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 John Fallon, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This small prospective unblinded randomised control trial demonstrates that conversion to sirolimus form antimetabolite following initial CMV infection has a significant effect to reduce recurrent infection. Within the sirolimus cohort no episodes of CMV infection or disease occurred within the study period. Whereas the control group had a recurrence rate of 43%. All the patients in this study are high risk for CMV with all recipients being CMV positive pre-operative, but received no pre-emptive pharmacological treatment, simply weekly blood monitoring. Upon CMV infection/disease intravenous ganciclovir was commenced and once treated the antimetabolite switch to sirolimus and the study period commenced. Within the study group they saw no significant difference in biopsy confirmed acute rejection, de novo DSA, proteinuria, graft survival or death. The generalisability of these findings is limited due to the strict inclusion criteria, within their study period they randomised 72 patients out of a total of 1309 with a first-treated CMV infection/disease, all of whom were low-immunological risk. The patient cohort and small sample size limits safety and efficacy conclusion as well as conclusion in broader recipient populations, such as D+/R-. While there is insufficient evidence to change current practice it sits along side other trials, some of which multi-centre and larger supporting mTORi in improving CMV related outcomes, although often with higher discontinuation rates.
Expert Review
Reviewer:
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Review:
Pre-emptive treatment of CMV after renal transplantation is associated with a considerable risk of later CMV infection recurrence, and further changes to immune suppression and acute rejection. Sirolimus and other MTORi are associated with lower risk of CMV infection. The study is a small but interesting one and of good quality. Patients could be included after the first episode of CMV infection or disease, and were then randomised to convert to sirolimus or stay on mycophenolate/azathioprine. Tacrolimus was continued in both groups. There was no recurrence of CMV in the group randomised to sirolimus, which is in stark contrast to the 43% recurrence in the control arm. Importantly there was no significant difference in the incidence of treated biopsy proven acute rejection within 12 months after randomisation. This study provides convincing evidence for a potential method to tailoring immune suppression and reduce the risk of further complications for CMV. However, the population was highly selected to be at low risk of rejection, and that needs to be kept in mind.
Aims:
The investigators aim to assess if switching from mycophenolate or azathioprine to sirolimus following first cytomegalovirus (CMV) infection post-transplant reduces recurrence rate of CMV infections.
Interventions:
Once randomised the intervention group were abruptly converted from antimetabolite (mycophenolate sodium 720mg twice daily or azathioprine 2mg/kg once daily) to sirolimus (5-8 ng/mL), tacrolimus was continued, but the maintained concentrations were lowered to 3-5 ng/mL. The control group continued tacrolimus (5-10 ng/mL) and their antiproliferative agent.
Participants:
72 adult kidney transplant recipients who had a treated CMV infection within the first 6 months after transplant.
Outcomes:
The primary endpoint was the incidence of recurrent CMV infection within 12 months following randomisation. The secondary endpoints were: Incidence of de novo DSA, kidney function, proteinuria, acute rejection, graft loss and death.
Follow Up:
Participants were followed-up for 12 months
BACKGROUND:
Although mammalian target of rapamycin inhibitors (mTORi) are associated with a lower incidence of the first episode of cytomegalovirus (CMV) infection/disease in kidney transplant recipients receiving calcineurin inhibitors (CNIs), the efficacy and safety of the conversion from the antimetabolite to an mTORi for the prevention of CMV recurrence are unknown.
METHODS:
In this single-center prospective randomized trial, low-immunological-risk, CMV-positive kidney transplant recipients receiving preemptive therapy were randomized to be converted (sirolimus [SRL]) or not (control [CTR]) immediately after the treatment of the first episode of CMV infection/disease and were followed for 12 mo. A sample size of 72 patients was calculated to demonstrate a 75% reduction in the incidence of CMV recurrence (80% power, 95% confidence level).
RESULTS:
Of 3247 adult kidney transplants performed between September 13, 2015, and May 7, 2019, 1309 (40%) were treated for the first CMV infection/disease, and 72 were randomized (35 SRL and 37 CTR). In the SRL group, there were no episodes of CMV recurrence, compared with 16 patients in the CTR group (0% versus 43%; P < 0.0001). Four patients had a second and 1 a third recurrent CMV event. Three of them were converted to SRL and did not develop any further CMV events. There were no differences in the incidence of acute rejection, drug discontinuation, kidney function, and patient and graft survival at 12 mo.
CONCLUSIONS:
These data suggest that, in CMV-positive kidney transplant recipients, the conversion from an antiproliferative drug to SRL after the first CMV episode is an effective and safe strategy for recurrent episodes.
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This is another very interesting study on vaccine responses in kidney transplant recipients. In this complex study kidney transplant recipients were randomised to receive either an mRNA vaccine of 100 or 200 micrograms (mRNA-1273) versus a viral vector vaccine (Ad26.COV2-s) . A small group was also randomised to continue or discontinue mycophenolate for 1 week before and 1 week after. The study showed again, as has been seen elsewhere, that a significant proportion of transplant recipients do not seroconvert after two or even three doses of SARS-CoV-2 vaccine (34% and 20%). Vaccination with 200 micrograms mRNA vaccine was not significantly better than 100 micrograms or the viral vector vaccine. Stopping mycophenolate for 1 week and before and 1 week after did not have any significant impact on vaccine response either. The study was adequately randomised and powered, however it was not blinded. Given the objective nature of the results this is not of significant concern for systematic bias in the reporting of the results. The study was funded by The Netherlands Organization for Health Research and Development and the Dutch Kidney Foundation.
