Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This is a well-conducted systematic review that searched multiple databases and included data from 966 renal transplant patients with FSGS (38% recurrence after transplantation). A review protocol was recorded in advance and the literature search and data extraction was completed in duplicate. Significant heterogeneity was identified between studies and was not explored by the authors with sensitivity analysis. This identified one study as a key source of heterogeneity, that was then later removed from statistical analysis. Publication bias was also checked statistically and was only present for one risk factor analysis (age at transplantation); correcting for this had no effect on the pooled estimate. In summary, this study showed that the overall recurrence risk of FSGS after renal transplantation is high. Age at transplant, age at onset, time from diagnosis to kidney failure, proteinuria prior to transplant, related donor and native nephrectomy were all associated with a higher risk of FSGS recurrence. Multiple other risk factors were examined and not found to be associated with risk of recurrence of FSGS: HLA mismatch, duration of dialysis, sex, living donor, tacrolimus and previous transplant.
Expert Review
Reviewer:
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating
3
Review:
Whilst transplantation is the treatment of choice for renal failure due to focal segmental glomerular sclerosis (FSGS), it is one of the few indications for transplantation with a known risk of recurrent disease in the transplant kidney that can affect graft survival post-transplant. Treatments such as pre-emptive plasmapheresis with or without rituximab have been used to prevent or treat post-transplant recurrence, but the evidence for effectiveness is limited (1). A number of publications have attempted to correlate demographic and clinical features with risk of recurrence post-transplant. In a recent systematic review and meta-analysis, Bai and colleagues have attempted to summarise and synthesise this literature (2). They identified 22 studies with 966 patients, showing an overall rate of FSGS recurrence of 38%. Risk factors for recurrence were identified as younger age at transplant, older age of disease onset, shorter time from diagnosis to kidney failure, higher levels of proteinuria prior to transplant, a related living donor transplant and native nephrectomy. The review methodology was sound, with searches in multiple databases, multiple reviewers screening the literature and an evaluation of risk of bias. As might be expected when exploring retrospective cohort studies, there was heterogeneity seen in some outcomes, in particular age at transplant and pre-transplant proteinuria. Most underlying studies included in the meta-analysis explored risks in univariate analysis, without correction for confounding, and there is no way in meta-analysis to explore the interactions between risks. Limited data are available on the distinction between primary and secondary FSGS, and the impact of testing for genetic mutations and risk of recurrence (3). Despite the limitations, the review still provides a useful guide when assessing patients with FSGS for transplantation. The findings allow us to stratify risk of recurrence and set realistic expectations during the consent process. References 1. Boonpheng B, Hansrivijit P, Thongprayoon C et al. Rituximab or plasmapheresis for prevention of recurrent focal segmental glomerulosclerosis after kidney transplantation: A systematic review and meta-analysis. World Journal of Transplantation 2021; 11: 303. 2. Bai J, Zhang T, Wang Y et al. Incidence and risk factors for recurrent focal segmental glomerulosclerosis after kidney transplantation: a meta-analysis. Renal Failure 45: 2201341. 3. Uffing A, Hullekes F, Riella LV, Hogan JJ. Recurrent Glomerular Disease after Kidney Transplantation. Clinical Journal of the American Society of Nephrology : CJASN 2021; 16: 1730
Aims:
This study aimed to investigate the incidence and risk factors associated with focal segmental glomerulosclerosis (FSGS) following kidney transplantation.
Interventions:
A literature search was conducted on PubMed, Cochrane Library, Medline, Embase, Web of Science, CNKI, CBMdisc, Wanfang, and Weipu (VIP). Study selection and data extraction were performed by two independent authors. The methodological quality of the included studies were assessed using the Newcastle–Ottawa Scale (NOS).
Participants:
22 studies were included in the review.
Outcomes:
FSGS recurrence rate posttransplantation and risk factors of FSGS.
Follow Up:
N/A
AIMS:
To systematically review the incidence and risk factors for recurrent FSGS after kidney transplantation.
METHODS:
We searched PubMed, Embase, Medline, Web of Science, the Cochrane Library, CNKI, CBMdisc, Wanfang, and Weipu for case-control studies related to recurrent FSGS from the establishment until October 2022. The protocol was registered on PROSPERO (CRD42022315448). Data were analyzed using Stata 12.0, with odds ratios (counting data) and standardized mean difference (continuous data) being considered as effect sizes. If the I2 value was greater than 50%, the random-effects model was used; otherwise, a fixed-effects model was used. A meta-analysis on the incidence and risk factors for recurrent FSGS after kidney transplantation was performed.
RESULTS:
A total of 22 studies with 966 patients and 12 factors were included in the meta-analysis. There were 358 patients with recurrent FSGS and 608 patients without FSGS after kidney transplantation. The results showed that the recurrence rate of FSGS after kidney transplantation was 38% (95% CI: 31%-44%). Age at transplantation (SMD = -0.47, 95% CI -0.73 to -0.20, p = .001), age at onset (SMD = -0.31, 95% CI -0.54 to -0.08, p = .008), time from diagnosis to kidney failure (SMD = -0.24, 95% CI -0.43 to -0.04, p = .018), proteinuria before KT (SMD = 2.04, 95% CI 0.91 - 3.17, p < .001), related donor (OR 1.99, 95% CI 1.20 - 3.30, p = .007) and nephrectomy of native kidneys (OR 6.53, 95% CI 2.68 - 15.92, p < .001) were associated with recurrent FSGS, whereas HLA mismatches, duration of dialysis before KT, sex, living donor, tacrolimus use and previous transplantation were not associated with recurrent FSGS after kidney transplantation.
CONCLUSIONS:
The recurrence of FSGS after kidney transplantation remains high. Clinical decision-making should warrant further consideration of these factors, including age, original disease progression, proteinuria, related donor, and nephrectomy of native kidneys.
