Abstract
INTRODUCTION: We aimed to provide evidence for the efficacy of calcineurin inhibitor (CNI) treatment in children with steroid-resistant nephrotic syndrome (SRNS). METHODS: In 278 SRNS children receiving first-line CNI treatment, cumulative remission and kidney failure incidence were estimated using competing risk analysis. Kaplan-Meier and Cox regression analyses were performed to analyze kidney survival, identify predictors of CNI responsiveness and estimate the cumulative incidence of breakthrough proteinuria episodes on or off CNI treatment. The impact of CNI dosage and trough levels on proteinuria was assessed using multivariable linear-mixed effects modeling. RESULTS: Within 6 months of CNI administration, proteinuria was reduced by 84% (interquartile range: 80%-87%) in 219 nongenetic SRNS cases and by 58% (42%-70%) in 59 genetic SRNS cases but returned to pretreatment level in the latter group within 9 to 12 months. Whereas complete remission was observed in 91 of 219 nongenetic SRNS cases (42%) and 6 of 59 genetic SRNS cases (10%), remission was sustained in 53 nongenetic (24%) and 2 genetic (3%) cases only. Proteinuria reduction, but not attainment of complete remission, was associated with the use of higher CNI doses. The cumulative risk of breakthrough proteinuria on CNI treatment was 51% (40%-62%) and 65% (54%-75%) after 12 and 24 months, respectively, in nongenetic SRNS. The postdiscontinuation relapse risk in patients with complete remission was 40% (22%-59%) and 50% (30%-69%) after 12 and 24 months, respectively. Kidney survival in nongenetic SRNS was superior in CNI-responsive children (92% vs. 42% at 15 years), independent of breakthrough proteinuria episodes. CONCLUSION: Our study provides real-world evidence regarding the extent, dynamics, dose-response relationship, and long-term functional impact of CNI therapy in nongenetic and genetic forms of SRNS.