IMPORTANCE:

Delayed graft function in kidney-transplant recipients is associated with increased financial cost and patient burden. In donors with high Kidney Donor Profile Index whose kidneys are not pumped, therapeutic hypothermia has been shown to confer a protective benefit against delayed graft function.

OBJECTIVE:

To determine whether hypothermia is superior to normothermia in preventing delayed graft function in low-risk nonpumped kidney donors after brain death.

DESIGN, SETTING, AND PARTICIPANTS:

In a multicenter randomized clinical trial, brain-dead kidney donors deemed to be low risk and not requiring machine perfusion per Organ Procurement Organization protocol were prospectively randomized to hypothermia (34.0-35 °C) or normothermia (36.5-37.5 °C) between August 10, 2017, and May 21, 2020, across 4 Organ Procurement Organizations in the US (Arizona, Upper Midwest, Pacific Northwest, and Texas). The final analysis report is dated June 15, 2022, based on the data set received from the United Network for Organ Sharing on June 2, 2021. A total of 509 donors (normothermia: n = 245 and hypothermia: n = 236; 1017 kidneys) met inclusion criteria over the study period.

INTERVENTION:

Donor hypothermia (34.0-35.0 °C) or normothermia (36.5-37.5 °C).

MAIN OUTCOMES AND MEASURES:

The primary outcome was delayed graft function in the kidney recipients, defined as the need for dialysis within the first week following kidney transplant. The primary analysis follows the intent-to-treat principle.

RESULTS:

A total of 934 kidneys were transplanted from 481 donors, of which 474 were randomized to the normothermia group and 460 to the hypothermia group. Donor characteristics were similar between the groups, with overall mean (SD) donor age 34.2 (11.1) years, and the mean donor creatinine level at enrollment of 1.03 (0.53) mg/dL. There was a predominance of Standard Criteria Donors (98% in each treatment arm) with similar low mean (SD) Kidney Donor Profile Index (normothermia: 28.99 [20.46] vs hypothermia: 28.32 [21.9]). Cold ischemia time was similar in the normothermia and hypothermia groups (15.99 [7.9] vs 15.45 [7.63] hours). Delayed graft function developed in 87 of the recipients (18%) in the normothermia group vs 79 (17%) in the hypothermia group (adjusted odds ratio, 0.92; 95% CI, 0.64-1.33; P = .66).

CONCLUSIONS AND RELEVANCE:

The findings of this study suggest that, in low-risk non-pumped kidneys from brain-dead kidney donors, therapeutic hypothermia compared with normothermia does not appear to prevent delayed graft function in kidney transplant recipients.

TRIAL REGISTRATION:

ClinicalTrials.gov Identifier: NCT02525510.

To address the challenges of assessing the impact of a reasonably likely surrogate endpoint on long-term graft survival in prospective kidney transplant clinical trials, the Transplant Therapeutics Consortium established a real-world evidence workgroup evaluating the scientific value of using transplant registry data as an external control to supplement the internal control group. The United Network for Organ Sharing retrospectively simulated the use of several distinct contemporaneous external control groups, applied multiple cause inference methods, and compared treatment effects to those observed in the BENEFIT study. Applying BENEFIT study enrollment criteria produced a smaller historical cyclosporine control arm (n = 153) and a larger, alternative (tacrolimus) historical control arm (n = 1069). Following covariate-balanced propensity scoring, Kaplan-Meier 5-year all-cause graft survivals were 81.3% and 81.7% in the Organ Procurement and Transplantation Network (OPTN) tacrolimus and cyclosporine external control arms, similar to 80.3% observed in the BENEFIT cyclosporine treatment arm. Five-year graft survival in the belatacept-less intensive arm was significantly higher than the OPTN controls using propensity scoring for comparing cyclosporine and tacrolimus. Propensity weighting using OPTN controls closely mirrored the BENEFIT study's long-term control (cyclosporine) arm's survival rate and the less intensive arm's treatment effect (significantly higher survival vs control). This study supports the feasibility and validity of using supplemental external registry controls for long-term survival in kidney transplant clinical trials.

IMPORTANCE:

The effectiveness of goal-directed care to reduce loss of brain-dead potential donors to cardiac arrest is unclear.

OBJECTIVE:

To evaluate the effectiveness of an evidence-based, goal-directed checklist in the clinical management of brain-dead potential donors in the intensive care unit (ICU).

