Objectives: Induction immunosuppression for simultaneous pancreas-kidney transplant has helped reduce graft loss due to early rejection. Both thymoglobulin and interleukin 2 receptor antagonists are the most commonly used induction agents; however, some high-volume centers prefer alemtuzumab. This network meta-analysis aimed to compare different induction regimens for simultaneous pancreas-kidney transplant in terms of both pancreas and patient graft survival, as well to assess acute rejection.Materials and Methods: A systematic review was conducted to identify randomized clinical trials up to October 31, 2019, that examined induction regimens for simultaneous pancreas-kidney transplant. Study characteristics, postoperative data (patient, pancreas, and kidney graft survival), complications (eg, bleeding), infection rates, and malignancy rates were extracted. We compared all regimens using random-effects network meta-analyses to maintain randomization within trials.Results: This study identified 7 randomized clinical trials that involved 536 patients, which reported 5 induction regimens. These regimens included antithymocyte globulin (97 patients), alemtuzumab (42 patients), 2 doses (113 patients) or 5 doses (164 patients) of daclizumab, and no induction therapy (120 patients). In the network meta-analysis, a regimen with 2 doses of daclizumab was consistently ranked first for patient survival and kidney and pancreas graft survival. In contrast, alemtuzumab was ranked best for acute rejection (both pancreas and kidney). Rates of major infection (ie, cytomegalovirus) and malignancy were reported in 3 studies, precluding a reliable analysis.Conclusions: Daclizumab with 2 doses, given before simultaneous pancreas-kidney transplant, was associated with the best rates of patient and graft survival. Despite the recent withdrawal of daclizumab, an alternative anti-interleukin 2 induction regimen (basiliximab) has demonstrated promising results in nonrandomized series, warranting that further high-quality large-scale randomized clinical trials are still needed.
Key words : Immunosuppression, Monoclonal antibody therapy, Patient survival
Simultaneous pancreas-kidney (SPK) transplant is a well-established treatment option for patients with type 1 diabetes and end-stage renal failure.1-4 The foremost challenge in SPK transplant is to prevent alloreactivity and recurrence of autoimmunity against ?-cells. Recurrent autoimmunity and alloreactivity can be effectively reduced by maintenance immunosuppressive and induction therapy.5-7
Thymoglobulin (antithymocyte globulin [ATG]) has been widely accepted in the United States as an effective form of induction therapy for pancreas transplant, whereas, in Europe, alternative agents are also used.8 In the United Kingdom and Europe, ATG is more commonly used for vascular rejection and steroid-resistant rejection.9 Unfortunately, ATG can cause a number of unwanted side effects, the most important being prolonged immunodeficiency
and a subsequent increased risk of opportunistic infections.10 Monoclonal antibodies directed against specific T-cell surface molecules have also been developed for induction immunosuppression. One of these is anti-CD25 (daclizumab), a humanized immunoglobulin G1 (IgG1) monoclonal antibody directed against the low-affinity interleukin 2 receptor ?-chain.11 This antibody solely affects activated T cells.12 Its use in the clinical setting was initially encouraging; however, since March 2018, it has been withdrawn from the market.13-16
Similar immunosuppressive properties for both ATG and daclizumab in terms of preventing alloreactivity have been reported.11 Despite several randomized clinical trials (RCTs), there are no established induction regimens for SPK transplant. Hence, this review aimed to identify the best induction regimen for SPK transplant recipients in the context of overall and graft (ie, pancreas and kidney) survival through a network meta-analysis.
Materials and Methods
A systematic search of available databases, including PubMed, EMBASE, Cochrane Collaboration Central Register of Controlled Clinical Trials, Cochrane Systematic Reviews, ClinicalTrials.gov, and the American Society of Clinical Oncology database, were conducted on October 31, 2019 by 2 independent investigators (SKK, JRB). The search terms were “pancreas transplant” or “simultaneous pancreas-kidney” and “induction therapy” individually or in combination. Search terms used for this review are presented in Table 1. A manual search of reference lists of included trials and related reviews were also undertaken. This review was reported according to the PRISMA guidelines (Figure 1).17
Inclusion and exclusion criteria
The study inclusion criteria were as follows: (1) phase 3 RCTs that compared induction regimens in patients undergoing SPK transplant and (2) studies published in English. The exclusion criteria were as follows: (1) conference abstracts, case reports (<5 patients), and review articles; (2) phase 1 or 2 RCTs; and (3) studies that reported induction regimens for other transplant types (kidney only, pancreas only), in which outcomes for SPK were not reported. After exclusion of duplicates, 2 researchers (SKK, JRB) independently reviewed the titles and abstracts of studies identified from the literature search. Full texts of all relevant studies were reviewed, and the reference lists of these studies were also searched to ensure no relevant studies were missed. Any areas of disagreement between the 2 primary researchers were resolved through discussion with all authors.
