Advances In Immunosuppressive Therapy Research Articles

Genitourinary malignancies in kidney transplant recipients.

Advances in immunosuppressive therapy and postoperative management have greatly improved the graft and patient survival rates after kidney transplantation; however, the incidence of post-transplant malignant tumors is increasing. Post-renal transplantation malignant tumors are associated with renal failure, immunosuppression, and viral infections. Moreover, the risk of developing cancer is higher in kidney transplant recipients than in the general population, and the tendency to develop cancer is affected by the background and environment of each patient. Recently, cancer after kidney transplantation has become the leading cause of death in Japan. Owing to the aggressive nature and poor prognosis of genitourinary malignancies, it is crucial to understand their epidemiology, risk factors, and best practices in kidney transplant recipients. This review has a special emphasis on the epidemiology, risk factors, and treatment protocols of genitourinary malignancies in kidney transplant recipients to enhance our understanding of the appropriate management strategies. Optimal immunosuppressive therapy and cancer management for these patients remain controversial, but adherence to the general guidelines is recommended.

Acute Kidney Injury after Liver Transplantation

Abstract Liver transplantation is the only curative treatment for terminal liver failure. Advances in immunosuppressive therapy and improvements in surgical techniques have improved patient survival in the post-transplant period. At the same time, however, the incidence of late complications is increasing, which has been contributed to by the broadening of the indication criteria in liver allocation. The most common complications include chronic kidney disease, the aetiology of which is multifactorial with a predominance of calcineurin inhibitor toxicity in the post-transplant period. The prevalence ranges from 30% to 90% depending on the definition used and the methodology used to measure renal function. Early detection of risk factors and early intervention lead to a significant improvement in the quality of life of recipients in the post-transplant period.

Managing Lupus Nephritis in Children and Adolescents.

Lupus nephritis is an important manifestation of systemic lupus erythematosus, which leads to chronic kidney disease, kidney failure, and can result in mortality. About 35%-60% of children with systemic lupus erythematosus develop kidney involvement. Over the past few decades, the outcome of patients with lupus nephritis has improved significantly with advances in immunosuppressive therapies and clinical management. Nonetheless, there is a paucity of high-level evidence to guide the management of childhood-onset lupus nephritis, because of the relatively small number of patients at each centre and also because children and adolescents are often excluded from clinical trials. Children and adults differ in more ways than just size, and there are remarkable differences between childhood- and adult-onset lupus nephritis in terms of disease severity, treatment efficacy, tolerance to medications and most importantly, psychosocial perspective. In this article, we review the 'art and science' of managing childhood-onset lupus nephritis, which has evolved in recent years, and highlight special considerations in this specific patient population.

Matrix Metalloproteinases and Heart Transplantation-A Pathophysiological and Clinical View.

Heart transplantation is undergoing a continuous development, with rates of success increasing substantially due to advances in immunosuppressive therapy and surgical techniques. The most worrying complication occurring after cardiac transplantation is graft rejection, a phenomenon that is much affected by matrix metalloproteinases (MMPs), with the role of these proteases in the cardiac remodeling process being well established in the literature. A detailed investigation of the association between MMPs and cardiac rejection is necessary for the future development of more targeted therapies in transplanted patients, and to discover prognostic serum and immunohistochemical markers that will lead to more organized therapeutic management in these patients. The aim of this review is therefore to highlight the main MMPs relevant to cardiovascular pathology, with particular emphasis on those involved in complications related to heart transplantation, including cardiac graft rejection.

