Yumeng Wen, Steven Menez, Heather Thiessen Philbrook, Dennis Moledina, Steven G Coca, Jiashu Xue, James Kaufman, Vernon Chinchillil, Paul L Kimmel, T Alp Ikizler, Chi-Yuan Hsu, Tanika Kelly, Ana Ricardo, Jonathan Himmelfarb, Chirag R Parikh
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引用次数: 0
Abstract
Background: Urine proteomics may provide mechanistic insights on why patients experience a higher risk of kidney function decline after hospitalization.
Methods: In 174 patients with and without acute kidney injury (AKI) from the Assessment, Serial Evaluation, and Subsequent Sequelae in AKI (ASSESS-AKI) cohort, we used Olink to profile 2783 urinary proteins collected at 3 months after hospitalization and determined their association with estimated glomerular filtration rate (eGFR) decline during median [IQR] of 5.1 [4.0 to 6.0] years follow-up. In 4 independent cohorts, including the Kidney Precision Medicine Project (KPMP), we determined whether proteins were differentially expressed with AKI. We used weighted correlation network analysis to determine proteins' cellular enrichment in the kidney transcriptome (single-cell and spatial transcriptomics) in patients with AKI receiving research kidney biopsy.
Results: We identified 387 and 10 proteins associated with faster and slower eGFR decline, respectively, most of which were differentially expressed in patients at the time of AKI. Among these proteins, 283 (71%) were expressed by kidney cells in participants with AKI from KPMP. The expression formed 3 clusters enriched in the proximal tubule, degenerative tubule and myeloid cells, and stromal cells, and correlated with histopathological features of AKI, such as tubular injury, interstitial inflammation, and fibrosis, respectively.
Conclusion: Urinary proteins reflecting degenerative tubular injury, inflammation, and fibrosis are associated with eGFR decline in recently hospitalized patients.
Funding: National Institute of Diabetes and Digestive Kidney Diseases grants U01DK133081, U01DK133091, U01DK133092, U01DK133093, U01DK133095, U01DK133097, U01DK114866, U01DK114908, U01DK133090, U01DK133113, U01DK133766, U01DK133768, U01DK114907, U01DK114920, U01DK114923, U01DK114933, U24DK114886, UH3DK114926, UH3DK114861, UH3DK114915, UH3DK114937, K23DK128358, R01DK128087, and R01DK140717.
背景：尿蛋白质组学可能为患者住院后肾功能下降风险较高的原因提供机制见解。方法：在来自AKI评估、系列评估和后续后遗症（Assessment -AKI）队列的174例有或无急性肾损伤（AKI）患者中，我们使用Olink分析了住院后3个月收集的2783种尿蛋白，并确定了它们与中位[IQR] 5.1[4.0-6.0]年随访期间估计肾小球滤过率（eGFR）下降的关系。在包括肾脏精准医学项目（KPMP）在内的四个独立队列中，我们确定了AKI中蛋白质是否存在差异表达。我们使用加权相关网络分析来确定接受研究肾活检的AKI患者肾脏转录组（单细胞和空间转录组）中蛋白质的细胞富集。结果：我们分别鉴定出387种和10种与eGFR下降更快和更慢相关的蛋白，其中大多数在AKI患者中存在差异表达。在这些蛋白中，283个（71%）在KPMP患者的肾细胞中表达。该表达在近端小管、变性小管及髓细胞、基质细胞中形成3个富集簇，分别与肾小管损伤、间质炎症、纤维化等AKI组织病理特征相关。结论：反映退行性小管损伤、炎症和纤维化的尿蛋白与近期住院患者的eGFR下降有关。资助:肾脏精准医学项目（KPMP）由国家糖尿病与消化肾脏疾病研究所（NIDDK）通过以下项目资助：su01dk133081、U01DK133091、U01DK133092、U01DK133093、U01DK133095、U01DK133097、U01DK114866、U01DK114908、U01DK133090、U01DK133113、U01DK133766、u01dk114968、U01DK114907、U01DK114920、U01DK114923、U24DK114886、UH3DK114926、UH3DK114861、UH3DK114915、u01dk114915、u01dk114926、UH3DK114861、UH3DK114915、我们非常感谢我们的患者参与者的重要贡献和美国公众通过他们的税款的支持。SM由NIDDK Grant K23DK128358支持。
期刊介绍：
JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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