Immunosuppressive Monotherapy Research Articles

Relative carcinogenicity of tacrolimus vs mycophenolate after solid organ transplantation and its implications for liver transplant care.

De novo malignancy is a leading cause of late morbidity and mortality in liver transplant recipients. Cumulative immunosuppression has been shown to contribute to post-transplant malignancy (PTM) risk. There is emerging evidence on the differential carcinogenic risk profile of individual immunosuppressive drugs, independent of the net effect of immunosuppression. Calcineurin inhibitors such as tacrolimus may promote tumourigenesis, whereas mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil, may limit tumour progression. Liver transplantation (LT) is relatively unique among solid organ transplantation in that immunosuppression monotherapy with either tacrolimus or MPA is often achievable, which makes careful consideration of the risk-benefit profile of these immunosuppression agents particularly relevant for this cohort. However, there is limited clinical data on this subject in both LT and other solid organ transplant recipients. To investigate the relative carcinogenicity of tacrolimus and MPA in solid organ transplantation. A literature search was conducted using MEDLINE and Embase databases using the key terms "solid organ transplantation", "tacrolimus", "mycophenolic acid", and "carcinogenicity", in order to identify relevant articles published in English between 1st January 2002 to 11th August 2022. Related terms, synonyms and explosion of MeSH terms, Boolean operators and truncations were also utilised in the search. Reference lists of retrieved articles were also reviewed to identify any additional articles. Excluding duplicates, abstracts from 1230 records were screened by a single reviewer, whereby 31 records were reviewed in detail. Full-text articles were assessed for eligibility based on pre-specified inclusion and exclusion criteria. A total of 6 studies were included in this review. All studies were large population registries or cohort studies, which varied in transplant era, type of organ transplanted and immunosuppression protocol used. Overall, there was no clear difference demonstrated between tacrolimus and MPA in de novo PTM risk following solid organ transplantation. Furthermore, no study provided a direct comparison of carcinogenic risk between tacrolimus and MPA monotherapy in solid organ transplantation recipients. The contrasting carcinogenic risk profiles of tacrolimus and MPA demonstrated in previous experimental studies, and its application in solid organ transplantation, is yet to be confirmed in clinical studies. Thus, the optimal choice of immunosuppression drug to use as maintenance monotherapy in LT recipients is not supported by a strong evidence base and remains unclear.

Safety and Immunogenicity of Live Viral Vaccines in a Multicenter Cohort of Pediatric Transplant Recipients

Live vaccines (measles-mumps-rubella [MMR] and varicella-zoster virus [VZV]) have not been recommended after solid organ transplant due to concern for inciting vaccine strain infection in an immunocompromised host. However, the rates of measles, mumps, and varicella are rising nationally and internationally, leaving susceptible immunocompromised children at risk for life-threating conditions. To determine the safety and immunogenicity of live vaccines in pediatric liver and kidney transplant recipients. This cohort study included select pediatric liver and kidney transplant recipients who had not completed their primary MMR and VZV vaccine series and/or who displayed nonprotective serum antibody levels at enrollment between January 1, 2002, and February 28, 2023. Eligibility for live vaccine was determined by individual US pediatric solid organ transplant center protocols. Exposure was defined as receipt of a posttransplant live vaccine. Transplant recipients received 1 to 3 doses of MMR vaccine and/or 1 to 3 doses of VZV vaccine. Safety data were collected following each vaccination, and antibody levels were obtained at 0 to 3 months and 1 year following vaccination. Comparisons were performed using Mann-Whitney U test, and factors associated with development of postvaccination protective antibodies were explored using univariate analysis. The cohort included 281 children (270 [96%] liver, 9 [3%] kidney, 2 [1%] liver-kidney recipients) from 18 centers. The median time from transplant to enrollment was 6.3 years (IQR, 3.4-11.1 years). The median age at first posttransplant vaccine was 8.9 years (IQR, 4.7-13.8 years). A total of 202 of 275 (73%) children were receiving low-level monotherapy immunosuppression at the time of vaccination. The majority of children developed protective antibodies following vaccination (107 of 149 [72%] varicella, 130 of 152 [86%] measles, 100 of 120 [83%] mumps, and 124 of 125 [99%] rubella). One year post vaccination, the majority of children who initially mounted protective antibodies maintained this protection (34 of 44 [77%] varicella, 45 of 49 [92%] measles, 35 of 42 [83%] mumps, 51 of 54 [94%] rubella). Five children developed clinical varicella, all of which resolved within 1 week. There were no cases of measles or rubella and no episodes of graft rejection within 1 month of vaccination. There was no association between antibody response and immunosuppression level at the time of vaccination. The findings suggest that live vaccinations may be safe and immunogenic after solid organ transplant in select pediatric recipients and can offer protection against circulating measles, mumps, and varicella.

