Clinical and Apoptotic Factors Defining and Predicting Steroid Resistance in Nephrotic Syndrome in Children

Abstract

Background. Nephrotic syndrome (NS) is a kidney disease characterized by albuminuria, hyperlipidemia, edema, and hypoalbuminemia. Recent data shown that more than 80% of children with nephrotic syndrome respond to steroid treatment, remain steroid-sensitive during subsequent relapses, and consequently have a favorable long-term prognosis. However, above 20 % of nephrotic children do not show response to steroid treatment. Steroid resistance is believed to be associated with a high risk of developing chronic renal failure. Recent reports suggest different clinical, genetic and molecular markers to be accompanied with phenomenon of steroid resistance. However, molecular markers controlling apoptosis have not been studied as a predictors of steroid resistant NS (SRNS) and steroid sensitive NS (SSNS).Aim of the study. To identify clinical and molecular markers which define and predict the steroid-resistance phenomenon in children with NS.Methods. We analyzed 56 clinical cases of children hospitalized in Pediatric Hospital №7 (Kyiv, Ukraine) with NS (26 SSNS and 30 SRNS). Clinical data (age, gender, disease duration, blood pressure), conventional laboratory markers (serum creatinine, serum urea, serum cholesterol, GFR, proteinuria, blood WBC, PLT, RBC), markers of apoptosis (Bax, BcL-xL, caspase-3, caspase-8), transcriptional factors (NF-kB, HIF-1alfa, Mn-SOD) analyzed. Stepwise logistic regression models use to identify candidates with the potential to be related to have influence of steroid resistance in children with NS. Data processed using GraphPad Prism 9.0 Software for Windows (USA, San Diego, CA).Results. Stepwise logistic regression models identified arterial hypertension as a candidate among clinical characteristics (β - 0,31, SE 0.15, 95% CI -0.6 to -0.007, p<0.05) as a candidate predictive of SRNS. Among basic laboratory factors WBC level (OR: 1.4; OR 95% CI: 1.12–1.85) and RBC level (OR: 1.14; OR 95% CI: 0.38–3.48), serum creatinine (OR: 1.04; OR 95% CI: 0.92–1.14), serum urea (OR: 1.14; OR 95% CI: 0.89–1.49), serum cholesterol (OR: 1.97; OR 95% CI: 1.37–3.18) were found to be a factors defining SRNS.Apoptosis regulating BcL-xL (OR: 1.4; OR 95% CI: 1.17–1.91), Bax (OR: 1.15; OR 95% CI: 1.04–1.37), caspase-3 (OR: 1.66; OR 95% CI: 1.27–2.68) but not caspase-8 (OR: 0.95; OR 95% CI: 0.84–1.05) (AUC: 0.93; SE: 0.03; 95% CI: 0.87-0.99; p<0.001) found to be those defining SRNS. Finally, in group of transcriptional factors HIF-1alfa selected as a factor defining steroid resistance phenomenon (OR: 1.02; OR 95% CI: 0.98–1.07).For SSNS group significant negative correlation was observed between BcL-xL and Bax, BcL-xL and caspase-3, significant positive correlation was observed between marker of cellular hypoxia HIF-1alfa and proapoptotic factor caspase-3.For SRNS group significant negative correlation was observed between BcL-xL and Bax, BcL-xL and caspase-3 level, significant positive correlation was observed between HIF-1alfa and proapoptotic factor caspase-3.Conclusion. Arterial hypertension, serum creatinine level, serum urea level, serum cholesterol level, WBC and RBC count, BcL-xL, Bax, caspase-3 and HIF-1alfa indentified as candidate biomarkers to predict and define SRNS in pediatric NS.