients

Monitoring of patients after liver transplantation in the early postoperative period

• In the early postoperative period following liver transplantation, the liver recipient is recommended to undergo advanced clinical, laboratory, and instrumental monitoring in the ICU with a frequency determined by the severity of the condition and the center's protocol; the minimum monitoring volume includes [27]:

  ✔ continuous electrocardiogram recording (with documented strips at least once daily);

  ✔ continuous pulse oximetry;

  ✔ measurement of respiratory rate;

  ✔ general thermometry;

  ✔ measurement of hourly diuresis;

  ✔ monitoring of output from each drain individually;

  ✔ tracking of nasogastric tube drainage.

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Puncture biopsy

Comments: prior to the procedure, testing of INR and platelet aggregation is mandatory. If INR increases above 2, or platelets decrease below 40,000, biopsy is contraindicated without additional measures: transfusion of two doses of fresh frozen plasma and/or 6 doses of platelet concentrate with laboratory monitoring. The procedure must be performed under systemic antimicrobial coverage. After the procedure, strict bed rest in the right lateral position is prescribed for 4 hours with hourly measurement of peripheral blood pressure, heart rate, and respiratory rate. 4 hours after the biopsy, total blood hemoglobin is tested; in case of a decrease, an immediate comprehensive ultrasound examination of the abdominal organs is performed. If dyspnea, inspiratory pain, or subscapular pain occurs, pneumothorax must be ruled out.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Organ transplantation stimulates the development of an immune response, which can lead to graft dysfunction and loss. Immunosuppressive therapy is aimed at suppressing the recipient's immune system response and prevents the development of rejection. Off-label medicinal products may be used only with the ICD-10 code Z94.8 (in accordance with Decree of the Government of the Russian Federation No. 1180-r dated May 16, 2022, "On Approval of the List of Diseases or Conditions (Groups of Diseases or Conditions) for Which the Use of a Medicinal Product in Accordance with Indicators (Characteristics) of the Medicinal Product Not Specified in Its Instructions for Use is Allowed").

Comment: after conservative treatment options have been exhausted and the need for liver transplantation has been established, 3 main questions must be answered:

1. Will the patient be able to tolerate the surgery and the early postoperative period;

2. Will the patient be compliant with therapy and the regimen required for survival after liver transplantation;

3. Does the patient have comorbid conditions that could compromise their survival or graft function.

The results of the answers to these questions determine the presence of contraindications to liver transplantation [27].

The issue of contraindications to liver transplantation is based, in addition to evidence-based medicine principles, on the legislative level in each country performing transplantation. Currently, the need for liver transplantation in cirrhosis of viral etiology is unquestionable, while the presence of HIV is mostly considered a contraindication to liver transplantation [27]. However, in some countries, the presence of controlled HIV infection is not a contraindication to liver transplantation [28].

A separate issue regarding contraindications to liver transplantation is the technical feasibility of the surgery. The most important anatomical feature in liver cirrhosis is the presence of portal vein thrombosis (PVT). Stage 1-2 PVT (Yerdel) is not a contraindication to liver transplantation [29, 30]. However, widespread PVT (stage 3-4 Yerdel) is considered a relative contraindication, depending on the liver transplantation center [27-30]. Currently, performing liver transplantation in widespread PVT is possible in centers with extensive experience in such interventions, using various modifications of portal blood flow restoration. At the same time, the results of such transplantations do not differ from those without PVT [30].

3.1 Conservative Treatment

Preoperative preparation of pediatric recipients before liver transplantation

• In all children who are potential liver recipients in the preoperative period, it is recommended to optimize conservative therapy of the underlying disease and correct its complications, including active search for and eradication (including systemic antibacterial drugs) of infection foci (with pre-transplantation infectious screening), nutritional support, correction of metabolic/water-electrolyte disorders and acid-base balance, correction of anemia and coagulopathy, as well as treatment of portal hypertension complications (ascites [by prescribing diuretics and draining the abdominal and pleural cavities] and episodes of gastrointestinal bleeding) as indicated in preparation for liver transplantation [76, 77, 83, 84, 86, 87, 88, 155].

GCR CLEL 4Grade of Recommendation C (Level of Evidence - 4)

Desensitization preparation of recipients for ABO-incompatible transplantation

• In potential recipients, it is recommended that natural blood group antibody titers of no more than 1:8 and immune titers of no more than 1:4 be considered acceptable (threshold values are determined by the center's local protocol). All recipients are recommended to undergo monitoring of group-specific antibody levels (α/β agglutinins and immune anti-A/anti-B antibodies) at least once a week, as well as additionally based on clinical indications (including changes in therapy/preparation for interventions) to prevent the development of humoral rejection and liver graft dysfunction [87, 89].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