Expert Review
Reviewer:
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Review:
The study by Kho et al is from four centres in the Netherlands, and includes 345 patients, although the study was complex with multiple subdivisions and randomisations. Kidney transplant recipients who remained seronegative after two, or three, doses of mRNA vaccine were included. Patients were randomised to receive an mRNA vaccine of 100 or 200 microg (mRNA-1273) versus a viral vector vaccine (Ad26.COV2-s). In addition, a small group receiving 100 microg mRNA vaccine was also randomised to continue or discontinue mycophenolate for 1 week before until 1 week after the third vaccine dose (n=108). A significant proportion of these recipients still did not seroconvert after two or even three doses of SARS-CoV-2 vaccine (34% and 20%). There was no significant difference in seroconversion rate comparing 200 microg mRNA vaccine to 100 microg, or the viral vector vaccine. Stopping mycophenolate for 1 week before and 1 week after did not have any significant impact on vaccine response either. This study highlights the need for the third and even fourth COVID-19 booster vaccines to improve seroconversion in transplant recipients. Whilst this second study did not show an improved vaccine response when stopping mycophenolate, it was for a relatively short period only. Stopping mycophenolate for a longer period may be necessary to improve the immune response, however it may require the addition of another immune suppressant (such as sirolimus) to therapy during the switch period. Published studies assessing this concept have so far been small and therefore not reliable in assessing safety.
Aims:
This study aimed to compare the immunogenicity of a double dose vaccine, heterologous vaccination, and temporary discontinuation of mycophenolate mofetil or mycophenolic acid to that of a control single dose mRNA-1273 vaccination, in kidney transplant recipients who do not respond to two or three doses of an mRNA vaccine.
Interventions:
In the first cohort, participants were randomised to receive a single dose of mRNA-1273, two doses of mRNA-1273, or the Ad26.COV2-S vaccine. In the second cohort, patients receiving triple immunosuppressive therapy were randomised to either continue mycophenolate mofetil or mycophenolic acid, or discontinue mycophenolate mofetil or mycophenolic acid, from 1 week before until 1 week after being vaccinated with a single 100 μg dose of mRNA-1273.
Participants:
230 kidney transplant recipients were randomised in the first cohort and 103 kidney transplant recipieints were randomised in the second cohort.
Outcomes:
The primary endpoint was the percentage of participants with a spike protein (S1)-specific IgG concentration ≥10 BAU/mL 28 days following vaccination. Secondary endpoints included the presence of virus neutralising antibodies, serum concentration of S1-specific IgG, and SARS-CoV-2 specific T-cell response and safety.
Follow Up:
28 days
BACKGROUND:
An urgent need exists to improve the suboptimal COVID-19 vaccine response in kidney transplant recipients (KTRs). We aimed to compare three alternative strategies with a control single dose mRNA-1273 vaccination: a double vaccine dose, heterologous vaccination, and temporary discontinuation of mycophenolate mofetil or mycophenolic acid.
METHODS:
This open-label randomised trial, done in four university medical centres in the Netherlands, enrolled KTRs without seroconversion after two or three doses of an mRNA vaccine. Between Oct 20, 2021, and Feb 2, 2022, 230 KTRs were randomly assigned block-wise per centre by a web-based system in a 1:1:1 manner to receive 100 μg mRNA-1273, 2 × 100 μg mRNA-1273, or Ad26.COV2-S vaccination. In addition, 103 KTRs receiving 100 μg mRNA-1273, were randomly assigned 1:1 to continue (mycophenolate mofetil+) or discontinue (mycophenolate mofetil-) mycophenolate mofetil or mycophenolic acid treatment for 2 weeks. The primary outcome was the percentage of participants with a spike protein (S1)-specific IgG concentration of at least 10 binding antibody units per mL at 28 days after vaccination, assessed in all participants who had a baseline measurement and who completed day 28 after vaccination without SARS-CoV-2 infection. Safety was assessed as a secondary outcome in all vaccinated patients by incidence of solicited adverse events, acute rejection or other serious adverse events. This trial is registered with ClinicalTrials.gov, NCT05030974 and is closed.
FINDINGS:
Between April 23, 2021, and July 2, 2021, of 12 158 invited Dutch KTRs, 3828 with a functioning kidney transplant participated in a national survey for antibody measurement after COVID-19 vaccination. Of these patients, 1311 did not seroconvert after their second vaccination and another 761 not even after a third. From these seronegative patients, 345 agreed to participate in our repeated vaccination study. Vaccination with 2 × mRNA-1273 or Ad26.COV2-S was not superior to single mRNA-1273, with seroresponse rates of 49 (68%) of 72 (95% CI 56-79), 46 (63%) of 73 (51-74), and 50 (68%) of 73 (57-79), respectively. The difference with single mRNA-1273 was -0·4% (-16 to 15; p=0·96) for 2 × mRNA-1273 and -6% (-21 to 10; p=0·49) for Ad26.COV2-S. Mycophenolate mofetil- was also not superior to mycophenolate mofetil+, with seroresponse rates of 37 (80%) of 46 (66-91) and 31 (67%) of 46 (52-80), and a difference of 13% (-5 to 31; p=0·15). Local adverse events were more frequent after a single and double dose of mRNA-1273 than after Ad26.COV2-S (65 [92%] of 71, 67 [92%] of 73, and 38 [50%] of 76, respectively; p<0·0001). No acute rejection occurred. There were no serious adverse events related to vaccination.
INTERPRETATION:
Repeated vaccination increases SARS-CoV-2-specific antibodies in KTRs, without further enhancement by use of a higher dose, a heterologous vaccine, or 2 weeks discontinuation of mycophenolate mofetil or mycophenolic acid. To achieve a stronger response, possibly required to neutralise new virus variants, repeated booster vaccination is needed.
FUNDING:
The Netherlands Organization for Health Research and Development and the Dutch Kidney Foundation.
Reshma Rana Magar, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This systematic review and meta-analysis investigated the role of heparin thromboprophylaxis in simultaneous pancreas-kidney (SPK) transplantation, pancreas after kidney (PAK) transplantation and pancreas transplant alone (PTA). Study selection and data extraction were performed in duplicate. Only 11 studies, all of which were retrospective, were included. However, all the included studies were considered high quality (MINORS score > 60%). The authors found that heparin thromboprophylaxis reduced early pancreas thrombosis and pancreas loss by over two-folds for SPK, PAK and PTA, without resulting in an increase in the incidence of bleeding or acute return to the operating room. Heterogeneity was high for some of the outcomes but was not explored. No adjustments for confounders were made in the analyses.
