Editorial
Clinical Transplantology
The aim: to analyze the waiting list for heart transplantation from 2010 to 2017 and to characterize recipients with chronic heart failure III–IV NYHA Class.
Methods. The study comprised 997 patients (139 [14%] females and 858 [86%] males) included in the waiting list for heart transplantation the period from January 2010 to December 2017. The average age of patients on the waiting list was 49.0 ± 12.0 (from 10 to 78 years). Before making a decision on inclusion in the waiting list, all patients underwent clinical and instrumental examination, including general clinical studies, echocardiography, measurement of central hemodynamic parameters using a Swan–Gans catheter, computer and/or magnetic resonance imaging of the chest, abdominal and brain.
Results. Heart transplantation was performed on 728 patients (99 females – 13.6% and 629 males – 86.4%) including 18 children aged 12 to 17 years (14.18 ± 2.07 years). Mortality in the waiting list in 2010 was 16.1%, compared with 3.2% in 2017.
Aim. To study the effect of ACE inhibitors (ACEI) in heart recipients on the prognosis and myocardial remodeling.
Materials and methods. Three hundred and eighty-six patients who received orthotopic heart transplantation (HT) were consequently enrolled to the study from February 2009 to November 2016.
Results. Thirty days after the HT, ACEIs were assigned to 141 recipients. Arterial hypertension was diagnosed in all cardiac recipients who received ACEI and among 48 patients (19.5%) from non-ACEI group. Patients receiving ACEI had significantly better event-free survival than control group (p = 0.045) during the follow-up for 1361,6 ± 36,9 days. Left ventricle (LV) end-diastolic dimension did not change over the time in both groups, whereas LV posterior wall thickness in non-ACEI group significantly increased from 1.35 ± 0.03 cm to 1,23 ± 0.05 cm (p < 0.05).
Conclusion. Cardiac recipients who received ACE inhibitors had better survival and less transplant left ventricle progression, that could reflect beneficial effects of renin-aldosterone-angiotensin system inhibition after heart transplantation.
Aim. To estimate the frequency and expressiveness of atherosclerotic lesions of the transplant coronary arteries of the determined by an angiographic method.
Materials and methods. Coronary angiography was executed to 518 recipients of heart aged from 10 till 72 years (average 56,92 ± 12,1) within the first week after transplantation of heart (a median 6; 3–42 days). Men – 466, women – 52. Initial status of recipients: UNOS 1A – 217 of people, UNOS 1B – 89 of people, UNOS 2 – 212 people. Included the following criteria of the donor in the analysis: sex, age, cause of brain death.
Results. Angiographic signs of atherosclerotic lesions of coronary arteries are discovered in 166 cases, in 65 cases defined as significant stenosis which demanded performance of the percutaneous coronary intervention (PCI). In 352 cases symptoms of atherosclerosis are not revealed (group of comparison). At recipients in the status UNOS 1A and UNOS 1B discovered the transmission of atherosclerosis (TA) more often, than recipients in the status UNOS 2 (54% and 36%, respectively). Age of donors in group with transmission of atherosclerosis was 50,2 ± 0,7 years, and in group of comparison – 41 ± 0,6 years (r = 0,0005). Range of donors age in groups did not differ and made 18–66 years for group of comparison and 20–67 years for group with transmission of atherosclerosis, but in subgroup of PCI made 31–67 years. Gender influence on the frequency of transmission of coronary atherosclerosis it is not revealed. Acute violation of brain blood circulation as the cause of brain death was observed in 76% of cases at TA group and 61% in group of comparison.
Conclusion. The age of the donor and acute violation of brain blood circulation are the factors associations with probability of transmission of coronary atherosclerosis, however it is important to consider the status of the recipient.
Lung transplantation (LT) for idiopathic pulmonary arterial hypertension (IPAH) now is the only radical treatment of this disease.
Aim: to analyze own experience of performing LT in patients with IPAH.
Materials and methods. 8 adult IPAH patients, who underwent LT between 2014 and october 2018, were included. In 7 of 8 patients undergoing bilateral lung transplantation on intraoperative venoarterial extracorporeal membrane oxygenation (VA ECMO) with prolongation into the postoperative period.
