Steroid Treatment of Childhood Idiopathic Nephrotic Syndrome: Epidemiology, Therapeutic Adequacy, Medium and Long Term Outcomes. A Prospective Observational Cohort Study.

Background Idiopathic nephrotic syndrome (INS) is the most frequent glomerular disease in childhood, with an incidence of 2-4 cases per 100,000 children. Currently, all children with INS are treated at onset with steroids. Approximately 80% of cases respond to oral corticosteroid therapy, but 75-80% of these children will experience relapses which can recur over many years. The optimal duration and dosage of steroid therapy at onset and during subsequent relapses is debated. For each patient, the challenge is to minimise potential side effects of steroid therapy (hypertension, bone disease, Cushing syndrome, obesity, growth retardation, cataracts and a variety of psychological, social and behavioural disturbances) while achieving a good clinical response. This is particularly difficult at the beginning of the illness, because of the lack of reliable indicators that allow the identification of patients who will respond poorly or will experience frequent relapses. In 2006 the Cochrane Collaboration published the first systematic review of corticosteroid therapy for childhood idiopathic nephrotic syndrome. They concluded that children with the first episode of steroid sensitive INS should be treated for a minimum of three months, to achieve a reduction in the subsequent relapse rate.

The fine border between the optimal dose of steroids and the collateral effects can not be overlooked given the results of some recent studies (relative to patients with chronic inflammatory bowel disease or children with acute lymphoblastic leukemia subject to prolonged cycles of steroid therapy) based on the pharmacogenetic evaluation of the diverse individual responses to steroids. Clinical data supports the concept that the collateral effects of steroids are not exclusively dose related, but can depend on constitutional hypersensitivity or resistance, at times specific for a particular corticosteroid.

This diverse individual response can depend on a number of factors. The activity of the corticosteroids is mediated by interactions with the DNA (genomic mechanism) or by a direct interaction with the cellular membranes (non-genomic mechanism). The genomic effects are by far the most important and are mediated by the interactions of the steroids with a specific cytoplasmic receptor (GR). The binding of the steroid determines the activation of the receptor and its translocation within the nucleus where it induces (transactivation) or inhibits (transcriptional interference) the synthesis of numerous regulatory proteins. The mechanism of transactivation is likely responsible for the major part of collateral effects (suppression of the hypothalamic-hypophysial-adrenal axis, genesis of glaucoma and diabetes), while the anti-inflammatory effects are for the most part tied to transcriptional inhibition (with reduced synthesis of pro-inflammatory cytokines, cyclic oxygenase2, inducible forms of nitrite synthesis and finally a reduction in synthesis of receptors for Fc and C3).

There are individual diverse molecular anomalies of the gene for the glucocorticoid receptors (hGR/NR3C1) that have bean uncovered: for example the presence of polymorphisms of the gene hGR is correlated with receptor hyperactivity (Bcl1 e N3635) or relative resistance of the glucocorticoid receptor (polymorphism ER22/23EK); a further 15 mutations have already been identified to be associated with corticosteroid resistance.

These facts open interesting possibilities for pharmacological research with the hypothesis of being able to adjust steroid therapy in response to an individuals genetic make-up and predict the appearance of side effects.