Steroid-resistant Rejection Research Articles

Hepatobiliary Quiz (Answers)—15 (2015)

Hepatobiliary Quiz (Answers)—15 (2015)

Daclizumab Versus Rabbit Antithymocyte Globulin in High-Risk Renal Transplants: Five-Year Follow-up of a Randomized Study

We previously reported a randomized controlled trial in which 227 de novo deceased-donor kidney transplant recipients were randomized to rabbit antithymocyte (rATG, Thymoglobulin) or daclizumab if they were considered to be at high immunological risk, defined as high panel reactive antibodies (PRA), loss of a first kidney graft through rejection within 2 years of transplantation, or third or fourth transplantation. Patients treated with rATG had lower incidences of biopsy-proven acute rejection (BPAR) and steroid-resistant rejection at 1 year. Patients were followed to 5 years posttransplant in an observational study; findings are described here. Treatment with rATG was associated with a lower rate of BPAR at 5 years (14.2% vs. 26.0% with daclizumab; p = 0.035). Only one rATG-treated patient (0.9%) and one daclizumab-treated patient (1.0%) developed BPAR after 1 year. Five-year graft and patient survival rates, and renal function, were similar between the two groups. Overall graft survival at 5 years was significantly higher in patients without BPAR (81.0% vs. 54.8%; p < 0.001). In conclusion, rATG is superior to daclizumab for the prevention of BPAR among high-immunological-risk renal transplant recipients. Overall graft survival at 5 years was approximately 70% with either induction therapy, which compares favorably to low-risk cohorts.

Initial Experience of Dual Maintenance Immunosuppression With Steroid Withdrawal in Vascular Composite Tissue Allotransplantation

Current immunosuppression in VCA is largely based on the experience in solid organ transplantation. It remains unclear if steroids can be reduced safely in VCA recipients. We report on five VCA recipients who were weaned off maintenance steroids after a median of 2 months (mean: 4.8 months, range 2-12 months). Patients were kept subsequently on a low dose, dual maintenance consisting of tacrolimus and mycophenolate mofetil/mycophenloic acid with a mean follow-up of 43.6 months (median = 40 months, range 34-64 months). Early and late acute rejections responded well to temporarily augmented maintenance, topical immunosuppression, and/or steroid bolus treatment. One late steroid-resistant acute rejection required treatment with thymoglobulin. All patients have been gradually weaned off steroids subsequent to the treatment of acute rejections. Low levels of tacrolimus (<5 ng/mL) appeared as a risk for acute rejections. Although further experience and a cautious approach are warranted, dual-steroid free maintenance immunosuppression appears feasible in a series of five VCA recipients.

Thymoglobulin for Steroid-Resistant Immune-Mediated Graft Dysfunction During Simeprevir-Based Antiviral Treatment for Post-Transplantation Hepatitis C: Case Report

IntroductionImmune-mediated graft dysfunction (IGD), a recently established disease entity with unfavourable outcome, is an antigraft immune reaction during interferon-based antiviral treatment for hepatitis C virus (HCV) infection after liver transplantation (LT). We report a case having steroid-resistant acute cellular rejection (ACR) type IGD, which was successfully treated using thymoglobulin. Case ReportA 56-year-old woman with recurrent HCV after LT was commenced on antiviral treatment including simeprevir, pegylated-interferon (IFN) 2a, and ribavirin. A negative serum HCV-RNA was confirmed after 4 weeks. After 12 weeks of therapy, severe liver dysfunction developed, despite a constantly negative HCV-RNA. Liver biopsy revealed portal and periportal inflammatory infiltrates including numerous eosinophils, lymphocytes, and bile duct damages, indicating ACR. IFN therapy was ceased, and she was treated with steroid pulse treatment, followed by high-level immunosuppression maintenance. However, ACR was irremediable. Thereafter she was treated with thymoglobulin (75 mg/d for 5 days). Her serum alanine aminotransaminase and total bilirubin levels decreased immediately, and her liver biopsy specimen showed no activity. During these periods of the treatment, the HCV-RNA became positive and the liver enzyme elevated, but other liver function tests still remained within normal range. ConclusionThymoglobulin could be the best choice in steroid-resistant IGD during antiviral treatment for post-transplantation recurrent hepatitis C.

