Randomized, multicentric, open label, parallel group trial to compare the efficacy of 6-months versus 3-months therapy with prednisolone for the first episode of idiopathic nephrotic syndrome in children younger than 4 years

Nephrotic syndrome is a common renal disorder in childrencharacterized by proteinuria, hypoalbuminemia and edema. The long-termprognosis for steroid-sensitive nephrotic syndrome is excellent for resolutionof disease and maintenance of renal function. About 80% patients with steroid-sensitivenephrotic syndrome will relapse one or more times, requiring repeated treatmentwith corticosteroids. Of these, 50-60% show frequent relapses or steroiddependence and require therapy with long-term corticosteroids and othermedications. Patients with multiple relapses are at risk for life-threateninginfections, malnutrition and thrombotic episodes. They are also likely to showserious side effects of long-term steroid therapy and those related to use ofother medications, including toxicity to bone marrow, gonads, central nervoussystem and kidneys. Repeated relapses also result in multiple hospitalizationsand school absence. Strategies effectivein reducing relapse rates and proportion of patients with frequent relapses orsteroid dependence shall therefore be extremely valuable in improving thelong-term management of nephrotic syndrome.

Basedon information from multiple studies that prolonged duration of initial therapybeyond 8-weeks reduced the risk of an early relapse and lowered frequency ofsubsequent relapses, it is agreed upon that the initial therapy withprednisolone should continue for 12 weeks (3 months), administered daily for aduration of 6 weeks, and then on alternate days for another 6 weeks. However, the optimal dose and duration ofcorticosteroid therapy remains to be determined. Data fromvarious prospective studies, systematically reviewed in the Cochrane Registry,suggests the beneficial effects of prolongation of treatment beyond 3 months,with benefit seen up to 6-months. However, the advantages of extending therapyfrom 3- to 6-months are not unambiguous; there are also concerns of thecorticosteroid toxicity with the latter regimens. Recent placebo controlledtrials reported in 2013, including from this center, suggest that extending initial prednisolone treatment from 3months to 6 months, with or without an increase in cumulative dose, does notinfluence the course of disease in children with nephrotic syndrome. However,in the study conducted in India, we found that prolongedtherapy was useful in postponing the first relapse, and was associated with aninsignificantly decreased risk of frequent relapses, in the subgroup ofchildren younger than 4 years. Since the subgroups were not defined a priori, a prospective study isrequired to clarify the efficacy of this intervention in young patients.

Further,the lack of clarity regarding disease pathogenesis makes the administration ofcorticosteroid therapies largely empirical. While clear insight into thepathogenic pathways targeted by prednisolone is lacking, there is some evidencethat disease remission is associated with down regulation of T cell activation,altered B-T cell crosstalk, upregulation of T helper type 1(Th1) and/or Tregulatory compartments.

Thispresent study proposes to examine the benefits of prolongation of initialtherapy of idiopathic nephrotic syndrome from the current standard of 3 to 6months among children younger than 4-yr-old an onset of disease. Prolongationof treatment at the first episode would have considerable promise, if foundeffective in reducing future relapses and without concomitant risks of corticosteroidtoxicity. The proposal also aims to examinethe proportions of T and B lymphocyte subsets in 20 patients with the initialepisode of nephrotic syndrome. The evaluation shall be conducted at onset ofdisease, following prednisolone induced disease remission, and at one year fromrandomization or at first relapse of the disease to determine differences inthe immune profiles at different stages of the disease. Apart from improvingour knowledge of pathogenesis of nephrotic syndrome, this approach shallenhance our understanding of the immunological alterations influenced bytherapy.