Results. VA ECMO support was prolonged into postoperative period 6 and 7 days respectively in 2 (25,0%) patients and 3 days in 6 (75,0%) patients. Hospital mortality in IPAH patients was 1.
Conclusions. Own experience demonstrates that LT is an effective method of treatment in patients with IPAH. Hospital, 1- and 3-year survival rates for the patient collective were 87.5, 75.0 and 75.0% respectively.
Blood level of transforming growth factor beta 1 (TGF-β1) is associated with liver function and immune homeostasis, which suggests it as a potential biomarker for immunosuppressant tacrolimus dose requirement at liver transplantation (LT).
Aim. To evaluate diagnostic efficacy of TGF-β1 blood level at determination of individual tacrolimus dose requirement in children at LT.
Materials and methods. 89 children with end stage liver disease aged from 3 to 73 months were examined. Children underwent living related LT, then the recipients received 2–3 component immunosuppressive therapy, including tacrolimus. Blood concentration of tacrolimus and TGF-β1 was measured by ELISA.
Results. TGF-β1 blood level in children before LT was significantly lower than in healthy children: 3.7 (1.3–8.4) and 19.3 (12.6–25.5) ng/ml, p = 0.001. A month after LT, its concentration increased to 8.1 (1.8–15.3) ng/ml (p = 0.02). A year after LT, the cytokine level remained higher than before transplantation: 6.6 (1.9–12.6) ng/ml, p = 0.01. TGF-β1 level did not correlate with tacrolimus blood concentration, determined 12 hours after the last administration of the drug, neither a month, nor a year after transplantation. At the same time, the cytokine level one month after LT was associated with a tacrolimus daily dose one year after the operation (r = –0.23, p = 0.04). In the recipients, who received smaller daily doses (0.4–2.5 mg) of tacrolimus, TGF-β1 level was higher than in those receiving large doses (3.0–6.0 mg) of the drug: 9.1 (2.6–16.2) ng/ml vs. 4.2 (1.3–9.2) ng/ ml, p = 0.04. Evaluation of diagnostic efficacy of the TGF-β1 level as a test for the detection of tacrolimus dose requirement showed that the area under the ROC curve (AUC) was 0.66 ± 0.07; 95% CI [0.53–0.79], the sensitivity and specificity of the test were 60 and 74% at threshold value 6.7 ng/ml. Relative risk of higher tacrolimus dose requirement was 3.14 ± 0.48; 95% CI [1.24–7.96].
Conclusion. TGF-β1 blood level in one month after LT less than 6.7 ng/ml is 3 times higher risk factor of tacrolimus dose requirement more than 3.0 mg per day. The likehood of the test is 66%, the sensitivity and specificity – 60 and 74%.
Heart Transplantation and Assisted Circulation
Aim: to analyze the results of the regional center for the creation and maintenance of vascular access for hemodialysis.
Materials and methods. We performed a retrospective analysis. In five years (2012–2016) we performed 3,837 different operations on vascular access (VA) in 1,862 patients.
Results. There is a strong dependence of type VA and the cause of CKD 5D. At the time of the HD start, the proportion of arteriovenous fistula (AVF), synthetic vascular graft (SVG) and central venous catheter (CVC) was 73.7, 0.3 and 26% for glomerulonephritis; 58.4, 0.4 and 41% for pyelonephritis; 53, 1 and 26% for diabetes mellitus; 32, 8 and 60% for polycystic disease and 33, 2 and 65% for systemic processes, respectively. After one year on HD the shares of AVF, SVG and CVC were 89, 2 and 9% for glomerulonephritis; 76, 6 and 18% of pyelonephritis; 70, 5 and 25% for diabetes mellitus; 68, 10 and 22% for polycystic disease and 53, 5 and 42% for systemic processes, respectively. In a case of start of HD via AVF, five years survival was 61% [95% CI 51.8; 71.9]; in a case of start HD via CVC with followed by conversion to AVF – 53.9% [95% CI 42.5; 67]; in a case of CVC remained the only access – 31.6% [21.4; 41.4]. Non-maturation of AVF was observed in 5.9% of new AVF (the risk increased in a case of diabetes mellitus), early thrombosis (before the first use of AVF) was observed in 12.7% of new AVF (the risk increased with diabetes, polycystic and systemic diseases). Creation of AVF a week before the start of HD or 1–2 weeks later significantly increased the risk of thrombosis. Primary patency in a year, three and five years was 77.2% (95% CI 71.7; 81.7); 48% (95% CI 41.6, 54.1); 34.1% (95% CI 27.8, 40.5) respectively; secondary patency – 87% [95% CI 83.7; 89.7]; 74.4% [95% CI 70.3; 78,12]; 60.9% [95% CI 56.4; 65.1] respectively. The use of temporary CVC is associated with a three-fold increase of the risk of infection compared with permanent CVC: IRR 3,31 (2,46; 4,43), p < 0,0001.
