Varga Cindy, Eichinger Felix, Nair Viji, Naik Abhijit S, Nasr Samih H, Fogo Agnes B, Toskic Denis, Kretzler Matthias, Comenzo Raymond L
Plasma Cell Disorders Division, Atrium Health Levine Cancer Institute, Charlotte, North Carolina, USA.
Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA.
Kidney Int Rep. 2024 Jul 11;9(9):2786-2797. doi: 10.1016/j.ekir.2024.07.002. eCollection 2024 Sep.
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.
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.
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; = 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.
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.
了解淀粉样蛋白沉积驱动肾脏改变的机制仍存在未满足的需求。我们利用肾脏AL淀粉样变性参与和NEOD00（RAIN）试验（NCT03168906）中淀粉样轻链（AL）淀粉样变性参与者的肾活检进行转录谱分析，并采用一种新的组织学评分工具。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。
将临床数据与组织学和分子学发现相关联。为每个活检标本分配一个复合瘢痕损伤和淀粉样蛋白评分（AS）。对肾小球和肾小管间质（TI）部分进行显微切割并分别测序。将表达数据与健康活体供体和局灶节段性肾小球硬化（FSGS）图谱进行比较。确定差异表达基因。
聚类分析基于基因表达揭示了2个不同的患者聚类（G1和G2）。G2的TI部分的AS更高（6.5对4.5；P = 0.0290）。肾小球显示纤维化途径激活和LPS/IL-1的经典信号增加。TI中观察到TNF激活。富集的 Ingenuity 经典途径包括“凝血系统”、“GADD45信号传导”和“Wnt/Ca+途径”等。对于AL与活体供体，Ingenuity途径分析确定PI3K/Akt信号传导富集。细胞增殖的基因调节因子在淀粉样蛋白组中富集。
尽管样本量小，但我们基于分子特征识别出了2组不同的AL患者。对更大队列进行详细研究，以单细胞分辨率涵盖组学技术，将进一步有助于确定单个肾细胞类型对淀粉样蛋白沉积的反应，可能导致开发新的治疗靶点。
