Editorial
Clinical Transplantology
Allograft rejection would entail an increase in certain blood biomarkers and active substances derived from activated inflammatory cells which could influence entire vascular endothelial function and deteriorate arterial wall stiffness. We propose that carotid wall functional indices measured with non-invasive ultrasound could we valuable markers of the subclinical cardiac allograft rejection. Aim. Our goal was to analyze the clinical utility of functional common carotid wall (CCW) variables measured with high-resolution Doppler ultrasound as a non-invasive screening tool for allograft rejection in cardiac transplant patients (pts). Methods. One hundred and seventy one pts included 93 cardiac recipients, 30 dilated cardiomyopathy waiting list pts, and 48 stable coronary artery disease (SCAD) pts without decompensated heart failure were included. Along with resistive index (Ri), pulsative index (Pi), and CCW intima-media thickness (IMT), CCW rigidity index (iRIG) was estimated using empirical equation. Non-invasive evaluation was performed in cardiac transplant recipients prior the endomyo- cardial biopsy. Results. Neither of Ri, Pi, or CCW IMT were different in studied subgroups. iRIG was signifi- cantly lower in SCAD pts when compared to the dilated cardiomyopathy subgroup. The later had similar values with cardiac transplant recipients without rejection. Antibody-mediated and cellular rejection were found in 22 (23.7%) and 17 (18.3%) cardiac recipients, respectively. Mean iRIG in pts without rejection was significantly lower in comparison to antibody-mediated rejection and cell-mediated (5514.7 ± 2404.0 vs 11856.1 ± 6643.5 and 16071.9 ± 10029.1 cm/sec2, respectively, p = 0.001). Area under ROC for iRIG was 0.90 ± 0.03 units2. Analysis showed that iRIG values above estimated treshold 7172 cm/sec2 suggested relative risk of any type of rejection 17.7 (95%CI = 6.3–49.9) sensitivity 80.5%, specificity – 81.1%, negative predictive value – 84.3%.
Conclusions. Increased carotid wall stiffness is found in patients with both antibody-mediated and cellular car- diac allograft rejection. Non-invasive measurement of carotid artery wall rigidity index with triplex ultrasound is a simple screening tool for risk stratification. Having a functional marker would enable preventive measures to be taken at the early stages.
Aim of study: multiplex analysis of the levels of biomarkers of neoangiogenesis and inflammation in cardiac transplant recipients.
Materials and methods. 59 pts. with heart failure III–IV according to NYHA FC, waiting for a heart transplant, aged 22 to 73 years, 48 males and 11 females. 41 recipient (30 men and 11 women) had dilated cardiomyopathy, 18 – coronary heart disease (CHD). The concentration of VEGF-A, VEGF-D, PlGF, PDGF-BB, FGF, sCD40L, MCP-1 was measured using xMAP technology, the sets of reagents Simplex ProcartaPlexTM (Affymetrix, USA).
Results. There are four levels of seven biomarkers of neoangiogenesis and inflammation method for multiplex analysis in patients with heart failure. A year after transplantation, the mean levels of biomarkers VEGF-A (p = 0.001), PDGF-BB (p = 0.018), MCP-1 (p = 0.003) was significantly decreased, and the others had a tendency to decrease relative to the level before transplantation. It was shown individual differences of levels of VEGF-A, VEGF-D and PlGF before and after transplantation. There were found different dynamics of the concentrations of biomarkers and growth factors before and after heart transplantation in patients with cardiovascular complications and without them.
Conclusion. Multiplex analysis allows to measure the concentration range of analyte biomarkers of neoangiogenesis, inflammation in one sample of blood serum of patients with severe heart failure and after transplantation. There are marked individual differences in the concentration of biomarkers in different clinical situations that may have clinical significance in the conduct and supervision of recipients after transplantation.
