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Three Part Question

In [children with steroid dependent nephrotic syndrome (NS) on alternate day prednisolone with a viral upper respiratory tract infection (URTI)], does [changing to daily prednisolone] compared to continuing alternate day prednisolone [reduce the risk of relapse]?

Clinical Scenario

You see a 6 year old boy in clinic with nephrotic syndrome who is on low dose alternate day prednisolone. He has coryzal symptoms but is otherwise well, with 1+ proteinuria and no oedema. You know that he has previously relapsed following a viral infection and you wonder what you can do to prevent a further relapse. You ask the consultant who suggests increasing his prednisolone dose to daily and you wonder what the evidence is for that.

Search Strategy

Searches were carried out through PubMed, TRIP database and the Cochrane library using the terms (“corticosteroids” OR “glucocorticoids” OR “prednisolone” OR “prednisone”) AND “nephrotic syndrome” AND “relapse”. A pyramidal approach was used.
TRIP database
The above search revealed 147 results, 8 of which were systematic reviews. None of these were relevant. There were 5 Evidence-based synopses, of which 1 was relevant. Of the 47 controlled trials, 2 were relevant, one of which was included in the evidence-based synopsis.
The Cochrane Library
The search below yielded 46 results, of which 18 were Cochrane reviews (none relevant), 27 were trials (3 relevant) and 1 was a Cochrane Group update.
PubMed
Using the same search terms, 314 papers were retrieved. Using the filter “clinical trials”, this was narrowed down to 76 papers. Only 3 of these were relevant, all of which had been identified earlier using the previous search databases.

Search Outcome

In total, the search revealed one systematic review 1 (comprising of two trials) and one further relevant randomised controlled trial 2 conducted after the systematic review was published.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Mattoo TK, Mahmoud MA 2000 Saudi Arabia	36 children with steroid sensitive frequently relapsing nephrotic syndrome on maintenance low dose alternate day prednisolone	Randomised, non-placebo controlled, non-blinded trial (Level IIb)	Difference in number of relapses over 2 years	Relapse rate 2.2±0.87 v 5.5±1.33 (p=0.04)	Numbers were small (36 patients) and there was no blinding as well as inadequate concealment with patients being randomised alternately. An intention to treat approach was not used with losses to follow-up and non-compliers being excluded from the analysis.
Abeyagunawardena AS, Trompeter RS 2008 Sri Lanka	48 children aged 1-16 years with steroid dependent nephrotic syndrome on maintenance low dose alternate day prednisolone	Double blinded, randomised placebo controlled cross-over study with follow-up over the course of two URTIs (Level Ib)	Absolute reduction in risk (ARR) of relapse following URTI	ARR 30% (95% CI 11% to 50%)	Double blinded but had small numbers (48 patients) and a non-intention to treat analysis with exclusions occurring from pre-defined criteria. It was not explained when the exclusions were made and which groups they had been randomised to.
			umber of URTIs needed to prevent 1 relapse	4 (95% CI 2 to 10)
Gulati A, Sinha A, Sreenivas V, et al 2011 India	100 children aged 1-16 years with steroid dependent nephrotic syndrome on maintenance low dose alternate day prednisolone	Randomised, non-placebo controlled, non-blinded trial (Level IIb)	Difference in number of infection-associated relapses over 1 year	Relapse rate 0.7±0.3 v 1.4±0.5 (p<0.01)	Stratified randomisation with adequate allocation concealment. However, there was no placebo arm so blinding was not possible. Results were based on intention to treat analysis. This study looked at intervention with any infection, although 92% were URTIs.
			Difference in total relapses over 1 year	Relapse rate 0.9±0.4 v 1.8±0.5 (p<0.0001)

Comment(s)

Background 70-80% of children with NS develop relapses requiring further courses of high dose prednisolone. These relapses are associated with a risk of significant complications, and high dose prednisolone treatment has major adverse effects. It is well recognised that more than half of these relapses are precipitated by viral URTI, and that in those children with steroid sensitive NS, a viral URTI results in relapse in over 50%. Any intervention to reduce the risk of relapse, and thereby morbidity and cost associated with its treatment is therefore important. Summary of studies The three studies included were all randomised-controlled trials involving children with steroid dependent nephrotic syndrome on alternate day prednisolone. In Mattoo et al, patients were randomised to receive daily prednisolone for 5 days during each URTI over a two year period, or continue on their usual dose. In Abeyagunawardena et al, patients were randomised to 7 days of daily prednisolone during the first URTI and alternate daily placebo and prednisolone for second viral URTI and vice versa. Gulati et al conducted the largest of the three studies, and patients were randomised to receive their usual dose of prednisolone daily for 7 days during each URTI over a one year period, or continue on their usual dose. Validity of studies The three studies included were all randomised controlled trials (RCTs) with adequate baseline similarities between groups. The criteria for development of an URTI, and therefore commencing on the appropriate treatment pathway, were clearly defined in all the studies. There was adequate homogeneity between the studies, with all of them using a 5 to 7 day course of daily prednisolone as the intervention. Although one study followed the patients up over a period of 2 relapses only, the other two studies followed them up over 1 and 2 years. In the first study, numbers were small (36 patients) and there was no blinding as well as inadequate concealment with patients being randomised alternately. An intention to treat approach was not used with losses to follow-up and non-compliers being excluded from the analysis. The second RCT was double blinded but again had small numbers (48 patients) and a non-intention to treat analysis with exclusions occurring from pre-defined criteria. It was not explained when the exclusions were made and which groups they had been randomised to. In the third RCT there was stratified randomisation with adequate allocation concealment. However, there was no placebo arm so blinding was not possible. Results were based on intention to treat analysis. This study looked at intervention with any infection, although 92% were URTIs. Applicability These three studies were all based in developing countries where the pattern of childhood URTI is different (higher incidence of fever, presence of diarrhoea) but we know that in our population, there is a similar risk of relapse following an URTI and therefore the data can be extrapolated. None of the studies looked at children on other immunosuppressive therapies, with or without long-term maintenance prednisolone therapy. Conclusion We know that viral infections trigger relapses in nephrotic syndrome 5, and therefore any intervention to reduce the risk of such relapses is important. Although these studies had methodological flaws, they all showed that daily prednisolone significantly reduced the risk of relapse, with a low number needed to treat. Furthermore, one of the studies showed that the cumulative prednisolone dosages between the two groups were not statistically significant and there was no difference in steroid-related side-effects. Increasing to a daily dose is an easy treatment option and would be cost-effective compared to treating multiple relapses. Further studies with larger population groups that included children on other immunosuppressive therapies, with or without long-term maintenance prednisolone therapy would be of benefit.

Clinical Bottom Line

 In children with steroid dependent nephrotic syndrome, changing from alternate day to daily prednisolone for 5-7 days during an intercurrent viral illness appears to significantly reduce their risk of relapse (Grade B).

References

1. Mattoo TK, Mahmoud MA Increased maintenance corticosteroids during upper respiratory infection decrease the risk of relapse in nephrotic syndrome. Nephron 2000;85:343-5
2. Abeyagunawardena AS, Trompeter RS Increasing the dose of prednisolone during viral infection reduced the risk of relapse in nephrotic syndrome: a randomised controlled trial. Archives of Disease in Childhood 2008;93:226-8
3. Gulati A, Sinha A, Sreenivas V, et al Daily corticosteroids reduce infection-associated relapses in frequently relapsing nephrotic syndrome: a randomized controlled trial. Clin J Am Soc Nephrol 2011;6:63-9