Efficacy and safety of tacrolimus versus corticosteroid as initial monotherapy in adult-onset minimal change disease: a meta-analysis

Objective The objective of this meta-analysis was to compare the efficacy and safety of tacrolimus (TAC) monotherapy versus corticosteroid as initial monotherapy in adult-onset minimal change disease (MCD) patients. Methods Databases including PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, and Wanfang database were searched from the inception to March 20, 2021. Eligible studies comparing TAC monotherapy and corticosteroid as initial monotherapy for adult-onset MCD patients were included. Data were analyzed using Review Manager Version 5.3. Results Four randomized controlled trials (RCTs) involving 196 patients were included in the meta-analysis. For initial monotherapy for adult-onset MCD, TAC and corticosteroid had similar complete remission (OR 1.06, 95% CI 0.47–2.41, P = 0.89), total remission (OR 1.30, 95% CI 0.39–4.35, P = 0.67), relapse rate (OR 0.63, 95% CI 0.28–1.42, P = 0.26). Main drug-related adverse effects of two therapeutic regimens had no difference concerning infection (OR 0.54, 95% CI 0.23–1.27, P = 0.15), glucose intolerance (OR 0.55, 95% CI 0.16–1.84, P = 0.33) and acute renal failure (OR 1.37, 95% CI 0.36–7.31, P = 0.71). Conclusion TAC monotherapy is comparable with corticosteroid monotherapy in initial therapy of MCD. To further confirm the conclusion, more large multicenter RCTs are necessary.


Introduction
Minimal change disease (MCD) causes up to 10-15% of primary nephrotic syndrome (NS) in adults [1]. Persistent NS results in infections, thromboembolic events, hyperlipidemia, cardiovascular disease [2][3][4]. Acute kidney injury accompanies the presentation of MCD in up to 20-25% of cases [5]. High doses of corticosteroid have been recommended as initial therapy of MCD according to Kidney Disease Improving Global Outcomes (KDIGO). Compared with children, adults often have a delayed response to corticosteroid [6]. The relapse of adult-onset MCD is over 50%. One-third of patients become frequent relapse or steroid-dependent [7]. This necessitates repeated or long-term use of corticosteroid. However, the adverse effects of highdose corticosteroid also become common, which include in cosmetic changes, weight gain, impaired glucose tolerance, osteoporosis, infection, and gastrointestinal bleeding [8,9]. Tacrolimus (TAC), an immunosuppressive macrolide of calcineurin inhibitors (CIN) group, is a relatively attractive alternative to corticosteroid for treatment of MCD. TAC can suppresses IL-2 transcription, inhibit the growth and differentiation of T cells, thereby reduce the immune damage of podocyte finally [10]. Compared with another calcineurin inhibitors such as ciclosporin, TAC showed stronger immunosuppressive effect and fewer side effects [11][12][13]. Some studies reported successful TAC treatment of frequently Jingkui Lu and Zhongxiu Xu have contributed equally to this work and should be considered as co-first authors.

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relapsing, steroid-dependent, and steroid-resistant MCD [14,15]. However, compared with corticosteroid, the efficacy of TAC monotherapy as the first-line initial agent in adult-onset MCD is uncertain. Our meta-analysis was conducted to compare the efficacy and safety between TAC with corticosteroid in initial monotherapy of adult-onset MCD.

Search strategy
We searched PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, and Wanfang database from the inception to March 20, 2021. The combined text and MeSH terms included minimal change disease, corticosteroid, and tacrolimus. In addition, the cited papers and relevant references were searched manually to identify eligible studies. There was no language restrictions.

Inclusion criteria
The inclusion criteria were defined as follows: 1. Randomized controlled trials (RCTs), cohort or casecontrol studies; 2. Age > 18 years, NS, a kidney biopsy showing MCD and serum creatinine level of < 133 μmol/L; 3. Studies were designed to compare TAC with corticosteroid as initial monotherapy for adult-onset MCD; 4. The main endpoint of the review was complete remission (CR) and total remission (TR). Secondary endpoints were relapse and drug-related adverse effects. CR is defined as proteinuria < 0.3 g/day with normal serum albumin and creatinine. Partial remission (PR) is defined as proteinuria 0.3-3.5 g/day which had declined to ≤ 50% of the baseline value. TR is defined as either CR or PR. Relapse is defined as proteinuria > 3.5 g/d in patients who had achieved CR or PR.

Exclusion criteria
The exclusion criteria were defined as follows: Data extraction and quality assessment Data were extracted independently by two investigators using standard data extraction forms. In the case of disagreement, a third investigator was consulted. We extracted characteristics including first author, year of publication, location, study design, follow-up period, age, sex, sample size, specific drug treatment program, and outcomes. The Cochrane assessment tool was used to evaluate the quality of RCTs [16].

Statistical analysis
We performed the data analysis using Review Manager Version 5.3 (Cochrane Collaboration). Heterogeneity between studies was assessed using I 2 statistics. We considered I 2 > 50% and P < 0.10 to imply significant heterogeneity. Homogeneous data were performed using the fixed-effects model. Heterogeneous data were performed using the random-effects model. We presented categorical variables as Odds Ratios (OR). Summary estimates and 95% confidence intervals (CIs) were calculated. Overall effects were determined by the using Z test. A p value < 0.05 was considered significant. Publication bias was assessed using sensitivity analysis.