Expert Review
Reviewer:
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating
2
Review:
Graft thrombosis is a recognised and feared complication of pancreas transplantation, resulting from a thromboinflammatory response and relatively low flow through the graft (1). It is more frequently seen in circulatory death (DCD) grafts and following pancreas transplant alone (PTA) compared to simultaneous pancreas kidney transplant (SPK) (1,2). Most centres employ some form of anticoagulation protocol in the peri-operative period to reduce the risk of thrombosis, although exact protocols vary considerably, and the evidence-base is limited. Use of anticoagulation is often monitored and adjusted using measures such as the activated partial thromboplastin clotting time (APTT) or thromboelastogram (TEG), with limited evidence that TEG monitoring may be beneficial (3,4). In their recent systematic review, Ai Li et al. attempt to summarise the literature regarding heparin thromboprophylaxis following pancreas transplantation (5). They identified 11 studies investigating heparin use in SPK and PTA recipients, of which just 4 were comparative and none were prospective. They conclude that heparinization significantly decreases the risk of early pancreatic thrombosis and graft loss due to thrombosis, with no evidence of increased bleeding or reoperation risk. Whilst the limited amount of observational data published in the literature does appear to support this conclusion overall, there are significant limitations to this study. There is no randomised controlled trial evidence available, and very limited comparative data meaning that the authors resort to comparing single-arm observational data to the control cohorts of other studies. Given the differences in protocols and surgical techniques between centres, the validity of this is uncertain. Even in the four comparative studies, there is significant heterogeneity in treatment protocols and monitoring strategies, meaning that the optimum regimen is unclear. The authors employ fixed effects methods in some of their meta-analysis. Given the heterogeneous and observational nature of the data, the assumptions of a fixed effects analysis are probably not met. Indeed, re-analysis using a random effects model increases uncertainty and loses the significant treatment effects seen in fixed effects analysis. It is unlikely that there is enough equipoise to undertake a large RCT of heparin versus no heparin following pancreas transplantation as most centres now use some form of anticoagulation. However, there is scope for future studies to investigate the optimal protocol and monitoring strategy for anticoagulation, including the use of TEG monitoring.
Aims:
This study aimed to assess the effect of heparin thromboprophylaxis in simultaneous pancreas-kidney (SPK) transplantation, pancreas after kidney (PAK) transplantation and pancreas transplant alone (PTA).
Interventions:
A literature search was performed on PubMed, EMBASE, BIOSIS, MEDLINE, Cochrane Library and Web of Science. Two reviewers independently selected studies for inclusion and extracted the data. Risk of bias was assessed using the Methodological Index for Non-Randomized Studies (MINORS).
Participants:
11 studies were included in the review.
Outcomes:
Outcomes of interest were pancreas thrombosis during early post-transplant period, incidence of postoperative bleeding, pancreas graft loss due to thrombosis, acute return to the operating room, and units of packed red blood cells (pRBC) used.
Follow Up:
N/A
Thrombosis is a leading causes of pancreas graft loss after simultaneous pancreas kidney (SPK), pancreas after kidney (PAK), and pancreas transplant alone (PTA). There remains no standardized thromboprophylaxis protocol. The aim of this systematic review and meta-analysis is to evaluate the impact of heparin thromboprophylaxis on the incidence of pancreas thrombosis, pancreas graft loss, bleeding, and secondary outcomes in SPK, PAK, and PTA. Following PRISMA guidelines, we systematically searched BIOSIS®, PubMed®, Cochrane Library®, EMBASE®, MEDLINE®, and Web of Science® on April 21, 2021. Primary peer-reviewed studies that met inclusion criteria were included. Two methods of quantitative synthesis were performed to account for comparative and non-comparative studies. We included 11 studies, comprising of 1,122 patients in the heparin group and 236 patients in the no-heparin group. When compared to the no-heparin control, prophylactic heparinization significantly decreased the risk of early pancreas thrombosis and pancreas loss for SPK, PAK and PTA without increasing the incidence of bleeding or acute return to the operating room. Heparin thromboprophylaxis yields an approximate two-fold reduction in both pancreas thrombosis and pancreas loss for SPK, PAK and PTA. We report the dosage, frequency, and duration of heparin administration to consolidate the available evidence.
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This is a very interesting pilot study on vaccine responses on different immunosuppressive regimens. For 2 weeks prior and 2 weeks after vaccination (ChAdOx-1), recipients were randomised to switch Mycophenolate to Sirolimus, or stay on usual immune suppression. The study was conducted in a single centre, and patients were randomly assigned by computer algorithm in an unblinded manner. Only 28 recipients met the inclusion criteria. Whilst the anti-SARS-CoV-2 S antibody levels increased significantly in both groups, the switching group had a significantly higher level in comparison. It is critical to consider adverse events, and in this study 2 patients in the sirolimus group experienced mouth ulcers that healed after returning to mycophenolate at the end of study. There were no significant changes in serum creatinine, urine albumin or any other significant symptoms. This study shows that a very short conversion window from mycophenolate to sirolimus can significantly improve vaccine antibody responses in kidney transplant recipients.