DESIGN, SETTING, AND PARTICIPANTS:

The Donation Network to Optimize Organ Recovery Study (DONORS) was an open-label, parallel-group cluster randomized clinical trial in Brazil. Enrollment and follow-up were conducted from June 20, 2017, to November 30, 2019. Hospital ICUs that reported 10 or more brain deaths in the previous 2 years were included. Consecutive brain-dead potential donors in the ICU aged 14 to 90 years with a condition consistent with brain death after the first clinical examination were enrolled. Participants were randomized to either the intervention group or the control group. The intention-to-treat data analysis was conducted from June 15 to August 30, 2020.

INTERVENTIONS:

Hospital staff in the intervention group were instructed to administer to brain-dead potential donors in the intervention group an evidence-based checklist with 13 clinical goals and 14 corresponding actions to guide care, every 6 hours, from study enrollment to organ retrieval. The control group provided or received usual care.

MAIN OUTCOMES AND MEASURES:

The primary outcome was loss of brain-dead potential donors to cardiac arrest at the individual level. A prespecified sensitivity analysis assessed the effect of adherence to the checklist in the intervention group.

RESULTS:

Among the 1771 brain-dead potential donors screened in 63 hospitals, 1535 were included. These patients included 673 males (59.2%) and had a median (IQR) age of 51 (36.3-62.0) years. The main cause of brain injury was stroke (877 [57.1%]), followed by trauma (485 [31.6%]). Of the 63 hospitals, 31 (49.2%) were assigned to the intervention group (743 [48.4%] brain-dead potential donors) and 32 (50.8%) to the control group (792 [51.6%] brain-dead potential donors). Seventy potential donors (9.4%) at intervention hospitals and 117 (14.8%) at control hospitals met the primary outcome (risk ratio [RR], 0.70; 95% CI, 0.46-1.08; P = .11). The primary outcome rate was lower in those with adherence higher than 79.0% than in the control group (5.3% vs 14.8%; RR, 0.41; 95% CI, 0.22-0.78; P = .006).

CONCLUSIONS AND RELEVANCE:

This cluster randomized clinical trial was inconclusive in determining whether the overall use of an evidence-based, goal-directed checklist reduced brain-dead potential donor loss to cardiac arrest. The findings suggest that use of such a checklist has limited effectiveness without adherence to the actions recommended in this checklist.

TRIAL REGISTRATION:

ClinicalTrials.gov Identifier: NCT03179020.

IMPORTANCE:

Patients with advanced chronic kidney disease (CKD) have the best chance for a longer and healthier life if they receive a kidney transplant. However, many barriers prevent patients from receiving a transplant.

OBJECTIVES:

To evaluate the effect of a multicomponent intervention designed to target several barriers that prevent eligible patients from completing key steps toward receiving a kidney transplant.

DESIGN, SETTING, AND PARTICIPANTS:

This pragmatic, 2-arm, parallel-group, open-label, registry-based, superiority, cluster randomized clinical trial included all 26 CKD programs in Ontario, Canada, from November 1, 2017, to December 31, 2021. These programs provide care for patients with advanced CKD (patients approaching the need for dialysis or receiving maintenance dialysis).

INTERVENTIONS:

Using stratified, covariate-constrained randomization, allocation of the CKD programs at a 1:1 ratio was used to compare the multicomponent intervention vs usual care for 4.2 years. The intervention had 4 main components, (1) administrative support to establish local quality improvement teams; (2) transplant educational resources; (3) an initiative for transplant recipients and living donors to share stories and experiences; and (4) program-level performance reports and oversight by administrative leaders.

MAIN OUTCOMES AND MEASURES:

The primary outcome was the rate of steps completed toward receiving a kidney transplant. Each patient could complete up to 4 steps: step 1, referred to a transplant center for evaluation; step 2, had a potential living donor contact a transplant center for evaluation; step 3, added to the deceased donor waitlist; and step 4, received a transplant from a living or deceased donor.

RESULTS:

The 26 CKD programs (13 intervention, 13 usual care) during the trial period included 20 375 potentially transplant-eligible patients with advanced CKD (intervention group [n = 9780 patients], usual-care group [n = 10 595 patients]). Despite evidence of intervention uptake, the step completion rate did not significantly differ between the intervention vs usual-care groups: 5334 vs 5638 steps; 24.8 vs 24.1 steps per 100 patient-years; adjusted hazard ratio, 1.00 (95% CI, 0.87-1.15).

