Immunosuppressive therapy in children with primary nephrotic syndrome: single center experience, Karachi, Pakistan

Abstract

Background Majority of children with nephrotic syndrome are steroid sensitive, but treatment of difficult to treat nephrotic (frequent relapsing, steroid dependent and steroid resistant) syndrome is challenging. Low dose steroid, levamisole, cyclophosphamide (CPM), mycophenolate mofetil (MMF) and calcineurin inhibitors (CNIs) are the common options of treatment. Objective of the study was to determine the response to steroid and alternative immunosuppressive agents (ISAs) in children with difficult nephrotic syndrome (DNS). Methods This is a retrospective cohort study of 176 children with DNS, managed over 12 years at The Kidney Center-Postgraduate Training Institute, Karachi- Pakistan from 2005 to 2017. Initial episode was treated with daily oral prednisolone (OP) for 4–8 weeks followed by alternate day OP for 12–24 weeks. Subsequently low dose OP, levamisole (Leva)and cyclophosphamide was used for frequent relapsing (FR)/ steroid dependent (SD). All with initial steroid resistance and non- responders to leva and or cyclophosphamide were biopsied and treated with CNIs and MMF. Data was analyzed using descriptive statistics. Results There were 130(73.86%) children with FR/SD and 46(26.13%) with SRNS. All children with SR (46) and 86 with FR/SD were biopsied. Minimal change disease (60.60%) and focal segmental glomerulosclerosis (FSGS 23%) were the two common lesions. Majority (73.86%) received single OP whereas divided doses were administered in 26.13% cases. Daily OP was used for 4, 6 and 8 weeks in 61.36,28.4 and10.22% respectively. Steroids were tapered over 3 (31.81%),4 (52.27%) and 6 months (15.90%). Levamisole, CPM, cyclosporin (CS) and MMF were used sequentially in 45, 54.23, 50 and 20% respectively. Combination of MMF and CS was used in 11.29% of cases. Levamisole was effective in 80%, CPM induced complete remission (CR, 57.77%) or partial remission (PR, 22.22%), CS induced CR 46.59% and PR 39.77%. MMF showed PR and CR 69 and 12.82% respectively. At last follow up, 46% were maintaining remission while off treatment, whereas 35% are maintaining remission on therapy,10.23% lost- to-follow, 5.68% progressed to chronic kidney disease. Mortality was 2.84% and it was due to infection and uremia. Conclusion Majority had steroid sensitive MCD. Levamisole and cyclophosphamide were effective in maintaining remission in FR/ SD. FSGS was responsible for resistance to steroid and alternative ISAs. Cyclosporin was effective in inducing remission in SRNS. Mortality was less than 3%.

Efficacy of Levamisole in children with Frequent Relapsing and Steroid Dependent Nephrotic Syndrome at Tertiary Care Center-Karachi

“…We recently published data on experience of immunosuppressive agents in primary nephrotic syndrome at tertiary care center but current study aimed at determining the effectiveness of using levamisole in children with FR and SD. 12 …”

“…It is a retrospective data, lack of equal number of FR and SD, use of different dosage schedule (daily in 33 and alternate day in 48 cases), lack of strict definition of effectiveness which may have led to exclusion of SD cases who were switched to cyclophosphamide/CNI before completion of 6 months of minimum duration, lack of strict monitoring for side effects like anti-nuclear cytoplasmic antibodies (ANCA) and variation of steroid dosage for treatment of relapse which was high during initial years and lower in the later years of practice as reported previously. 12 …”

“…6,10,[14][15][16] We recently published data on experience of immunosuppressive agents in primary nephrotic syndrome at tertiary care center but current study aimed at determining the effectiveness of using levamisole in children with FR and SD. 12 It was found that use of leva in children with FR and SDNS was effective in maintaining relapse free remission over 12 months while on treatment and more than 12 months after discontinuation of levamisole (Table III and IV). Levamisole use resulted in significant reduction of relapse rate per patient, from 3.30±0.50 to 0.98±1.1 on levamisole and even after discontinuation of levamisole to 0.79±1.27 (p=0.001).…”

“…Based on subsequent number and frequency of relapses, patients were categorized as FR if >2 relapses in 6 months or > 4 in a 12 months’ period and SDNS if child develops two consecutive relapses on steroid therapy or within 14 days of switching to AD prednisolone. 12 …”

“…Based on subsequent number and frequency of relapses, patients were categorized as FR if >2 relapses in 6 months or > 4 in a 12 months' period and SDNS if child develops two consecutive relapses on steroid therapy or within 14 days of switching to AD prednisolone. 12 Levamisole was used for 6-36 moths in a dose of 2-2.5 mg/ kg/day either daily or AD along with low dose OP (0.25-0.5 mg/kg dose) on AD after induction of remission with daily OP for relapse. Patients were followed initially at one month with spot urine protein creatinine ratio (spot Ur PCR) and complete blood count, subsequently 2-3 monthly with tapering of AD prednisolone from 1.5 mg/kg to 1 mg/kg at one month then 0.5 mg/ kg on alternate day for first 3-6 months and then 0.25mg/kg on alternate day.…”