Remarkable 107-year-old kidney with a 49-year of long-term allograph survival through continuous azathioprine monotherapy

BackgroundThe main goal of kidney allograft transplantation is to improve survival in patients with end-stage kidney failure. Herein, we report a 49-year long-term allograft survival with non-identical human leukocyte antigens (HLA). The purpose of this study was to report the successful clinical outcome of 49 years of transplant survival in a 79-year-old patient with a 107-year-old kidney undergoing continued immunosuppressive monotherapy. Material and methodsThe patient was evaluated clinically and immunologically with HLA typing and anti-HLA antibodies before transplantation. Post-transplant, the patient's clinical and immunological survival were monitored for 49 years. The state of the chimerism was assessed using the polymerase chain reaction to amplify 24 short tandem repeats using a DNA thermocycler and DNA analyzer. ResultsThe patient and donor were haploidentical and the patient was treated with azathioprine monotherapy. Donor-specific antibodies were detected only for the HLA-DPB1* 03:01 mismatch. This patient developed multiple skin tumors 26 years after transplant, which were successfully treated with topical therapy or surgical removal. The patient developed an intestinal adenocarcinoma 43 years after kidney transplantation, which was surgically removal; six years later, adenocarcinoma was diagnosed in a finger, followed by axillar and hepatic metastases. After 49 years of graft survival of a kidney of 107 years old in a patient with 79 years of age, the patient's health worsened with severe dehydration, anemia, and bacterial infection. The patient was hospitalized with a serum creatinine level of 3.45 mg/dL, urea level of 188 mg/dL, and estimated glomerular filtration rate of 22 mL/1.72 m2; septicemia developed and was treated with antibiotics. The patient had poor clinical progress, was intubated, and later died due to septic shock. ConclusionsTo the best of our knowledge, this is the first case of a 107-year-old kidney, transplanted into a recipient who was treated with azathioprine monotherapy for 49 years.

Immunosuppression after pediatric liver transplant: The parents' perspective.

For children with liver transplants (LT), achieving an "ideal outcome" is a balancing act: too little immunosuppression begets graft injury; too much begets systemic complications. We aimed to delineate the parental perspective on this tightrope. Parents of children with LT completed an internet-based survey about their child's immunosuppression. Children of respondents (n=82) were a median 4 years from primary LT (range 0-22); 73% were on immunosuppression monotherapy. Parents' top concerns were related to immunosuppression complications; 46% were more concerned about immunosuppression complications than rejection; only 17% were more concerned about rejection than immunosuppression complications. Among parents of children on immunosuppression monotherapy, 29% still worried more about immunosuppression complications than rejection, 48% expressed equal concern for both. Time since LT (0-4vs.>4 years) was not associated with concern level for rejection or immunosuppression complications. Caregivers were significantly more certain that their child's immunosuppression regimen was correct to prevent rejection than to mitigate complications (p<.005). Caregivers of children with LTs reported higher levels of concern and uncertainty about immunosuppression complications than rejection risk. Understanding parent and patient perspectives on IS, and incorporating them into immunosuppression counseling and decision-making, is critical to achieving truly "ideal" long-term outcomes.

Immunogenicity and 1-year boostability of a three-dose intramuscular rabies pre-exposure prophylaxis schedule in adults receiving immunosuppressive monotherapy: a prospective single-centre clinical trial.

For immunocompromised patients (ICPs), administration of rabies immunoglobulins (RIG) after exposure is still recommended regardless of prior vaccination, due to a lack of data. We aimed to assess the 1-year boostability of a three-dose rabies pre-exposure prophylaxis (PrEP) schedule in individuals using immunosuppressive monotherapy. In this prospective study, individuals on immunosuppressive monotherapy with a conventional immunomodulator (cIM) or a TNF-alpha inhibitor (TNFi) for a chronic inflammatory disease received a three-dose intramuscular PrEP schedule (days 0,7,21-28) with 1mL Rabipur®, followed by a two-dose simulated post-exposure prophylaxis (PEP) schedule (days 0,3) after 12months. Rabies neutralizing antibodies were assessed at baseline, on day 21-28 (before the third PrEP dose), day 60, month 12 and month 12 + 7days. The primary outcome was 1-year boostability, defined as the proportion of patients with a neutralizing antibody titre of ≥ 0.5IU/mL at month 12 + 7days. Secondary outcomes were geometric mean titres (GMTs) and factors associated with the primary endpoint. We included 56 individuals, of whom 52 completed the study. The 1-year boostability was 90% (47/52) with a GMT of 6.16 (95% CI 3.83-9.91). All participants seroconverted at some point in the study. Early response to PrEP (at day 21-28) was significantly associated with 100% boostability (Odds Ratio 51; 95% confidence interval [5.0-6956], P < 0.01). The vaccination schedule was safe and well tolerated. No vaccine-related serious adverse events occurred. In patients using immunosuppressive monotherapy, a three-dose rabies PrEP schedule followed by a two-dose PEP schedule is immunogenic, with all patients seroconverting at some point in the study. Although boostability 7days after PEP was not 100%, nobody would wrongly be denied RIG when only administered to those who responded early to PrEP while reducing the administration of RIG by 73%.

