Efficacy and safety of cyclosporine a for patients with steroid-resistant nephrotic syndrome: a meta-analysis

Background The purpose of this study was to determine efficacy and safety of cyclosporine A (CsA) for patients with steroid-resistant nephrotic syndrome (SRNS). Methods The Cochrane Library and PubMed were searched to extract the associated studies on Oct 10, 2018, and the meta-analysis method was used to pool and analyze the applicable investigations included in this study. The P(opulation) I(ntervention) C(omparison) O(utcome) of the study were defined as follows: P: Patients with SRNS; I: treated with CsA, cyclophosphamide (CYC), tacrolimus (TAC) or placebo/not treatment (P/NT); C: CsA vs. placebo/nontreatment (P/NT), CsA vs. CYC, CsA vs. TAC; O: complete remission (CR), total remission (TR; complete or partial remission (PR)), urine erythrocyte number, proteinuria levels, albumin, proteinuria, serum creatinine, and plasma cholesterol, etc. Data were extracted and pooled using RevMan 5.3. Results In the therapeutic regimen of CsA vs. placebo/nontreatment (P/NT), the results indicated that the CsA group had high values of CR, TR, and low values of proteinuria, serum creatinine, and plasma cholesterol when compared with those in the placebo group. In comparing CsA vs. cyclophosphamide (CYC), the results indicated that the CsA group had higher TR than the CYC group. In comparing CsA vs. tacrolimus (TAC), the results revealed insignificant differences in CR, and TR between the CsA and TAC groups. The safety of CsA was also assessed. The incidence of gum hyperplasia in CsA group was higher than that in the P/NT group, with no differences in incidence of infections or hypertension between CsA and P/NT groups. There was no difference in the incidence of hypertension between the CsA and TAC groups. Conclusions CsA is an effective and safe agent in the therapy of patients with SRNS.


Background
Nephrotic syndrome (NS), characterized by hypoalbuminemia, massive proteinuria, peripheral edema, and hyperlipidemia, is a major cause of end-stage renal disease (ESRD), and related damage of the glomerular filtration barrier [1][2][3]. Based on the response to steroid therapy, NS is classified as steroid-sensitive nephrotic syndrome (SSNS, approximately 50% of SSNS patients develop frequently-relapsing nephrotic syndrome or steroiddependent nephrotic syndrome), or steroid-resistant nephrotic syndrome (SRNS) [1,[4][5][6]. Patients who do not enter remission after administration of daily prednisolone for 4 weeks are regarded as SRNS [7]. SRNS is regarded as one of the most common causes of the development of ESRD in children [8]. The current therapeutic options for SRNS are often ineffective, it frequently progresses to a loss of kidney function, and treatment is often complicated by significant toxicity associated morbidities, mortality, and cost [1,8].
Cyclosporine A (CsA) is one of the most widely used immunosuppressants in organ transplantation and in the treatment of various immunological diseases [9,10]. CsA is frequently used to treat SRNS and can induce remission [11,12]. However, CsA also exerts nephrotoxic effects, as demonstrated by increased tubulointerstitial fibrosis, inflammation and podocyte damage [13,14]. In the current study, we performed a meta-analysis to assess the safety and efficacy of CsA in the treatment of patients with SRNS.

Data sources and search strategy
The systematic search strategy was conducted in the Cochrane Library and PubMed without language restrictions, from inception to Oct 10, 2018. We conducted searches by using the search strategy: cyclosporine AND (nephrotic syndrome OR glomerulonephritis membranoproliferative OR focal segment glomerulosclerosis OR minimal change nephrotic syndrome OR membranoproliferative glomerulonephritis). We also checked the references cited in the published studies for additional studies.

Inclusion and exclusion criteria Inclusion criteria
In this study, the inclusion criteria were as follows: (1) investigation type: randomized controlled trials; (2) object of the study: patients were diagnosed with NS and the NS was resistant to the steroid treatment; (3) type of interventions: treatment regimens based on CsA, the controls should have been treated with another immunotherapy or placebo.

Exclusion criteria
Exclusion criteria for the study were as follows: (1) Reviews, case reports, letters, systematic reviews, and metaanalysis; (2) Patients with nephrotic syndrome were sensitive to steroid or dependent to steroid; (3) studies that do not contain different therapeutic regimens; (4) the diagnostic criteria were not clear.

Analyzed outcomes
Efficacy of CsA: primary outcomes were complete remission (CR) and total remission (TR; CR or partial remission (PR)). The secondary outcomes were biological indicators including proteinuria levels, serum creatinine, serum albumin and plasma cholesterol.
Safety of CsA: adverse events including infection, hypertension and gum hyperplasia.
The CR was defined as proteinuria < 4 mg/m 2 /hr. (children) or 0.2 g/day (adults), for three non-consecutive days. PR was defined as the proteinuria < 40 mg/m 2 /hr. (children) or 3.5 g/day (adults) for three different non-consecutive days.

Data collection
According to the predetermined inclusion criteria, two independent reviewers scanned the titles and abstracts of the included records. Full texts of potentially literature were read for further screening. Discordant opinions were discussed and resolved by other reviewers.

