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Three Part Question

In [a child with steroid-dependent nephrotic syndrome on alternate daily prednisolone with a viral upper respiratory tract infection], does [changing to daily steroids compared to placebo or continuing alternate daily prednisolone] reduce [the risk of relapse]?

Clinical Scenario

A 4-year-old boy with steroid-dependent minimal change disease has symptoms of a viral upper respiratory tract infection (URTI). Will changing from alternate daily to daily steroids reduce the risk that this infection will provoke a relapse?

Search Strategy

Searches were carried out in March 2008. Search terms were ("corticosteroids" OR "glucocorticoids" OR "prednisone" OR "prednisolone") AND "nephrotic".

PubMed, filter "Systematic Reviews": 32 references, one relevant Cochrane Review discussing one study

Search Outcome

PubMed, filter "therapy": 62 references, two relevant, one previously identified and one randomised controlled trial published after the Cochrane Review.2 3 Repeated without "therapy" filter: 70 references, no additional relevant studies. Additional information relating to the first trial was obtained from the Cochrane Review and directly from the authors

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Mattoo and Mahmoud, 2000,	36 children with steroid-dependent nephrotic syndrome, on 0.5 mg/kg alternate daily prednisolone Group 1, n = 18, daily prednisolone for 5 days during each URTI over a 2-year period Group 2, n = 18, continued alternate daily prednisolone during each URTI	Randomised, non-placebo controlled, non-blinded trial (level IIb)	Difference in number of relapses over 2 years	Weighted mean difference –3.3 (95% CI –4.0 to –2.6)	Inadequate concealment with randomisation by alternate patient assignment. Nevertheless, adequate baseline similarity between patient groups. Not intention to treat: losses to follow-up and non-compliers excluded from analysis (and these patients unmentioned in study publication)
Abeyagunawardena and Trompeter, 2008,	48 children with steroid-dependent nephrotic syndrome, on <0.6 mg/kg alternate daily prednisolone Group 1, n = 24, 7 days daily prednisolone for 1st viral URTI. Alternate daily placebo and prednisolone for 2nd viral URTI. Group 2, n = 24, vice versa	Double blinded, randomised placebo controlled cross-over study with follow-up over the course of two URTIs (level Ib)	Absolute reduction in risk of relapse following URTI	ARR 30% (95% CI 11% to 50%)	Not intention to treat: 8 exclusions from analysis (on pre-defined criteria) 4 needed additional immunosuppression, 1 had stable disease no longer requiring prednisolone and 3 did not suffer from 2 viral URTIs. Unclear whether exclusions were made before or after randomisation and to which groups excluded patients were randomised
			Number of URTIs needed to treat to prevent 1 relapse	4 (95% CI 2 to 10)

Comment(s)

Cytokine release secondary to viral infection is a potential trigger of relapse in nephrotic syndrome (McDonald). Relapse carries serious risks, with morbidity and mortality relating to hospital admissions, sepsis, thromboembolism and hypovolaemia. Longer term treatment of relapse is associated with further risks relating to steroid treatment or immunosuppression. Any intervention to reduce the risk of relapse is, therefore, potentially very important. The evidence relating to prednisolone in the prevention of infection-related relapse is limited to two small studies. There are methodological issues with both which may have inflated the treatment effects seen. Nevertheless, the results demonstrate that daily prednisolone was associated with a significant reduction in the absolute risk of relapse, with a low number needed to treat. Neither study was large enough to detect small increases in side effects. However, it is likely that long term steroid doses would be reduced if short courses of daily steroids obviated the need for prolonged courses of steroids for the treatment of relapse. Furthermore, this intervention would be expected to reduce the number of children requiring additional immunosuppression, although the current evidence is insufficient to demonstrate this. An increase in prednisolone is an easy, feasible treatment option, and is likely to be cost effective in comparison to the treatment of multiple relapses. It is possible that this could be extended or modified to other scenarios including children already on daily maintenance prednisolone or other immunosuppressants.

Editor Comment

ARR, absolute reduction in risk; URTI, upper respiratory tract infection.

Clinical Bottom Line

Changing from alternate daily to daily prednisolone for 7 days during an intercurrent viral infection significantly reduced the risk of relapse for children with steroid-dependent nephrotic syndrome. (Grade B)

References

1. Hodson EM, Willis NS, Craig JC. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev 2007;(4):CD001533.
2. Mattoo TK, Mahmoud MA. Increased maintenance corticosteroids during upper respiratory infection decrease the risk of relapse in nephrotic syndrome. Nephron 2000;85:343–5.
3. Abeyagunawardena AS, Trompeter RS. Increasing the dose of prednisolone during viral infections reduces the risk of relapse in nephrotic syndrome: a randomised controlled trial. Arch Dis Child 2008;93:226–8.
4. MacDonald NE, Wolfish N, McLaine P, et al. Role of respiratory viruses in exacerbations of primary nephrotic syndrome. J Pediatr 1986;108:378–82.