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Russian Journal of Transplantology and Artificial Organs

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Vol 26, No 3 (2024)
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Editorial

8-31 1612
Abstract

Objective: to study current trends and advancements in organ donation and transplantation in the Russian Federation based on data from the year 2023.

Materials and methods. Heads of organ transplant centers were surveyed through questionnaires. The Russian Ministry of Health’s information accounting system was used for data control. A comparative analysis of data collected over years from various federal subjects of the Russian Federation and transplant centers was conducted.

Results. Based on data retrieved from the National Registry in 2023, there were 50 kidney, 34 liver and 22 heart transplant programs existing in the Russian Federation as of the year 2023. Organ donation activity in 2023 was 6.3 per million population (p.m.p.), with a 77.2% multi-organ procurement rate and an average of 2.9 organs procured from one effective donor. In 2023, 3,057 organ transplants were performed in the Russian Federation, which included 1,817 kidney, 829 liver and 388 heart transplants. Same year, the number of transplant surgeries performed in the Russian Federation increased by 19.6% compared to 2022. Organ donation activity in Moscow was 29.1 p.m.p. The city of Moscow and Moscow Oblast alone had a total of 12 transplant centers, which accounted for 50.2% of all kidney transplants and 63.1% of all extrarenal transplants nationwide. There are more than 143.4 p.m.p. organ recipients in the Russian Federation.

Conclusion. The geographic spread of transplant centers in the Russian Federation continues to expand. In 2023, five new centers were opened. Over the past year, the country has seen an increase in the number of effective donors and organ transplants. Because medical facilities still have untapped resources, the number of organ transplants performed is expected to rise. Moscow is the powerhouse of Russian transplantology. Shumakov National Medical Research Center of Transplantology and Artificial Organs and its branch perform 27.4% of the total number of organ transplants in the country. Among the successful regional initiatives, the following should be noted: the Republic of Tatarstan, Kemerovo Oblast (Kuzbass), St. Petersburg, Tyumen Oblast, Irkutsk Oblast. In the Russian Federation, pediatric transplant care is prioritized.

Clinical Transplantology

32-42 304
Abstract

Objective: to identify the risk factors and predictors of recurrent variceal hemorrhage in cirrhotic patients awaiting liver transplantation (LT).

Materials and methods. A comparative retrospective study was conducted in 51 patients with decompensated cirrhosis, who were on the waiting list for LT. Demographic, clinical and laboratory parameters, MELD-Na score, Child–Turcotte–Pugh score, hepatic encephalopathy grade, ascites grade, class of varicose veins, number of consecutive variceal ligations, as well as manometric study with calculation of intrahe- patic venous pressure gradient index in groups of patients with (n = 39) and without recurrent bleeding (n = 12) were analyzed. The proportions of patients in different groups were compared by the Kaplan–Meier method with determination of the logarithmic test (Log-Rank). The accumulated risks in the compared groups were estimated using the mathematical model of proportional hazards (Cox regression) in univariate and multivariate analysis.

Results. Within 60 months from the beginning of follow-up and simultaneous prophylaxis by combination of non-selective beta-blockers and endoscopic variceal ligation (EVL), 39 out of 51 patients (75.6%) developed recurrent bleeding. Analysis revealed significant differences (risk factors for recurrent bleeding): creatinine le- vels, MELD-Na score, hepatic encephalopathy grade, mean hepatic venous pressure gradient (HVPG) and its level >14 mmHg. By the Kaplan–Meier method with the Log-Rank test, it was established that the proportion of patients without recurrent bleeding was significantly higher in the group of patients with HVPG ≤14 mmHg than in the group with HVPG >14 mmHg (p = 0.027).

Conclusion. The main independent predictor of variceal rebleeding is HVPG >14 mm Hg, which increases the risk by 3.837 times if the gradient value is changed by 1 mm. The second independent predictor is higher hepatic encephalopathy grade: if the grade increases by one, the risk of recurrent hemorrhage increases 1.8 times.

43-55 310
Abstract

Objective: to evaluate the possible influence of different graft perfusion preparation variations on the incidence of biliary and vascular complications of orthotopic liver transplantation (OLT).

Materials and methods. Data on 287 full-size liver transplants from donors with brain death and beating heart were processed. There were 262 and 25 primary and repeat OLTs, respectively. Before completion of portal anastomosis formation and inclusion into systemic blood flow, the graft was perfused with hypo- (group 2) and isotonic (group 4) saline in order to minimize hemodynamic disorders.

