Immunosuppressive Therapy Protocol Research Articles

Dysregulation of Immune Tolerance to Autologous iPSCs and Their Differentiated Derivatives.

Induced pluripotent stem cells (iPSCs), capable of differentiating into any cell type, are a promising tool for solving the problem of donor organ shortage. In addition, reprogramming technology makes it possible to obtain a personalized, i.e., patient-specific, cell product transplantation of which should not cause problems related to histocompatibility of the transplanted tissues and organs. At the same time, inconsistent information about the main advantage of autologous iPSC-derivatives - lack of immunogenicity - still casts doubt on the possibility of using such cells beyond immunosuppressive therapy protocols. This review is devoted to immunogenic properties of the syngeneic and autologous iPSCs and their derivatives, as well as to the reasons for dysregulation of their immune tolerance.

Role of HLA in cardiothoracic transplantation.

In current clinical practice, transplant clinicians create collaborative working relationships with histocompatibility laboratory scientists to identify the risk of long-term graft failure, which may assist in establishing strategies for treatment and surveillance. Transplant immunology research also focuses on optimizing human leukocyte antibody tissue typing and defines the most effective test for detecting the presence of donor-specific antibodies. Although several studies have been conducted, data on pediatric heart transplant recipients are limited. Epitope load information may be utilized to identify donors with permissible human leukocyte antibody mismatches to increase transplant success. Although current guidelines do not consider human leukocyte antibody epitope-based matching tools, these guidelines could be useful for identifying recipients at a high risk of donor-specific antibody production, which would be appropriate for routine donor-specific antibody screening to initiate early interventions to prevent antibody-mediated rejection. Human leukocyte antibody matching at the epitope level offers an effective approach for identifying acceptable mismatches in sensitized patients and provides information about epitope loads. In the future, eplet matching may be used to define the best immunosuppressive therapy protocol for cardiothoracic organ transplantation. This report provides an overview of the role of human leukocyte antibodies in heart and lung transplantation.

Hormonal imbalance in patients with chronic kidney disease in the pre-dialysis and dialysis periods (part 2)

In the previous article, we presented the results of literature review showing the changes in hormone concentrations (parathyroid hormone, insulin, growth factor, prolactin) in patients with chronic renal failure (CRF) at the pre-dialysis and dialysis stages, described pathological relationships between renal failure and serum hormones concentrations, as well as changes in their biological effects. In this article, that continues the general topic, we provide the results of literature review that shows changes in serum concentrations of thyroid, adrenal, sex hormones and the features of the functioning of hypothalamus-pituitary-peripheral glands axis in patients with CRF. The presence of close pathogenic interactions of renal functional condition with hormonal activity of the thyroid gland was evaluated, as well as the ability of thyroid gland to influence the CRF progression both during pre-dialysis and dialysis sta­ges of CRF. Most patients with CRF have low serum triiodothyronine and thyroxine levels. It means that CRF is a pathological condition associated with thyroid hypofunction that progressively worsening as glomerular filtration rate decreases. For patients receiving dialysis treatment, hypothyroidism is associated with higher mortality. Secondary adrenal insufficiency is usually progresses in patients on renal replacement therapy. Non-diagnosed chronic adrenal failure may be life-threating that’s why the analysis of adrenal function is especially actual for patients on both pre-­dialysis and dialysis stages of CRF. Secondary adrenal insufficiency caused by long-lasting treatment with corticoids is a diagnostic problem for patients on dialysis treatment, because many nephrological diseases are treated by corticoids, and immunosuppressive therapy protocols used after the kidney transplantation are usually include prednisone. As the endocrine dysfunction progresses in patients with CRF, sexual dysfunction develops due to sex hormone imbalance. Abnormal androgen concentration is a typical fin­ding in CRF. A negative correlation was found between endogenic testosterone concentration and CRF stages I–V that indicated an abnormal profile of male sex hormones. There are gender-specific features of the development and progression of clinical symptoms of hormonal imbalance. The number of experimental studies show that continuous estradiol treatment may prevent the development of glomerulosclerosis. The results of clinical trials concluded that lower CRF progression and the lower incidence of CRF observed in young females compared to males, as well as the absence of gender protection in post-menopausal period, shows the important role of female sex hormones.