Expert Review
Reviewer:
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Review:
Bangonjit et al, from Bangkok, Thailand is a relatively small pilot study from a single centre. Transplant patients in this study had previously received two doses of ChAdOx-1 vaccine (viral vector) and one dose of BNT162b2 (mRNA) vaccine (n=28). Patients received a booster dose of BNT162b2 vaccine, but were randomised to switch from mycophenolic acid to sirolimus for two weeks prior and up to two weeks post-vaccination. The COVID-19 antibody levels post-vaccination were significantly higher in the sirolimus group than the mycophenolate group, without a significant number of adverse events. However, the study was very small and hence less common, although potentially very severe, events related to switching immune suppression may not have been revealed. There was only one seronegative patient, who remained seronegative after the booster dose. The results from this study support those found by the team from the OPTIMIZE trial in the Netherlands, published earlier this year (De Boer et al). Although there are some slight differences in patient group and immune suppression. They also echo the results of another study also published earlier this year (Schrezenmeier et al). Reference: 1) Enhanced Humoral Immune Response After COVID-19 Vaccination in Elderly Kidney Transplant Recipients on Everolimus Versus Mycophenolate Mofetil-containing Immunosuppressive Regimens. de Boer, S. E., Berger, S. P., van Leer-Buter, C. C., Kroesen, B. J., van Baarle, D., Sanders, J. F. Transplantation. 2022;106(8):1615-1621 2) Temporary antimetabolite treatment hold boosts SARS-CoV-2 vaccination-specific humoral and cellular immunity in kidney transplant recipients. Schrezenmeier, E., Rincon-Arevalo, H., Jens, A., et al. JCI Insight. 2022 May 9;7(9):e157836. doi: 10.1172/jci.insight.157836.
Aims:
The aim of this study was to compare the immune response to the booster dose of BNT162b2 in renal transplant patients who remain on the standard immunosuppressive regimen (tacrolimus (TAC), MPA, and prednisolone) versus those who switch to the mammalian target of rapamycin inhibitor (mTORi), TAC, and prednisolone regimen.
Interventions:
Participants were randomised to either continue the standard regimen or switch to a sirolimus (an mTORi), TAC, and prednisolone regimen.
Participants:
28 kidney transplant recipients.
Outcomes:
The main outcomes of interest were change in anti-SARS-CoV-2 S antibody level pre- and post-BNT162b2 vaccination, and adverse events.
Follow Up:
6 months
Kidney transplant recipients (KTRs) have a suboptimal immune response to COVID-19 vaccination due to the effects of immunosuppression, mostly mycophenolic acid (MPA). This study investigated the benefits of switching from the standard immunosuppressive regimen (tacrolimus (TAC), MPA, and prednisolone) to a regimen of mammalian target of rapamycin inhibitor (mTORi), TAC and prednisolone two weeks pre- and two weeks post-BNT162b2 booster vaccination. A single-center, opened-label pilot study was conducted in KTRs, who received two doses of ChAdOx-1 and a single dose of BNT162b2. The participants were randomly assigned to continue the standard regimen (control group, n = 14) or switched to a sirolimus (an mTORi), TAC, and prednisolone (switching group, n = 14) regimen two weeks before and two weeks after receiving a booster dose of BNT162b2. The anti-SARS-CoV-2 S antibody level after vaccination in the switching group was significantly greater than the control group (4051.0 [IQR 3142.0-6466.0] BAU/mL vs. 2081.0 [IQR 1077.0-3960.0] BAU/mL, respectively; p = 0.01). One participant who was initially seronegative in the control group remained seronegative after the booster dose. These findings suggest humoral immune response benefits of switching the standard immunosuppressive regimen to the regimen of mTORi, TAC, and prednisolone in KTRs during vaccination.
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This multicentre RCT investigated the use of Maribavir (a UL97 protein kinase inhibitor) in post-transplant (HCT or SOT) patients with refractory CMV infection. Maribavir was compared to investigator assigned treatment with either valganciclovir/ganciclovir, foscarnet, or cidofovir. CMV clearance was significantly more likely in the Maribavir group (55.7% vs 23.9%) and demonstrated less nephrotoxicity than foscarnet, and less myelosuppression than valganciclovir/ganciclovir. Whilst unblinded, the study is pragmatic and well designed. There is some variability in included patients (“refractory” patients had to have failed to respond to one first line therapy, but this was not specified in detail) and in the investigator assigned comparator group, but this likely reflects real-world variations in practice. The results encouraging for the use of Maribavir as an alternative, potentially less toxic, alternative to existing therapies in this setting.
Expert Review
Reviewer:
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating
4
Review:
Treatment of refractory cytomegalovirus (CMV) infection in solid organ transplant recipients is challenging, with existing therapies limited by toxicity and drug resistance. Ganciclovir resistance is frequently seen, and foscarnet is associated with renal dysfunction in around 50% of patients treated (1). Safer, more effective treatments are needed to improve outcomes. Avery and colleagues have recently reported the outcomes of a multicentre, phase 3 randomised controlled trial of Maribavir, a novel UL97 protein kinase inhibitor that interferes with CMV DNA replication and encapsidation (2). The study randomised solid organ or stem cell transplant recipients with refractory CMV infection to Maribavir or investigator assigned treatment (IAT; valganciclovir/ganciclovir, foscarnet or cidofovir). Maribavir-treated patients demonstrated significantly higher clearance of viraemia after 8 weeks of treatment compared to IAT (55.7% vs. 23.9%). This response also appeared more sustained with Maribavir, with more patients achieving viraemia clearance and symptom control through to week 16. Perhaps as importantly, Maribavir also appeared to have an improved safety profile compared to other agents. Incidence of renal dysfunction was lower than with foscarnet, and neutropenia was less frequent than valganciclovir/ganciclovir. Dysguesia was the most frequently reported side effect in Maribavir-treated patients. Overall, fewer patients discontinued therapy due to side effects than in the IAT group. The study is pragmatic and well designed. It is not blinded, although this would be challenging give n the different routes of administration of the various agents. There is some variability in included patients (“refractory” patients had to have failed to respond to one first line therapy, but this was not specified in detail) and in the investigator assigned comparator group, but this likely reflects real-world variations in practice. Overall, the results are very encouraging and suggest that Maribavir offers an effective, better tolerated alternative to existing therapies for refractory CMV. References 1. Avery RK, Arav-Boger R, Marr KA et al. Outcomes in Transplant Recipients Treated With Foscarnet for Ganciclovir-Resistant or Refractory Cytomegalovirus Infection. Transplantation 2016; 100: e74. 2. Avery RK, Alain S, Alexander BD et al. Maribavir for Refractory Cytomegalovirus Infections With or Without Resistance Post-Transplant: Results from a Phase 3 Randomized Clinical Trial. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America 2021; : ciab988.