Results. There was a statistically significant difference between groups 2 and 4 in the development of late (p = 0.04) and cumulative biliary complications (p = 0.01). The presence of these complications and the perfusion type were found to be associated (Fisher’s exact test = 0.02). There were no differences in incidence of thrombosis in the studied groups.

Conclusion. The conducted analysis suggests that it is inexpedient to use hypothermic solutions when preparing a liver transplant for perfusion before introducing it into systemic circulation.

56-65 317
Abstract

Mucormycosis is a severe mycotic infection with high mortality among immunocompromised patients. Its in- cidence in solid organ transplant recipients is 2–8% of all invasive fungal infections. In most cases, it occurs in the late posttransplant period. Risk factors in this patient cohort are graft-versus-host disease (GvHD) and use of immunosuppressive drugs. The article describes clinical cases of mucormycosis and analysis of literature data on the problem of invasive mucormycosis in solid organ transplant recipients. It also reviews the main methods of diagnosis and treatment of the disease according to international guidelines.

66-71 331
Abstract

Chronic hepatitis B virus (HBV) infection is one of the main problems of modern transplantology and transplant hepatology, often leading to potentially fatal complications. The only definitive treatment for HBV-related cirrhosis is liver transplantation. However, recurrence of HBV after transplantation may jeopardize both recipient and graft survival. Therefore, all HBsAg-positive recipients should receive prophylactic therapy with nucleos(t)ide analogues with or without hepatitis B immune globulin (HBIG), regardless of the hepatitis B e-antigen (HBeAg) status and HBV DNA level before transplantation. However, HBIG therapy has a number of disadvantages, and nucleos(t) ide analogues do not inhibit replication of super and co-infection. In addition, there is no unified understanding of the time limits for achieving a virologic response. In our clinical case, we report a rapid suppression (5 days) of high HBV (560,000 copies/mL) viral load in a patient suffering from HBV- and HDV-related cirrhosis, who was operated on with positive HBeAg at the time of transplantation. In our study, the use of standard therapy tenofovir disoproxil fumarate reduced the HBV viral load titer to undetectable values. In turn, given the positive
HBeAg at the time of transplantation, HBV infection recurred in the early post-transplant period, which was eliminated without the use of HBIG therapy. The use of tenofovir disoproxil fumarate makes it possible to plan transplantation for patients with positive replication and high viral load, avoiding the use of HBIG, against the background of limited liver transplant wait time.

72-90 679
Abstract

Biliary complications (BCs) are the most frequent complications following liver transplantation (LT). They are a major source of morbidity after LT. The incidence of BCs after LT is reported to range from 5% to 45%. The main post-LT biliary complications are strictures, biliary fistulas and bilomas, cholelithiasis, sphincter of Oddi dysfunction, hemobilia, and mucocele. Risk factors for biliary complications are diverse. In this article we seek to review the main types of biliary complications and modern approaches to their diagnosis and treatment.

91-98 435
Abstract

Introduction. Despite improvements in immunosuppressive therapy procedures, immunological complications continue to be a major cause of kidney graft loss. The level of pre-existing and de novo synthesized anti-HLA antibodies (AB) has shown high significance in modern diagnosis of graft rejection and assessment of the efficacy of anti-crisis therapy.

Objective: to analyze the frequency and specificity of pre-existing and de novo synthesized (including donor-specific), anti-HLA antibodies, to assess their impact on acute rejection crisis and kidney transplant (KT) outcomes in the early postoperative period.

Materials and methods. We retrospectively analyzed the treatment outcomes of 637 patients, who received a deceased-donor kidney transplant at Sklifosovsky Research Institute of Emergency Care from 2020 to 2022. Pre-existing and de novo synthesized anti-HLA AB, including donor-specific antibodies (DSA), were determined and their impact on the incidence of acute rejection crisis (ARC) in the early postoperative period and on kidney graft function was assessed.

