The role of soluble B cell-activating factor in further stratifying the risk of antibody-mediated rejection post-renal transplant: A meta-analysis
International Immunopharmacology. 2020;79:106059
BACKGROUND We conducted a meta-analysis to evaluate the predictive value of serum soluble B cell-activating factor (sBAFF) for antibody-mediated rejection (ABMR), which remains controversial. METHODS Systematic literature search was performed in PubMed, EMBASE, Scopus, Cochrane Library, Web of Science and three Chinese databases. Studies of any relevant design were included. Random and fixed-effects meta-analytical models were used. Study quality, publication bias, and heterogeneity were assessed. This study was registered with PROSPERO (CRD42019109198). RESULTS Nine observational studies were included in the meta-analysis, including 1302 cases (median NOS quality score = 8, range 6-8). The incidence of ABMR was significantly higher in the high sBAFF group than in the low sBAFF level group (Risk ratio [RR] 2.04 [95% CI 1.52-2.74], I2 = 26%, P < 0.01, N = 1014). The subgroup analysis showed that regardless of pre-transplant donor-specific antibody (DSA) status, the high sBAFF level group still had a significantly higher incidence of ABMR. sBAFF was not associated with the risk of TCMR. The sBAFF level was significantly higher in the anti-HLA-antibody (+) group than in anti-HLA-antibody (-) patients before or after kidney transplantation (Standardized mean difference [SMD] 0.43 [0.29-0.56], P < 0.01, I2 = 34%, N = 1001). CONCLUSION sBAFF is a promising biomarker to further stratify the risk of ABMR post-renal transplant.
Peritransplant eculizumab does not prevent delayed graft function in deceased donor kidney transplant recipients: Results of two randomized controlled pilot trials
American Journal of Transplantation. 2020;20(2):564-572
This report aimed to explore the safety/efficacy of anti-C5 monoclonal antibody eculizumab (Ecu) administered in the operating room prior to reperfusion, to prevent delayed graft function (DGF) in recipients of deceased donor kidney transplants in two, randomized controlled trials: the pilot study and multicentre study.
Patients in the pilot study were randomized to receive either saline placebo or Ecu at a dose of 1200mg, prior to transplant surgery. Patients in the Multicenter study were randomized to either saline placebo or two doses of Ecu (an initial dose of 1200mg and second dose of 900mg after 12-24hrs of the initial dose). All patients were treated with rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil, and followed for 6 months.
8 participants were recruited for the pilot study. The inclusion criteria for participation was ≥18 years of age, recipient of a primary kidney transplant from a deceased, “standard criteria donor” (SCD) with cold ischemia time (CIT) of >24 hours, or from an “extended criteria donor” (ECD) kidney. A total of 19 participants from the multicenter trial were included; these subjects were eligible on the basis of being ≥18 years of age, the recipient of a primary, HLA‐mismatched, kidney transplant from a deceased, SCD kidney with CIT of 18 to 40 hours, or from an ECD kidney.
The primary outcome of the pilot study was the composite of DGF alongside slow graft function (SGF). DGF was defined by at least one dialysis treatment during the first 7 days after transplantation. Whereas, for the multicenter study, the primary endpoint was the need for at least one dialysis treatment during the first 7 days after transplantation, regardless of cause.
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
This is a well-written report of two small randomised controlled trials. A small pilot trial was conducted and then a larger multicentre trial started, however, after the conclusion of the much larger PROTECT study, this study was closed early. Both of the trials reported here were double blinded and adequately randomised using a centralised system that stratified by centre. The administration of eculizumab was slightly different between the 2 studies reported here (single dose 1200mg versus 2 doses of 1200mg) as was the definition of DGF, although this probably has no impact on the overall conclusions. The primary outcome of
the study was to assess the safety of eculizumab in this population and it does appear that it can be safely administered. However, in the DBD population included here, it does not lower DGF rates. The small size of the studies, even in combination, mean that no significant difference in graft survival or eGFR was likely to be found.
