Data-driven kidney transplant phenotyping as a histology- independent framework for biomarker discovery

Konrad Buscher, Barbara Heitplatz, Veerle van Marck, Jian Song, Sophie Loismann, Rebecca Rixen, Birte Huchtmann, Sunil Kurian, Erik Ehinger, Dennis Wolf, Klaus Ley, Hermann Pavenstadt, Stefan Reuter

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Background In transplant medicine, clinical decision making largely relies on histology of biopsy specimens. However, histology suffers from low specificity, sensitivity, and reproducibility, leading to suboptimal stratification of patients. We developed a histology-independent immune framework of kidney graft homeostasis and rejection. Methods We applied tailored RNA deconvolution for leukocyte enumeration and coregulated gene network analysis to published bulk human kidney transplant RNA transcriptomes as input for unsupervised, high-dimensional phenotype clustering. We used framework-based graft survival analysis to identify a biomarker that was subsequently characterized in independent transplant biopsy specimens. Results We found seven immune phenotypes that confirm known rejection types and uncovered novel signatures. The molecular phenotypes allow for improved graft survival analysis compared with histology, and identify a high-risk group in nonrejecting transplants. Two fibrosis-related phenotypes with distinct immune features emerged with reduced graft survival. We identified lysyl oxidase-like 2 (LOXL2)-expressing peritubular CD681 macrophages as a framework-derived biomarker of impaired allograft function. These cells precede graft fibrosis, as demonstrated in longitudinal biopsy specimens, and may be clinically useful as a biomarker for early fibrogenesis. Conclusions This study provides a comprehensive, data-driven atlas of human kidney transplant phenotypes and demonstrates its utility to identify novel clinical biomarkers.

Original languageEnglish (US)
Pages (from-to)1933-1945
Number of pages13
JournalJournal of the American Society of Nephrology
Volume32
Issue number8
DOIs
StatePublished - Aug 2021
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine

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