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This manuscript reports the findings of the CELLIMIN trial from the BIO-DrIM consortium. The study aimed to stratify renal transplant recipients by immunological risk assessed by pre-transplant donor-specific ELISPOT assay, randomising low-risk recipients to standard immunosuppression or tacrolimus monotherapy. The study was terminated early due to slow recruitment and is therefore underpowered to draw firm conclusions, but rejection rates were numerically higher in the minimization arm leading to concerns that ELISPOT alone may not select patients suitable for monotherapy. Despite the early termination, there are some interesting findings here. Firstly, T-cell ELISPOT was able to differentiate those patients at highest risk of post-transplant rejection, suggesting that it may have a role to play in guiding pre-transplant risk stratification. Secondly, retrospective analysis showed that patients with a negative ELISPOT and good class-II eplet matching demonstrated the lowest post-transplant risk, suggesting that a combination of reactivity and eplet matching may improve patient selection for minimization in future studies.
Expert Review
Reviewer:
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating
3
Review:
Historically, most transplant centres have used a “one size fits all” regimen for immunosuppression, or applied various tiers of immunosuppression depending on easily measured pre-transplant risk factors such as degree of sensitisation, donor-recipient mismatch or donor type. The advent of newer biomarkers to assess immunological risk has led to interest in the ability to further personalise immunosuppression. Until now, few prospective studies have assessed the clinical impact of such personalisation. In this multicentre study from the BIO-DrIM consortium, the investigators attempted to stratify immunosuppression based upon pre-transplant donor-reactive T-cell memory using a standardised IFN-gamma ELISPOT assay. Recipients without pre-transplant DSA or donor-specific T-cells were randomised to tacrolimus monotherapy or standard triple therapy following renal transplantation. Patients with detectable donor-reactive T-cell memory received triple therapy. Unfortunately, perhaps due to the stringent inclusion criteria or a reluctance on the behalf of investigators to recruit to a study of monotherapy, the study failed to recruit at the required rate with only 167 of the 673 required patients included. Whilst underpowered with respect to the non-inferiority outcome planned, the study does still offer some interesting insights. Rates of biopsy-proven acute rejection were numerically higher in the low-immunosuppression group compared to triple therapy (25% vs. 11.3% at 12 months), suggesting that T-cell ELISPOT alone may be insufficient to select patients suitable for tacrolimus monotherapy. However, in post-hoc analysis, T-cell ELISPOT was able to predict those patients at highest risk of post-transplant rejection, suggesting that it may have some role to play. Further post-hoc analysis also demonstrated that patients with a negative post-transplant ELISPOT and good class-II eplet matching (DQ eplet mismatches < 10) were at lower risk of both biopsy-proven rejection and de-novo donor-specific antibody (DSA) formation. These findings suggest that refining risk stratification using a combination of ELISPOT, eplet-matching and DSA may improve the safety of immunosuppression minimisation. However, given the difficulties recruiting to the current study, demonstrating non-inferiority in prospective studies with even more stringent inclusion criteria is going to be challenging without large-scale multicentre collaboration.
Aims:
This study reports the findings of the CELLIMIN trial, which aimed to examine whether minimisation of posttransplant immunosuppression with tacrolimus (TAC) monotherapy would be effective enough while also reducing drug-related toxicity in low immunological-risk renal transplant recipients without pretransplant donor-specific alloantibodies (DSA) and donor-specific T cells.
Interventions:
Participants were first allocated into two groups based on the results of their pretransplant donor-specific IFN-γ ELISPOT assessment. ELISPOT negative (E−) patients were then randomised to either the low immunosuppression (LI) group or the standard of care immunosuppression (SOC) group.
Participants:
167 kidney transplant patients were recruited, out of which 101 ELISPOT negative (E−) patients were randomised.
Outcomes:
The primary outcome was the incidence of biopsy-proven acute rejection BPAR at 6 months posttransplant. The secondary outcomes were the incidence of clinical and subclinical BPAR, estimated glomerular filtration rate (eGFR), de novo DSA, graft survival, patient survival and impact of donor/recipient human leukocyte antigens (HLA) molecular mismatches on BPAR and dnDSA between the groups at 12 months posttransplant.
Follow Up:
12 months
Personalizing immunosuppression is a major objective in transplantation. Transplant recipients are heterogeneous regarding their immunological memory and primary alloimmune susceptibility. This biomarker-guided trial investigated whether in low immunological-risk kidney transplants without pretransplant DSA and donor-specific T cells assessed by a standardized IFN-γ ELISPOT, low immunosuppression (LI) with tacrolimus monotherapy would be non-inferior regarding 6-month BPAR than tacrolimus-based standard of care (SOC). Due to low recruitment rates, the trial was terminated when 167 patients were enrolled. ELISPOT negatives (E-) were randomized to LI (n = 48) or SOC (n = 53), E+ received the same SOC. Six- and 12-month BPAR rates were higher among LI than SOC/E- (4/35 [13%] vs. 1/43 [2%], p = .15 and 12/48 [25%] vs. 6/53 [11.3%], p = .073, respectively). E+ patients showed similarly high BPAR rates than LI at 6 and 12 months (12/55 [22%] and 13/66 [20%], respectively). These differences were stronger in per-protocol analyses. Post-hoc analysis revealed that poor class-II eplet matching, especially DQ, discriminated E- patients, notably E-/LI, developing BPAR (4/28 [14%] low risk vs. 8/20 [40%] high risk, p = .043). Eplet mismatch also predicted anti-class-I (p = .05) and anti-DQ (p < .001) de novo DSA. Adverse events were similar, but E-/LI developed fewer viral infections, particularly polyoma-virus-associated nephropathy (p = .021). Preformed T cell alloreactivity and HLA eplet mismatch assessment may refine current baseline immune-risk stratification and guide immunosuppression decision-making in kidney transplantation.