Animal models and observational human data indicate that complement, including C5a, pathogenically participates in ischemia reperfusion (IR) injury that manifests as delayed graft function (DGF) following deceased donor kidney transplantation. We report on the safety/efficacy of anti-C5 monoclonal antibody eculizumab (Ecu) administered in the operating room prior to reperfusion, to prevent DGF in recipients of deceased donor kidney transplants in two related, investigator-sponsored, randomized controlled trials. Eight recipients from a single center were enrolled in a pilot study that led to a 19-subject multicenter trial. Together, 27 deceased donor kidney transplant recipients, 16 Ecu-treated and 11 controls, were treated with rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil with or without glucocorticoids, and followed for 6 months. Data analysis showed no epidemiological or transplant-related differences between study arms. Ecu was well tolerated with a similar severe adverse event incidence between groups. The DGF rate did not differ between Ecu-treated (44%) and control (45%, P = 1.0) subjects. Serum creatinine reduction in the first week after transplantation, and graft function up to 180-days post-transplant, were also similar. Ecu administration was safe but did not reduce the rate of DGF in a high-risk population of deceased donor recipients.
Efficacy and Safety of a Quadruple Regimen Compared with Triple Regimens in Patients with Mycophenolic Acid-Related Gastrointestinal Complications After Renal Transplantation: A Short-Term Single-Center Study
Annals of Transplantation. 2020;25:e919875
BACKGROUND At present, there is no ideal conventional triple regimen that can effectively treat gastrointestinal (GI) complications in patients after kidney transplantation. We aimed to investigate the efficacy and safety of a quadruple regimen including standard-dose tacrolimus, low-dose enteric-coated mycophenolate sodium (EC-MPS), low-dose mizoribine (MZR), and corticosteroids, compared with regimens containing standard-dose tacrolimus, corticosteroids, plus either low-dose EC-MPS or standard-dose MZR in patients with mycophenolic acid (MPA)-related GI complications after renal transplantation. MATERIAL AND METHODS Between August 2016 and October 2018 in Qilu Hospital of Shandong University, 115 living donor kidney transplant recipients with MPA-related GI complications were enlisted in a single-center, prospective, randomized, control study. Thirty-six recipients were assigned to the low-dose EC-MPS plus low-dose MZR group, 37 recipients were assigned to the low-dose EC-MPS group, and 39 recipients were assigned to the standard-dose MZR group. We analyzed the Gastrointestinal Symptom Rating Scale (GSRS), estimated glomerular filtration rate (eGFR), graft rejection, serum creatinine, human leukocyte antigen (HLA) antibody, and the occurrence of adverse events among the 3 groups. RESULTS Compared with baseline, gastrointestinal symptoms improved significantly in all 3 groups. The reduction in mean subscale scores from baseline to month 3 was more significant in the standard-dose MZR group compared with the other 2 groups. The low-dose EC-MPS plus low-dose MZR group had better renal function. The incidence of graft rejection and cytomegalovirus (CMV) and polyomavirus BK (BKV) infection, as well as the incidence of hyperuricemia, in the low-dose EC-MPS plus low-dose MZR group were all significantly reduced. CONCLUSIONS This quadruple regimen may be equivalent to regimens containing standard-dose tacrolimus, corticosteroids plus either low-dose EC-MPS or standard-dose MZR in improving GI symptoms after kidney transplant, and is also advantageous for kidney function, graft rejection, and the rates of adverse events.
Canadian Cardiovascular Society/Canadian Cardiac Transplant Network Position Statement on Heart Transplantation: Patient Eligibility, Selection, and Post-Transplantation Care
Canadian Journal of Cardiology. 2020;36(3):335-356
Significant practice-changing developments have occurred in the care of heart transplantation candidates and recipients over the past decade. This Canadian Cardiovascular Society/Canadian Cardiac Transplant Network Position Statement provides evidence-based, expert panel recommendations with values and preferences, and practical tips on: (1) patient selection criteria; (2) selected patient populations; and (3) post transplantation surveillance. The recommendations were developed through systematic review of the literature and using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The evolving areas of importance addressed include transplant recipient age, frailty assessment, pulmonary hypertension evaluation, cannabis use, combined heart and other solid organ transplantation, adult congenital heart disease, cardiac amyloidosis, high sensitization, and post-transplantation management of antibodies to human leukocyte antigen, rejection, cardiac allograft vasculopathy, and long-term noncardiac care. Attention is also given to Canadian-specific management strategies including the prioritization of highly sensitized transplant candidates (status 4S) and heart organ allocation algorithms. The focus topics in this position statement highlight the increased complexity of patients who undergo evaluation for heart transplantation as well as improved patient selection, and advances in post-transplantation management and surveillance that have led to better long-term outcomes for heart transplant recipients.