The diagnosis and treatment of late acute rejection after adult orthotopic liver transplantation

To explore the diagnosis, treatment and long-term outcome of late acute rejection (LAR) following adult orthotropic liver transplantation (OLT). A total of 398 consecutive adult patients who underwent OLT in Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University between January 2007 and December 2012 were reviewed retrospectively. There were 48 patients (12. 1%) developed to LAR, including 43 male patients and 5 female patients, with an average age of (52 ± 13) years(18 - 70 years). The mean body mass index was (22.1 ± 4. 5) kg/m2 (15. 4 - 30. 4 kg/m2). The indications of the liver transplantation recipients included 16 cases of end-staged liver cirrhosis after hepatitis B or C(33. 3%), 14 cases with severe hepatitis (29. 2%), 9 cases of primary liver cancer(18. 5%), 5 cases of alcoholic liver cirrhosis (10. 4%), 1 case with autoimmune liver disease (2. 1%) , the other 3 cases (6. 3%). They were followed up by outpatient service, telephone and other means. Survival curves were generated with the Kaplan-Meier method and Cox proportional hazards modeling was used for predictors of mortality. Statistically significant variables found by single factor regression analysis were put into the Cox proportional hazards regression model of multivariate analysis. The time-to-event was 23. 6 months after OLT which were more common in the first year to the third year post-transplant (26/48,52. 4%). Thirty-five cases were assessed as mild, 11 cases were assessed as moderate, and 2 cases were assessed as severe ,based on the Banff schema. After adjustment to the immunosuppressive regimen, the overall recovery rate reached to 81. 3%. The rate of steroid-resistant acute rejection was 11. 8% (4/34). Inadequate immunosuppression and steroid pulsation were two independent risk factors affecting the prognosis of LAR (P = 0. 008, P = 0. 003, respectively). LAR is an uncommon complication after OLT. Inadequate immunosuppression and steroid pulsation are the major risk factors for prognosis of LAR. Improving patient compliance and strengthening blood concentration surveillance can increase the patient survival.

Management of Steroid-resistant Late Acute Cellular Rejection Following Face Transplantation: A Case Report

Face transplants have been clinically established, and early acute rejections have been reported. Late acute rejections have been less common. Immediate and accurate diagnosis along with successful treatment is critical to prevent graft damage. This case report describes the successful treatment of a severe, steroid-resistant rejection 2 years after a full face transplant.

Challenges in renal transplantation in Yemen.

Background Renal replacement therapy was first introduced in Yemen in 1978 in the form of hemodialysis. Twenty years later, the first renal transplantation was performed. Kidney transplantations were started in socially and financially challenging circumstances in Yemen in 1998. A structured program was established and has been functioning regularly since 2005. A pediatric transplantation program was started in 2011. Material and Methods This was a prospective study of 181 transplants performed at the Urology and Nephrology Center between May 1998 and 2012. All transplants were from living related donors. The immunosuppressive protocol consisted initially of double therapy with steroid and mycophenolate mofetil (MMF). Subsequently, triple therapy with addition of a calcineurin inhibitor was introduced. Primary graft function was achieved in 176 (97.2%) recipients. Results Cold ischemia time was 48-68 min. Episodes of acute rejection in 12 patients were treated with high-dose steroids. Anti-thymocyte globulin (ATG) was used in cases of vascular or steroid-resistant rejection in 2 patients. The post-transplant complications, either surgical or medical, were comparable to those recorded in the literature. Conclusions Renal transplantation is a good achievement in our country. The patients and graft survival rates are comparable to other reports.

Interleukin-2 receptor antagonists for pediatric liver transplant recipients: a systematic review and meta-analysis of controlled studies.

IL-2RA are frequently used as induction therapy in liver transplant recipients to decrease the risk of AR while allowing the reduction of concomitant immunosuppression. The exact association with the use of IL-2RA, however, is uncertain. We performed a systematic literature search for relevant studies. Random effects models were used to assess the incidence of AR, steroid-resistant rejection, graft loss, patient death, and adverse drug reaction, with or without IL-2RA. Six studies (two randomized and four non-randomized) met the eligibility criteria. Acute rejection at sixmonths or later favored the use of IL-2RA significantly (RR 0.38; 95% CI 0.22-0.66, p=0.0005). Although not statistically significant, IL-2RA showed a substantial reduction of the risk of steroid-resistant rejection (RR 0.32; CI 0.19-1.03, p=0.0594). Graft loss and patient death showed a reductive tendency through the use of IL-2RA. The use of IL-2RA is safe and is associated with a statistically significantly lower incidence of AR after transplantation and substantial reduction of steroid-resistant rejection, graft loss, and patient death.

