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

Abstract Introduction Nephrotic syndrome (NS) is a kidney disease that affects both children and adults. Glucocorticoids have been the primary therapy for >60 years, but are ineffective in ∼20% of children and ∼50% of adult patients. Unfortunately, patients with steroid resistant NS (SRNS; vs. steroid sensitive NS, SSNS) are at high risk for both glucocorticoid-induced side effects and disease progression. Methods We performed 1HNMR metabolomic analyses on plasma samples (n=86) from 45 NS patients (30 SSNS and 15 SRNS) obtained at initial disease presentation prior to glucocorticoid initiation and after ∼7 weeks of glucocorticoid therapy to identify candidate biomarkers able to either predict SRNS prior to treatment or define critical molecular pathways/targets regulating steroid resistance. Results Step-wise logistic regression models identified creatinine concentration and glutamine concentration (OR= 1.01; 0.99-1.02 95% CI) as two candidate biomarkers predictive of SRNS, and malonate concentration (OR=0.94; 0.89-1.00 95% CI) as a third candidate predictive biomarker using a similar model (only in children >3 years). In addition, paired sample analyses identified several candidate biomarkers with the potential to identify mechanistic molecular pathways/targets that regulate clinical steroid resistance, including lipoproteins, adipate, pyruvate, creatine, glucose, tyrosine, valine, glutamine and sn-glycero-3-phosphcholine. Conclusion Metabolomic analyses of serial plasma samples from children with SSNS and SRNS identified elevated creatinine and glutamine concentrations, and reduced malonate concentrations, as auspicious candidate biomarkers to predict SRNS at disease onset in pediatric NS, as well as additional candidate biomarkers with the potential to identify mechanistic molecular pathways which may regulate clinical steroid resistance.