Effects of Induction Therapy on Graft Functions in Terms of Immunologic Risk

Advances in immunosuppressive therapies and surgical techniques have led to a significant reduction in the incidence of rejection within 1 year after kidney transplantation. Immunologic risk is an important factor affecting graft functions and guiding the clinician in the selection of induction therapy. The aim of this study was to investigate graft functions based on serum creatinine levels, Chronic Kidney Disease Epidemiology Collaboration (CKD- EPI) and proteinuria levels, frequency of leukopenia, cytomegalovirus (CMV) and BK virus polymerase chain reaction (PCR) positivity in patients with low and high immunologic risk. This retrospective study included 80 renal recipients. Recipients were divided into 2 groups: patients at low immunologic risk who received basiliximab only and those with high immunologic risk who received low-dose (1.5 mg/kg for 3 days) antithymocyte globulin and basiliximab. No significant differences were observed between the 2 risk groups in terms of first, third, sixth, and 12th-month creatinine levels, CKD-EPI, proteinuria levels, leukopenia frequency, and CMV and BK virus PCR positivity. One-year graft survivals did not differ significantly between these 2 treatment modalities. The combined use of low-dose antithymocyte globulin and basiliximab in the induction treatment of patients with high immunologic risk seems promising in terms of graft survival, leukopenia frequency, and CMV and BK virus PCR positivity.

#2519 THE EFFECT OF TRPC5 AND PALLADIN EXPRESSION ON TREATMENT RESPONSE AND RENAL OUTCOME IN FOCAL SEGMENTAL GLOMERULOSCLEROSIS

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) is a disease that is among the primary glomerulopathies and often progresses to chronic renal failure. Despite advances in immunosuppressive therapy for the treatment of glomerular diseases, some FSGS patients are resistant to single or combination immunosuppressive regimens containing; glucocorticoids, cyclophosphamide, calcineurin inhibitors, mycophenolate mofetil (MMF), and/or rituximab. FSGS-related nephrotic syndrome, the degree of proteinuria and response to steroid therapy are the most important factors associated with long-term prognosis, independent of histological findings. Failure to respond to immunosuppressive therapy, including corticosteroids, has been evaluated as one of the most important markers of the risk of developing renal failure. Unfortunately, there is no reliable marker that can predict steroid response. One of the earliest manifestations of podocyte damage is cytoskeletal remodeling, known as deletion of foot ridges. It was recently shown that transient receptor potential channel 5 (TRPC5) plays an important role in initiating this process. However, the role of TRPC5 in disease progression is unknown. It is thought that calcium influx caused by sustained TRPC5 activation in the chronic disease setting may lead to calcium toxicity and podocyte death. It is known that the actin regulatory protein palladin, which is highly expressed here, is also highly related to podocyte function and podocytopathies, and plays an important role in the stability of the actin cytoskeleton. The aim of our study was to define the frequency of TRPC5 and palladin renal expressions in podocytes in focal segmental glomerulosclerosis (FSGS) and its relationship with prognosis and treatment response. Method A total of 182 patients were enrolled for baseline clinical and histopathological features and 103 patients with a clinical follow-up for more than 2 years were evaluated for outcomes. Immunohistochemical staining was performed with TRPC5 and palladin antibodies on kidney biopsies and glomerular staining was evaluated. Results Baseline characteristics, and health parameters were similar between TRPC5+/TRPC5− and palladin+/palladin− groups. TRPC5 expression was observed in 69% of the patient biopsies and palladin expression in 73%. We found that TRPC5 and palladin expression was a significant predictor of FSGS severity and poor treatment response (both p<0.05). In addition, TRPC5 expression was significantly associated with the development of end-stage renal disease and ongoing proteinuria. Conclusion The development of proven treatments that delay the progression of FSGS is critical to patient survival. The development of new treatments is possible only by knowing the underlying pathophysiological mechanism of the disease. Podocyte loss is a critical step in the development of irreversible glomerulosclerosis, which causes chronic kidney disease. Therefore, blocking TRPC5 channel and palladin may be an effective treatment strategy, especially in treatment-resistant FSGS patients with positive staining on biopsy. Our study is the first in the literature to show these two antigens in kidney tissue in FSGS and to associate them with disease prognosis. TRPC5 and palladin expression may serve as a biomarker to facilitate diagnosis and choose new treatment regimens of proteinuric kidney diseases in the future.

Inhibiting NFAT5 With KRN2 Mitigates Acute Allograft Rejection in a Murine Heart Transplantation Model.

