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Liver Perfusate Natural Killer Cells From Deceased Brain Donors and Association With Acute Cellular Rejection After Liver Transplantation

A Time-to-Rejection Analysis

Pagano, Duilio, MD, PhD1; Badami, Ester, MS2; Conaldi, Pier Giulio, MD3; Seidita, Aurelio, MD1; Tuzzolino, Fabio, MS, PhD4; Barbàra, Marco, BS1; di Francesco, Fabrizio, MD, PhD1; Tropea, Alessandro, MD1; Liotta, Rosa, MD5; Chiarello, Gaia, MD5; Luca, Angelo, MD5; Gruttadauria, Salvatore, MD, PhD1

doi: 10.1097/TP.0000000000002322
Original Clinical Science—Liver

Background The ability to predict which recipients will successfully complete their posttransplant clinical course, which is crucial for liver transplant (LT) programs. The assessment of natural killer (NK) cell subset determined by flow cytometry from a monocentric series of consecutive liver perfusates could help identify risk factors portending adverse LT outcomes.

Methods Liver perfusates were collected during the back-table surgical time after the procurement procedures for donors after brain death. Lymphocytic concentrations and phenotypes were matched with donors after brain death characteristics and indications, timing, surgical techniques, outcomes, and biopsy-proven acute cellular rejections (ACRs) in 46 adult recipients who underwent LT between 2010 and 2014 at our institute. Cox regression models were used to study relevant risk factors in order to estimate hazard ratios for episodes of rejection after LT.

Results Percentage of NK cells was significantly associated with donor age (P = 0.05) and the percentage of NK T cellular subset (P = 0.001). The length of follow-up after LT was 41.0 ± 20.9 months, and 11 (23.9%) recipients experienced biopsy-proven ACR. At time-to-rejection proportional regression analysis, a cutoff value of 33.7% was optimal, with a sensitivity of 1, specificity of 0.57, and positive and negative predictive values of 0.42 and 1, respectively. The liver perfusate NK cell subset was strongly associated with biopsy-proven ACR (hazard ratio, 10.7; P = 0.02).

Conclusions Liver perfusate cytofluorimetric phenotyping may contribute as a targeted preoperative tool to predict the risk of ACR, and as clinical test in translational studies that aim to improve donor allograft procurement and transplant outcomes.

In this single center study, ex situ liver perfusates (LP) from deceased brain liver donors are collected and cytofluorimetric LP analysis is performed to obtain the lymphocyte phenotype and identify the potential clinical impact of natural killer cell fraction variety on the probability to experience an acute cellular rejection event.

1 Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS-ISMETT (Istituto di Ricovero e Cura a Carattere Scientifico-Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), UPMC (University of Pittsburgh Medical Center) Italy, Palermo, Italy.

2 Fondazione Ri.MED, Palermo, Italy.

3 Regenerative Medicine and Biomedical Technologies Unit, Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS-ISMETT, UPMC Italy, Palermo, Italy.

4 Research Office, IRCCS-ISMETT, UPMC Italy, Palermo, Italy.

5 Department of Diagnostic and Therapeutic Services, IRCCS-ISMETT, UPMC Italy, Palermo, Italy.

Received 27 March 2018. Revision received 21 May 2018.

Accepted 7 June 2018.

D.P. and E.B. contributed equally to this study. The first author has been selected to receive a Young Investigator Award for the 2018 Joint International Congress of ILTS, ELITA and LICAGE being held from 23 to 26 May 2018 in Lisbon, Portugal.

The authors declare no funding or conflicts of interest.

D.P. participated in the concept/design, data analysis/interpretation, and drafting of the article. E.B. participated in the concept/design, data analysis/interpretation, and drafting of the article. P.G.C. participated in the critical revision of the article and approval of the article. A.S. and F.d.F. participated in the critical revision of the article. A.T. participated in the data collection. R.L. and G.C. participated in the histology revision. F.T. and M.B. participated in the statistics. A.L. participated in the critical revision of the article and approval of the article. S.G. participated in the critical revision of article and approval of the article.

Correspondence: Salvatore Gruttadauria, PhD, MD, IRCCS-ISMETT, Via E. Tricomi 5, 90127 Palermo, Italy. (sgruttadauria@ismett.edu).

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