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肾特异性无细胞 DNA 甲基化标志物在实时监测脓毒症诱导的急性肾损伤中的应用前景。

A promising application of kidney-specific cell-free DNA methylation markers in real-time monitoring sepsis-induced acute kidney injury.

机构信息

Department of Nephrology, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China.

Genomics Institute, GenePlus-Beijing, Beijing, China.

出版信息

Epigenetics. 2024 Dec;19(1):2408146. doi: 10.1080/15592294.2024.2408146. Epub 2024 Oct 7.

DOI:10.1080/15592294.2024.2408146
PMID:39370847
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11459754/
Abstract

Sepsis-induced acute kidney injury (SI-AKI) is a common clinical syndrome that is associated with high mortality and morbidity. Effective timely detection may improve the outcome of SI-AKI. Kidney-derived cell-free DNA (cfDNA) may provide new insight into understanding and identifying SI-AKI. Plasma cfDNA from 82 healthy individuals, 7 patients with sepsis non-acute kidney injury (SN-AKI), and 9 patients with SI-AKI was subjected to genomic methylation sequencing. We deconstructed the relative contribution of cfDNA from different cell types based on cell-specific methylation markers and focused on exploring the association between kidney-derived cfDNA and SI-AKI.Based on the deconvolution of the cfDNA methylome: SI-AKI patients displayed the elevated cfDNA concentrations with an increased contribution of kidney epithelial cells (kidney-Ep) DNA; kidney-Ep derived cfDNA achieved high accuracy in distinguishing SI-AKI from SN-AKI (AUC = 0.92, 95% CI 0.7801-1); the higher kidney-ep cfDNA concentrations tended to correlate with more advanced stages of SI-AKI; strikingly, SN-AKI patients with potential kidney damage unmet by SI-AKI criteria showed higher levels of kidney-Ep derived cfDNA than healthy individuals. The autonomous screening of kidney-Ep ( = 24) and kidney endothelial (kidney-Endo,  = 12) specific methylation markers indicated the unique identity of kidney-Ep/kidney-Endo compared with other cell types, and its targeted assessment reproduced the main findings of the deconvolution of the cfDNA methylome. Our study first demonstrates that kidney-Ep- and kidney-Endo-specific methylation markers can serve as a novel marker for SI-AKI emergence, supporting further exploration of the utility of kidney-specific cfDNA methylation markers in the study of SI-AKI.

摘要

脓毒症相关性急性肾损伤（SI-AKI）是一种常见的临床综合征，与高死亡率和高发病率相关。有效的及时检测可能会改善 SI-AKI 的预后。肾脏来源的无细胞游离 DNA（cfDNA）可能为理解和识别 SI-AKI 提供新的见解。对 82 名健康个体、7 名脓毒症非急性肾损伤（SN-AKI）患者和 9 名 SI-AKI 患者的血浆 cfDNA 进行了基因组甲基化测序。我们根据细胞特异性甲基化标记物对来自不同细胞类型的 cfDNA 的相对贡献进行了重构，并重点探讨了肾脏来源的 cfDNA 与 SI-AKI 之间的关联。基于 cfDNA 甲基组的重构：SI-AKI 患者的 cfDNA 浓度升高，肾脏上皮细胞（肾-Ep）DNA 的贡献增加；肾-Ep 衍生的 cfDNA 能够准确地区分 SI-AKI 与 SN-AKI（AUC = 0.92，95%CI 0.7801-1）；肾-Ep cfDNA 浓度越高，SI-AKI 分期越晚；令人惊讶的是，不符合 SI-AKI 标准的潜在肾损伤的 SN-AKI 患者的肾-Ep 衍生 cfDNA 水平高于健康个体。肾-Ep（ = 24）和肾内皮（肾-Endo， = 12）特异性甲基化标记物的自动筛选表明肾-Ep/肾-Endo 与其他细胞类型相比具有独特的身份，其靶向评估复制了 cfDNA 甲基化组重构的主要发现。本研究首次证明，肾-Ep 和肾-Endo 特异性甲基化标记物可作为 SI-AKI 发生的新型标志物，支持进一步探索肾脏特异性 cfDNA 甲基化标志物在 SI-AKI 研究中的应用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3d8/11459754/44a76c80a057/KEPI_A_2408146_F0008_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3d8/11459754/7773d3a6a0c8/KEPI_A_2408146_UF0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3d8/11459754/8ee9a49bff66/KEPI_A_2408146_F0001_OC.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3d8/11459754/2611f8c1b7a1/KEPI_A_2408146_F0003_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3d8/11459754/e00dbbe52db1/KEPI_A_2408146_F0004_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3d8/11459754/2ca5752196aa/KEPI_A_2408146_F0005_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3d8/11459754/a1f9e48179e9/KEPI_A_2408146_F0006_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3d8/11459754/183eca0d642a/KEPI_A_2408146_F0007_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3d8/11459754/44a76c80a057/KEPI_A_2408146_F0008_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3d8/11459754/7773d3a6a0c8/KEPI_A_2408146_UF0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3d8/11459754/8ee9a49bff66/KEPI_A_2408146_F0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3d8/11459754/c259243265be/KEPI_A_2408146_F0002_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3d8/11459754/2611f8c1b7a1/KEPI_A_2408146_F0003_OC.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3d8/11459754/2ca5752196aa/KEPI_A_2408146_F0005_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3d8/11459754/a1f9e48179e9/KEPI_A_2408146_F0006_OC.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3d8/11459754/44a76c80a057/KEPI_A_2408146_F0008_OC.jpg

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