Long-term Follow-up of ABO-Incompatible Kidney Transplantation in Freiburg, Germany: A Single-Center Outcome Report.

BACKGROUND: ABO-incompatible kidney transplantation (ABOi-KT) is an established way to enlarge the donor pool around the world. Comparability of long-term success and complications to ABO-compatible kidney transplantation (ABOc-KT) are still under debate. METHODS: We evaluated all patients with a living donor kidney transplantation performed between April 1, 2004, and March 31, 2019. RESULTS: A total of 137 ABOi-KT and 346 ABOc-KT were analyzed. We excluded 4 ABOi-KT recipients and 178 ABOc-KT recipients with cyclosporine A-based immunosuppression or without basiliximab induction. Three patients of the ABOi-KT cohort and 6 patients of the ABOc-KT cohort were lost to follow-up and therefore excluded. The patient characteristics were comparable except for the higher age of transplant recipients in the ABOc-KT cohort and longer follow-up of the ABOi-KT cohort. The mean estimated 15-year recipient survival was 89% in the ABOi-KT cohort and 91% in the ABOc-KT cohort (P = .39). Mean estimated graft survival was 71% in the ABOi-KT cohort and 87% in the ABOc-KT cohort (P = .68). The estimated glomerular filtration rate (Modification of Diet in Renal Disease) measured in the last follow-up was 51 mL/min/1.73 m2 in the ABOi-KT cohort and 50 mL/min/1.73 m2 in the ABOc-KT cohort (P = .36). The incidence for antibody-mediated rejection, T cell-mediated rejections, and infectious complications requiring hospitalization was not different between the cohorts. In the ABOi-KT cohort, we found significantly more lymphoceles and consequent surgical revision procedures. CONCLUSIONS: At our center, ABOi-KT has as good long-term results as ABOc-KT in terms of patient survival, graft survival, and complications, with the exception of increased lymphocele formation.

Malignancy With Immunosuppression After Renal Transplantation: A Competing Risk Analysis.

OBJECTIVES: This study analyzed clinical characteristics of renal transplant recipients who developed malignancy with immunosuppression after transplantation by applying a competing risk analysis to reduce the effects of competing events. METHODS: All patients who underwent renal transplantation at our institution from 1973 to 2017 were included in this analysis. All data were collected from patient medical records and retrospectively analyzed. The cumulative incidence of malignancy before allograft loss and its risk factors were calculated by a competing risk analysis, the Gray test, and the Fine-Gray proportional hazard model. RESULTS: Of the 596 recipients, 78 developed malignancies. The mean age at transplantation was 38.5 ± 13.1 years. The median time from transplantation to the initial malignancy was 147.0 (5.2-407.3) months. The most common initial malignancy was skin cancer (21.8%), followed by posttransplant lymphoproliferative disease (14.1%). The cumulative incidence of malignancy at 20 years was 16.2% according to a competing risk analysis, whereas the conventional Kaplan-Meier method estimated the cumulative incidence at 20 years to be 25.6%. Increasing age at transplantation was significantly associated with the incidence of malignancy (P = .0091). Overall 10-year survival rates of recipients with and without malignancy were 81.7% and 88.5%, respectively (P < .001). CONCLUSIONS: Results of time-to-event analysis must be interpreted with caution in situations with competing events when estimating the cumulative incidence of malignancy with immunosuppression after renal transplantation. Renal transplant recipients with increasing age should be more carefully monitored as a high-risk population for developing malignancies.

Increased Immunosuppression Is Related to Increased Amounts of Ascites and Inferior Prognosis in Ovarian Cancer.

BACKGROUND/AIM: The presence of ascites in ovarian cancer patients is considered a negative prognostic factor. The underlying mechanisms are not clearly understood. MATERIALS AND METHODS: The amount of ascites was evaluated, preferably, using diffusion-weighted MRI at primary diagnosis in a retrospective cohort of 214 women with ovarian cancer, in an ordinal manner (amount of ascites: none, limited, moderate, abundant). In a prospective cohort comprising 45 women with ovarian cancer, IL-10 (interleukin), VEGF (vascular endothelial growth factor), TGF-ß (transforming growth factor) and CCL-2 [chemokine (C-C) motif ligand 2] were measured at diagnosis (and at interval debulking, when available). RESULTS: Gradually increasing amounts of ascites were correlated significantly, even after correction for FIGO stage, with reduced survival (p<0.0001) and stronger immunosuppression (IL10 and VEGF). Neoadjuvant chemotherapy reduced immunosuppression, which was observed as a reduction in CCL-2, IL-10 and VEGF. CONCLUSION: The amount of ascites is an independent predictor of survival and correlates with increased immunosuppression.

