Journal Article

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

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

2022

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Acute kidney injury / Bioinformatics / Biological response modifiers / Biomedical and Life Sciences / Biomedicine / Biopsy / Cancer Research / Coronaviruses / COVID-19 / Critical illness / Distal tubules / Epithelium / Gene expression / Genomes / Genomics / Health aspects / Human Genetics / Hypoxia / Illnesses / Intensive care / Interferon / Kidney diseases / Kidneys / Medicine/Public Health / Mesenchyme / Metabolomics / Nephrectomy / Oxidative stress / Patients / Proximal tubules / Severe acute respiratory syndrome coronavirus 2 / Single-cell sequencing / Systems Biology / Transcriptomes / Transcriptomics