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:
Whilst many studies have demonstrated associations between biomarkers and acute rejection in renal transplantation, few have prospectively assessed the value of routine monitoring. This study randomised de novo kidney recipients to monitoring with urine CXCL10, or to routine care. In the control arm, CXCL10 measurements were taken but concealed. In the study arm, response to CXCL10 measurements was protocolised, with a biopsy undertaken in patients with elevated levels to inform clinical management. The authors found no difference in one-year clinical outcomes in either intent-to-treat or per-protocol analysis with monitoring. This is an interesting study as it highlights the challenges of translating biomarker association into real-world clinical monitoring. It is possible that the timepoints selected for monitoring, or the frequency of monitoring, was not optimum. Successful monitoring also requires adequate response to an abnormal result – both by undertaking biopsy and treating abnormal findings. In this study, 23% indicated biopsies were not completed, and 24% detected rejection episodes were not treated. Successful monitoring also assumes that the biomarker detects an abnormality (e.g. rejection) at a stage where intervention can have an impact on clinical outcome.
Aims:
This study aimed to examine whether renal allograft monitoring by urine CXCL10 led to an improvement in clinical outcomes posttransplantation.
Interventions:
Participants were randomised into two groups: the intervention arm, where a renal allograft biopsy were performed if levels of urine CXCL10 were above a predefined cutoff without the presence of confounders; and the control arm, in which the urine CXCL10 analyses was also assessed but the results were concealed.
Participants:
241 adult kidney transplant recipients.
Outcomes:
The primary outcome was a combined endpoint at 1 year following transplantation, including death-censored graft loss, clinical rejection, acute rejection, chronic active T-cell–mediated rejection, development of de novo donor-specific HLA antibodies, or an estimated glomerular filtration rate (eGFR) of 25 ml/min.
Follow Up:
1 year
SIGNIFICANCE STATEMENT:
This study is the first randomized controlled trial to investigate the clinical utility of a noninvasive monitoring biomarker in renal transplantation. Although urine CXCL10 monitoring could not demonstrate a beneficial effect on 1-year outcomes, the study is a rich source for future design of trials aiming to explore the clinical utility of noninvasive biomarkers. In addition, the study supports the use of urine CXCL10 to assess the inflammatory status of the renal allograft.
BACKGROUND:
Urine CXCL10 is a promising noninvasive biomarker for detection of renal allograft rejection. The aim of this study was to investigate the clinical utility of renal allograft monitoring by urine CXCL10 in a randomized trial.
METHODS:
We stratified 241 patients, 120 into an intervention and 121 into a control arm. In both arms, urine CXCL10 levels were monitored at three specific time points (1, 3, and 6 months post-transplant). In the intervention arm, elevated values triggered performance of an allograft biopsy with therapeutic adaptations according to the result. In the control arm, urine CXCL10 was measured, but the results concealed. The primary outcome was a combined end point at 1-year post-transplant (death-censored graft loss, clinical rejection between month 1 and 1-year, acute rejection in 1-year surveillance biopsy, chronic active T-cell-mediated rejection in 1-year surveillance biopsy, development of de novo donor-specific HLA antibodies, or eGFR <25 ml/min).
RESULTS:
The incidence of the primary outcome was not different between the intervention and the control arm (51% versus 49%; relative risk (RR), 1.04 [95% confidence interval, 0.81 to 1.34]; P = 0.80). When including 175 of 241 (73%) patients in a per-protocol analysis, the incidence of the primary outcome was also not different (55% versus 49%; RR, 1.11 [95% confidence interval, 0.84 to 1.47]; P = 0.54). The incidence of the individual end points was not different as well.
CONCLUSIONS:
This study could not demonstrate a beneficial effect of urine CXCL10 monitoring on 1-year outcomes (ClinicalTrials.gov_ NCT03140514 ).