Immunosuppression reduction in kidney transplant recipients during bacterial infection-A retrospective study.

BACKGROUND: Immunosuppression reduction is a common practice in the management of bacterial infection among kidney transplant recipients (KTRs). This practice, however, is based on limited evidence. METHODS: Retrospective study comparing clinical outcomes of KTRs whose antimetabolite was discontinued vs continued during hospitalization due to bacterial infection, considering calcineurin inhibitors (CNI) levels. Primary outcome was a composite of clinical failure at day 5; all-cause mortality; and/or re-hospitalization at 90 days. Multivariable analysis of risk factors for the primary outcome was performed using a propensity-matched cohort. RESULTS: We included 183 KTRs hospitalized with bacterial infection. Neither discontinuation of antimetabolites nor lower levels of CNI at infection onset were associated with a significant decrease the composite primary outcome. No significant difference in graft loss or rejection was demonstrated between patients with low vs high CNI levels or discontinuation vs continuation of antimetabolite. In multivariable analysis, CNI levels and management of antimetabolite were not significantly associated with adverse outcome. CONCLUSIONS: Immunosuppression reduction in hospitalized KTRs with bacterial infection did not offer a clinical advantage in terms of mortality, re-hospitalization, or clinical success. An interventional study evaluating continuation of immunosuppression vs reduction should be considered.

The impact of immunosuppression on postoperative graft function after graft-unrelated surgery: a retrospective controlled cohort study.

BACKGROUND: Physicians are faced with a growing number of patients after renal transplantation undergoing graft-unrelated surgery. So far, little is known about the postoperative restitution of graft function and the risk factors for a poor outcome. METHODS: One hundred one kidney transplant recipients undergoing graft-unrelated surgery between 2005 and 2015 were reviewed retrospectively. A risk analysis was performed and differences in creatinine, GFR and immunosuppressive treatment were evaluated. Additional, a comparison with a case-matched non-transplanted control group were performed. RESULTS: Preoperative creatinine averaged 1.88 mg / dl [0.62-5.22 mg / dl] and increased to 2.49 mg / dl [0.69-8.30 mg / dl] postoperatively. Acute kidney failure occurred in 18 patients and 14 patients had a permanent renal failure. Significant risk factors for the development of postoperative renal dysfunction were female gender, a preoperative creatinine above 2.0 mg / dl as well as a GFR below 40 ml / min and emergency surgery. Patients with tacrolimus and mycophenolate mofetil treatment showed a significant lower risk of renal dysfunction than patients with other immunosuppressants postoperatively. Contrary to that, the risk of patients with cyclosporine treatment was significantly increased. Transplanted patients showed a significantly increased rate of postoperative renal dysfunction. CONCLUSIONS: The choice of immunosuppressant might have an impact on graft function and survival of kidney transplant recipients after graft-unrelated surgery. Further investigations are needed.

Comparison of Outcomes of Frontline Immunosuppressive Therapy and Frontline Haploidentical Hematopoietic Stem Cell Transplantation for Children with Severe Aplastic Anemia Who Lack an HLA-Matched Sibling Donor.

We compared the outcomes of immunosuppressive therapy (IST) with those of T cell-replete haploidentical donor hematopoietic stem cell transplantation (haplo-HSCT) in children and adolescents with severe aplastic anemia (SAA). The medical records of 49 patients with SAA who received frontline IST (n = 29) or frontline haplo-HSCT (n = 20) between 2012 and 2016 were analyzed retrospectively. Fourteen patients responded after the first IST, and 1 patient responded after the second IST in the frontline IST group; 12 patients underwent salvage HSCT after IST failure. Sixteen of the 20 patients who underwent frontline haplo-HSCT survived without treatment failure. The 3-year overall survival of the frontline IST group was comparable to that of the frontline haplo-HSCT group (79.3 ± 7.5% versus 85.0 ± 8.0%; χ2 = 0.110; P = .740). The 3-year failure-free survival was lower in the frontline IST group compared with the frontline haplo-HSCT group (35.9 ± 10.9% versus 80.0 ± 8.9%; χ2 = 4.089; P = .043). Five patients of the IST group who underwent salvage HSCT achieved long survival without event. The event-free survival was lower in the salvage HSCT group compared with the haplo-HSCT group (41.7 ± 14.2% versus 80.0 ± 8.9%; χ2 = 3.992; P = .046), and the incidences of acute GVHD, grade II-IV acute GVHD, chronic GVHD, and severe infection were comparable between the 2 groups. Our results suggest that frontline haplo-HSCT may be a better treatment than IST for children and adolescents with SAA who lack an HLA age-matched familial donor.