Results. In non-sensitized patients, the ARC rate was 10.7% (n = 58), primary initial graft function was noted in 354 patients (65.6%), and satisfactory function at discharge was observed in 377 patients (70%). Pre-existing anti-HLA AB was detected in 97 recipients (15.2%); ARC developed in 14 recipients (14.4%) from this group, 51 (52.6%) patients had primary initial function, and 62 (63.9%) exhibited satisfactory function at discharge. De novo anti-HLA AB synthesis after transplantation was noted in 70 (11%) patients, ARC in 10 of them (16.7%), 38 (54.3%) had primary function, and 43 (61.4%) had satisfactory function at discharge. DSA synthesis was detected in 10 patients, ARC was diagnosed in 5 (50%) of them, primary initial function and satisfactory function at discharge were noted in 3 (30%) recipients.

Conclusions. The presence of pre-existing and/or de novo anti-HLA AB synthesis after KT under rationally selected immunosuppressive therapy did not statistically significantly affect the early outcomes of graft function. However, DSA synthesis statistically significantly increased the incidence of acute rejection, kidney graft dysfunction and increased the time of recovery of nitrogen excretory function.

99-110 293
Abstract

Objective: to determine the predictors and risk of recurrent bleeding after implantation of a transjugular intrahepatic portosystemic shunt (TIPS) combined with selective gastric vein embolization in patients with decompensated cirrhosis awaiting liver transplantation (LT).

Materials and methods. A comparative retrospective study was performed in 54 patients waitlisted for LT between 2017 and 2023, who suffered recurrent variceal hemorrhage after secondary prophylaxis of bleeding prior to inclusion in the study. Demographic, clinical and laboratory parameters, clinical indices, hepatic encephalopathy, severity of ascites, degree of varices, manometric study before and after TIPS implantation with gastric vein embolization, with calculation of portal pressure gradient in patients with (n = 16) and without rebleeding (n = 38), were analyzed. The proportions of patients were compared using the Kaplan–Meier method with determination of the logarithmic test (Log-Rank). Cumulative risks were estimated by means of univariate and multivariate analysis of the Cox proportional hazards model.

Results. Within 30 weeks from the date of TIPS combined with gastric vein embolization, 16 of 54 patients (29.6%) developed rebleeding. The following risk factors were identified: age, hemoglobin level, white blood cell count, platelet count, creatinine level, severity of ascites, and mean portal pressure gradient after TIPS implantation. It was found that the proportion of patients without bleeding was significantly higher in patients with portal pressure gradient ≤10 mmHg than in patients with this index >10 mmHg (Log Rank = 0.029). The following independent predictors of recurrent hemorrhage were determined: severity of ascites, shunt thrombosis, portal pressure gradient after TIPS implantation, portal pressure gradient after TIPS implantation <30% of the basal level. It has been shown that the risk of recurrent bleeding at portal pressure gradient >10 mmHg progressively increases and reaches maximum values (HR = 1.713) in patients who underwent TIPS combined with gastric vein embolization between 32 and 40 weeks from the time of surgery, while it is absent at portal pressure gradient ≤10 mmHg.

111-116 382
Abstract

Introduction. The high prevalence of chronic kidney disease (CKD) has a negative impact on the length and quality of life of patients, especially in the older age group. Renal replacement therapy is required when the disease progresses to end-stage renal failure. In elderly patients with comorbidities, dialysis therapy has its own peculiarities and challenges, often prolonging life for a short period. The increase in the number of patients aged ≥70 years requesting to be placed in the kidney transplant waitlist (KTWL) at Sklifosovsky Research Institu- te of Emergency Care has led to the need to evaluate kidney transplant (KT) outcomes in this patient cohort.

Objective. To analyze the early and long-term outcomes of deceased-donor KT in recipients aged ≥70 years.

Materials and methods. The retrospective study included 23 kidney recipients aged ≥70 years who underwent a deceased-donor KT in the period from 2014 to 2023 at the Kidney and Pancreas Transplantation Department, Sklifosovsky Research Institute of Emergency Care. Recipient survival was computed using the Kaplan–Meier estimate.

Results. Sixteen recipients (69.6%) had primary function and 7 (30.4%) had delayed function. Nineteen recipients (82.6%) showed a drop in blood creatinine below 200 μmol/L after KT. Hospital, 1- and 3-year survival were 96% (n = 22), 84.8% [95% CI 72–95] and 79% [95% CI 65–92], respectively; 1- and 3-year graft survival were 84.8 [95% CI 72–95] and 73% [95% CI 59–87], respectively.

Conclusion. KT for patients aged ≥70 is a feasible treatment option for CKD stage 5.

