Evaluation of a proteomic signature coupled with the kidney failure risk equation in predicting end stage kidney disease in a chronic kidney disease cohort.

IF 2.8 3区 医学 Q2 BIOCHEMICAL RESEARCH METHODS Clinical proteomics Pub Date : 2024-05-18 DOI:10.1186/s12014-024-09486-5
Carlos Raúl Ramírez Medina, Ibrahim Ali, Ivona Baricevic-Jones, Moin A Saleem, Anthony D Whetton, Philip A Kalra, Nophar Geifman
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Abstract

Background: The early identification of patients at high-risk for end-stage renal disease (ESRD) is essential for providing optimal care and implementing targeted prevention strategies. While the Kidney Failure Risk Equation (KFRE) offers a more accurate prediction of ESRD risk compared to static eGFR-based thresholds, it does not provide insights into the patient-specific biological mechanisms that drive ESRD. This study focused on evaluating the effectiveness of KFRE in a UK-based advanced chronic kidney disease (CKD) cohort and investigating whether the integration of a proteomic signature could enhance 5-year ESRD prediction.

Methods: Using the Salford Kidney Study biobank, a UK-based prospective cohort of over 3000 non-dialysis CKD patients, 433 patients met our inclusion criteria: a minimum of four eGFR measurements over a two-year period and a linear eGFR trajectory. Plasma samples were obtained and analysed for novel proteomic signals using SWATH-Mass-Spectrometry. The 4-variable UK-calibrated KFRE was calculated for each patient based on their baseline clinical characteristics. Boruta machine learning algorithm was used for the selection of proteins most contributing to differentiation between patient groups. Logistic regression was employed for estimation of ESRD prediction by (1) proteomic features; (2) KFRE; and (3) proteomic features alongside KFRE.

Results: SWATH maps with 943 quantified proteins were generated and investigated in tandem with available clinical data to identify potential progression biomarkers. We identified a set of proteins (SPTA1, MYL6 and C6) that, when used alongside the 4-variable UK-KFRE, improved the prediction of 5-year risk of ESRD (AUC = 0.75 vs AUC = 0.70). Functional enrichment analysis revealed Rho GTPases and regulation of the actin cytoskeleton pathways to be statistically significant, inferring their role in kidney function and the pathogenesis of renal disease.

Conclusions: Proteins SPTA1, MYL6 and C6, when used alongside the 4-variable UK-KFRE achieve an improved performance when predicting a 5-year risk of ESRD. Specific pathways implicated in the pathogenesis of podocyte dysfunction were also identified, which could serve as potential therapeutic targets. The findings of our study carry implications for comprehending the involvement of the Rho family GTPases in the pathophysiology of kidney disease, advancing our understanding of the proteomic factors influencing susceptibility to renal damage.

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评估蛋白质组特征与肾衰竭风险方程在预测慢性肾病队列中终末期肾病方面的作用。
背景:早期识别终末期肾病(ESRD)高风险患者对于提供最佳治疗和实施有针对性的预防策略至关重要。虽然与基于静态 eGFR 的阈值相比,肾衰竭风险方程(KFRE)能更准确地预测 ESRD 风险,但它并不能深入了解驱动 ESRD 的患者特异性生物机制。这项研究的重点是评估 KFRE 在英国晚期慢性肾脏病(CKD)队列中的有效性,并研究蛋白质组特征的整合是否能提高 5 年 ESRD 预测能力:索尔福德肾脏研究(Salford Kidney Study)生物库是英国的一个前瞻性队列,包含 3000 多名非透析慢性肾脏病患者,其中 433 名患者符合我们的纳入标准:两年内至少进行过四次 eGFR 测量,且 eGFR 轨迹呈线性。我们采集了血浆样本,并使用 SWATH 质谱仪分析了新的蛋白质组信号。根据每位患者的基线临床特征,为其计算 4 变量英国校准 KFRE。Boruta 机器学习算法用于选择最有助于区分患者组别的蛋白质。采用逻辑回归法通过(1)蛋白质组特征;(2)KFRE;(3)蛋白质组特征和KFRE对ESRD预测进行估算:我们生成了包含 943 个量化蛋白质的 SWATH 图谱,并结合现有临床数据进行研究,以确定潜在的病情进展生物标志物。我们确定了一组蛋白质(SPTA1、MYL6 和 C6),当它们与 4 变量 UK-KFRE 一起使用时,可改善 ESRD 5 年风险的预测(AUC = 0.75 vs AUC = 0.70)。功能富集分析显示,Rho GTP酶和肌动蛋白细胞骨架通路的调节具有统计学意义,推断出它们在肾功能和肾病发病机制中的作用:SPTA1、MYL6和C6蛋白与4变量UK-KFRE一起使用时,在预测ESRD的5年风险方面取得了更好的效果。研究还发现了与荚膜细胞功能障碍发病机制有关的特定通路,这些通路可作为潜在的治疗靶点。我们的研究结果对理解 Rho 家族 GTP 酶参与肾脏疾病的病理生理学具有重要意义,有助于我们进一步了解影响肾脏损伤易感性的蛋白质组学因素。
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来源期刊
Clinical proteomics
Clinical proteomics BIOCHEMICAL RESEARCH METHODS-
CiteScore
5.80
自引率
2.60%
发文量
37
审稿时长
17 weeks
期刊介绍: Clinical Proteomics encompasses all aspects of translational proteomics. Special emphasis will be placed on the application of proteomic technology to all aspects of clinical research and molecular medicine. The journal is committed to rapid scientific review and timely publication of submitted manuscripts.
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