Unveiling Systemic Responses in Kidney Transplantation: Interplay between the Allograft Transcriptome and Serum Proteins

Immunity, as defined by systems biology, encompasses a holistic response throughout the body, characterized by intricate connections with various tissues and compartments. However, systemic effects have been rarely studied in kidney transplantation. In this proof of concept study we explored a direct association between the allograft phenotype and serum protein signatures. Time-matched samples of graft biopsies and blood serum were collected in a heterogenous cohort of kidney transplanted patients (n=15) for bulk RNA sequencing and proteomics, respectively. RNA transcripts exhibit distinct and reproducible co-regulated gene networks with specific functional profiles. We measured 159 serum proteins and investigated correlations with gene network activity. Two opposing axes - one related to metabolism and the other to inflammation - were identified. They represent a biological continuum between the allograft and the serum, and correlate with allograft function, but not with interstitial fibrosis or proteinuria. For signature validation we used two independent proteomic datasets (n=21). Our findings establish a biological link between the allograft transcriptome and the blood serum proteome, highlighting systemic immune effects in kidney transplantation and offering a promising framework for developing allograft-linked biomarkers.