Naïve T Cell-Depleted Hematopoietic Graft Combined with Solid Organ Transplantation As Strategy to Induce Tolerance By Transient Mixed Chimerism

BACKGROUND The major challenge of solid organ transplantation (SOT) is to prevent graft rejection. The chronic use of pharmacological immunosuppression has been associated with increased rates of infection, cardiovascular, metabolic, endocrine disorders, and cancer. The induction of chimerism by donor hematopoietic stem cell transplantation (HSCT) together with SOT is an active tolerance induction approach. Here, we present a new model for inducing transient mixed chimerism in 2 patients undergoing SOT employing a non-myeloablative conditioning (NMA) regimen and a partially T cell-depleted (TCD) graft consisting of CD34+ hematopoietic progenitor cells and CD45RA− memory lymphocytes. METHODS SOT and HSCT were performed at University Hospital La Paz, Madrid. Bone marrow harvesting was performed on the iliac crest and lumbar and dorsal vertebrae of the deceased donor for patient#1 and mobilized leukoapheresis from sibling donor for patient#2. First we obtained the enriched by CD34+ selection using the CliniMACS system (Miltenyi Biotec) and afterwards the CD45RA− cells were purified. Lineage-specific chimerism analysis was analyzed using quantitative real-time polymerase chain reaction. Immune cell recovery was monitored by multiparametric flow cytometry. We obtained the permission of the Organización Nacional de Trasplantes and the informed consent was obtained from the patient and donor and/or caregivers. RESULTSPatient 1 A 15-year-old boy was diagnosed with intestinal epithelial dysplasia in 2008. After two previous intestinal and multivisceral acute cellular rejections forced a third MVT. With the imptemption to induce donor tolerance, a T cell-depleted bone marrow graft from the same deceased donor was employed. Bone marrow harvesting was performed obtaining a total volume of 141 ml with 4x109 total nucleated cells. Peripheral blood was obtained after unclasping the thoracic aorta. The stem cell fraction from bone marrow was enriched by CD34+ selection, obtaining 8.75x105/kg CD34+cells/kg. Memory lymphocytes were purified and aliquots containing 1x106/kg CD3+CD45RO+ and 2.1x104/kg CD3+CD45RA+ T cells. Both products were cryopreserved. The conditioning regimen before HSCT included fludarabine and cyclophosphamide. On day 88 after MVT, we infused all the CD34+ cells and 1x106/Kg CD3+CD45RO+ T cells. The CD3+CD45RO+ T cells were also infused periodically on a monthly basis for 1 year. Donor chimerism in CD3+ T cells ranged from 0.05 to 5.1 during the first year after HSCT. We observed a peak of the percentage of regulatory T cells (Tregs). No degree of graft-versus-host disease (GvHD) was observed, and the patient became independent of total parenteral and enteral nutrition. Serial follow-up intestinal biopsies did not show any sign of immune rejection. The patient continued to receive sirolimus to maintain drug concentrations at 6 ng/ml as the only immunosuppression treatment. No signs of rejection were detected after 27 months of follow-up. Patient 2 A 49-year-old woman was diagnosed with chronic kidney failure secondary to rapidly progressive glomerulonephritis. The patient had received 3 previous kidney transplants from deceased donors. A kidney transplant from her sibling was performed in March 2021. Hematopoietic progenitor cells were obtained from mobilized peripheral blood leukapheresis. A NMA conditioning regimen employing total lymphoid irradiation (8 Gy) with antithymocyte globulin (7.5 mg/kg). Two weeks after the kidney transplantation, we infused a graft consisting of 1.27x107/kg CD34+, 4.43x106/kg CD3+CD45RO+, and 5x104/kg CD3+CD45RA+ cells. Controls for hematopoietic chimerism demonstrated the presence of transient mixed hematopoietic chimerism during the first 2 months after SOT of between 0.1% and 40% CD3+ cells. The patient continued on monotherapy with tacrolimus. Immune reconstitution analysis showed a Treg peak. The patient did not have acute rejection, GvHD, viral reactivations or episodes of bacterial infection during the 17 months of follow-up. CONCLUSIONS We describe for the first time the use of non-myeloablative conditioning and a CD45RA− T cell-depleted graft to induce transitory mixed chimerism using both hematopoietic progenitors and a solid organ coming from the same donor, for tolerance induction purposes. The patients continue to progress favorably 17 months or more after SOT, receiving immunosuppressive monotherapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P2.13: Immunosuppression Monotherapy Does Not Protect Donor Leukocytes From Depletion Post MHC-Mismatched Kidney Transplantation in Mice