P8.123: A Retrospective Comparison of ABO Incompatible With ABO Compatible and Cadaveric Renal Transplant: Single Centre Experience

Introduction: ABO incompatibility was a major barrier in kidney transplantation. Advances in immunosuppressive therapy and desensitization protocol have made ABO incompatible transplants safe and effective. The present study is a retrospective comparison of ABO incompatible with ABO compatible and Cadaveric renal transplant in single centre. Method: The study includes 7 ABO incompatible, 14 similar age and HLA matched ABO compatible and 7 cadaveric kidney transplant recipients. All ABO incompatible recipients underwent desensitization with Rituximab and plasmapheresis with IVIg. Their outcomes at 6 months in terms of eGFR calculated by MDRD formula, incidence of rejection and infection as well as graft survival and patient survival were compared. Result: The outcome in terms of eGFR at 6 months was equivalent in ABO compatible (66.90ml/min/1.73m2) and ABO incompatible (60.42ml/min/m2) group and was significantly lower in the cadaveric group (45.32ml/min/m2). The incidence of infection at 6 months was equal in ABO incompatible (28.5%) and ABO compatible group (28.5%) and it was significantly higher in cadaveric transplant groups (42.85%). There was one incidence of acute rejection and one graft loss in cadaveric transplant group whereas no rejection and graft loss in ABO compatible and ABO incompatible transplant group. All three groups had 100% patient survival. Conclusion: The graft function, risk of infection and graft survival at 6 months in ABO incompatible transplant is non inferior to ABO compatible transplant and is superior to Cadaver transplant. ABO incompatible transplant also circumvents the waiting period on dialysis and mortality and morbidity associated with it.

Acquired severe aplastic anaemia: how medical therapy evolved in the 20th and 21st centuries.

The progress in aplastic anaemia (AA) management is one of success. Once an obscure entity resulting in death in most affected can now be successfully treated with either haematopoietic stem cell transplantation (HSCT) or immunosuppressive therapy (IST). The mechanisms that underly the diminution of haematopoietic stem cells (HSCs) are now better elucidated, and include genetics and immunological alterations. Advances in supportive care with better antimicrobials, safer blood products and iron chelation have greatly impacted AA outcomes. Working somewhat 'mysteriously', anti-thymocyte globulin (ATG) forms the base for both HSCT and IST protocols. Efforts to augment immunosuppression potency have not, unfortunately, led to better outcomes. Stimulating HSCs, an often-sought approach, has not been effective historically. The thrombopoietin receptor agonists (Tpo-RA) have been effective in stimulating early HSCs in AA despite the high endogenous Tpo levels. Dosing, timing and best combinations with Tpo-RAs are being defined to improve HSCs expansion in AA with minimal added toxicity. The more comprehensive access and advances in HSCT and IST protocols are likely to benefit AA patients worldwide. The focus of this review will be on the medical treatment advances in AA.

Comparison of serum monocide chemoattractant protein levels with immunosuppressive therapy protocols in patients with renal transplantation.

Renal transplantation stands out with lower cost advantages in life expectancy, quality of life and especially in the long-term perspective compared to dialysis. Having significant side effects of immunosuppressive drugs in terms of patient and graft survival limits the use of these drugs. A variety of markers are being explored to prolong the renal graft life. One of these molecules, monocide chemoattractant protein (MCP-1) is a marker involved in renal inflammation. The production of MCP-1 was blocked in kidney diseases and the disease was improved. Along with these promising developments, we decided to investigate whether there is a significant relationship between immunosuppressive therapies used in renal transplantation therapy and serum MCP-1 levels. Our study was performed in 80 patients who underwent kidney transplantation followed in Haydarpaşa Numune Training and Research Hospital. These 80 patients were examined in 4 groups as Group 1 (cyclosporin), Group 2 (tacrolimus), Group 3 (sirolimus) and Group 4 (everolimus). Serum MCP-1 levels were compared between the groups by using ELISA method. In our study, serum MCP-1 levels were significantly higher in cyclosporine and tacrolimus groups than in sirolimus (p<0.05). When calcineurin inhibitors and everolimus were compared, it was not statistically significant, although calcineurin inhibitors were higher. Understanding the role of MCP-1 in monocyte homeostasis and the effects of MCP-1 inhibition in kidney disease will help to design better diagnostic and treatment strategies in patients with inflammatory kidney disease (Tab. 2, Fig. 7, Ref. 45).

