Published July 19, 2023 | Version v1
Journal article Open

A spatially anchored transcriptomic atlas of the human kidney papilla identifies significant immune injury in patients with stone disease

Description

Kidney stone disease causes significant morbidity and increases health care utilization. In this work, we decipher the cellular and molecular niche of the human renal papilla in patients with calcium oxalate (CaOx) stone disease and healthy subjects. In addition to identifying cell types important in papillary physiology, we characterize collecting duct cell subtypes and an undifferentiated epithelial cell type that was more prevalent in stone patients. Despite the focal nature of mineral deposition in nephrolithiasis, we uncover a global injury signature characterized by immune activation, oxidative stress and extracellular matrix remodeling. We also identify the association of MMP7 and MMP9 expression with stone disease and mineral deposition, respectively. MMP7 and MMP9 are significantly increased in the urine of patients with CaOx stone disease, and their levels correlate with disease activity. Our results define the spatial molecular landscape and specific pathways contributing to stone-mediated injury in the human papilla and identify associated urinary biomarkers.

Data availability

All sequencing data were analyzed using the GRCh38 (hg38) reference genome. For published data from the KPMP/HuBMAP atlas, access to the raw snRNAseq data has been detailed in the Lake et al manuscript (Nature 2023, in press, https://doi.org/10.1038/s41586-023-05769-3). These raw sequencing data are under controlled access (human data) as they are potentially identifiable and can be accessed from the following respective sources: 1) KPMP data has been deposited at https://atlas.kpmp.org/repository/ and can be requested and made available by signing a data use agreement (DUA) with KPMP. KPMP will respond to initial data requests within 12–36 h and provide data up to one month after DUA has been signed. Manuscripts resulting from KPMP controlled access data are requested to go through the KPMP Publications and Presentations Committee which reviews and approves manuscripts every two weeks. Any analysis resulting from KPMP data may be published or shared so long as it does not re-identify KPMP participants. 2) The HuBMAP raw data are available for download from the database of Genotypes and Phenotypes (dbGaP, phs002249) by requesting for authorized access following instructions on the dbGaP website. The process to request access to this dbGaP study is here: https://dbgap.ncbi.nlm.nih.gov/aa/wga.cgi?adddataset=phs002249&page=login. Briefly, to download the human sequence data for this study after obtaining authorization from the NIH Data Access Committee, one would go through the Sequence Read Archive here: https://www.ncbi.nlm.nih.gov/bioproject/PRJNA671343. Processed data (published in the Lake et al manuscript) for both of these sources is available in the GEO Super-series: GSE183279 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE183279). The new snRNAseq data generated for this study (raw sequencing and processed), along with all the Visium spatial transcriptomic data are available in GEO as the Super-series GSE231630 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE231630 or deposited in the HuBMAP portal (https://portal.hubmapconsortium.org/). A breakdown of the data availability of all papillary samples is presented in Supplementary Table 2. Source data are provided with this paper. For the imaging data: the source data for all the main and supplementary figures (3D imaging, CODEX, and smFISH) are available at the following repository: https://doi.org/10.5281/zenodo.7653239 and https://zenodo.org/record/7653239#.ZGIuGc7MKUk Source data are provided with this paper.

The R packages and code used in the snRNAseq and spatial transcriptomics analysis are described in the methods. For image analysis, the VTEA software is available for download through the FIJI plugin updater with the source code is available on GitHub, https://github.com/icbm-iupui/volumetric-tissue-exploration-analysis. Additional descriptions and vignettes demonstrating the use of VTEA are available at https://vtea.wiki.

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Additional details

Identifiers

DOI
10.1038/s41467-023-38975-8
Other
oai:uchicago.tind.io:6811

Funding

National Institute of Health
P01 DK056788
National Institute of Health
U01 DK114923
National Institute of Health
P30 DK079312
National Institute of Health
R01 DK111651
National Institute of Health
U54 DK134301

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Medicine