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

Plasma Cytokine Profiling to Predict Steroid Resistance in Pediatric Nephrotic Syndrome

Shipra Agrawal  1   2 , Michael E Brier  3   4 , Bryce A Kerlin  1   2 , William E Smoyer  1   2 ; Pediatric Nephrology Research Consortium
Collaborators, Affiliations

Plasma Cytokine Profiling to Predict Steroid Resistance in Pediatric Nephrotic Syndrome

Shipra Agrawal et al. Kidney Int Rep. .

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+ TH1 cells and TH2 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.

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Figures

None
Graphical abstract
Figure 1
Figure 1
Hypothesis and study model. Cytokine profile analysis of paired (before [Pre] and after [Post] ∼7 weeks of GC therapy) steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS) plasma samples can be used to identify novel predictive biomarkers and molecular pathways of steroid resistance.
Figure 2
Figure 2
Cytokines predictive of steroid resistance in pretreatment samples. Cytokines found to be significantly different in pretreatment plasma samples between SSNS versus SRNS are shown. These 13 cytokines were identified using univariate analysis and t tests between the pretreatment samples of 26 children with SSNS and 14 children with SRNS, as depicted in Table 3. FGF, fibroblast growth factor; IFN-γ, interferon-γ; IL, interleukin; MCP-1, monocyte chemoattractant protein–1; MIP-1β, macrophage inflammatory protein 1β; SRNS, steroid-resistant nephrotic syndrome; SSNS, steroid-sensitive nephrotic syndrome; TNF-α, tumor necrosis factor α.
Figure 3
Figure 3
ROC curves for sequential models of cytokines to optimize prediction of SRNS. Changes in the ROC values with the progression of the modeling starting with 13 cytokines are shown at 4 steps. ROC values ranged between 0.887 and 0.846 for the full and final models, respectively. Sensitivity ranged from 0.714 to 0.643, and specificity ranged from 0.885 to 0.846. The final, parsimonious, statistically robust model consisted of 3 cytokines, IL-7, IL-9, and MCP-1, which yielded an ROC value of 0.846, with a sensitivity of 0.643 and a specificity of 0.846. IL, interleukin; MCP-1, monocyte chemoattractant protein–1; ROC, receiver operating characteristic; SRNS, steroid-resistant nephrotic syndrome.
Figure 4
Figure 4
Identification of cytokines different between pre- versus post-treatment samples in SSNS versus SRNS. Glucocorticoid treatment resulted in statistically significantly decreased levels of IFN-γ, TNF-α, IL-7, IL-13, and IL-5 among children with both SSNS and SRNS. The plasma levels of these cytokines are shown for 26 children with SSNS (pre- and post-treatment) and 14 children with SRNS (pre- and post-treatment). Notably, the relative differences in pre- and post-treatment levels were statistically similar between those children with SSNS and SRNS as depicted in Table 5. Furthermore, levels of IFN-γ, IL-7, IL-13, and IL-5 were different in both Pre and post-treatment samples in SSNS versus SRNS (Table 5). IFN-γ, interferon-γ; IL, interleukin; SRNS, steroid-resistant nephrotic syndrome; SSNS, steroid-sensitive nephrotic syndrome; TNF-α, tumor necrosis factor α.
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