CONCLUSIONS AND RELEVANCE:

This novel multicomponent intervention did not significantly increase the rate of completed steps toward receiving a kidney transplant. Improving access to transplantation remains a global priority that requires substantial effort.

TRIAL REGISTRATION:

ClinicalTrials.gov Identifier: NCT03329521.

AIMS:

Ischemia-reperfusion injury (IRI) during kidney transplant procedures is associated with adverse outcome. Alkaline phosphatase (AP) is an enzyme that has the potential to dampen IRI. Prior to this study, it had not been tested in the setting of kidney transplantation. This study aimed to evaluate the safety and feasibility of peri-procedural AP administration in living donor kidney transplantation.

METHODS:

In this double blind, randomized, placebo-controlled, single-center pilot study, all eligible recipients of living donor kidneys were asked to give informed consent. AP (bRESCAP) or a placebo was administered intravenously over 24 hours after the transplantation procedure. The primary outcome-graft function at 1 year-was represented by iohexol measured glomerular filtration rate (mGFR). Serum and urine biomarkers within seven days after surgery were used as surrogate markers of kidney function and injury.

RESULTS:

Eleven patients were enrolled of whom five were treated with bRESCAP and six with placebo. After 1 year, mGFR was not different between groups. No specific adverse events were observed in the bRESCAP group. Urine expression of injury biomarkers CCL14, NGAL and Cystatin C was lower in the bRESCAP group at day seven. This was statistically significant.

CONCLUSION:

This study illustrates that bRESCAP treatment is feasible in kidney transplantation, might have a dampening effect on IRI induced renal inflammation, and raises no safety concerns. Future research will evaluate the effects of bRESCAP treatment in donation after circulatory death kidney transplantation where IRI is more pronounced.

Brain death triggers an inflammatory cascade that damages organs before procurement, adversely affecting the quality of grafts. This randomized clinical trial aimed to compare the efficacy of liraglutide compared to placebo in attenuating brain death-induced inflammation, endoplasmic reticulum stress, and oxidative stress. We conducted a double-blinded, placebo-controlled, randomized clinical trial with brain-dead donors. Fifty brain-dead donors were randomized to receive subcutaneous liraglutide or placebo. The primary outcome was the reduction in IL-6 plasma levels. Secondary outcomes were changes in other plasma pro-inflammatory (IL-1β, interferon-γ, TNF) and anti-inflammatory cytokines (IL-10), expression of antiapoptotic ( BCL2 ), endoplasmic reticulum stress markers ( DDIT3/CHOP , HSPA5/BIP ), and antioxidant ( superoxide dismutase 2 , uncoupling protein 2 ) genes, and expression TNF, DDIT3, and superoxide dismutase 2 proteins in liver biopsies. The liraglutide group showed lower cytokine levels compared to the placebo group during follow-up: Δ IL-6 (-28 [-182, 135] vs. 32 [-10.6, 70.7] pg/mL; p = 0.041) and Δ IL-10 (-0.01 [-2.2, 1.5] vs. 1.9 [-0.2, 6.1] pg/mL; p = 0.042), respectively. The administration of liraglutide did not significantly alter the expression of inflammatory, antiapoptotic, endoplasmic reticulum stress, or antioxidant genes in the liver tissue. Similar to gene expression, expressions of proteins in the liver were not affected by the administration of liraglutide. Treatment with liraglutide did not increase the organ recovery rate [OR = 1.2 (95% CI: 0.2-8.6), p = 0.82]. Liraglutide administration reduced IL-6 and prevented the increase of IL-10 plasma levels in brain-dead donors without affecting the expression of genes and proteins related to inflammation, apoptosis, endoplasmic reticulum stress, or oxidative stress.

OBJECTIVE:

To provide mechanistic insight into key biological alterations in donation after circulatory death kidneys during continuous pefusion we performed mass spectrometry profiling of perfusate samples collected during a phase 3 randomized double-blind paired clinical trial of hypothermic machine perfusion with and without oxygen (COMPARE).

BACKGROUND:

Despite the clinical benefits of novel perfusion technologies aiming to better preserve donor organs, biological processes that may be altered during perfusion have remained largely unexplored. The collection of serial perfusate samples during the COMPARE clinical trial provided a unique resource to study perfusate proteomic profiles, with the hypothesis that in-depth profiling may reveal biologically meaningful information on how donor kidneys benefit from this intervention.