Despite advancements in immunosuppressive therapy, acute allograft rejection remains an important challenge for heart transplantation patients. Nuclear factor of activated T-cells 5 (NFAT5), a member of the family of Rel homology domain-containing factors that plays an important role in regulating immune responses of T lymphocytes, may be closely associated with cardiac rejection. KRN2, as a specific inhibitor of NFAT5, is injected intraperitoneally daily starting from day 0 after murine heart transplantation. When compared with saline treatment, KRN2 treatment can improve allograft survival. Histologic examination revealed that the KRN2 treatment group experienced less-severe rejection, and enzyme-linked immunosorbent assay revealed lower levels of inflammatory cytokines in circulating serum. The proportion and number of T-cell subpopulations in the spleens were analyzed by flow cytometry. We found that KRN2 treatment reduced the proportions of CD4 + IFN-γ + , CD4 + IL-17A + , and CD4 + IL-4 + Th cells, whereas increasing CD4 + Foxp3 + Treg cells compared with the control group. These findings suggest that KRN2 attenuates acute allograft rejection by regulating CD4 + T lymphocyte responses. NFAT5 could be a promising therapeutic target for preventing acute allograft rejection.

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.

Validation of a Simple, Rapid, and Cost-Effective Method for Acute Rejection Monitoring in Lung Transplant Recipients.

Despite advances in immunosuppression therapy, acute rejection remains the leading cause of graft dysfunction in lung transplant recipients. Donor-derived cell-free DNA is increasingly being considered as a valuable biomarker of acute rejection in several solid organ transplants. We present a technically improved molecular method based on digital PCR that targets the mismatch between the recipient and donor at the HLA-DRB1 locus. Blood samples collected sequentially post-transplantation from a cohort of lung recipients were used to obtain proof-of-principle for the validity of the assay, correlating results with transbronchial biopsies and lung capacity tests. The results revealed an increase in dd-cfDNA during the first 2 weeks after transplantation related to ischemia-reperfusion injury (6.36 ± 5.36%, p < 0.0001). In the absence of complications, donor DNA levels stabilized, while increasing again during acute rejection episodes (7.81 ± 12.7%, p < 0.0001). Respiratory tract infections were also involved in the release of dd-cfDNA (9.14 ± 15.59%, p = 0.0004), with a positive correlation with C-reactive protein levels. Overall, the dd-cfDNA percentages were inversely correlated with the lung function values measured by spirometry. These results confirm the value of dd-cfDNA determination during post-transplant follow-up to monitor acute rejection in lung recipients, achieved using a rapid and inexpensive approach based on the HLA mismatch between donor and recipient.

MO993: Incidence of Ptld and Its Relationship with Cmv-Serostatus Positivity Among Childhood and Adulthood Population: A Registry Data Study

Abstract BACKGROUND AND AIMS It is unknown how the epidemiology of post-transplant lymphoproliferative disease (PTLD) and its relationship with CMV infection differ between adult and pediatric kidney transplant recipients. In addition, with current advancements in immunosuppressive therapy, the incidence of PTLD has changed dramatically. The aim of our study is to elucidate the relationship between PTLD and CMV infection. Moerover, to assess the incidence of PTLD among Adult and pediatric renal transplant patients in the current era. METHOD All renal transplant patients registered in the Organ Procurement and Transplantation Network between 2005 and 2019 were retrospectively reviewed. Patient were followed up till December 2020. Patients who had multiple organ transplant or those with previous renal transplants were excluded from the study. Data about recipient factors (age, sex ethnicity, diabetes, CMV serostatus, and EBV serostatus), donor factors (living or deceased), transplant factors (PRA, Cold ischemia time, HLA mismatches, induction and immunosuppressive therapy) were reviewed. Incidence rate of PTLD at one year and five years post-transplant were calculated among the Adult and Pediatric population. Univariate and Multivariate cox-hazard regression models were performed to assess the relationship between CMV serostatus and occurrence of PTLD. RESULTS About 10 947 pediatric renal transplant patients were included. About 315 pediatric patients developed PTLD during the follow-up time (2.88%). About 50.55% of PTLD occurred within the first-year post-transplant. 60% occurred within two-year post-transplant, while 80.63% of them occurred within five years post-transplant. CMV recipient infection was not associated with PTLD occurrence in the pediatric population (HR = 0.88, Pvalue = 0.81, 95% confidence interval ranged between 0.66 and 1.18). Proportional hazard assumption was not violated with P = 0.55. Among the adult population, 1990/277 955 developed PTLD (0.77%). About 25.77% of PTLD among the adult population occurred within the first-year post-transplant. About 39.39% of PTLD in the adult occurred within two-year post-transplant. About 66.55% of PTLD in the adult occurred within five-years post-transplant. CMV recipient positive serostatus was associated with a protective effect against occurrence of PTLD (HR = 0.82, Pvalue &amp;lt;0.01, 95% confidence interval ranged between 0.73 and 0.94). The most common type of PTLD among the pediatric and adult population was monomorphic PTLD ( 40% and 34%, respectively). CONCLUSION PTLD is a rare complication of renal transplantation in the current era. The risk of development of PTLD is highest during the first-year post-transplant. CMV recipient positive serostatus has a protective effect against development of PTLD.