Liver transplant recipients were randomised in a 4:1 ratio to immune suppression withdrawal or maintenance. The method of randomisation is not described and the trial was open-label, so unblinded. Whilst 57 patients were randomised, only 40 had complete follow up and it is unclear exactly why, when and how many dropped out from each arm. 31 patients were randomised to immune suppression withdrawal and completed follow up. Of these 31, 22 failed withdrawal due to acute rejection (59%), elevated liver tests (27%), graft dysfunction (5%), protocol deviation (5%) and PI decision (5%). Nine patients were kept immune suppression free; only 2 of these developed DSA during minimisation and a further 4 after withdrawal. Acute rejection episodes were strongly associated with DSA development and the majority of de novo DSA were against HLA-DQ antigens. This study demonstrates some evidence that de novo DSA positivity should be considered before immune suppression withdrawal in liver transplant recipients. Patients who were immune suppression-free subsequently had the highest prevalence of de novo DSA, particularly HLA-1, but these did not seem to be associated with adverse outcomes.
Expert Review
Reviewer:
Dr James Neuberger, Liver Unit, Queen Elizabeth Hospital, Birrmingham, B15 2TH, UK
Conflicts of Interest:
No
Clinical Impact Rating
4
Review:
Key findings: In this analysis of a subgroup of liver allograft recipients undergoing immunosuppresison withdrawal, de novo Donor Specific Antibodies (dnDSA) were associated with episodes of acute rejection. Generalizability: These findings are potentially generalizable to liver allograft recipients. Extrapolation to those who did not meet the criteria for entry into the study is less certain. It is likley that these observations will be relevant to a wider cohort of liver allograft recipients but validation in a separate cohort is needed. Implications for clinical practice: Complete withdrawal of immunosuppression and development of operational tolerance has long been a goal of solid organ transplantation: it has clear that some recipients do develop tolerance. There have been many studies to identify biomarkers for those recipients who will develop operational tolerance but, as yet, none has reached wide clinical acceptance. This study suggests dnDSA may be useful for those in whom complete withdrawal is unlikley to be successful. However, the findings, although exciting and informative, should be treated with caution, Firstly, as with so many 'real world' studies, there are criticisms of the study with some heterogeneity of selection and management and the findings are not binary. dnDSA need characerisation and interpretation for their signficance. If confirmed, then these observations not ony shed some more light on our understanding of the role of dnDSA in graft health but also may provide a marker to help identify those in whom immunosuppressionwithdrawal should not proceed.
Aims:
To determine whether early immunosuppression (IS) withdrawal affects development of de novo donor-specific antibodies (dnDSA), and whether dnDSA have an impact on liver transplant outcomes during IS minimization.
Interventions:
Liver transplant recipients receiving calcineurin inhibitor monotherapy were randomized (4:1) to either IS minimization or IS maintenance.
Presence and prevalence of de novo DSA. Impact of DSA on liver transplantation during IS minimisation or withdrawal assessed as association of de novo DSA with episodes of acute rejection (according to the Banff criteria).
Follow Up:
Up to 1 year
The development of human leukocyte antigen (HLA) donor-specific antibody/antibodies (DSA) is not well described in liver transplant (LT) patients undergoing immunosuppression (IS) withdrawal protocols despite the allograft risk associated with de novo DSA (dnDSA). We analyzed the development of dnDSA in 69 LT patients who received calcineurin inhibitor monotherapy and were enrolled in the ITN030ST study. Of these 69 patients, 40 stable patients were randomized to IS maintenance (n = 9) or IS minimization (n = 31). Nine of the 31 IS minimization patients achieved complete withdrawal and were free of IS. Among patients who achieved stable IS monotherapy 1 year after transplantation, the prevalence of dnDSA was 18.8%. Acute rejections and the biopsy-proven findings disqualifying patients from IS withdrawal attempt were factors associated with dnDSA development (P = 0.011 and P = 0.041, respectively). Among randomized patients, dnDSA prevalence was 51.7% after IS minimization and 66.7% in IS-free patients. dnDSA prevalence in patients on IS maintenance was 44.4%. dnDSA development during IS minimization was a risk factor for acute rejection (P = 0.015). The majority of dnDSA were against HLA-DQ antigens (78.7%). Conclusion. During the first year following transplantation, acute rejections increase the risk of developing dnDSA, so dnDSA positivity should be considered for IS withdrawal eligibility; during IS minimization, dnDSA development was associated with acute rejection, which prevented further IS withdrawal attempts.
Professor Anthony Warrens, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Conflicts of Interest:
No
Clinical Impact Rating
2
Review:
This study compares once daily and twice daily tacrolimus regimes in a population that includes about 14% patients with preformed donor-specific antibodies and 25% who have ABO incompatibility. The authors note that these preparations have been found not to be different in populations without these high risk patients but that a cohort including these groups have not previously been reported. They found that in such a cohort neither preparation meets the criterion of being inferior. However, it would have been much more helpful to look at the high risk populations alone in order to come to a useful conclusion. Without doing so, the power to analyse those groups is compromised. In addition, there are significant differences between the two group of sensitised patients: HLA-incompatible transplants have a much worse prognosis than ABO-incompatible transplants. Accordingly, I do not feel that we are able to draw firm conclusions about either group from this study. I recognise that it would have been difficult to recruit large numbers of these highly sensitised patients to generate a study of adequate power. But that is what would have been necessary to produce a conclusive study of non-inferiority. As it is, at least one can conclude that there is no massive difference between the two regimens in this mixed group.