Favorable impact of extracorporeal photopheresis in acute and chronic graft versus host disease: Prospective single-center study.

BACKGROUND: Graft vs host disease (GVHD) is the most severe complication of allogeneic hematopoietic cell transplantation. Conventional immunosuppressive therapy increases morbidity and mortality without improving survival. Extracorporeal photopheresis (ECP) has been introduced as an alternative treatment in steroid-dependent and steroid-refractory disease. STUDY DESIGN AND METHODS: We studied the safety and efficacy of ECP as a second- or third-line treatment in GVHD. RESULTS: ECP was administered in 21 patients with grade III-IV acute GVHD and 88 patients with extensive chronic GVHD, without ECP-related adverse events. Eight patients receiving four or less ECP sessions were not further analyzed. The majority of acute GVHD patients (84%) presented partial (15) or complete (1) response to ECP. Immunosuppression was reduced in 10 of 19 patients and ceased in 1 of 19 patients. One-year cumulative incidence (CI) of transplant-related mortality (TRM) (17.6%) was associated with the lack of response to ECP and steroid refractoriness. With a follow-up of 17.5 (1.8-58.3) months, 1-year overall survival (OS) (52.5%) was independently associated with a higher number of ECP sessions. Regarding chronic GVHD, complete response was achieved in 35 patients, whereas partial response in 25 patients, leading to an overall response rate of 73%. Cutaneous sclerosis manifestations were associated with higher response rates. With a follow-up of 68.1 (5.4-283.1) months, 5-year CI of TRM (24.1%) was associated only with a number of ECP sessions. The 5-year OS (64.5%) was independently associated with number of ECP sessions and cutaneous manifestations. CONCLUSION: Our findings suggest that ECP is safe and effective for GVHD and should be considered early in the course of GVHD, before irreversible end-organ damage has been established.

Outcomes among North American patients with diffuse large B-cell lymphoma are independent of tumor Epstein-Barr virus positivity or immunosuppression.

The prevalence, presenting clinical and pathological characteristics, and outcomes for patients with diffuse large B-cell lymphoma that is Epstein-Barr virus positive remain uncertain as does the impact of congenital or iatrogenic immunosuppression. Patients with newly diagnosed diffuse large B-cell lymphoma with available tissue arrays were identified from the University of Iowa/Mayo Clinic Molecular Epidemiology Resource. Patients infected with human immunodeficiency virus or who had undergone a prior organ transplant were excluded. Epstein-Barr virus-associated ribonucleic acid testing was performed on all tissue arrays. A history of significant congenital or iatrogenic immunosuppression was determined for all patients. At enrollment, 16 of the 362 (4.4%) biopsies were positive for Epstein-Barr virus. Thirty-nine (10.8%) patients had a significant history of immunosuppression. Patients with Epstein-Barr-positive diffuse large B-cell lymphoma had no unique clinical characteristics but on pathology exhibited a higher frequency of CD30 positivity (25.0% versus 8.1%, respectively; P<0.01), and non-germinal-center subtype (62.5% versus 34.1%, respectively; P<0.01). No baseline clinical characteristics were associated with a history of immunosuppression. With a median follow up of 59 months, and after adjustment for International Prognostic Index, there was no association of Epstein-Barr virus positivity or immunosuppression with event-free survival at 24 months (odds ratio=0.49; 95% confidence interval: 0.13-1.84 and odds ratio=0.81; 95% confidence interval: 0.37-1.77) or overall survival (hazard ratio=0.86; 95% confidence interval: 0.38-1.97 and hazard ratio=1.00; 95% confidence interval: 0.57-1.74). In contrast to non-Western populations, our North American population had a low prevalence of Epstein-Barr virus-positive diffuse large B-cell lymphoma that did not convey an adverse prognosis. A history of immunosuppression, while known to be a risk factor for the development of diffuse large B-cell lymphoma, did not affect subsequent prognosis.

Maintenance immunosuppression for adults undergoing liver transplantation: a network meta-analysis.