117-123 245
Abstract

Increased arterial stiffness is an important preclinical indicator of cardiovascular dysfunction, arterial hypertension and target organ injury. This condition increases the risk of long-term adverse events. Solid organ recipients face multiple risk factors for cardiovascular complications due to transplant rejection, lifelong medication use and adaptive features of the transplanted organ. The review presents an analysis of the results of studies on the main functional indicators of peripheral arterial stiffness, as well as the potential effect of immunosuppressive therapy on indicators of vascular stiffness in solid organ recipients.

124-133 589
Abstract

The article presents a review of the literature on the current problem of modern transplantology – BK viral nephropathy after nephrotransplantation. Risk factors for BK virus reactivation in immunocompromised patients are reflected. The issues of screening and diagnosis of BK viral infection in people with a transplanted kidney are considered. The role of BK viral nephropathy in renal graft loss is emphasized. The clinical manifestations and treatment strategies of BK viral nephropathy in kidney transplantation are discussed.

Heart Transplantation and Assisted Circulation

134-140 256
Abstract

Background. Acute mitral valve insufficiency has a high mortality rate (up to 100%). Mechanical circulatory support and emergency surgery can improve the survival of this patient cohort.

Objectives: to analyze a 12-year single-center experience of treating acute post-infarction mitral valve insufficiency.

Materials and methods. This retrospective study included 12 adult patients with ST elevated myocardial infarction (STEMI) and corresponding acute mitral valve insufficiency who underwent surgery between 2009 and 2017. We analyzed the in-hospital period of all patients and long-term follow-ups whenever possible. All patients underwent preoperative coronary angiography and echocardiography. All patients underwent cardiopulmonary bypass and cold-blood cardio- plegia. If venoarterial extracorporeal membrane oxygenation (VA-ECMO) was required, the femoral approach was preferred.

Results. Seven patients needed VA-ECMO support, six of them preoperatively; four received mechanical circulatory support outside the hospital. All patients underwent percutaneous coronary intervention (PCI) with successful revascularization of the culprit artery. All but one patient underwent surgery within the first 24 hours. One patient underwent repeat surgery once the mitral valve could be repaired, and the other patient did not require any coronary bypass. In-hospital mortality occurred in one patient in the VA-ECMO group. Patients receiving VA-ECMO had longer duration of inotropic support, ventilation time, and intensive care unit stay (p < 0.01).

Conclusions. Acute mitral valve insufficiency due to STEMI remains a dramatic complication, but the perioperative use of VA-ECMO helps reduce 30-day mortality and improve outcomes in this group of patients.

141-146 250
Abstract

Objective: to study the predictive value of the local noninvasive elasticity index of the common carotid artery (CCA) wall in heart transplant recipients.

Materials and methods. The study included 101 heart recipients. All study subjects underwent ultrasound examination of carotid arteries with assessment of the damping function of arteries and measurement of local and regional indicators of elastic properties of the CCA. The vascular wall elasticity index (iCOMPL) of the CCA was calculated according to the formula using the CCA diameters in systole and diastole and measurements of systolic and diastolic blood pressure. All-cause death, heart retransplantation, and clinically significant heart transplant coronary artery disease were evaluated as combined endpoints (adverse outcomes).

Results. In heart recipients without morphological and immunohistochemical signs of heart graft rejection, detection of relatively low iCOMPL of CCA is a predictor of earlier development of adverse events (p = 0.03). Conclusion. iCOMPL of the CCA is a noninvasive and easily reproducible predictor of adverse out- comes in the long-term period after heart transplantation and can be used in clinical practice for the purpose of risk stratification in heart recipients.

 

Regenerative Medicine and Cell Technologies

147-158 371
Abstract

Objective: to examine how the severity of tissue metabolic disorders affects the dynamics of the state of blood cells and bone marrow (BM) cells in patients with progressive diabetes mellitus (DM).

Materials and methods. The genetic model of type 2 diabetes (T2DM) in db/db mutant mice (experimental group, n = 30) was used. Healthy mice of the same line – db/+m (n = 10) and line B10 (n = 5) served as control. The dynamics of laboratory and clinical parameters (blood glucose, glycosylated hemoglobin, body weight) and oxidative metabolism indicators in tissues were monitored FOR 6–6.5 months using Lasma-ST device. The state of blood cells (red blood cells, white blood cells, platelets) and BM cells were examined during the same period. Statistical processing of the results was done with preliminary use of the Shapiro–Wilk test; the significance of differences with the control was assessed using the parametric Student’s t test, at p < 0.05.