Efficacy of ursodeoxycholic acid as an adjuvant treatment to prevent acute cellular rejection after liver transplantation: a meta-analysis of randomized controlled trials

Acute cellular rejection (ACR) after liver transplantation (LT) is one of the most common problems faced by transplant recipients in spite of advances in immunosuppressive therapy. Recently, clinical trials reported that ursodeoxycholic acid (UDCA) reduced the incidence of ACR significantly. However, others have shown contradictory conclusion. Therefore, we performed a meta-analysis of rigorous randomized controlled trials (RCTs) to determine the efficacy of UDCA in reducing ACR after LT. All RCTs that evaluated efficacy of UDCA as an adjuvant treatment to prevent ACR after LT were searched from PubMed/MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ScienceDirect databases and Web of Science (from January 1981 to March 2012). There was no language limitation in these searches. Relevant abstracts of international meetings were also searched. References of each included study were searched manually. A total of 234 patients from four high-quality RCTs (Jadad score 4 to 5) were included in this meta-analysis. Prophylactic use of UDCA did not decrease the incidence of ACR (RR: 0.94, 95% CI: 0.77-1.16, P>0.05), steroid-resistant rejection (RR: 0.77, 95% CI: 0.47-1.27, P>0.05) and the number of patients with the multiple episodes of ACR (RR: 0.60, 95% CI: 0.28-1.30, P>0.05). Different intervention programs (high-dose vs low-dose UDCA; early vs delayed UDCA treatment) also did not alter the outcomes. UDCA, as an adjuvant treatment, was not able to prevent ACR and steroid-resistant rejection after LT. Further trials should be done to determine whether higher dose of UDCA will be beneficial.

Biologics in renal transplantation.

The biologics used in transplantation clinical practice include several monoclonal and polyclonal antibodies aimed at specific cellular receptors. The effect of their mechanisms of action includes depleting or blocking specific cell subpopulations, complement system, or removing circulating preformed antibodies and blocking their production. They are used in induction, desensitization ABO-incompatible renal transplantation, rescue therapy of steroid-resistant acute rejection, treatment of posttransplant recurrence of primary disease such as nephrotic syndrome or atypical hemolytic–uremic syndrome, and in late humoral rejection. There are various indications for the use of biologic agents before and early or late after renal transplantation in both high- and low-risk recipients. In the latter situation, the biologics-based induction is used to further minimize immunosuppression maintenance. The targets of several biologic agents are present across a variety of cells, and manipulation of the immune system with biologics may be associated with significant risk of acute and late-onset adverse events; therefore, clinical risk-versus-benefit ratio must be carefully balanced in every case. Several trials on novel biologics are reported in adults but not in the pediatric population.

Results of a Large Randomized Controlled Trial of Alemtuzumab-Versus Basiliximab-Based Induction Therapy in Kidney Transplantation.

