Predicting and Defining Steroid Resistance in Pediatric Nephrotic Syndrome Using Plasma Metabolomics

Gooding, Jessica; Agrawal, Shipra; McRitchie, Susan; Acuff, Zach; Merchant, Michael L.; Klein, Jon B.; Smoyer, William E.; Sumner, Susan; Mahan, John D.; Patel, Hiren P.; Ransom, Richard F.; Pan, Cynthia G.; Geary, Denis F.; Chang, Myra L.; Gibson, Keisha; Iorember, Franca M.; Brophy, Patrick D.; Srivastava, Tarak; Greenbaum, Larry A.

doi:10.1016/j.ekir.2019.09.010

Cited by 32 publications

(42 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As has been reported previously, children with SRNS presented at a later age than from those with SSNS (9.5 vs. 5.7 years; P = 0.004). 14 , 17 , 24 As expected, this difference in age was also reflected in significant differences in height and weight between the 2 cohorts ( P < 0.001, see Table 2 ). Moreover, although the SSNS cohort comprised 23% African Americans and 42% Caucasians, the SRNS cohort comprised 43% of each, thus reflecting a significantly greater incidence of SRNS in African American children ( P = 0.001).…”

Section: Resultssupporting

confidence: 74%

“…Although we utilized statistical analyses of the cytokine profiles generated from plasma samples of children with SSNS and SRNS to answer these questions in the present study, we and others have also made other efforts toward the same goal using proteomic, metabolomic, and transcriptomic approaches to identify additional interesting candidates that are either predictive of SRNS or molecularly associated with SRNS. 14 , 15 , 16 , 17 , 18 Over the past few years, serum concentrations of a few cytokines have been associated with relapse in NS. For example, elevated serum levels of IL-8 have been associated with NS relapse, and anti-IL8 antibodies have been shown to neutralize the ability of peripheral blood mononuclear cell culture supernatant to induce albuminuria in rats.…”

Section: Discussionmentioning

confidence: 99%

“…To try to better identify those patients highly unlikely to respond to GC, and thus avoid its unnecessary toxicity, a few studies have tried to identify urinary, plasma, and salivary biomarkers for SRNS in children using cytokine profiling and omics approaches such as proteomics, metabolomics, and transcriptomics. 8 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 As a result, recently T lymphocytes expressing inflammatory cytokines and macrophage migration inhibitory factor in plasma, and MCP-1 in urine have been implicated in persistent proteinuria and SRNS in childhood NS. 8 , 19 , 20 However, despite these efforts, we still lack understanding of the molecular mechanisms regulating GC resistance in NS, and there remain no plasma or urine biomarkers that have been validated to reliably predict GC resistance in NS prior to initiation of GC therapy.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Plasma Cytokine Profiling to Predict Steroid Resistance in Pediatric Nephrotic Syndrome

Agrawal

Brier

Kerlin

et al. 2021

Kidney International Reports

Self Cite

View full text Add to dashboard Cite

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 H 1 cells and T H 2 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.

show abstract

Section: Resultssupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Plasma Cytokine Profiling to Predict Steroid Resistance in Pediatric Nephrotic Syndrome

Agrawal

Brier

Kerlin

et al. 2021

Kidney International Reports

Self Cite

View full text Add to dashboard Cite

show abstract

“…Genetics are known to play a role in steroid-responsiveness (Adeyemo et al, 2018;Asharam et al, 2018;Govender et al, 2019;Gribouval et al, 2018Gribouval et al, , 2019. However, while genetic and other mechanisms underlying steroid-responsiveness in this small cohort were not evaluated in the present study, they have been the subject of previously reported biomarker studies (Agrawal et al, 2020;Gooding et al, 2020). Importantly, none of the children in this small cohort were diagnosed with venous thromboembolism, which occurs in ~3% of childhood NS cases (Kerlin et al, 2012a).…”

Section: Hypercoagulopathy Improves In Children With Steroid-sensitmentioning

confidence: 74%

Nephrotic syndrome‐associated hypercoagulopathy is alleviated by both pioglitazone and glucocorticoid which target two different nuclear receptors