Aims:
This study aimed to investigate the safety and efficacy of maribavir compared to investigator-assigned therapy (IAT) for the treatment of with or without resistance cytomegalovirus (R/R CMV) infection in solid-organ transplant (SOT) and hematopoietic-cell transplant (HCT) recipients.
Interventions:
Participants were randomised to either the maribavir group or the IAT group.
Participants:
352 HCT and SOT recipients.
Outcomes:
The primary outcome was confirmed CMV viremia clearance. Secondary outcomes included achievement of CMV clearance and symptom control.
Follow Up:
16 weeks
BACKGROUND:
Therapies for refractory cytomegalovirus infections (with or without resistance [R/R]) in transplant recipients are limited by toxicities. Maribavir has multimodal anti-cytomegalovirus activity through the inhibition of UL97 protein kinase.
METHODS:
In this phase 3, open-label study, hematopoietic-cell and solid-organ transplant recipients with R/R cytomegalovirus were randomized 2:1 to maribavir 400 mg twice daily or investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for 8 weeks, with 12 weeks of follow-up. The primary endpoint was confirmed cytomegalovirus clearance at end of week 8. The key secondary endpoint was achievement of cytomegalovirus clearance and symptom control at end of week 8, maintained through week 16.
RESULTS:
352 patients were randomized (235 maribavir; 117 IAT). Significantly more patients in the maribavir versus IAT group achieved the primary endpoint (55.7% vs 23.9%; adjusted difference [95% confidence interval (CI)]: 32.8% [22.80-42.74]; P < .001) and key secondary endpoint (18.7% vs 10.3%; adjusted difference [95% CI]: 9.5% [2.02-16.88]; P = .01). Rates of treatment-emergent adverse events (TEAEs) were similar between groups (maribavir, 97.4%; IAT, 91.4%). Maribavir was associated with less acute kidney injury versus foscarnet (8.5% vs 21.3%) and neutropenia versus valganciclovir/ganciclovir (9.4% vs 33.9%). Fewer patients discontinued treatment due to TEAEs with maribavir (13.2%) than IAT (31.9%). One patient per group had fatal treatment-related TEAEs.
CONCLUSIONS:
Maribavir was superior to IAT for cytomegalovirus viremia clearance and viremia clearance plus symptom control maintained post-therapy in transplant recipients with R/R cytomegalovirus. Maribavir had fewer treatment discontinuations due to TEAEs than IAT. Clinical Trials Registration. NCT02931539 (SOLSTICE).
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This is a very interesting study from the USA that posed kidney transplant offer scenarios to 605 wait-list patients. Respondents adapted their assessment of a kidney offer today in light of the potential offer that may be received in later months or years. As potential waiting time for a second offer increased, the relative importance of the graft survival for the offer on the table decreased. The average respondent was willing to forgo 4-5 years of normal transplant function to prevent waiting an additional 2 years. Younger patients, and pre-dialysis patients were prepared to wait for later, better kidney offers with longer predicted graft survival. The study was conducted in the USA and it is possible that the discard rate is higher than other countries; the authors compare to France where more marginal kidneys are used for transplantation. The implication is that the results are not necessarily translatable to countries outside of the USA. Given the variability of patient preferences, it is worth having an individualised approach to kidney offer assessment adapted to each patients’ priorities. A key limitation of the study is that future kidney offers were described in terms of certainty to avoid heuristics. It is possible therefore that in real world situations patients may be even more likely to accept a marginal offer, as any future offer is not guaranteed to give better graft survival.
Expert Review
Reviewer:
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating
3
Review:
Decline rates for kidneys offered for transplantation vary widely between countries, transplant centres and clinicians – a reflection of uncertainty as to quality and likely outcome. These disparities usually arise from a genuine desire to do the best thing for our patients, but patients are rarely involved in depth in these decisions and it is likely that their priorities sometimes differ from those of the clinicians treating them. In a recent paper from the US, Mehrotra et al. use a discrete choice experiment to explore patient preferences over organ offers and the impact of age, demographics and dialysis status on these preferences (1). They presented 605 patients with putative organ offers, with information about likely graft survival time and subsequent waiting list time if they were to decline the offer. They found that the average patient would accept a kidney with predicted graft survival of 6.5 years to avoid 2 years of additional waiting time for a better quality kidney with 11 years of predicted graft survival. However, younger patients and those still pre-dialysis were more likely to prefer to wait for a better kidney, and older, black or less educated patients were less willing to wait longer for a better-quality kidney. These findings suggest that in many cases, patients would much rather go ahead with a transplant now than wait longer for something slightly better. Of course, the real world is not quite as black and white as this - there is no guarantee that a subsequent kidney offer would be better than the one currently presented. Predictions of graft survival and waiting time are not exact – the current paper uses predicted survival based upon KDPI, which has a c-statistic of 0.62 indicating only moderate predictive ability for graft survival (2). The authors recognise some limitations – particularly that patients making hypothetical decisions may act differently to a real decision, and that some included patients were post-transplant and may feel differently about risk compared to their own pre-transplant status. If nothing else, this study demonstrates the importance of involving patients in the organ decision process. For example, the authors advocate recording patients’ risk preferences on the wait list so that these can be taken into account either during allocation or upon consideration of an offer. For this to work in real clinical practice, we need improved predictive models for transplant and wait-list outcomes, and tools to present these in a patient-friendly manner. References 1. Mehrotra S, Gonzalez JM, Schantz K, Yang J-C, Friedewald JJ, Knight R. Patient Preferences for Waiting Time and Kidney Quality. Clinical journal of the American Society of Nephrology: CJASN 2022; : CJN.01480222. 2. Rao PS, Schaubel DE, Guidinger MK et al. A Comprehensive Risk Quantification Score for Deceased Donor Kidneys: The Kidney Donor Risk Index. Transplantation 2009; 88: 231.