Background: The retention of donor tissue-resident leukocytes within a transplanted organ is likely to be important to graft health and survival post-transplantation. We have previously shown that in the absence of immunosuppression, donor tissue-resident leukocytes are depleted following MHC-mismatched transplants, due to infiltrating recipient effector leukocytes. We hypothesised, therefore, that the retention of donor leukocytes described following mismatched transplants in humans is a result of immunosuppressive therapy, which targets recipient effector cells. In this study, we investigated the impact of different immunosuppressive agents as monotherapies on the retention of donor leukocytes after MHC-mismatched transplantation. Methods: We developed immunosuppression regimens using clinically-relevant levels of immunosuppressive medications including tacrolimus and mycophenolate, and treated mice receiving MHC-mismatched kidney transplants. At seven days post-transplant, we compared the donor leukocyte retention and recipient leukocyte responses of mice on immunosuppression to those without. Results: As expected after immunosuppression treatment, the circulating lymphocyte count was decreased. Simultaneously, the absolute number and proliferation of recipient lymphocytes within the graft and peripheral organs were reduced in comparison to immunocompetent controls. Immunosuppression also altered macrophage polarisation within the graft, to a less pro-inflammatory phenotype. Interestingly, our preliminary data showed that despite the decrease in recipient leukocyte infiltration, and a less inflammatory microenvironment within the graft, treatment with a single immunosuppressive agent did not improve donor leukocyte retention post-transplantation. Conclusions: This highlights the requirement for the use of multiple immunosuppressive agents to sufficiently suppress recipient effector leukocyte responses, not only for graft tolerance but for donor leukocyte retention. Hackett Postgraduate Research Scholarship. Australian Government Research Training Program Scholarship. Sir Charles Gairdner and Osborne Park Health Care Group RAC Grant (MRGP21-22_24).

215.9: Achievement of Persistent Mixed Chimerism in Recipients of Matched and Mismatched Living Donor Kidney Transplants in a Tolerance Induction Protocol

Purpose: The induction of tolerance to kidney transplants after development of specific unresponsiveness of recipient immune cells to donor alloantigens allows elimination of maintenance immunosuppressive (IS) drugs while preventing graft loss due to rejection. We have previously reported successful induction of mixed chimerism and tolerance in recipients of fully HLA-matched living donor kidney and hematopoietic cell (HCT) transplants. This work continues in HLA-mismatched transplants, wherein achieving persistent mixed chimerism is more challenging. Methods: Living donors underwent hematopoietic stem cell mobilization and leukopheresis 6 weeks before kidney donation. The recipient conditioning regimen for the HCT consisted of 10 doses of total lymphoid irradiation (TLI) and 5 doses of anti-thymocyte globulin (ATG) following kidney transplant, with HCT on day 11. The HCT consisted of CD34+ hematopoietic progenitor cells and CD3+ cells. Twenty-nine patients received fully HLA-matched living donor transplants. Twenty-five patients received HLA-mismatched (1-haplotype matched) living donor transplants with an escalating dose of CD3+ cells to enhance HCT engraftment. Six patients recently received HLA-mismatched living donor transplants with substitution of a dose of total body irradiation (TBI) for the final dose of TLI. Results: Of the 29 fully HLA-matched living donor transplants, complete IS drug withdrawal was achieved in 24, all of whom had at least 6 months of persistent mixed chimerism. Of the 24, 17 are alive, well and have been off IS drugs from 4 to 14 years without evidence of rejection. Two off IS drugs died due to cardiovascular events at 2 and 3 years. Two returned to IS drugs after loss of chimerism at 1 year followed by acute rejection at 4 years off IS drugs, and 3 after relapse of kidney disease at 1, 5 and 6 years off IS drugs. In the 25 1-haplotype matched living donor transplants, mixed whole blood chimerism persisted in 10 (mean 20% chimerism) at the end of the 1st year posttransplant while immunosuppression was reduced to tacrolimus monotherapy. Chimerism was lost during the 2nd year in the 5 who were withdrawn from monotherapy; they returned to IS drug(s). Mixed chimerism without rejection has persisted in 3 maintained on IS monotherapy, for up to 5 years. The recent addition of a dose of TBI markedly increased levels and stability of mixed chimerism during the 1st year posttransplant. Conclusions: The loss of chimerism during withdrawal of IS drug monotherapy in the HLA-mismatched transplants may have been due to the low level of whole blood chimerism, a contrast to the HLA-matched. A very low single dose of TBI added to the TLI/ATG conditioning regimen increased early chimerism. The stability of high levels of mixed chimerism after complete IS drug withdrawal during the 2nd year posttransplant is the subject of continuing investigation.