Mr John Fallon, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
The investigators found both groups IVIG+ and IVIG- were associated with dnDSA MFI, but that the addition of IVIG to rituximab had no added benefit for dnDSA reduction at either 3 or 12 months. This reduction is significant when they were compared with a matched group of retrospective controls. Between the two groups they also found no difference in their secondary outcome measures of eGFR at 3 or 12 months, with no episodes of anti-body mediated rejection (ABMR) in the study cohort. They also reported no difference in protein-creatinine ratio. However, then generalisability of the study is somewhat limited due to its small sample size and possibility of selection bias given that nearly all the participants were living-related kidney transplant recipients. No episodes of ABMR occurred, which due to the size of the trial isn’t entirely surprising but given a core part of pre-emptive dnDSA reduction is to hopefully reduce the incidence and severity of ABMR it is hard to assess the potential importance of the interventions. There is also no mention or inclusion of the ABMR rate in their retrospectively matched control cohort which may have been of interest. The study contributes to baseline data on the potential benefit of pre-emptive treatment of dnDSA, however, a larger randomised trial of rituximab vs placebo in an adult population would be of benefit.
Aims:
This study aimed to evaluate the efficacy of pre-emptive treatment of De Novo DSA (dnDSA) using combination of high-dose intravenous immunoglobulin and rituximab (IVIG+) or rituximab alone (IVIG-) in reduction of dnDSA titre at 3 and 12 months after treatment compared to retrospective controls.
Interventions:
Both groups received rituximab (375mg/m2) on day 0, and the IVIG+ group additionally received high-dose IVIG (2g/kg) after rituximab infusion.
Participants:
50 adult kidney recipients with functioning graft (eGFR >20 ml/min/1.73 m2) and subclinical class II dnDSA with mean fluorescent intensity (MFI) ≥1000 of the DR or DQ DSA.
Outcomes:
The primary outcome measure was dnDSA titre at 3 and 12 months. Secondary outcomes were changes in eGFR and incidence of anti-body mediated rejection.
Follow Up:
Participants were followed-up for 12 months.
De novo donor-specific antibody (dnDSA) is associated with a higher risk of kidney graft failure. However, it is unknown whether preemptive treatment of subclinical dnDSA is beneficial. Here, we assessed the efficacy of high-dose intravenous immunoglobulin (IVIG) and rituximab combination therapy for subclinical dnDSA. An open-label randomized controlled clinical trial was conducted at two Korean institutions. Adult (aged ≥ 19 years) kidney transplant patients with subclinical class II dnDSA (mean fluorescence intensity ≥ 1000) were enrolled. Eligible participants were randomly assigned to receive rituximab or rituximab with IVIG at a 1:1 ratio. The primary endpoint was the change in dnDSA titer at 3 and 12 months after treatment. A total of 46 patients (24 for rituximab and 22 for rituximab with IVIG) were included in the analysis. The mean baseline estimated glomerular filtration rate was 66.7 ± 16.3 mL/min/1.73 m2. The titer decline of immune-dominant dnDSA at 12 months in both the preemptive groups was significant. However, there was no difference between the two groups at 12 months. Either kidney allograft function or proteinuria did not differ between the two groups. No antibody-mediated rejection occurred in either group. Preemptive treatment with high-dose IVIG combined with rituximab did not show a better dnDSA reduction compared with rituximab alone.Trial registration: IVIG/Rituximab versus Rituximab in Kidney Transplant With de Novo Donor-specific Antibodies (ClinicalTrials.gov Identifier: NCT04033276, first trial registration (26/07/2019).
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This is a very interesting study conducted across 13 transplant centres in the UK with 3-year graft survival as the primary outcome. The study tested the hypothesis that screening for the development of Donor Specific Antibodies (DSA), combined with an intervention to improve adherence and optimised oral treatment would prevent transplant failure. Patients developing DSA in the “biomarker-led care” group were changed to maximum tolerated doses of MMF/mycophenolic acid (MPA) and tacrolimus, and were encouraged to take prednisolone 20 mg daily for two weeks, reducing by 5 mg down to their previous maintenance dose. 2037 patients were randomised. The study again confirmed that the development of DSA after transplantation was strongly predictive of a poorer long term graft survival. The key output from the study however is the indication that measures taken in this at-risk group did not improve the outcome and prevent the inevitable negative impact on graft survival.
Aims:
This study aimed to determine whether allograft failure could be prevented through routine surveillance for human leukocyte antigens antibodies (HLA Ab), in combination with an intervention to improve adherence and optimization of immunosuppression.
Interventions:
Participants were randomised to either the blinded standard care (SC) arm or the unblinded biomarker led care (BLC) arm.