Comparative analysis of induction immunosuppressive therapy protocols in renal transplant recipients (retrospective review)

Objective: to evaluate the clinical efficacy and outcomes of kidney transplants performed using an alternative immunosuppressive therapy protocol that is based on double induction. Materials and methods. We examined 296 cases of kidney transplants performed in 295 patients between January 1, 2004 and December 31, 2018. Based on induction immunosuppressive therapy regimen, the patients were divided into two groups. Group 1 included patients who underwent transplantation from January 1, 2004 to June 30, 2013 and who used the standard induction immunosuppression protocol. Group 2 included patients who did transplant surgeries between the period January 7, 2013 and December 31, 2018 and who received the “double” induction protocol being analyzed. The method of dividing patients into these groups is associated with routine implementation of the analyzed protocol at the transplantation center since July 1, 2013. Results. Graft and recipient survival rates at all follow-up periods were higher in the group of patients who received the “double” induction immunosuppressive protocol than in the standard group. The studied protocol provides initially better and more stable graft function than in standard therapy. This is especially valuable in centers experiencing difficulties in assessing pre-transplant immunological risk. The graft and recipient survival rates achieved by the analyzed protocol are more pronounced in deceaseddonor kidney transplantation. Conclusion. Positive results obtained from retrospective analysis of the protocol under study justify a prospective randomized study.

P0327SUCCESSFUL ACHIEVMENT OF LONG-TERM COMPLETE REMISSION OF LUPUS NEPHRITIS IN A PATIENT WITH SEVERE SYSTEMIC LUPUS ERYTHEMATOSUS AND SECONDARY INFECTIOUS COMPLICATOINS