Aim: to assess the relationship between preand post-transplantation factors and degree of coronary artery lesion, reported by intravascular ultrasound study (IVUS) in patients who underwent orthotopic heart transplantation (OHT) surgery. Materials and methods. The study comprised of 27 patients who underwent OHT more than 2 years before. The age of patients was 46,8 ± 10,4 years old. All of them were preoperatively classified by HLA system. All patients received transthoracic echocardiography at terms of 1, 6, 12 and 24 months after OHT. Coronary angiography (CAG) and IVUS were performed at 24 ± 6 months. Results. In CAG none of the patients showed angiographic signs of CA stenosis, but changes of various degrees were detected by IVUS. Results obtained by IVUS were clustered to select two groups with different degree of coronary artery lesion. The donor’s age in Group 2 was evidently higher compared to Group 1 (34,77 ± 1,03 and 40,00 ± 2,04 years, respectively, p = 0,043). Donor-recipient coincidence frequency was lower in group with significant CA lesion (by 2,36, р = 0,003). The number of cardiac surgeries performed prior to OHT was higher in Group 2 (by 2,8, р = 0,008). Post-transplant factor analysis showed that the number of diabetes mellitus (DM) cases revealed after transplantation was more frequent in Group 2 (by 3,2 vs Group 1, р = 0,021). Conclusion. The degree of CA lesion according to IVUS at 24-month period after OTH was associated with several post-transplant factors, which were the presence of cardiac surgical interventions before transplantation, low HLA donor-recipient coincidence frequency, and donor’s age. The more significant CA lesion is, the more cases of DM after OHT occur.
Aim. To define influence of the left ventricle (LV) perfusion defects on the clinical status dynamics after coronary angioplasty in patients with the expressed myocardium dysfunction of ischemic etiology. Materials and methods. Examined 86 patients (81 men and 5 women aged from 46 to 73 years) before and in 2–3 days after percutaneous coronary intervention with diagnosis: CAD, CHF with NYHA class III–IV, echocardiography parameters of LV: ejection fraction less than 40%, end-diastolic volume is more than 200 ml. Perfusion defects of myocardium estimated with use of ECG-gated single photon emission computed tomography. Predictors were defined: perfusion defects on LV apex (in score), perfusion defects in the area of LAD, LCx and RCA (%), the LV global perfusion defects (in score and %). Results. In 42% of cases 6-minute walk test increased to 3 times; The NYHA class decreased by 2 classes (group 1). In 28 cases 6-minute walk test increased to 2 times and the NYHA class decreased on 1 class. In 22 patients 6-minute walk test increased less than 50% of reference values and there was no dynamics NYHA class (50 patients of the group 2). Initial extent of LV global perfusion defects in group 1 – 41,2 ± 4,0%, in group 2 – 58,3 ± 2,4% (р = 0,0004). Similar values are received for perfusion indicators in the area of LAD and the LV apex. Prevalence of myocardial perfusion defects at rest reflects prevalence of a cardiosclerosis in a cardiac muscle. Conclusion. Degree of LV myocardial perfusion defects in patients with the expressed heart failure of ischemic etiology is the key indicator influencing clinical efficiency of coronary angioplasty. Critical size for definition of the favorable forecast of revascularization are 60% and more perfusion defects testifying that in a cardiac muscle the focal cardiosclerosis prevails over the functioning myocardium.
The aim is to evaluate the possibility of optimizing the conditions for stent implantation due to remodeling of the occluded coronary artery under the influence of hemodynamic factors of restored antegrade flow. Materials and methods. Recanalization and stenting of chronic coronary artery occlusion were performed in two stages (Group 1) or simultaneously (Group 2). Group 1 consisted of 36 patients, Group 2 – 50 patients. Time interval between the intervention stages in Group 1 was on an average 68 days (from 18 to 176 days). Groups did not differ by age, sex or clinical status of the patients. Repeated surveys were carried out in the following terms: 1 month, 6 and 12, 24 and 36 months after PCI.
Results. At recanalization stage in Group 1, the difference of artery diameters at the proximal and distal ends of the occlusion zone exceeded the diameter of the distal segment and was 1.78 mm. In Group 2, the value was 0.53 ± 0.7 mm. At the second stage in Group 1, the difference of diameters of the proximal and distal segments decreased to 0.45 ± 0.26 mm by reducing the proximal and increasing the distal sizes of the artery. Remodeling of the coronary artery in Group 1 allowed performing adequate stent implantation at the second stage of intervention (in two months) in 34 cases. Two patients developed recanalized artery reocclusion in 43 and 176 days after the first stage. The clinical effect of recanalization of coronary arteries in both groups did not differ. Manifestations of angina decreased in both groups. According to the 36-month follow-up period not even one case of target lesion intervention was registered in both groups. Conclusion: Remodeling of coronary artery under the influence of blood flow factors observed within several weeks after recanalization, creates favorable conditions for the stent implantation. The method of delayed stenting for complicated forms of chronic occlusions when determining post-recanalization obliteration of the distal coronary bed is safe and acceptable since it allows obtaining an optimal clinical outcome.
