An open label randomised control trial comparing between solo prednisolone therapy versus steroid-sparing agent along with daily doses of prednisolone in achievement of remission among FRNS and SDNS patients

Idiopathic nephrotic syndrome (NS) is the clinical manifestation of glomerular diseases characterized by severe proteinuria, hypoalbuminemia, and/or the presence of edema. The incidence is 1-3 per 1,00,000 children aged below 16 years [1,2]. Glomerular lesions associated with idiopathic nephrotic syndrome include minimal change disease, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, C3 glomerulopathy, and membranous nephropathy. Without treatment, nephrotic syndrome in children is associated with a high mortality due to acute kidney injury, chronic kidney disease, systemic infections, and thromboembolic events. The underlying abnormality in nephrotic syndrome is increased permeability of the glomerular capillary wall, which leads to massive proteinuria and hypoalbuminemia. Podocytes are highly differentiated epithelial cells located on the outside of the glomerular capillary loop. Foot processes of neighboring podocytes interdigitate with each and are connected via slits called the slit diaphragm. Important component proteins of the slit diaphragm include nephrin, podocin, CD2AP, and alpha-actinin 4. Podocyte injury or genetic mutations of genes producing podocyte proteins may cause nephrotic range proteinuria.

The majority of patients (85-90%) achieve complete remission on 4-6 weeks of daily oral prednisolone therapy at standard doses and are termed as steroid-sensitive nephrotic syndrome (SSNS)[3]. The outcome in patients with SSNS is mostly satisfactory, while approximately 50% show frequent relapses or steroid dependence, and 3-10% show late steroid resistance [ 4,5]. The initial episode of nephrotic syndrome is treated with prednisolone at a dose of 60mg/m2/day (2mg/kg/day; maximum 60 mg in 1-2 divided doses) for 6 weeks, followed by 40mg/m2/day (1.5mg/kg; maximum 40 mg as a single dose) on alternate days for next 6 weeks and then discontinued.

Management of relapsing SSNS is a great challenge. Long or frequent use of high-dose steroids is associated with steroid toxicity and reduction in quality of life. Relapses are generally treated with prednisolone at 60mg/m2/day (2mg/kg/day; maximum 60 mg in 1-2 divided doses) until remission (protein trace/nil for 3 consecutive days), followed by 40mg/m2/day (1.5mg/kg; maximum 40 mg as a single dose) on alternate days for next 4 weeks. Remission is generally achieved in 7-10 days, and daily therapy is seldom necessary beyond 2 weeks. Frequent relapses are defined as the occurrence of two or more relapses in the first 6 months after initial response, or three or more relapses in any 12 months[8]. Steroid dependence is a patient with SSNS who experiences 2 consecutive relapses during recommended prednisolone therapy for the first presentation or relapse or within 14 days of discontinuation.[8]. Considering the spectrum of steroid associated adverse effects, and the anxiety associated with an increased number of relapses, treatment strategies should be more proactive toward prevention. Steroid-sparing agents(SSA) are recommended in patients who are not controlled on therapy or who suffer a complicated relapse or with SDNS[8]. The choice of a steroid SSA is unique to individual cases and depends on the balance between the risks and benefits of the intervention. The objective should be always to use a drug that appropriately controls the disease with minimal side effects. Commonly used SSA are cyclophosphamide, calcineurin inhibitors (cyclosporine, tacrolimus), mycophenolate mofetil, and levamisole. the choice of agent should be based on family and physician preferences and the risk profile for drug-associated complications. Factors to consider include disease type/severity, age, potential adherence, side effect profile, comorbidities, cost, and availability. There is insufficient data and evidence regarding which drug should be preferred and regarding the exact timing of starting therapy with steroid-sparing agents. Cyclophosphamide and levamisole are recommended to be started after the patient has achieved remission with the standard dose of prednisolone [8]. No such recommendations have been made regarding the commencement of therapy with calcineurin inhibitors and mycophenolate mofetil. Mycophenolate mofetil is generally started during alternate-day steroid therapy as its immunosuppressive effect is delayed [8]. Literature to date is lacking on the use of steroid-sparing agents before a child has achieved remission and whether it’s a more effective approach to induce early remission and limit the number of relapses occurring in FRNS/SDNS cases.

Hypothesis

Null hypothesis: Adding steroid-sparing agents with a daily dose of prednisolone does not help in the faster achievement of remission in patients aged 1-14 years diagnosed with FRNS or SDNS.

Alternate hypothesis: Adding steroid-sparing agents with daily dose of prednisolone before achievement of remission helps in faster achievement of remission among patients aged 1-14 years diagnosed with FRNS or SDNS.