Abstract Background and Aims A significant contribution to the structure of mortality in SLE is made by infectious complications, which complicate the course of SLE and complicate the management of patients due to the impossibility of prescribing immunosuppressive therapy in full. Method A clinical case of successful achievement of LN remission in a patient with severe SLE and secondary APS is described, despite the development of secondary infectious complications and the inability to fully immunosuppressive therapy. Results A 42-year-old woman has been observed at the clinic from autumn 2013 to the present. Since the end of Aug.2013 she got a severe dyspnea, generalized edema, ulcers of the legs, blood pressure persistently increased to 180/110 mm Hg, diuresis decreased. Laboratory examination at admission in Oct.2013: (table 1), polyserositis, non-inclusive thrombosis of the posterior tibial vein on the left. An immunological examination: anti-dsDNA 101.6 U/L, ANA 5.2, C3 complement fragment 0.29 g/L, antibodies to beta-2-glycoprotein-1 55.7 U/ml, positive lupus anticoagulant. Intravenous methylprednisolone at a dosе of 1000 mg/day for 3 days plus high dose CYC at a dosе of 800 mg/day for 1 days was started, followed by prednisone 60 mg/day. This intravenous pulsewas repeated after 3 weeks. Renal biopsy in Nov.2013: diffuse proliferative glomerulonephritis with 7% cellular crescents, ISN/RPS class IV LN. Positive dynamics in Dec.2013 (table 1). By mid-Dec.2013, the patient had complaints of pain and limited range of motion in the right shoulder joint, the appearance of edema in this region. According to the puncture of the joint cavity, MRI, purulent arthritis of the right shoulder joint was diagnosed with the formation of intermuscular phlegmon of this area. Sepsis was diagnosed. The patient underwent emergency surgical drainage of phlegmon, followed by repeated revisions of this area. Prescribed meropenem at a dose of 3 g/day. Implementation of the complete immunosuppressive therapy protocol was impossible; a gradual decrease in the dose of prednisone per os was started. Due to the continued activity of SLE, in January 2014, a repeated intravenous pulse methylprednisolone without СYС was performed. Since Dec.2013, the patient has not received cystostatics. But despite it positive dynamics in Feb.2014 (table 1) . In Mar.2014 current treatment was hydroxychloroquine 400 mg/day, prednisone 15 mg/day, azathioprine 100 mg/twid. After 2 years of complete remission of LN in April 2016: prednisone 10 mg/day, hydroxychloroquine 400 mg/day, azathioprine 50 mg/twid. After another 2 years of complete remission of LN in 2018: prednisone 5 mg/day, hydroxychloroquine 400 mg/day. During the observation, a complete clinical and laboratory remission of SLE was noted. Laboratory examination at admission in Oct.2019: complete remission of SLE (table 1). The patient takes prednisone 5 mg/day, hydroxychloroquine 400 mg/day. The patient has limited mobility of the right shoulder joint, but complete loss of function did not occur. According to the control MRI there are the formation of aseptic necrosis of the head of the right humerus. Conclusion Infectious complications remain one of the leading causes of mortality in patients with SLE. The uniqueness of this clinical case in the successful achievement of long-term complete remission of SLE, despite the secondary infectious complications. The success of achieving long-term remission of SLE is associated with the onset of immunosuppressive therapy as soon as possible from the debut of the disease, with the conduct in the maximum allowable volumes. The morphological picture with a small % cellular crescents was also a favorable factor.

Cord blood infusion-accelerated hematopoietic recovery after combined immunosuppressive therapy with fludarabine and rabbit ATG in severe aplastic anemia.

Immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and cyclosporine A (CsA) is currently the standard treatment for patients with severe aplastic anemia (SAA) who have no suitable donor or are ineligible for allogeneic stem cell transplantation. However, the delayed hematopoietic recovery, which accounts for most early deaths, remains a key problem. Thus, we designed an IST protocol with fludarabine, rabbit ATG, and CsA followed by unrelated cord blood (UCB) infusion to study whether hematopoiesis could be accelerated. Nineteen patients were enrolled in this study. The median neutrophil recovery time was 22days and the treatment-related mortality within 3 months was 5.3%. The median platelet recovery time was 180days. Six patients had transient or sustained UCB engraftment and the median platelet recovery time of these patients was significantly shorter than those who had no UCB engraftment (46 days vs 206 days, p = 0.006). The cumulative incidence of response rate at 12months was up to 88.7% with CR rate of 72.2%. The overall survival at 2 years and 5 years was 94.7% and 78.9%, respectively. These results suggest that UCB infusion may play an important role in accelerating hematopoietic recovery in this protocol.

Перекрестная пересадка комбинированного лицевого трансплантата в эксперименте на биообъектах

Facial graft transplantation remains the operation of choice for patients with extensive tissue defects in the maxillofacial region. This study aimed to set up an experiment on biological objects, develop and test a combined facial graft cross-transplantation technique, select the anesthetic aid allowing to reduce the risks of perioperative complications, improve survivability of the subjects by reducing the duration of surgical intervention, develop a postoperative therapy and rehabilitation protocol, assess detection of an acute rejection reaction and develop the immunosuppressive therapy protocol. We conducted three series of facial graft transplantation surgeries on 26 minipigs and tested the typical component combinations and flap designs. At all stages of the experiment, we managed to have the subjects surviving for over 30 days without disrupting their vital functions. The immunosuppression procedure was developed and tested. The chosen technique allows transplanting two grafts within a single surgery on one pair.