Personalized immunosuppression after kidney transplantation.

With advances in immunosuppressive therapy, there have been significant improvements in acute rejection rates and short-term allograft survival in kidney transplant recipients. However, this success has not been translated into long-term benefits by the same magnitude. Optimization of immunosuppression is important to improve the clinical outcome of transplant recipients. It is important to note that each patient has unique attributes and immunosuppression management should not be a one-size-fits-all approach. Elderly transplant patients are less likely to develop acute rejection but more likely to die from infectious and cardiovascular causes than younger patients. For those with post-transplant cancers and BK polyomavirus-associated nephropathy, reduction of immunosuppression can increase the risk of rejection. Therapeutic drug monitoring (TDM) is routinely used for dosage adjustment of several immunosuppressive drugs. It has been hoped that pharmacogenetics can be used to complement TDM in optimizing drug exposure. Among the various drug-genotype pairs being investigated, tacrolimus and CYP3A5 gives the most promising results. Different studies have consistently shown that CYP3A5 expressers require a higher tacrolimus dose and take longer time to achieve target blood tacrolimus levels than nonexpressers. However, for pharmacogenetics to be widely used clinically, further trials are necessary to demonstrate the clinical benefits of genotype-guided dosing such as reduction of rejection and drug-related toxicities. The development of different biomarkers in recent years may help to achieve true personalized therapy in transplant patients.

Infusion of haploidentical hematopoietic stem cells combined with mesenchymal stem cells for treatment of severe aplastic anemia in adult patients yields curative effects

Background aimsDespite the great advances in immunosuppressive therapy for severe aplastic anemia (SAA), most patients are not completely cured. Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has been recommended as an alternative treatment in adult SAA patients. However, haplo-HSCT presents a higher incidence of graft failure and graft-versus-host disease (GVHD). The authors designed a combination of haplo-HSCT and umbilical cord-derived mesenchymal stem cells (UC-MSCs) for treatment of SAA in adult patients and evaluated its effects. MethodsAdult patients (≥18 years) with SAA (N = 25) were given HLA-haploidentical hematopoietic stem cells (HSCs) combined with UC-MSCs after a conditioning regimen consisting of busulfan, cyclophosphamide, fludarabine and anti-thymocyte globulin and intensive GVHD prophylaxis, including cyclosporine, basiliximab, mycophenolate mofetil and short-term methotrexate. Additionally, the effects of the protocol in adult SSA patients were compared with those observed in juvenile SAA patients (N = 75). ResultsAll patients achieved myeloid engraftment after haplo-HSCT at a median of 16.12 days (range, 11–26). The median time of platelet engraftment was 28.30 days (range, 13–143). The cumulative incidence of grade II acute GVHD (aGVHD) at day +100 was 32.00 ± 0.91%. No one had grade III–IV aGVHD at day +100. The cumulative incidence of total chronic GVHD was 28.00 ± 0.85%. The overall survival was 71.78 ± 9.05% at a median follow-up of 42.08 months (range, 2.67–104). Promisingly, the protocol yielded a similar curative effect in both young and adult SAA patients. ConclusionsThe authors’ data suggest that co-transplantation of HLA-haploidentical HSCs and UC-MSCs may provide an effective and safe treatment for adult SAA.