BACKGROUND: As part of liver transplantation, immunosuppression (suppressing the host immunity) is given to prevent graft rejections resulting from the immune response of the body against transplanted organ or tissues from a different person whose tissue antigens are not compatible with those of the recipient. The optimal maintenance immunosuppressive regimen after liver transplantation remains uncertain. OBJECTIVES: To assess the comparative benefits and harms of different maintenance immunosuppressive regimens in adults undergoing liver transplantation through a network meta-analysis and to generate rankings of the different immunosuppressive regimens according to their safety and efficacy. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until October 2016 to identify randomised clinical trials on immunosuppression for liver transplantation. SELECTION CRITERIA: We included only randomised clinical trials (irrespective of language, blinding, or publication status) in adult participants undergoing liver transplantation (or liver retransplantation) for any reason. We excluded trials in which participants had undergone multivisceral transplantation or participants with established graft rejections. We considered any of the various maintenance immunosuppressive regimens compared with each other. DATA COLLECTION AND ANALYSIS: We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio, rate ratio, and hazard ratio (HR) with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS: We included a total of 26 trials (3842 participants) in the review, and 23 trials (3693 participants) were included in one or more outcomes in the review. The vast majority of the participants underwent primary liver transplantation. All of the trials were at high risk of bias, and all of the evidence was of low or very low quality. In addition, because of sparse data involving trials at high risk of bias, it is not possible to entirely rely on the results of the network meta-analysis. The trials included mainly participants undergoing primary liver transplantation of varied aetiologies. The follow-up in the trials ranged from 3 to 144 months. The most common maintenance immunosuppression used as a control was tacrolimus. There was no evidence of difference in mortality (21 trials; 3492 participants) or graft loss (15 trials; 2961 participants) at maximal follow-up between the different maintenance immunosuppressive regimens based on the network meta-analysis. In the direct comparison, based on a single trial including 222 participants, tacrolimus plus sirolimus had increased mortality (HR 2.76, 95% CrI 1.30 to 6.69) and graft loss (HR 2.34, 95% CrI 1.28 to 4.61) at maximal follow-up compared with tacrolimus. There was no evidence of differences in the proportion of people with serious adverse events (1 trial; 719 participants), proportion of people with any adverse events (2 trials; 940 participants), renal impairment (8 trials; 2233 participants), chronic kidney disease (1 trial; 100 participants), graft rejections (any) (16 trials; 2726 participants), and graft rejections requiring treatment (5 trials; 1025 participants) between the different immunosuppressive regimens. The network meta-analysis showed that the number of adverse events was lower with cyclosporine A than with many other immunosuppressive regimens (12 trials; 1748 participants), and the risk of retransplantation (13 trials; 1994 participants) was higher with cyclosporine A than with tacrolimus (HR 3.08, 95% CrI 1.13 to 9.90). None of the trials reported number of serious adverse events, health-related quality of life, or costs. FUNDING: 14 trials were funded by pharmaceutical companies who would benefit from the results of the trial; two trials were funded by parties who had no vested interest in the results of the trial; and 10 trials did not report the source of funding. AUTHORS' CONCLUSIONS: Based on low-quality evidence from a single small trial from direct comparison, tacrolimus plus sirolimus increases mortality and graft loss at maximal follow-up compared with tacrolimus. Based on very low-quality evidence from network meta-analysis, we found no evidence of difference between different immunosuppressive regimens. We found very low-quality evidence from network meta-analysis and low-quality evidence from direct comparison that cyclosporine A causes more retransplantation compared with tacrolimus. Future randomised clinical trials should be adequately powered; performed in people who are generally seen in the clinic rather than in highly selected participants; employ blinding; avoid postrandomisation dropouts or planned cross-overs; and use clinically important outcomes such as mortality, graft loss, renal impairment, chronic kidney disease, and retransplantation. Such trials should use tacrolimus as one of the control groups. Moreover, such trials ought to be designed in such a way as to ensure low risk of bias and low risks of random errors.

[Safety and efficacy of preoperative induction therapy using a single high dose ATG-F in renal transplantation: a meta-analysis of randomized controlled trials].

