Mycophenolate mofetil is inferior to tacrolimus in sustaining remission in children with idiopathic steroid-resistant nephrotic syndrome

Abstract

Studies of nephrotic syndrome show that substitution of calcineurin inhibitors by mycophenolate mofetil (MMF) enables sustained remission and corticosteroid sparing and avoids therapy associated adverse effects. However, controlled studies in patients with steroid resistance are lacking. Here we examined the effect of switching from therapy with tacrolimus to MMF on disease course in an open-label, one-to-one randomized, controlled trial on children (one to 18 years old), recently diagnosed with steroid-resistant nephrotic syndrome, at a referral center in India. Following six months of therapy with tacrolimus, patients with complete or partial remission were randomly assigned such that 29 received MMF while 31 received tacrolimus along with tapering prednisolone on alternate days for 12 months. On intention-to-treat analyses, the proportion of patients with a favorable outcome (sustained remission, infrequent relapses) at one year was significantly lower (44.8%) in the MMF group than in the tacrolimus group (90.3%). The incidence of relapses was significantly higher for patients treated with MMF than tacrolimus (mean difference: 1.05 relapses per person-year). While there was no difference in the proportion of patients with sustained remission, the risk of recurrence of steroid resistance was significantly higher for patients receiving MMF compared to tacrolimus (mean difference: 20.7%). Compared to tacrolimus, patients receiving MMF had a significantly (71%) lower likelihood of a favorable outcome and significantly increased risk of treatment failure (frequent relapses, steroid resistance). Thus, replacing tacrolimus with MMF after six months of tacrolimus therapy for steroid-resistant nephrotic syndrome in children is associated with significant risk of frequent relapses or recurrence of resistance. These findings have implications for guiding the duration of therapy with tacrolimus for steroid-resistant nephrotic syndrome.

Cyclophosphamide versus cyclosporine A therapy in steroid-resistant nephrotic syndrome: a retrospective study with a mean 5-year follow-up

“… 2 , 21 – 23 Currently, the most common immunosuppressive agents are CTX and CSA, but there are different reports of the efficacy of these agents in the published literature. 1 , 13 , 21 – 24 …”

“…CSA-induced nervous system side effects are rare, 1 , 7 , 12 , 22 , 26 but headache, insomnia, tremors, and anxiety may occur. 3 , 11 , 12 , 27 Some symptoms, such as aphasia, hallucinations, convulsions, and coma, may be encountered in severe cases.…”

“…This syndrome is a common disease of the urinary system in children. 1 – 3 Hormone therapy is effective for most children with nephrotic syndrome, but 10% to 30% of children show resistance to corticosteroids. 4 , 5 Hormone resistance continues to pose a therapeutic challenge.…”

Off‐label use of tacrolimus in children with glomerular disease: Effectiveness, safety and pharmacokinetics

“…92 The target C 0 and AUC 0-12 h level for treatment remission are higher than those in relapse in children with SRNS. 45 T A B L E 2 Number and proportion of adverse drug events in clinical studies of tacrolimus in the treatment of nephrotic syndrome in children 31,32,[36][37][38][39][40][41][42][47][48][49][50]66 In the first population pharmacokinetic model of tacrolimus in children with nephrotic syndrome, body weight, CYP3A5 genotype had significant impact on tacrolimus pharmacokinetics. 93 The mean clearance/bioavailability (CL/F) of tacrolimus is in agreement with previously reported values of tacrolimus in paediatric kidney transplant patients.…”

Advances in pediatrics in 2017: current practices and challenges in allergy, endocrinology, gastroenterology, genetics, immunology, infectious diseases, neonatology, nephrology, neurology, pulmonology from the perspective of Italian Journal of Pediatrics

“…The more commonly used immunosuppressive drugs are calcineurin inhibitors, mycophenolate mofetil (MMF), pulse intravenous methylprednisolone, and cytotoxic agents. In a randomized controlled trial, Sinha et al [ 122 ] showed that in children with idiopathic SRNS 61% of patients achieved complete remission and 38% partial remission after treatment with tacrolimus for 6 months. Then, children were randomized to receive tacrolimus or MMF both associated to prednisolone on alternate days for 12 months.…”