Shoulder arthroplasty in patients with immunosuppression following solid organ transplantation

The purpose was to determine the risk and outcomes of primary shoulder arthroplasties in patients with immunosuppression who had undergone solid organ transplantation. Using a single institution's total joint registry, we reviewed 30 primary shoulder arthroplasties in 25 post-transplantation patients, including 12 total shoulder arthroplasties, 10 hemiarthroplasties, and 8 reverse shoulder arthroplasties, between 1985 and 2012. Therapy and patient variables were recorded, including immunosuppressive therapy protocols, the date of preceding solid organ transplantation, and specific medications taken in the perioperative period. We matched a cohort of control patients for age, sex, type of implant, and year of surgery at a ratio of 4:1. Two groups were compared regarding mortality risk, complications, and clinical outcomes (pain score, range of motion, and American Shoulder and Elbow Surgeons score). No periprosthetic infections occurred in the post-transplantation group at a mean follow-up of 39 months. However, the post-transplantation group showed an increased risk of periprosthetic fractures compared with the control group (hazard ratio, 8.18; 95% confidence interval, 1.22-70.98; P = .03). Despite the increase in fractures, the overall number of complications did not differ between the groups. Furthermore, postoperative shoulder function and outcome scores were not significantly different between patients who had a prior transplant and those who did not. Primary shoulder arthroplasty in patients with immunosuppression who underwent solid organ transplantation is a successful procedure to treat glenohumeral arthritis. In contrast, there may be an increased risk of periprosthetic fractures in patients with a history of a solid organ transplant.

Management of acquired aplastic anemia in children : A single center experience

Acquired aplastic anemia (AAA) is a rare and potentially life threatening disorder. We retrospectively compared the outcomes of 29 children with AAA who received immunosuppressive therapy (IST) or underwent hematopoietic stem cell transplantation (HSCT). Median age at diagnosis was 9.0 years (range, 2–18 years) and median follow-up period was 36 months (range, 3–108 months). Viral infection associated/post hepatitis AAA was in 6 patients (20.6%). According to the initial laboratory findings, 8 patients were classified as very severe AA (vSAA), 8 as severe AA (SAA), and 13 patients as transfusion-dependent moderate AA (MAA). Out of 13, 5 transfusion-dependent MAA patients progressed SAA in median one month (range, 1–5 months), another 6 MAA patients developed remission or became transfusion free during follow-up. Eight patients underwent upfront matched family donor (MFD) HSCT at median 6 months (range, 1–9 months) and achieved complete response (100%). Fifteen cycles of IST were given to 10 (34%) patients lacking MFD at median 3 months (range, 2–6 months). Fifty percent of patients had complete/partial response after IST protocol. Three patients who were unresponsive to IST, proceeded to alternative donor HSCT, in 2nd or 3rd year after the diagnosis and only 1 patient was sustained remission. Several drugs such as mycophenolatemofetil, high-dose cyclophosphamide, levamisole and eltrombopag have been investigated in order to improve the outcome of patients with AAA. Early intervention in AAA patients results in significantly better outcomes.

Preventive anterior abdominal wall repair in recipients of renal allograft

Retrospective analysis of safety and efficacy of preventive anterior abdominal wall repair in recipients of renal allograft. Kidney transplantation was performed in 396 patients with terminal renal failure within January 2015 - May 2017. Preventive endoprosthetics (PE) was applied in 28 (7.1%) patients. There were 7 women (26.9%) and 19 men (73.1%) aged 25-69 years (mean 44.5 (35, 56) years). Median of body mass index (BMI) was 27.5 (23.9, 29.9) kg/m2. Postoperative morbidity was 42.3%. Complications were mild (type I and II) and did not require invasive treatment. Postoperative morbidity was similar regardless protocol of immunosuppressive therapy (IST). Preventive abdominal wall repair after kidney transplantation is effective and safe to prevent postoperative hernia.

Correlation Between Immunosuppressive Therapy and CD4(+) T-Cell Intracellular Adenosine Triphosphate Levels in Liver Transplant Recipients.

