Evaluation of Daily Low-Dose Prednisolone During Upper Respiratory Tract Infection to Prevent Relapse in Children With Relapsing Steroid-Sensitive Nephrotic Syndrome

Abstract

IMPORTANCEIn children with corticosteroid-sensitive nephrotic syndrome, many relapses are triggered by upper respiratory tract infections. Four small studies found that administration of daily low-dose prednisolone for 5 to 7 days at the time of an upper respiratory tract infection reduced the risk of relapse, but the generalizability of their findings is limited by location of the studies and selection of study population.OBJECTIVE To investigate the use of daily low-dose prednisolone for the treatment of upper respiratory tract infection-related relapses.DESIGN, SETTING, AND PARTICIPANTS This double-blind, placebo-controlled randomized clinical trial (Prednisolone in Nephrotic Syndrome [PREDNOS] 2) evaluated 365 children with relapsing steroid-sensitive nephrotic syndrome with and without background immunosuppressive treatment at 122 pediatric departments in the UK from February 1, 2013, to January 31, 2020. Data from the modified intention-to-treat population were analyzed from July 1, 2020, to December 31, 2020.INTERVENTIONS At the start of an upper respiratory tract infection, children received 6 days of prednisolone, 15 mg/m 2 daily, or matching placebo preparation. Those already taking alternate-day prednisolone rounded their daily dose using trial medication to the equivalent of 15 mg/m 2 daily or their alternate-day dose, whichever was greater. MAIN OUTCOMES AND MEASURESThe primary outcome was the incidence of first upper respiratory tract infection-related relapse. Secondary outcomes included overall rate of relapse, changes in background immunosuppressive treatment, cumulative dose of prednisolone, rates of serious adverse events, incidence of corticosteroid adverse effects, and quality of life. RESULTSThe modified intention-to-treat analysis population comprised 271 children (mean [SD] age, 7.6 [3.5] years; 174 [64.2%] male), with 134 in the prednisolone arm and 137 in the placebo arm. The number of patients experiencing an upper respiratory tract infection-related relapse was 56 of 131 (42.7%) in the prednisolone arm and 58 of 131 (44.3%) in the placebo arm (adjusted risk difference, −0.02; 95% CI, −0.14 to 0.10; P = .70). 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. A post hoc subgroup analysis assessing the primary outcome in 54 children of South Asian ethnicity (risk ratio, 0.66; 95% CI, 0.40-1.10) vs 208 children of other ethnicity (risk ratio, 1.11; 95% CI, 0.81-1.54) found no difference in efficacy of intervention in those of South Asian ethnicity (test for interaction P = .09). CONCLUSIONS AND RELEVANCEThe results of PREDNOS 2 suggest that administering 6 days of daily low-dose prednisolone at the time of an upper respiratory tract infection does not reduce the risk of relapse of nephrotic syndrome in children in the UK. Further work is needed to investigate interethnic differences in treatment response.

Pulmonary surfactants and the respiratory-renal connection in steroid-sensitive nephrotic syndrome of childhood

“…This would suggest that steroids while they are effective in accelerating podocyte recovery and achieve remission, oral steroids may not block the initial triggering mechanism. This is consistent with a recent double blind clinical trial which concluded that oral steroids do not reduce the risk of new relapses in patients with MCD with upper respiratory tract infections (Christian et al, 2022).…”

IPNA clinical practice recommendations for the diagnosis and management of children with steroid-sensitive nephrotic syndrome

“…The PREDNOS 2 RCT [ 82 ], which was adequately powered, generalizable to the overall SSNS population, and at low risk of bias, evaluated 271 children with NS and URTI. The study found no benefit of administering five days of low dose PDN (15 mg per m 2 BSA which is equivalent to 0.5 mg/kg) at the onset of URTI in preventing relapse.…”

Economic Evaluation of Using Daily Prednisolone versus Placebo at the Time of an Upper Respiratory Tract Infection for the Management of Children with Steroid-Sensitive Nephrotic Syndrome: A Model-Based Analysis

“…To our knowledge, this is the first model-based economic evaluation to explore the cost effectiveness of 6-day lowdose prednisolone at the time of a URTI in a UK population. A strength of the study is that it used data from the largest ever clinical trial of an investigational medicinal product in children with nephrotic syndrome [14]. The study used a Markov model to capture disease progression and perform the cost-utility analysis; Markov models account for the repetitive nature of events while handling concomitant treatment consequences on both costs and health outcomes [30].…”

“…A multicentre, placebo-controlled, randomised controlled trial (PREDNOS2) recently reported that administering daily low-dose prednisolone at the time of a URTI leads to no reduction in URTI-associated relapse [14]. However, it is still unknown if this leads to a cost-effective use of public resources, therefore the objective of this study was to conduct an economic evaluation using the data from the PREDNOS2 trial [15].…”