Single-cell transcriptomics reveals common epithelial response patterns in human acute kidney injury

Christian Hinze; Christine Kocks; Janna Leiz; Nikos Karaiskos; Anastasiya Boltengagen; Shuang Cao; Christopher Mark Skopnik; Jan Klocke; Jan-Hendrik Hardenberg; Helena Stockmann; Inka Gotthardt; Benedikt Obermayer; Laleh Haghverdi; Emanuel Wyler; Markus Landthaler; Sebastian Bachmann; Andreas C Hocke; Victor Corman; Jonas Busch; Wolfgang Schneider; Nina Himmerkus; Markus Bleich; Kai-Uwe Eckardt; Philipp Enghard; Nikolaus Rajewsky; Kai M Schmidt-Ott

doi:10.1186/s13073-022-01108-9

Single-cell transcriptomics reveals common epithelial response patterns in human acute kidney injury

Genome Med. 2022 Sep 9;14(1):103. doi: 10.1186/s13073-022-01108-9.

Authors

Christian Hinze^{1

2

3}, Christine Kocks⁴, Janna Leiz^{2

3}, Nikos Karaiskos⁴, Anastasiya Boltengagen⁴, Shuang Cao^{1

2

3}, Christopher Mark Skopnik^{2

5}, Jan Klocke^{2

5

6}, Jan-Hendrik Hardenberg², Helena Stockmann², Inka Gotthardt², Benedikt Obermayer⁷, Laleh Haghverdi⁴, Emanuel Wyler⁴, Markus Landthaler⁴, Sebastian Bachmann⁸, Andreas C Hocke^{6

9}, Victor Corman¹⁰, Jonas Busch¹¹, Wolfgang Schneider¹², Nina Himmerkus¹³, Markus Bleich¹³, Kai-Uwe Eckardt^#², Philipp Enghard^#^{2

5}, Nikolaus Rajewsky^#⁴, Kai M Schmidt-Ott^#^{14

15

16}

Affiliations

¹ Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.
² Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.
³ Max Delbrueck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
⁴ Berlin Institute for Medical Systems Biology, Max Delbrueck Center in the Helmholtz Association, Berlin, Germany.
⁵ Deutsches Rheumaforschungszentrum, an Institute of the Leibniz Foundation, Berlin, Germany.
⁶ Berlin Institute of Health, Berlin, Germany.
⁷ Core Unit Bioinformatics, BIH/Charité/MDC, Berlin, Germany.
⁸ Institute for Functional Anatomy, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.
⁹ Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.
¹⁰ Institute of Virology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.
¹¹ Department of Urology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.
¹² Department of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.
¹³ Institute of Physiology, Christian-Albrechts-Universität, Kiel, Germany.
¹⁴ Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany. [email protected].
¹⁵ Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany. [email protected].
¹⁶ Max Delbrueck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. [email protected].

^# Contributed equally.

Abstract

Background: Acute kidney injury (AKI) occurs frequently in critically ill patients and is associated with adverse outcomes. Cellular mechanisms underlying AKI and kidney cell responses to injury remain incompletely understood.

Methods: We performed single-nuclei transcriptomics, bulk transcriptomics, molecular imaging studies, and conventional histology on kidney tissues from 8 individuals with severe AKI (stage 2 or 3 according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria). Specimens were obtained within 1-2 h after individuals had succumbed to critical illness associated with respiratory infections, with 4 of 8 individuals diagnosed with COVID-19. Control kidney tissues were obtained post-mortem or after nephrectomy from individuals without AKI.

Results: High-depth single cell-resolved gene expression data of human kidneys affected by AKI revealed enrichment of novel injury-associated cell states within the major cell types of the tubular epithelium, in particular in proximal tubules, thick ascending limbs, and distal convoluted tubules. Four distinct, hierarchically interconnected injured cell states were distinguishable and characterized by transcriptome patterns associated with oxidative stress, hypoxia, interferon response, and epithelial-to-mesenchymal transition, respectively. Transcriptome differences between individuals with AKI were driven primarily by the cell type-specific abundance of these four injury subtypes rather than by private molecular responses. AKI-associated changes in gene expression between individuals with and without COVID-19 were similar.

Conclusions: The study provides an extensive resource of the cell type-specific transcriptomic responses associated with critical illness-associated AKI in humans, highlighting recurrent disease-associated signatures and inter-individual heterogeneity. Personalized molecular disease assessment in human AKI may foster the development of tailored therapies.

Keywords: Acute kidney injury; Critical illness; Single-cell sequencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute Kidney Injury* / genetics
COVID-19* / genetics
Critical Illness
Humans
Kidney
Transcriptome