• In cases where, despite transfusion therapy, blood group antibody titers exceed acceptable (target) values, as well as when rapid recipient preparation is necessary (urgent indications for transplantation) or in case of initially high antibody titers (greater than 1:32), recipients are recommended to undergo therapeutic plasmapheresis (plasma exchange) with replacement of the removed plasma volume with AB(IV) fresh frozen plasma until target titers are achieved/antibody levels are reduced [80, 87, 89, 90].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

• In the absence of contraindications (persistent infection, severe cytopenia), patients with elevated blood group antibody titers persisting despite transfusion therapy with AB(IV) fresh frozen plasma are recommended to receive #rituximab** at a dose of 375 mg/m² prior to transplantation [80, 87, 89, 90].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Standard protocol for preparing recipients with initially high blood group antibody titers for ABO-incompatible liver transplantation

• Following clinical and laboratory-confirmed sanitation of all foci of infection, 14–20 days prior to the planned transplantation date, children are recommended to receive a single intravenous infusion of #rituximab** 375 mg/m² [82, 87, 152, 153].

GCR CLEL 4Grade of Recommendation C (Level of Evidence - 4)

Comment: following the administration of #rituximab**, a course of plasmapheresis is performed with complete replacement of the circulating plasma volume with AB(IV) fresh frozen plasma until the target level of group-specific antibodies is reached, which must be monitored after each session.

• In young patients with a high risk of infectious complications, as well as severe cytopenia, the administration of #rituximab** is recommended to be considered inappropriate; therefore, specific preoperative preparation in these patients includes only plasmapheresis—several sessions until acceptable blood group antibody titers are achieved [152].

GRCLEL 4Grade of Recommendation C (Level of Evidence - 4).

3.2 Surgical Treatment

Surgical intervention in the recipient includes the following stages:

● Hepatectomy;

● Creation of vascular anastomoses (in the following sequence: caval, portal, and arterial reconstruction);

● Hemostasis and formation of the biliary anastomosis.

Comment: removal of the diseased liver in most cases represents the most laborious step. In cases of tumor lesions of the liver, this is associated with marked hepatomegaly. In cases of cirrhosis, despite a significant reduction in liver size, hepatectomy is complicated by the presence of venous collaterals in the liver ligaments and its hilum, adhesions, as well as altered normal topographic-anatomical relationships in the upper abdomen and blood coagulation disorders. Biliary drainage can be established using either a bilio-biliary anastomosis or a Roux-en-Y jejunal loop.

3.3 Other Treatment

Therapy in the early postoperative period

Antibacterial and antimycotic therapy

Comments: systemic antibacterial drugs should be prescribed taking into account the epidemiological situation in the hospital; therapy is adjusted when necessary based on microbiological monitoring results.

Concomitant therapy

Comments: it is extremely important to strictly monitor the water balance. The patient's volume status requires special attention: ascites, pleural effusion, edema, anasarca, CVP. Weight, volume of intake (fluids consumed, administered solutions affecting water-electrolyte balance) and output (urine, vomiting, bile, unmeasured losses – 500 ml/day in the absence of fever), waist circumference at the umbilicus, and CVP must be recorded every morning.

All postoperative wounds (postoperative sutures, drain sites, etc.) must be inspected daily. All sutures are treated with antiseptic and disinfectant solutions.

Initial immunosuppressive therapy after liver transplantation [27]

Comments: tacrolimus** (capsules) and tacrolimus** (prolonged-release capsules) are the main immunosuppressants used after liver transplantation as monotherapy or as part of a two- or three-drug regimen in more than 90% of patients.

Comment: a concentration drop below 5 ng/mL is permissible if GFR decreases below 40 mL/min, in which case the administration of other immunosuppressants is required.

Comment: #tacrolimus** (capsules) and #tacrolimus** (prolonged-release capsules) are metabolized by the liver continuously in severe early graft dysfunction; high concentrations can lead to adverse drug reactions. The appearance of nephro- or neurotoxicity serves as a reason to reduce the dose of #tacrolimus** (capsules) and #tacrolimus** (prolonged-release capsules).

Comments: despite all the advantages of liver transplantation associated with the high resistance of the graft to the recipient's immune response, medical immunosuppressive therapy is a decisive component of patient treatment, since the risk of graft loss due to acute or chronic rejection always exists and poses a threat to the patient's life. The use of various drug combinations ensures the personalized selection of immunosuppressive therapy appropriate for graft function, the recipient's underlying disease and comorbid status, as well as the severity of side effects.

Comment: induction of immunosuppressive therapy during liver transplantation is desirable not so much from the standpoint of rejection prophylaxis, but rather to provide temporary cover during periods when the use of other immunosuppressants is impossible, undesirable, or restricted. The use of induction allows for the free and safe modification of initial immunosuppressive therapy, up to its delayed administration, in the event of non-standard clinical situations and complications (renal and multiorgan failure, leukopenia and thrombocytopenia, infection, neurological disorders).