Background Calcineurin inhibitors reduce short-term kidney transplant failure, but may contribute to late transplant loss. The role of alemtuzumab (a potent lymphocyte-depleting antibody) as induction therapy followed by an early reduction in CNI exposure after kidney transplantation is uncertain. The 3C Study aims to assess the efficacy and safety of alemtuzumab (followed by low-dose CNI) compared to basiliximab (with standard dose CNI) among patients receiving kidney transplants. Methods This randomized trial included 852 patients scheduled to receive a kidney transplant who were randomly assigned alemtuzumab-based induction therapy (followed by low-dose tacrolimus and mycophenolate) or basiliximab-based induction therapy (followed by standard-dose tacrolimus, mycophenolate and steroids). The primary outcome is biopsy-proven acute rejection at 6 months. Key secondary outcomes include delayed graft function, steroid resistant rejection, transplant survival, serious infections (defined as opportunistic infections or infection requiring hospitalisation) and cause-specific mortality. Tertiary outcomes include the incidence of the primary outcome in different types of transplant recipient. Results 426 participants were assigned alemtuzumab and 426 to basiliximab. Average age was 51 years and 65% were male. Approximately one-third of transplants followed each of donation after brain death, donation after cardiac death and living donation. During the first 6 months of follow-up, about 100 participants had biopsy-proven acute rejection, about 30 transplants failed and over 250 participants had a serious infection. Conclusion The 3C Study is the largest randomized trial to assess the clinical efficacy and safety of alemtuzumab-based induction in kidney transplantation and the unblinded clinical efficacy results would be presented for the first time during the WTC meeting. With about 100 rejection episodes and 250 serious infections, the study has excellent statistical power to detect clinically important treatment effects. These results should have an important impact on the choice of induction therapy at the time of kidney transplantation. DISCLOSURE:Haynes, R.: Grant/Research Support, Novartis. Harden, P.: Grant/Research Support, Novartis. Landray, M.: Grant/Research Support, Novartis. Baigent, C.: Grant/Research Support, Novartis. Friend, P.: Grant/Research Support, Novartis.

Experience With Donors With Positive Serology for Chagas Disease in Liver Transplantation.

Introduction: Utilization of marginal donors in liver transplant (LTx) has been one of the options to increase the availability of grafts. Incidence of donors with positive serology for Chagas has varied from 0,4 to 1,1% of the donors pool in Brazil. Despite the possibility of disease transmission to recipients, our policy has been to utilize these grafts in hepatocellular carcinoma (HCC) or in urgent clinical conditions. Purpose: To analyze the results of LTx using donors with positive serology for Chagas. Methods and patients: From Sept/1997 to Dec/2013, 5 grafts with positive serology for Chagas disease were transplanted into 5 recipients with negative serology for that disease. Donors and recipients demographic date, waiting time on list (WTL), LTx indicators, patient survival and Chagas disease transmission incidence were analyzed. Serologies for Chagas were collected every 15 days in the first 3 months following the LTx, and monthly after for one year, or if recipients showed any symptom of acute Chagas disease. Results: All 5 recipients were male, age and weight ranging from 44-59 yrs and 74-86 kg, respectively, and WTL (days): 20 -1006. Donors age ranged from 48-72yrs, TGP: 13-69(U/L), Sodium: 142 -170 mMol/L, days on UTI: 3-8. All patients underwent LTx due to cirrhosis and hepatocarcinoma, except for one patient who needed urgent LTx due to acute hepatic artery thrombosis. One patient presented acute Chagas disease 6 months after LTx with good evolution after clinical treatment. 3 patients died after LTx; 1 due to bacterian meningitis (following use of OKT3 for treating steroid-resistant acute rejection) and 2 due to HCC recurrence at 22 and 48 months. The other 2 patients are alive at 9 and 10 years after LTx. Conclusion: Despite the small number of cases (n=5) of LTx using grafts with positive serology for Chagas disease, only 1 patient developed acute Chagas disease with good evolution after clinical treatment. From these still incipient results, our recommendation is that these grafts don't be automatically discarded and be destined preferably to recipients with tumors or in urgent LTx.

Basiliximab Induction in Renal Transplantation: Histopathologic Correlation.

INTRODUCTION: Acute rejection during the first year post-transplant is a key predictor of graft survival after renal transplantation. Use of induction therapy with interleukin-2 receptor (IL-2R) antagonist has been proven to be effective in reducing the rate of acute rejection in the first critical weeks and months post-transplant. PURPOSE: In this study, we retrospectively investigated the role of the anti-IL-2 receptor, basiliximab, as an induction immunosuppression and compared the histopathological patterns of rejection in the immediate post transplantation period between renal transplant recipients with or without IL-2 induction. RESULTS: Total of 92 biopsy proven acute rejection were seen within 3 months of transplantation. Majority of the rejection were acute T-cell mediated rejection, tubulointerstitial and vascular type (82 cases). Of the remaining 10 cases, eight were antibody mediated rejection and two were mixed rejection. IL-2 minus Group was associated with increased risk of early acute rejection (14.3%) as compared to IL-2 plus Group (9%). All T-cell mediated rejection were steroid responsive except for 2 cases of steroid-resistant rejection in IL-2 minus Group. In addition, higher Banff grade of rejection was seen in IL-2 minus Group (46.5%) as compared to IL-2 plus Group (42.5%) CONCLUSION: Induction treatment with IL-2 receptor antagonist was associated with a reduction in acute rejection episodes in the immediate post transplant period and majority of the rejection are of lower histologic grade.