Low-dose Thymoglobulin vs Basiliximab Induction Therapy in Low-Risk Living Related Kidney Transplant Recipients: A Prospective Randomized Trial
Transplantation Proceedings. 2020;[record in progress]
CONTEXT Thymoglobulin is used effectively as induction agent in kidney transplantation but the optimal dose is not well established. OBJECTIVE Demonstrate that low-dose thymoglobulin (3 mg/kg) has similar efficacy and safety compared to basiliximab induction in low-risk kidney transplantation under standard maintenance immunosuppression DESIGN, SETTING, PARTICIPANTS Prospective randomized study in kidney transplant patients (12/2016-05/2018). INCLUSION CRITERIA Recipients > 18 years, first living donor transplant. EXCLUSION CRITERIA Second and multiorgan transplant, ABO incompatibility, positive cross-match, panel reactive antibodies (PRA) > 30%, positive donor-specific antibody, human immunodeficiency virus, hepatitis B surface antigen, hepatitis C virus positive, white blood cells < 2000 cells/mm3, platelets < 75,000 cells/mm3 and malignancy. INTERVENTION Group A: basiliximab (20 mg D0 and D4). Group B: thymoglobulin (3 mg/kg total). Maintenance immunosuppression: tacrolimus, mycophenolate mofetil, and steroids. MAIN OUTCOME MEASURES Biopsy-proven acute rejection (BPAR), delayed graft function, slow graft function, leukopenia, infections, adverse events, graft loss, estimated glomerular filtration rate, and death within 12 months. RESULTS 100 patients (basiliximab, n = 53) (thymoglobulin, n = 47) were included. Donor and recipient characteristics were similar except for longer dialysis (basiliximab), PRA class I (1.2% basiliximab, 4.5% thymoglobulin), HLA match (basiliximab 2.8, thymoglobulin 2.2), and cytomegalovirus status. BPAR rate was basiliximab 3.8% and thymoglobulin 6.4% (P = ns). Delayed graft function (basiliximab 3.8%; thymoglobulin 4.3%), slow graft function, and 12-month leukopenia (basiliximab 11.3%, thymoglobulin 21.3%) were similar between groups (P = ns). There was no difference in infections and adverse events between groups. Patient and graft survival were as follows: basiliximab 98.1% and 92.5%, thymoglobulin 100% and 93.6% (P = ns). CONCLUSION Low-dose thymoglobulin induction (3 mg/kg) can be used effectively and safely in low-risk kidney transplantation with good results during the first year post-transplant.
Update to the study protocol, including statistical analysis plan, for the multicentre, randomised controlled OuTSMART trial: a combined screening/treatment programme to prevent premature failure of renal transplants due to chronic rejection in patients with HLA antibodies
Trials [Electronic Resource]. 2019;20(1):476
BACKGROUND Chronic rejection is the single biggest cause of premature kidney graft failure. HLA antibodies (Ab) are an established prognostic biomarker for premature graft failure so there is a need to test whether treatment decisions based on the presence of the biomarker can alter prognosis. The Optimised TacrolimuS and MMF for HLA Antibodies after Renal Transplantation (OuTSMART) trial combines two elements. Firstly, testing whether a routine screening programme for HLA Ab in all kidney transplant recipients is useful by comparing blinding versus unblinding of HLA Ab status. Secondly, for those found to be HLA Ab+, testing whether the introduction of a standard optimisation treatment protocol can reduce graft failure rates. METHODS OuTSMART is a prospective, open-labelled, randomised biomarker-based strategy (hybrid) trial, with two arms stratified by biomarker (HLA Ab) status. The primary outcome was amended from graft failure rates at 3 years to time to graft failure to increase power and require fewer participants to be recruited. Length of follow-up subsequently is variable, with all participants followed up for at least 43 months up to a maximum of 89 months. The primary outcome will be analysed using Cox regression adjusting for stratification factors. Analyses will be according to the intention-to-treat using all participants as randomised. Outcomes will be analysed comparing standard care versus biomarker-led care groups within the HLA Ab+ participants (including those who become HLA Ab+ through re-screening) as well as between HLA-Ab-unblinded and HLA-Ab-blinded groups using all participants. DISCUSSION Changes to the primary outcome permit recruitment of fewer participants to achieve the same statistical power. Pre-stating the statistical analysis plan guards against changes to the analysis methods at the point of analysis that might otherwise introduce bias through knowledge of the data. Any deviations from the analysis plan will be justified in the final report. TRIAL REGISTRATION ISRCTN registry, ID: ISRCTN46157828 . Registered on 26 March 2013; EudraCT 2012-004308-36 . Registered on 10 December 2012.