Systemic corticosteroids

Comments: in patients transplanted for autoimmune liver diseases (primarily autoimmune hepatitis; when necessary, other autoimmune/cholestatic diseases), the administration of glucocorticoids with a gradual dose reduction to the minimum maintenance dose (the tapering schedule is determined by the clinical situation and the center's protocol) may be considered to prevent recurrence of the underlying disease and maintain graft function [27, 179, 168].

Comment: cyclosporine** has been the main calcineurin inhibitor since the early 1970s and has been widely used in transplantation of various organs. With the advent of #tacrolimus**, cyclosporine** has lost its position in most immunosuppressive protocols for liver transplantation. However, it can be prescribed in certain situations, mainly in case of intolerance or manifestation of #tacrolimus** neurotoxicity or the presence of severe baseline neurological disorders (e.g., Wilson's disease, diabetes mellitus).

Comment: the use of mycophenolate mofetil** / #mycophenolic acid** as part of initial immunosuppressive therapy allows for a reduction in calcineurin inhibitor doses or their temporary withdrawal, thereby preserving and improving renal function. The addition of mycophenolate mofetil** / #mycophenolic acid** may be especially useful in patients with a higher risk of rejection, such as young patients undergoing liver transplantation for fulminant hepatic failure and patients with autoimmune liver disease [27, 176, 177].

Comment: the use of everolimus** as part of immunosuppressive therapy allows reducing the doses of calcineurin inhibitors or temporarily withdrawing them, thereby preserving and improving renal function. The addition of everolimus** may be particularly beneficial for patients with a history of hepatocellular carcinoma due to the potential for recurrence prevention [27, 176, 177].

Rejection After Liver Transplantation

Comment: with modern immunosuppressive therapy regimens, the incidence of acute cellular rejection is no more than 30% during the first 12 months post-transplantation [92, 93]. As a rule, it is suppressed by intensifying immunosuppressive therapy, and cases of graft loss resulting from acute rejection are currently very rare.

Rejection of the transplanted liver can develop at any time and should be suspected if graft dysfunction develops, manifesting clinically (ascites, jaundice, hepatomegaly, pruritus, fever) or solely by biochemical abnormalities. Differential diagnosis is performed between the following conditions (Table 3).

Table 3. Differential diagnosis of graft rejection

Morphological diagnosis of transplanted liver pathology based on puncture biopsy results

• Morphological assessment of liver graft rejection in liver recipients is recommended to be performed by examining fine-needle aspiration biopsy specimens. A biopsy specimen is considered adequate if the histological sections contain at least seven portal tracts. It is precisely within these tracts that changes characteristic of rejection and other types of pathology appear. The underlying pathology in acute rejection involves inflammatory and necrotic processes [94, 95].

LeR CLoE 4Level of Recommendation C (Level of Evidence — 4)

Acute Liver Graft Rejection

In accordance with the accepted international Banff-95 classification [96], acute liver rejection is defined as "allograft inflammation caused by genetic differences between the donor and recipient, primarily damaging interlobular bile ducts, portal vein and hepatic venule endothelium, and occasionally the hepatic artery and its branches." The Banff-95 expert panel advises against using such synonyms found in literature for acute liver rejection as: early rejection, cellular rejection, non-ductopenic rejection, rejection without duct loss, reversible rejection. In accordance with Banff-95 criteria, there is a qualitative and semiquantitative assessment of the degree of acute rejection.

Qualitative assessment of acute rejection is based on the degree and extent of the inflammatory process in the portal tracts (Table 4).

Table 4. Qualitative assessment of transplanted liver acute rejection

Semiquantitative assessment of the degree of acute rejection is performed based on the so-called rejection activity index (RAI). The index is obtained by summing the inflammation degrees of three biopsy structures: portal tracts, bile ducts, and veins (RAI = portal tract inflammation degree + bile duct inflammation degree + vein inflammation degree) (Tables 5 – 7).

Table 5. Acute rejection activity score by the degree of portal inflammation

Table 6. Acute rejection activity score by the degree of inflammatory bile duct injury

Table 7. Acute rejection activity score by the degree of venous inflammation

The degree of acute rejection depends on the activity index value: RAI 0-2 – no rejection; RAI 3 – indeterminate degree of acute rejection; RAI 4-5 – mild acute rejection; RAI 6-7 – moderate acute rejection; RAI 8-9 – severe acute rejection.

Chronic Liver Allograft Rejection

Chronic liver allograft rejection is characterized by irreversible loss of bile ducts and small arteries, as well as obliterative arteriopathy. This leads to hepatocellular cholestasis, hepatocyte degeneration and necrosis, and centrilobular atrophy. A characteristic feature is the presence of sclerosis and hyalinosis of the arterial walls. Surviving bile ducts may show slight mononuclear epithelial infiltration, basement membrane disruption, and connective tissue proliferation. In accordance with Banff-95 criteria, early and late chronic rejection are distinguished. Early chronic rejection is reversible and curable with immunosuppressants. Late chronic rejection features severe structural changes in small bile ducts, microcirculatory pathways, as well as large arteries and large bile ducts [97] (Tables 8 – 10).