Tacrolimus (TAC) is available as a twice-daily capsule (TAC-BID), once-daily capsule (TAC-QD), and once-daily tablet. Recipients with ABO-incompatible/anti-human leukocyte antigen (HLA)-incompatible transplantation were excluded in previous trials and have thus not been evaluated. We conducted a 5-year trial to determine whether TAC-QD is noninferior to TAC-BID for transplant outcomes. Adults who underwent de novo living kidney transplantation were randomly assigned (62 TAC-QD; 63 TAC-BID). We did not exclude ABO-/HLA- incompatible transplantation. TAC was initiated 7 days preoperatively (0.10 mg/kg/d). Mycophenolate mofetil, methylprednisolone, and basiliximab were administered. The primary endpoint was graft failure (non-censored for death). We performed a noninferiority test. The noninferiority margin was 10% in risk difference. Five-year graft failure rates were 6.5% and 9.5% for TAC-QD and TAC-BID, respectively (noninferiority, P = 0.009). The estimated glomerular filtration rates were similar between the groups (noninferiority, P < 0.001). TAC-QD did not have point estimates of risk difference above the inferiority margin in any assessed endpoints. However, a tendency of interaction was observed between biopsy-proven acute rejection and the follow-up period. In a living kidney transplant population with 40% of patients with ABO/HLA incompatibility, the effect of TAC-QD was not appreciably worse on various clinical transplant outcomes than that of TAC-BID over 5 years.
Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This post-hoc analysis from the BENEFIT and BENEFIT-EXT studies investigates the impact of belatacept-based immunosuppression on kidney transplant recipients with pre-existing DSA. The authors conclude that with belatacept-based immunosuppression, particularly at higher doses, more patients exhibited stable or declining DSA levels compared to CsA-based immunosuppression. Whilst this is an interesting finding, the post-hoc analysis should be interpreted with caution. The original study excluded DSA-positive patients, so only those with low-level DSA detected on central testing are included (10-14 patients in each group). These small numbers mean that whilst there are numerical differences between groups, these do not reach statistical significance. Furthermore, the contribution of other immunosuppression changes cannot be determined. A prospective study including these patients would be required to confirm these findings.
Expert Review
Reviewer:
Mario Abbud-Filho, Director, Organ Transplantation Centre, Hospital de Base, Medical School FAMERP/FUNFARME, Sao Jose do Rio Preto, Sao Paulo, Brazil. Jorge Neumann, Director, Immunology Transplant Laboratory, Santa Casa de Porto Alegre, RS.
Conflicts of Interest:
No
Clinical Impact Rating
2
Review:
In the present study, Bray et al examined the effect of belatacept-based and cyclosporine-based immunosuppression on the MFI of patients with preexisting DSAs. Antibody screening was performed using CDC crossmatching a method less sensitive than the single-antigen bead assay to detect DSA. This could have influenced one of some limitations of the study that is the small number of patients with DSAs prior to transplant: groups belatacept MI (10/219; 4.6% ), belatacept LI (11/226; 4.9%), and cyclosporine (14/221; 6.3%). It is noteworthy the baseline high range of MFI levels observed among transplant patients with DSA (upper limit greater than 20,000) fact that could lead us to speculate that either the CDC crossmatch was too little sensitive to the point of not detecting DSAs - at this level it should - or they are against Class II, and then a B cell crossmatch would be positive. In the same line, it was not reported whether patients with acute rejection were those associated with the higher MFI levels. Another point would be to explain why patients with preexisting DSAs tended to improve GFR over time. Similarly, the rates of death or graft loss were similar among the subgroups and such observation would deserve a more elaborate discussion, since a worst outcome would be expected in patients with DSAs. Overall, in spite of the small number of patients, the study raises important questions about the mechanisms involving belatacept and the production of donor-specific antibodies, the immunological risk profile of patients suitable to receive the drug and in which phase of the transplant it should be given. Unfortunately, only larger prospective randomized trials probably would be capable of answer these questions.
Aims:
To assess changes in level of pre-existing DSAs post transplantation after belatacept- versus cyclosporine-based immunosuppression in patients enrolled from the BENEFIT and BENEFIT- EXT trials. Efficacy and safety were assessed at 7 years (84 months) post transplantation.
Interventions:
Patients were randomized (1:1:1) to receive belatacept more intense (MI)- based, belatacept less intense (LI)- based, or cyclosporine- based immunosuppression for 3 years. Randomized treament was extended beyond 3 years following a protocol amendment.
Participants:
BENEFIT and BENEFIT- EXT were 3-year, international, partially blinded, randomized phase III studies. 35 patients from BENEFIT (received a living or standard- criteria deceased donor kidney) and 38 patients from BENEFIT- EXT (received an extended criteria donor kidney) with DSAs prior to transplant were included in this study.
Outcomes:
HLA antibody class, absence/presence of DSAs and changes in level of preexisting DSAs post transplantation (assessed as change in mean fluorescence intensity (MFI) of DSAs by solid-phase immunoassay). Efficacy and safety outcomes included death or graft loss, renal function and biopsy-proven acute rejection.
Follow Up:
DSA levels (MFI) from baseline (pretransplant) to 24 months; efficacy and safety at 84 months
BENEFIT and BENEFIT-EXT were phase III studies of cytotoxic T-cell crossmatch-negative kidney transplant recipients randomized to belatacept more intense (MI)-based, belatacept less intense (LI)-based, or cyclosporine-based immunosuppression. Following study completion, presence/absence of HLA-specific antibodies was determined centrally via solid-phase flow cytometry screening. Stored sera from anti-HLA-positive patients were further tested with a single-antigen bead assay to determine antibody specificities, presence/absence of donor-specific antibodies (DSAs), and mean fluorescent intensity (MFI) of any DSAs present. The effect of belatacept-based and cyclosporine-based immunosuppression on MFI was explored post hoc in patients with preexisting DSAs enrolled to BENEFIT and BENEFIT-EXT. In BENEFIT, preexisting DSAs were detected in 4.6%, 4.9%, and 6.3% of belatacept MI-treated, belatacept LI-treated, and cyclosporine-treated patients, respectively. The corresponding values in BENEFIT-EXT were 6.0%, 5.7%, and 9.2%. In both studies, most preexisting DSAs were of class I specificity. Over the first 24 months posttransplant, a greater proportion of preexisting DSAs in belatacept-treated versus cyclosporine-treated patients exhibited decreases or no change in MFI. MFI decline was more apparent with belatacept MI-based versus belatacept LI-based immunosuppression in both studies and more pronounced in BENEFIT-EXT versus BENEFIT. Although derived post hoc, these data suggest that belatacept-based immunosuppression decreases preexisting DSAs more effectively than cyclosporine-based immunosuppression.
