Nephrotic syndrome is a chronic kidney condition of children, which is widely treated by corticosteroids. However, there is a lack of consensus on the most appropriate way to use this treatment and a Cochrane Review has been examining the relevant evidence for more than 15 years. In March 2015, Deirdre Hahn and colleagues from Sydney, Australia published the latest update of the review and she tells us what they found in this podcast.
John: Nephrotic syndrome is a chronic kidney condition of children, which is widely treated by corticosteroids. However, there is a lack of consensus on the most appropriate way to use this treatment and a Cochrane Review has been examining the relevant evidence for more than 15 years. In March 2015, Deirdre Hahn and colleagues from Sydney, Australia published the latest update of the review and she tells us what they found in this Evidence Pod.
Dee: Nephrotic syndrome is a chronic kidney condition which causes widespread oedema and increased risk of clots and infection due to extensive leakage of important circulating proteins across the kidney into urine.
Most children who develop nephrotic syndrome experience remission with corticosteroid treatment (prednisone or prednisolone) -- though around 80% will have one or more disease relapses and these relapses can continue into adult life.
Prednisone therapy has been successfully used to treat nephrotic syndrome for over 60 years but despite this we still do not have consensus about the best way to prescribe prednisone that provides sustained disease remission while minimizing side-effects.
While prednisone is effective at switching off the disease processes in the kidney that cause nephrotic syndrome, steroids are a non-targeted therapy that have many side effects that are particularly important to children. Treatment toxicity is especially significant for children who need repeated courses of therapy. Major complications include slowed growth, cataracts causing blindness, and weight gain or obesity, and in the longer term, increased heart disease. Studies have recently reported that behavioural and psychological changes due to prednisone are common even with only 12 weeks of therapy.
To try and answer the questions about the best dose and duration of prednisone therapy that is optimal for nephrotic syndrome remission and minimises potential treatment toxicity, we brought together evidence from all available randomised studies in children.
In previous versions of this Cochrane Review published in 2000 and which were updated in 2005 and 2007, we observed that increasing the length of prednisone treatment beyond two or three months and increasing the total dose of prednisone better prevented disease relapse and helped children avoid frequent relapses of disease after their first episode of nephrotic syndrome.
In the last two years, three new studies have contradicted this evidence by showing no significant prevention of frequently relapsing disease by prolonging prednisone therapy beyond two or three months.
Therefore, to address this new conflict in the available studies, we have updated this Cochrane review in 2015 combining earlier studies with ten new study publications. In the updated review, we included 34 trials with approximately 3000 children that evaluated treatment for 8- 24 weeks on average. Twenty one studies evaluated prednisone treatment among children with their first episode of nephrotic syndrome and 13 studies focussed on treatment for children with frequently relapsing disease.
In general, the studies, especially those published in the last few years, had relatively few methodological limitations, which gave us moderately high confidence in the results.
Fifteen trials assessed disease relapse and the chances of frequently relapsing disease among 1500 children. The trials compared prednisone treatment for two to three months on average against longer treatment courses of up to seven months. With the inclusion of these newer studies in the review, treatment with prednisone for 12 to 24 months was still better overall than shorter treatment courses for preventing relapsing disease as was seen in the original versions of the review. However there was now marked variation in the results seen among different studies, which had not been evident in previous versions of the review.
To learn about which factors might be causing this variation among different trials, we divided studies into those with substantial methodological limitations separately from those with higher quality methods. We then noticed that in trials that had transparent processes for randomly allocating treatments, masked caregivers and research teams from knowing which treatment was being used and ensured most children were included in the study results, prednisone treatment for two to three months offered similar protection against disease relapse as much longer treatment courses of several months. By contrast, in studies with important risks of bias because of the way the study was carried out showed that longer term prednisone treatment prevented disease relapse and recurrently relapsing disease better than short-course treatment. We looked at other possible explanations for the variability but found no indication that other factors including severity of disease, other lengths of treatment, or different ways of defining disease relapse impacted on the ways children responded to prednisone treatment.
When we examined treatment among children who already had frequently relapsing disease, 4 trials involving just over 200 children found that daily prednisone started at the time a child had an infection and given for five to seven days prevented relapse better than continuing prednisone on alternate days or giving a placebo.
When thinking about the possible harms of treatment, we found that treatment toxicity was poorly reported and sadly we don’t know whether different treatment approaches minimise longer-term treatment consequences. In particular, we lack knowledge about whether different lengths of prednisone have favourable or harmful consequences on child growth, psychological symptoms, or quality of life.
To sum up, children presenting with their first episode of nephrotic syndrome should be treated with two or three months of prednisone as high quality studies show no benefit with longer periods of treatment. Short courses of daily prednisone at the onset of infection prevent relapse among children with relapsing disease, although further studies are needed to confirm these findings. There is little information about the impact of different approaches to prednisone treatment on child health in the longer term
John: If you'd like to read more about this topic, you can find the full review in the Cochrane Library. Just go to Cochrane Library dot com, and search for 'nephrotic syndrome and children'.