Cyclophosphamide, Calcineurin Inhibitors Equally Effective for Pediatric Nephrotic Syndrome

Cal Robinson, MBChB

Credit: The Hospital for Sick Children (SickKids)

Cyclophosphamide and calcineurin inhibitors are equally efficacious for preventing childhood nephrotic syndrome relapses, according to findings from a recent study.¹

The target trial emulation analysis found no significant difference in time to relapse, relapse rates, subsequent immunosuppression use, or kidney function between the medications, suggesting they are both effective first-line nonsteroid immunosuppressive options for pediatric patients with nephrotic syndrome.¹

Nephrotic syndrome has an estimated annual incidence of 2-7 new cases per 100,000 children less than 18 years of age and is associated with high disease-related and treatment-related morbidity. In children with frequently relapsing or steroid-dependent nephrotic syndrome, alternative immunosuppressive agents are often necessary, including cyclophosphamide, mycophenolate mofetil, calcineurin inhibitors, and levamisole.²

“The comparative effectiveness of cyclophosphamide and calcineurin inhibitors in childhood nephrotic syndrome remains unclear, which is a key knowledge gap,” Cal Robinson, MBChB, a pediatric nephrologist at The Hospital for Sick Children, and colleagues wrote.¹

To address this gap in research, investigators emulated a pragmatic, open-label clinical trial using data from the Insight Into Nephrotic Syndrome: Investigating Genes, Health, and Therapeutics (INSIGHT) study, a multicenter, prospective cohort study in the Greater Toronto Area of Canada. The present analysis included INSIGHT participants 1-18 years of age who were diagnosed with nephrotic syndrome between 1996 and 2019 and who initiated cyclophosphamide or calcineurin inhibitor treatment during follow-up.¹

Investigators noted oral cyclophosphamide was typically administered at a dose of 2 mg/kg daily for 8-12 weeks at INSIGHT centers, adjusted based on weekly blood cell counts. The typical initial tacrolimus trough level target was 3-5 ng/mL, which was increased to 5-7 ng/mL if relapses continued. Target cyclosporine levels were typically 100-200 ng/mL. If effective, calcineurin inhibitors were continued for 2 years before attempted weaning.¹

The primary outcome was time to relapse after cyclophosphamide or calcineurin inhibitor initiation, defined as recurrent nephrotic range proteinuria for ≥ 3 consecutive days. Relapses were detected by home urine monitoring and typically confirmed by laboratory urine testing. Secondary outcomes included relapse rates, subsequent immunosuppression, kidney function, hypertension, adverse events, and quality of life.¹

Participants were followed up until transition to adult services, nephrology clinic discharge after 4-5 relapse-free years, loss to follow-up, or administrative censoring on December 31, 2019.¹

In total, the study included 578 participants with a median age of 3.7 (interquartile range [IQR, 2.8-6.0) years at diagnosis who were primarily male (6.4%). Among the cohort, 252 participants initiated cyclophosphamide, 131 initiated calcineurin inhibitors, and 87 sequentially initiated both medications. After propensity score weighting, investigators noted population overlap was achieved and all baseline covariates were well-balanced.¹

During a median 5.5 years of follow-up, relapses occurred in 180 cyclophosphamide-treated children (71%) versus 115 calcineurin inhibitor-treated children (88%). Upon analysis, there was no significant difference in time to relapse between the treatments (hazard ratio [HR], 1.25; 95% CI, 0.84-1.87). Investigators pointed out there were also no significant differences in relapse count or relapse occurrence by year 1, year 2, or year 5.¹

Further analysis revealed relapses were more common after calcineurin inhibitor treatment than cyclophosphamide (85% vs 73%) in the weighted cohorts, but not statistically significant. There were also no significant differences in subsequent relapse rates, nonsteroid immunosuppression use, or kidney function between medications.¹

Investigators noted calcineurin inhibitor treatment was associated with more hospitalizations (HR, 1.83; 95% CI, 1.14-2.92) and intravenous albumin use (HR, 2.81; 95% CI, 1.65-4.81) than cyclophosphamide.¹

Investigators outlined multiple limitations to these findings, some of which included the fact that most children received cyclophosphamide before calcineurin inhibitors; the limited generalizability for centers that target higher initial tacrolimus trough levels; and the potential for missed relapses.¹

“These findings can inform therapeutic decision-making and patient counseling,” investigators concluded.¹ “The safety, cost, and burden of the 2 medications should be considered when selecting between them, particularly in resource-limited practice settings.”

References

1. ^{Robinson CH, Aman N, Banh T, et al. Comparative Efficacy of Nonsteroid Immunosuppressive Medications in Childhood Nephrotic Syndrome. JAMA Pediatr. doi:10.1001/jamapediatrics.2024.5286}
2. ^{Tapia C, Bashir K. Nephrotic Syndrome. StatPearls. May 29, 2023. Accessed January 27, 2025. https://www.ncbi.nlm.nih.gov/books/NBK470444/}