Retrospective Cohort Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Transplant. May 29, 2020; 10(5): 117-128
Published online May 29, 2020. doi: 10.5500/wjt.v10.i5.117
Links between donor macrosteatosis, interleukin-33 and complement after liver transplantation
Kelley Núñez, Mohammad Hamed, Daniel Fort, David Bruce, Paul Thevenot, Ari Cohen
Kelley Núñez, Mohammad Hamed, Paul Thevenot, Institute of Translational Research, Ochsner Clinic Foundation, New Orleans, LA 70121, United States
Daniel Fort, Center for Outcomes and Health Services Research, Research Administration, Ochsner Clinic Foundation, New Orleans, LA 70121, United States
David Bruce, Ari Cohen, Multi-Organ Transplant Program, Ochsner Clinic Foundation, New Orleans, LA 70121, United States
Author contributions: Thevenot P and Cohen A designed the research; Núñez K and Hamed M performed the research; Núñez K, Fort D, Bruce D, and Thevenot P analyzed the data; Núñez K wrote the manuscript; Hamed M, Thevenot P, and Cohen A revised the manuscript.
Institutional review board statement: This study was reviewed and approved by the Ochsner Institutional Review Board.
Informed consent statement: All patients in this study provided informed consent.
Conflict-of-interest statement: Authors have no conflict of interests to disclose.
Data sharing statement: No additional data are available for this study.
STROBE statement: Authors have read the STROBE Statement checklist of items and the manuscript was prepared and revised according to the STROBE Statement checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Ari Cohen, MD, Professor, Surgeon, Multi-Organ Transplant, Ochsner Clinic Foundation, 1514 Jefferson Hwy, New Orleans, LA 70121, United States. acohen@ochsner.org
Received: December 31, 2019
Peer-review started: December 31, 2019
First decision: March 26, 2020
Revised: April 7, 2020
Accepted: May 5, 2020
Article in press: May 5, 2020
Published online: May 29, 2020
Abstract
BACKGROUND

As prevalence of nonalcoholic fatty liver disease increases in the population, livers with steatosis will continue to infiltrate the donor pool. Safe utilization of these extended criteria grafts is paramount given the increased risk associated with their use in transplantation. Prognostic factors that can predict liver dysfunction immediately after transplantation with macrosteatotic grafts are lacking.

AIM

To understand the relationship between interleukin-33 (IL-33) and complement in recipients immediately following liver reperfusion as a marker of liver dysfunction.

METHODS

Cohort consisted of patients who received a liver transplant from September 2016–September 2019 at our institution. Clinical variables were retrospectively extracted from the electronic medical record. Back-table donor biopsies were obtained with donor steatosis percentage retrospectively determined by a board-certified pathologist. Blood samples were available immediately following liver transplantation. Quantification of plasma IL-33 and complement proteins, C3a and C5a, were determined by enzyme-linked immunosorbent assay. For mRNA expression, RNA was extracted from donor biopsies and used against a 780 gene panel.

RESULTS

Cohort consisted of 99 donor and recipients. Donor median age was 45 years and 55% male. Recipients had a median age of 59 years with 62% male. The main etiologies were alcoholic hepatitis, nonalcoholic steatohepatitis, and hepatocellular carcinoma. Median MELD-Na at transplant was 21. Donors were grouped based on moderate macrosteatosis (≥ 30%). Recipients implanted with moderate macrosteatotic grafts had significantly higher peak alanine aminotransferase/aspartate aminotransferase (P < 0.001 and P < 0.004), and increased incidence of early allograft dysfunction (60% compared to 18%). Circulating IL-33 levels were significantly elevated in recipients of ≥ 30% macrosteatotic grafts (P < 0.05). Recipients with detectable levels of circulating IL-33 immediately following reperfusion had significantly higher alanine aminotransferase/aspartate aminotransferase (P < 0.05 and P < 0.01). Activated complement (C3a and C5a) were elevated in recipients implanted with moderate macrosteatotic grafts. RNA expression analysis of donor biopsies revealed moderate steatotic grafts upregulated genes inflammatory processes while downregulated hepatocyte-produced complement factors.

CONCLUSION

Circulating IL-33 and activated complement levels immediately following liver reperfusion in recipients of moderate macrosteatotic grafts may identify which patients are at risk of early allograft dysfunction.

Keywords: Liver transplantation, Interleukin-33, Donor macrosteatosis, Complement, Early allograft dysfunction, Reperfusion

Core tip: As nonalcoholic fatty liver disease incidence continues to rise, steatosis, both micro- and macro- will continue to infiltrate the donor pool. While many transplant centers have success utilizing these extended criteria donor grafts, macrosteatotic grafts remain at increased risk. In this study, elevations in interleukin-33 and activated complement (C3a and C5a) in recipients immediately following reperfusion indicate that patients receiving macrosteatotic grafts may have more injury post-transplant. Through mRNA expression of donor biopsies, we identify potential target genes present in macrosteatotic grafts that could aid in deciphering which macrosteatotic grafts are safe for implantation.