Steroid Treatment Of Childhood Idiopathic Nephrotic Syndrome

Project location: ITALY
Project start date: December 2010 - Project end date: December 2013
Project number: 2010-72
Beneficiary: Associazione Il Sogno di Stefano ONLUS

This project received a grant from the Nando Peretti Foundation. The project's aim is to understand the genesis of a severe disease named "childhood idiopathic nephrotic syndrome" and consequently an efficient therapeutic strategy. The Study will take place in four Italian regions; Emilia-Romagna, Tuscany, Lombardy and Marche. A good number of the pediatric departments of these regions have agreed to take part to the study. The research team will be coordinated by Dr. Giovanni Montini, who has a good experience in conducting and participating to medical trials in children with nephrological problems.
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 cytochines, 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.
The aim of the study is to assess the benefits and potential adverse effects of a prolonged initial corticosteroid regimen across four Italian regions, for the treatment of the initial episode of INS. The results will be compared with data obtained retrospectively from the analysis of a control group of INS, treated with a short steroid regimen during the previous 3 years in the same area. In addition genetic studies will be undertaken with the aim of evaluating pharmacogenetics and pharmacodynamics of steroid treatment with the ultimate goal to individualise treatment in single patients.

The following Centers will participate in the Study:

Emilia Romagna:
Pediatric Departments from the Hospitals of : S.Orsola (Bologna), Maggiore (Bologna), Piacenza, Parma, Fiorenzuola D'Arda, Reggio Emilia, Modena, Sassuolo, Carpi, Mirandola, Bentivoglio, Imola, Faenza, Forlì, Ravenna, Cesena, Rimini, Ferrara, Delta di Lagosanto, Guastalla, Montecchio, Pavullo, Fidenza, S.Marino (24).

Pediatric Departments from the Hospitals of: De Marchi (Milano), Bergamo, Mantova, Asola (MN), Cremona, Manerbio (BS), Vimercate (MI), Carate Brianza (MI), Desio(MI), Sesto S.Giovani (MI), Garbagnate (MI), Rho (MI), Lecco, Magenta, Lodi, Melegnano, Cernusco sul Naviglio, Iseo, Milano HSR, MMilano Sacco, Milano Fatebenefratelli, Milano S.Carlo, Milano H.Buzzi, Milano Niguarda, Cinisello Balsamo, Cantù, Vigevano, Pavia, Sondrio, Busto Arsizio, Tradate, Saronno, Esine, Varese (34).

Pediatric Departments from the Hospitals of: Meyer Firenze, Pisa, Siena, Massa Carrara, Versilia, Livorno, Cecina, Piombino, Portoferraio, Grosseto, Orbetello, Montepulciano, Arezzo, Montevarchi, Poggibonsi, Pistoia, Prato, Pescia, Empoli, Lucca, Santa Maria Annunziata (FI), San Giovanni di Dio (FI), Pontedera (23)

Pediatric Departments from the Hospitals of: Ancona, Ascoli Piceno, Civitanova Marche, Fabriano, Fano, Fermo, Iesi, Macerata, Osimo, Pesaro, Recanati, San Severino, San Benedetto del Tronto, Senigallia, Urbino (15)

The Coordinator will obtain from each partner responsible for a work package (genetics, behavioral changes) a written progress report preceding each study group meeting indicating the scientific progress and potential problems. An additional efficient tool to monitor progress will be given by the 6-monthly partners meetings. Each group will present their results and discuss them openly with the members of the consortium. The same target is aimed for by the regular posting of progress reports by mails. Eventually, quality will be assured by scientific publications in peer-reviewed journals and to some extent by presentations at high ranking scientific meetings or symposia.

Patients with an onset INS will be enrolled in the study between January 2011 and December 2012 and will be followed for 24 months. Last follow-up will be on December 2014. Final results will be available on June 2015.

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