Everolimus-based Immunosuppression Possibly Suppresses Mean Fluorescence Intensity Values of De Novo Donor-specific Antibodies After Primary Kidney Transplantation
Transplantation proceedings. 2019;51(5):1378-1381
PURPOSE We evaluated de novo donor-specific antibody (DSA) production of everolimus (EVR)-based immunosuppression for primary kidney transplant recipients involved in the A1202 study at our institute. METHODS From March 2008 to August 2009, 24 recipients were prospectively randomized into 2 groups. The EVR group received reduced cyclosporin A and EVR. The standard protocol (STD) group received standard cyclosporin A and mycophenolate mofetil. Both groups received basiliximab and steroids. De novo DSA was identified using LABScreen single antigen beads (One Lambda, Canoga Park, Calif., United States). Mean fluorescence intensity (MFI) values > 1000 were considered positive. P < .05 was considered significant. RESULTS Graft survival was 100% in the EVR group and 90.9% in the STD group. All patients remained on the primary protocol in the EVR group, but 3 patients in the STD group (27.3%) were converted to tacrolimus due to DSA and non-adherence. Estimated glomerular filtration rate was similar in both groups. No EVR group recipients and 9.1% of STD group recipients were treated for T-cell-mediated rejection. No recipients of the EVR group exhibited peritubular capillaritis, while 9.1% in STD group developed chronic active antibody-mediated rejection. LABScreen revealed an accumulative class II DSA production rate of 15.4% in the EVR group and 18.3% in the STD group at 10 years. When the MFI cut-off level was set to 6000, anti-HLA antibody and de novo DSA-free survival was significantly better in the EVR group. CONCLUSIONS EVR-based immunosuppression provided equivalent or even better clinical outcomes. EVR suppressed de novo DSA production at 10 years follow-up; however, further follow-up is inevitable.
Prediction models to measure transplant readiness of patients with renal failure: A systematic review
Saudi Journal of Kidney Diseases & Transplantation. 2019;30(1):1-14
Predicting the future of illness, a patient is facing helps the physicians to choose the best strategy to manage the disease. Models for predicting the readiness of candidates for kidney transplant can be very promising. This study sought to systematically review the predictive models and algorithms that assess the readiness of renal transplant candidates in different countries. This systematic review study was according to PRISMA-P protocol in PubMed and Science Direct databases and general search engines up to March 2017. Eligible studies were those that introduced a model to assess the readiness for renal transplantation of patients with chronic renal failure from cadavers and this assessment led to scoring prioritization or superiority among patients. We found 28 studies from 11 countries that met the search criteria and >50% of them were published from 2015 onward. Of the studies, nine models and algorithms were extracted that included 12 factors. Some models, including the European and Scandinavian models, were used jointly between different countries. All the models had at least four factors, and nearly 90% of the models considered four or five factors to measure kidney transplantation readiness. More than 50% of the models had age, dialysis duration, HLA type, and emergency status factors and, dialysis duration. Predictive models are important for renal transplant because of the significant reduction in number of cadavers and longer wait of candidates for a kidney transplant. Further studies can examine the effect of these models on the survival of the kidney transplant.
Effects of immunoadsorption combined with membrane filtration on complement markers - Results of a randomized, controlled, crossover study
Transplant International. 2019;32(8):876-883
To investigate whether adding a membrane filtration (MF) to a circuit during semi-selective immunoadsorption (IA) can enhance the elimination of ABO reactivity to remove additional macromolecular complement components, such as mannose-binding lectin (MBL) and properdin.
Patients were randomized into two intervention sequences : a single session of IA combined with MF (IA+MF) followed by a single session of IA alone, or vice versa.
14 kidney transplant recipients.
Outcomes included impact of apheresis on complement activation, effect of IA+MF versus IA on properdin and MBL concentration.