Quality assessment
Two abstractors independently evaluated the methodological quality of all the eligible clinical trials according to the Modified Jadad Scale [15]. The studies were scored by answering the following questions: Randomization: 1. Was the trial random? 2. Was the randomization procedure adequately explained?
Allocation concealment: 1. Did the trial use a random assignment method? 2. Was the allocation concealment appropriate so that the clinicians and the subjects could not predict how the sequence would be assigned?
Blinding method: 1. Was the trial double-blind? 2. Did the trial use a placebo or similar methods?
Withdrawals and dropouts: 1. Were the numbers and reasons for withdrawals and dropouts adequately explained?
If the answer to each question was YES, the study would get 1 point; if NO, the study would get 0 point. A score of more than 3 was considered as high quality.

Statistical analysis
The data were extracted from the included literature, and the results were evaluated using Review Manager Version 5.3 software (Revman the Cochrane Collaboration; England). Continuous data were expressed using weighted mean differences (WMDs), and dichotomous data were expressed using the odds ratio (OR). 95% confidence intervals (95% CI) with the Mantel-Haenszel (M-H) method were used for the included studies. Heterogeneity was analyzed using I 2 statistics and calculated for all the meta-analyses. On the basis test of the heterogeneity, when the p-value less than 0.1 or the I 2 < 50%, a fixed effect model was used. Otherwise, the results were counted using a random effects model, and a p-value < 0.05 denoted significance.

The comparison of CsA vs. placebo/nontreatment (P/NT)
Three studies [17,19,21] were included in the metaanalysis to assess the efficacy of CsA in patients with SRNS. The results indicated that the CsA group had a higher CR (OR = 11.24, 95% CI: 1.90-66.68, P = 0.008; Fig. 1 Fig. 1). The safety of CsA was also assessed in patients with SRNS. The incidence rate of gum hyperplasia in the CsA group was higher than that in P/NT group (OR = 13.50, 95% CI: 1.66-109.84, P = 0.01). The incidence rates of infection or hypertension were similar between the CsA and P/NT groups (infections: 95% CI: 0.24-2.33, OR = 0.75, P = 0.62; hypertension: 95% CI: 0.12-8.56, OR = 1.00, P = 1.00).

Comparing CsA vs. CYC
One study [20] including two comparisons was considered in the meta-analysis to assess the efficacy of CsA in patients with SRNS compared with CYC. The results indicated that the CsA group had a higher TR than the
The safety of CsA was also assessed in patients with SRNS. There were no significant group differences in rates of hypertension (OR = 4.51, 95% CI: 0.21-96.06, P = 0.33).

Discussion
In this systemic review and meta-analysis, we assessed the efficacy of CsA in the treatment of SRNS as well as the safety of CsA. In comparing CsA vs. placebo, the results indicated that CsA treatment increases CR, and TR and decreases proteinuria, serum creatinine, and plasma cholesterol. However, the patients from two selected studies included adults, and there was only one study on children. More studies on children or adults should be conducted to broadly assess the efficacy of CsA in the treatment of SRNS. CsA treatment did not increase rates of serious adverse events, such as infections or hypertension, but it did increase rates of gum hyperplasia. These results indicate that the CsA might be a good agent for the treatment of SRNS.
We also performed comparisons of CsA vs. CYC and CsA vs. TAC. CsA treatment results in a higher TR when compared to CYC. The CsA group also had a higher CR than the CYC group, although this difference was not significant. However, the number of included studies was small, and more investigations are needed to confirm these findings. In comparing CsA vs. TAC, the results indicated no group differences in TR, CR or adverse events. This may indicate that CsA has similar efficacy and safety to TAC. CsA and TAC are two most important members of calmodulin inhibitors, and the efficacy and safety may be due to this similarity.
The number of included studies used to assess differences between CsA and mycophenolate mofetil (MMF) in the treatment of SRNS in the current analysis was small. Geng et al. [18] compared the efficacy and safety of CsA versus MMF in the treatment of children suffering from primary refractory nephrotic syndrome, and reported that CsA was superior to MMF in preventing relapses in children with frequently relapsing nephrotic syndrome and inducing complete remission in SRNS patients. Although most patients with SRNS are able to tolerate CsA and MMF, the toxicity and safety of CsA should be monitored closely. More RCTs should be conducted to assess the differences between CsA and MMF in the treatment of SRNS.  There have been two previous two meta-analyses assessing the efficacy of CsA in the treatment of SRNS. Jiang et al. [23] conducted a meta-analysis to detect the efficacy of CsA, TAC, and CYC in treating SRNS, and included four studies of CsA. They reported that CsA has superior efficacy compared to CYC and placebo. Hodson et al. [24] reported that CsA significantly increases the number of children who achieve CR when compared with P/NT. In our meta-analysis, we also assessed the safety of CsA in the treatment of SRNS, and found it to be a safe and effective immunosuppressive agent in the treatment of children with SRNS.
We used the modified Jadad Scale to score the included trials and observed that only one study [17] was scored less than 3. We excluded, performed the metaanalysis again, and the results were similar to the initial analysis. However, the number of included studies in the current analyses was small, and additional analyses should be conducted to confirm the present findings.
There were some limitations in the current metaanalysis. Most of studies were of children, but some studies included both children and adults. Independent assessment of the efficacy and safety of CsA in the treatment of SRNS in children and adults is needed. The target renal histological characteristics were MCD, mesangioproliferative glomerulonephritis, MN or FSGS, but not all the studies included these histological characteristics, which increased heterogeneity among the recruited studies.

Conclusions
In the current meta-analysis, we conclude that CsA is an effective and safe therapy for SRNS. However, additional RCT studies are needed to thoroughly assess the role of CsA in the treatment of SRNS.