This small study investigates the role of rituximab, combined with IvIG, for renal transplant recipients with chronic antibody-mediated rejection (CAMR). The study is placebo-controlled. Despite being multicentre and spanning a 3-year period, only 25 of the planned 50 patients were recruited. The authors conclude that this regimen is unlikely to be useful in the management of CAMR, as no differences were seen in renal function, proteinuria, biopsy scores or MFI of donor-specific antibodies. The major limitation here is the small number of patients recruited, leading to a significant difference in baseline renal function between the groups. 95% confidence intervals for the outcomes are not presented, but it is likely that there is insufficient power to draw any firm conclusions on the basis of these data.
Expert Review
Reviewer:
Professor John Kanellis, Department of Nephrology, Department of Medicine, Monash University, Clayton, Melbourne.
Conflicts of Interest:
No
Clinical Impact Rating
3
Review:
This double-blind, placebo controlled study examined the use of IVIG and rituximab to treat chronic antibody-mediated rejection (cAMR). Participants had donor specific antibody (DSA), transplant glomerulopathy and an eGFR of >20ml/min. No benefit was seen after analysis of change in eGFR and proteinuria, biopsy scores and DSA MFI. This study is of significant interest as it suggests no benefit from currently used treatments for cAMR. The use of IVIG and rituximab is onerous and has significant side effects, therefore it is important to have studies that reveal benefit. The results need to be interpreted with caution however, as the study was small with only half the planned participants being recruited. It is therefore significantly underpowered. Furthermore, as the authors also acknowledge, subjects already had significant injury present and the baseline eGFR differed in the two arms (placebo 45±18 ml/min vs treatment arm 35±17 ml/min). These issues may also have influenced the results. Further well designed and adequately powered studies in cAMR are desperately needed as there is a significant clinical challenge and few proven therapeutic options. It is hoped that new therapies being currently trialled (IL-6 blockade, IdeS therapy) will show significant benefit.
Aims:
To evaluate the efficacy and safety of intravenous immunoglobulins (IVIG) combined with rituximab (RTX) in renal transplant patients with chronic antibody mediated rejection (ABMR), displaying transplant glomerulopathy and donor-specific antibodies (DSA).
Interventions:
Participants were randomised to receive either four consecutive doses of IVIG (0.5 g/kg) every 3 weeks and one single dose of RTX (375 mg/m2), 1 week after the last IVIG dose (treatment group), versus an isovolumetric saline solution following the same schedule (control group).
Participants:
25 stable renal transplant recipients aged ≥18 years with biopsy proven chronic ABMR diagnosed < 6 months prior to randomisation.
Outcomes:
The primary outcome measured was the delicine in estimated glomerular filtration rate. Secondary measured outcomes included proteinuria renal lesions, and DSA at 1 year. Adverse events, opportunistic infections and hospitalisations were also measured.
Follow Up:
12 months
There are no approved treatments for chronic antibody mediated rejection (ABMR). We conducted a multicenter, prospective, randomized, placebo-controlled, double-blind clinical trial to evaluate efficacy and safety of intravenous immunoglobulins (IVIG) combined with rituximab (RTX) (EudraCT 2010-023746-67). Patients with transplant glomerulopathy and anti-HLA donor-specific antibodies (DSA) were eligible. Patients with estimated glomerular filtration rate (eGFR) <20 mL/min per 1.73m2 and/or severe interstitial fibrosis/tubular atrophy were excluded. Patients were randomized to receive IVIG (4 doses of 0.5 g/kg) and RTX (375 mg/m2 ) or a wrapped isovolumetric saline infusion. Primary efficacy variable was the decline of eGFR at one year. Secondary efficacy variables included evolution of proteinuria, renal lesions, and DSA at 1 year. The planned sample size was 25 patients per group. During 2012-2015, 25 patients were randomized (13 to the treatment and 12 to the placebo group). The planned patient enrollment was not achieved because of budgetary constraints and slow patient recruitment. There were no differences between the treatment and placebo groups in eGFR decline (-4.2 ± 14.4 vs. -6.6 ± 12.0 mL/min per 1.73 m2 , P-value = .475), increase of proteinuria (+0.9 ± 2.1 vs. +0.9 ± 2.1 g/day, P-value = .378), Banff scores at one year and MFI of the immunodominant DSA. Safety was similar between groups. These data suggest that the combination of IVIG and RTX is not useful in patients displaying transplant glomerulopathy and DSA.
Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This paper reports the results of the Borteject Trial, in which kidney transplant recipients with donor-specific antibody and histological evidence of antibody-mediated rejection were randomised to Bortezomib or placebo. Despite the suggestion from a number of observational studies that Bortezomib reduces DSA and improves outcomes, this blinded RCT demonstrated no benefit in terms of renal function or DSA levels. Haematological and gastrointestinal toxicity were higher in the Bortezomib arm. The study is small (just 44 patients), powered to demonstrate a relatively large difference in GFR slope of 5 ml/min/year. However, given the absence of even a trend towards benefit or a reduction in DSA levels, it seems safe to say that in a late AMR population such as this, Bortezomib alone does not confer any clinical benefit.
Expert Review
Reviewer:
Mr Nicos Kessaris, Paediatric Renal Transplant Surgery, King’s College London and Guy's Hospital, United Kingdom.
