Celebrating the 50th anniversary of the Shumakov National Medical Research Center of Transplantology and Artificial Organs and the 20th anniversary of the Russian Journal of Transplantology and Artificial Organs.

Aim: to monitor current trends and developments in organ donation and transplantation in the Russian Federation based on the 2018 data.

Materials and methods. Heads of organ transplant centers were surveyed. Data obtained over years from constituent entities of the Russian Federation (also called regions) and from organ transplant centers located in these regions was analyzed and compared.

Results. According to data retrieved from the 2018 National Registry, only 49 kidney, 28 liver and 18 heart transplant centers were functional in Russia. As of the end of 2018, there were about 6,219 people on the kidney transplant waiting list. This is about 13.8% of the total number of the 45,000 patients receiving dialysis. Donation rate in 2018 was 4.3 donors per million population, while multi-organ procurement level stood at 67.3%. An average of 2.9 organs were procured from one effective donor. In 2018, there were 9.3 kidney transplants, 3.4 liver transplants and 1.9 heart transplants per million population. In the same year, the number of transplants performed in Russia in creased by 12.3% from the year 2017. In Moscow and Moscow Oblast alone, there are 15 functioning organ transplantation centers. These centers perform half of all kidney transplants and 70% of all liver and heart transplants in the country. The number of organ transplant recipients in Russia is approaching 16,000.

Conclusion. Russia continues to witness a long-term trend of growing number of organ transplants – 10–15% per year. The geographical presence or organ transplant centers continues to expand. The number of transplant centers and their activity is increasing. Donor programs are becoming more effective and efficient. Extrarenal transplantation technologies are being deployed in Russian regions. The number of patients on the national waiting list for organ transplantation is increasing, while their mortality is decreasing. The number of patients with transplanted organs is increasing. Shortages in donor organs in Russia is still down to human causes – poor organization. The number of organ transplants in Russian regions depends on government funding. The quality and safety of transplant programs rely on the transplant activity of centers. In order to achieve the clinical and economic benefits of organ transplantation as a treatment method, monitoring and follow-up after transplant will be required.

MicroRNAs are small RNA molecules stable in blood serum (plasma) samples. Their level of expression is associated with the severity and nature of physiological and pathological processes in the body.

Aim: to evaluate the expression levels of five microRNAs (miR-27, miR-101, miR-142, miR-339 and miR-424) in potential lung recipients with end-stage chronic lung diseases of various etiologies.

Materials and methods. The study included 16 patients with end-stage chronic lung diseases (potential lung recipients) aged 4 to 74 years (average 36 ± 18). Among them were two children (12.5%) – girls aged 4 and 14 years, and 14 adults aged from 21 to 74 (40 ± 16) years – 6 men (42.9%) and 8 women. The control group consisted of 12 healthy individuals. The main diseases that caused severe respiratory failure were: cystic fibrosis (n = 5), primary pulmonary hypertension (PPH; n = 4), pulmonary fibrosis of various etiologies (idiopathic pulmonary fibrosis – 1; pulmonary fibrosis associated with exogenous allergic alveolitis – 1; radiation-induced pulmonary fibrosis – 1), lymphangioleiomyomatosis (n = 2), histiocytosis (n = 1) and pulmonary emphysema (n = 1). MicroRNA expression was detected through real-time PCR. The level of microRNA expression in plasma was estimated in accordance with instructions for reagent kits (Qiagen, USA).

Results. The levels of miR-27, miR-101 and miR-339 in potential lung recipients were significantly higher than in healthy individuals. The levels differed depending on the etiology of diseases: the levels of miR-27, miR-101, miR-142 and miR-339 were higher in patients with cystic fibrosis than in healthy individuals; in patients with other lung diseases, only miR-101 levels where higher than in healthy individuals. The miR-424 level in healthy individuals did not differ from that in potential lung recipients or in subgroups.

Conclusion. Results obtained show the features of a number of microRNA levels (miR-27, miR-101, miR-142, and miR-339) under certain lung diseases and suggest a possibility of a diagnostic value in patients with chronic respiratory failure during pre-transplant examination.

