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  • Collins MG
  • Fahim MA
  • Pascoe EM
  • Hawley CM
  • Johnson DW
  • et al.
Lancet. 2023 Jul 8;402(10396):105-117 doi: 10.1016/S0140-6736(23)00642-6.
CET Conclusion
Reviewer: Mr John Fallon, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This large, multi-centre, double-blinded, randomised control trial found a reduction in DGF rate with the use of balanced crystalloid (30%) compared with normal saline (40%), a RR of 0.74 (p<0.0001). The trial was well designed, with exceptional blinding, the Plasma-Lyte and saline were packaged in custom identical bags only identifiable by serial numbers, so all parties were blinded for the duration of the trial. The trial was conducted across 16 sites, with a representative trial cohort of deceased donor kidneys (DBD:DCD of 3:1), containing only 16 (2%) of pre-emptive recipients and 20 (2%) kidneys that received HMP as preservation, which is crucial given their primary outcome. This reduction in DGF equated to 190 fewer dialysis sessions in the balanced crystalloid group and a number needed to treat of 10 to prevent 1 case of DGF. Their hypothesised effect of the fluid on post-transplant biochemistry, with reduced chloride burden, increase bicarbonate and pH with minimal effect on potassium was demonstrated and thus reduced tubular acidosis and improve blood flow leading to lower rates of DGF is sound. The trial has few limitations, laboratory data wasn’t collected beyond post-operative day 2 and other minor data points such as blood pressure and surgical anastomosis time, however given the trial size and randomisation strategy limiting centre effect, this is likely of no consequence. It is important to note that the effect is not necessarily generalisable to other balanced crystalloids such as Hartman’s, given that contains more chloride as well as lactate and further work would be needed to assess their benefit. This trial provides robust evidence sufficient to warrant consideration of changing practice, Plasma-Lyte is readily available, relatively inexpensive and in the context of renal transplant providing likely reduction in DGF.
Aims: To assess if use of balanced crystalloid vs saline reduces rates of delayed graft function.
Interventions: The intervention group received a balanced crystalloid in the form of Plasma-Lyte 148 intra- and post-operatively for intravenous volume replacement vs standard care who received 0.9% sodium chloride.
Participants: 808 participants, adults and children receiving kidney only transplant.
Outcomes: The primary outcome was DGF, which they defined as need for dialysis within the first 7 days. Secondary outcomes included: number of dialysis treatments, duration of dialysis in days, ranked composite of DGF and day2 creatinine reduction ratio, post-op hyperkalaemia, peak potassium, fluid overload, urine output, use of inotropes, acute rejection, number of biopsies, mortality, graft survival, graft function and hospital stay.
Follow Up: 52 weeks
BACKGROUND:

Delayed graft function (DGF) is a major adverse complication of deceased donor kidney transplantation. Intravenous fluids are routinely given to patients receiving a transplant to maintain intravascular volume and optimise graft function. Saline (0·9% sodium chloride) is widely used but might increase the risk of DGF due to its high chloride content. We aimed to test our hypothesis that using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce the incidence of DGF.

METHODS:

BEST-Fluids was a pragmatic, registry-embedded, multicentre, double-blind, randomised, controlled trial at 16 hospitals in Australia and New Zealand. Adults and children of any age receiving a deceased donor kidney transplant were eligible; those receiving a multi-organ transplant or weighing less than 20 kg were excluded. Participants were randomly assigned (1:1) using an adaptive minimisation algorithm to intravenous balanced crystalloid solution (Plasma-Lyte 148) or saline during surgery and up until 48 h after transplantation. Trial fluids were supplied in identical bags and clinicians determined the fluid volume, rate, and time of discontinuation. The primary outcome was DGF, defined as receiving dialysis within 7 days after transplantation. All participants who consented and received a transplant were included in the intention-to-treat analysis of the primary outcome. Safety was analysed in all randomly assigned eligible participants who commenced surgery and received trial fluids, whether or not they received a transplant. This study is registered with Australian New Zealand Clinical Trials Registry, (ACTRN12617000358347), and ClinicalTrials.gov (NCT03829488).

FINDINGS:

Between Jan 26, 2018, and Aug 10, 2020, 808 participants were randomly assigned to balanced crystalloid (n=404) or saline (n=404) and received a transplant (512 [63%] were male and 296 [37%] were female). One participant in the saline group withdrew before 7 days and was excluded, leaving 404 participants in the balanced crystalloid group and 403 in the saline group that were included in the primary analysis. DGF occurred in 121 (30%) of 404 participants in the balanced crystalloid group versus 160 (40%) of 403 in the saline group (adjusted relative risk 0·74 [95% CI 0·66 to 0·84; p<0·0001]; adjusted risk difference 10·1% [95% CI 3·5 to 16·6]). In the safety analysis, numbers of investigator-reported serious adverse events were similar in both groups, being reported in three (<1%) of 406 participants in the balanced crystalloid group versus five (1%) of 409 participants in the saline group (adjusted risk difference -0·5%, 95% CI -1·8 to 0·9; p=0·48).

