Cindy Varga , Felix Eichinger , Viji Nair , Abhijit S. Naik , Samih H. Nasr , Agnes B. Fogo , Denis Toskic , Matthias Kretzler , Raymond L. Comenzo
{"title":"Gene Expression Sets and Renal Profiling from the Renal AL Amyloid Involvement and NEOD00 (RAIN) Trial","authors":"Cindy Varga , Felix Eichinger , Viji Nair , Abhijit S. Naik , Samih H. Nasr , Agnes B. Fogo , Denis Toskic , Matthias Kretzler , Raymond L. Comenzo","doi":"10.1016/j.ekir.2024.07.002","DOIUrl":null,"url":null,"abstract":"<div><h3>Introduction</h3><p>There is an unmet need to understand the mechanisms by which amyloid deposition drives alterations in the kidney. We leveraged renal biopsies from amyloid light-chain (AL) amyloidosis participants of the Renal AL Amyloid Involvement and NEOD00 (RAIN) trial (NCT03168906) to perform transcriptional profiling and to employ a novel histologic scoring tool. Our objective was to utilize a transcriptome-driven approach to identify AL molecular signatures that may be prognostic.</p></div><div><h3>Methods</h3><p>Clinical data were correlated to histologic and molecular findings. A composite scarring injury and amyloid score (AS) were assigned to each biopsy. Glomerular and tubulointerstitial (TI) compartments were microdissected and sequenced separately. Expression data were compared to healthy living donors and focal segmental glomerulosclerosis (FSGS) profiles. Differentially expressed genes were determined.</p></div><div><h3>Results</h3><p>Cluster analysis revealed 2 distinct patient clusters (G1 and G2) based on gene expression. The AS was higher in the TI compartment (6.5 vs. 4.5; <em>P</em> = 0.0290) of G2. Glomeruli showed activation of fibrotic pathways and increased canonical signaling of LPS/IL-1. TNF activation was noted in TI. Enriched ingenuity canonical pathways included “coagulation system,” “GADD45 signaling,” and “Wnt/Ca+ pathway,” among others. For AL versus living donors, ingenuity pathway analysis identified enrichment in PI3K/Akt signaling. Gene regulators of cellular proliferation were enriched in the amyloid group.</p></div><div><h3>Conclusion</h3><p>Despite the small sample size, we identified 2 distinct groups of patients with AL based on molecular signatures. Detailed studies of a larger cohort encompassing omics technologies at a single cell resolution will further help to identify the response of individual kidney cell types to amyloid deposits, potentially leading to the development of novel therapeutic targets.</p></div>","PeriodicalId":17761,"journal":{"name":"Kidney International Reports","volume":"9 9","pages":"Pages 2786-2797"},"PeriodicalIF":5.7000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2468024924018187/pdfft?md5=cae6b0b92fff7c63a0283b7b0572215a&pid=1-s2.0-S2468024924018187-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Kidney International Reports","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2468024924018187","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"UROLOGY & NEPHROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Introduction
There is an unmet need to understand the mechanisms by which amyloid deposition drives alterations in the kidney. We leveraged renal biopsies from amyloid light-chain (AL) amyloidosis participants of the Renal AL Amyloid Involvement and NEOD00 (RAIN) trial (NCT03168906) to perform transcriptional profiling and to employ a novel histologic scoring tool. Our objective was to utilize a transcriptome-driven approach to identify AL molecular signatures that may be prognostic.
Methods
Clinical data were correlated to histologic and molecular findings. A composite scarring injury and amyloid score (AS) were assigned to each biopsy. Glomerular and tubulointerstitial (TI) compartments were microdissected and sequenced separately. Expression data were compared to healthy living donors and focal segmental glomerulosclerosis (FSGS) profiles. Differentially expressed genes were determined.
Results
Cluster analysis revealed 2 distinct patient clusters (G1 and G2) based on gene expression. The AS was higher in the TI compartment (6.5 vs. 4.5; P = 0.0290) of G2. Glomeruli showed activation of fibrotic pathways and increased canonical signaling of LPS/IL-1. TNF activation was noted in TI. Enriched ingenuity canonical pathways included “coagulation system,” “GADD45 signaling,” and “Wnt/Ca+ pathway,” among others. For AL versus living donors, ingenuity pathway analysis identified enrichment in PI3K/Akt signaling. Gene regulators of cellular proliferation were enriched in the amyloid group.
Conclusion
Despite the small sample size, we identified 2 distinct groups of patients with AL based on molecular signatures. Detailed studies of a larger cohort encompassing omics technologies at a single cell resolution will further help to identify the response of individual kidney cell types to amyloid deposits, potentially leading to the development of novel therapeutic targets.
来自 RAIN(Renal AL Amyloid Involvement and NEOD00)试验的基因表达集和肾脏图谱分析
导言:了解淀粉样蛋白沉积驱动肾脏改变的机制是一项尚未得到满足的需求。我们利用淀粉样轻链(AL)淀粉样变性参与肾AL淀粉样变性和NEOD00(RAIN)试验(NCT03168906)的肾活检组织进行转录组分析,并采用一种新型组织学评分工具。我们的目标是利用转录组驱动的方法来识别可能具有预后意义的 AL 分子特征。对每份活检样本进行瘢痕损伤和淀粉样蛋白综合评分(AS)。对肾小球和肾小管间质(TI)进行显微解剖并分别测序。将表达数据与健康供体和局灶节段性肾小球硬化症(FSGS)概况进行比较。结果聚类分析显示,根据基因表达,有两个不同的患者群(G1 和 G2)。G2患者TI区的AS较高(6.5 vs. 4.5; P = 0.0290)。肾小球显示出纤维化途径的激活和 LPS/IL-1 信号的增加。TI中出现TNF激活。丰富的巧妙典型通路包括 "凝血系统"、"GADD45 信号传导 "和 "Wnt/Ca+ 通路 "等。对于AL与活体供体,萌发通路分析确定了PI3K/Akt信号的富集。尽管样本量较小,但我们根据分子特征确定了两组不同的 AL 患者。在单细胞分辨率下对更大样本群进行包含全息技术的详细研究,将进一步帮助确定单个肾细胞类型对淀粉样蛋白沉积的反应,从而有可能开发出新型治疗靶点。
期刊介绍:
Kidney International Reports, an official journal of the International Society of Nephrology, is a peer-reviewed, open access journal devoted to the publication of leading research and developments related to kidney disease. With the primary aim of contributing to improved care of patients with kidney disease, the journal will publish original clinical and select translational articles and educational content related to the pathogenesis, evaluation and management of acute and chronic kidney disease, end stage renal disease (including transplantation), acid-base, fluid and electrolyte disturbances and hypertension. Of particular interest are submissions related to clinical trials, epidemiology, systematic reviews (including meta-analyses) and outcomes research. The journal will also provide a platform for wider dissemination of national and regional guidelines as well as consensus meeting reports.