The role of calcineurin inhibitors in monogenic pediatric steroid resistant nephrotic syndrome: a retrospective, multicenter study

Abstract Background and Aims Response to calcineurin inhibitors (CNI) is associated with a significant improvement in long-term kidney survival of children with non-genetic steroid resistant nephrotic syndrome (SRNS). On the contrary, these agents are considered non-efficacious in monogenic SRNS and are contraindicated according to the latest International Pediatric Nephrology Association (IPNA) Clinical Practice Recommendations for SRNS. However, there is evidence suggesting that remission with CNI therapy in this subgroup of children with SRNS is possible, but no studies to date have assessed this question in a systematic way. We aimed to study the incidence of response to CNI in children with monogenic SRNS, factors predictive of remission and the effect of treatment on kidney survival. Method Retrospective cohort study of children 0–18 years with genetically confirmed SRNS treated with a CNI for at least 3 months. Demographic, clinical, genetic, biochemical, histopathologic and treatment data were collected at various time points; at clinical diagnosis, 6, 12, 24 months from CNI onset, and last available follow-up. Pathogenicity of all reported variants was assessed by a dedicated geneticist according to the American College of Medical Genetics guidelines and only patients with a pathogenic genotype were included in the analysis[1]. Patients were classified according to their response to CNI as complete, partial or non-responders based on the IPNA Clinical Practice Recommendations for SRNS[2]. Results 141 patients from 37 international paediatric nephrology centers were included in the study. At 6 months from CNI initiation and at last visit, 27.6% and 22.5%, respectively, demonstrated either complete or partial response (“at least partial response”). Median observation time between CNI initiation and last visit was 42.1 months (IQR 20.1–65.6) and was comparable between patients with no response and at least partial response (42.3 vs 41.6 months; P>0.05). No serious adverse effects mandating treatment discontinuation were reported. Children demonstrating at least partial response at 6 months had a lower risk of progression to kidney failure at last visit versus non-responders (hazard ratio [95%CI] 0.25, [0.10–0.62]; P = 0.003). Subgroup analysis of patients with a follow-up of at least 2 years revealed similar results with a hazard ratio of 0.35 (95%CI 0.14–0.91; P = 0.03). Of the various clinical, biochemical, genetic, histopathologic and treatment parameters tested in a multivariable logistic regression model only higher serum albumin at CNI onset was associated with higher likelihood of response at 6 months (odds ratio [95% CI] 1.16, [1.08–1.24]; P < 0.001). Conclusion Our findings suggest that CNI use could be considered in monogenic SRNS and that achievement of response in this setting can alter an otherwise dismal long-term kidney outcome.