Most patients with steroid sensitive nephrotic syndrome show highly satisfactory renal outcomes [2]. While morbidity due to infections has declined with rapid diagnosis and use of vaccines, toxicities associated with repeated course of corticosteroids remain a major concern in managing patients with frequent relapses or steroid dependence. While the International Study for Kidney Diseases in Children (ISKDC) arbitrarily proposed that the initial corticosteroid therapy comprise of 4-weeks daily followed by 4-weeks intermittent therapy, refinements have been proposed over the last four decades. A randomized controlled trial in 1993 showed reduced relapse rates on prolonging therapy from 8 to 12 weeks [3]. Further randomized studies confirmed these findings and suggested that extending initial therapy to 6-months was even better. Results from a Cochrane meta-analysis showed that therapy for 6-months versus 3-months was associated with reduced risk of frequent relapses (RR 0.55; 95% CI 0.39,0.80) and fewer relapses per year. The review suggested an inverse relationship between the risk for relapse and duration of induction therapy, such that the relative risk for relapse at 12-24 months would fall by 11% of baseline relapse rate for every one month increase in duration of therapy from 2-7 months [4]. While studies included in the analysis had methodological concerns, the results unequivocally suggested that (i) 12-weeks therapy was better than 8-weeks, and (ii) therapy could be extended to 6-months with further benefits in rates of sustained remission and reduced frequency of relapses.

Results from these three studies that enrolled almost 600 patients on two continents emphasize that prolongation of initial therapy to 6 months is not useful in modifying the course of the disease, or reducing subsequent needs for corticosteroids and steroid-sparing agents. The Indian study, but not the others, showed that the benefit of extended initial therapy was limited to the period while the steroids were being administered [1,5,6]. Since the intent of intensification of therapy is to alter the disease course rather than delaying the first relapse, lower rates of relapses during steroid tapering alone should not lead to consideration of prolonged therapy. Furthermore, the benefits of therapy prolongation should be balanced against the risk of corticosteroid adverse effects. Given the current data, prolongation of initial therapy beyond that proposed by the ISKDC [2] and the APN [4] is perhaps not justified. Recommendations of the Indian Society of Pediatric Nephrology [7], Kidney Diseases Improving Global Outcomes [8] and the Canadian Society of Pediatric Nephrology [9] are likely to remain unchanged in endorsing 12 weeks therapy for the initial episode of nephrotic syndrome.

Aditi Sinha and Arvind Bagga

In clinical practice, the major challenge in treating nephrotic syndrome is to reduce the rate of relapses and minimize the adverse effects of steroid therapy. While there seems to be new evidence that supports the hypothesis that initial duration of steroid therapy has limited impact on relapse rates, a few essential points need to be considered at this juncture. First, the interpretation of relapses in most studies is based on follow up period of 12-24 months, which is relatively a short time span compared to the well-known highly variable clinical course of nephrotic syndrome that lasts for more than a decade. The impact of initial cumulative dose of steroid therapy, besides the duration, needs further evaluation. Second, it would be essential to consider the baseline rate of relapse in a particular community, as most relapses are triggered by infections that may be independent of the duration or dose of initial steroid therapy. Third, we need clarity on the precise effect of age of the child at onset of nephrotic syndrome, on the occurrence of relapses. To conclude, though we may not be ready with a recommendation, we are encouraged to be conscious of the fact that intentional prolongation of initial steroid therapy, though may not predispose to higher steroid toxicity, may not be as beneficial as we believed it to be, in reducing relapse rates in nephrotic syndrome.

Arpana Iyengar

Critical appraisal: Two angles need exploration viz (i) appraisal of the trial itself, and (ii) contextualizing the evidence from this trial, in terms of the clinical question viz what is the optimal steroid regimen in children with NS?

In terms of methodological quality, the trial utilized an adequate method for generation of randomization sequence. Allocation concealment was not described and blinding was absent. Of 255 enrolled children, the authors could report outcomes in 246 with comparable loss in both groups. Unlike most such trials, the authors chose a non-inferiority design with its associated (appropriate) calculation of sample size. They chose risk ratio of time to frequently relapsing NS (FRNS) as the primary outcome, rather than the more commonly presented frequency of relapses or FRNS. Standard definitions were used for the various conditions. Steroid adverse effects were comparable between the groups, generally occurred early, and were transient. The authors concluded that this indicates that the shorter duration could be recommended since it delivers a lower total dose. However, this conclusion is not supported by the data in the trial. The meta-analysis presented as a Supplement contains some methodological errors (incorrect data entry), hence need not be considered.

