Proteomic Analysis of Idiopathic Nephrotic Syndrome Triggered by Primary Podocytopathies in Adults: Regulatory Mechanisms and Diagnostic Implications

Idiopathic nephrotic syndrome (NS) is a heterogeneous
group of
glomerular disorders which includes two major phenotypes: minimal
change disease (MCD) and focal segmental glomerulosclerosis (FSGS).
MCD and FSGS are classic types of primary podocytopathies. We aimed
to explore the molecular mechanisms in NS triggered by primary podocytopathies
and evaluate diagnostic value of the selected proteomic signatures
by analyzing blood proteome profiling. Totally, we recruited 90 participants
in two cohorts. The first cohort was analyzed using label-free quantitative
(LFQ) proteomics to discover differential expressed proteins and identify
enriched biological process in NS which were further studied in relation
to clinical markers of kidney injury. The second cohort was analyzed
using parallel reaction monitoring-based quantitative proteomics to
verify the data of LFQ proteomics and assess the diagnostic performance
of the selected proteins using receiver-operating characteristic curve
analysis. Several biological processes (such as immune response, cell
adhesion, and response to hypoxia) were found to be associated with
kidney injury during MCD and FSGS. Moreover, three proteins (CSF1,
APOC3, and LDLR) had over 90% sensitivity and specificity in detecting
adult NS triggered by primary podocytopathies. The identified biological
processes may play a crucial role in MCD and FSGS pathogenesis. The
three blood protein markers are promising for diagnosing adult NS
triggered by primary podocytopathies.

特发性肾病综合征（Idiopathic nephrotic syndrome, NS）是一组异质性肾小球疾病，包含两大经典表型：微小病变肾病（MCD）与局灶节段性肾小球硬化症（FSGS）。MCD与FSGS均为原发性足细胞病的典型类型。本研究旨在探究原发性足细胞病诱发NS的分子机制，并通过分析血液蛋白质组谱，评估筛选得到的蛋白质组学标志物的诊断价值。本研究共纳入两个队列的90名受试者。第一队列采用无标记定量（LFQ）蛋白质组学技术，筛选差异表达蛋白并鉴定NS中富集的生物学过程，同时结合肾损伤临床标志物开展进一步关联分析。第二队列采用基于平行反应监测的定量蛋白质组学技术，验证LFQ蛋白质组学的研究结果，并通过受试者工作特征曲线（receiver-operating characteristic curve, ROC）分析评估筛选出的蛋白的诊断性能。研究发现，免疫应答、细胞黏附以及缺氧应答等多种生物学过程与MCD及FSGS患者的肾损伤显著相关。此外，CSF1、APOC3与LDLR三种蛋白在检测原发性足细胞病诱发的成人NS时，灵敏度与特异性均超过90%。本研究鉴定出的生物学过程可能在MCD与FSGS的发病机制中发挥关键作用，而这三种血液蛋白标志物有望用于原发性足细胞病诱发的成人NS的临床诊断。