Plasma Exchange in ANCA-Associated Vasculitis: A Narrative Review.

Therapeutic plasma exchange (TPE) is an adjunctive intervention to immunosuppression for the treatment of severe renal involvement or lung hemorrhage in patients with ANCA-associated vasculitis (AAV). Patients with AAV have an increased risk for progression to end-stage kidney disease (ESKD) or death despite advances in immunosuppressive therapy. The potential pathogenicity of ANCA makes TPE a reasonable treatment approach for the life-threatening complications of AAV. The efficacy of intensive TPE in rapidly progressive glomerulonephritis was originally described in small studies almost four decades ago. Further randomized trials examined the addition of TPE to standard of care, exhibiting mixed results in both patient and renal survival. The largest clinical trial to date, PEXIVAS, failed to demonstrate a clear benefit for TPE in severe AAV. In light of new evidence, the role of TPE remains controversial across the vasculitis medical community. The purpose of this review is to summarize the clinical indications and the current available data for the use of TPE in patients with severe AAV.

Underlying Causes and Risk Factors of Chronic Renal Allograft Dysfunction Among Renal Transplant Recipients

Objective: Dialysis or renal transplantation are the two treatment options for end-stage renal disease patients. Renal transplantation from an appropriate donor increases survival and quality of life compared to treatment with dialysis. Recent advances in immunosuppressive therapy have significantly improved the success in 1-year graft survival. However, the long-term graft survival remains the same. Therefore, we aimed to determine the underlying causes and risk factors of chronic allograft dysfunction in renal transplant recipients.&#x0D; Materials and Methods: From 2000 to 2012, all consecutive renal transplant recipients followed in our tertiary referral center who underwent renal biopsy due to an increase in serum creatinine level were enrolled. Etiologies of chronic allograft dysfunction were assessed according to pathologic results of renal biopsy specimens and laboratory findings. The immunological and non-immunological risk factors of chronic allograft dysfunction were screened and recorded retrospectively.&#x0D; Results: Eighty (80) renal transplant recipients with a mean age of 38±10 years were included in the study. Delayed graft function (p=0.007), history of acute rejection (p&lt;0.001), positive panel reactive antibody (p=0.033) (Class I (p=0.013), Class II (p=0.006)), positive donor specific antibodies (p=0.001), number of recurrent acute rejections (p&lt;0.001), number of human leukocyte antigens mismatches (p=0.051), cold ischemia time (p=0.001) were found to be risk factors for chronic allograft dysfunction. The donor specific antibodies positivity (p&lt;0.001) and the panel reactive antibody positivity (Class I (p=0.003), Class II (p=0.001)) were significantly higher in patients with antibody mediated rejection than patients without antibody mediated rejection (p=0.002).&#x0D; Conclusion: Delayed graft function, presence and the number of acute rejections, increased cold ischemia time, panel reactive antibody positivity, donor specific antibodies positivity, and the number of human leukocyte antigens mismatches were risk factors for chronic allograft dysfunction.

BK Virus-Associated Nephropathy after Renal Transplantation.

Recent advances in immunosuppressive therapy have reduced the incidence of acute rejection and improved renal transplantation outcomes. Meanwhile, nephropathy caused by BK virus has become an important cause of acute or chronic graft dysfunction. The usual progression of infection begins with BK viruria and progresses to BK viremia, leading to BK virus associated nephropathy. To detect early signs of BK virus proliferation before the development of nephropathy, several screening tests are used including urinary cytology and urinary and plasma PCR. A definitive diagnosis of BK virus associated nephropathy can be achieved only histologically, typically by detecting tubulointerstitial inflammation associated with basophilic intranuclear inclusions in tubular and/or Bowman’s epithelial cells, in addition to immunostaining with anti-Simian virus 40 large T-antigen. Several pathological classifications have been proposed to categorize the severity of the disease to allow treatment strategies to be determined and treatment success to be predicted. Since no specific drugs that directly suppress the proliferation of BKV are available, the main therapeutic approach is the reduction of immunosuppressive drugs. The diagnosis of subsequent acute rejection, the definition of remission, the protocol of resuming immunosuppression, and long-term follow-up remain controversial.