Results. In the development of T2DM, 3 stages of progressive metabolic disorders were identified: I – adaptation stage (1–2 months); II – progressive maladaptation stage (2.5–4.5 months); III – decompensation stage (from 5.0–6.5 months to death). It was found that in T2DM mice, blood content of red blood cells, Hb and leukocytes was reduced already in stages I–III; but in stage II and especially in stage III, there was increased platelet count and percentage of neutrophils, monocytes, eosinophils with a decrease in lymphocytes. A high percentage of live cells is preserved in the BM in stages I, II and early periods of stage III; in late periods of stage III, live cell percentages are frequently found to be low; in all periods of stage III, the total cell content in the BM is clearly reduced.

Conclusion. Hematopoietic processes are inhibited in the BM as T2DM progresses. Individual assessment of the state of BM and its cells at the progressive stages of T2DM may be useful for prognostic purposes.

Transplantomics

159-167 252
Abstract

One of the most pressing issues in contemporary transplantology is the ongoing search for less invasive methods that would identify potential complications that recipients of solid organ transplants may encounter. Profibrogenic factor galectin-3 (Gal-3) is a potential marker of such complications. It is presumed that it may be involved in regulatory processes in both physiological and pathological conditions; Gal-3 is of particular importance in diseases associated with chronic inflammation and fibrosis.

Objective: to assess the predictive significance of Gal-3, determined in the recipients’ serum, in the pathology of a transplanted kidney.

Materials and methods. The study included 138 kidney recipients aged from 5 to 68 years and a group of healthy individuals (n = 11). Recipients’ serum Gal-3 levels were measured by immunoenzymatic method.

Results. Among the kidney recipients, 91 patients had kidney graft dysfunction according to laboratory and clinical data, which served as an indication to perform a graft biopsy with morphologic examination of the samples. In kidney recipients, Gal-3 levels were significantly different and higher than in healthy individuals, p = 0.017; it did not correlate with most blood test parameters, but there was an inverse correlation with graft glomerular filtration rate (GFR) (r = –0.174; p = 0.043). Recipients’ Gal-3 levels were independent of their tacrolimus blood levels. Kidney recipients with graft dysfunction had considerably higher Gal-3 levels (p = 0.0003) compared to those without. Comparative analysis significantly showed higher Gal-3 concentrations in recipients with acute cellular rejection (ACR, p = 0.005), antibody-mediated rejection (AMR, p = 0.016) and сalcineurin inhibitor (CNI) nephrotoxicity (p = 0.006) compared to recipients without dysfunction. Recipients with signs of CNI nephrotoxicity tended to have higher Gal-3 levels when compared to recipients with graft dysfunction of other etiology (p = 0.08). Kidney recipients with Gal-3 levels above the calculated threshold value of 7.63 ng/mL had a 2.89-fold higher risk of developing chronic graft dysfunction and/or requiring hemodialysis compared with the rest of the kidney recipients (RR = 2.89 ± 0.46 [95% CI 1.17–7.11]), with 76.2% sensitivity and 56.1% specificity of the test.

Conclusion. The threshold serum Gal-3 level in kidney recipients can be considered a predictor of an unfavorable graft outcome (chronic graft dysfunction and/or a need for renal replacement therapy).

168-175 229
Abstract

Objective: to evaluate the occurrence of single nucleotide polymorphisms (SNPs) in transforming growth factor beta 1 (TGFB1) – rs1800469, rs1800470, rs1800471 – and their haplotypes in children with biliary atresia (BA).

Materials and methods. We studied 106 pediatric liver recipients aged 4 to 150 (median 8) months, of whom 44 were boys, and 199 healthy individuals aged 32.7 ± 9.6 years, of whom 79 were boys. The indication for pediatric liver transplantation was BA. Genomic DNA was isolated from peripheral blood using a commercial QIAamp DNA Blood Mini Kit on a QIAcube automated analyzer. SNPs rs1800469, rs1800470, and rs1800471 in the TGFB1 gene were determined by real-time polymerase chain reaction using TaqMan probes on a CFX96 amplifier.

