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Rapamycin and inulin for third-dose vaccine response stimulation (RIVASTIM): Inulin - study protocol for a pilot, multicentre, randomised, double-blinded, controlled trial of dietary inulin to improve SARS-CoV-2 vaccine response in kidney transplant recipients
  • Singer J
  • Tunbridge M
  • Perkins GB
  • Salehi T
  • Ying T
  • et al.
BMJ Open. 2022 Dec 1;12(12):e062747 doi: 10.1136/bmjopen-2022-062747.
CET Conclusion
Reviewer: Mr John Fallon, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This manuscript describes the protocol of an upcoming multi-centre, double blinded RCT of a size larger than many previous RCTs, attempting to assess gut biome effects on vaccine responses. Of the 26 previously conducted RCTs around 50% have demonstrated some beneficial effects of probiotics on vaccine response. It has been commented that the response may be reduced as none of these trials contained patients who had a disrupted microbiome, including immunosuppressed renal recipients. The intervention has been previously demonstrated to improve the gut biome and increase reactivity to parenteral vaccines. The authors propose a well-designed study with sound methodology, containing a clearly defined primary outcome which can be unambiguously tested. The proposed intervention is unlikely to have any serious adverse events and is inexpensive. Based on previous literature it is a study that has good potential.
Aims: This study aims to examine whether dietary fibre supplementation will lead to attenuation of gut dysbiosis and promote vaccine responsiveness in renal transplant patients.
Interventions: Patients will be randomly assigned to receive either inulin (active) or maltodextrin (placebo).
Participants: Kidney transplant recipients (age ≥ 18 years).
Outcomes: The primary endpoint is the proportion of participants to achieve in vitro neutralisation of live SARS-CoV-2 virus four weeks after the third dose of the COVID-19 vaccine. Secondary endpoints are safety and tolerability of dietary inulin, vaccine-specific immune cell populations and responses, and the diversity and differential abundance of gut microbiota.
Follow Up: 4- 6 weeks following vaccination.
INTRODUCTION:

Kidney transplant recipients (KTRs) are at an increased risk of hospitalisation and death from COVID-19. Vaccination against SARS-CoV-2 is our primary risk mitigation strategy, yet vaccine effectiveness in KTRs is suboptimal. Strategies to enhance vaccine efficacy are therefore required. Current evidence supports the role of the gut microbiota in shaping the immune response to vaccination. Gut dysbiosis is common in KTRs and is a potential contributor to impaired COVID-19 vaccine responses. We hypothesise that dietary fibre supplementation will attenuate gut dysbiosis and promote vaccine responsiveness in KTRs.

METHODS AND ANALYSIS:

Rapamycin and inulin for third-dose vaccine response stimulation-inulin is a multicentre, randomised, prospective, double-blinded, placebo-controlled pilot trial examining the effect of dietary inulin supplementation prior to a third dose of COVID-19 vaccine in KTRs who have failed to develop protective immunity following a 2-dose COVID-19 vaccine schedule. Participants will be randomised 1:1 to inulin (active) or maltodextrin (placebo control), administered as 20 g/day of powdered supplement dissolved in water, for 4 weeks prior to and following vaccination. The primary outcome is the proportion of participants in each trial arm that achieve in vitro neutralisation of live SARS-CoV-2 virus at 4 weeks following a third dose of COVID-19 vaccine. Secondary outcomes include the safety and tolerability of dietary inulin, the diversity and differential abundance of gut microbiota, and vaccine-specific immune cell populations and responses.

ETHICS AND DISSEMINATION:

Ethics approval was obtained from the Central Adelaide Local Health Network (CALHN) Human Research Ethics Committee (HREC) (approval number: 2021/HRE00354) and the Sydney Local Health District (SHLD) HREC (approval numbers: X21-0411 and 2021/STE04280). Results of this trial will be published following peer-review and presented at scientific meetings and congresses.