Monotherapy Immunosuppression in Pediatric Heart Transplant Recipients

<h3>Purpose</h3> Although dual-drug immunosuppression is standard for rejection prophylaxis in pediatric heart transplant (HT), single-drug immunosuppression (monotherapy) may be sufficient for certain patients. We describe the experience with monotherapy at a single institution. <h3>Methods</h3> Retrospective review of HT patients at a single pediatric transplant center who underwent HT between from 1/2001- 12/2020 and were treated with calcineurin-inhibitor monotherapy for > 1 month. Patients were transitioned to monotherapy per primary clinician due to concerns for over-immune suppression or post-transplant lymphoproliferative disorder (PTLD). Clinical characteristics and patient outcomes were analyzed. <h3>Results</h3> During the study period, 12/333 (3.6%) patients were placed on monotherapy at a median of 4.6 years post-HT [IQR 1.9-6.7 years]. Ten (83%) were transplanted as infants and 6 (50%) were transplanted for congenital heart disease. Nine (75%) were on tacrolimus monotherapy and 3 were on cyclosporine monotherapy. Indication for monotherapy was serious or chronic infection in 6 (50%), PTLD in 4 (33%), and neutropenia in 2 (16%). At a median follow-up of 1.5 years [IQR 1.1-2.2 years], 2 (16%) patients experienced grade 1B/1R cellular rejection, one of which required mechanical support and was transitioned back to dual therapy immunosuppression. All patients remain alive, with the remaining 11 (91%) still on monotherapy at time of last follow-up. <h3>Conclusion</h3> Monotherapy immunosuppression with calcineurin inhibitors can be safely used in a subset of pediatric HT patients with evidence of over-immune suppression without significant increase in rejection.

Immune response to influenza and pneumococcal vaccines in adults with inflammatory bowel disease: A systematic review and meta-analysis of 1429 patients

BackgroundPatients with inflammatory bowel disease (IBD) have a high risk for infection. Pneumonia related to influenza and pneumococcal infection is one of the most common infection-related complications in IBD. AimsTo evaluate the immunogenicity of pneumococcal and influenza vaccination in patients with IBD receiving different treatments. MethodsWe searched four databases for studies evaluating seroprotection and seroconversion rates after influenza or pneumococcal vaccination in IBD on 20th October 2020. In the meta-analysis, odds ratios (OR) were calculated with 95% confidence intervals (CI). ResultsWe included twelve studies (1429 patients with IBD) in this meta-analysis. The seroconversion rate after pneumococcal vaccination and the seroprotection rate after influenza vaccination were not significantly lower in patients receiving conventional immunosuppressive treatment compared to the non-immunosuppressed patients. Meanwhile, the seroconversion rate following pneumococcal vaccine was significantly lower in patients with anti-TNF mono- or combination therapy (OR = 0.28, CI: 0.15–0.53, and OR = 0.27, CI: 0.15–0.49, respectively). In the analysis of patients with IBD on conventional immunosuppressive monotherapy versus anti-TNF therapy, the seroprotection rate after influenza immunization did not differ between patients receiving either anti-TNF mono-or combination therapy (OR = 1.45, CI: 0.62–3.38 and OR = 0.91, CI: 0.37–2.22, respectively). ConclusionOur data suggest that the immunization against Pneumococcus and influenza is safe and immunogenic despite immunosuppression.

Antibody durability 6 months after two doses of SARS-CoV-2 mRNA vaccines in patients with rheumatic and musculoskeletal disease.

