Cyclosporine in the treatment of childhood idiopathic steroid resistant nephrotic syndrome: a single centre experience in Nigeria

Introduction Children with steroid resistant nephrotic syndrome usually require treatment with second-line agents and calcineurin inhibitors such as cyclosporine are now recommended as initial therapy. These agents only recently become available in our environment and their impact on care is unknown. We reviewed the short-term treatment outcomes of their use in comparison with previous outcomes. Methods Medical records of children managed for idiopathic steroid resistant nephrotic syndrome over a 5 year period were reviewed. Remission rates and improvement in renal function following use of various agents were compared. Results Of 103 children with idiopathic nephrotic syndrome, 25(24.3%) were steroid resistant, of whom 17 received additional medications. Full remission rate for cyclosporine was 70% (7/10). Remission rates prior to the availability of cyclosporine were 40% (2/5) for cyclophosphamide and 66% (2/3), (partial remission only) with enalapril, an angiotensin converting enzyme inhibitor used in combination with alternate day prednisolone. One child with cyclophosphamide resistance subsequently achieved remission with cyclosporine. Remission was not related to sex (p=0.96), age (p=0.54), serum albumin (p=0.37) or hypertension (p=0.43) but to serum cholesterol (p= 0.02). The estimated glomerular filteration rate (eGFR) among children treated with cyclosporine ranged from 30-167 ml/min/1.73m2 as follows: >90 (5); 60-89 (3); 30-59 (2) while the mean pre and post treatment eGFR in those with eGFR <90 were 60 and 104ml/min/1.73m2 respectively (p=0.03). Mortality rate was 10% (1/10) in children treated with cyclosporine compared with 28.6% (2/7) in those treated with other medications (p=0.54). Conclusion Cyclosporine resulted in improved treatment outcomes in children with idiopathic steroid resistant nephrotic syndrome.


Introduction
Nephrotic Syndrome (NS) is a glomerular disease characterized by severe proteinuria, hypoalbuminemia, anasarca and hypercholesterolemia [1]. The idiopathic form accounts for about 90% of cases and responds to first-line therapy with corticosteroids in about 80% of affected children [1]. consequently, varying outcomes [3][4][5][6]. In order to standardize care, the Kidney Disease: Improving Global Outcomes (KDIGO) group [7] in 2012, made several recommendations on the treatment of childhood idiopathic SRNS. These include the use of calcineurin inhibitors as the first line drugs for the management of steroid resistant nephrotic syndrome which we have since adopted at our centre. The objective of this study therefore was to determine the short-term outcome of the treatment of childhood iSRNS with cyclosporine, and compare this with outcome prior to adoption of the KDIGO guidelines.

Study centre
The study was conducted at the Paediatric Nephrology Unit of the

Results
Of the 129 children managed for NS during the study period, 103 had the idiopathic form (iNS) of whom 25(24.3%) were steroid resistant. Children with iSRNS were aged between 0.6-15.2years (median 8.8) with the majority (64%) being >5years. A summary of their baseline characteristics is shown in Table 1. Median age was significantly higher in children with idiopathic SRNS compared with the steroid sensitive form (9.1 vs 5years respectively, p=0.008) Two children were referred to other centers on request, one died from complications of acute kidney injury before treatment for SRNS could be commenced while five defaulted from follow-up.

