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 steroid-dependent 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.

Methods

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 meta-analysis; (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/m2/hr. (children) or 0.2 g/day (adults), for three non-consecutive days. PR was defined as the proteinuria < 40 mg/m2/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.

The extraction data included the (1) the first author and publication year, (2) study design features, (3) baseline characteristics of study participants, and (4) study outcomes (e.g., efficacy and safety outcomes). The P(opulation) I(ntervention) C(omparison) O(utcome) of the study were defined as follows: P: Patients with SRNS; I: treated with CsA, CYC, tacrolimus (TAC) or placebo/not treatment (P/NT); C: CsA vs. placebo/nontreatment (P/NT), CsA vs. cyclophosphamide (CYC), CsA vs. TAC; O: CR, TR, urine erythrocyte number, proteinuria levels, albumin, proteinuria, serum creatinine, and plasma cholesterol, etc.

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. 1.

    Was the trial random?

  2. 2.

    Was the randomization procedure adequately explained?

Allocation concealment:

  1. 1.

    Did the trial use a random assignment method?

  2. 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. 1.

    Was the trial double-blind?

  2. 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 I2 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 I2 < 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.

Results

Search results

Seven randomized controlled trials [16,17,18,19,20,21,22] related to CsA for SRNS were included (Table 1), three studies [17, 19, 21] for CsA vs. Placebo and two studies [16, 22] for CsA vs. TAC (Table 1). The quality assessment details, obtained using the Modified Jadad Scale, are presented in Table 2.

Table 1 Characteristics of the studies included in this meta-analysis
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Table 2 Quality Assessment of Included Studies (7-point)
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The comparison of CsA vs. placebo/nontreatment (P/NT)

Three studies [17, 19, 21] were included in the meta-analysis 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), and TR (OR = 16.70, 95% CI: 4.69–59.49, P < 0.0001; Fig. 1). The CsA treatment group displayed elevated levels of albumin when compared with the P/NT group, although this was not statistically different (WMD = 3.38, 95% CI: − 2.30-9.06, P = 0.24; Fig. 1). The CsA group had lower levels of proteinuria, serum creatinine, and plasma cholesterol when compared with the P/NT group (proteinuria: WMD = -93.47, 95% CI: − 108.52 to − 78.42, P < 0.00001; serum creatinine: WMD = -16.08, 95%CI: − 23.43 to − 8.73, P < 0.0001; plasma cholesterol: WMD = -0.03, 95% CI: − 0.04 to − 0.03, P < 0.00001; Fig. 1).

Fig. 1
figure 1

Assessment of the efficacy of CsA in patients with SRNS. SRNS: steroid-resistant nephrotic syndrome; CsA: cyclosporine A; CR: complete remission; TR: total remission, complete or partial remission, M-H: Mantel-Haenszel

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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 CYC group (OR = 12.83, 95% CI: 3.85–42.81, P < 0.0001). The CsA group had a higher CR than the CYC group, although there was no statistical difference (OR = 1.59, 95% CI: 0.33–7.76, P = 0.57).

Comparing CsA vs. TAC

Two studies [16, 22] of CsA vs. TAC were included into the meta-analysis to assess the efficacy of CsA in patients with SRNS. There were no significant group differences in CR or TR (CR: OR = 1.71, 95%CI: 0.58–5.04, P = 0.33; TR: OR = 0.50, 95% CI: 0.10–2.44, P = 0.39).

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 meta-analysis 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 meta-analysis. 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.