The aim of this work was to analyze the correlation between immunosuppressive therapy and CD4(+) T-cell intracellular adenosine triphosphate (iATP) levels after liver transplantation and to describe the distribution characteristics of iATP in CD4(+) T cells among liver transplant recipients. We studied 172 patients who were followed regularly after liver transplantation with long-term stable conditions from July 2010 to October 2012. CD4(+) T-cell iATP levels were detected with the use of the Cylex Immuknow Assay method and analyzed retrospectively according to immunosuppressive therapy protocol. There was a significant difference in CD4(+) T-cell iATP level among the recipients receiving different immunosuppressive therapy protocols after liver transplantation. CD4(+) T-cell iATP level in the FK506 group and FK506+ prednisone (Pred) groups was higher than in the FK506+ mycophenolate mofetil (MMF), FK506+ MMF+ Pred, and rapamycin (Rapa) groups. CD4(+) T-cell iATP level in patients receiving an MMF protocol was lower than in the group without MMF. There is a relationship between distribution immunosuppressive therapy protocol and CD4(+) T-cell iATP level after liver transplantation. MMF and Rapa lower the CD4(+) T-cell iATP level significantly.

ACUTE TACROLIMUS-INDUCED KIDNEY INSUFFICIENCY IN PATIENT AFTER HEART TRANSPLANTATION

In recent years the success of transplantation is associated primarily with extensive use of calcineurin inhibitors (CNIs) – cyclosporine and tacrolimus which became the basis of the various immunosuppressive therapy protocols. These drugs despite their effectiveness in the prevention of transplant rejection have serious side effects. Nephrosclerosis due to chronic nephrotoxic effect is recognized as the most important of them. But along with chronic nephrotoxic effects there are cases of acute kidney injury on the background of calcineurin inhibitors usage. The article presents a clinical case demonstrating the development of severe reversible nephropathy in a patient after heart transplantation receiving tacrolimus in standard dose.

Long-Term Efficacy of the Combined Immunosuppressive Therapy (IST): Cyclosporine with/without Splenectomy - in Patients with Different Forms of Myelodysplastic Syndromes