Conclusion. A more detailed analysis is required to identify risk factors for complications of vascular access and to optimize approaches to its creation and maintenance.
Clinical Cases
HCV infection is one of the most common causes leading to the development of terminal liver diseases – cirrhosis and hepatocellular carcinoma, the main treatment for which is orthotopic liver transplantation. However, with continued virus replication, 100% reinfection occurs, which leads to the rapid progression of cirrhosis of the graft and the loss of its function. Standard interferon-containing therapy is ineffective for HCV infection, especially genotype 1, both before and after transplantation, and also has a wide range of adverse events. The article presents the successful experience of treating the recurrence of HCV infection 1 genotype in a patient who underwent liver transplantation and several courses of ineffective antiviral therapy.
Issue of the day. Treatment of hepatitis C in donor organ recipients
Aim. To study the efficacy and safety of the use of paritaprevir, ritonavir, ombitasvir and dasabuvir in combination or without ribavirin in liver recipients with recurrence of HCV 1 genotype after transplantation.
Materials and methods. The study included 46 patients after orthotopic liver transplantation with recurrence of HCV 1 genotype. 37 patients completed a 24-week course of antiviral therapy, including paritaprevir, ritonavir, ombitasvir and dasabuvir in combination or without ribavirin. The effectiveness of the therapy was calculated as the proportion of patients who achieved aviremia 12 weeks after the end of the course of treatment. The safety of therapy was assessed by the number of adverse events that occurred during the course of antiviral therapy.
Results. A sustained virologic response at 12 weeks after the end of the course of antiviral therapy, including paritaprevir, ritonavir, ombitasvir and dasabuvir, reached 100% of the recipients of the liver. Reduction in the intensity of cytolytic and cholestatic syndromes was noted at week 4 of therapy. Adverse events were recorded in 56.7% of the subjects, mostly they were not severe and were stopped on their own. Acute cellular rejection of the transplant developed in 1 patient (2.7%). There have been no cases of irreversible liver transplant dysfunction or death of the recipient.
The conclusion. The use of paritaprevir, ritonavir, ombitasvir and dasabuvir is safe and effective in the treatment of relapse of HCV infection of 1 genotype after liver transplantation.
Regenerative Medicine and Cell Technologies
Aim. To develop the protocols for liver and kidney tissue decellularization, and to develop an analysis of the proliferative activity of human Hep-G2 hepatocarcinoma cells on various carriers.
Materials and methods. Decellularization of the liver and kidneys was performed by perfusion of detergent solutions with gradually increasing concentrations of Triton X-100 (1, 2 and 3%). A histological analysis of the obtained samples was performed, and the method of optical and scanning electron microscopy was used to study the obtained samples. The proliferative activity of human Hep-G2 hepatocarcinoma cells was studied on the obtained samples of decellularized liver and kidney tissue.
Results. Decellularization of the organ does not lead to changes in the specific structure of the tissue matrix. Microparticles with an average size of 200 μm were made from their decellularized matrix of liver and kidney tissues. The level of proliferative activity of human Hep-G2 hepatocarcinoma cells cultured on microparticles from a decellularized liver was significantly higher than on microparticles from a decellularized kidney.
Conclusion. The decellularized matrix retains the native three-dimensional structure of the tissue. The level of cell proliferative activity is significantly higher on microparticles from the decellularized liver, which confirms the preservation of the specificity of the extracellular matrix of the tissue after the process of decellularization.
