Transplant Evidence Alert

The Transplant Evidence Alert provides a monthly overview of the 10 most important new clinical trials in organ transplantation, selected and reviewed by the Peter Morris Centre for Evidence in Transplantation (Oxford University).

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Renal Protective Effect of Everolimus in Liver Transplantation: A Prospective Randomized Open-Label Trial

Transplant Direct. 2021 Jun 8;7(7):e709 doi: 10.1097/TXD.0000000000001159.
Abstract
UNLABELLED:

Renal dysfunction is associated with poor long-term outcomes after liver transplantation. We examined the renal sparing effect of everolimus (EVR) compared to standard calcineurin inhibitor (CNI) immunosuppression with direct measurements of renal function over 24 months.

METHODS:

This was a prospective, randomized, open-label trial comparing EVR and mycophenolic acid (MPA) with CNI and MPA immunosuppression. An Investigational New Drug Application (IND # 113882) was obtained with the Food and Drug Administration as EVR is only approved for use with low-dose tacrolimus. Serum creatinine, 24-hour urine creatinine clearance, iothalamate clearance, Cockcroft-Gault creatinine clearance (CrCl), and Modification of Diet in Renal Disease estimated glomerular filtration rate were prospectively measured at 4 study visits. Nonparametric statistical tests were used for analyses, including the Mann-Whitney U test for continuous outcomes and Pearson's chi-square test for binary outcomes. Effect size was measured using Cohen's d. Patients also completed quality of life surveys using the FACT-Hep instrument at each study visit. Comparison between the 2 groups was performed using the Student t test.

RESULTS:

Each arm had 12 subjects; 4 patients dropped out in the EVR arm and 1 in the CNI arm by 24 months. Serum creatinine (P = 0.015), Modification of Diet in Renal Disease estimated glomerular filtration rate (P = 0.013), and 24-hour urine CrCL (P = 0.032) were significantly better at 24 months with EVR. Iothalamate clearance showed significant improvement at 12 months (P = 0.049) and a trend toward better renal function (P = 0.099) at 24 months. There was no statistical significance with Cockcroft-Gault CrCl. Adverse events were not significantly different between the 2 arms. The EVR group also showed significantly better physical, functional, and overall self-reported quality of life (P = 0.01) at 24 months.

CONCLUSIONS:

EVR with MPA resulted in significant long-term improvement in renal function and quality of life at 24 months after liver transplantation compared with standard CNI with MPA immunosuppression.

CET Conclusion
Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This is an RCT in liver transplantation examining the effect of using everolimus instead of CNI in terms of renal function. The study was small, with only 12 patients per arm, and a significant proportion (4/12) did not complete the follow up in the everolimus arm, one of whom had hepatic artery thrombosis (HAT). 105 patients were screened for the study and 93 were not suitable. Confusingly, the study was powered for a reduction in estimated GFR, but the primary outcome is described as difference in measured creatinine clearance with 24 hour urine sample. The results show a significantly improved serum creatinine and measured clearance at 24 months in the everolimus arm. However, this is based upon available data. The authors did make imputations for missing data and this is included in the supplemental digital content, showing similar outcomes. It is a highly selected population, and even then there were a concerning proportion of dropouts and with HAT in one case.
Methodological quality
Jadad score 3
Allocation concealment YES
Data analysis INTENTION TO TREAT
Study Details
Aims: This study aimed to compare the renal protective effect of everolimus (EVR) versus standard calcineurin inhibitor (CNI)-based immunosuppression in liver transplant recipients.
Interventions: Participants were randomly assigned to either the EVR arm or the standard of care (SOC) arm.
Participants: 24 liver transplant recipients.
Outcomes: Primary outcome: renal function (assessed by 24-hour urine Cockcroft-Gault creatinine clearance (CrCl)). Secondary outcomes: CrCl, modification of diet in renal disease (MDRD), estimated glomerular filtration rate (eGFR), iothalamate clearance, 24-h urine protein, white blood cell count, absolute neutrophil count, and testosterone.
Follow Up: 24 months
Metadata
Funding: Industry funding
Publication type: Randomised Controlled Trial
Trial registration: ClinicalTrials.Gov - NCT01936519
Organ: Liver
Language: English
Author email: zkadry@pennstatehealth.psu.edu
MeSH terms: Liver Transplantation