Conflicts of Interest:
No
Clinical Impact Rating
3
Review:
Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection [BORTEJECT] Trial is a randomised, double blind, placebo controlled, single centre trial, evaluating the use of two cycles of bortezomib (first generation proteasome inhibitor) in preventing GFR decline in late antibody-mediated kidney transplant rejection. Following a cross-sectional screening process to identify patients with DSA and antibody mediated rejection (ABMR) > 6 months post-transplant, 21 patients were randomised to bortezomib and 23 to placebo therapy. The statistical analysis comparing the demographic and baseline DSA characteristics between the bortezomib and the placebo groups was not shown but the two groups were said to be similar in the text. There was no significant deference in GFR decline and overall graft and patient survival at 24 months post treatment in either group. In addition, there was no statistical difference in DSA reduction, proteinuria level, or histological and molecular ABMR features between the two groups in the same period. Severe adverse events were higher in the bortezomib group but not significantly. This paper complements previous uncontrolled studies in strengthening the evidence against the use of bortezomib as a single agent to treat late ABMR. Further studies using new proteasome inhibitors, combinatorial treatments, multiple cycles or prolonged treatments periods are necessary, but these should always be balanced against the risk of toxicity.
Aims:
To investigate the effect of the proteasome inhibitor bortezomib on late antibody-mediated rejection (ABMR) in kidney transplant recipients.
Interventions:
Participants were randomised to receive two cycles at 3-month intervals of either bortezomib 1.3 mg/m2 administered intravenously twice weekly and oral valacyclovir for antiviral prophylaxis, (bortezomib group) versus 0.9% sodium chloride solution and hard gelatin capsules filled with maltodextrin (control group).
Participants:
44 kidney transplant recipients aged >18 years, who were ≥180 days posttransplantation, had an estimated glomerular filtration rate (eGFR) >20 ml/min per 1.73 m2 with the detection of HLA class I and/or II donor-specific antibody (DSA) and showing ≥ one morphologic feature suggestive of ABMR
Outcomes:
The primary outcome measured was the slope of eGFR computed from eGFR measurements at 0, 6, 12, 18, and 24 months. Secondary outcomes included the course of DSA, measured GFR, urinary protein excretion, patient and graft survival, occurrence of acute rejection necessitating treatment, and protocol biopsies at 24 months.
Follow Up:
24 months
Late antibody-mediated rejection (ABMR) is a leading cause of kidney allograft failure. Uncontrolled studies have suggested efficacy of the proteasome inhibitor bortezomib, but no systematic trial has been undertaken to support its use in ABMR. In this randomized, placebo-controlled trial (the Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection [BORTEJECT] Trial), we investigated whether two cycles of bortezomib (each cycle: 1.3 mg/m2 intravenously on days 1, 4, 8, and 11) prevent GFR decline by halting the progression of late donor-specific antibody (DSA)-positive ABMR. Forty-four DSA-positive kidney transplant recipients with characteristic ABMR morphology (median time after transplant, 5.0 years; pretransplant DSA documented in 19 recipients), who were identified on cross-sectional screening of 741 patients, were randomly assigned to receive bortezomib (n=21) or placebo (n=23). The 0.5-ml/min per 1.73 m2 per year (95% confidence interval, -4.8 to 5.8) difference detected between bortezomib and placebo in eGFR slope (primary end point) was not significant (P=0.86). We detected no significant differences between bortezomib- and placebo-treated groups in median measured GFR at 24 months (33 versus 42 ml/min per 1.73 m2; P=0.31), 2-year graft survival (81% versus 96%; P=0.12), urinary protein concentration, DSA levels, or morphologic or molecular rejection phenotypes in 24-month follow-up biopsy specimens. Bortezomib, however, associated with gastrointestinal and hematologic toxicity. In conclusion, our trial failed to show that bortezomib prevents GFR loss, improves histologic or molecular disease features, or reduces DSA, despite significant toxicity. Our results reinforce the need for systematic trials to dissect the efficiency and safety of new treatments for late ABMR.
This paper reports the results of the ELEVATE trial, a multicentre RCT comparing early (week 10-14) conversion to everolimus with continuation of CNI-based therapy in standard criteria kidney recipients. The primary endpoint, change in MDRD eGFR from randomisation to month 12, did not differ between groups. Incidence of biopsy-proven acute rejection was higher in the CNI arm, which is attributed mainly to the cyclosporine-treated patients. There is also a suggestion of increased incidence of donor-specific antibodies in the everolimus group, but the data are very incomplete making firm conclusions difficult. Around 25% of patients did not tolerate everolimus therapy, in keeping with previous mTOR trials. These results suggest that there is little if any benefit of conversion to everolimus in patients with a relatively well-preserved graft function. It should be noted that only 50-60% of patients were within the everolimus trough target range at any one study visit, much lower than tacrolimus (70-75%) and cyclosporine (60-80%). This may reflect poor compliance due to adverse effects, and possibly explain the inferior protection against BPAR seen in the study.
Expert Review
Reviewer:
Dr Georg A. Böhmig, Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Austria.
Conflicts of Interest:
No
Clinical Impact Rating
4
Review:
In this randomized controlled trial (ELEVATE), de Fijter and co-workers evaluated the effect of early conversion of maintenance immunosuppression (week 10-14) from tacrolimus or cyclosporine to everolimus. The study included 715 recipients (intention-to-treat population) of a deceased or living donor ABO-compatible kidney transplant, who had a functioning graft with less than 1g/day proteinuria. A few recipients had DSA, but patients with broad HLA sensitization or repeated rejection episodes were not included. A key result was that everolimus- and CNI-treated patients did not differ regarding the primary endpoint (change in eGFR from randomization to month 12). Everolimus, however, was associated with de novo DSA, rejection, proteinuria, and discontinuation of study drug due to adverse events. Importantly, there was no benefit regarding chronic transplant injury in protocol biopsies, cardiovascular endpoints or new-onset diabetes. Limitations of the trial were the open study design, a comparably short follow-up, and incomplete HLA antibody data. A caveat was that 40-50% of the subjects converted to everolimus did not achieve target trough levels. This trial may have important implications for clinical practice. Its results argue against early conversion to everolimus in standard risk recipients with preserved kidney function, especially in the context of tacrolimus- and mycophenolic acid-based immunosuppression.
Aims:
To assess the effect of early conversion from calcineurin inhibitor (CNI) therapy to everolimus in kidney transplant recipients.