METHODS:

Multiplexed liquid chromatography-tandem mass spectrometry was used to obtain a proteome profile of 210 perfusate samples. Partial least squares discriminant analysis and multivariate analysis involving clinical and perfusion parameters were used to identify associations between profiles and clinical outcomes.

RESULTS:

Identification and quantitation of 1716 proteins indicated that proteins released during perfusion originate from the kidney tissue and blood, with blood-based proteins being the majority. Data show that the overall hypothermic machine perfusion duration is associated with increasing levels of a subgroup of proteins. Notably, high-density lipoprotein and complement cascade proteins are associated with 12-month outcomes, and blood-derived proteins are enriched in the perfusate of kidneys that developed acute rejection.

CONCLUSIONS:

Perfusate profiling by mass spectrometry was informative and revealed proteomic changes that are biologically meaningful and, in part, explain the clinical observations of the COMPARE trial.

BACKGROUND:

Living donor kidney transplantation (LDKT) is the optimal treatment for eligible patients with kidney failure, although it is underutilized. Contextually tailored patient- and family-centered interventions may be effective to increase LDKT.

OBJECTIVE:

We outline a protocol to test the feasibility of the Multidisciplinary Support To Access living donor Kidney Transplant (MuST AKT) intervention designed to increase LDKT.

DESIGN:

Non-blinded single-center pilot randomized controlled trial with a qualitative interview component.

SETTING:

Academic transplant referral center in Northern Alberta Region with a population of more than 2 million in its catchment area.

PATIENTS:

English-speaking patients of the age range 18 to 75 years who are referred for kidney transplantation are eligible to participate.

MEASUREMENTS:

Feasibility will be assessed by indicators of recruitment, retention, and completion rates, treatment fidelity, adherence to intervention, engagement in intervention, and acceptability.

METHODS:

Participants will be randomly assigned 1:1 to either standard care (control) or the experimental group who receive standard care plus the MuST AKT intervention, a person-centered program designed to assist and enable the kidney transplant candidate to achieve what is required to receive an LDKT. The intervention consists of an introductory session and 4 intervention sessions delivered in-person or virtually.

LIMITATIONS:

Inferences cannot be drawn regarding the efficacy/effectiveness of the MuST AKT intervention. This study is non-blinded.

CONCLUSIONS:

This pilot study is the first step in our broader initiative to increase LDKT in our health care jurisdiction. The results of this study will be used to inform the development of a future definitive randomized controlled trial.

TRIAL REGISTRATION NUMBER:

NCT04666545.

INTRODUCTION:

Ischaemia/reperfusion injuries (IRIs) are associated with poorer survival of kidney grafts from expanded criteria donors. Preclinical studies have shown that mineralocorticoid receptor antagonists (MRAs) prevent acute and chronic post-ischaemic renal dysfunction by limiting IRI. However, data concerning the safety of MRAs in brain-dead donor patients are scarce. We seek to investigate the tolerance of MRAs on the haemodynamics in this population.

METHODS AND ANALYSIS:

CANREO-PMO is a randomised, controlled, single-centre, double-blind study. Brain-dead organ donors hospitalised in intensive care are randomised 1:1 after consent to receive 200 mg potassium canrenoate or its matching placebo every 6 hours until organ procurement. The primary outcome is a hierarchical composite endpoint that includes: (1) cardiocirculatory arrest, (2) the impossibility of kidney procurement, (3) the average hourly dose of norepinephrine/epinephrine between randomisation and departure to the operating room, and (4) the average hourly volume of crystalloids and/or colloids received. Thirty-six patients will be included. The secondary endpoints evaluated among the graft recipients are the: (1) vital status of the kidney graft recipients and serum creatinine level with estimated glomerular filtration rate (GFR) according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) at 3 months after renal transplantation, (2) percentage of patients dependent on dialysis and/or with an estimated GFR <20 mL/min/1.73 m2 at 3 months, (3) vital status of the kidney graft recipients at 3 months, and (4) vital status of the kidney graft recipients and creatinine levels (in μmol/L), with the estimated GFR according to CKD-EPI (in mL/min/1.73 m2), at 1 year, 3 years and 10 years after transplantation.

ETHICS AND DISSEMINATION:

This trial has full ethical approval (Comité de Protection des Personnes: CPP Ouest II-ANGERS, France), and the written consent of relatives will be obtained. Results will be reported at conferences, peer-reviewed publications and using social media channels.

TRIAL REGISTRATION NUMBER:

NCT04714710.