Plasma Cytokine Profiling to Predict Steroid Resistance in Pediatric Nephrotic Syndrome

Shipra Agrawal; Michael E Brier; Bryce A Kerlin; William E Smoyer; Pediatric Nephrology Research Consortium

doi:10.1016/j.ekir.2020.12.027

Plasma Cytokine Profiling to Predict Steroid Resistance in Pediatric Nephrotic Syndrome

Kidney Int Rep. 2021 Jan 6;6(3):785-795. doi: 10.1016/j.ekir.2020.12.027. eCollection 2021 Mar.

Authors

Shipra Agrawal^{1

2}, Michael E Brier^{3

4}, Bryce A Kerlin^{1

2}, William E Smoyer^{1

2}; Pediatric Nephrology Research Consortium

Collaborators

Pediatric Nephrology Research Consortium:
John Mahan, Hiren Patel, Richard F Ransom, Cynthia Pan, Denis F Geary, Myra L Chang, Keisha L Gibson, Franca M Iorember, Patrick D Brophy, Tarak Srivastava, Larry A Greenbaum

Affiliations

¹ Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
² Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
³ Kidney Disease Program, University of Louisville, Louisville, Kentucky, USA.
⁴ Robley Rex Veterans Administration Medical Center, Louisville, Kentucky, USA.

Abstract

Introduction: Glucocorticoids (GCs) are the primary treatment for nephrotic syndrome (NS), although ∼10% to 20% of children develop steroid-resistant NS (SRNS). Unfortunately, there are no validated biomarkers able to predict SRNS at initial disease presentation. We hypothesized that a plasma cytokine panel could predict SRNS at disease presentation, and identify potential pathways regulating SRNS pathogenesis.

Methods: Paired plasma samples were collected from 26 children with steroid-sensitive NS (SSNS) and 14 with SRNS at NS presentation and after ∼7 weeks of GC therapy, when SSNS versus SRNS was clinically determined. Plasma cytokine profiling was performed with a panel of 27 cytokines.

Results: We identified 13 cytokines significantly different in Pretreatment SSNS versus SRNS samples. Statistical modeling identified a cytokine panel (interleukin [IL]-7, IL-9, monocyte chemoattractant protein-1 [MCP-1]) able to discriminate between SSNS and SRNS at disease presentation (receiver operating characteristic [ROC] value = 0.846; sensitivity = 0.643; specificity = 0.846). Furthermore, GC treatment resulted in significant decreases in plasma interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), IL-7, IL-13, and IL-5 in both SSNS and SRNS patients.

Conclusions: These studies suggest that initial GC treatment of NS reduces the plasma cytokines secreted by both CD4⁺ T_H1 cells and T_H2 cells, as well as CD8⁺ T cells. Importantly, a panel of 3 cytokines (IL-7, IL-9, and MCP-1) was able to predict SRNS prior to GC treatment at disease presentation. Although these findings will benefit from validation in a larger cohort, the ability to identify SRNS at disease presentation could greatly benefit patients by enabling both avoidance of unnecessary GC-induced toxicity and earlier transition to more effective alternative treatments.

Keywords: Steroids; biomarkers; cytokines; glucocorticoids; steroid-resistant nephrotic syndrome; steroid-sensitive nephrotic syndrome.

Abstract

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