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Tolerance Biomarkers in Liver Transplantation

Independent External Validation of the Predictive Strength of SENP6 and FEM1C Gene Expression

Pérez-Sanz, Fernando MS1; Revilla-Nuin, Beatriz PhD2; Martínez-Alarcón, Laura PhD2; Herrero, José I. PhD, MD3,4,5; Ramírez, Pablo PhD, MD2,6; Pons, José A. PhD, MD2,7; Baroja-Mazo, Alberto PhD2

doi: 10.1097/TP.0000000000002587
Original Clinical Science—Liver

Background. Numerous studies have emphasized the genetic and phenotypic profiles of tolerant transplant patients. Moreover, different groups have defined several biomarkers, trying to distinguish patients who are going to be tolerant from those who are going to reject. However, most of these biomarkers have not been validated by other groups or even established for clinical practice.

Methods. We reanalyzed and stratified the predictive capacity of 20 previously described biomarkers for liver transplantation tolerance in a cohort of 17 liver transplant patients subjected to an independent, nonrandomized, prospective study of immunosuppression drug withdrawal.

Results. Only 4 of the 20 studied biomarkers (expression of SENP6, FEM1C, miR31, and miR95) showed a strong predictive capacity in the present study. miR31 and FEM1C presented an area under the ROC curve of 96.7%, followed by SENP1 with 93.3%. Finally, miR95 had an area under the ROC curve value <86.7%.

Conclusions. Even though this independent analysis seems to confirm the predictive strength of SENP6 and FEM1C in liver transplantation tolerance, there are also risks in establishing biomarkers for clinical phenotypes without an understanding of how they are biologically relevant. Future collaborations between groups should be promoted so that the most promising biomarkers can be validated and implemented in daily clinical practice.

1 Biomedical Informatic and Bioinformatic Platform, Biomedical Research Institute of Murcia (IMIB-Arrixaca-UMU), University Clinical Hospital “Virgen de la Arrixaca,” University of Murcia, Murcia, Spain.

2 Experimental Gastroenterology and Solid Organ Transplantation Lab, Biomedical Research Institute of Murcia (IMIB-Arrixaca-UMU), University Clinical Hospital “Virgen de la Arrixaca,” University of Murcia, Murcia, Spain.

3 Liver Unit, Clínica Universidad de Navarra, Pamplona, Spain.

4 Experimental Hepatology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Pamplona, Spain.

5 Experimental Hepatology, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.

6 General Surgery and Liver Transplantation Unit, University Hospital Virgen de la Arrixaca, Murcia, Spain.

7 Division of Gastroenterology and Hepatology, University Hospital Virgen de la Arrixaca, Murcia, Spain.

Received 1 October 2018. Revision received 23 November 2018.

Accepted 16 December 2018.

J.A.P. and A.B-M. are senior authors.

The authors declare no conflicts of interest.

This work was supported by a grant from Instituto de Salud Carlos III (PI12/02042 and PI17/00489) for J.A.P. and Fundación Mutua Madrileña (FMM13) for A.B.-M. as Principal Investigators.

Clinical trial notation:; number ISRCTN15775356.

A.B-M. and B.R-N. are included in execution of experiments; A.B-M., B.R-N., L.M-A., J.I.H, P.R., and J.A.P. provided human clinical data; F.P. performed the bio-statistical analysis; F.P-S., A.B-M., B.R-N., P.R., and J.A.P. analyzed, presented, and interpreted experiments; F.P., A.B-M., and J.A.P. prepared the manuscript; A.B-M. and J.A.P. conceived, designed, and supervised this study; and A.B-M. and J.A.P. provided funding.

Correspondence: Alberto Baroja-Mazo, PhD, Murcia’s BioHealth Research Institute-Virgen de la Arrixaca, LAIB Bldg, Lab 4.20, Ctra Buenavista s/n, 30120 Murcia, Spain. (

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