The Antibody Treatment of Steroid-Resistant Rejection Following Pediatric Living Donor Liver Transplantation: A Single Center Experience.

The Antibody Treatment of Steroid-Resistant Rejection Following Pediatric Living Donor Liver Transplantation: A Single Center Experience.

Steroid-resistant acute rejection after cadaveric liver transplantation: Experience from one single center

Steroid-resistant acute rejection (SRAR) is an infrequent event under current immunosuppressant but still a risk factor leading to graft loss and patients' death after liver transplantation. There are several strategies for managing this complication according to current literatures, but none of the treatment seems convincing and widely accepted. Here we retrospectively analyzed the clinical data of a cohort of patients to gain an insight into this complication. A total of 962 adult patients receiving whole liver grafts at a single center between January 2004 and December 2012 were studied. One hundred and forty-two recipients experienced 158 episodes of acute rejection after the operation, 14 recipients had no response to steroid bolus treatment. The clinical data was analyzed retrospectively. Incidence rate of acute rejection after liver transplant in our single center was 14.7% (142/962), among them 8.8% (14/158) were steroid-resistant. These episodes occurred on 19days (6-72days) after the operation, 3 were controlled by anti-T3-receptor antibody (OKT3) treatment, 4 were reversed by IL-2 receptor inhibitors combining with MMF treatment, 2 were reversed by antithymocyte globulin (ATG) treatment. Five did not recover and 2 received retransplantation. Mortality associated with SRAR was 28.6% (4/14, 1 died from acute liver failure, 1 from chronic liver failure, 1 from renal failure after retransplantation and 1 from pulmonary infection after OKT3 treatment). SRAR is a severe complication with high mortality after liver transplantation; ATG might serve as a potential treatment.

Recurrence of primary sclerosing cholangitis in pediatric liver transplant recipients

There is little detailed clinical information on recurrent primary sclerosing cholangitis (rPSC) after liver transplantation in children. Our purpose was to describe the characteristics of children who had experienced rPSC after liver transplantation so that we could identify potential risk factors for recurrence. Clinical information for pediatric patients undergoing transplantation for primary sclerosing cholangitis (PSC) was retrospectively reviewed, and variables related to the pretransplant diagnosis of PSC and posttransplant variables were abstracted. The studied variables included the following: cytomegalovirus/Epstein-Barr virus status, early/late rejection, induction regimen, immunosuppression in the first year, steroid-resistant rejection, diagnosis of inflammatory bowel disease, and human leukocyte antigen markers commonly associated with PSC. A diagnosis of rPSC was made on the basis of radiographic features, histology, or both. Twelve patients underwent liver transplantation for PSC between 1993 and 2012. Patients received tacrolimus for maintenance immunosuppression after induction with steroids (n = 6) or thymoglobulin (n = 6). Three patients were diagnosed with rPSC 44, 60, and 62 months after transplantation. A fourth patient underwent retransplantation for graft failure with features of both hepatic artery stenosis and rPSC. This patient had distinct histological features of rPSC in the second graft. Three of the 4 patients were 7 years old or younger at the diagnosis of PSC. The patient and graft survival rates were similar for the steroid and thymoglobulin groups. All 4 children with rPSC received steroid-free thymoglobulin induction. In conclusion, our observation of an association between thymoglobulin, and age less than 10 years at the diagnosis of PSC, and rPSC adds to the existing suggestion of a link between the immune environment and the pathogenesis of rPSC. Defining the natural history of rPSC and searching for the etiology and risk factors of rPSC are important for the long-term outcomes of pediatric patients.