Aim: to evaluate the efficacy and safety of early use of everolimus in combination with a reduced dose of calcineurin inhibitors (CNI) after kidney transplantation and define approaches to the selection and management of patients on everolimus-based therapy.

Materials and methods. Sixty-seven kidney transplant recipients were included in the study, forty of them began taking everolimus from the first day after transplantation in combination with prednisolone and CNI, and twenty-seven patients were converted from mofetil mycophenolate to everolimus 2.9 ± 2.0 months after surgery, and their dose of CNI was reduced. The duration of follow-up was 51.2 ± 35.1 months. Four-years patient and uncensored by death graft survival rate were assessed regardless of the duration of everolimus use and was compared with the data in the control group of recipients (n = 89) who did not receive everolimus. The survival rate of the method of treatment with everolimus and the event-free graft survival were also evaluated. When calculating the survival rate of method of everolimus treatment, the event that required the discontinuation of the drug was taken as the ed-point. Events such as rejection, development or progression of renal dysfunction and proteinuria have been accepted as end-points in the calculation of event – free survival rate. The number of patients discharged from their surgical hospital and taken under the supervision of a nephrologist was adopted as 100%.

Results. Patient and graft survival rate at 4 years after transplantation in the everolimus-based and control groups did not differ (p < 0.79 and p < 0.4, respectively). The 4-year survival rate of the method of everolimus treatment was 57.2%, and the event-free graft survival rate was 47.9%. The most frequent causes of everolimus withdrawal were rejection (25.8% of all causes), proteinuria (19%), progressive graft dysfunction (16, 1%) and adverse events (16.1%). The 4-year event-free graft survival depended on the initial kidney function and was significantly decreased (up to 32%) in the group of patients having the baseline Pcr >0.13 mmol/l in comparison with 59.3% in patients with normal baseline function, p < 0.04. The average level of Pcr Increased during the treatment from 0.14 ± 0.04 to 0.16 ± 0.09 mmol/l (p < 0.04), and the daily proteinuria increased from 0.18 ± 0.12 g/day to 0.66 ± 1.31 g/day (p < 0.004) by the end of follow-up.

Conclusion. Everolimus with reduced dose CNI can be start from the first days or months after kidney transplantation. However, its applicability is limited to four years in almost 43% of patients due to rejection, progressive graft dysfunction, proteinuria and adverse events.

Aim: to evaluate the immediate results of reconstruction of the valve heart apparatus and the great vessels of the heart graft before implantation.

Materials and methods. The analysis included 24 cardiac transplants with pathology of the valve apparatus and the great vessels, as well as 24 recipients who needed emergency heart transplantation and were in the clinic under UNOS status code 1A and 1B.

Results. Before performing heart transplantation, the valve apparatus and great vessels were corrected.

Conclusion. With a shortage of donor organs for recipients requiring emergency care, cardiovascular transplantation from “suboptimal” donors is one of the most affordable ways. Given the possibility of reconstructive operations on the valve apparatus and the great vessels of the donor heart, and evaluating satisfactory immediate results of demonstrated observations, it can be argued that the above way out would reduce urgent waitlist mortality, achieve satisfactory survival results in the early postoperative period, increase the donor resource and optimize the transplant program.

Aim: to study plasma galectin-3 levels in heart recipients and to determine the potential significance of galectin-3 level in acute transplant rejection and fibrosis.

Methods. The study included 107 heart transplant recipients, aged 16 to 70 (48 ± 13) years, of which 90 (84%) were men. Dilated cardiomyopathy was diagnosed in 57 patients prior to heart transplantation, end-stage ischemic heart disease in 50. Galectin-3 concentrations and placental growth factor (PlGF) were measured using enzyme-linked immunosorbent assay (ELISA); vascular endothelial growth factors (VEGF-D and VEGF-A), monocyte chemoattractant protein-1 (MCP-1), platelet-derived growth factors (PDGF-BB), and soluble CD40 ligand (sCD40L) were measured using multiplex technology xMAP. Acute graft rejection and myocardial fibrosis were verified through morphological examination of endomyocardial biopsy specimens.