TRIAL REGISTRATION NUMBER:

ACTRN12621001465842.
Rapamycin and inulin for booster vaccine response stimulation (RIVASTIM)-rapamycin: study protocol for a randomised, controlled trial of immunosuppression modification with rapamycin to improve SARS-CoV-2 vaccine response in kidney transplant recipients
  • Tunbridge M
  • Perkins GB
  • Singer J
  • Salehi T
  • Ying T
  • et al.
Trials. 2022 Sep 15;23(1):780 doi: 10.1186/s13063-022-06634-w.
UNLABELLED:

Kidney transplant recipients are at an increased risk of severe COVID-19-associated hospitalisation and death. Vaccination has been a key public health strategy to reduce disease severity and infectivity, but the effectiveness of COVID vaccines is markedly reduced in kidney transplant recipients. Urgent strategies to enhance vaccine efficacy are needed.

METHODS:

RIVASTIM-rapamycin is a multicentre, randomised, controlled trial examining the effect of immunosuppression modification prior to a third dose of COVID-19 vaccine in kidney transplant recipients who have failed to develop protective immunity to a 2-dose COVID-19 vaccine schedule. Participants will be randomised 1:1 to either remain on standard of care immunosuppression with tacrolimus, mycophenolate, and prednisolone (control) or cease mycophenolate and commence sirolimus (intervention) for 4 weeks prior to and following vaccination. The primary outcome is the proportion of participants in each trial arm who develop protective serological neutralisation of live SARS-CoV-2 virus at 4-6 weeks following a third COVID-19 vaccination. Secondary outcomes include SARS-CoV-receptor binding domain IgG, vaccine-specific immune cell populations and responses, and the safety and tolerability of sirolimus switch.

DISCUSSION:

Immunosuppression modification strategies may improve immunological vaccine response. We hypothesise that substituting the mTOR inhibitor sirolimus for mycophenolate in a triple drug regimen will enhance humoral and cell-mediated responses to COVID vaccination for kidney transplant recipients.

TRIAL REGISTRATION:

Australia New Zealand Clinical Trials Registry ACTRN12621001412820. Registered on 20 October 2021; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382891&isReview=true.
Staged versus concurrent native nephrectomy and renal transplantation in patients with autosomal dominant polycystic kidney disease: A systematic review
  • Xu J
  • D'Souza K
  • Lau NS
  • Leslie S
  • Lee T
  • et al.
Transplant Rev (Orlando). 2022 Jan;36(1):100652 doi: 10.1016/j.trre.2021.100652.
BACKGROUND:

Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) frequently undergo native nephrectomy before transplantation. The nephrectomy may be a staged procedure or undertaken simultaneously with transplantation. When performed simultaneously, the transplant procedure is more prolonged, involves a larger operative field and incision. There is also a concern of a greater risk of graft loss with simultaneous nephrectomy and transplantation. Moreover, staged surgery may allow nephrectomy to be performed before immunosuppression introduction via a smaller incision or involving a minimally invasive approach. However, staged nephrectomy may require a period of dialysis not otherwise necessary if a transplant and nephrectomy were simultaneous. Moreover, only a single procedure is needed, implying the avoidance of a prior nephrectomy and its attendant morbidity in a patient with chronic renal insufficiency. To account for these issues, this study aims to compare the cumulative morbidity of two-staged procedures versus a single simultaneous approach in term of morbidity and graft outcomes.

OBJECTIVES:

This study aims to systematically review the literature to determine whether a staged or simultaneous approach to native nephrectomy in ADPKD is the optimal approach in terms of morbidity and graft outcomes.

METHODS:

A literature search of MEDLINE and EMBASE was conducted to identify published systematic reviews, randomized control trials, case-controlled studies and case studies. Data comparing outcomes of staged and simultaneous nephrectomy for patients undergoing kidney transplantation was extracted and analyzed. The main outcomes analyzed were length of hospitalization, blood loss, operative time, other early postoperative complications and risk of graft thrombosis. Meta-analysis was conducted where appropriate.

