Document Type

Article

Publication Date

3-2023

Identifier

DOI: 10.1016/j.kint.2022.10.023

Abstract

The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Kidney tissue transcriptomic profile-based clustering identified three patient subgroups with shared molecular signatures across independent, North American, European, and African cohorts. One subgroup had significantly greater disease progression (Hazard Ratio 5.2) which persisted after adjusting for diagnosis and clinical measures (Hazard Ratio 3.8). Inclusion in this subgroup was retained even when clustering was limited to those with less than 25% interstitial fibrosis. The molecular profile of this subgroup was largely consistent with tumor necrosis factor (TNF) pathway activation. Two TNF pathway urine markers were identified, tissue inhibitor of metalloproteinases-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1), that could be used to predict an individual's TNF pathway activation score. Kidney organoids and single-nucleus RNA-sequencing of participant kidney biopsies, validated TNF-dependent increases in pathway activation score, transcript and protein levels of TIMP-1 and MCP-1, in resident kidney cells. Thus, molecular profiling identified a subgroup of patients with either MCD or FSGS who shared kidney TNF pathway activation and poor outcomes. A clinical trial testing targeted therapies in patients selected using urinary markers of TNF pathway activation is ongoing.

Journal Title

Kidney international

Volume

103

Issue

3

First Page

565

Last Page

579

MeSH Keywords

Humans; Glomerulosclerosis, Focal Segmental; Nephrosis, Lipoid; Tissue Inhibitor of Metalloproteinase-1; Nephrology; Nephrotic Syndrome; Tumor Necrosis Factors

Keywords

Humans; Glomerulosclerosis, Focal Segmental; Nephrosis, Lipoid; Tissue Inhibitor of Metalloproteinase-1; Nephrology; Nephrotic Syndrome; Tumor Necrosis Factors

Comments

This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.

Publisher's Link: https://www.kidney-international.org/article/S0085-2538(22)00966-8/fulltext

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