Incidence of remission and relapse of proteinuria, end-stage kidney disease, mortality, and major outcomes in primary nephrotic syndrome: the Japan Nephrotic Syndrome Cohort Study (JNSCS)

BackgroundDespite recent advances in immunosuppressive therapy for patients with primary nephrotic syndrome, its effectiveness and safety have not been fully studied in recent nationwide real-world clinical data in Japan.MethodsA 5-year cohort study, the Japan Nephrotic Syndrome Cohort Study, enrolled 374 patients with primary nephrotic syndrome in 55 hospitals in Japan, including 155, 148, 38, and 33 patients with minimal change disease (MCD), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and other glomerulonephritides, respectively. The incidence rates of remission and relapse of proteinuria, 50% and 100% increases in serum creatinine, end-stage kidney disease (ESKD), all-cause mortality, and other major adverse outcomes were compared among glomerulonephritides using the Log-rank test. Incidence of hospitalization for infection, the most common cause of mortality, was compared using a multivariable-adjusted Cox proportional hazard model.ResultsImmunosuppressive therapy was administered in 339 (90.6%) patients. The cumulative probabilities of complete remission within 3 years of the baseline visit was ≥ 0.75 in patients with MCD, MN, and FSGS (0.95, 0.77, and 0.79, respectively). Diabetes was the most common adverse events associated with immunosuppressive therapy (incidence rate, 71.0 per 1000 person-years). All-cause mortality (15.6 per 1000 person-years), mainly infection-related mortality (47.8%), was more common than ESKD (8.9 per 1000 person-years), especially in patients with MCD and MN. MCD was significantly associated with hospitalization for infection than MN.ConclusionsPatients with MCD and MN had a higher mortality, especially infection-related mortality, than ESKD. Nephrologists should pay more attention to infections in patients with primary nephrotic syndrome.

Evaluation and Treatment of Acute Rejection in Kidney Allografts.

Advances in immunosuppressive therapy have drastically improved acute rejection rates in kidney transplant recipients over the past five decades. Nevertheless, it should remain high on any differential diagnosis of unexplained graft dysfunction because of the potential negative effect on graft longevity. Understanding the pre- and post-transplant risk factors for acute rejection can help estimate the probability of immunologic graft damage, and accurate identification of the type and severity of acute rejection will guide appropriate treatment. Tissue biopsy remains the gold standard for evaluating immunologic graft damage, and the histologic definition of acute rejection has evolved in recent years. Intravenous steroids and T cell depletion remain the standard therapy for T cell-mediated rejection and are effective in reversing most cases. Plasma exchange and intravenous Ig, with or without rituximab, are most commonly used for the treatment of antibody-mediated rejection and several newer agents have recently been investigated for severe cases. This review aims to provide the general nephrologist caring for transplant recipients with an approach to immunologic risk assessment and a summary of recent advances in the diagnosis and treatment of acute graft rejection.

CD47 blockade alleviates acute rejection of allogeneic mouse liver transplantation by reducing ischemia/reperfusion injury