Table 8. Structural changes in bile ducts in early and late chronic rejection

Table 9. Structural changes of microcirculatory pathways in early and late chronic rejection

Table 10. Structural changes of large branches of the hepatic artery and large bile ducts in early and late chronic rejection

Comment: treatment efficacy is evaluated based on the dynamics of laboratory parameters [178].

Comment: persistence of graft dysfunction and the absence of clear positive dynamics in the morphological picture of the graft on follow-up biopsy after pulse therapy indicates steroid-resistant rejection, which may also include a humoral component. There are indications of a predisposition to steroid resistance in recurrent rejection crises, as well as an increased proportion of steroid-resistant crises in patients treated with systemic corticosteroids for a long time prior to transplantation.

Infection prophylaxis in liver transplantation

• Patient isolation is recommended only in cases of leukopenia (less than 1 × 10⁹/L) and/or neutropenia (less than 0.5 × 10⁹/L) or active C. difficile or MRSA infection. However, visits by more than 2–3 relatives, and contact with young children or individuals with viral, skin, or respiratory diseases, are not recommended [98].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Infection prophylaxis

Infection prophylaxis after liver transplantation can be performed in two regimens [98]:

1. Standard – standard risk

Transplantation in a recipient selected from the waitlist, in satisfactory condition, without complications.

2. Enhanced – high risk

✔ urgent transplantation;

✔ fulminant hepatitis;

✔ severe encephalopathy;

✔ severe condition of the recipient, low BMI;

✔ treatment of recurrent ascites-peritonitis;

✔ treatment on the waitlist in the intensive care unit or hospitalization for more than 48 hours within the last 3–6 months;

✔ retransplantation;

✔ severe bleeding before surgery (with transfusion of more than 6 units of red blood cell mass);

✔ biliary, septic complications, arterial thrombosis.

Prophylaxis of systemic bacteremia

Diagnosis and treatment of infection after liver transplantation

Patients receiving immunosuppressive therapy are recommended to receive antibiotic prophylaxis during any invasive procedures to prevent infectious complications [98].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Comment: even "trivial" infections are dangerous for immunocompromised patients after transplantation and account for a significant proportion of tertiary mortality [98, 100]. Bacterial infections develop in one-third of recipients. Risk factors for infectious complications include: Roux-en-Y anastomosis, donor CMV infection, duration of surgery, presence of biliary stricture. The risk of opportunistic infection significantly increases in the presence of graft dysfunction.

Empiric antibacterial therapy

Comment: before switching to #valganciclovir** per os, the virological response (PCR) must be checked; if absent, treatment should be continued until aviremia is achieved [202, 203].

Comment: daily doses for ganciclovir** and valganciclovir** are calculated based on GFR. CMV infection is quite common among solid organ recipients. In the absence of prophylaxis, CMV infection usually develops between 1 and 4 months after orthotopic liver transplantation (CMV incubation period), but may also manifest in the first week after transplantation. It is possible that CMV infection may play a role in the development of acute and especially chronic rejection. The risk of infection varies depending on the absence or presence of infection in the donor. The highest risk is when the donor is CMV-positive and the recipient is CMV-negative (59%); if the recipient is also CMV-positive, the risk decreases to 25%. The risk of endogenous reactivation is 11%. When both donor and recipient are CMV-negative, the risk of developing CMV infection persists.

Treatment of viral hepatitis associated with liver cirrhosis and recurrence of viral hepatitis after liver transplantation

Viral hepatitis C

• HCV recurrence after liver transplantation is universal in patients with detectable HCV RNA during surgery [101]. Liver recipients are recommended to undergo antiviral therapy before liver transplantation to prevent disease recurrence after surgery [102].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Comment: furthermore, achieving aviremia in some patients is accompanied by stabilization and improvement of liver function (recompensation) and, consequently, an improvement in the patient's condition up to removal from the waitlist for an indefinite period [103, 104].

• Patients with decompensated liver cirrhosis and a MELD score of ≥ 18–20 are indicated for liver transplantation and treatment of HCV recurrence after liver transplantation [105].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

• Antiviral therapy is recommended for all patients with recurrent HCV infection after liver transplantation to achieve HCV eradication [104–108, 110, 111, 113, 114].

LoR AGoE 1Level of Recommendation A (Level of Evidence - 1)

Comment: HCV recurrence after transplantation significantly reduces liver recipient survival, being a leading cause of mortality in this patient cohort [106]. Effective antiviral therapy improves transplantation outcomes in liver recipients with recurrent HCV [107–109]. HCV recurrence is an adverse factor that reduces graft survival by an average of 30% compared to other diseases leading to liver transplantation. Within the first 5 years after surgery, approximately one-third of patients with recurrent HCV develop graft cirrhosis, and half of the recipients develop it within the first 10 years [110]. Effective antiviral therapy increases post-liver transplantation survival [111, 112, 113, 127, 131, 132, 192, 193, 194].

