Two Non-Steroid Options for Childhood Nephrotic Syndrome Show Similar Benefits

For children with nephrotic syndrome, there was no difference in time to relapse between two commonly used non-steroid immunosuppressive medications, according to an observational study that emulated a pragmatic trial.

Among nearly 600 children, there was no significant difference in time to relapse between those taking a calcineurin inhibitor compared with those taking cyclophosphamide (HR 1.25, 95% CI 0.84-1.87, P=0.30) over a median follow-up of 5.5 years, reported Cal H. Robinson, MBChB, of the SickKids Research Institute in Toronto, and colleagues.

Although relapses were numerically higher with calcineurin inhibitors than cyclophosphamide in the weighted cohorts (85% vs 73%), the difference wasn’t statistically significant, the researchers wrote in JAMA Pediatrics.

There were also no significant differences in mean annualized estimated glomerular filtration rate slope, any subsequent steroid-sparing medication use, infection, antihypertensive medication use, and pediatric quality of life score between the two medications, but 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). Hospitalizations most commonly occurred within the first year of calcineurin inhibitor treatment, and 71% of hospitalized children relapsed prior to the hospitalization.

“Nephrotic syndrome is the most common kidney disease managed by pediatricians worldwide and is associated with high disease-related and treatment-related morbidity,” Robinson’s group wrote. “Nephrotic syndrome is treated initially and at each relapse with steroid immunosuppression. Currently, approximately 90% of children are steroid sensitive, but most relapse and receive repeated steroid courses.”

Because of this, half of all children with nephrotic syndrome receive non-steroid immunosuppressive medications in order to prevent relapse.

Robinson and co-authors pointed out that current guidelines recommend both cyclophosphamide and tacrolimus, but no randomized clinical trials have ever directly compared the two, largely due to “the anticipated sample size, costs, and patient and physician medication preferences.”

“This is a global health concern, since higher drug cost, limited access, and laboratory surveillance burden are major barriers to calcineurin inhibitor use in resource-limited healthcare systems,” they wrote.

“Cyclophosphamide is typically administered daily for 8 to 12 weeks, whereas calcineurin inhibitors are given for longer than 1 to 2 years with regular laboratory and therapeutic drug monitoring,” they noted. “Despite concerns about long-term infertility and cancer risks after cyclophosphamide treatment, it remains one of the most commonly prescribed immunosuppressive medications worldwide.”

As for cost differences, 2 years of tacrolimus and cyclosporine treatment are estimated to be $1,319 and $1,561, respectively, while 8 weeks of cyclophosphamide is $19 for a 44-lb child in the U.S.

Because time to relapse was similar between the two treatments, the researchers said cyclophosphamide came out on top as the preferred first-line non-steroid immunosuppressive medication due to its lower cost, shorter duration, and greater global accessibility versus calcineurin inhibitors.

For this study, the researchers emulated a pragmatic, open-label clinical trial using available data from the multicenter, prospective cohort Insight Into Nephrotic Syndrome: Investigating Genes, Health, and Therapeutics (INSIGHT) study in the greater Toronto area.

They included 578 children with steroid-sensitive nephrotic syndrome diagnosed from 1996 to 2019. Median age at diagnosis was 3.7 years, and 64% were boys. Of these patients, 252 initiated cyclophosphamide, 131 initiated calcineurin inhibitors, and 87 initiated both medications sequentially.

Cyclophosphamide was consistently used during the study period, but cyclosporine was the only calcineurin inhibitor used before 2004 and tacrolimus was most common after 2004. Median treatment duration was 9 weeks for cyclophosphamide and 2.3 years for calcineurin inhibitors.

Incidence of chronic kidney disease was low, occurring in 2.4% and 5.3% of the cyclophosphamide and calcineurin inhibitor groups, respectively.

One limitation of the trial emulation was that most children received cyclophosphamide before calcineurin inhibitors. Those who received both medications were included in both arms, with separate propensity scores calculated using updated covariates, the researchers noted. Also, some relapses may have been missed if home urine monitoring wasn’t performed and spontaneous remission occurred, or if a relapse treated at another clinical center wasn’t documented.

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