Introduction. Modern techniques of tissue engineering in the treatment of some degenerative diseases suggest the prospective viability of the biomedical technologies based on the creation of the equivalent of the damaged tissue (organ), including the tissue-engineered construct (TEC) of the endocrine pancreas (EP). Obtaining viable islets of Langerhans (IL) from the pancreas is a decisive step towards the creation of a TEC EP. The classic method of IL separation is based on enzymatic digestion of pancreatic tissue and further islet purification in ficoll density gradient during centrifugation, which adversely affects the morphofunctional state of IL.
The aim of the study was the development of a method for separating viable pancreatic islets from a fragment of human pancreatic tail with different cold ischemia times.
Materials and methods. A procedure of IL separation is proposed to be conducted without the use of EP tissue collagenase perfusion in the Ricordi chamber at the stage of IL separation and without ficoll solution with a varying density gradient at the stage of IL purification. Identification of IL obtained was performed by dithizone staining. The IL viability was evaluated using the LIVE/DEAD ® Cell Viability Kit. Histological analysis of the initial material included routine staining methods as well as immunohistochemical staining of the main types of islet cells.
Results. The morphological study of the EP fragments at different times of cold ischemia did not reveal significant differences in the histological presentation of the organ parenchyma; the islet structure appeared intact. Vital staining confirmed the separated IL viability in vitro for at least 1–3 days.
Conclusion. The proposed method of pancreatic tissue treatment allowed to reduce the number of stages, thereby minimizing the adverse effects of centrifugation and ficoll on the integrity of IL. It is possible to obtain the necessary amount of viable IL from a small EP fragment with the cold ischemia time of up to 19 hours, which can be used to create a TEC of a pancreas.
Aim: to create a model of stable experimental diabetes mellitus (DM) in laboratory rats using streptozotocin (STZ).
Materials and methods. The dynamics of changes in glycemia and survival in 60 Wistar rats was determined. STZ at a dosage of 70 mg/kg was administered to these rats in two ways: once and fractionally (within 5 days).
Results. After a single injection of the STZ, 6 out of 30 rats (20%) died, in 7 cases (23.3%) a spontaneous reversion of the diabetic status occurred and in 17 animals (56.6%) the DM remained stable throughout the observation period (8 weeks). After the fractional administration of the STZ no mortality was observed. Spontaneous reversal of DM occurred only in 2 of 30 rats (6.6% of cases). In other 28 animals hyperglycemia was stable until the end of the experiment. It is important to note that in all rats with a stable course of DM, the level of glycemia after 2 weeks after the injection of the STZ was at least 20 mmol/l.
Conclusion. Fractional intraperitoneal injection of STZ has an obvious advantage compared with a single injection, providing 100% survival and stable course of DM in 93.4%. The main criterion for a stable course of experimental DM is the level of hyperglycemia not less than 20 mmol/l after 2 weeks after intraperitoneal administration of STZ.
Aim. Clinical and functional evaluation of the implantation of autologous bone marrow cells treated with erythropoietin in laser channels during coronary bypass grafting in patients with end-stage coronary lesion.
Materials and methods. 60 patients with coronary artery disease with diffuse and (or) distal right coronary artery disease were randomized into two groups: patients of group 1 (n = 30) underwent coronary bypass grafting, implantation of autologous bone marrow cells treated with erythropoietin in laser channels, patients of the 2nd group (n = 30) were operated with coronary bypass grafting of the left coronary artery system. Assessment of the clinical status, myocardial perfusion and contractility was performed initially, 6 months after the operation.
Results. Six months after the operation, there was a more pronounced decrease in angina pectoris (CCS) in the main group compared to the control group, also we revealed a 6-minute walk test scores improvement. Based on two-stage scintigraphy (Tc99) in the main group before the surgical treatment, a rest perfusion defect was 8.5% [3.5, 18.5], a stress-induced perfusion defect – 7.0% [6.0, 12, 3]. In the control group, the rest defect was 9.1% [5.6, 12.4], the stress-induced perfusion defect was 7.3% [6.1, 8.7]. 6 months after surgery rest perfusion defect at the indirect revascularization group was 6.0% [2.5, 16.5] (p = 0.008), a stress-induced defect was 4.0% [1.5, 6.3] (p = 0.05). In the control group, the rest defect was 8.7% [5.3, 10.3], the stress-induced perfusion defect was 6.8% [5.3, 9.1] (p = 0.21). The results of scintigraphy with MIBG showed a left ventricle innervation defect (PID) significant decrease in the main group: initially 15.4% [14.2, 16.3], after 6 months 11.7% [9.3, 13, 2] (p = 0.045). In the control group, there was an unreliable decrease in PID: initially 14.3% [10.2, 17.3], after 6 months 13.8% [9.1, 14.2] (p = 0.14).