Results. In children with BA, the occurrence of the investigated SNPs in TGFB1 was as follows: rs1800469 – 38% GG homozygotes, 50% AG heterozygotes and 12% AA homozygotes; rs1800470 – 39% AA, 44% AG, 17% GG; rs1800471 – 88% CC, 12% GC, 0% GG. The distributions of all the three SNPs followed the Hardy–Weinberg principle. For rs1800469 and rs1800470, the genotype and allele frequencies in children with BA did not differ from those in healthy individuals, whereas for rs1800471, the heterozygous GC genotype was three-fold more frequent in children with BA than in healthy individuals. Haplotype analysis showed the presence of 6 major combinations: 2 most frequent were present in a total of about 66% of patients and 91% of healthy individuals, each of the frequencies practically did not differ between the comparison groups. Significant differences were found in the frequency of 3 rarer haplotypes, A-A-C, G-G-C and G-A-G at position rs1800469, rs1800470, rs1800471, which were observed more frequently in patients with BA by 3.10 (CI 1.59 to 6.04) (p = 0.001), 3.10 (CI 1.55 to 6.17) (p = 0.0015), and 17.02 (CI 1.94 to 149.30) (p = 0.011) times, respectively, than in healthy individuals.

Conclusion. In children with BA, the occurrence of CG heterozygotes in rs1800471 and the distribution of three rare haplotypes A-A-C, G-G-C and G-A-G of the rs1800469, rs1800470 and rs1800471 SNPs in the TGFB1 gene significantly differs from that in healthy individuals. It is possible that carriage of rare genotypes and haplotypes of TGFB1 may predispose to BA in children.

Экспериментальные исследования

176-182 228
Abstract

Objective: to develop and validate a hydrodynamic test bench (HTB) with a small filling volume for ex vivo normothermic machine perfusion (NMP) of donor lungs of small experimental animals (rats) using the open- loop technique.

Materials and methods. An HTB was developed for ex vivo NMP of donor lungs of rats. It is a prefabricated structure with stands that hold the following equipment: a ventilator for small laboratory animals, a heating element, a low priming volume membrane oxygenator and a dome for donor lung storage, as well as roller peristaltic pump, sensors and device for invasive pressure measurement in the circuit, bubble filter and a line kit. Wistar rats (n = 6) were used to investigate the effectiveness of the HTB. Following the removal of donor lungs, the graft was positioned on the HTB and ex vivo lung perfusion (EVLP) was initiated with selected parameters. During the rat donor lung perfusion procedure, ex vivo PaO2/FiO2 ratio, oxygenation index (OI), pulmonary artery pressure (PAP) and peripheral pulmonary vascular resistance (pPVR) were measured.

Results. High OI values were obtained at the end of the procedure (460 ± 32 at p = 0.028); constant PAP values were recorded in all cases throughout the EVLP procedure – from 9.13 to 7.93 mmHg at p > 0.05. The criterion for HTB functionality was pPVR, which tended to decrease in all cases – from 603.3 ± 56 to 89.1 ± 15 dynes/sec/cm–5 at p = 0.000. No design flaws impacting the donor lungs’ functional condition during ex vivo NMP procedure were found in the circuit of the hydrodynamic low priming volume bench during experimental studies.

Conclusion. The efficiency and technical functionality of the HTB were demonstrated by the results of the experimental study conducted on the laboratory animals, rats. The observed dynamics of decrease in pPVR and the high OI values at stable PAP allowed for the conclusion that both the ex vivo perfusion itself and the technical design of the HTB are efficient.

183-194 416
Abstract

Lung transplantation (LT) is the only treatment for many end-stage lung diseases. Despite significant progress in transplantology and surgery, LT remains a high-tech surgical procedure performed at select research centers. Primary graft dysfunction, acute rejection, and chronic lung allograft dysfunction are serious problems that can worsen lung transplant outcomes significantly. Using animal models in experimental studies to investigate these pathologic conditions is one of the more rational approaches. A literature review was conducted in order to select a suitable model that reproduces pathologic processes developing after LT. The literature was searched and ana- lyzed in MEDLINE and Elibrary databases, and the US National Institute of Health guidelines for the period up to December 2023 were reviewed. It was found that the most frequently used models are small laboratory animal models (without LT) and large animal models (with LT).

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ISSN 1995-1191 (Print)