Mr John O'Callaghan, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Antibody depletion prior to ABO or HLA incompatible transplantation has been used to facilitate transplantation in these patient groups. This good quality RCT was previously reported and the new paper describes the effect on complement depletion of combined immunoadsorption (IA) + membrane filtration (MF), compared to IA. The trial was open label, but the results presented are very objective. Levels of C5b-9b, the terminal complex of the complement cascade, were used as a marker of complement system activation. There was no significant difference in C5b-9 levels between groups pre- or post-intervention and nor was there a significant change in levels
in either group. The combination of IA+MF significantly reduced levels of properdin and mannose-binding lectin compared to IA alone. Conversely, levels of properdin and mannose-binding lectin returned to pre-treatment levels at day 7 in the IA+MF group, but not in the IA alone group. This is difficult to explain and the exact mechanisms of clearance and recovery are unclear. The authors acknowledge that the carry-over effect from cross-over treatments may be the cause; the clinical implications are uncertain.
The complement system has been implicated in several kidney diseases, such as antibody-mediated rejection after kidney transplantation. Antibody-depletion techniques allow successful ABO- and/or HLA-incompatible transplantation. Considering the IgG removal, the use of semi-selective immunoadsorption (IA) has been advocated. However, because of results on incomplete IgM depletion, the adjunctive use of membrane filtration (MF) has been proposed to enhance the removal of macromolecules and to interfere with complement activation. This secondary endpoint analysis of a recently published randomized, controlled, cross-over trial was designed to investigate the effect of combined treatment IA+MF compared to IA alone on complement depletion. Two treatment sequences, a single session of IA+MF followed by IA (and vice versa), were analyzed with regards to C5b-9, properdin, and mannose-binding lectin (MBL) levels. Neither IA alone nor IA+MF provoked complement activation as demonstrated by stable low levels of C5b-9 after the procedure as compared to before. The combined treatment substantially lowered properdin (77% vs. 26% reduction, P<0.0001) as well as MBL concentrations (81% vs. 11% reduction, P <0.0001). Recovery of properdin and MBL levels appears to belonger after IA alone compared to IA+MF. Depletion of properdin and MBL levels may have potential clinical implications in the setting of kidney transplantation. This article is protected by copyright. All rights reserved.
Diagnostic Biomarkers to Diagnose Acute Allograft Rejection After Liver Transplantation: Systematic Review and Meta-Analysis of Diagnostic Accuracy Studies
Frontiers in Immunology. 2019;10(1):758
Objective: A systematic review and meta-analysis of diagnostic biomarkers for noninvasive diagnosis of acute allograft rejection following liver transplantation. Background: Noninvasive blood and urine markers have been widely explored in recent decades for diagnosing acute rejection after liver transplantation. However, none have been translated into routine clinical use so far due to uncertain diagnostic accuracy, and liver biopsy remains the gold standard. Methods: Systematic literature searches of Medline, Cochrane and Embase were conducted up to February 2019 to identify studies evaluating the use of noninvasive markers in diagnosing allograft rejection following liver transplantation. Meta-analysis was performed using a random effects model with DerSimonian-Laird weighting and the hierarchical summary receiver operating curve. Results: Of 560 identified studies, 15 studies (1,445 patients) met the inclusion criteria. The following markers were tested: acid labile nitroso-compounds (NOx), serum amyloid A protein, procalcitonin, peripheral blood eosinophil count, peripheral blood T-cell activation and interleukin 2 (IL-2) receptor, guanylate-binding protein-2 mRNA, graft-derived cell-free DNA, pi-glutathione S-transferase, alpha-glutathione S-transferase and serum HLA class I soluble antigens. Only eosinophil count was tested in multiple studies, and they demonstrated high heterogeneity (I 2 = 72% [95% CI: 0.5-0.99]). IL-2 receptor demonstrated the highest sensitivity (89% [95% CI: 0.78-0.96]) and specificity (81% [95% CI: 0.69-0.89]). Conclusion: IL-2 receptor expression demonstrated the highest diagnostic accuracy, while the peripheral eosinophil count was the only marker tested in more than one study. Presently, liver biopsy remains superior to noninvasive diagnostic biomarkers as most studies exhibited inferior designs, hindering possible translation into clinical application.