Gene expression biomarkers for kidney transplant rejection – The entire landscape (2019)

We read with interest the article and editorial in your most recent issue on non-invasive testing to detect rejection in kidney transplant recipients [[1]Christakoudi S. Mobillo P. Tsui T.L. Duff C. Domingo-Vila C. Kamra Y. et al.Development of a multivariable gene-expression signature targeting T-cell-mediated rejection in peripheral blood of kidney transplant recipients validated in cross-sectional and longitudinal samples.eBioMedicine. 2019; https://doi.org/10.1016/j.ebiom.2019.01.060Summary Full Text Full Text PDF Scopus (25) Google Scholar,[2]Viklicky O. Are we ready to implement non-invasive tests to detect allograft rejection in a daily praxis?.EBioMedicine. 2019; https://doi.org/10.1016/j.ebiom.2019.03.001Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. The prospective, serial presentation of gene expression data is a strength of the study. We were surprised, however, to read the claims that there were no other studies evaluating biomarkers for subclinical rejection. Our recently published, prospective CTOT-08 clinical trial (NCT01289717) [[3]Friedewald J.J. Kurian S.M. Heilman R.L. Whisenant T.C. Poggio E.D. Marsh C. et al.Development and clinical validity of a novel blood-based molecular biomarker for sub-clinical acute rejection following kidney transplant.Am J Transplant. 2019; 19: 98-109https://doi.org/10.1111/ajt.15011Summary Full Text Full Text PDF PubMed Scopus (81) Google Scholar] was designed to detect and study subclinical kidney transplant rejection and led to the development and validation of a blood-based gene expression profile for subclinical rejection. Importantly, the clinical phenotype of subclinical rejection was tightly-defined and always proven with contemporaneous biopsy in our trial, allowing for an accurate assessment of the rate of true positives and true negatives. We did find that subclinical rejection as detected by biopsy or blood gene expression profile test was associated with progression to future episodes of clinical acute rejection, but not in all cases. And our study and others demonstrate that outcomes were worse even in patients with subclinical rejection that did not progress to clinical acute rejection [[4]Mehta R. Bhusal S. Randhawa P. Sood P. Cherukuri A. Wu C. et al.Short-term adverse effects of early subclinical allograft inflammation in kidney transplant recipients with a rapid steroid withdrawal protocol.Am J Transplant. 2018; 18: 1710-1717https://doi.org/10.1111/ajt.14627Summary Full Text Full Text PDF PubMed Scopus (37) Google Scholar]. We agree with the editorial statement regarding a priori bias in biomarker gene selection. For that reason, we chose an unbiased, whole transcriptome “microarray-based approach” to discover and validate our 57-gene biomarker panel (GEO Accession #GSE107509). Subsequent studies using our biomarker have further validated its utility in clinical practice [[5]Marsh C.L. Kurian S.M. Rice J.C. Whisenant T.C. David J. Rose S. et al.Application of TruGraf® v1: a novel molecular biomarker for managing kidney transplant recipients with stable renal function.Transplant Proc. 2019; https://doi.org/10.1016/j.transproceed.2019.01.054Crossref Scopus (14) Google Scholar]. So, we believe that the answer to “Are we ready to implement non-invasive tests to detect allograft rejection in a daily praxis” is definitely, yes. Development of a multivariable gene-expression signature targeting T-cell-mediated rejection in peripheral blood of kidney transplant recipients validated in cross-sectional and longitudinal samplesMolecular marker alterations in blood emerge well ahead of the time of clinically overt TCMR. Monitoring a TCMR-signature in peripheral blood could unravel T-cell-related pro-inflammatory activity and hidden immunological processes. This additional information could support clinical management decisions in cases of patients with stable but poor kidney function or with inconclusive biopsy results. Full-Text PDF Open Access