OBJECTIVE: This study aimed to evaluate the safety and efficacy of preoperative induction therapy using a single high dose (9 mg/kg) of antithymocyte globulin-Fresenius S (ATG-F) for patients undergoing renal transplantation. METHODS: Randomized controlled clinical trials (RCTs) on the safety and efficacy of preoperative induction therapy using a single high dose of ATG-F for patients undergoing renal transplantation were searched in Cochrane Library, PubMed, EMBASE covering a period from the beginning of databases to July 2015. The meta-analysis was conducted using RevMan 5.2. RESULTS: Five RCTs with 346 patients were included in this study. The meta-analysis showed that the incidences of acute rejection for the patients with renal transplantation were 20.6% (37/180) in the induction therapy group using a single high dose of ATG and 42.8% (71/166) in the control group, with a combined relative risk (RR) of 0.49 and 95% confidence interval (CI) of[0.36, 0.69](P<0.000 1). The patient survival rate (1 year: RR=1.02, 95% CI[0.98, 1.06], P=0.43; 5 years: RR=1.01, 95% CI[0.94, 1.08], P=0.83) and the graft survival rate (RR=1.04, 95% CI[0.97, 1.12], P=0.24) of the two groups were similar. The incidences of CMV infection, urinary tract infection, and malignant tumor were also similar in the two groups. CONCLUSION: The induction therapy using a single high dose of ATG-F significantly reduced the incidence of acute rejection after transplantation and showed no increased incidence of urinary tract infection, CMV infection, or malignant tumor. The results of our meta-analysis suggest that the application of a high dose of ATG-F may be a safe and effective induction therapy.

Induction Immunosuppressive Therapy Use in Deceased Donor Kidney Transplantation: 11-Year Experience in Veracruz, Mexico.

BACKGROUND: Induction therapy reduces the frequency of acute rejection and delayed graft function in renal transplantation. Basiliximab and Thymoglobulin are most commonly used agents for induction. METHODS: A retrospective study of two transplant centers in Veracruz, Mexico compared induction therapy in deceased donor renal transplantation from 2003 to 2014. Efficacy and safety outcomes evaluated were primary graft nonfunction, delayed graft function, acute rejection episodes and hospitalizations during first year, and patient and graft survival. P < .05 was considered statistically significant. RESULTS: Seventy deceased kidney donors (40 male) were studied. Mean donor age was 32.9 ± 14.3 years, mean donor BMI 25.6 ± 4.3 kg/m(2), and mean donor creatinine 1.13 ± 0.58 mg/dL. Main cause of death was trauma (62.9%). In total, 125 kidney transplantations were performed, with female predominance (53.6%) and mean age 33.8 ± 11.8 years. Of these, 66.4% used basiliximab and 33.6% Thymoglobulin. Thymoglobulin patients were significantly older, with lower weight and BMI, and were on dialysis longer than basiliximab patients. DGF was present in 19.3% of basiliximab patients vs 16.7% in Thymoglobulin patients, acute rejection occurred in 16.9% of basiliximab patients vs 19% Thymoglobulin patients. A total of 33.7% basiliximab patients were hospitalized during the first year vs 47.6% Thymoglobulin-induced patients (P > .05). Mean graft survival was 84.2 ± 5.3 months (73.8-94.7) basiliximab vs 32.4 ± 28.7 months (28.7-36.1) Thymoglobulin, Kaplan-Meier survival did not show statistically significant differences between groups (P = .276; CI 95%). CONCLUSION: Similar transplant outcomes were obtained using basiliximab or Thymoglobulin induction in our population.

Analysis of adult 20-year survivors after liver transplantation.

BACKGROUND: Liver transplantation (LT) is the treatment of choice for chronic and acute liver failure; however, the status of long-term survivors and allograft function is not well known. AIM: To evaluate the clinical outcome and allograft function of survivors 20 years post-LT, cause of death during the same period and risk factors of mortality. METHODS: A retrospective study was conducted from prospective, longitudinal data collected at a single center of adult LT recipients surviving 20 years. A comparative sub-analysis was made with patients who were not alive 20 years post-transplantation to identify the causes of death and risk factors of mortality. RESULTS: Between 1988 and 1994, 132 patients received 151 deceased-donors LT and 28 (21%) survived more than 20 years. Regarding liver function in this group, medians of AST, ALT and total bilirubin at 20 years post-LT were 33 IU/L (13-135 IU/L), 27 (11-152 IU/L) and 0.6 mg/dL (0.3-1.1 mg/dL). Renal dysfunction was observed in 40% of patients and median eGFR among 20-year survivors was 64 mL/min/1.73 m(2) (6-144 mL/min/1.73 m(2)). Sixty-one percent of 20-year survivors had arterial hypertension, 43% dyslipidemia, 25% de novo tumors and 21% diabetes mellitus. Infections were the main cause of death during the 1st year post-transplant (32%) and between the 1st and 5th year post-transplant (25%). After 5th year from transplant, hepatitis C recurrence (22%) became the first cause of death. Factors having an impact on long-term patient survival were HCC indication (p = 0.049), pre-transplant renal dysfunction (p = 0.043) and long warm ischemia time (p = 0.016); furthermore, post-transplant factors were diabetes mellitus (p = 0.001) and liver dysfunction (p = 0.05) at 1 year. CONCLUSION: Our results showed the effect of immunosuppression used during decades on long-term outcome in our LT patients in terms of morbidity (arterial hypertension, diabetes mellitus, dyslipidemia and renal dysfunction) and mortality (infections and hepatitis C recurrence).

