Challenging Clinical Practice Guideline Definitions in Childhood Nephrotic Syndrome.

KEY POINTS: Three quarters of children with steroid-resistant nephrotic syndrome respond to other immunosuppression and have good kidney outcomes. Children classified as frequently relapsing by International Pediatric Nephrology Association versus Kidney Disease Improving Global Outcomes criteria have similar relapse rates and risk of CKD. These findings support defining treatment resistance by response to any immunosuppression and implementing the International Pediatric Nephrology Association criteria for frequent relapses.

BACKGROUND

In childhood nephrotic syndrome, definitions of immunosuppression response, frequently relapsing nephrotic syndrome (FRNS), and long-term remission are conflicting and based on limited evidence. Our goal was to define treatment response, FRNS, and long-term remission on the basis of associated disease outcomes.

METHODS

We included children (6 months–18 years) diagnosed with nephrotic syndrome between 1993 and 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 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 age at diagnosis, 3.8 years; 63% male; median follow-up, 4.7 years). Among them, 1054 (95%) were steroid sensitive, 60 (5%) were steroid resistant (steroid-resistant nephrotic syndrome [SRNS]), and 73% with SRNS achieved complete remission with steroid-sparing immunosuppression. No child with treatment-responsive SRNS developed CKD. Within 1 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 (versus KDIGO) had a similar number of relapses (adjusted rate ratio, 0.95; 95% confidence interval, 0.81 to 1.12) and CKD risk (2% each) but less often received steroid-sparing immunosuppression (hazard ratio, 0.42; 95% confidence interval, 0.32 to 0.56). Ninety-eight percent of relapses occur within 3 years of the initial diagnosis or the last relapse event.

CONCLUSIONS

Children with SRNS who achieve remission have a similar CKD risk to 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 3-year relapse-free survival as a surrogate for long-term remission.