Results. Galectin-3 concentrations in patients with congestive heart failure (15.92 [11.80; 23.65] ng/ ml) were significantly higher than in healthy individuals (11.08 [7.71; 14.47] ng/ml), p = 0.00. No correlation was found between galectin-3 levels and sex, age and pre-transplant diagnosis. A month after transplantation, plasma galectin-3 level was significantly higher than before transplantation; a year later, the levels decreased to pre-transplant levels (18.71 [13.14; 25.41] ng/ml). By the end of the first year after transplantation, the levels were significantly higher both in patients with 1-2 episodes and in the patients after 3 or more episodes of acute rejection, in contrast to recipients who were not diagnosed with rejection. By the end of the first year after heart transplantation in patients with fibrosis, plasma galectin-3 levels were significantly higher than in patients without fibrosis. By the end of the first year after heart transplantation, galectin-3 levels in the recipients were associated with the nature of myocardial fibrosis: in patients with diffuse focal fibrosis (22.52 [20.98; 26.08] ng/ml), plasma concentrations of galectin-3 were significantly higher than in patients without fibrosis (15.36 [11.95; 22.42] ng/ ml, p = 0.01).

Conclusion. Plasma levels of galectin-3 in heart recipients by the end of the first year after transplantation is associated with previous crises of acute graft rejection, irrespective of the number of rejection episodes. Elevated plasma levels of galectin-3 in heart recipients in the long term after transplantation is associated with myocardial fibrosis; galectin-3 levels are associated with the morphological characteristic of fibrosis in the transplanted heart (diffuse focal fibrosis). 

This paper proposes a new method of generating pulsatile flow using non-pulsating pumps (NPP) without modulating the rotation speed of the pump rotor. At the initial stage, this method was proposed for NPP-based cardiopulmonary bypass (CPB) systems. The method is based on parallel connection to the NPP shunt (input-output) on which a controlled valve is installed. This valve ensures periodically clamps and opens the shunt partially. A comparative evaluation of the operation of pumps with and without a pulsator was done on a hydrodynamic bench with simulation of heart failure (HF) conditions. The pump-shunt system was connected according to the “veinartery” CPB scheme under copulsation mode. Rotaflow (Maquet Inc.) was used as the NPP. For a comparative assessment of the hemodynamic efficiency of the method, the following were used: aortic pulsatility index Ip, energy equivalent pressure (EEP) and surplus hemodynamic energy (SHE). The indices in the pulsating mode compared with the non-pulsating mode increased: Ip by 3 times, EEP index by 3.76% and SHE index increased by 4 times. Results show that the proposed method of generating a pulsating flow is effective.

In this present case report during liver transplantation a patient was developed dissection of hepatic artery (HA) which was noticed after arterial reconstruction step. In one hour after surgery at intervention operating room stent placement of HA was performed. At early postoperative period by hepatic angiography study indicated for a second stent placement of HA, also embolization of splenic artery to treat a steal syndrome. After 2 weeks a patient developed thrombosis of recently placed stents which was required vascular reconstruction of HA by using autovenous graft. The condition complicated by development of a cholangiogenous hepatic abscesses and sepsis despite of all used possible methods of liver graft revascularization. However, used methods of vascular correction, which combined of timely carried out intensive care and antibiotic therapy according microbiology laboratory results allows saving graft function. After treatment of septic complications and patient’s somatic status stabilization and normalization of laboratory results liver retransplantation was performed. 

Primary schwannoma of the heart is a rare disease. It arises from vagus nerve branches and plexus. Most schwannomas are benign tumors, but sometimes they can be primary malignant neoplasms. In the MedLine database, we found only 21 publications on benign and 13 publications on primary malignant cardiac schwannoma. Moreover, according to localization in the right atrium, only eight benign schwannoma observations are described. We report a 73-year-old woman who, with echocardiography and magnetic resonance imaging of the heart, revealed a right atrial tumor with sprouting of the right atrial free wall. The tumor was radically excised through cardiopulmonary bypass and pharmaco-cold cardioplegia. Pathohistological and immunohistochemical examination of the excised tumor showed that it is benign schwannoma. 