The report of the Russian Renal Replacement Therapy Registry covers the period from the year 1998 to 2011 and represents data on the national, regional, and individual patient levels. We summarize information about epidemiology of treated end-stage renal disease in Russia, and describe in details incidence and prevalence for all modalities of renal replacement therapy. The article contains broad spectrum of data on quality of treatment indicators, waiting list, pharmacological treatment, mortality, and survival patterns in patients on hemodialysis, peritoneal dialysis and with functioning renal graft.
The aim of the study was the evaluation of pharmacokinetic parameters and clinical efficacy of generic cyclosporine (Ecoral) and Sandimmune Neoral. Materials and methods’. The pharmacokinetic parameters of different cyclosporine formulations. In 197 kidney graft recipients 319 comprehensive pharmacokinetic studies were performed. In 42 patients received in consecutive order original and generic Cyclosporine in the same dosage the complete pharmacokinetic study was perforfomed. AUC calculations based on dosing interval concentration values were fulfilled using linear trapezoidal rule. To evaluate clinical efficacy 235 short pharmacokinetic studies with concentration examination at 0, 1, 2 and 3 hours after taking Cyclosporine (Co, C1 C2 and C3) were performed in patients treated with Neoral (n = 75) or generic cyclosporine (n = 160). Clinical efficacy of generic cyclosporine was estimated by the prevalence of allograft dysfunction and biopsy proved acute rejection episodes as well as by one-years graft survival and events-free survival. The graft survival rate was calculated by Kaplan–Meyer method. Results. At 100–200 ng/ml maintenance concentration (estimated by C0 concentration) pharmacokinetic parameters did not significantly differ according to Cyclosporine formulation in both complete or short pharmacokinetic studies: AUC-4265 vs. 4204 and 3834 vs. 3670 ng/ml/h respectively; (p > 0.05), Cmax (1036 vs 931 and 813 vs 741 ng/ml respectively; (p > 0.05). Allograft dysfunction occurred in 5% of patients subjected to Neoral immunosuppression and in 8% of Equoral recipients (p > 0.05). However biopsy-proven acute rejection as a cause of graft dysfunction was seen only in patients receiving Ecoral (7% vs 0; p < 0.05). One-years graft survival rate did not differ between groups (99% and 94% in generic CyA and Neoral respectively; p > 0.05), whereas events-free graft survival was significantly lower in patients, receiving generic CyA than in Neoral group (88 vs 94% respectively; p = 0,03). Conclusion. Pharmacokinetic studies have shown the absorption profile of generic formulations Equoral do not differ significantly from that of Neoral. Prospective pilot trial demonstrated no difference between one-year graft survival or graft dysfunction rate, but lower eventsfree one-year graft survival as well as the tendency to higher acute rejection rate in patients treated with generics in comparison with those receiving Neoral should be noted. This issue is to be studied further.
Ratios of subpopulations of mononuclear blood cells in 68 patients were registered by method of flow cytometry during one month before or after transplantation of a cadaveric liver with the aim of a comparative assessment of the contribution of cellular factors into graft acceptance. Results. The obtained data allow considering the changes of separate Treg subpopulation after transplantation as a partial outcome of generalized shift of the whole process of lymphocytes differentiation, involving hematopoietic stem cells and prelymphocytes. This shift is followed by an increase of young hematopoietic stem cells, precursors of lymphocytes, angiogenic cells, and by a concomitant reduction of the majority of more matured subpopulations of lymphocytes.
Conclusion. Diminishment of «tolerogenic» liver activity of before transplantation and its restoration after the organ’s replacement is explained by morphogenic/trophic mechanism. The basis of this mechanism is an increase in blood of hematopoietic stem cells and other cells transferring angiogenic and regenerative information to the graft.
Regenerative Medicine and Cell Technologies
Aim. Development of the tissue engineered matrix for the atrioventricular valve graft in a large animal model. Materials and мethods. The study was performed on ovine mitral valves (n = 100). The decellularization of the whole mitral valve grafts was performed using 21 different detergent-based protocols.