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background: Thrombosis is a potentially life-threatening nephrotic syndrome (NS) complication. We have previously demonstrated that hypercoagulopathy is proportional to NS severity in rat models and that pioglitazone (Pio) reduces proteinuria both independently and in combination with methylprednisolone (MP), a glucocorticoid (GC). However, the effect of these treatments on NS-associated hypercoagulopathy remains unknown. We thus sought to determine the ability of Pio and GC to alleviate NS-associated hypercoagulopathy. Methods: Puromycin aminonucleoside-induced rat NS was treated with sham, Lowor High-dose MP, Pio, or combination (Pio + Low-MP) and plasma was collected at day 11. Plasma samples were collected from children with steroid-sensitive NS (SSNS) and steroid-resistant NS (SRNS) upon presentation and after 7 weeks of GC therapy. Plasma endogenous thrombin potential (ETP), antithrombin (AT) activity, and albumin (Alb) were measured using thrombin generation, amidolytic, and colorimetric assays, respectively. Results: In a rat model of NS, both High-MP and Pio improved proteinuria and corrected hypoalbuminemia, ETP and AT activity (p < .05). Proteinuria (p = .005) and hypoalbuminemia (p < .001) were correlated with ETP. In childhood NS, while ETP was not different at presentation, GC therapy improved proteinuria, hypoalbuminemia, and ETP in children with SSNS (p < .001) but not SRNS (p = .330). Conclusions: Both Pio and GC diminish proteinuria and significantly alleviate hypercoagulopathy. Both Pio and MP improved hypercoagulopathy in rats, and successful GC therapy (SSNS) also improved hypercoagulopathy in childhood NS. These data suggest that even a partial reduction in proteinuria may reduce NS-associated thrombotic risk. How to cite this article: Waller AP, Agrawal S, Wolfgang KJ, et al. Nephrotic syndrome-associated hypercoagulopathy is alleviated by both pioglitazone and glucocorticoid which target two different nuclear receptors.

show abstract

“…These logistic regression findings suggest additional studies on the mechanistic candidate biomarkers are justified. Notably, this same group of patient samples has also undergone plasma metabolomics analyses, 46 and future studies will benefit from identification of additional relevant molecular pathways and biomarkers of SRNS using approaches that integrate the proteomics and metabolomics datasets.…”

Section: Resultsmentioning

confidence: 99%

Predicting and Defining Steroid Resistance in Pediatric Nephrotic Syndrome Using Plasma Proteomics

Agrawal

Merchant

Kino

et al. 2020

Kidney International Reports

Self Cite

View full text Add to dashboard Cite

Introduction: Nephrotic syndrome (NS) is a characterized by massive proteinuria, edema, hypoalbuminemia, and dyslipidemia. Glucocorticoids (GCs), the primary therapy for >60 years, are ineffective in approximately 50% of adults and approximately 20% of children. Unfortunately, there are no validated biomarkers able to predict steroid-resistant NS (SRNS) or to define the pathways regulating SRNS. Methods: We performed proteomic analyses on paired pediatric NS patient plasma samples obtained both at disease presentation before glucocorticoid initiation and after approximately 7 weeks of GC therapy to identify candidate biomarkers able to either predict steroid resistance before treatment or define critical molecular pathways/targets regulating steroid resistance. Results: Proteomic analyses of 15 paired NS patient samples identified 215 prevalent proteins, including 13 candidate biomarkers that predicted SRNS before GC treatment, and 66 candidate biomarkers that mechanistically differentiated steroid-sensitive NS (SSNS) from SRNS. Ingenuity Pathway Analyses and protein networking pathways approaches further identified proteins and pathways associated with SRNS. Validation using 37 NS patient samples (24 SSNS/13 SRNS) confirmed vitamin D binding protein (VDB) and APOL1 as strong predictive candidate biomarkers for SRNS, and VDB, hemopexin (HPX), adiponectin (ADIPOQ), sex hormone-binding globulin (SHBG), and APOL1 as strong candidate biomarkers to mechanistically distinguish SRNS from SSNS. Logistic regression analysis identified a candidate biomarker panel (VDB, ADIPOQ, and matrix metalloproteinase 2 [MMP-2]) with significant ability to predict SRNS at disease presentation (P ¼ 0.003; area under the receiver operating characteristic curve ¼ 0.78). Conclusion: Plasma proteomic analyses and immunoblotting of serial samples in childhood NS identified a candidate biomarker panel able to predict SRNS at disease presentation, as well as candidate molecular targets/pathways associated with clinical steroid resistance.

show abstract

Predicting and Defining Steroid Resistance in Pediatric Nephrotic Syndrome Using Plasma Metabolomics

Cited by 32 publications

References 40 publications

Plasma Cytokine Profiling to Predict Steroid Resistance in Pediatric Nephrotic Syndrome

Plasma Cytokine Profiling to Predict Steroid Resistance in Pediatric Nephrotic Syndrome

Nephrotic syndrome‐associated hypercoagulopathy is alleviated by both pioglitazone and glucocorticoid which target two different nuclear receptors

Predicting and Defining Steroid Resistance in Pediatric Nephrotic Syndrome Using Plasma Proteomics

Contact Info

Product

Resources

About