Aims:
This study aimed to investigate patient preferences when presented with choices between a lower-quality kidney offered today or a higher-quality kidney offered in the future.
Interventions:
Each participant was randomised to receive one of 24 sets of questions, with each set including six questions.
Participants:
605 patients who were waiting for or had received a kidney transplant.
Outcomes:
To quantify patients’ assessment of the trade-off between kidney quality and waiting time.
Follow Up:
N/A
BACKGROUND AND OBJECTIVES:
Approximately 20% of deceased donor kidneys are discarded each year in the United States. Some of these kidneys could benefit patients who are waitlisted. Understanding patient preferences regarding accepting marginal-quality kidneys could help more of the currently discarded kidneys be transplanted.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:
This study uses a discrete choice experiment that presents a deceased donor kidney to patients who are waiting for, or have received, a kidney transplant. The choices involve trade-offs between accepting a kidney today or a future kidney. The options were designed experimentally to quantify the relative importance of kidney quality (expected graft survival and level of kidney function) and waiting time. Choices were analyzed using a random-parameters logit model and latent-class analysis.
RESULTS:
In total, 605 participants completed the discrete choice experiment. Respondents made trade-offs between kidney quality and waiting time. The average respondent would accept a kidney today, with 6.5 years of expected graft survival (95% confidence interval, 5.9 to 7.0), to avoid waiting 2 additional years for a kidney, with 11 years of expected graft survival. Three patient-preference classes were identified. Class 1 was averse to additional waiting time, but still responsive to improvements in kidney quality. Class 2 was less willing to accept increases in waiting time for improvements in kidney quality. Class 3 was willing to accept increases in waiting time even for small improvements in kidney quality. Relative to class 1, respondents in class 3 were likely to be age ≤61 years and to be waitlisted before starting dialysis, and respondents in class 2 were more likely to be older, Black, not have a college degree, and have lower Karnofsky performance status.
CONCLUSIONS:
Participants preferred accepting a lower-quality kidney in return for shorter waiting time, particularly those who were older and had lower functional status.
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This donor intervention study randomised 199 deceased brain dead donors to 4 groups – levothyroxine, methylprednisolone, both or control. Primary outcome was the vasoactive inotropic score (VIS), a measure of inotropic requirement at various time points prior to procurement. Both per-protocol and ITT analyses are presented due to relatively high rates of crossover to the combination arm. VIS improved in the methylprednisolone and combination groups, and was worse in the levothyroxine alone group, suggesting that methylprednisolone is the main driver of improved donor stability. Importantly in a donor intervention study, the authors looked at organ utilisation and outcomes following transplantation. These outcomes did not differ significantly between groups, although the study is not powered to these outcomes. These findings are interesting and do question the role of levothyroxine in donor management. The one main caveat is the lack of blinding – this may have increased the crossover rate and impacted inotrope administration, introducing the potential for treatment bias.
Expert Review
Reviewer:
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating
3
Review:
The haemodynamic instability seen in many brain dead (DBD) donors is thought in part to result from disruption in the hypothalamo-pituitary axis, resulting in reduced levels of thyroid hormone and vasopressin (1). For this reason, donor management often includes supplementation of thyroid hormones and vasopressin, and use of corticosteroids. Existing evidence as to the benefits of hormone replacement in the DBD donor is conflicting, with potential benefits of thyroid hormone and desmopressin administration seen in observational registry studies not borne out in prospective randomised controlled trials (2,3). In a recent issue of Transplantation, Van Bakel and colleagues report the results of a prospective randomised controlled trial of donor management in 199 brain-dead organ donors (4). Donors were randomised to four groups: high-dose levothyroxine, high-dose methylprednisolone, combination therapy and no hormonal therapy. Vasopressor requirements were assessed using a validated score (the vasoactive-inotropic score; VIS). The reduction in VIS from baseline was significant in the methylprednisolone and combination groups, but no improvement was seen in the levothyroxine alone or control groups. Unlike many donor intervention studies, the investigators were careful to report organ utilisation and graft outcomes for all groups. No differences were found between groups, although the study was not powered for these outcomes. Of note, the study was not blinded and this may have contributed to significant crossover from other arms to the combination arm and possibly impacted inotrope use. However, the findings above were confirmed in both intent-to-treat and per-protocol analyses. Overall, these results support the existing RCT evidence that thyroid hormone replacement alone does not improve cardiovascular stability in DBD donors, and that the largest impact on stability comes from corticosteroid use. References 1. Howlett TA, Keogh AM, Perry L, Touzel R, Rees LH. Anterior and posterior pituitary function in brain-stem-dead donors. A possible role for hormonal replacement therapy. Transplantation 1989; 47: 828. 2. Macdonald PS, Aneman A, Bhonagiri D et al. A systematic review and meta-analysis of clinical trials of thyroid hormone administration to brain dead potential organ donors. Critical Care Medicine 2012; 40: 1635. 3. Rech TH, Moraes RB, Crispim D, Czepielewski MA, Leitão CB. Management of the brain-dead organ donor: a systematic review and meta-analysis. Transplantation 2013; 95: 966. 4. Van Bakel AB, Hino SA, Welker D et al. Hemodynamic Effects of High-dose Levothyroxine and Methylprednisolone in Brain-dead Potential Organ Donors. Transplantation : 10.1097/TP.0000000000004072
Aims:
The aim of this study was to examine whether high-dose levothyroxine, high-dose methylprednisolone, or a combination of the two hormones, when administered early in the course of donor management, would lead to improvements in donor hemodynamics, allowing significant reduction in vasopressor support.
Interventions:
Participants were randomly assigned to receive high-dose levothyroxine, high-dose methylprednisolone, a combination of both, or no hormonal therapy (control).
Participants:
199 consecutive adult organ donors.