Participants:
2037 renal transplant patients.
Outcomes:
The primary endpoint was graft failure. The secondary endpoints included time to graft failure, patient survival, levels of graft dysfunction or change in eGFR, presence of biopsy-proven acute rejection, adverse effect profiles, the cost effectiveness of the screening/treatment protocol, and the impact of HLA Ab screening and treatment on the patients’ drug therapy adherence and their perceptions of risk to the health of the transplant.
Follow Up:
64 months
BACKGROUND:
3% of kidney transplant recipients return to dialysis annually upon allograft failure. Development of antibodies (Ab) against human leukocyte antigens (HLA) is a validated prognostic biomarker of allograft failure. We tested whether screening for HLA Ab, combined with an intervention to improve adherence and optimization of immunosuppression could prevent allograft failure.
METHODS:
Prospective, open-labelled randomised biomarker-based strategy (hybrid) trial in 13 UK transplant centres [EudraCT (2012-004308-36) and ISRCTN (46157828)]. Patients were randomly allocated (1:1) to unblinded or double-blinded arms and screened every 8 months. Unblinded HLA Ab+ patients were interviewed to encourage medication adherence and had tailored optimisation of Tacrolimus, Mycophenolate mofetil and Prednisolone. The primary outcome was time to graft failure in an intention to treat analysis. The trial had 80% power to detect a hazard ratio of 0.49 in donor specific antibody (DSA)+ patients.
FINDINGS:
From 11/9/13 to 27/10/16, 5519 were screened for eligibility and 2037 randomised (1028 to unblinded care and 1009 to double blinded care). We identified 198 with DSA and 818 with non-DSA. Development of DSA, but not non-DSA was predictive of graft failure. HRs for graft failure in unblinded DSA+ and non-DSA+ groups were 1.54 (95% CI: 0.72 to 3.30) and 0.97 (0.54-1.74) respectively, providing no evidence of an intervention effect. Non-inferiority for the overall unblinded versus blinded comparison was not demonstrated as the upper confidence limit of the HR for graft failure exceeded 1.4 (1.02, 95% CI: 0.72 to 1.44). The only secondary endpoint reduced in the unblinded arm was biopsy-proven rejection.
INTERPRETATION:
Intervention to improve adherence and optimize immunosuppression does not delay failure of renal transplants after development of DSA. Whilst DSA predicts increased risk of allograft failure, novel interventions are needed before screening can be used to direct therapy.
FUNDING:
The National Institute for Health Research Efficacy and Mechanism Evaluation programme grant (ref 11/100/34).
Mr Keno Mentor, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This pilot study explores the possibility of reducing immunosuppression therapy in patients undergoing kidney transplantation. With previous studies showing that weaning of tacrolimus results in significantly poorer graft and patient survival, this study focused on withdrawal of MMF in those patients with low immunological risk. It was intended as a feasibility study for a larger trial, but the findings suggest that with careful patient selection, long-term graft survival can be achieved with tacrolimus monotherapy while significantly reducing the incidence of infectious complications. Being a pilot study, the main weakness is the small sample size. The older patient cohort (average age 59) means the conclusions may also not be generalisable to younger patients. However, the findings did demonstrate the feasibility of investigating this study question in a larger non-inferiority trial.
Aims:
This study aimed to examine the feasibility and safety of tacrolimus (TAC) monotherapy in renal transplant patients with low immunological risk.
Interventions:
Participants were randomly assigned to either TAC/mycophenolate mofetil (MMF) or to taper and discontinue MMF at month 9.
Participants:
79 kidney transplant recipients.
Outcomes:
The main outcomes of interest were biopsy-proven acute rejection (BPAR), kidney function, hospital admission, infectious burden, patient survival, death-censored graft survival and proteinuria.
