Urinary single-cell sequencing captures kidney injury and repair processes in human acute kidney injury

Klocke, Jan; Kim, Seung Joon; Skopnik, Christopher Mark; Hinze, Christian; Boltengagen, Anastasiya; Metzke, Diana; Grothgar, Emil; Prskalo, Luka; Wagner, Leonie; Freund, Paul; Görlich, Nina; Muench, Frédéric; Schmidt‐Ott, Kai M.; Mashreghi, Mir‐Farzin; Kocks, Christine; Rajewsky, Nikolaus; Enghard, Philipp

doi:10.1016/j.kint.2022.07.032

Cited by 23 publications

(14 citation statements)

References 78 publications

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“…Recent studies demonstrated the possibility to perform scRNAseq analyses on urine sample. 26 This would open the opportunity to recalibrate the system and to develop diagnostic tools with a broader clinical applicability.…”

Section: Discussionmentioning

confidence: 99%

A transfer learning framework to elucidate the clinical relevance of altered proximal tubule cell states in kidney disease

Legouis,

Rinaldi,

Malpetti

et al. 2024

iScience

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Section: Discussionmentioning

confidence: 99%

A transfer learning framework to elucidate the clinical relevance of altered proximal tubule cell states in kidney disease

Legouis,

Rinaldi,

Malpetti

et al. 2024

iScience

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“…Recent studies have validated the use of urinary cell transcriptomes as a reliable method to detect and quantify the transcriptome of almost all types of cells found in the kidneys and urinary tract [57]. This technique can be used to characterize kidney injury and ongoing repair [58] along with other kidney diseases [59]. Analysis of first-morning urine cell bulk transcriptomes of 47 nondiabetic hypertensive patients from the SPRINT trial (systolic blood pressure intervention) revealed increased representation of proinflammatory networks in the 29 BP difficult-to-control group compared to the 18 control patients [34 Obesity, partially characterized by chronic lowgrade inflammation [60], correlates with an increased risk of hypertension [61], and the rates of worldwide obesity continue to increase, thereby concurrently increasing the rates of hypertension [61].…”

Section: Recent Updates: Clinical Evidence Of the Role Of Interferon ...mentioning

confidence: 99%

Interferon gamma in the pathogenesis of hypertension − recent insights

Benson,

2024

Current Opinion in Nephrology &Amp; Hypertension

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Purpose of review The mounting body of evidence underscores the pivotal role of interferon gamma (IFNγ) in the pathogenesis of hypertension, prompting exploration of the mechanisms by which this cytokine fosters a pro-inflammatory immune milieu, subsequently exacerbating hypertension. In this review, we delve into recent preclinical and clinical studies from the past two years to elucidate how IFNγ participates in the progression of hypertension. Recent findings IFNγ promotes renal CD8+ T cell accumulation by upregulating tubular PDL1 and MHC-I, intensifying cell-to-cell interaction. Intriguingly, a nucleotide polymorphism in LNK, predisposing towards hypertension, correlates with augmented T cell IFNγ production. Additionally, anti-IFNγ treatment exhibits protective effects against T cell-mediated inflammation during angiotensin II infusion or transverse aortic constriction. Moreover, knockout of the mineralocorticoid receptor in T cells protects against cardiac dysfunction induced by myocardial infarction, correlating with reduced IFNγ and IL-6, decreased macrophage recruitment, and attenuated fibrosis. Interestingly, increased IFNγ production correlates with elevated blood pressure, impacting individuals with type 2 diabetes, nondiabetics, and obese hypertensive patients. Summary These revelations spotlight IFNγ as the critical mediator bridging the initial phase of blood pressure elevation with the sustained and exacerbated pathology. Consequently, blocking IFNγ signaling emerges as a promising therapeutic target to improve the management of this ‘silent killer.’

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“…Since obtaining kidney biopsy samples from these patients would have been invasive and challenging, we adopted urine sediment scRNA-seq to identify cell-type specific transcriptomic changes due to severe COVID-19. Urine sediment scRNA-seq has been shown to be a powerful tool for investigating the differential transcriptomic signature of the injured kidney cells in the context of AKI as well as COVID-AKI [49][50][51] . We obtained urine sediment scRNA-seq data from a subset of urine samples (n=40) analyzed using proteomics.…”

Section: Integrated Multiomic Analysis Of Clinical Datasets Show Adhe...mentioning

confidence: 99%

Integrated multiomics implicates dysregulation of ECM and cell adhesion pathways as drivers of severe COVID-associated kidney injury

Anandakrishnan,

Yi,

Sun

et al. 2024

Preprint

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COVID-19 has been a significant public health concern for the last four years; however, little is known about the mechanisms that lead to severe COVID-associated kidney injury. In this multicenter study, we combined quantitative deep urinary proteomics and machine learning to predict severe acute outcomes in hospitalized COVID-19 patients. Using a 10-fold cross-validated random forest algorithm, we identified a set of urinary proteins that demonstrated predictive power for both discovery and validation set with 87% and 79% accuracy, respectively. These predictive urinary biomarkers were recapitulated in non-COVID acute kidney injury revealing overlapping injury mechanisms. We further combined orthogonal multiomics datasets to understand the mechanisms that drive severe COVID-associated kidney injury. Functional overlap and network analysis of urinary proteomics, plasma proteomics and urine sediment single-cell RNA sequencing showed that extracellular matrix and autophagy-associated pathways were uniquely impacted in severe COVID-19. Differentially abundant proteins associated with these pathways exhibited high expression in cells in the juxtamedullary nephron, endothelial cells, and podocytes, indicating that these kidney cell types could be potential targets. Further, single-cell transcriptomic analysis of kidney organoids infected with SARS-CoV-2 revealed dysregulation of extracellular matrix organization in multiple nephron segments, recapitulating the clinically observed fibrotic response across multiomics datasets. Ligand-receptor interaction analysis of the podocyte and tubule organoid clusters showed significant reduction and loss of interaction between integrins and basement membrane receptors in the infected kidney organoids. Collectively, these data suggest that extracellular matrix degradation and adhesion-associated mechanisms could be a main driver of COVID-associated kidney injury and severe outcomes.

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Urinary single-cell sequencing captures kidney injury and repair processes in human acute kidney injury

Cited by 23 publications

References 78 publications

A transfer learning framework to elucidate the clinical relevance of altered proximal tubule cell states in kidney disease

A transfer learning framework to elucidate the clinical relevance of altered proximal tubule cell states in kidney disease

Interferon gamma in the pathogenesis of hypertension − recent insights

Integrated multiomics implicates dysregulation of ECM and cell adhesion pathways as drivers of severe COVID-associated kidney injury

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