Patients with sepsis-induced AKI can be classified into two distinct sub-phenotypes (AKI-SP1, AKI-SP2) that differ in clinical outcomes and response to treatment. The biologic mechanisms underlying these sub-phenotypes remains unknown. Our objective was to understand the underlying biology that differentiates AKI sub-phenotypes and associations with kidney outcomes. We prospectively enrolled 173 ICU patients with sepsis from a suspected respiratory infection (87 without AKI and 86 with AKI on enrollment). Among the AKI patients, 66 were classified as AKI-SP1 and 20 as AKI-SP2 using a three-plasma biomarker classifier. Aptamer-based proteomics assessed 5,212 proteins in urine collected on ICU admission. We compared urinary protein abundances between AKI sub-phenotypes, conducted pathway analyses, tested associations with risk of RRT and blood bacteremia, and predicted AKI-SP2 class membership using LASSO. In total, 117 urine proteins were higher in AKI-SP2, 195 were higher in AKI-SP1 (FDR < 0.05). Urinary proteins involved in inflammation and chemoattractant of neutrophils and monocytes (CXCL1 and REG3A) and oxidative stress (SOD2) were abundant in AKI-SP2, while proteins involved in collagen deposition (GP6), podocyte derived (SPOCK2), proliferation of mesenchymal cells (IL11RA), anti-inflammatory (IL10RB and TREM2) were abundant in AKI-SP1. Pathways related to immune response, complement activation and chemokine signaling were upregulated in AKI-SP2 and pathways of cell adhesion were upregulated in AKI-SP1. Overlap was present between urinary proteins that differentiated AKI sub-phenotypes and proteins that differentiated risk of RRT during hospitalization. Variable correlation was found between top aptamers and ELISA based protein assays. A LASSO derived urinary proteomic model to classify AKI-SP2 had a mean AUC of 0.86 (95% CI: 0.69–0.99). Our findings suggest AKI-SP1 is characterized by a reparative, regenerative phenotype and AKI-SP2 is characterized as an immune and inflammatory phenotype associated with blood bacteremia. We identified shared biology between AKI sub-phenotypes and eventual risk of RRT highlighting potential therapeutic targets. Urine proteomics may be used to non-invasively classify SP2 participants.

中文翻译：

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尿液蛋白质组学鉴定脓毒症相关 AKI 亚表型的不同免疫学特征


脓毒症诱导的 AKI 患者可分为两种不同的亚型（AKI-SP1、AKI-SP2），它们在临床结果和对治疗的反应上有所不同。这些亚表型的生物学机制仍然未知。我们的目标是了解区分 AKI 亚表型和与肾脏结果关联的潜在生物学。我们前瞻性地招募了 173 例疑似呼吸道感染引起的脓毒症 ICU 患者 （87 例无 AKI，86 例入组时有 AKI）。在 AKI 患者中，使用三血浆生物标志物分类器将 66 例分类为 AKI-SP1,20 例分类为 AKI-SP2。基于适配子的蛋白质组学评估了入住 ICU 时收集的尿液中的 5,212 种蛋白质。我们比较了 AKI 亚型之间的尿蛋白丰度，进行了通路分析，测试了与 RRT 和血液菌血症风险的关联，并使用 LASSO 预测了 AKI-SP2 类成员。总共有 117 种尿蛋白在 AKI-SP2 中较高，195 种在 AKI-SP1 中较高 （FDR < 0.05）。AKI-SP2 中涉及中性粒细胞和单核细胞 （CXCL1 和 REG3A） 的炎症和趋化因子 （CXCL1 和 REG3A） 以及氧化应激 （SOD2） 的尿蛋白丰富，而参与胶原沉积 （GP6） 、足细胞衍生 （SPOCK2）、间充质细胞增殖 （IL11RA） 、抗炎 （IL10RB 和 TREM2） 的蛋白质在 AKI-SP1 中丰富。AKI-SP2 中免疫应答、补体激活和趋化因子信号转导相关的通路上调，AKI-SP1 中细胞粘附通路上调。区分 AKI 亚表型的尿蛋白与区分住院期间 RRT 风险的蛋白之间存在重叠。在顶级适配体和基于 ELISA 的蛋白质测定之间发现了可变的相关性。 用于对 AKI-SP2 进行分类的 LASSO 衍生的尿液蛋白质组学模型的平均 AUC 为 0.86 （95% CI： 0.69–0.99）。我们的研究结果表明，AKI-SP1 的特征是修复性、再生性表型，而 AKI-SP2 的特征是与血液菌血症相关的免疫和炎症表型。我们确定了 AKI 亚表型和 RRT 的最终风险之间的共同生物学，突出了潜在的治疗靶点。尿液蛋白质组学可用于对 SP2 参与者进行无创分类。