There is uncertainty about the safety of kidney transplantation during the SARS-CoV-2 pandemic due to the risk of donor transmission, nosocomial infection and immunosuppression use. We describe organ donation and transplant practice in the UK and assess whether kidney transplantation conferred a substantial risk of harm. Data from the UK transplant registry were used to describe kidney donation and transplant activity in the UK, and a detailed analysis of short-term, single-center, patient results in two periods: during the pre-pandemic era from 30th December 2019 to 8th March 2020 ("Pre-COVID era") and the 9th March 2020 to 19th May 2020 ("COVID era"). Donor and recipient numbers fell by more than half in the COVID compared to the pre-COVID era in the UK, but there were more kidney transplants performed in our center (42 vs. 29 COVID vs. pre-COVID respectively). Overall outcomes, including re-operation, delayed graft function, primary non-function, acute rejection, length of stay and graft survival were similar between COVID and pre-COVID era. 6/71 patients became infected with SARS-CoV-2 but all were discharged without critical care requirement. Transplant outcomes have remained similar within the COVID period and no serious sequelae of SARS-CoV-2 infection were observed in the peri-transplant period.
Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This small placebo-controlled trial investigates the use of a novel anti-B lymphocyte stimulator antibody (Belimumab) following renal transplantation. The antibody is designed to reduce B-cell activation and was used in conjunction with standard immunosuppression. This study demonstrated no excess in adverse events or rejections but failed to meet the co-primary endpoint of a significant reduction in concentration of naive B-cells by week 24. The study is interesting, and Belimumab is certainly worthy of further investigation in a larger cohort. The sample size here was small (28 patients) and loss to follow-up and non-compliance with dosing mean that only 8 patients in each group received treatment and provided data as per protocol. It is therefore unclear whether the non-significant reduction in B-cell activity seen is real, and whether this could translate into clinical benefit.
Expert Review
Reviewer:
Professor Yvon Y Lebranchu, Emeritus Professor, University of Tours, France.
Conflicts of Interest:
No
Clinical Impact Rating
5
Review:
To prevent or to treat antibody-mediated rejection, we need immunotherapeutic strategies that target B cells and plasma cells while preserving the immunoregulatory aspects of B-cell function. Activated B cells secrete the cytokine BLyS (Baff) to enhance B cell activation and proliferation. Belimumab,an anti-BLyS antibody previously used in systemic lupus erythematosus,was studied in a double blind, randomised, placebo-controlled phase 2 trial. Belimumab was used in addition to standard of care immunosuppression in 25 adult kidney transplants. Safety was the co-primary endpoint. No excess infection, death, graft loss and acute rejection were observed. The other co-primary endpoint, a reduction of 59 cells per mcL from baseline to Week 24,was not met. Adjusted mean difference was only -34.4 in the mITT population, but - 61.6 in the per protocol population. Despite the modest number of patients included, some very interesting informations on secondary endpoints were observed in the Belimumab group:1) an increased IL10 secretion and a decreased IL6 secretion by ex vivo stimulated B cells, 2) a decrease in activated memory B cells and plasmablasts, 3) a reduced de novo IgG formation, 4) a significant reduction in anti-endothelial cell (anti-EDIL3) and anti-kidney (anti-GDNF) specific antibodies, and 5) interestingly, a reduced expression of cell cycle genes in CD4+ purified T cells. These results suggest the potential efficacy of Belimumab in transplantation, in particular in sensitized patients. Further studies are needed.
Aims:
To determine the safety and activity of belimumab, in addition to standard-of-care immunosuppression among adult kidney transplant recipients.
Interventions:
Participants were randomised to receive either belimumab (10 mg/kg) or placebo (0·9% sodium chloride solution) in addition to standard-of-care immunosuppression (basiliximab, mycophenolate mofetil, tacrolimus, and prednisolone).
Participants:
28 patients aged 18–75 years with satisfactory liver function, scheduled to receive a kidney transplant.
Outcomes:
Primary outcomes measured were changes in the concentration of naive B cells from baseline to week 24 & safety which included adverse events, incidence & severity of infections, vital signs and safety laboratory assessments. Secondary measured outcomes included non-parametric sensitivity analysis of the change in naive B-cell count, transitional B-cell, memory B-cell, activated memory B-cell, circulating plasmablast, activated & regulatory T-cell concentrations, serum creatinine concentrations, estimated glomerular filtration rate, HLA antibody levels, immunosuppressant use & acute rejection.
Follow Up:
6 months
BACKGROUND:
B cells produce alloantibodies and activate alloreactive T cells, negatively affecting kidney transplant survival. By contrast, regulatory B cells are associated with transplant tolerance. Immunotherapies are needed that inhibit B-cell effector function, including antibody secretion, while sparing regulators and minimising infection risk. B lymphocyte stimulator (BLyS) is a cytokine that promotes B-cell activation and has not previously been targeted in kidney transplant recipients. We aimed to determine the safety and activity of an anti-BLyS antibody, belimumab, in addition to standard-of-care immunosuppression in adult kidney transplant recipients. We used an experimental medicine study design with multiple secondary and exploratory endpoints to gain further insight into the effect of belimumab on the generation of de-novo IgG and on the regulatory B-cell compartment.
METHODS:
We undertook a double-blind, randomised, placebo-controlled phase 2 trial of belimumab, in addition to standard-of-care immunosuppression (basiliximab, mycophenolate mofetil, tacrolimus, and prednisolone) at two centres, Addenbrooke's Hospital, Cambridge, UK, and Guy's and St Thomas' Hospital, London, UK. Participants were eligible if they were aged 18-75 years and receiving a kidney transplant and were planned to receive standard-of-care immunosuppression. Participants were randomly assigned (1:1) to receive either intravenous belimumab 10 mg per kg bodyweight or placebo, given at day 0, 14, and 28, and then every 4 weeks for a total of seven infusions. The co-primary endpoints were safety and change in the concentration of naive B cells from baseline to week 24, both of which were analysed in all patients who received a transplant and at least one dose of drug or placebo (the modified intention-to-treat [mITT] population). This trial has been completed and is registered with ClinicalTrials.gov, NCT01536379, and EudraCT, 2011-006215-56.