IntroductionThe majority of clinical recommendations on MDS indicate the use of IST for low-risk hypoplastic MDS patients. ATG followed by cyclosporine A (CSA) is recommended for younger pts with normal karyotype or with +8, CSA - for older patients with autoimmune phenomenon or hypoplastic bone marrow. There are no reports on the use of CSA with splenectomy as a combined IST for MDS patients. Here we report the long term (20 years) results of the single center trial comprising 61 MDS pts treated with CSA as the first or the second line treatment + splenectomy.Patients and methods. Since 1995 till June 2015, 61 patients were included in the combined IST protocol. There were 34 males, 27 females; median age constituted 39 years (16-74), refractory cytopenias with multileaneage dysplasia = 46, RAEB1/2 = 15; IPSS - low-risk= 4, intermediate 1 =40, intermediate-2 =9, high =4; no risk evaluation - 4 patients. All patients had trepanobiopsy evaluation, half of them - bilateral. It worth to note that bilateral trepanobiopsy permitted to redefine cellularity in 15% of patients. Pure hypoplastic forms of MDS were registered in 38 patients (63%), combination of hypoplasia with hyperplasia or normal cellularity - in 10 (16%), hyperplastic forms - in 13 (21%); non-clonal lymphoid nodules in b/m were detected in 29 pts (46%); fibrosis - in 7. Cytogenetics was done in 57 pts, 32 had normal karyotype; 5 had trisomy 8; 8 - high risk cytogenetics (-7/7q-, complex); 8 - different intermediate.Cyclosporine A was applied at a dose 5 mg/kg per day, followed by reevaluation of response at 2-3 months. In case of response CSA was continued, if there was no response or it was inadequate - splenectomy was done followed again by CSA; if progression occurred - CSA was stopped. We consider splenectomy as a component of the programmed IST as it leads to removement of a big lymphoid organ. For younger patients ATG for 20 mg/kg for 5 days could become the 2nd or the 3rd line of treatment. For patients with sibling donors allogeneic HSCT was an option.Analysis was carried out in June 2015. The patients were grouped for analysis according to cellularity (hypo vs hyper, in case of combination hypo with hyper/normal the case was considered as hypocellular), % of b/m blast cells (<> 5%), IPSS index (low/int-1 vs int-2/high), cytogenetics, the presence of lymphoid nodules.Results. CSA was started as the 1st line treatment in 42 patients, as the second line (after ATG or splenectomy or ESA) - in 20. 5 patients were transplanted from sibling donors. 35 patients received CSA as monotherapy (16 of them had a progression or a transformation to AML). Totally splenectomy was performed in 20 patients, in 8 patients it was followed by additional immunosuppression with ATG (9 patients) or MMF (1 patient). Splenectomy was performed by laparoscopy, no deaths or sever complications were noted. Half of the splenectomized patients achieved sustained response after operation and continuation of CSA. On the whole 18 patients had progression to RAEB or transformation to AML (1 from low-risk group, 7 - int1, 6 - int2, 5 - from high risk). Complete remission was achieved in 15 patients (24%), with overall response rate of 56% (n=34) with a median duration of response - 21 months (1-230 mo).The 20-years survival data revealed highly statistical difference between hypoplastic forms of MDS vs hyperplastic (38% vs 0%), bone marrow blast cells less vs more than 5% (43% vs 5%), IPSS categories low/int1 vs int2/high (50% vs 0%), cytogenetics favorable vs intermediate vs high (62% vs 35% vs 0%) (Pic.1). No differences were detected in patients with or without lymphoid nodules in b/m (38% vs 35%).ConclusionsOur small but prolonged study has demonstrated a substantial long-term efficacy of the combined IST. CSA followed by splenectomy is a reasonable treatment approach in MDS patients with hypoplastic features in bone marrow, normal or intermediate karyotype, low blast cell count, low/int1 IPSS score.Pic.1 Overall survival of MDS patients treated with combined IST depending on cellularity, blast cells count, cytogenetic features and IPSS score. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

THE FIRST EXPERIENCE OF KIDNEY TRANSPLANTАTION IN THE CLINICAL HOSPITAL OF ALMATY

Aim:To estimate results of kidney transplantation in city clinical hospital No. 7 of Almaty.Materials and methods. 100 patients who underwent kidney transplantation in our institution were analyzed; males – 54 (54%), females – 46 (46%), aged from 14 till 58 years old (39 ± 10.3). In 91 cases hand – assisted laparoscopic nephrectomy (HALN) was performed and in 3 cases – open method (2 with mini-lumbotomic and 1 with pararectal access) was used.Results. The survival rate was 98% (98 patients). The causes of death were the nonfunctioning transplant due to noncompliance of immunosuppression, post traumatic septic complications, multiple organ failure. The most frequent complications were hematoma (12%), acute rejection (8%), and tubular necrosis (2%). Less aggressive schemes of immunosuppressive therapy allow reducing risk of drug toxic impact on the patient's organism and, thus, can extend functioning of a transplant.Conclusion.Kidney transplantation is an effective treatment method of end stage renal diseases. The use of modern immunosuppressive therapy protocols and adequate immunological selection of donor – recipient provide high survival of transplants. Operative treatment and further case management of this group of patients are possible in highly specialized medical hospital.

Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry cohort.

Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome. Since August of 2009, clinical, biochemical, genetic, and histopathologic information was collected both retrospectively and prospectively from 1655 patients with childhood-onset steroid-resistant nephrotic syndrome, congenital nephrotic syndrome, or persistent subnephrotic proteinuria of likely genetic origin at 67 centers in 21 countries through an online portal. Steroid-resistant nephrotic syndrome manifested in the first 5 years of life in 64% of the patients. Congenital nephrotic syndrome accounted for 6% of all patients. Extrarenal abnormalities were reported in 17% of patients. The most common histopathologic diagnoses were FSGS (56%), minimal change nephropathy (21%), and mesangioproliferative GN (12%). Mutation screening was performed in 1174 patients, and a genetic disease cause was identified in 23.6% of the screened patients. Among 14 genes with reported mutations, abnormalities in NPHS2 (n=138), WT1 (n=48), and NPHS1 (n=41) were most commonly identified. The proportion of patients with a genetic disease cause decreased with increasing manifestation age: from 66% in congenital nephrotic syndrome to 15%-16% in schoolchildren and adolescents. Among various intensified immunosuppressive therapy protocols, calcineurin inhibitors and rituximab yielded consistently high response rates, with 40%-45% of patients achieving complete remission. Confirmation of a genetic diagnosis but not the histopathologic disease type was strongly predictive of intensified immunosuppressive therapy responsiveness. Post-transplant disease recurrence was noted in 25.8% of patients without compared with 4.5% (n=4) of patients with a genetic diagnosis. The PodoNet cohort may serve as a source of reference for future clinical and genetic research in this rare but significant kidney disease.

Current State of Immunosuppression: Past, Present, and Future.

The success of solid-organ transplantation was made possible by recognizing that destruction of the graft is caused by an alloimmune-mediated process. For the past decade, immunosuppressive protocols have used a combination of drugs that significantly decreased the rate of acute organ rejection. Despite advances in surgical and medical care of recipients of solid-organ transplants, long-term graft survival and patient survival have not improved during the past 2 decades. Current immunosuppression protocols include a combination of calcineurin inhibitors, such as tacrolimus, and antiproliferative agents (most commonly mycophenolate mofetil), with or without different dosing regimens of corticosteroids. Mammalian target of rapamycin inhibitors were introduced to be used in combination with cyclosporine-based therapy, but they did not gain much acceptance because of their adverse event profile. Belatacept, a costimulatory inhibitor, is currently being studied in different regimens in an effort to replace the use of calcineurin inhibitors to induce tolerance and to improve long-term outcomes. Induction therapy is now being used in more than 90% of kidney transplants and more than 50% cases of other solid-organ transplantation such as lung, heart, and intestinal transplants. As a result of these combination immunosuppressive (IS) therapy protocols, not only the incidence but also the intensity of episodes of acute rejection have decreased markedly, and at present 1-year graft and patient survival is almost 98% for kidney transplant recipients and approximately greater than 80% for heart and lung transplants. Evolving concepts include the use of donor-derived bone marrow mesenchymal cells to induce tolerance, to minimize the use of maintenance IS agents, and to prevent the development of adverse events associated with long-term use of maintenance IS therapy.

Aplastic anemia: therapeutic updates in immunosuppression and transplantation

Abstract Advances in hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) have improved survival in severe aplastic anemia (SAA) from 10%-20% in the 1960s to 80%-90% today. A matched sibling HSCT is the treatment of choice in younger patients, whereas IST is often used in older patients or in those who lack a histocompatible sibling. Graft rejection, GVHD, and poor immune reconstitution (with associated infectious complications) limit the success of HSCT, whereas lack of response, relapse, and clonal evolution limit the success of IST. The historically high rate of graft rejection in SAA is now less problematic in the matched setting, but with greater rates observed with unrelated and umbilical cord donors. The correlation of increasing age with the risk of GVHD and the significant morbidity and mortality of this transplantation complication continue to affect the decision to pursue HSCT versus IST as initial therapy in adults with SAA. Outcomes with matched unrelated donor HSCT have improved, likely due to better donor selection, supportive care, and improved transplantation protocols. Results with mismatched unrelated donor and umbilical HSCT are not as favorable, with higher rates of graft rejection, GVHD, and infectious complications. Investigation of several upfront alternative IST protocols has not improved outcomes beyond horse antithymocyte globulin and cyclosporine. More recently, the role of alemtuzumab in SAA has been better defined and an oral thrombomimetic, eltrombopag, is showing promising activity in refractory cases. The most recent advances in HSCT and IST in SAA are discussed in this review.