Treatment of iSRNS
A summary of the treatment response of the remaining 17 children is shown in Table 2 and Table 3 Two children developed 1+ proteinuria at serum CsA levels <30ng/ml which resolved once the doses were increased, A summary of response to treatment is shown in Figure 1.
With regards to renal function, median serum creatinine at presentation was 56.5µmol/l with 6 children having serum creatinine greater than 88µmol/l. Several studies also report similar good outcomes with use of CsA.
In Tunisia [11], overall remission rates among 30 children with iSRNS following a CsA-prednisone combination was 80%, howbeit partial in 30% of children. Progression to ESRD was however higher in their study occurring in 9 (30%) patients for reasons which are not very clear. Similarly, in Japan [12], remission rates of 82-85% were reported among 30 children with iSRNS treated for 121 months. However, in this latter study [12], children with FSGS additionally received pulse methylprednisolone which may have contributed to the higher remission rates observed.
In Iran [13], complete and partial remission rates of 32.4% and 5.4% were reported among 37 children treated with CsA and prednisolone combination for 6 months while remission rates of 53% and 65% were reported from Saudi Arabia [14] and Brazil [15] respectively. It is important to highlight the fact that differences in treatment duration before diagnosis of CsA resistance in the aforementioned studies exist and may account for variability in reported CsA response rates. For instance, while response to CsA was determined after 4 months in Tunisia and Japan [11,12], in Iran (13) and Brazil [15], diagnosis was made after 6months of failure of at least partial remission as recommended by the KDIGO and as was the case in the current study. Non-uniformity of access to drugs due to cost-constraints may be another contributing factor as experienced in the group from Saudi Arabia [14]  patients in Saudi Arabia [14]. The major constraint to the shortterm use of CsA in our environment therefore is the cost, both of the drug and of serum level determination which precluded the monitoring of serum levels as desired. Long term use remains controversial because of it's association with nephrotoxicity [17,18], a side effect of major concern, although there are suggestions that long-term use in moderate doses with closely monitored levels can reduce it's incidence [18]. CsA has also been associated with a high rate of relapse after discontinuation of the drug [17] and optimal duration of treatment remains undetermined.
Page number not for citation purposes 5 Our combined remission rates using cyclophosphamide or enalapril with alternate day prednisolone of 50% is similar to that from another Nigerian study [19] that reported a cumulative remission rate of 57.12% with use of pulse intravenous cyclophosphamide and intravenous dexamethasone ± lisinopril or spironolactone. In contrast to this, amongst three children treated with cyclophosphamide in the USA [5], only one (33.3%) achieved partial remission while 2 were CYC resistant while in Iran [20], 10 out of 41 (24.4%) patients with iSRNS responded to cyclophosphamide.
These studies demonstrate the superiority of CsA over CYC in the management of iSRNS both in efficacy and side effect profile as has been highlighted by the KDIGO [7]. In our cohort, CsA also resulted in improved renal survival as only 1 patient, who was non-compliant with treatment progressed to ESKD.
Histological patterns from our study were FSGS, MCNS and MPGN in order of predominance agreeing with the general pattern in other studies [3,5,11,14,19]. The KDIGO [7] recommends a kidney biopsy for all children with SRNS before instituting therapy, even though opinions on the relationship between histological type and response to treatment differ [11,13]. A kidney biopsy nevertheless remains important as it aids in the diagnosis of secondary causes, is important in disease prognostication [7] and helps in identifying changes in disease epidemiology. It however does not influence the choice of medication in children with idiopathic steroid resistant nephrotic syndrome. Identifying factors that may predict outcome may be useful in prognostication. In this study, only serum cholesterol at presentation was significantly associated with remission. Lower serum albumin levels at presentation has also been negatively associated with remission [11] and even though this was so in our study, the association was not statistically significant.
A limitation of this study was our inability to correlate serum levels of CsA with remission though none of our patients experienced relapses or increased proteinuria with CsA serum levels above 50ng/ml. This study also looked only at short -term outcome hence  There is a need for long-term studies to determine optimal duration of treatment with cyclosporine as well as controlled studies comparing outcome with other newer immunosuppressants in our environment.

Competing interests
The authors declare no competing interests. Tables and figure   Table 1: Demographics of children with idiopathic steroid resistant nephrotic syndrome     CsA has been discontinued in patients 2 and 5 after 24 and 16 months of treatment respectively.

Authors' contributions
Patient 7 was switched to MMF because of acne and has been referred to another centre for follow-up.