The main outcome of this network meta-analysis was overall patient survival, defined as time from surgery to last follow-up or death. Secondary outcome measures included graft survival (ie, pancreas, kidney) and acute rejection episodes (ie, pancreas, kidney). Acute rejection was defined as rejection that occurred within 3 months from surgery.
Two researchers (SKK, JRB) were responsible for data extraction on study level (author, year of publication, country of origin, study design, patient number), patient level (age, sex), technique level (method and details of SPK), induction regimens, and reported clinical outcomes (ie, survival, infection, acute rejections, and malignancy).
Assessment of methodological quality
The quality of the studies included within this review was formally assessed by 2 independent researchers (SKK, JRB) using the Cochrane Risk of Bias Tool for RCTs.18,19 This tool consists of a fixed set of domains of bias, focussing on different aspects of trial design, conduct, and reporting. Each of these domains can be assessed as “high,” “low,” or “some concerns.”
This systematic review and network meta-analyses were performed according to the Cochrane Library and PRISMA guidelines.17 Categorical variables were evaluated using odds ratio with random effects modeling. Funnel plots were used to visually assess publication bias of included studies. Details of the network meta-analysis have been described previously.20-23 Induction regimens were then ranked using the P score provided by the netmeta package, as this was previously reported to be similar to the surface under the cumulative ranking areas for all outcomes, to assess the probability of the superiority of each treatment.24-26 Statistical significance was considered when P < .05. Statistical analyses were undertaken using the netmeta package R Foundation Statistical software (R 3.2.1) as previously described.20,21,27
Of the 2035 studies identified in the literature search, this study included 7 RCTs, which included 536 patients reporting 5 different induction strategies. A PRISMA diagram of included studies is presented in Figure 1. Twelve studies were excluded because 5 were duplicated studies included in the review,28-33 4 did not stratify outcomes by induction regimens,5,9,14,34 1 did not provide survival data,35 and 1 did not include patients undergoing SPK.36 Characteristics of included studies are presented in Table 2.
Inductions regimens included 2 doses of daclizumab (113 patients), 5 doses of daclizumab (164 patients), ATG (97 patients), and alemtuzumab (42 patients). We also included 120 patients who did not receive any induction. A network map of all induction regimens considered in this network meta-analysis is presented in Figure 2. Methodological quality A summary of Cochrane Bias Risk assessment is presented in Table 3. Most of the included studies in this review were deemed low risk of bias overall.
All 7 RCTs reported information on patient survival and were included in the network meta-analysis. Results of the random-effects network meta-analysis for overall survival are summarized in Figure 3A. Alemtuzumab was ranked first, followed by the regimen of 2 doses of daclizumab and the ATG regimen (Figure 3A).
Kidney and pancreas graft survival
All 7 RCTs reported information on kidney and pancreas graft survival and were included in the network meta-analysis. Results of the random-effects network meta-analysis for kidney graft survival are summarized in Figure 3B. The regimen of 2 doses of daclizumab was ranked first followed by the regimen of 5 doses of daclizumab and the no induction therapy regimen (Figure 3B). Results of the random-effects network meta-analysis for pancreas survival are summarized in Figure 3C. The regimen of 2 doses of daclizumab was ranked first followed by the regimen of 5 doses of daclizumab and the ATG regimen.
All 7 RCTs reported information on acute rejection of the pancreas and were included in the network meta-analysis. Results of the random-effects network meta-analysis for acute pancreas rejections are summarized in Figure 4. The alemtuzumab regimen was ranked first followed by the ATG and the 2 doses of daclizumab. Acute rejections of the kidney were only reported in 1 study and hence not included in the network meta-analysis.
Infection and malignancy
Infection and malignancy outcomes were reported in only 3 and 2 studies, respectively; hence, data were not sufficient to be included in the network meta-analysis.
To date, there is no strong evidence to suggest the best induction therapy for patients undergoing SPK transplants. This is reflected by guidelines from the British Transplant Society advocating any induction therapy, although depleting antibodies are preferred. This network meta-analysis, which included 7 RCTs on induction therapy, demonstrated that the regimen of 2 doses of daclizumab was consistently ranked best for long-term patient and graft survival for both pancreas and kidney, despite alemtuzumab being ranked best for acute rejection. Despite the rising costs associated with immunosuppression therapy, standardized use of immunosuppression therapy will result in improved patient and graft outcomes.