Antibody induction versus placebo, no induction, or another type of antibody induction for liver transplant recipients.

BACKGROUND: Liver transplantation is an established treatment option for end-stage liver failure. To date, no consensus has been reached on the use of immunosuppressive T-cell antibody induction for preventing rejection after liver transplantation. OBJECTIVES: To assess the benefits and harms of immunosuppressive T-cell specific antibody induction compared with placebo, no induction, or another type of T-cell specific antibody induction for prevention of acute rejection in liver transplant recipients. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) until September 2013. SELECTION CRITERIA: Randomised clinical trials assessing immunosuppression with T-cell specific antibody induction compared with placebo, no induction, or another type of antibody induction in liver transplant recipients. Our inclusion criteria stated that participants within each included trial should have received the same maintenance immunosuppressive therapy. We planned to include trials with all of the different types of T-cell specific antibodies that are or have been used for induction (ie., polyclonal antibodies (rabbit of horse antithymocyte globulin (ATG), or antilymphocyte globulin (ALG)), monoclonal antibodies (muromonab-CD3, anti-CD2, or alemtuzumab), and interleukin-2 receptor antagonists (daclizumab, basiliximab, BT563, or Lo-Tact-1)). DATA COLLECTION AND ANALYSIS: We used RevMan analysis for statistical analysis of dichotomous data with risk ratio (RR) and of continuous data with mean difference (MD), both with 95% confidence intervals (CIs). We assessed the risk of systematic errors (bias) using bias risk domains with definitions. We used trial sequential analysis to control for random errors (play of chance). We presented outcome results in a summary of findings table. MAIN RESULTS: We included 19 randomised clinical trials with a total of 2067 liver transplant recipients. All 19 trials were with high risk of bias. Of the 19 trials, 16 trials were two-arm trials, and three trials were three-arm trials. Hence, we found 25 trial comparisons with antibody induction agents: interleukin-2 receptor antagonist (IL-2 RA) versus no induction (10 trials with 1454 participants); monoclonal antibody versus no induction (five trials with 398 participants); polyclonal antibody versus no induction (three trials with 145 participants); IL-2 RA versus monoclonal antibody (one trial with 87 participants); and IL-2 RA versus polyclonal antibody (two trials with 112 participants). Thus, we were able to compare T-cell specific antibody induction versus no induction (17 trials with a total of 1955 participants). Overall, no difference in mortality (RR 0.91; 95% CI 0.64 to 1.28; low-quality of evidence), graft loss including death (RR 0.92; 95% CI 0.71 to 1.19; low-quality of evidence), and adverse events ((RR 0.97; 95% CI 0.93 to 1.02; low-quality evidence) outcomes was observed between any kind of T-cell specific antibody induction compared with no induction when the T-cell specific antibody induction agents were analysed together or separately. Acute rejection seemed to be reduced when any kind of T-cell specific antibody induction was compared with no induction (RR 0.85, 95% CI 0.75 to 0.96; moderate-quality evidence), and when trial sequential analysis was applied, the trial sequential monitoring boundary for benefit was crossed before the required information size was obtained. Furthermore, serum creatinine was statistically significantly higher when T-cell specific antibody induction was compared with no induction (MD 3.77 µmol/L, 95% CI 0.33 to 7.21; low-quality evidence), as well as when polyclonal T-cell specific antibody induction was compared with no induction, but this small difference was not clinically significant. We found no statistically significant differences for any of the remaining predefined outcomes - infection, cytomegalovirus infection, hepatitis C recurrence, malignancy, post-transplant lymphoproliferative disease, renal failure requiring dialysis, hyperlipidaemia, diabetes mellitus, and hypertension - when the T-cell specific antibody induction agents were analysed together or separately. Limited data were available for meta-analysis on drug-specific adverse events such as haematological adverse events for antithymocyte globulin. No data were found on quality of life.When T-cell specific antibody induction agents were compared with another type of antibody induction, no statistically significant differences were found for mortality, graft loss, and acute rejection for the separate analyses. When interleukin-2 receptor antagonists were compared with polyclonal T-cell specific antibody induction, drug-related adverse events were less common among participants treated with interleukin-2 receptor antagonists (RR 0.23, 95% CI 0.09 to 0.63; low-quality evidence), but this was caused by the results from one trial, and trial sequential analysis could not exclude random errors. We found no statistically significant differences for any of the remaining predefined outcomes: infection, cytomegalovirus infection, hepatitis C recurrence, malignancy, post-transplant lymphoproliferative disease, renal failure requiring dialysis, hyperlipidaemia, diabetes mellitus, and hypertension. No data were found on quality of life. AUTHORS' CONCLUSIONS: The effects of T-cell antibody induction remain uncertain because of the high risk of bias of the randomised clinical trials, the small number of randomised clinical trials reported, and the limited numbers of participants and outcomes in the trials. T-cell specific antibody induction seems to reduce acute rejection when compared with no induction. No other clear benefits or harms were associated with the use of any kind of T-cell specific antibody induction compared with no induction, or when compared with another type of T-cell specific antibody. Hence, more randomised clinical trials are needed to assess the benefits and harms of T-cell specific antibody induction compared with placebo, and compared with another type of antibody, for prevention of rejection in liver transplant recipients. Such trials ought to be conducted with low risks of systematic error (bias) and low risk of random error (play of chance).