• In the event of fibrosing cholestatic hepatitis associated with recurrent HCV infection or signs of rapid graft disease progression (including worsening portal hypertension) in liver recipients, it is recommended to immediately initiate direct-acting antiviral therapy as soon as clinically feasible (after assessing drug-drug interactions and tolerability). These clinical scenarios correspond to a severe/aggressive course of HCV recurrence and are associated with a high risk of rapid fibrosis/graft dysfunction progression, therefore delaying therapy is undesirable [114, 118, 119].

LeveL of Recommendation BGrade of Evidence 3LeveL of Recommendation B (Grade of Evidence - 3)

• The use of peginterferon alfa-2b** in combination with ribavirin** is not recommended for the treatment of recurrent HCV infection in liver recipients [117-123].

LoR AGoE 1Level of Recommendation A (Level of Evidence - 1)

Comment: the efficacy of standard therapy (including peginterferon alfa-2b** in combination with ribavirin**) after liver transplantation is low (a sustained virological response is achieved by no more than 30–40% of recipients), and it is accompanied by poor treatment tolerability and an increased risk of graft rejection [117-123].

• When administering antiviral therapy, it is recommended to follow the current clinical guidelines (Chronic Viral Hepatitis C).

Viral Hepatitis B

When administering antiviral therapy, it is recommended to follow the current clinical guidelines (Chronic Viral Hepatitis B).

4. Medical Rehabilitation and Sanatorium-Resort Treatment

4.1 Maintenance immunosuppression after liver transplantation

Comments: currently, one year after transplantation [92], the majority of patients (over 60%) receive monotherapy with #tacrolimus** (capsules) or #tacrolimus** (prolonged-release capsules), 20% receive a combination of #tacrolimus** (capsules) or #tacrolimus** (prolonged-release capsules) with mycophenolate mofetil** (#mycophenolic acid**), the rest receive a combination of #tacrolimus** (capsules), #tacrolimus** (prolonged-release capsules)/#cyclosporine** with mycophenolate mofetil** (#mycophenolic acid**) and/or systemic corticosteroids, less than 10% receive #tacrolimus** (capsules), #tacrolimus** (prolonged-release capsules) and #methylprednisolone**, and 5% receive #everolimus**.

Comments: after 6 months, maintaining trough levels of #cyclosporine** within 100 to 125 ng/mL may be sufficient to prevent rejection and minimize toxic effects.

The use of mycophenolate mofetil** (#mycophenolic acid**) provides the opportunity to adjust immunosuppressive therapy for a specific patient depending on the clinical situation. For instance, mycophenolate mofetil** (#mycophenolic acid**) may be added in the event of acute or refractory rejection, when there is a need to rapidly reduce the dose of systemic corticosteroids, or to maintain a low concentration of calcineurin inhibitors in cases of their pronounced nephrotoxic effect.

#Everolimus** inhibits the growth of a number of tumors, particularly hepatocellular carcinoma, making its use especially attractive after liver transplantation for oncological diseases in combination with #tacrolimus**, as well as to reduce the nephrotoxicity of the latter. The main limitations to the use of this drug in the early period after liver transplantation include impaired wound healing and the development of arterial thrombosis; it should be introduced into the immunosuppressive regimen no earlier than the 2nd month post-transplantation.

4.2 Immunosuppressive therapy in liver recipients and renal function

Comments: liver recipients have an initial and progressively increasing risk of renal dysfunction [145]. This problem is exacerbated by the expansion of transplantation indications in recipients with a high MELD score.

The possibility of reducing the dose of calcineurin inhibitors and using mycophenolate mofetil** (#mycophenolic acid**) to improve renal function has been investigated in many large studies. It was found that using mycophenolate mofetil** (#mycophenolic acid**) in combination with a reduction in the dose of #cyclosporine** or #tacrolimus** by at least 50% significantly improves recipient renal function one year after regimen modification without a substantial risk of rejection.

Typically, the calcineurin inhibitor minimization strategy is applied to patients who have already developed calcineurin inhibitor-induced nephropathy, usually one year or more post-surgery. Attempts at complete withdrawal of calcineurin inhibitors may be successful at later stages, more than 3 years post-surgery. In this case, renal function improves in 46% of patients, while the risk of rejection significantly increases on mycophenolate mofetil** (#mycophenolic acid**) monotherapy. For this very reason, toxic nephropathy must be clearly differentiated from nephropathy caused by other etiologies, such as diabetes mellitus, vasculitis, or glomerulonephritis. Renal biopsy is a reliable diagnostic tool.