RESULTS:

Seven retrospective cohort studies were included in the review. There was a total of 385 patients included in the analysis, of whom 273 patients underwent simultaneous native nephrectomy and kidney transplantation. Meta-analysis showed an increased cumulative operative time in staged procedures (RR 1.86；95% CI 0.43-3.29 p = 0.01) and increased risk of blood transfusions (RR 2.69; 95% CI 1.92-3.46 p < 0.00001). For the transplant procedure, there were no significant difference in the length of stay (RR 1.03; 95% CI -2.01-4.14 p = 0.52), major postoperative complications (RR 0.02; 95% CI -0.15-0.10 p = 0.74) and vascular thromboses (RR 1.42 95% CI 0.23-8.59 p = 0.7).

CONCLUSION:

The results suggest that staged nephrectomy followed by kidney transplantation is associated with a longer cumulative operative time and increased cumulative risk of blood transfusions. There is no evidence to suggest that performing a simultaneous nephrectomy and kidney transplant procedure increases the perioperative mortality rate, major postoperative complication rates or risk of vascular thrombosis.
Comparison of the effect of single vs dual antiplatelet agents on post-operative haemorrhage after renal transplantation: A systematic review and meta-analysis
  • Lee T
  • D'Souza K
  • Hameed A
  • Yao J
  • Lam S
  • et al.
Transplant Rev (Orlando). 2021 Jan;35(1):100594 doi: 10.1016/j.trre.2020.100594.
CET Conclusion
Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This is a good quality systematic review of dual versus single antiplatelet therapy and the impact on post-operative haemorrhage in renal transplantation. A search was conducted in multiple databases and a good description of study exclusion is presented in the flow chart. Search and study selection was conducted in duplicate, but the data extraction was not. Another good indicator is that the authors attempted to address missing data by first contacting each study authors. Studies were assessed for risk of bias using a recognised method by two authors independently. Only 6 studies met the inclusion criteria, including a total of 130 recipients on dual and 781 on single antiplatelet therapy. Four of the studies were cohort studies and 2 were case-control series, so there is the potential for bias due to the lack of randomisation. Post-operative haemorrhage was defined by each of the studies individually, but this did not result in any statistical heterogeneity. Five studies were included in meta-analysis, and this showed that dual antiplatelet therapy was convincingly associated with a higher risk of haemorrhage (RR= 1.58, 95%CI: 1.19-2.09). It is unclear if this translated to a higher risk of re-operation as this is not clearly documented in the included studies, and not all had this as part of their definition of post-operative haemorrhage; most relied on the requirement for transfusion or drop in haemoglobin. All included studies tended towards the conclusion that dual antiplatelet therapy increased this risk. Post-operative cardiac events were only reported by 3 included studies. In two of the studies, it was clear that the dual antiplatelet group had a proven history of coronary events, indicating that they were a higher risk group for this event. No meta-analysis was performed for this outcome due to heterogeneity and this is reasonable. There was no clear evidence of increased risk of cardiac event comparing dual and single antiplatelet groups in these studies. Whilst this review has a number of good quality indicators, the included patient population is small in number and the studies are not high level. Many transplant centres do not list patients on dual anti-platelet agents for kidney transplant surgery for two key perceptions: the increased risk of post-operative haemorrhage, and the requirement for dual antiplatelet therapy may indicate a higher risk of cardiac event after surgery. This review does give good support for the first assertion, but contains insufficient data to support the second one. The discussion gives a good account of the limitations and reasons for this.
Aims: The aim of this systematic review was to compare the perioperative outcomes of patients receiving single versus dual antiplatelet therapy during kidney transplantation, focusing particularly on postoperative haemorrhage.
Interventions: Electronic databases including Embase, Medline and Cochrane were searched. Two independent reviewers conducted the literature search. The risk of bias was assessed using the Newcastle-Ottawa scale.
Participants: 6 studies were included in the review.
Outcomes: The primary outcomes were the incidence of postoperative haemorrhagic events and major adverse cardiac events. The secondary outcomes were the need for surgical intervention for haemorrhage, and graft survival and function.
Follow Up: N/A
OBJECTIVES:

A significant proportion of renal transplant patients have cardiovascular comorbidities for which they receive treatment with antiplatelet agents. The aim of this study was to systematically review the current literature reporting perioperative outcomes for patients receiving dual antiplatelet therapy compared to single antiplatelet therapy at the time of kidney transplantation with particular reference to the risks of postoperative haemorrhage.

MATERIALS AND METHODS:

Embase, Medline and Cochrane databases were utilized to identify articles reporting outcomes of renal transplant recipients on single antiplatelet therapy and dual antiplatelet therapy. These outcomes were compared using a random effects model meta-analysis where appropriate.

RESULTS:

Six articles were incorporated in the analysis, including 130 receiving dual antiplatelet therapy, and 781 in the single antiplatelet therapy group. There was a significantly higher risk of post-operative haemorrhagic events in the dual antiplatelet therapy group compared to the single antiplatelet therapy group (RR 1.58, 95% CI 1.19-2.09, p = 0.001). Post-operative cardiovascular event rates were similar between both groups in individual studies, although this could not be quantitatively analysed.

CONCLUSIONS:

The use of dual antiplatelet therapy was associated with a higher risk of post-operative haemorrhage compared to the use of single antiplatelet therapy without increased rates of surgical intervention. However, the use of dual antiplatelet therapy may provide protection from cardiovascular events in an inherently higher risk patient group.
Canadian-Australasian Randomised trial of screening kidney transplant candidates for coronary artery disease-A trial protocol for the CARSK study
  • Ying T
  • Gill J
  • Webster A
  • Kim SJ
  • Morton R
  • et al.
Am Heart J. 2019 Aug;214:175-183 doi: 10.1016/j.ahj.2019.05.008.

Transplantation is the preferred treatment for patients with kidney failure, but the need exceeds the supply of transplantable kidneys, and patients routinely wait >5 years on dialysis for a transplant. Coronary artery disease (CAD) is common in kidney failure and can exclude patients from transplantation or result in death before or after transplantation. Screening asymptomatic patients for CAD using noninvasive tests prior to wait-listing and at regular intervals (ie, annually) after wait-listing until transplantation is the established standard of care and is justified by the need to avoid adverse patient outcomes and loss of organs. Patients with abnormal screening tests undergo coronary angiography, and those with critical stenoses are revascularized. Screening is potentially harmful because patients may be excluded or delayed from transplantation, and complications after revascularization are more frequent in this population. CARSK will test the hypothesis that eliminating screening tests for occult CAD after wait-listing is not inferior to regular screening for the prevention of major adverse cardiac events defined as the composite of cardiovascular death, nonfatal myocardial infarction, urgent revascularization, and hospitalization for unstable angina. Secondary outcomes include the transplant rate, safety measures, and the cost-effectiveness of screening. Enrolment of 3,306 patients over 3 years is required, with patients followed for up to 5 years during wait-listing and for 1 year after transplantation. By validating or refuting the use of screening tests during wait-listing, CARSK will ensure judicious use of health resources and optimal patient outcomes.
De Novo Or Early Conversion To Everolimus And Long-Term Cancer Outcomes In Kidney Transplant Recipients: A Trial-Based Anzdata Linkage Study. Abstract No 6
  • Ying T
  • Wong G
  • Lim W
  • Russ G
  • Pilmore H
  • et al.
36th Annual Meeting of Transplantation Society of Australia and New Zealand, 29th April - 1st May, Melbourne, Australia.. 2018.
36th Annual Meeting of Transplantation Society of Australia and New Zealand, 29th April - 1st May, Melbourne, Australia.