Vascular calcification is common in patients with chronic kidney disease and in kidney transplant recipients. It leads to increased arterial stiffness, left ventricular hypertrophy, complicates formation of arteriovenous fistula for hemodialysis, decreases coronary artery perfusion, and generally increases cardiovascular morbidity and mortality. Vascular calcification affects arteries of all sizes – starting from the intimal and medial layers of the arterial wall. In clinical practice, several non-invasive imaging techniques have been used to evaluate the location and severity of vascular calcification. There is a report positing a possibility of evaluating vascular calcification by dual-energy x-ray absorptiometry (DXA). This paper presents the experience of successful diagnosis of peripheral arterial calcification by DXA in kidney transplant recipients and end-stage renal disease patients. 

Aim: to conduct a comparative assessment of the effectiveness of liver regeneration occurring after induction of chronic fibrosing liver disease (CFLD) using bone marrow mononuclear cells (BMMCs) and total RNA (tRNA) extracted from BMMCs.

Materials and methods. The study involved 140 Wistar rats. CFLD was modeled in 100 rats, of which 25 died. The surviving 75 rats (CFLD formed by the third month) were divided into 3 groups: Group 1 – control (administered with physiological saline); Group 2 – a single injection of tRNA from BMMCs at a dose of 30 μg/100g body weight; Group 3 – a single injection of BMMCs at a dose of (30–35) × 106 cells. The dynamics of regenerative processes in the liver was evaluated based on the animal mortality, dynamics of restoration of biochemical markers (ALAT, ASAT, alkaline phosphatase and total protein) and morphological picture of the liver on the seventh day and after three, six and nine months. The significance of differences in the compared values was determined through Student’s t-test for <0.05.

Results. Mortality in Group 1 was 12%, in Groups 2 and 3 – 4%; In Group 1, ALAT and ASAT were restored to normal values after two months, alkaline phosphatase after 3 months, and total protein remained low for over 4 months. In Groups 2 and 3, all hepatic homeostasis markers returned to the values they were before CFLD modeling faster than in Group 1 (after two months). However, in Group 2, the regeneration rate was higher than in Group 3. It was revealed that normalization of functional liver parameters in all groups were ahead of restoration of the histological structure of the liver. Liver defibrotic processes in Group 2 were activated after 3 months, and in Groups 1 and 3 – after 6 months. The histological structure of the liver was restored in Group 2 after 6 months, and in Groups 1 and 3 after 9 months.

Conclusion. BMMCs and tRNA extracted from them in biologically effective doses trigger liver regeneration in CFLD. However, regulatory effect from the use of tRNA appears earlier and is more effective. 

Aim: to obtain a stable population of the human labial mucosal epithelium without feeder cells through explant culture technique and simplified formulation of the culture media.

Materials and methods. Labial mucosa samples were obtained from 6 patients in the operating room after the patients had signed an informed consent. Samples were trimmed of the substantia propria and cut into uniformed explants. Cell culture was done using DMEM/F12 (1:1) (1.05 mM calcium) and EpiLife (0.06 mM calcium) media, supplemented with 5% fetal bovine serum, antibioticantimycotic, insulin (5 μg/mL), hydrocortisone (5 μg/mL) and epidermal growth factor (10 ng/mL). Primary cells were stained for stemness and proliferative markers (anti-p63), intermediate filaments (anti-vimentin), and tight junction protein-1 (anti-ZO-1). Image analysis was performed in Fiji (ImageJ).

Results. Primary cell culture was obtained from all the samples in both media. Cellular morphology was characterized as a classic “coble-stone” phenotype. 34.7% p63-expressing cells (median, n = 3) was detected in the 1.05 mM Ca medium, while ZO-1 expression was estimated at 17.05 μm per cell (median, n = 3). In cells cultured in 0.06 mM Ca medium, positive p63 expression was 39.2% (median, n = 3), while the length of the ZO-1 expression was 5.18 μm per cell (median, n = 3).

Conclusion. This study presents a detailed protocol on how to obtain cell culture of human labial mucosal epithelium from a small biopsy with high proliferative activity without feeder cells condition. The 1.05 mM Ca medium promoted generation of the tight junction and may be used in in vitro epithelium differentiation models. In contrast, the 0.06 mM Ca medium maintained reduced level of maturation in the cell culture. Thus, the media formulations, cell culture source and method described in this study, may be used for transplantation of autologous labial mucosal epithelium in patients with bilateral limbal stem cell deficiency. 