Antibody durability 6 months after two doses of SARS-CoV-2 mRNA vaccines in patients with rheumatic and musculoskeletal disease.

Long-Term Outcomes of IgG4-Related Ophthalmic Disease in a Chinese IgG4-Related Disease Cohort.

Purpose: To define the treatment response and long-term outcomes of a large IgG4-related ophthalmic disease (IgG4-ROD) cohort.Methods: A total of 132 patients with a minimum follow-up of 1 year were included in this study. Demographic, clinical, and laboratory data were collected. Treatment response was assessed by the IgG4-RD responder index (IgG4-RD RI). Risk factors for relapse were analyzed with the multivariate Cox regression analysis.Results: The median follow-up time was 39 months. Lacrimal gland involvement was detected in 87.9% of cases. Extraocular muscles, the trigeminal nerve, and other soft tissue were affected in 25.8, 6.1, and 18.2% of patients. The relapse rate of watchful waiting, glucocorticoid monotherapy, immunosuppressant monotherapy, and combination therapy was 50.0, 51.7, 50.0, and 26.7% (p = 0.038), respectively. The combination therapy group exhibited shorter glucocorticoids therapy duration (36 vs. 48 months, p = 0.009) and maintenance period (24 vs. 42 months, p = 0.003). At the 6th month, the median IgG4-RD RI declined from 12 to 1 and 105 (79.5%) patients achieved complete response (CR). Relapse occurred in 49 (37.1%) patients. The multivariate Cox regression analysis exhibited that CR at the 6th month was an independent protective factor for relapse. Patients with multiple ocular lesions suffered from a higher risk of relapse. No patient had severe adverse reactions to the treatment in this study.Conclusion: Relapse was common in patients with IgG4-ROD. Patients receiving combination therapy showed a lower relapse rate and a shorter glucocorticoids therapy period. The presence of multiple ocular lesions was associated with a higher risk of relapse. CR at the 6th month might be a predictor for a better prognosis in IgG4-ROD. Thus, a more aggressive regimen should be prescribed for patients with a poor initial response.

Immunologic benefits of maternal living donor allografts in pediatric liver transplantation: fewer rejection episodes and no evidence of de novo allosensitization.

Pediatric liver transplant (LT) recipients of maternal living liver donor (LLD) grafts have been reported to experience fewer rejection episodes. However, it is unclear whether this benefit translates to reduction in developing donor-specific antibody (DSA) among maternal-LLD recipients. The aim of this study was to compare immunologic outcomes among maternal-LLD, non-maternal-LLD, and deceased donor liver transplant (DDLT) recipients. Children (≤18years) who underwent LT between 1/1998 and 12/2019 at two high-volume LT centers in North America were evaluated. Patients were divided into three groups by type of graft received (maternal-LLD, non-maternal LLD, and DDLT). Clinical variables and outcomes were compared according to each graft type. A total of 450 pediatric primary LT were analyzed: 275 (61.1%) DDLT, 73 (16.2%) maternal-LLD, and 102 (22.6%) non-maternal-LLD. Children receiving LLD grafts were less likely to develop rejection when compared to the DDLT group (DDLT 46.9% vs. maternal-LLD 31.5% vs. non-maternal-LLD 28.4%, p=0.001). There was no difference in rejection rates between maternal and non-maternal-LLD recipients. A higher percentage of maternal-LLD recipients were on immunosuppression monotherapy compared to non-maternal-LLD and DDLT recipients (6.7% vs. 1.2 vs. 2.4%, respectively). A subgroup of 68 patients were tested for DSA post-LT. Maternal-LLD recipients were less likely to develop de novo DSA (maternal-LLD 11.8% vs. non-maternal-LLD 19.3% vs. DDLT 43%, p=0.018). None of the maternal-LLD recipients developed antibody-mediated rejection. These data support the concept of immunologic benefit of maternal-LLD in pediatric LT, with lower rates of rejection and allosensitization post-LT when compared to DDLT recipients.

Development of Exogenous Insulin Antibody Syndrome in a Patient with Newly Diagnosed Type1 Diabetes Successfully Treated with Oral Immunosuppressive Monotherapy.