INTERPRETATION:

Among patients receiving a deceased donor kidney transplant, intravenous fluid therapy with balanced crystalloid solution reduced the incidence of DGF compared with saline. Balanced crystalloid solution should be the standard-of-care intravenous fluid used in deceased donor kidney transplantation.

FUNDING:

Medical Research Future Fund and National Health and Medical Research Council (Australia), Health Research Council (New Zealand), Royal Australasian College of Physicians, and Baxter.

  • Irish GL
  • Weightman A
  • Hersch J
  • Coates PT
  • Clayton PA
Clin Transplant. 2023 Apr;37(4):e14928 doi: 10.1111/ctr.14928.
BACKGROUND:

Decisions about solid organ transplantation are complex. Patient decision aids (PDAs) enhance traditional education, by improving knowledge and supporting patients to align their values with treatments. There are increasing numbers of transplantation PDAs, however, it is unclear whether these are effective. We conducted a systematic review of studies assessing the impact of PDA use in transplantation.

METHODS:

We searched the Cochrane Register of Controlled Trials, CINAHL, EMBASE, MEDLINE, and PsycINFO databases from database inception to October 26, 2020. We included primary studies of solid organ transplantation PDAs defined by the International Patient Decision Aids Standards. All comparators and reported outcomes were included. Mean difference in knowledge (before vs. after) was standardized on a 100-point scale. Pooled-effect for PDAs was calculated and compared to the standard of care for randomized controlled trials (RCTs) and meta-analyzed using random effects. Analysis of all other outcomes was limited due to heterogeneity (PROSPERO registration, CRD42020215940).

RESULTS:

Seven thousand four hundred and sixty-three studies were screened, 163 underwent full-text review, and 15 studies with 4278 participants were included. Nine studies were RCTs. Seven RCTs assessed knowledge; all demonstrated increased knowledge with PDA use (mean difference, 8.01;95%CI 4.69-11.34, p < .00001). There were many other outcomes, including behavior and acceptability, but these were too heterogenous and infrequently assessed for meaningful synthesis.

CONCLUSIONS:

This review found that PDAs increase knowledge compared to standard education, though the effect size is small. PDAs are mostly considered acceptable; however, it is difficult to determine whether they improve other decision-making components due to the limited evidence about non-knowledge-based outcomes.

  • 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.

  • Collins MG
  • Fahim MA
  • Pascoe EM
  • Hawley CM
  • Johnson DW
  • et al.
Transplant Direct. 2022 Nov 4;8(12):e1399 doi: 10.1097/TXD.0000000000001399.
UNLABELLED:

Delayed graft function (DGF) is a major complication of deceased donor kidney transplantation. Saline (0.9% sodium chloride) is a commonly used intravenous fluid in transplantation but may increase the risk of DGF because of its high chloride content. Better Evidence for Selecting Transplant Fluids (BEST-Fluids), a pragmatic, registry-based, double-blind, randomized trial, sought to determine whether using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce DGF. We sought to evaluate the generalizability of the trial cohort by reporting the baseline characteristics and representativeness of the trial participants in detail.

METHODS:

We compared the characteristics of BEST-Fluids participants with those of a contemporary cohort of deceased donor kidney transplant recipients in Australia and New Zealand using data from the Australia and New Zealand Dialysis and Transplant Registry. To explore potential international differences, we compared trial participants with a cohort of transplant recipients in the United States using data from the Scientific Registry of Transplant Recipients.

RESULTS:

During the trial recruitment period, 2373 deceased donor kidney transplants were performed in Australia and New Zealand; 2178 were eligible' and 808 were enrolled in BEST-Fluids. Overall, trial participants and nonparticipants were similar at baseline. Trial participants had more coronary artery disease (standardized difference [d] = 0.09; P = 0.03), longer dialysis duration (d = 0.18, P < 0.001), and fewer hypertensive (d = -0.11, P = 0.03) and circulatory death (d = -0.14, P < 0.01) donors than nonparticipants. Most key characteristics were similar between trial participants and US recipients, with moderate differences (|d| ≥ 0.2; all P < 0.001) in kidney failure cause, diabetes, dialysis duration, ischemic time, and several donor risk predictors, likely reflecting underlying population differences.

CONCLUSIONS:

BEST-Fluids participants had more comorbidities and received slightly fewer high-risk deceased donor kidneys but were otherwise representative of Australian and New Zealand transplant recipients and were generally similar to US recipients. The trial results should be broadly applicable to deceased donor kidney transplantation practice worldwide.

  • 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.

  • Huuskes BM
  • Scholes-Robertson N
  • Guha C
  • Baumgart A
  • Wong G
  • et al.
Transpl Int. 2021 Aug;34(8):1517-1529 doi: 10.1111/tri.13934.

