Daily low-dose prednisolone for six days at the time of upper respiratory infection in children with relapsing corticosteroid-sensitive nephrotic syndrome did not reduce the risk of relapse of nephrotic syndrome, according to results from the Prednisolone in Nephrotic Syndrome 2 (PREDNOS 2) study, published in JAMA Pediatrics.
“Steroid-sensitive nephrotic syndrome (SSNS) is the most common glomerular disease of childhood, with an incidence of approximately two per 100,000 children, although it is up to six times more common in children of South Asian ethnic origin. At least 80% of children with SSNS will relapse, and relapses are associated with a risk of significant complications, including sepsis, thrombosis, dyslipidemia, and malnutrition. At least 50% of relapses follow intercurrent infections, most commonly upper respiratory tract infections (URTIs); furthermore, in children with relapsing SSNS, half or more URTIs will trigger a relapse,” wrote Martin T. Christian, MD, of the Nottingham Children’s Hospital, Nottingham, U.K., and colleagues.
“Previous research in Saudi Arabia, Sri Lanka, and India has suggested that giving low-dose daily prednisolone for 5 to 7 days when a URTI is diagnosed reduces the risk of an ensuing relapse,” they added.
In this double-blind, placebo-controlled, randomized trial, Christian and colleagues sought to assess the use of daily low-dose prednisolone for the treatment of URTI-related relapses in 271 children (mean age: 7.6 years; 64.2% boys) with relapsing corticosteroid-sensitive nephrotic syndrome in their modified intention-to-treat analysis.
Most children were White (67%-72% of both groups), while 20%-22% were South Asian. Mean age at diagnosis of nephrotic syndrome was roughly 2.5 to 4 years. Among children treated with prednisolone, 30.0% were on long-term maintenance prednisolone, as were 24.8% of those in the placebo group; 32.1% and 35.0%, respectively, were on other immunosuppressant therapy plus long-term maintenance prednisolone; and 14.9% and 17.5% were on other immunosuppressant therapy only.
At the beginning of URTI, children were given prednisolone for six days (15 mg/m2 daily; n=134) or placebo (n=137). Children already receiving alternate-day prednisolone were given the greater of rounded doses to the equivalent of 15 mg/m2 daily or their alternate-day dose.
Researchers defined URTI as the presence of at least two of the following symptoms for at least 24 hours: sore throat, ear pain or discharge, runny nose, cough, hoarseness, or body temperature >37° C (98.6° F). The children were followed for 12 months, with three-month hospital outpatient visits.
The primary outcome of the study was the incidence of first URTI-related relapse, and secondary outcomes included overall relapse rates, changed immunosuppressive treatment, cumulative prednisolone dose, serious adverse event rates, adverse effects of corticosteroids, and quality of life.
In all, there were 384 URTIs and 82 URTI-related relapses in children treated with prednisolone, and 407 URTIs and 82 URTI-related relapses in those treated with placebo. Thus, infection-related relapse occurred in 42.7% of children in the prednisolone arm, compared with 44.3% of those in the placebo arm (adjusted risk difference: −0.02; 95% CI: −0.14 to 0.10; P=0.70).
In a post-hoc analysis of a subgroup of 54 children of South Asian ethnicity who had a risk ratio of 0.66, compared with 208 children of other ethnicities (risk ratio: 1.11), researchers also found no difference in the efficacy of prednisolone (test for interaction P=0.09).
“No evidence was found that the treatment effect differed according to background immunosuppressive treatment. No significant differences were found in secondary outcomes between the treatment arms,” wrote Christian and fellow researchers.
Indeed, there were 216 relapses in 91 children treated with prednisolone compared with 237 relapses in 98 children treated with placebo (adjusted risk difference: −0.05; 95% CI: −0.16 to 0.06; P=0.33). Background treatment was escalated at least once in 44.6% of children in the prednisolone arm, compared with 44.5% of those in the placebo arm (P=0.96). Median cumulative doses of prednisolone were 2,060 mg and 1,880 mg, respectively (P=0.72), and at least one treatment reduction was required in 43.0% compared with 48.1% (P=0.42). No significant differences were seen in either the number of serious adverse events or corticosteroid adverse effects, or in behavior scores.
“The findings do not support the conclusions of 4 previously published trials, which reported a benefit of daily prednisolone therapy at the time of URTI. However, these previous studies have methodologic issues, such as lack of blinding, small sample size, postrandomization exclusions, and crossover design. These issues limit the impact of these studies, leading to the latest Cochrane review concluding that ’clinicians are unlikely to use this regimen without additional data to confirm its efficacy and safety,’” noted Christian et al.
However, they also noted a limitation in their trial.
“In contrast to previous studies, we did not review and examine children at the time of their URTI, and it is possible that some excluded children had experienced URTIs that were not captured within the trial definition. If we had made a type 2 error by failing to find a significant result that is present, we would have expected to see an increased number of relapses. However, the small increase in patients experiencing any relapses in the placebo arm was non-significant.”
In the end, Christian et al concluded that more studies are needed.
“In the largest ever clinical trial, to our knowledge, of an investigational medicinal product in children with nephrotic syndrome, for a nonselected population of children with relapsing SSNS, PREDNOS 2 found no benefit to a short course of daily low-dose prednisolone at the time of a URTI. The size of the trial is larger than all previous studies combined and is therefore likely to change the Cochrane meta-analysis on this issue. Further work is needed to investigate interethnic differences in treatment response and the pathogenesis of individual viral infections and their effect on nephrotic syndrome,” they wrote.
In the randomized clinical PREDNOS 2 trial, daily low-dose corticosteroid therapy resulted in no difference in the frequency of upper respiratory tract infection–related relapses in nephrotic syndrome compared with placebo.
Results of this trial contradict those from four, small, previous studies that found that predisolone did reduce relapse risks in this patient population.
Liz Meszaros, Deputy Managing Editor, BreakingMED™
This project was funded by the NIHR Health Technology Assessment program.
Christian reported serving as a member of the Clinical Practice Guideline Group for Steroid Sensitive Nephrotic Syndrome of the International Pediatric Nephrology Association during the conduct of the study.
Cat ID: 138
Topic ID: 85,138,730,138,192,653,155,925