Study selection and characteristics
A flow diagram of the selection process is shown in Fig. 1. Finally, four RCTs were included in this analysis [17][18][19][20]. As a whole, 100 patients were included in TAC monotherapy group and 96 patients were included in steroid group. The follow-up period was from 36 to 82 weeks. The risks of bias in included RCTs were moderate. The baseline characteristics of these studies are listed in Table 1. Specific drug treatment program are listed in Table 2. The Cochrane assessment is listed in Table 3.

CR and TR
Data about CR were reported in eight articles, 78/92 (84.8%) for TAC group and 75/89 (84.2%) for steroid group. The heterogeneity among studies was not substantial (P = 0.23, I 2 = 30%), so finally the fixed-effects model was used for the meta-analysis. There was no significant difference between two groups concerning CR (OR 1.06, 95% CI 0.47-2.41, P = 0.89) (Fig. 2). Data about TR were reported in three articles, 60/66 (90.9%) for TAC group and 58/65 (89.2%) for steroid group. The heterogeneity among studies was not substantial (P = 0.66, I 2 = 0%), so finally the fixed-effects model was used for the meta-analysis. There was no significant difference between two groups concerning TR (OR 1.30, 95% CI 0.39-4.35, P = 0.67) (Fig. 3).

Relapse rate
Data about relapse rate were reported in three articles, 26/68 (38.2%) for TAC group and 30/65 (46.2%) for steroid group. The heterogeneity among studies was not substantial (P = 0.91, I 2 = 0%), so finally the fixed-effects model was used for the meta-analysis. Relapse rate of steroid group was higher than TAC group, but the difference was not statistically significant (OR 0.63, 95% CI 0.28-1.42, P = 0.26) (Fig. 4).

Sensitivity analyses
The sensitivity analyses for all outcomes after the two therapy regimens were used to judge the dependability of the    results. We deleted one study at a time, the results of metaanalysis still showed no difference.

Discussion
Corticosteroids are recommended as initial therapy of MCD, which is effective [6]. At the same time, the adverse effects of corticosteroids are significant, so the clinicians need consider alternative treatments. The current guidelines lack advice on the effectiveness of steroid-free regimens used as initial therapy of MCD. In some studies, TAC was reported to be effective in treatment of frequently relapsing, steroiddependent, and steroid-resistant MCD [21][22][23]. Our metaanalysis was conducted to compare the efficacy and safety between TAC monotherapy with corticosteroid monotherapy for initial therapy of MCD. We found that TAC monotherapy is comparable with corticosteroid monotherapy for MCD concerning remission, relapse and drug-related adverse effects. At present, corticosteroid monotherapy is effective in the treatment of MCD, which can achieve CR in 80% of patients with MCD [6]. Our meta-analysis showed that CR of corticosteroid monotherapy group was 84.2% and was comparable to the remission rates reported in other studies. In our meta-analysis TAC monotherapy also achieved high remission rates of 84.8%. In Thomas study included in our meta-analysis, treatment times of TAC or corticosteroid were relatively short, but CR of the two treatment method were both high and close to 90%. In general, TAC  MCD is easy to recur. Our meta-analysis showed that relapse rates were similar in corticosteroid and TAC treatment groups, which were lower than the 48-76% relapse rates reported in other studies [5,9,24,25]. In Li Xiayu and Patil study included in our meta-analysis, the followup time was not long enough, which might not reflect the final relapse rates. Regimens of longer treatment time and higher dose may decrease relapse rates [20].
Long-term use of corticosteroid therapy can increase the incidence of drug-related adverse effects, so clinicians should evaluate the beneficial and adverse effects when prescribing treatment regimens for MCD patients. There are some significant unpleasant cosmetic drugrelated adverse effects associated with corticosteroid such as obesity, acne, striae, and moon facies, which can be debilitating for patients, especially the young adults, and have an impact on adherence with treatment. Neither of these cosmetic drug-related adverse effects occurred in the TAC treatment. Concerning other common adverse effects, such as infection, glucose intolerance, acute renal failure, TAC and corticosteroid have no significant difference. The nephrotoxicity of TAC is of great concern. It has been reported in the literature that the nephrotoxicity of TAC is related to its dose and concentration. The initial dose of TAC was 0.15 mg/kg/d, which can lead to acute reversible nephrotoxicity. The initial dose of TAC was 0.08 mg/kg/d, which do not occur nephrotoxicity [26].
There were some limitations in our meta-analysis. First, there were some differences concerning the specific treatment regimen and definition of outcomes, which might affect the heterogeneity among the studies. Second, most included studies had small sample size and the number of included studies was small, so our meta-analysis may not be adequate to judge effectiveness and safety of the two treatment.

Conclusions
Our meta-analysis revealed TAC monotherapy is comparable with corticosteroid monotherapy in initial therapy of MCD. To further confirm the conclusion, more large multicenter RCTs are necessary.