Conclusion. Our preliminary results revealed more pronounced effect of the new indirect revascularization method expressed as in myocardial perfusion improve, myocardial sympathetic innervation restoration and clinical status improvement in comparison with control group.
Literature Reviews
Up-to-date technologies have led to significant improvement of haemodialysis membranes biocompatibility and permeability. The new classes of membranes, high cut-off and middle cut-off, allow enhanced removal of middle molecules such as β2-microglobulin and even larger molecules. High membrane permeability along with the wide use of convective modalities are accompanied by increased albumin loss during dialysis. What is the acceptable upper limit for this loss and where is the right balance between the benefit of enhanced uremic substances removal and potential adverse effects of albumin deprivation are the active areas of research.
Questions of Ethics and Philosophy
In today’s world, state cooperation is carried out in almost all aspects of political, social and economic life. The interaction of States on high technologies in medicine is not something new and is carried out in a wide range of clinical areas. The cooperation of States in the field of organ donation and transplantation is not limited to the exchange of clinical experience between specialists from different countries or the provision of medical care in a particular case. On the one hand, this direction affects many aspects of social life of man, and needs special legal regulation. On the other hand, it is an effective organizational mechanism, the use of which by States can contribute to saving the lives and health of their own citizens through the inter-state exchange of donor organs. The most important goal of inter-state cooperation is to unite the efforts of the relevant state institutions and services to combat the illegal organ donation and transplantation tourism.
The article describes existing strategies for popularization and promotion ideas of deceased organ donation. The significance of this activity is outlined as the main one for the solution of the main medical problems of transplantation. Promotion of organ donation practices in the countries with developed deceased organ donation system and maximum quantity of deceased donors were highlighted. Negative tendencies in promotion of ideology of organ donation, which are clearly traced in Western transplant community were analyzed. A number of Russian initiatives to promote the idea of deceased donation on various on-line platforms are analyzed. Specific actions are proposed to make the practice of promoting ideas of deceased donation based on ethical principles and altruism in order to be more acceptable by the general public.
Aim. The Aim of the article is to investigate the ethical and epistemological problems that have arisen in recent years in connection with the emergence of incidents that have caused the problematization of traditional approaches to the definition and ascertainment of death (in particular, cases that reflect the history of Jahi McMath and Anahita Meshkin) and the spread in the West such practices, as «controlled donation» and «donation after euthanasia».
Materials and methods. The article uses the method of socio-ethical analysis and the bioethical case study methodology.
Results. The analysis of the development of ethical support for the practice of organ donation is presented.
Conclusion. The conclusion is made about the pronounced liberalization of the ethics of organ donation, characterized by the dictates of local moral contingency, linguistic manipulations with the categories of «gift», «harm», «autonomy» and the threat of trends in technological instrumentality in the system of development of transplantology and organ donation with the initial minimum of ethical grounds.
According to the Materials of the IX All-Russian Congress of Transplant
Terminal stage heart failure represents a substantial worldwide problem for the healthcare system. Despite significant improvements (medical heart failure treatment, implantable cardioverters, cardiac resynchronization devices), long-term survival and quality of life of these patients remain poor. Heart transplantation has been an effective therapy for terminal heart failure, but it remains limited by an increasing shortage of available donor organs along with strict criteria defining acceptable recipients.
Cardiac transplantation is an established therapy for end-stage heart failure. The number of heart transplant procedures performed worldwide has remained relatively unchanged in recent years. Although mortality rates on the waiting list have improved due to improved ventricular assist devices and rhythm correction techniques, it remains imperative to maximize use of all potential donor hearts. The recipient now presents with multiple complexities. The continued divergence between the rising number of transplant candidates added to the transplant waiting list and the number of suitable organ donors has increased pressure on clinicians to maximize the use of available thoracic organs for transplantation.