Interventions:
Participants were randomized at 10–14 weeks posttransplant to convert from CNI therapy to everolimus, or remain on a standard CNI regimen. All patients received basiliximab induction with tacrolimus or cyclosporine, enteric-coated mycophenolate sodium and steroids.
Participants:
715 adult recipients of a first or second kidney transplant from a deceased or living donor with a cold ischemia time <24 h.
Outcomes:
The primary outcome measured was the change in estimated glomerular filtration rate from randomization to month 12. Secondary measured outcomes were also measured from randomization to month 12 and included the change in left ventricular mass index, and a composite of treated biopsy proven acute rejection, graft loss or death.
Follow Up:
24 months
In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10-14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.732 versus -1.5(1.5) mL/min/1.732 (p = 0.116). Biopsy-proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNI overall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus-treated patients (2.6%, p < 0.001) but similar to cyclosporine-treated patients (8.8%, p = 0.755). Reporting on de novo donor-specific antibodies (DSA) was limited but suggested more frequent anti-HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10-14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.
Mr John O'Callaghan, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This report details a well conducted randomised controlled trial. Renal transplant recipients were randomised to conversion from maintenance immune suppression to either prednisolone and cyclosporine or prednisolone and everolimus. There was also a third arm (prednisolone and mycophenolate) that was terminated early due to poor results. At 24 months a protocol biopsy was taken and these showed significantly less fibrosis with everolimus than cyclosporine. Everolimus also showed a better renal function with about 5ml/min better eGFR over several months than cyclosporine. There was no significant difference in rates of clinical rejection over the same time period, development of DSA, patient or graft survival. Importantly there were significantly more serious adverse events with everolimus than cyclosporine, with much higher rates of change in regimen and cardiovascular events. This is of concern given the proven increased risk of hypercholesterolaemia with everolimus.
Expert Review
Reviewer:
Professor Edward Cole, University Health Network, University of Toronto.
Conflicts of Interest:
No
Clinical Impact Rating
2
Review:
This randomised controlled trial shows less interstitial fibrosis and better renal function at 24 months in patients randomised to prednisone/everolimus vs prednisone/cyclosporine. While well done, the impact of these results on clinical practice, in my opinion, is tempered by the following. Twenty-four per cent of patients withdrew before randomization. This seems, at least in part to relate to difficulties with the intense monitoring used. The dosing of both cyclosporine and everolimus was by multiple timed samples and AUC. This is inconsistent with routine clinical practice. Some patients were on 10 mg daily of prednisone, much higher than the dose in some constituencies. The use of cyclosporine as opposed to tacrolimus does not conform to the preferred calcineurin inhibitor in many centres. The incidence of serious adverse events was about twice as high in everolimus treated patients. Forty percent of everolimus vs 18% of cyclosporine treated patients switched immunosuppression during the study. The impact of cyclosporine nephrotoxicity on graft failure is controversial. In this study, while everolimus patients had better graft function at 2 years, the lines look parallel. Thus it is unclear whether the functional difference will lead to substantial difference in long term graft survival. There were 4 deaths in the everolimus arm vs 1 in the other arm. While not significant, there is another systematic review*, in addition to the one quoted by the authors, that shows a higher death rate in transplant recipients treated with TOR inhibitors despite a lower cumulative incidence in that group. *Knoll GA, et al. Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data. BMJ. 2014 Nov 24;349.
Aims:
To determine whether minimizing exposure to calcineurin inhibitors and total amount of immunosuppression by switching to a non-nephrotoxic double drug regimen early after transplantation would maintain efficacy in renal transplant recipients.
Interventions:
Patients started with basiliximab, prednisolone (P), mycophenolate sodium (MPS) and CsA. At 6 months, patients without rejection were randomized to receive one of three treatment arms; P/CsA, P/MPS, or P/everolimus.
Participants:
224 patients aged 18-70 years receiving a first or second renal transplant from a deceased or living donor.
Outcomes:
The primary measured outcome was the development of interstitial fibrosis at the 24-month protocol biopsy. Secondary outcomes included the estimated glomerular filtration rate, incidence of acute rejection, and drug-related adverse events.
Follow Up:
24 months
In renal transplantation, use of calcineurin inhibitors (CNIs) is associated with nephrotoxicity and immunosuppression with malignancies and infections. This trial aimed to minimize CNI exposure and total immunosuppression while maintaining efficacy. We performed a randomized controlled, open-label multicenter trial with early cyclosporine A (CsA) elimination. Patients started with basiliximab, prednisolone (P), mycophenolate sodium (MPS), and CsA. At 6 months, immunosuppression was tapered to P/CsA, P/MPS, or P/everolimus (EVL). Primary outcomes were renal fibrosis and inflammation. Secondary outcomes were estimated glomerular filtration rate (eGFR) and incidence of rejection at 24 months. The P/MPS arm was prematurely halted. The trial continued with P/CsA (N = 89) and P/EVL (N = 96). Interstitial fibrosis and inflammation were significantly decreased and the eGFR was significantly higher in the P/EVL arm. Cumulative rejection rates were 13% (P/EVL) and 19% (P/CsA), (p = 0.08). A post hoc analysis of HLA and donor-specific antibodies at 1 year after transplantation revealed no differences. An individualized immunosuppressive strategy of early CNI elimination to dual therapy with everolimus was associated with decreased allograft fibrosis, preserved allograft function, and good efficacy, but also with more serious adverse events and discontinuation. This can be a valuable alternative regimen in patients suffering from CNI toxicity.
Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This large multicentre study from Germany randomised low-risk kidney transplant recipients to three groups – Basiliximab induction with maintenance steroids, Basilixmab induction with early steroid withdrawal, or ATG induction with steroid withdrawal. All patients received standard immunosuppression with low-dose tacrolimus and 2g/day MMF. Two important observations are made; Firstly, BPAR rates did not differ between arms suggesting that in low-risk recipients, Basiliximab is as effective as ATG, even in the absence of maintenance steroids. Secondly, even the low doses of maintenance steroids used (2.5-5mg/day) significantly increased the risk of post-transplant diabetes. There were no differences in safety outcomes including infection or malignancy between arms. Power was reduced by a large number of drop-outs from the study, but there are no trends to suggest that a larger sample would have resulted in any different conclusions. Certainly it would appear that in a low-risk, predominantly Caucasian population, Basiliximab induction with early steroid withdrawal is a safe strategy.
Expert Review
Reviewer:
Miss Lorna Marson, Transplant Surgery, University of Edinburgh.
Conflicts of Interest:
No
Clinical Impact Rating
2
Review:
Multi-centre, open label, randomised controlled trial with 3 arms: basiliximab induction, low dose tacrolimus, MMF, and steroid maintenance (A), rapid steroid withdrawal on day 8 with either basiliximab (B) or ATG (C) induction. Included were 18-75 year old low immunological risk recipients of a single renal transplant from living donor or donor after brain death, and primary end point was incidence of biopsy-proven acute rejection (BPAR) at 12 months. 587 patients were included, recruited over a 5-year period. There was no significant difference in incidence of BPAR between the three groups over the 12-month follow up. There was a significant reduction in post-transplant diabetes in the steroid withdrawal groups, with comparable patient and graft survival across the three groups. Limitations of the study include: low rate of BPAR, (11% across all groups), nearly a third of patients were discontinued from the study, the study was not powered to compare rate of post-transplant diabetes, and the follow up time was short. Nevertheless, this is an important study, demonstrating no superiority of ATG over basiliximab in these patients with low immunological risk, and short-term safety of steroid withdrawal. Longer-term follow-up of these patients will be important.
Aims:
To examine the efficacy and safety parameters of rapid steroid withdrawal after induction therapy with either rabbit antithymocyte globulin (rabbit ATG) or basiliximab in immunologically low-risk patients during the first year after kidney transplantation.
Interventions:
Participants were randomly assigned to one of three study arms and received basiliximab induction with low-dose tacrolimus, mycophenolate mofetil, and steroid maintenance therapy. Those in Arm A (control group) continued with this regimen, while rapid corticosteroid withdrawal on day 8 (Arm B), and rapid corticosteroid withdrawal on day 8 after rabbit ATG (Arm C).
Participants:
615 patients with a low immunological risk, scheduled to receive a single-organ renal transplant from either a living donor or a deceased donor, aged between 18-75 years.
Outcomes:
The primary outcome measured was the incidence of biopsy-proven acute rejection (BPAR) within the first year after renal transplantation. Secondary outcomes included patient and graft survival, graft function, percentage of patients in which steroid-free immunosuppressive treatment was maintained after 12 months, incidence of posttransplantation diabetes, systolic and diastolic blood pressure, lipids, bodyweight, infections, incidence of malignancy, wound healing disorders, cataract formation, and osteoporosis.
Follow Up:
12 months
BACKGROUND:
Standard practice for immunosuppressive therapy after renal transplantation is quadruple therapy using antibody induction, low-dose tacrolimus, mycophenolate mofetil, and corticosteroids. Long-term steroid intake significantly increases cardiovascular risk factors with negative effects on the outcome, especially post-transplantation diabetes associated with morbidity and mortality. In this trial, we examined the efficacy and safety parameters of rapid steroid withdrawal after induction therapy with either rabbit antithymocyte globulin (rabbit ATG) or basiliximab in immunologically low-risk patients during the first year after kidney transplantation.
METHODS:
In this open-label, multicentre, randomised controlled trial, we randomly assigned renal transplant recipients in a 1:1:1 ratio to receive either basiliximab induction with low-dose tacrolimus, mycophenolate mofetil, and steroid maintenance therapy (arm A), rapid corticosteroid withdrawal on day 8 (arm B), or rapid corticosteroid withdrawal on day 8 after rabbit ATG (arm C). The study was done in 21 centres across Germany. Only participants aged between 18 and 75 years with a low immunological risk who were scheduled to receive a single-organ renal transplant from either a living donor or a deceased donor were considered for enrolment. Patients receiving a second renal transplant were eligible, provided that the first allograft was not lost due to acute rejection within the first year after transplantation. Donor and recipient had to be ABO compatible. Grafts with pre-transplant existing donor-specific human leukocyte antigen (HLA) antibodies were not eligible and the recipients had to have a panel-reactive antibody concentration of 30% or less. Pregnant women and nursing mothers were excluded from the study. The primary endpoint was the incidence of biopsy-proven acute rejection (BPAR) at 12 months. All analyses were done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00724022.
FINDINGS:
Between Aug 7, 2008, and Nov 30, 2013, 615 patients were randomly assigned to arm A (206), arm B (189), and arm C (192). BPAR rates were not reduced by rabbit ATG (9·9%) compared with either treatment arm A (11·2%) or B (10·6%; A versus C: p=0·75, B versus C p=0·87). As a secondary endpoint, rapid steroid withdrawal reduced post-transplantation diabetes in arm B to 24% and in arm C to 23% compared with 39% in control arm A (A versus B and C: p=0·0004). Patient survival (94·7% in arm A, 97·4% in arm B, and 96·9% in arm C) and censored graft survival (96·1% in arm A, 96·8% in arm B, and 95·8% in arm C) after 12 months were excellent and equivalent in all arms. Safety parameters such as infections or the incidence of post-transplantation malignancies did not differ between the study arms.
INTERPRETATION:
Rabbit ATG did not show superiority over basiliximab induction for the prevention of BPAR after rapid steroid withdrawal within 1 year after renal transplantation. Nevertheless, rapid steroid withdrawal after induction therapy for patients with a low immunological risk profile can be achieved without loss of efficacy and is advantageous in regard to post-transplantation diabetes incidence.
FUNDING:
Investigator Initiated Trial; financial support by Astellas Pharma GmbH, Sanofi, and Roche Pharma AG.
CET Conclusion