An alternative strategy for minimizing or eliminating calcineurin inhibitors is conversion to #everolimus** with or without mycophenolate mofetil** (#mycophenolic acid**). In this case, improvement in renal function is observed in 25–43% of patients. These results support the concept of selecting an individualized, patient-specific, nephroprotective immunosuppressive regimen in which renal function plays a critical role in decision-making.

4.3 Minimization of systemic corticosteroid administration in liver transplantation

Comments: the side effects of systemic corticosteroids contribute significantly to post-transplant morbidity and mortality, making the minimization of systemic corticosteroid use still a relevant objective. Data from numerous studies and registries prove that liver transplantation can be safely performed under minimized glucocorticoid immunosuppression without reducing patient or graft survival. The current trend in clinical practice is the increasing adoption of "steroid-free" protocols instead of protocols involving the tapering of systemic corticosteroids at various times post-surgery.

Patients with early glucocorticoid withdrawal have a significantly lower incidence of diabetes mellitus, hypercholesterolemia, arterial hypertension, osteoporosis, and hepatocellular carcinoma recurrence.

The need to resume systemic corticosteroid therapy may arise in patients with extrahepatic manifestations of liver disease, autoimmune disorders, and renal dysfunction.

Comments: nevertheless, the following rules apply equally to all patients:

Immunosuppressive therapy, even at minimal doses, is extremely important [27].

Toxicity, regardless of its type (nephrotoxicity, neurotoxicity, etc.), indicates excessive immunosuppressive therapy [27].

In a multi-drug protocol, the doses of two immunosuppressants must not be changed simultaneously [27].

Treatment of various complications of immunosuppression (hypertension, hyperuricemia, hypercholesterolemia, etc.) should begin with reducing immunosuppressive therapy rather than prescribing additional drugs. The prescription of a large number of additional drugs should be avoided, as polypharmacy reduces patient adherence to immunosuppressive therapy.

Every significant modification of immunosuppressive therapy must be coordinated with the transplant center [27].

5. Prevention and Dispensary Observation

The highest number of deaths or retransplantations occurs in the early postoperative period. Within the first year after liver transplantation, about 60% of losses are due to infection, perioperative, and intraoperative causes. After 12 months, cardiovascular diseases and malignant tumors come to the forefront. As the time after liver transplantation increases, the underlying disease—especially hepatocellular carcinoma or autoimmune liver disease—plays an increasingly significant role in the structure of graft loss causes.

Over time, the risk of graft rejection decreases. By day 90 after liver transplantation, the need for immunosuppression is significantly reduced. However, the risk of rejection persists at any time after transplantation, which is why most recipients take immunosuppressants permanently. This is associated with well-known negative consequences, such as an increased risk of bacterial, viral, and fungal infections; metabolic disorders, and neoplasms, including post-transplant lymphoproliferative disorder [146]. Developing hypertension, diabetes mellitus, hyperlipidemia, obesity, and gout often require additional therapy [147]. The leading non-hepatic causes of morbidity and mortality are cardiovascular diseases and renal failure.

5.1 Immunosuppressive therapy

Comment: there is no single universal immunosuppression protocol for all patients. The choice of immunosuppressant is made taking into account numerous factors, such as:

✔ the effect of the immunosuppressant on the course and recurrence of the underlying disease: malignancy or autoimmune disease, and comorbidities;

✔ side effects of immunosuppressants (in particular, calcineurin inhibitors have a nephrotoxic effect);

✔ pregnancy potential: mycophenolate mofetil**(#mycophenolic acid**) and immunosuppressive agents with protein kinase inhibitory activity, such as #everolimus**, are potential teratogens;

✔ history of severe or recurrent rejection;

✔ previous experience with various immunosuppressants;

✔ infection history.

5.2 Late rejection

Comment: rejection developing after 90 days post-liver transplantation is defined as late rejection. Traditionally, two forms of late rejection are distinguished: cellular and ductopenic (vanishing bile duct syndrome), which may manifest only as biochemical and morphological changes.

5.3 Comorbidities after liver transplantation

5.4 Kidney diseases

Comment: some liver recipients who survive 6 months post-surgery experience a decline in renal function and develop chronic kidney disease (CKD). With the development of CKD, the risk of death in a liver recipient increases 4.48-fold within a year. End-stage renal disease (ESRD) develops in 5–8% of cases within the first 10 years after liver transplantation. Kidney transplantation is the method of choice for renal replacement therapy, improving long-term patient survival by 44–60% compared to maintenance hemodialysis.

Causes of ESRD after liver transplantation include both risk factors common in the general population—such as arterial hypertension, diabetes mellitus, obesity, atherosclerosis, and hyperlipidemia—and factors specific to liver recipients: calcineurin inhibitor toxicity, chronic HCV infection, pre-existing kidney disease in liver cirrhosis, and perioperative acute kidney injury.

Comment: the treatment of CKD in the general population is based on strict blood pressure control and the use of angiotensin II receptor blockers. These same measures should be effective for liver recipients.