Outcomes:
The primary outcome was the difference in vasopressor requirement to maintain goal hemodynamics among the four treatment groups. Secondary mechanistic outcomes included the assessment of thyroid hormone (TH) levels, cortisol levels and markers of inflammation (C-reactive protein [CRP] and multiple cytokines). Secondary clinical outcomes were the number, types, and proportion of organs procured versus consented, rate of transplantation of procured organs, and patient and graft outcomes of organ recipients exposed to the various treatments.
Follow Up:
120 days
BACKGROUND:
Hormonal replacement therapy is administered to many brain-dead organ donors to improve hemodynamic stability. Previous clinical studies present conflicting results with several randomized studies reporting no benefit.
METHODS:
Consecutive adult donors (N = 199) were randomized to receive high-dose levothyroxine, high-dose methylprednisolone, both (Combo), or no hormonal therapy (Control). Vasopressor requirements using the vasoactive-inotropic score (VIS) were assessed at baseline, 4 h, and at procurement. Crossover to the Combo group was sufficient to require separate intention-to-treat and per-protocol analyses.
RESULTS:
In the intention-to-treat analysis, the mean (±SD) reduction in VIS from baseline to procurement was 1.6 ± 2.6, 14.9 ± 2.6, 10.9 ± 2.6, and 7.1 ± 2.6 for the levothyroxine, methylprednisolone, Combo, and Control groups, respectively. While controlling for the baseline score, the reduction in VIS was significantly greater in the methylprednisolone and Combo groups and significantly less in the levothyroxine group compared with controls. Results were similar in the per-protocol analysis.
CONCLUSIONS:
High-dose methylprednisolone alone or in combination with levothyroxine allowed for significant reduction in vasopressor support in organ donors. Levothyroxine alone offered no advantage in reducing vasopressor support. Organ yield, transplantation rates, and recipient outcomes were not adversely affected.
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This phase IV multicentre study compared the use of LCP-tacrolimus with standard of care (either standard (SR) or prolonged release (PR) tacrolimus depending on centre preference) in de-novo kidney transplant recipients. The authors demonstrated that despite a significantly lower total daily dose in the LCP-tacrolimus group, there was no difference in trough levels or short-term clinical outcomes between groups. The study is fairly well-designed, although the decision to allow the control arm to receive SR or PR tacrolimus at centre discretion is slightly odd as the study is left underpowered to show a difference in comparison to either in isolation. It is not really clear if there is any clinical benefit to an overall dose reduction; trough levels are similar so overall exposure is likely to be equivalent. Certainly, the study provides confirmation that the LCP-tacrolimus formulation is safe and equivalent in clinical efficacy to SR and PR formulations.
Expert Review
Reviewer:
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating
2
Review:
Tacrolimus has become the calcineurin inhibitor (CNI) of choice for maintenance immunosuppression following solid organ transplantation, demonstrating lower risk of acute rejection and improved graft survival compared to cyclosporine (1). It does have some drawbacks, including an increased risk of new-onset diabetes and an unfavourable pharmacokinetic profile with a rapid peak and narrow therapeutic window. There have been a number of attempts to produce a tacrolimus formulation with a flatter pharmacokinetic profile and less pronounced peak, allowing once-daily dosing. Such a profile may have potential to reduce toxicity by reducing peak levels, and once-daily dosing may have an impact on compliance by reducing pill burden. The most-recent of these formulations is LCP-tacrolimus, which is reported to increase bioavailability and reduce first-pass metabolism compared to earlier formulations (2). In a recent, phase 4 multicentre study, Budde and colleagues investigated the role of LCP-tacro in 401 de novo kidney transplant recipients across 10 European countries (3). Recipients were randomised to receive LCP-tacro or “standard care”, which could be immediate-release (IR) or prolonged-release (PR) tacrolimus alongside basiliximab, mycophenolate and corticosteroids. The authors demonstrated a significantly lower daily tacrolimus dose for the LCP-tacrolimus group to achieve slightly higher trough levels, confirming the improved bioavailability seen in earlier studies. However, there were no significant differences in clinical outcomes including rejection rates, graft survival, graft function or toxicity. This large study was well-designed and reported, with central block-randomisation stratified by site and use of a modified intent-to-treat analysis. Whilst reflective of real-world variation in practice, the decision to allow either IR or PR tacrolimus as standard of care does limit the conclusions somewhat, as there is insufficient power to compare LCP-tacrolimus to either alternative formulation in isolation. In reality, this study is unlikely to have much impact on clinical practice. A reduction in daily dose of tacrolimus alone is not sufficient to justify switching to what is presumably a more expensive formulation, although no health economic analysis is presented. Extended follow-up would be required to see if there is any benefit to the flattened pharmacokinetic profile on the risk of CNI toxicity in the longer-term. References 1. Webster A, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. The Cochrane Database of Systematic Reviews 2005; : CD003961. 2. Budde K, Bunnapradist S, Grinyo JM et al. Novel once-daily extended-release tacrolimus (LCPT) versus twice-daily tacrolimus in de novo kidney transplants: one-year results of Phase III, double-blind, randomized trial. American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2014; 14: 2796. 3. Budde K, Rostaing L, Maggiore U et al. Prolonged-Release Once-Daily Formulation of Tacrolimus Versus Standard-of-Care Tacrolimus in de novo Kidney Transplant Patients Across Europe. Transplant International 2022; 35: 10225.
Aims:
This study aimed to compare the posttransplant outcomes of LCP-tacrolimus (LCPT) versus current standard-of-care tacrolimus (immediate-release tacrolimus (IR-Tac) or prolonged-release tacrolimus (PR-Tac), according to centre preference) in de novo kidney transplant recipients.
Interventions:
Participants were randomly assigned to receive either LCPT or current standard-of-care tacrolimus.
Participants:
403 de novo kidney transplant recipients (≥18 years).
Outcomes:
The primary outcome was the tacrolimus total daily dose (TDD). The secondary clinical outcomes were treatment failure, treatment discontinuation, delayed graft function, local diagnosis of acute rejection requiring treatment, and concomitant immunosuppressive medications.