The effectiveness of the decellularization was investigated by immunofluorescent staining for DNA (as a marker of intracellular antigens) and α-GAL (as a marker of membrane-associated antigens), as well as DNA quantification. The mechanical properties and the repopulation potential were analyzed. The structure and repopulation rate analysis included hematoxylin-eosin, Movat’s pentachrome and Van Gieson histological staining, and immunofluorescent staining for collagen I and IV, as well as endothelial cell markers. Results. The protocols that included the gradual rise of the detergent solution were shown to be the most effective for the decellularization of the whole mitral valve graft. At the same time, the detergents alone failed to remove α-GAL. The reducing agent enhanced the decellularization, which resulted in complete removal of DNA and α-GAL, according to immunofluorescent staining. DNA quantification showed a 96.4% reduction in DNA content. The mechanical properties were shown to be comparable to the native tissue. The reseeding of the decellularized tissue showed a potential for the repopulation. Conclusions. A new matrix for the atrioventricular valve substitute could be developed using the decellularization as the initial step of the valve tissue engineering. The detergent combined with a reducing agent showed significantly better results compared to the detergents alone for the mitral valve decellulrization. The matrix demonstrated mechanical properties, comparable with the native one, and the potential for the repopulation.
The aim of this study is an analysis of the functional effectiveness of a biomedical cell product consisting of a biopolymer microheterogeneous collagen-containing hydrogel (BMCH), human adipose-derived mesenchymal stromal cells (hADMSCs), and chondrogenic induction medium in the regeneration of articular cartilage. Materials and methods. The test model of the adjuvant arthritis was used (female Soviet Chinchilla rabbits) with the further development into osteoarthrosis (OA) combined with the clinical, biochemical, radiological, and histochemical trials. Results. On Day 92 of the OA model it has been found that the intra-articular introduction of a BMCH with hADMSCs into the left knee joint (n = 3) 30 days after the OA modeling, as opposed to the right joint (negative control, n = 3), stimulates the regenerative processes of the cartilaginous tissue structure characterized by the formation of chondrocyte «columns», the emergence of isogenic groups in the intracellular matrix and the regeneration of its structure. Upon the intra-articular introduction of a BMCH (n = 3) such effects are markedly less pronounced. Conclusions. A significant regenerative potential of a cell-engineered construct of human articular tissue (CEC ATh) has been proven. It is possible to presume that biostimulating properties of CEC ATh are due to the activating effect of a biomedical cell product on the stem cell migration processes from the surrounding tissue into the injured area with their subsequent differentiation.
Implants and Artificial Organs
The article describes complex software to calculate the main parameters of the axial pump (pressure drop and flow rate) on the basis of an analysis of its technical characteristics (current consumption and pump speed). It is shown that the calculated value of pressure drop and flow rate throughout the range of operating loads and pump speeds is different from the measured one by no more than 10%. It is shown that this software package may be included in the control system of axial pump.
Hyperhydration, the sum of persistent (PH) and intermittent (IH) ones is the strong predictor of mortality in patients on program haemodialysis (PHD). The aim of this research was to investigate the complex of methods for minimization of PH as well as IH. Materials and methods. The bioimpedance multifrequency analysis (BIA), relative blood volume (RBV) monitoring and plasma conductivity evaluation by ionic dialysance device were performed in candidates for kidney transplantation. Results. In 380 PHD patients, comparing with 26 healthy persons the expansion of extracellular volume was only observed even in the cases of the huge (3.5–15 L) overload. PH of more than 15% of extracellular volume was observed in 41% of patients. The deviation of hydration status from reference value was 3.7 ± 1.4 L at first measurement and 1.9 ± 1.2 L at last one in every patient. RBV decreased insignificantly (less than 2.5% / L ultrafiltration) during PHD sessions in patients with PH. This value increased after dry weight consummation and it appeared as surrogate of intravascular refueling capacity. The minimization of sodium dialysate – plasma gradient resulted in decrease of IH. Conclusion. The elimination of both PH and IH in PHD patients is the paramount goal; it demands the complex approaches and further investigations.