Trends of Immunosuppression and Outcomes Following Liver Transplantation: An Analysis of the United Network for Organ Sharing Registry.

Advances in immunosuppression (IS) agents and strategies have resulted in reduced rejection rates and improved survival outcomes after liver transplantation. The use of induction and maintenance IS agents is both associated with reductions in acute rejection (AR) risk within the first 6 to 12 months posttransplant and with superior failure-free survival. With the lowered incidence of allograft losses attributable to rejection, the long-term sequelae of IS have become the major therapeutic challenge. The long-term use of calcineurin inhibitors and corticosteroids in maintenance immunotherapy regimens has been implicated in the development of renal dysfunction, infections, metabolic derangements, de novo and recurrent malignancies, and the propagation of hepatitis C virus reinfection. Our analysis of the United Network for Organ Sharing registry shows the use of induction and maintenance therapy is each associated with reductions in AR risk, thereby improving post-transplant survival. The administration of intensive induction regimens appears to be safe and exhibits an additive beneficial effect. Therefore, the use of intensive induction regimens may be warranted to allow for reductions in long-term maintenance IS to minimize drug toxicities while preserving graft outcomes.

Completely steroid-free immunosuppression in liver transplantation: a randomized study.

INTRODUCTION: Corticosteroids (CS) have been standard immunosuppression to prevent and treat rejection. However, CS are associated with increased risk of infection, obesity, hypertension, hyperlipidemia, diabetes, and accelerated hepatitis C virus (HCV) recurrence post-orthotopic liver transplantation (OLT). This study assesses the safety and efficacy of CS-free immunosuppressive regimen in adult OLT. METHODS: A two-yr, prospective, randomized study of CS with delayed withdrawal (CS) or CS-free regimen with basiliximab, tacrolimus, and enteric-coated mycophenolate sodium (EC-MPS) was performed in 39 patients (CS=20; CS-free=19). CS group received intra-operative methylprednisolone weaned by six months. HCV patients had HCV PCR pre-OLT and 0.5, one, three, and six months post-OLT. Protocol liver biopsies were performed at OLT, 2 and 24 wk post-OLT or when indicated. RESULTS: Rejection occurred in two patients. Patient survival at one yr (100% vs. 95%), three yr (85% vs. 63%), and five yr (80% vs. 63%) post-OLT were similar between CS and CS-free group, respectively. Death-censored graft survival at one yr (100% vs. 95%), three yr (85% vs. 63%), and five yr (75% vs. 63%) were also similar. The risk of new-onset DM, hypertension, hypercholesterolemia, and weight gain was similar between groups. CONCLUSION: CS avoidance with basiliximab, calcineurin inhibitor, and EC-MPS is safe and effective as CS- containing immunosuppression in adult OLT.