Follow Up:
5 years
In this randomized-controlled pilot study, the feasibility and safety of tacrolimus monotherapy in immunologically low-risk kidney transplant recipients was evaluated [NTR4824, www.trialregister.nl]. Low immunological risk was defined as maximal 3 HLA mismatches and the absence of panel reactive antibodies. Six months after transplantation, recipients were randomized if eGFR >30 ml/min, proteinuria <50 mg protein/mmol creatinine, no biopsy-proven rejection after 3 months, and no lymphocyte depleting therapy given. Recipients were randomized to tacrolimus/mycophenolate mofetil (TAC/MMF) or to taper and discontinue MMF at month 9 (TACmono). 79 of the 121 recipients were randomized to either TACmono (n = 38) or TAC/MMF (n = 41). Mean recipient age was 59 years and 59% received a living donor transplant. The median follow-up was 62 months. After randomization, 3 TACmono and 4 TAC/MMF recipients experienced a biopsy-proven rejection. At 5 years follow-up, patient survival was 84% in TACmono versus 76% in TAC/MMF with death-censored graft survival of 97% for both groups and no differences in eGFR and proteinuria. Eleven TACmono recipients had an infectious episode versus 22 TAC/MMF recipients (p < 0.03). Donor-specific anti-HLA antibodies were not detected during follow-up in both groups. Tacrolimus monotherapy in selected immunologically low-risk kidney transplant recipients appears safe and reduces the number of infections.
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This paper reports the 5-year outcomes from a previously published trial comparing 3 different immune suppression regimens. The number lost to follow up was small and similar between the study arms. The primary outcome was a composite “treatment failure” defined as biopsy proven rejection >1A, graft loss, death or loss to follow up. There was no significant difference in the rate of this primary outcome. There was no significant difference GFR. There was however a higher risk of post-transplant diabetes with the groups receiving everolimus (30-33% versus 15%). In this group of low/moderate risk renal transplant recipients, all three immune suppression regimens were associated with acceptable outcomes. Similar proportions of each group were still receiving their randomised therapy at 5 years.
Aims:
This post hoc analysis aimed to report the 5-year follow-up outcomes of a randomised controlled trial investigating the efficacy and safety of everolimus compared to mycophenolate in kidney transplant recipients receiving tacrolimus-based immunosuppressive regimen.
Interventions:
Participants in the original trial were randomised to one of three groups: rabbit antithymocyte globulin ( r-ATG) plus everolimus, basiliximab plus everolimus, or basiliximab plus mycophenolate.
Participants:
300 de novo kidney transplant recipients.
Outcomes:
The main outcomes included assessment of treatment failure, treated clinical acute rejection episodes, serum HLA antibodies, estimated glomerular filtration rate (eGFR), proteinuria, blood pressure, body mass index (BMI), high-density lipoprotein cholesterol (HDL)/ low-density lipoprotein cholesterol (LDL), posttransplant diabetes mellitus (PTDM), use of lipidlowering agents, major adverse cardiovascular events (MACEs), and malignancies.
Follow Up:
5 years
BACKGROUND:
The short-term efficacy and safety of everolimus in combination with tacrolimus have been described in several clinical trials. Yet, detailed long-term data comparing the use of everolimus or mycophenolate in kidney transplant recipients receiving tacrolimus are lacking.
METHODS:
This is a 5-y follow-up post hoc analysis of a prospective trial including 288 patients who were randomized to receive a single 3-mg/kg dose of rabbit antithymocyte globulin, tacrolimus, everolimus (EVR), and prednisone (rabbit antithymocyte globulin/EVR, n = 85); basiliximab, tacrolimus, everolimus, and prednisone (basiliximab/EVR, n = 102); or basiliximab, tacrolimus, mycophenolate, and prednisone (basiliximab/mycophenolate, n = 101).
RESULTS:
There were no differences in the incidence of treatment failure (31.8% versus 40.2% versus 34.7%, P = 0.468), de novo donor-specific HLA antibodies (6.5% versus 11.7% versus 4.0%, P = 0.185), patient (92.9% versus 94.1% versus 92.1%, P = 0.854), and death-censored graft (87.1% versus 90.2% versus 85.1%, P = 0.498) survivals. Using a sensitive analysis, the trajectories of estimated glomerular filtration rate were comparable in the intention-to-treat (P = 0.145) and per protocol (P = 0.354) populations. There were no differences in study drug discontinuation rate (22.4% versus 30.4% versus 17.8%, P = 0.103).
CONCLUSIONS:
In summary, this analysis in a cohort of de novo low/moderate immunologic risk kidney transplant recipients suggests that the use of a single 3 mg/kg rabbit antithymocyte globulin dose followed by EVR combined with reduced tacrolimus concentrations was associated with similar efficacy and renal function compared with the standard of care immunosuppressive regimen.