This necessitates a fresh look at the available evidence. As 3 months therapy is the current recommended standard of care [7-9,15], the following comparisons of efficacy are meaningful: (i) 3 months therapy versus >3 months; (ii) 3 months versus 2 months; and (iii) 2 months versus >2 months. It is also important to compare trials using the same dose (over different durations) as well as same duration (with different doses). Therefore, a fresh systematic review was undertaken searching PubMed and the Cochrane Library. Two sets of searches were conducted through PubMed using the terms: "(nephrotic syndrome) AND steroid" with filters: Meta-Analysis, Systematic Reviews, Randomized Controlled Trial, Child: birth-18 years; and "(nephrotic syndrome) AND steroid AND duration" without any filters. The Cochrane Library was searched using the term "nephrotic syndrome" without any filters. Seventeen trials [1,12-27] were identified that compared different durations and/or dose of prednisolone therapy and evaluated relapse as an outcome over a period of at least 12 months follow-up (Web Table I). One trial [27] comparing 12 months versus 5 months therapy was not included.

Summary of the meta-analyses of efficacy (risk ratio, random effects model) is presented in Table I, showing that therapy >3 months (with higher steroid dose) is more efficacious than 3 months. Limited data suggest that longer duration or higher dose alone did not make a difference. Therapy for 3 months was comparable to 2 months (with or without higher total dose). When therapy >2 months was compared against 2 months, the former appeared more efficacious. These findings are contrary to the results in Yoshikawa’s trial [1]. While the overall results are in agreement with the outdated Cochrane review [4], the assertion therein that longer duration rather than higher dose is responsible for greater efficacy [4,15], could not be substantiated. However, it should be remembered that the quality of individual trials in the meta-analysis leaves a lot to be desired.

TABLE I Summary Of Meta-Analyses

Fig 1A Comparison of >3 mo (with higher dose) vs 2 mo therapy. Outcome: Relapse

Fig 1B Comparison of >3 mo (with higher dose) vs 2 mo therapy. Outcome: Frequent relapses

Fig 2A Comparison of >3 mo vs 3 mo therapy (with same total dose in both groups). Outcome: Relapse

Fig 2B Comparison of >3 mo vs 3 mo therapy (with same total dose in both groups). Outcome: Frequent relapses

Fig 3A Comparison of Higher vs Lower steroid dose (administered over same duration i.e 3 mo). Outcome: Relapse

Fig 3B Comparison of Higher vs Lower steroid dose (administered over same duration i.e 3 mo). Outcome: Frequent relapses

Fig 4A Comparison of 3 mo (with higher dose) vs 2 mo therapy. Outcome: Relapse

Fig 4B Comparison of 3 mo (with higher dose) vs 2 mo therapy. Outcome: Frequent relapses

Fig 5A Comparison of >3 mo (with higher dose) vs 2 mo therapy. Outcome: Relapse

Fig 5B Comparison of>3 mo (with higher dose) vs 2 mo therapy. Outcome: Frequent relapses

Fig 6A Comparison of 3 mo vs 2 mo therapy (with same total dose). Outcome: Relapse

Fig 6B Comparison of 3 mo vs 2 mo therapy (with same total dose). Outcome: Frequent relapses

It is also important to consider safety issues. The diverse sets of data made meta-analysis difficult. However, almost all the trials showed comparable frequency of adverse events. More importantly, most adverse events occurred during the initial (more intensive) phase of therapy, wherein the dosage and duration are more comparable. An indirect point to note is that the lower efficacy of shorter duration/lower total dose may be associated with more relapses and hence more doses of prednisolone, thereby increasing the potential for adverse events.

Extendibility: The issues of optimal management of childhood nephrotic syndrome and the ideal steroid regimen are relevant to the Indian setting. Although the results of the trial cannot be extended to our setting, the findings of the new systematic review presented here are applicable.

Conclusions: Although the trial suggests that 2 months steroid therapy may be non-inferior to 6 months therapy, the overall conclusion based on evaluation of all available data (through a fresh systematic review) suggests that prednisolone therapy longer than 3 months (with higher dose) is more efficacious than that for 3 months or less.

Joseph L Mathew

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