Despite advances in immunosuppressive therapies, acute rejection response is still a serious concern especially in the early phase after liver transplantation. This study aimed to evaluate whether blocking the TSP1-CD47 signaling pathway could attenuate the acute rejection after liver transplantation. An allogeneic mouse orthotopic liver transplantation model (Balb/c→C3H) with prolonged cold ischemic phase was used to induce severe IRI and lethal acute rejection. CD47mAb or isotype matched-control IgG2a was administered to donor liver during graft perfusion. Recipients were sacrificed at 1d, 3d, 5d and 7d after reperfusion. Blood samples were collected to evaluate serum alanine aminotransferase, total bilirubin, HMGB-1,TNF-α, IL-2 and INF-γ level. Flow cytometric analysis was used to detect the strength of innate and adaptive immune response. Liver tissue was obtained for HE, TUNEL staining and F4/80 immumohistochemical staining. Moreover, we conducted a mixed lymphocyte reaction treated with IgG2a or CD47mAb. Mice in CD47mAb-treated group demonstrated improved survival and significantly lower increase in Suzuki score, apoptosis index, acute rejection index, serum alanine aminotransferase, total bilirubin, HMGB-1, TNF-α, IL-2, INF-γ level and the degree of Kupffer cells' activation especially in the early phase of acute rejection. In addition, Pearson's correlation analysis confirmed significant correlation between Suzuki score/ALT and acute rejection index. The in vitro inhibition assay showed that CD47 blockade couldn’t directly inhibit recipient lymphocyte proliferation. Based on the evidence that TSP1-CD47 signaling blockade with CD47mAb could alleviate acute rejection by reducing the extent of IRI after liver transplantation indirectly, this study provided a basis for new interventions and management methods to support better transplant outcomes.

PIN149 RETROSPECTIVE SURVEY FOR HEPATITIS B VIRUS REACTIVATION DURING IMMUNOSUPPRESSIVE THERAPIES FOR RHEUMATOID WITH ADMINISTRATIVE DATA

Risk of hepatitis B virus (HBV) reactivation has increased because of advances in immunosuppressive therapies. People having a previously-resolved HBV infection and those with serum HBs-antigen positivity are likely to develop liver injuries after the therapies. However, the risk of HBV reactivation for rheumatoid arthritis (RA) patients is still unclear. This study described a validity of detecting prHBV infection from administrative data by comparing with chart abstraction, and to determine an incidence of HBV reactivation during immunosuppressive therapy of Japanese RA patients. Adult patients who had been diagnosed with RA between 1 April 2011 and 31 March 2015 were extracted from the Medical Information Analysis (MIA) databank managed by the Clinical Research Center at the National Organization Hospitals (NHO) Headquarters. We also conducted chart abstraction in three hospitals to verify whether those patients actuary had records of prHBV infection, de novo hepatitis, and HBsAg carriers. A positive predictive value (PPV) of the algorithm of HBV-DNA testing with immunosuppressive therapy performed four times or more / year for the detection of prHBV infection from administrative data and an incidence rate of HBV reactivation among preHBV infections during immunosuppressive therapy for RA were calculated. The PPV and its 95% confidence interval (CI) of administrative data for the identification of suspected prHBV infections was 85.8% (95% CI: 81.7% - 89.3%). The incidence rate of de novo hepatitis was 1.23 / 100 person-years. The main concerns of epidemiological studies using administrative health data are lack of health information to identify true patients and the validity of recorded diagnoses and other information is critical. For HBV reactivation, monitoring data of serum HBV-DNA levels after immunosuppressive therapies were unavailable in the database and the chart review was useful approach. This validity study provided a good example to help our future HBV projects.

It takes a village: primary care of the pediatric liver transplant recipient.

Long-term survival is now the rule rather than the exception for infants and children who undergo liver transplantation for end-stage liver disease, metabolic liver conditions and a variety of other indications. Pediatricians and primary care providers play vital roles in the care and management of this patient population. The purpose of this review is to highlight key aspects important to the care of the pediatric liver transplant recipient. Significant advances in immunosuppressive therapies and surgical techniques have contributed to improved graft and patient survival rates, shifting the focus beyond immediate survival to strategies to minimize comorbidities related to long-term immunosuppression during growing years, attend to patient and parent-reported outcomes and enhance quality of life. A multidisciplinary approach allows for monitoring and surveillance of both routine (growth, nutritional rehabilitation, cognitive development, mental and psychosocial health, contraception and daily activities) and transplant-related (adverse effects of immunosuppression, susceptible infections, extra-hepatic systems, transition from childhood to adolescence to adulthood) themes. Effective communication between the primary care physician and the transplant team is imperative for optimizing best outcomes. The primary care provider should be aware of the multifacet nature of posttransplant management, which includes medication regimens, common complications and infections.