The COVID-19 pandemic has challenged the delivery of health services. Telehealth allows delivery of care without in-person contacts and minimizes the risk of vial transmission. We aimed to describe the perspectives of kidney transplant recipients on the benefits, challenges, and risks of telehealth. We conducted five online focus groups with 34 kidney transplant recipients who had experienced a telehealth appointment. Transcripts were thematically analyzed. We identified five themes: minimizing burden (convenient and easy, efficiency of appointments, reducing exposure to risk, limiting work disruptions, and alleviating financial burden); attuning to individual context (depending on stability of health, respect patient choice of care, and ensuring a conducive environment); protecting personal connection and trust (requires established rapport with clinicians, hampering honest conversations, diminished attentiveness without incidental interactions, reassurance of follow-up, and missed opportunity to share lived experience); empowerment and readiness (increased responsibility for self-management, confidence in physical assessment, mental preparedness, and forced independence); navigating technical challenges (interrupted communication, new and daunting technologies, and cognizant of patient digital literacy). Telehealth is convenient and minimizes time, financial, and overall treatment burden. Telehealth should ideally be available after the pandemic, be provided by a trusted nephrologist and supported with resources to help patients prepare for appointments.

  • Chadban SJ
  • McDonald M
  • Wyburn K
  • Opdam H
  • Barry L
  • et al.
Kidney Int. 2020 Dec;98(6):1616-1618 doi: 10.1016/j.kint.2020.10.007.
  • Coates PT
  • Wong G
Kidney Int. 2020 Aug;98(2):251-252 doi: 10.1016/j.kint.2020.06.002.
  • Coates PT
  • Wong G
  • Drueke T
  • Rovin B
  • Ronco P
  • et al.
Kidney Int. 2020 Jun;97(6):1074-1075 doi: 10.1016/j.kint.2020.04.001.
  • Rao NN
  • Stokes MB
  • Rajwani A
  • Ullah S
  • Williams K
  • et al.
Circulation. 2019 Jun 18;139(25):2809-2818 doi: 10.1161/CIRCULATIONAHA.118.038505.
CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion: This small single-centre study investigates whether the ligation of an AV fistula following successful transplantation can reduce cardiac risk. Recipients with stable function were randomized to ligation or maintenance of the AV fistula. Ligation resulted in a reduction in left ventricular mass, left ventricular end diastolic volume and end-systolic volumes compared to controls. There were no differences in LVEF, blood pressure or graft function. The study is well designed and described. Ultimately, larger studies with longer follow-up will be required to see if the changes in cardiac MRI observed in this study translate to a reduction in cardiac morbidity or mortality. Also, it is unclear whether ligation is beneficial in all recipients, or whether it would be better targeted to those with higher flow or existing cardiac dysfunction.
Aims: The study aimed to evaluate the effect of AVF ligation on cardiac structure and function in stable kidney transplant recipients.
Interventions: Recipients were randomized to either AVF ligation or no intervention.
Participants: 64 kidney transplant recipients.
Outcomes: The primary outcome was the change in left ventricular (LV) mass. Secondary outcomes included changes in LV volumes, left and right atrial areas, LV ejection fraction, N-Terminal pro-BNP levels (NT pro-BNP), cardiac output/index, brachial flows (ipsilateral to AVF) and pulmonary artery velocity.
Follow Up: 6 months.
BACKGROUND:

Cardiovascular morbidity and mortality remain high in recipients of a kidney transplant. The persistence of a patent arteriovenous fistula (AVF) after transplantation may contribute to ongoing maladaptive cardiovascular remodeling. The ability to reverse this maladaptive remodeling by ligation of this AVF is unknown. We conducted the first randomized controlled trial to evaluate the effect of AVF ligation on cardiac structure and function in stable kidney transplant recipients.

METHODS:

In this randomized controlled trial, kidney transplant recipients (>12 months after transplantation with stable graft function) were randomized to AVF ligation or no intervention. All participants underwent cardiac magnetic resonance imaging at baseline and at 6 months. The primary outcome was the change in left ventricular (LV) mass. Secondary outcomes included changes in LV volumes, left and right atrial areas, LV ejection fraction, NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, cardiac output/index, brachial flows (ipsilateral to AVF), and pulmonary artery velocity.

RESULTS:

A total of 93 patients were screened, of whom 64 met the inclusion criteria and were randomized to the AVF ligation (n=33) or control (n=31) group. Fifty-four participants completed the study: 27 in the AVF ligation group and 27 in the control group. On the second cardiac magnetic resonance scan, a mean decrease of 22.1 g (95% CI, 15.0-29.1) was observed in LV mass in the AVF ligation group compared with a small increase of 1.2 g (95% CI, -4.8 to 7.2) in the control group ( P<0.001). Significant decreases in LV end-diastolic volumes, LV end-systolic volumes, cardiac output, cardiac index, atrial volumes, and NT-proBNP were also seen in the AVF closure group ( P<0.01). No significant changes were observed in LV ejection fraction ( P=0.93) and pulmonary artery velocity ( P=0.07). No significant complications were noted after AVF ligation. No changes in estimated glomerular filtration rate or systolic and diastolic blood pressures were observed between cardiac magnetic resonance scans.

CONCLUSIONS:

Elective ligation of patent AVF in adults with stable kidney transplant function resulted in clinically significant reduction of LV myocardial mass.

CLINICAL TRIAL REGISTRATION:

Australian and New Zealand Clinical Trials Registry URL: https://www.anzctr.org.au . Unique Identifier: ACTRN12613001302741.