Daclizumab is a monoclonal antibody directed against the interleukin 2 receptor and has demonstrated effectiveness as an induction agent in preventing acute rejections in kidney transplant recipients.16,37,38 Within the RCTs included in our study, daclizumab was administered as 1 mg/kg/dose every 14 days for a total of 5 doses.16,37,38 Results from pharmacokinetic studies in kidney and liver transplant recipients demonstrated that alternative dosing regimens of daclizumab may also be safe and effective.39-41 Previously, Stratta and colleagues reported that daclizumab induction was safe and effective in reducing the incidence of acute rejection compared with no antibody induction and that the alternative regimen of daclizumab (2 mg/kg/dose every 14 days for 2 doses) was comparable with a standard dosing regimen of daclizumab (1 mg/kg/dose every 14 days for 5 doses) in SPK transplant recipients receiving tacrolimus, mycophenolate mofetil, and corticosteroids as primary immunosuppression at 6 months.42 However, there was no difference in the rates of acute rejection at 36 months.
Recently, daclizumab was withdrawn worldwide due to safety concerns following cases of inflammatory brain disorders.43 However, basiliximab (Simulect; Novartis), an interleukin 2 receptor antagonist, which inhibits T?cell activation by binding to, and blocking, the interleukin 2 receptor alpha subunit, and thus a non?T?cell-depleting antibody, has also been used. Basiliximab is thought to have efficacy similar to daclizumab, given its same mechanism of action. To date, there are no RCTs comparing basiliximab with other induction regimens such as alemtuzumab and ATG. Results from nonrandomized retrospective studies comparing basiliximab with alemtuzumab44,45 and ATG46 have demonstrated similar patient and kidney and pancreas graft survival and acute rejection rates. Notably, basiliximab has been associated with lower rates of viral infections, particularly cytomegalovirus viremia, compared with alemtuzumab and ATG.5,44,47 Cytomegalovirus infection rates in the form of viremia in these studies ranged from 16% to 46% with depleting antibody induction and around 7% with nondepleting induction.
The long-term impacts of antibody therapy on allograft and patient survival have long been questioned in renal transplantation, especially since the introduction of potent maintenance immunosuppressive agents such as tacrolimus. In pooled analyses of 2 placebo-controlled phase 3 RCTs in renal transplant recipients, daclizumab was associated with lower incidence of acute rejections at 6 months. However, there was no beneficial effect of daclizumab on graft survival at 3 years.48 Data from the United Network for Organ Sharing have suggested that use of either depleting or nondepleting antibody induction therapy does not offer any advantages in terms of prolonged allograft survival in SPK transplant recipients.
This study has limitations. First, the reporting of postoperative complications such as bleeding, thrombosis, major infections, and overall complications was incomplete and inconsistent in the included studies. As a result, these outcomes were not evaluated in our network meta-analysis. Second, our analyses were performed with summary statistics rather than individual patient data, limiting adjustment of these confounding factors within the analysis. However, evaluation of individual patient data may increase power and validate findings of the study.
This network meta-analysis demonstrated that a regimen of 2 doses of daclizumab was associated with the best patient and allograft survival, despite alemtuzumab having a better acute rejection rate profile. Review of current guidelines will help standardize current practices on pancreas transplant moving forward.
Volume : 19
Issue : 5
Pages : 397 - 404
DOI : 10.6002/ect.2020.0231
From the 1Department of HPB and Transplant Surgery, The Freeman Hospital, Newcastle upon Tyne, Tyne and Wear; the 2Institute of Cellular Medicine, University of Newcastle, Newcastle upon Tyne, Tyne and Wear; and the 3Department of Surgery, St. James University Hospital, Leeds, United Kingdom
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Author contributions: SKK designed the research, performed research, collected data, analyzed data, and wrote the paper; JRB performed the research, collected data, and analyzed data; DM performed the research, collected data, analyzed data, and wrote the paper; and SAW designed the research, performed the research, collected data, analyzed data, and wrote the paper.
Corresponding author: Sivesh K. Kamarajah, Department of Hepatobiliary, Pancreatic and Transplant Surgery, Freeman Hospital, Newcastle upon Tyne, Tyne and Wear, UK
Table 1. Summary of Search Terms Used for Literature Review
Figure 1. PRISMA Diagram on Included Studies in the Review
Figure 2. Network Map of Induction Regimens Included in This Network Meta-Analysis
Table 2. Baseline Demographics of Included Studies
Table 3. Summary of Cochrane Risk of Bias Assessment for Included Studies
Figure 3. Forest Plots on Network Meta-Analysis for Survival Comparing Different Induction Regimens Arranged From Those Ranked First to Last
Figure 4. Forest Plot on Network Meta-Analysis for Acute Rejections