Clinical Cases
Introduction. Acute antibody-mediated rejection (AMR) is one of the severe complications of early and late period after heart transplantation (HT). Only few case reports and studies presented of mechanical circulatory support (MCS) application for refractory acute rejection causing hemodynamic compromise. Aim. We report the case of a woman with cardiogenic shock caused by severe AMR that was successfully treatment by peripheral venoarterial extracorporeal membrane oxygenation (VA ECMO). Material and methods. In december 2014, a 60-year-old woman with dilated cardiomyopathy was operated for HT. The patient had a good initial cardiac allograft function and no and was discharged from ICU on the 4th day after HT. 1st endomyocardial biopsy (EMB) (the 7th day after HT) showed absence of acute cellular and antibody-mediated rejection. On the 11th day after HT patient aggravated and presented clinical signs of life-threatening acute cardiac allograft dysfunction: arterial blood pressure 78/49/38 mm Hg, HR 111 in min, CVP 20 mm Hg, PAP 47/34/25 mm Hg, PCWP 25 mm Hg, CI 1.5 l/min/m2, adrenalin 110 ng/kg/min, dopamine 15 mcg/kg/min. ECG showed impairment of systolic left (LVEF 25%) and right (RVEF 15%) ventricle function, left and right ventricle diffuse hypokinesis, thickness of IVS, LV and RV wall 1.7, 1.4 and 0.8 cm, tricuspid and mitral valve regurgitation 2–3 degrees. EMB presented AMR. In conscience peripheral VA ECMO was installed. We used peripheral transcutaneous cannulation technique via femoral vessels – arterial cannula 15 F, venous cannula – 23 F, vascular catheter 14 G for anterograde leg’s perfusion. ACT 130–150 sec. AMR therapy included: methylprednisolon pulse-therapy (10 mg/kg for 5 day), IgG, plasmapheresis (No 7), rituximab. Results. Under MCS by VA ECMO we noted quick improvement of hemodynamic, metabolic homeostasis and organ functions. On the 6th day of VA ECMO (blood flow 1.8 l/min): arterial blood pressure 133/81/54 mm Hg, CVP 5 mm Hg, PAP 31/21/12 mm Hg, PCWP 12 mm Hg, CI 3,4 l/min/м2, HR 85 in min, LVEF 53%, IVS 1.3 cm, mitral valve regurgitation <1 degree, inotropic support was discontinued. Control EMB showed resolution of AMR. Duration of VA ECMO was 7 days. Patient was discharged from ICU on the 2nd and 26th day after VA ECMO in stable clinical status. Conclusion. VA ECMO should be crucial component of treatment of cardiac allogaft antibody-mediated rejection with severe hemodynamic compromise.
This article describes the first experience of laparoscopic donor nephrectomy with transvaginal kidney graft extraction. The surgical technique and long-term results are shown. The advantage of surgery is the absence of pain in the early postoperative period and good cosmetic results compared to standard laparoscopic nephrectomy. However, candidates for this operation should be carefully selected to maintain donor safety and graft viability.
Aim. The purpose of this study is to conduct clinic-morphological analysis following intramyocardial administration of a mononuclear fraction of bone marrow stem cells in a CHF patient suffering from ischemic heart disease. In October 2007 the patient underwent surgery, with a mononuclear fraction of bone marrow stem cells implanted with the use of a NOGA system. The patient was then put on a waiting list for heart transplantation. After 2-year follow-up amelioration was observed, LVEF increased from 22 to 27%, LF end systolic volume dropped from 265 ml to 250 ml. All these positive developments indicated the stabilization of hemodynamic indicators and enabled to wait for orthotopic heart transplantation which was performed in December 2009.
Literature Reviews
Living donor liver transplantation is a highly effective method to help children with end stage liver diseases. Projected success of operation is largely determined at the stage of selection of potential donor. In our review of the literature is presented historical information, are considered «eastern» and «western» way of development of pediatric living donor liver transplantation, are analyzed the ethical and psychosocial aspects of living donor liver transplantation, and also are set out principles and protocols for evaluation potential donors. In addition, the modern views on volumetry of the potential donor liver and on choice of graft type for transplantation, including for children with low weight are presented.
Ischemic and reperfusion injury is a complex, multifactorial process that damage kidney transplant. Knowledge and understanding of pathogenic mechanisms of damage processes allows the use of various biological agents to reduce this damage. However, the application of most of biological agents is still only in the experiment. The purpose of this survey show participants of pathogenetic mechanisms, mainly inflammatory mediators (cytokines, chemokines), their interactions, and the consequences of their damaging effects on the fabric kidney transplant.