FINDINGS:
Between Sept 13, 2013, and Feb 8, 2015, of 303 patients assessed for eligibility, 28 kidney transplant recipients were randomly assigned to receive belimumab (n=14) or placebo (n=14). 25 patients (12 [86%] patients assigned to the belimumab group and 13 [93%] patients assigned to the placebo group) received a transplant and were included in the mITT population. We observed similar proportions of adverse events in the belimumab and placebo groups, including serious infections (one [8%] of 12 in the belimumab group and five [38%] of 13 in the placebo group during the 6-month on-treatment phase; and none in the belimumab group and two [15%] in the placebo group during the 6-month follow-up). In the on-treatment phase, one patient in the placebo group died because of fatal myocardial infarction and acute cardiac failure. The co-primary endpoint of a reduction in naive B cells from baseline to week 24 was not met. Treatment with belimumab did not significantly reduce the number of naive B cells from baseline to week 24 (adjusted mean difference between the belimumab and placebo treatment groups -34·4 cells per μL, 95% CI -109·5 to 40·7).
INTERPRETATION:
Belimumab might be a useful adjunct to standard-of-care immunosuppression in renal transplantation, with no major increased risk of infection and potential beneficial effects on humoral alloimmunity.
The trial from Newcastle investigated an immunosuppressive regimen consisting of daclizumab induction, MMF and steroids, with either tacrolimus or sirolimus commenced once the creatinine was less than 350 micromol/L or on the 10th post-operative day. The trial was based on a paired design, with pairs of DCD kidneys allocated to the same centre randomised to either delayed tacrolimus or delayed sirolimus. Incidence of BPAR was higher in the sirolimus arm (26% vs 11%), with 9 of 10 recipients in the sirolimus group switching to tacrolimus due to either rejection or side effects. Despite this, intent-to-treat renal function was equivalent at 1 year. The power calculations performed for the study necessitated at least 30 patients in each group in order to demonstrate a 15 ml/min difference in eGFR at 1 year. 12 of the 31 randomised pairs were withdrawn from the study, resulting in a lack of eventual power which means that the results are not conclusive. However, the results reported are strongly suggestive that delayed-onset sirolimus therapy with non-depleting antibody induction does not provide any benefit over a tacrolimus-based regimen due to excess acute rejection and intolerable side effects.
Expert Review
Reviewer:
Professor Ron Shapiro, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
Conflicts of Interest:
No
Clinical Impact Rating
2
Review:
This is a prospective randomized trial comparing tacrolimus with sirolimus in recipients of DCD kidneys. All patients received non-depleting antibody induction, MMF and steroids. Out of 31 pairs, 12 were excluded for a number of reasons, including a somewhat high incidence of renal vein thrombosis. Of the 19 patients randomized to sirolimus, over half were converted to tacrolimus because of rejection or side effects. While the incidence of rejection was not statistically higher in the sirolimus group, it was numerically higher (26% vs. 11%), and the small number of patients in the study likely accounted for the lack of statistical difference. Renal function was not different between the two groups. While the small size of the study makes it difficult to come up with generalizable conclusions, the findings suggest that sirolimus-based immunosuppression in the setting of DCD kidneys and non-depleting antibody induction represents a suboptimal strategy.
Aims:
To assess the impact on renal function of sirolimus versus tacrolimus, after delayed introduction, in donation after circulatory death (DCD) kidney transplantation.
Interventions:
One kidney from each pair was randomised to a delayed introduction of tacrolimus while the other received delayed introduction of sirolimus.
Participants:
31 pairs of kidneys from locally retrieved donors after circulatory death.
Outcomes:
The primary outcome was renal function post-transplant. Secondary outcomes were rate of biopsy-proven acute rejection and patient and graft survival.
Follow Up:
12 months
INTRODUCTION:
With calcineurin inhibitors potentiating damage from ischaemia-reperfusion injury in kidneys from donors after cardiac death we wanted to investigate the role of substituting sirolimus for tacrolimus in the delayed introduction of calcineurin inhibitor regime used in our centre.
METHOD:
A prospective randomised paired open-label study was performed taking pairs of kidneys from each donor and randomising one to a tacrolimus-based regime and the other to a similar regime based on sirolimus. Graft function at one year was the primary endpoint.
RESULTS:
Total 31 pairs of kidneys were randomised to each group, with 19 pairs of recipients available for analysis after post-randomisation study exclusions. Despite a higher incidence of biopsy proven acute rejection in the sirolimus group, renal allograft function was similar in both groups at three-monthly intervals up to one year post-transplant. All episodes of acute rejection in the sirolimus group occurred in the first three months. Graft and patient survival at one year was 100% in the tacrolimus group, with one death with functioning graft in the sirolimus group (95% survival). Unfortunately, 10 of the 19 patients in the sirolimus arm required switch of medication to tacrolimus due to acute rejection or intolerable drug side effects.
CONCLUSIONS:
Graft survival and function were very similar in the two groups despite the higher rate of acute rejection in the sirolimus arm, raising the possibility that the damage done by acute rejection was adequately offset by the nephron-sparing effect of sirolimus compared to tacrolimus. Sirolimus may have a role as a longer-term maintenance immunosuppressant after initial treatment with a different agent such as tacrolimus or belatacept.
CET Conclusion