Challenging Clinical Practice Guideline Definitions in Childhood Nephrotic Syndrome

Background: In childhood nephrotic syndrome, definitions of immunosuppression response, frequent relapses (FRNS), and long-term remission are conflicting and based on limited evidence. Our goal was to define treatment response, FRNS, and long-term remission based on associated disease outcomes. Methods: We included children (six months-18 years) diagnosed with nephrotic syndrome between 1993-2023 in combined Canadian cohorts. We evaluated different definitions of 1) immunosuppressive treatment response, 2) FRNS, including Kidney Disease Improving Global Outcomes (KDIGO) 2021 and International Pediatric Nephrology Association (IPNA) 2023 criteria, and 3) long-term remission. Outcomes were time-to-chronic kidney disease (CKD), relapse count throughout follow-up, and time-to-relapse, analyzed by Cox proportional hazards and negative binomial regression. Results: We included 1114 children with nephrotic syndrome (median 3.8-years at diagnosis, 63% male, median 4.7-year follow-up). Of these, 1054 (95%) were steroid-sensitive, 60 (5%) were steroid-resistant (SRNS), and 73% with SRNS achieved complete remission with steroid-sparing immunosuppression. No child with treatment-responsive SRNS developed CKD. Within one-year of diagnosis, 281 steroid-sensitive children (27%) were classified with FRNS by KDIGO and 383 (36%) by IPNA criteria. Children with FRNS by IPNA criteria (vs. KDIGO) had a similar number of relapses (adjusted rate ratio 0.95, 95% confidence interval [CI] 0.81-1.12) and CKD risk (2% each) but less often received steroid-sparing immunosuppression (hazard ratio 0.42, 95% CI 0.32-0.56). Ninety-eight percent of relapses occur within three-years of the initial diagnosis or last relapse event. Conclusions: Children with SRNS that achieve remission have a similar CKD risk as steroid-sensitive children. Children with FRNS by IPNA 2023 and KDIGO 2021 criteria experience similar rates of relapse and CKD. This supports defining treatment resistance by response to any immunosuppressive medication, implementation of the IPNA FRNS criteria, and use of three-year relapse-free survival as a surrogate for long-term remission.