Follow Up:
6 months
Background: Tacrolimus is the calcineurin inhibitor of choice for preventing acute rejection episodes in kidney transplant patients. However, tacrolimus has a narrow therapeutic range that requires regular monitoring of blood concentrations to minimize toxicity. A new once-daily tacrolimus formulation, LCP-tacrolimus (LCPT), has been developed, which uses MeltDose™ drug-delivery technology to control drug release and enhance overall bioavailability. Our study compared dosing of LCPT with current standard-of-care tacrolimus [immediate-release tacrolimus (IR-Tac) or prolonged-release tacrolimus (PR-Tac)] during the 6 months following de novo kidney transplantation. Comparisons of graft function, clinical outcomes, safety, and tolerability for LCPT versus IR-Tac/PR-Tac were also performed. Methods: Standard immunological risk patients with end-stage renal disease who had received a de novo kidney transplant were randomized (1:1) to LCPT (N = 200) or IR-Tac/PR-Tac (N = 201). Results: Least squares (LS) mean tacrolimus total daily dose from Week 3 to Month 6 was significantly lower for LCPT than for IR-Tac/PR-Tac. Although LS mean tacrolimus trough levels were significantly higher for LCPT than IR-Tac/PR-Tac, tacrolimus trough levels remained within the standard reference range for most patients. There were no differences between the groups in treatment failure measures or safety profile. Conclusion: LCPT can achieve similar clinical outcomes to other tacrolimus formulations, with a lower daily dose. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT02432833.
Dr Liset Pengel, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
The study analysed the strength of the evidence according to the fragility index as an alternative to p-values of randomised controlled trials (RCTs) in kidney transplantation. Medline was searched to identify RCTs of any type of intervention in kidney transplantation published in ten, selected high-impact journals over the last ten years. The authors did not provide a rationale for their selection of the high-impact journals. RCTs had to use 1:1 randomisation and report on at least one significant dichotomous outcome to be included. Two independent reviewers identified 57 studies to be included and extracted the data. Strength of the evidence was assessed using the fragility index, which was defined as the number of additional events required to change significant results to non-significant results. Data showed that 53% of the trials had a fragility index of ≤ 3 and 26% a fragility index of 10. Eighty percent of trials reported loss to follow up and 4% used a method of imputation for missing data. The authors suggest that the fragility index may be considered alongside p-values when interpreting data.
Expert Review
Reviewer:
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating
3
Review:
This is a really interesting paper that questions the methodology of randomised controlled trials in transplantation. It is a selected population of studies, being from only the top 10 transplant journals and with at least one significant result in the abstract (with p<0.05). However, a good number of trials were included, 57 in total, which may give some insight into this area. They were all studies with dichotomous outcomes , 1:1 randomisation, and without clustering or cross-over (because the fragility index can only be calculated for this specific group of RCTs). 93% of the included RCTs compared drugs, mostly immunosuppression and 80% of the trials were open-label. 79% included intention to treat analysis- although it seems that this was, as we say, “modified intention to treat”, to exclude dropouts, as only 4% of the included studies imputed an outcome for missing data. The authors found that in a large minority of trials (43%), the number of patients lost to follow up was high enough to potential change the outcome of the study if they had been included. The mean fragility index (FI) of all included studies was only 3 (this is the number of patients required to change from an event to non-event to change the outcome of the study). This is lower than the FI previously estimated for RCTs in both medicine and cardiovascular disease (8 and 13 respectively). The number of subjects who discontinued the study due to adverse events was higher than the study fragility index in 61% of included studies. 12% of included studies had a fragility index of 0! This is possible as the Fisher exact test was used to re-calculate (more appropriately) the p-value in small and non-parametric results where Chi-squared had been used. This paper encourages vigilance when assessing the robustness of significant conclusions from RCTs. It also throws a stark light on the issue of classifying study results into “significant” and “non-significant”. In this particular area, of immune suppression in transplantation, any reported “significant” results are very likely to be fragile. Furthermore, it highlights issues around study design in transplantation; 46% of the studies did not include information on power calculations, and it may be that they were either knowingly or unknowingly underpowered. There is also the question of adequately accounting for dropouts and the imputation of missing results to prevent skewing of outcome data.
Aims:
The review aims to assess the strength of the evidence of randomised controlled trials (RCTs) in kidney transplantation.
Interventions:
The study included RCTs reporting on pharmacological, surgical or educational interventions.
Participants:
The review included RCTs in kidney transplantation published over the last ten years that used 1:1 randomisation and reported at least one significant dichotomous outcome.
Outcomes:
Fragility index, the number of patients reported lost to follow up, and whether imputation was performed for missing data and subjects who discontinued.
Follow Up:
N/A
BACKGROUND:
The study aims is to use the fragility index (FI) to examine the strength of evidence of randomized controlled trials (RCTs) published in the last decade on kidney transplantation.
METHODS:
We searched MEDLINE for studies on kidney transplantation. We included the RCTs that compared 2 groups with 1:1 randomization and reported significant P values (<0.05) for a dichotomous outcome and were published in the top 10 transplant journals. We calculated the FI; a calculation used to determine the minimum number of subjects needed to change from a nonevent to an event to make the study results nonsignificant (P ≥ 0.05).
RESULTS:
Fifty-seven RCTs met our inclusion criteria. The median sample size was 100 participants in each arm, the median number of events was 16 (interquartile range, 8-30) in the intervention group. Among the included trials, 79% were industry-funded, 93% involved medications, and the majority were open label. The median FI was 3 (interquartile range, 1-11). In 43% of the trials, the number of patients reported lost to follow-up was higher than or equal to the FI. Only 4% of the RCTs imputed a value for the missing dichotomous outcome. Furthermore, the median number of subjects who discontinued the trial because of adverse effects was 21, which was greater than the FI in 60% of the RCTs.
CONCLUSIONS:
The arbitrary classification of results into "significant" and "nonsignificant" based on P value <0.05 should perhaps be interpreted with the help of other statistical parameters and FI is one of them.
CET Conclusion