Aim: to evaluate the osteo-replacement properties of the coral aquaculture skeleton of P. verrucosa and A. abrotanoides (CAS) on a model of a fenestral defect in the femur of rats in comparison with the natural coral skeleton of A. cervicornis (NCS).

Materials and methods. CAS grown at a Russian-Vietnamese tropical research and development technology center, as well as NCS were cleaned of organic residues, crushed into 300–600 μm granules, sterilized by γ-radiation (24 kGy) and used to fill bone defects in rat femur. Three groups of animals were formed according to the number of types of coral skeleton samples. Two animals were removed from the experiment every 3, 6, 9, 12 weeks. Tissues excised from implantation zones were fixed, decalcified in EDTA, and their histological slides stained with hematoxylin-eosin were prepared.

Results. There were no fundamental differences in the dynamics of replacement of bone defects with newly formed bone tissue after implantation of CAS and NCS. NCS, like CAS, were biocompatible and caused no inflammatory reactions in the implantation zone. In the defect area, there was good consolidation of NCS granules with the bone bed. Their bioresorption rates were also similar. Three weeks after implantation, periosteum grew over the defect zone and bone formation began by periosteal osteogenesis. By week 12, the defect area was filled with newly formed cancellous bone tissue with hematopoietic zones between the bone trabeculars.

Conclusion. The scleractinium coral aquaculture skeleton of P. verrucosa and A. abrotanoides has osteoplastic properties similar to those of the coral skeleton of A. cervicornis from natural settlements. 

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in many countries, involving about 25% of the population worldwide. This disease includes many genetic, metabolic, and environmental factors. It is closely associated with insulin resistance, metabolic syndrome, obesity, diabetes, and many other diseases. NAFLD is characterized by macrovesicular steatosis of the liver. In the natural course of NAFLD simple steatosis progresses to nonalcoholic steatohepatitis (NASH), fibrosis and ultimately, cirrhosis and hepatocellular carcinoma. Cirrhosis with Nash and hepatocellular carcinoma is an indication for liver transplantation. Obesity is a growing problem in liver transplant candidates. Cardiovascular complications related to metabolic syndrome and NASH recurrence in the transplanted liver may affect the outcome of surgery in these patients. The results after transplantation are similar to the results of liver transplantation for other indications, but cardiovascular complications are the main cause of death in patients with NASH after surgery. 

Substitution of defects in various tissues, especially bone tissues, is a major challenge in modern medicine. There is currently no universal method of filling defects which has no drawbacks. Hydrogels are one of the promising groups of alloplastic materials. At present, you can obtain materials with various biological properties like natural extracellular matrix using various methods of chemical and physical modification. These biomaterials can be used as a means of delivering stem cells and bioactive substances to the defect zone. This literature review is devoted to the various aspects of preparation and use of hydrogel-based biological materials. 

Cytomegalovirus (CMV) infection plays an important role in clinical transplantology – it increases the risk of complications, graft failure, and patient death. The virus has both direct (direct damage to organs and tissues) and indirect immunomodulatory effects. Based on studies conducted, an international group of experts developed general principles for managing CMV infection after transplantation. This paper discusses risk factors, pathogenetic mechanisms by which CMV infection develops after kidney transplantation, the principles of diagnosis, treatment and prevention of this complication, and ways to overcome drug resistance in the virus. The prospects for the use of immunological monitoring, new antiviral drugs, as well as the possibility of using CMV vaccines, T-cell therapy, immunosuppressants (antiviral mTOR inhibitors) are discussed. 

Post-kidney transplant urological complications (failure of a newly formed anastomosis, obstructive uropathy, necrosis of graft ureter, graft ureteral stricture, development of vesicoureteral reflux in the renal graft, recurrent urinary infection) are one of the main causes of graft loss and various deaths. This literature review aims at analyzing world studies on prevention methods (routine graft ureteric stenting) and surgical techniques for treating urological complications (laparoscopic correction of supravesical urinary tract obstruction in a graft kidney) in kidney recipients. 

Congratulations to Georgiy Pinkusovich Itkin.

On scientific and medical personnel training at V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs of the Ministry of Healthcare of the Russian Federation.