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This is a good quality randomised controlled trial in paediatric lung transplantation. The study was double-blinded and conducted in multiple centres. Patients were randomised to either standard immune induction with ATG (plus placebo) or to ATG and Rituximab. The primary outcome was composite graft dysfunction, death or re-listing. Unfortunately, only 11 subjects met criteria for the composite primary outcome, so the study was underpowered to demonstrate all but the most drastic of differences between the study arms. Whilst there was no significant difference in the primary outcome, there was a significantly lower generation of de novo DSA in the Rituximab arm (21% versus 73%). There was no significant difference in adverse event rates. A much larger study, and with longer follow up, is required.
Aims:
The aim of this study was to investigate whether rituximab in addition to rabbit anti-thymocyte globulin induction was effective in reducing the development of de novo donor-specific human leukocyte antigen antibodies (DSA) and improve outcomes, in paediatric lung transplant recipients.
Interventions:
Participants were randomly assigned to either the rituximab group or the placebo group
Participants:
27 paediatric lung transplant patients.
Outcomes:
The primary outcome was a composite of chronic allograft dysfunction, listing for re-transplant or death. The secondary outcomes were the incidence of primary graft dysfunction, antibody-mediated rejection and acute cellular rejection.
Follow Up:
24 months
We conducted a randomized, placebo-controlled, double-blind study of pediatric lung transplant recipients, hypothesizing that rituximab plus rabbit anti-thymocyte globulin induction would reduce de novo donor-specific human leukocyte antigen antibodies (DSA) development and improve outcomes. We serially obtained clinical data, blood, and respiratory samples for at least one year posttransplant. We analyzed peripheral blood lymphocytes by flow cytometry, serum for antibody development, and respiratory samples for viral infections using multiplex PCR. Of 45 subjects enrolled, 34 were transplanted and 27 randomized to rituximab (n = 15) or placebo (n = 12). No rituximab-treated subjects versus five placebo-treated subjects developed de novo DSA with mean fluorescence intensity >2000. There was no difference between treatment groups in time to the primary composite outcome endpoint (death, bronchiolitis obliterans syndrome [BOS] grade 0-p, obliterative bronchiolitis or listing for retransplant). A post-hoc analysis substituting more stringent chronic lung allograft dysfunction criteria for BOS 0-p showed no difference in outcome (p = .118). The incidence of adverse events including infection and rejection episodes was no different between treatment groups. Although the study was underpowered, we conclude that rituximab induction may have prevented early DSA development in pediatric lung transplant recipients without adverse effects and may improve outcomes (Clinical Trials: NCT02266888).
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This small pilot RCT investigated whether the addition of the disease-modifying anti-rheumatoid drug (DMARD) Iguratimod (IGU) can improve outcomes in poorly-mismatched renal transplant recipients. The study itself was unblinded, but nephrologists scoring protocol biopsies were blinded to treatment allocation. Both modified intent-to-treat and per-protocol analyses are reported. Patients receiving IGU had numerically lower incidence of biopsy-proven acute rejection, although not achieving statistical significance due to the small sample size. The results presented do show some promise for the use of IGU following renal transplantation, but larger studies will be required to confirm any benefit. It should be noted that the baseline rate for biopsy-proven acute rejection was relatively high for a Tac/MMF/Pred based regimen (29.6%). Another potential limitation is that patients were only eligible at least 2 weeks post-transplant – anti-inflammatory drugs of this nature may be most effective if given from the day of transplant.
Aims:
This study aimed to assess the effect and safety of Iguratimod (IGU) combined with standard immunosuppressive regimen in highly HLA-mismatched kidney transplant patients.
Interventions:
Patients were randomised to either the IGU or non-IGU group.
The primary outcomes were biopsy-proven acute rejection and functional allograft survival. The secondary outcomes were the safety profile, donor-specific antibody (DSA) and other indicators.