Exogenous insulin antibody syndrome (EIAS), which rarely occurs in the patient with type 1 diabetes, results in antibody-induced insulin resistance, hyperglycemia, ketosis, ketoacidosis, and hypoglycemia when insulin is released from the saturated insulin antibodies. Recommended treatment regimens include glucocorticoids, immunosuppressants, and plasmapheresis. In the patient with type 1 diabetes, glucocorticoids may by inducing and/or worsening ketoacidosis be contraindicated. With immunosuppressants, various anecdotal treatment regimens have been reported. Currently the most commonly recommended regimen is intravenous immunosuppressive therapy in combination with oral immunosuppressants. Herein we describe a patient in whom oral immunosuppressant monotherapy with mycophenolate resulted in the cure of EIAS, thus avoiding the expense associated with intravenous immunosuppressant therapy and/or hospitalization for plasmapheresis.

Metabolic Control and “Ideal” Outcomes in Liver Transplantation for Maple Syrup Urine Disease

To assess outcomes following liver transplantation for maple syrup urine disease by determining attainment and sustainability of metabolic control and apply an "ideal" outcome composite in long-term survivors. A single center, retrospective review collected clinical data including branched-chain amino acid (leucine, isoleucine, and valine) levels following liver transplant and determined achievement of an ideal long-term outcome profile of a first allograft stable on immunosuppression monotherapy, normal growth, and absence of common transplant-related sequelae. Of 77 patients meeting inclusion criteria identified, 23 were long-term (≥10-year) survivors and were additionally assessed for ideal outcome attainment. Patient and graft survival were 100% and 99%, respectively, and all patients were on an unrestricted protein intake diet. Although significant variation was noted in mean isoleucine (P<.01) and leucine (P<.05) levels postliver transplantation, no difference was seen in valine (P=.29) and overall clinical impact was likely negligible as metabolic stability was achieved and sustained beyond 3years postliver transplantation and no metabolic crises were identified. Of 23 long-term survivors with available data, 9 (39%) achieved all composite metrics determined to define "ideal" outcomes in pediatric postliver transplantation populations. Liver transplant enables long-term metabolic stability for patients with maple syrup urine disease. A combination of experience and improvement in both pre- and postliver transplantation care has enabled excellent survival and minimal comorbidities following transplant.

Presence of donor specific HLA class 2 antibodies (DSA class 2) is associated with development of graft fibrosis more than 10years after liver transplantation-a retrospective single center study.

Here the impact of donor specific human leukocyte antigen (HLA) class 2 antibodies (DSA cl 2) on long term outcome after liver transplantation (LT) was investigated. Altogether 156 (44 pediatric and 112 adult) LT recipients were included in the study. Graft fibrosis was assessed by liver elastography and biopsy. DSA cl 2 were determined by Luminex technology. 46% of LT recipients were positive for DSA cl 2 after a median follow-up of 15years. In the multivariate analysis DSA cl 2 were significantly associated with immunosuppressive monotherapy (OR 5.42; 95% CI: 1.02-28.90; p=.048). Compared to DSA cl 2 negative patients, positive recipients had significantly more graft fibrosis based on the liver stiffness (mean 9.4±9.0kPa vs. 6.5±6.3kPa; p<.002) and fibrosis stages determined by liver elastography (p=.016) and the performed liver biopsies (p=.002). Also, a significantly higher incidence of chronic rejections (11% vs. 2%; p=.045) and graft losses (6% vs. 0%; p=.043) were found. In the multivariate regression analysis DSA cl 2 were significantly associated with graft fibrosis (OR 4.57; 95% CI 1.59-13.10; p=.005). So, these data suggest that development of DSA cl 2 occurs more often with immunosuppressive monotherapy and may ultimately result in chronic rejection and graft fibrosis.

Efficacy and Safety of Immunosuppressive Monotherapy Agents for IgA Nephropathy: A Network Meta-Analysis.

Background: The efficacy and safety of immunosuppressive monotherapy agents were evaluated for immunoglobulin A nephropathy (IgAN) using a network meta-analysis approach. Methods: Randomized controlled trials (RCTs) published prior to October 1, 2019, using immunosuppressive agents for treating IgAN, were systematically searched in PubMed, Embase, Cochrane Library, and Web of Science databases. Relative risks (RRs) or standard mean differences with 95% confidence intervals (CIs) were estimated using the random-effects model. The primary outcomes were clinical remission, end-stage renal disease (ESRD), and serious adverse events (SAEs). The secondary outcomes were urinary protein excretion and serum creatinine. Results: Twenty-five RCTs with 2,005 participants were deemed eligible. Six medications were evaluated: corticosteroids, mycophenolate mofetil (MMF), tacrolimus (TAC), cyclosporine, leflunomide, and hydroxychloroquine (HCQ). Steroids (RR 1.50, 95% CI 1.17–1.93), MMF (RR 2.05, 95% CI 1.15–3.65), TAC (RR 3.67, 95% CI 1.06–12.63), and HCQ (RR 3.25, 95% CI 1.05–10.09) significantly improved clinical remission rates compared to supportive care alone. Only steroids reduced the risk of ESRD (RR 0.35, 95% CI 0.12–0.98); however, there were significantly more SAEs than in the control group (RR 2.90, 95% CI 1.37–6.13). No significantly different effects in serum creatinine levels were found among the therapies. MMF showed no significant improvement in remission when excluding studies with a follow-up of fewer than 2 years in the sensitivity analysis (RR 1.41, 95% CI 0.40–4.92). The effect of TAC in the decrease of proteinuria was reversed after discontinuing medication for 3 months; the long-term effects of HCQ could not be evaluated due to the short follow-up duration. Conclusion: Corticosteroids might induce remission and increase renal survival in IgAN; however, adverse reactions should be taken into consideration. MMF, TAC, and HCQ might improve the remission of proteinuria when treating IgAN, but showed no superiority compared to steroids, and the long-term effects require further study.