Immunosuppression with tacrolimus early after orthotopic heart transplantation: a comparison of prograf and advagraf.

BACKGROUND: We compared trough levels and clinical outcomes in patients who received Prograf or Advagraf (tacrolimus) de novo following heart transplantation surgery. METHODS: Eighty-two patients were included in this follow-up study. Biopsy results were controlled for the first 3 months after orthotopic heart transplantation. Trough levels were monitored for 4 weeks: daily during the first 7 days and once every week thereafter. The lengths of stay in the hospital and in intensive care were compared. The end point of the study was the 1-year mortality rate. RESULTS: We found significant differences between the groups for both biopsy results and trough levels. Trough levels differed for the first 5 days and then converged on the sixth day. The levels remained comparable throughout the monitoring period. The 1-year mortality rates for Prograf and Advagraf were 20% and 15%, respectively. CONCLUSIONS: Trough levels were comparable after an adjustment period. There were no differences between the 2 groups in their 1-year mortality rates. These results suggest that Advagraf is a safe alternative to Prograf for patients who have undergone heart transplantation.

Human leukocyte antigen mismatches associated with increased risk of rejection, graft failure, and death independent of initial immunosuppression in renal transplant recipients.

Human leukocyte antigen (HLA) mismatches have been shown to adversely affect renal allograft outcomes and remain an important component of the allocation of deceased donor (DD) kidneys. The ongoing importance of HLA mismatches on transplant outcomes in the era of more potent immunosuppression remains debatable. Using Australia and New Zealand Dialysis and Transplant Registry, live and DD renal transplant recipients between 1998 and 2009 were examined. The association between the number of HLA mismatches and HLA-loci mismatches and outcomes were examined. Of the 8036 renal transplant recipients, 59% had between 2 and 4 HLA mismatches. Compared with 0 HLA mismatch, increasing HLA mismatches were associated with a higher risk of graft failure and patient death in the adjusted models. HLA mismatches were associated with an incremental risk of rejection although the relative risk was higher for live donor kidney transplants. Increasing HLA-AB and HLA-DR mismatches were associated with a greater risk of acute rejection, graft failure, death-censored graft failure, and/or death. There was no consistent association between initial immunosuppressive regimen and outcomes. Our results corroborate and extend the previous registry analyses demonstrating that HLA mismatches are associated with poorer transplant outcomes independent of immunosuppression and transplant era.

Effect of reduced immunosuppression after kidney transplant failure on risk of cancer: population based retrospective cohort study.

OBJECTIVE: To compare cancer incidence in kidney transplant recipients during periods of transplant function (and immunosuppression) and after transplant failure (when immunosuppression is ceased or reduced). Design, setting, and participants Nationwide, population based retrospective cohort study of 8173 Australian kidney transplant recipients registered on the Australia and New Zealand Dialysis and Transplant Registry who first received a transplant during 1982-2003. Incident cancers were ascertained using linkage with national cancer registry records. MAIN OUTCOME MEASURES: Cancer-specific standardised incidence ratios for periods of transplant function and for dialysis after transplant failure. Incidence was compared between periods using multivariate incidence rate ratios adjusted for current age, sex, and duration of transplantation. RESULTS: All cases of Kaposi's sarcoma occurred during transplant function. Standardised incidence ratios were significantly elevated during transplant function, but not during dialysis after transplant failure, for non-Hodgkin's lymphoma, lip cancer, and melanoma. For each of these cancers, incidence was significantly lower during dialysis after transplant failure in multivariate analysis (incidence rate ratios 0.20 (95% CI 0.06 to 0.65) for non-Hodgkin's lymphoma, 0.04 (0.01 to 0.31) for lip cancer, and 0.16 (0.04 to 0.64) for melanoma). In contrast, standardised incidence ratios during dialysis after transplant failure remained significantly elevated for leukaemia and lung cancer, and cancers related to end stage kidney disease (kidney, urinary tract, and thyroid cancers), with thyroid cancer incidence significantly higher during dialysis after transplant failure (incidence rate ratio 6.77 (2.64 to 17.39)). There was no significant difference in incidence by transplant function for other cancers. CONCLUSIONS: The effect of immunosuppression on cancer risk is rapidly reversible for some, but not all, cancer types. Risk reversal was mainly observed for cancers with a confirmed infectious cause. Risk of other cancers, especially those related to end stage kidney disease, remained significantly increased after reduction of immunosuppression.