5.5 Arterial hypertension

Comment: arterial hypertension increases the risk of cardiovascular complications and CKD in liver recipients just as it does in the general population [148]. The target blood pressure level is 130/80 mm Hg. Overall, the management of arterial hypertension does not differ from standard regimens and should comply with current guidelines.

5.6 Hyperlipidemia

Comment: dyslipidemia, developing in 70% of liver recipients, is a leading risk factor for cardiovascular disease.

5.7 Oncological diseases

Comment: the incidence of de novo cancer in liver recipients is higher than in the general population [8]. The cumulative incidence is 3–5% at three years and 11–20% at ten years post-liver transplantation. Liver recipients should minimize cancer risk factors—avoiding sun exposure and smoking—and undergo standard screening for the most common neoplasms more frequently than the general population.

5.8 Immunosuppressive therapy and pregnancy

Comment: successful pregnancy is possible after liver transplantation. The rates of maternal and infant mortality do not exceed those in the general population, but prematurity and intrauterine growth restriction are observed more frequently. The following conditions must be met for pregnancy planning:

✔ stable graft function for at least one year after liver transplantation;

✔ management of comorbidities (diabetes mellitus, arterial hypertension, etc.);

✔ low maintenance level of immunosuppression [27].

Comment: immunosuppressive therapy regimen should be reviewed prior to pregnancy planning. All immunosuppressants cross the placenta, but #sirolimus**, #everolimus**, and #mycophenolic acid** have the highest teratogenic effect, especially when taken in early pregnancy. #Tacrolimus** (capsules) and #tacrolimus** (extended-release capsules) are considered the safest [27].

5.9 Infectious diseases

Comment: the period up to 6 months after liver transplantation carries the highest risk of infectious complications. After 6 months, the level of immunosuppression decreases, which significantly reduces the risk of infectious diseases. Beyond 3 months, the infectious process is most commonly localized in the abdominal cavity, lungs, or caused by community-acquired pathogens (gram-negative intestinal pathogens, S. pneumoniae, respiratory viruses).

6. Organization of Medical Care

Indications for emergency hospital admission:

● Transplanted liver dysfunction threatening graft loss;

● Acute liver failure;

● Availability of a graft from a deceased donor (call-up from the waiting list).

Indications for elective hospital admission:

● Severe graft dysfunction;

● Preparation for liver transplantation.

Indications for discharging a patient from a medical organization:

● Normalization or stabilization of key laboratory and clinical parameters.

7. Additional Information

No.

Criteria for Evaluating the Quality of Medical Care

Criteria for evaluating the quality of medical care for liver transplant recipients are presented in Table 14.

References

Appendix A1. Working Group Composition

Conflict of interest.

The working group declares no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

Medical specialists in the following fields:

✔ Surgeon

✔ General Practitioner

✔ District General Practitioner

✔ Surgeon

✔ Anesthesiologist-Intensivist

✔ Gastroenterologist

Table 1. Scale for grading levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing levels of evidence certainty (LEC) for methods of prevention, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for assessing the levels of evidence (LoE) for methods of prevention, diagnostics, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Related Documents

The management of patients with end-stage liver disease is carried out in accordance with the legislation of the Russian Federation and is presented in the following regulatory documents:

● Federal Laws of the Russian Federation

● Federal Law No. 323-FZ of November 21, 2011 (as amended on April 25, 2026) "On the Fundamentals of Health Protection of Citizens in the Russian Federation".

● Law of the Russian Federation No. 4180-I of December 22, 1992 (as amended on May 1, 2022) "On Transplantation of Human Organs and/or Tissues".

● Orders of the Russian Ministry of Health:

o Order of the Russian Ministry of Health No. 567n of October 31, 2012 (as amended on December 12, 2018) "On Approval of the Procedure for Providing Medical Care in the Field of 'Surgery (Human Organ and/or Tissue Transplantation)'" (Registered with the Ministry of Justice of Russia on December 21, 2012, No. 26306).

o Order of the Russian Ministry of Health No. 182n of April 11, 2025 "On Approval of the Instructions for Issuing a Medical Opinion by a Medical Organization's Medical Board on the Necessity of Human Organ and/or Tissue Transplantation and the Form of the Said Medical Opinion" (Registered with the Ministry of Justice of Russia on April 30, 2025, No. 82040).

o Order of the Russian Ministry of Health No. 508n of July 27, 2022 "On Approval of the Procedure for Giving Written Informed Voluntary Consent to Human Organ and/or Tissue Transplantation, and the Form of Written Informed Voluntary Consent to Human Organ and/or Tissue Transplantation" (Registered with the Ministry of Justice of Russia on August 26, 2022, No. 69806).

o Order of the Russian Ministry of Health No. 519n of July 29, 2022 "On Approval of the Procedure for Conducting a Medical Examination of a Donor Who Has Given Written Informed Voluntary Consent to the Removal of Their Organs and/or Tissues for Transplantation" (Registered with the Ministry of Justice of Russia on August 30, 2022, No. 69838).

o Order of the Russian Ministry of Health No. 355n of June 8, 2016 "On Approval of the Procedure for Accounting for Human Donor Organs and Tissues, Organ and Tissue Donors, Patients (Recipients), Forms of Medical Documentation and Statistical Reporting Forms for the Purpose of Accounting for Human Donor Organs and Tissues, Organ and Tissue Donors, Patients (Recipients) and the Procedure for Their Completion" (Registered with the Ministry of Justice of Russia on August 2, 2016, No. 43082).