A Single-Center Experience of the Use of Interleukin-2 Receptor Antagonists for Various Situations in Liver Transplant Recipients

BackgroundInterleukin-2 receptor antagonists (IL2Ra) are used mainly for (1) induction as an adjunct to conventional immunosuppression, (2) induction to facilitate calcineurin inhibitor (CNI) or steroid minimization, and (3) induction to facilitate steroid avoidance in hepatitis C virus (HCV)-positive recipients. The aim of this study was to present our strategy for IL2Ra rescue therapy and its outcome. MethodsA total of 20 patients were treated with IL2Ra at our institute for the following indications: (1) rescue for acute rejection (n = 13), (2) CNI sparing in cases of CNI toxicity (n = 5), and (3) induction for complicated cases (n = 2). ResultsRescue therapy for steroid-resistant rejection and rejection in HCV-positive recipients was successful in 11 cases, but 2 grafts were lost due to uncontrollable rejection. CNI cessation was successfully achieved with IL2Ra treatment in 3 cases with thrombotic microangiopathy and 2 cases of encephalopathy, with complete cure of these life-threatening complications of CNI. Induction with IL2Ra was successful in 2 complicated cases, 1 for CNI sparing due to renal failure and the other for adjunct immunosuppression in a case of positive lymphocytotoxic crossmatch. The overall patient/graft survival and the rate of infectious complications were comparable between those with and without IL2Ra treatment. ConclusionsIL2Ra could be safely and effectively used after liver transplantation in various situations.

Monoclonal antibody therapy and renal transplantation: focus on adverse effects.

A series of monoclonal antibodies (mAbs) are commonly utilized in renal transplantation as induction therapy (a period of intense immunosuppression immediately before and following the implant of the allograft), to treat steroid-resistant acute rejections, to decrease the incidence and mitigate effects of delayed graft function, and to allow immunosuppressive minimization. Additionally, in the last few years, their use has been proposed for the treatment of chronic antibody-mediated rejection, a major cause of late renal allograft loss. Although the exact mechanism of immunosuppression and allograft tolerance with any of the currently used induction agents is not completely defined, the majority of these medications are targeted against specific CD proteins on the T or B cells surface (e.g., CD3, CD25, CD52). Moreover, some of them have different mechanisms of action. In particular, eculizumab, interrupting the complement pathway, is a new promising treatment tool for acute graft complications and for post-transplant hemolytic uremic syndrome. While it is clear their utility in renal transplantation, it is also unquestionable that by using these highly potent immunosuppressive agents, the body loses much of its innate ability to mount an adequate immune response, thereby increasing the risk of severe adverse effects (e.g., infections, malignancies, haematological complications). Therefore, it is extremely important for clinicians involved in renal transplantation to know the potential side effects of monoclonal antibodies in order to plan a correct therapeutic strategy minimizing/avoiding the onset and development of severe clinical complications.

A Comparison of Outcomes Between OKT3 and Antithymocyte Globulin for Treatment of Steroid-Resistant Rejection in Hepatitis C Liver Transplant Recipients

The treatment of steroid-resistant rejection (SRR) is associated with severe recurrent hepatitis C virus (HCV) infection after liver transplantation (LTx). After OKT3 was recently withdrawn from the market, thymoglobulin (TG) became the principal treatment for SRR. A retrospective analysis of 32 HCV patients who were treated for SRR with OKT3 (n=15) or TG (n=17) using yearly protocol liver biopsies. Mean follow-up was 4.3 years (OKT3) and 3.2 years (TG). We compared both groups for patient survival, graft loss, and severity of HCV recurrence, manifested as the mean stage of fibrosis (MSF). Patient survival at 1, 2, and 5 years after LTx was 80%, 73%, and 67% in the OKT3 group and 82%, 77%, and 64% in the TG group, respectively. At 2 years after LTx, the graft losses were 3 versus 4 in the OKT3 and TG groups, respectively. At years 1 and 2, the MSF in the OKT3 group was 1.9 and 2.3 versus 2.4 and 2.8 in the TG group, respectively. None of the differences between both groups was statistically significant. There was no significant difference in patient survival, graft loss, or severity of recurrent HCV, measured as MSF, between both groups.

Analysis of the diagnosis and treatment of acute steroid-resistant rejection after liver transplantation

The main feature of acute steroid-resistant rejection (ASRR) after liver transplantation is a lack of response to steroids.Although some effective immunosuppressants are available,there is no uniform treatment presently available.This paper will focus on exploring the mechanism of ASRR and formulating individually approached strategies. Key words: Liver transplantation; Acute steroid-resistant rejections; Diagnosis; Treatment