Regulatory T cells for minimising immune suppression in kidney transplantation: phase I/IIa clinical trial

ObjectiveTo assess whether reshaping of the immune balance by infusion of autologous natural regulatory T cells (nTregs) in patients after kidney transplantation is safe, feasible, and enables the tapering of...

Bilateral polysegmentary pneumonia caused by SARS-CoV-2 in a transplanted liver recipient

Background. In December 2019, the humanity met a previously unknown infectious disease (COVID-19) caused by a new coronavirus called SARS-CoV-2. An important role in the treatment of COVID-19 belongs to anti-inflammatory and immunosuppressive drugs. In this regard, the cases of the disease in patients undergoing long-term immunosuppressive therapy, for example, organ transplant recipients, are of particular interest. We present our clinical observation of COVID-19 in a liver recipient patient, which, apparently, is the first in the Russian Federation.&#x0D; Clinical case description A 54-year-old man, 10 years ago at the A.I. Burnazyan Center underwent transplantation of the right lobe of the liver after resection of hepatocellular carcinoma, T2N0M0, and due to liver cirrhosis as a result of НСV hepatitis. At the time of hospitalization, he had been constantly receiving immunosuppressive monotherapy with everolimus. The patient was transferred to an infectious disease hospital due to a positive PCR test for SARS-CoV-2 RNA. No signs of respiratory failure were found upon admission. Subsequently, a mild course of COVID-19 was observed, without signs of an acute inflammatory reaction, with normal CRP values and a slight increase of ferritin. 7 days after the treatment, the patient was discharged for outpatient observation.&#x0D; Conclusion. This clinical case is of interest not only by the success of the treatment of the new coronavirus infection COVID-19 in an immunocompromised patient a recipient of a liver transplant, but also by the fact that the disease manifested itself primarily as a transient increase in hepatic aminotransferases, which can be attributed to the gastrointestinal manifestations of COVID-19.

Extrahepatic malignant neoplasms after liver transplantation: the experience of a single transplant center

Objective: to evaluate the incidence of de novo malignant neoplasms (MN) after liver transplantation (LT) and compare with indicators among the general Russian population. Materials and methods. The study included 182 patients who had at least a 6-month follow-up period after LT and had no extrahepatic malignancies before LT. All data were analyzed retrospectively. Statistical processing of the results was carried out using the Statistica program for Windows v.10. Results. MN incidence was 5.5% (10 of 182 patients). The average period from transplantation to diagnosis of de novo neoplasm was 47.8 months (8 to 144 months). The patients were 3 men and 7 women. Types of de novo tumors included digestive system tumor (2 out of 10), hematologic malignant tumor (3 out of 10), skin cancer – melanoma (1 out of 10), urologic cancer (1 out of 10), gynecological (2 out of 10) and base of tongue cancer (1 out of 10). Five patients (50.0%) died, mortality was higher than in other LT patients (Z = –2.6; p = 0.009). The average follow-up period after detection of neoplasms was 18.8 months. Incidence of malignant neoplasms following LT was 10 times higher than among the general Russian population. No significant differences were found in the incidence of late acute rejection between 10 patients with MN and other 172 patients (Z = 0.18, p = 0.8). Among surviving patients, 2 patients with lymphomas received tacrolimus immunosuppression monotherapy, while 3 had everolimus-based immunosuppression. Conclusion. Incidence of de novo extrahepatic malignancies after LT is significantly higher than in the general population. To reduce the incidence of neoplasms in the future, patients should undergo regular screening, proliferative signal blockers should be prescribed, although their effectiveness requires further research.