● International Acts

o WHO Guiding Principles on Human Cell, Tissue and Organ Transplantation (WHA 63.22).

Table 4. Main drugs used as maintenance immunosuppressive therapy after liver transplantation.

Table 5. Protocol of triple immunosuppressive therapy with induction after liver transplantation for adult recipients [179]

Table 6. "Steroid-free" protocol of dual immunosuppressive therapy with induction after liver transplantation [179]

Table 7. Monotherapy protocol with #tacrolimus ** (capsules), #tacrolimus ** (prolonged-release capsules) with induction after liver transplantation [179]

Appendix B. Physician Action Algorithms

1. Treatment selection algorithm for patients with end-stage liver failure / focal liver lesion

Appendix C. Patient Information

What is a liver transplantation?

Orthotopic liver transplantation is a universally recognized gold standard for the treatment of end-stage chronic liver failure, significantly improving prognosis and quality of life. The essence of the surgery is to replace the patient's damaged, non-viable organ with a donor organ.

How is a liver transplant performed?

Based on a comprehensive examination, physicians select the most optimal treatment strategy, and if a decision is made that a heart transplantation is necessary, the patient is placed on the waiting list and given recommendations on treatment and lifestyle while awaiting surgery.

How is the surgery performed?

Liver transplantation is completely painless for the patient. Although the surgery itself may last many hours, the patient feels neither pain nor discomfort because they are asleep under the influence of a combination of medications.

After waking up, the patient spends several days in the intensive care unit and, as soon as their condition allows, is transferred to the ward, where they will stay for another two to three weeks.

During the early postoperative period, the patient recovers under medical supervision and undergoes necessary examinations to evaluate graft function and prevent potential postoperative complications. Immunosuppressive therapy is also initiated and adjusted during this time.

How long do patients live with a transplanted liver?

With modern immunosuppressive therapy protocols, the life expectancy of liver transplant recipients is comparable to that of the general population.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Child-Turcotte-Pugh Scale for assessing the severity of liver cirrhosis

Source: https://www.hepatitisc.uw.edu/page/clinical-calculators/ctp

Type: rating scale.

Purpose: assessment of liver cirrhosis severity.

Content:

Key (Interpretation):

- 5–6 points: Class A (well-compensated liver function); 1-year survival rate is 100%.

- 7–9 points: Class B (marked liver function impairment); 1-year survival rate is 80%.

- 10–15 points: Class C (decompensation of the disease and liver function); 1-year survival rate is 45%.

Appendix G2. Model for End-Stage Liver Disease (MELD) severity score

Source: Kamath, Patrick S; Kim, W. Ray (2007). "The model for end-stage liver disease (MELD)". Hepatology. 45 (3): 797–805. doi:10.1002/hep.21563. PMID 17326206.

Type: rating scale.

Purpose:

— Stratification of patients on the liver transplant waiting list;

— Prediction of short-term survival in decompensated cirrhosis;

Content:

MELD = 11.2 x ln (INR) + 9.57 x ln (creatinine, mg/dL) + 3.78 x ln (bilirubin, mg/dL) + 6.43

Key (interpretation):

Notes: The lower limit of normal for each parameter is 1, the maximum value for creatinine level is 4; if the patient is on hemodialysis, the creatinine level is assumed to be "4".

ln — natural logarithm;

INR — international normalized ratio.

Appendix G3. Pediatric End-Stage Liver Disease (PELD) scale is a scoring system for assessing the severity of chronic liver disease in patients under 12 years of age, a modification of the MELD scale.

Source: "Pediatric Liver Clinic". mayoclinic.org. Retrieved 2019-10-12.

Type: rating scale.

Purpose:

— Stratification of patients on the liver transplant waiting list;

— Prediction of short-term survival in decompensated cirrhosis;

PELD = 4.80 x ln (bilirubin, mg/dL) + 18.57 x ln (INR) – 6.87 x ln (albumin, g/dL) + 4.36 x V + 6.67 x G.

Key (interpretation):

Notes: ln — natural logarithm;

INR — international normalized ratio.

V — age (less than 1 year — 1, more than 1 year — 0),

G — physical development (weight or height indicators more than 2 standard deviations below the mean — 1, less or normal — 0).