Follow Up:
52 weeks
Iguratimod (IGU) can mitigate the symptoms of rheumatoid arthritis through its anti-inflammatory effects. The objective of this study was to investigate the clinical efficacy and safety of IGU in highly HLA-mismatched renal transplant recipients, in combination with standard immunosuppressive regimen. This pilot study was designed as an open-label, blank-control, randomized clinical trial on patients recruited from a single transplant center in China. Patients who met the inclusion criteria were randomized to the IGU (n=27) and blank control (n=27) groups. IGU was administrated with the conventional triple immunosuppressive protocol for 52 weeks after kidney transplantation. The incidence of biopsy-proven acute rejection rate was 14.8% (4/27) in the IGU group and 29.6% (8/27) in the control group, P = 0.19. The clinical rejection rate was also substantially reduced in the IGU group (3.7% vs. 18.5%, P = 0.08). De novo donor-specific antibody also showed a decline trend in the IGU group after 52 weeks. The graft function and incidence of adverse events were similar between the two groups. In addition, IGU intervention significantly decreased the number of NK cells throughout the follow-up. In conclusion, our study has shown the possibility that IGU could reduce the allograft rejection rate and de novo DSA with appreciable safety in combination with conventional immunosuppressants. Formal clinical trials were warranted based on current findings.
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.
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This paper reports on sub-clinical inflammation in low-risk renal transplantation. It was performed within a trial of corticosteroid withdrawal, and hence the randomisation is not related directly to this paper. Protocol biopsies were performed at 3 months after transplant, during which time no patient had acute rejection or developed de novo DSA. The biopsies showed that 54% of recipients had sub-clinical inflammation (which is in agreement with previous studies). This inflammation was correlated significantly with the absolute number of HLA mismatches, and independently with Class II mismatches in multivariate analysis, but not Class I. At this level of breakdown, however, there is a question of adequate power to make this assessment. In the multivariate analysis, several other factors were assessed and found not to be independent predictors of sub-clinical inflammation: recipient age, DGF, transfusion prior to transplant, and tacrolimus. Subclinical inflammation is present in half of kidney transplants on protocol biopsies and there is evidence from other studies that these changes can lead to chronic damage and dysfunction. The study is limited by its small sample size and ethnic homogeneity (100% Caucasian). It also represents an analysis of results from an RCT, and therefore may show association but has not proven causation and does not have significant or novel implications for clinical practice.
Aims:
This study is a part of a randomised controlled trial comparing corticosteroid withdrawal versus standard immunosuppression in low-immunological-risk renal transplantation. The aim of this study was to determine the effect of human leukocyte antigen (HLA)-mismatching on early subclinical inflammation (SCI) in low-immunological-risk renal transplant patients.
Interventions:
Participants in the original trial were randomised to either the prednisone continuation group or the prednisone withdrawal group.
Participants:
105 Caucasian renal transplant patients.
Outcomes:
Association between HLA mismatches and SCI risk.
Follow Up:
3 months
The impact of human leukocyte antigen (HLA)-mismatching on the early appearance of subclinical inflammation (SCI) in low-immunological-risk kidney transplant (KT) recipients is undetermined. We aimed to assess whether HLA-mismatching (A-B-C-DR-DQ) is a risk factor for early SCI. As part of a clinical trial (Clinicaltrials.gov, number NCT02284464), a total of 105 low-immunological-risk KT patients underwent a protocol biopsy on the third month post-KT. As a result, 54 presented SCI, showing a greater number of total HLA-mismatches (p = 0.008) and worse allograft function compared with the no inflammation group (48.5 ± 13.6 vs. 60 ± 23.4 mL/min; p = 0.003). Multiple logistic regression showed that the only risk factor associated with SCI was the total HLA-mismatch score (OR 1.32, 95%CI 1.06-1.64, p = 0.013) or class II HLA mismatching (OR 1.51; 95%CI 1.04-2.19, p = 0.032) after adjusting for confounder variables (recipient age, delayed graft function, transfusion prior KT, and tacrolimus levels). The ROC curve illustrated that the HLA mismatching of six antigens was the optimal value in terms of sensitivity and specificity for predicting the SCI. Finally, a significantly higher proportion of SCI was seen in patients with >6 vs. ≤6 HLA-mismatches (62.3 vs. 37.7%; p = 0.008). HLA compatibility is an independent risk factor associated with early SCI. Thus, transplant physicians should perhaps be more aware of HLA mismatching to reduce these early harmful lesions.
CET Conclusion