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.
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.
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