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Clinical Research
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Tacrolimus Monotherapy after Intravenous Methylprednisolone in Adults with Minimal Change Nephrotic Syndrome

Xiayu Li, Zhangsuo Liu, Li Wang, Rong Wang, Guohua Ding, Wei Shi, Ping Fu, Yani He, Genyang Cheng, Shukun Wu, Bing Chen, Juan Du, Zhiming Ye, Ye Tao, Bengang Huo, Heng Li and Jianghua Chen
JASN April 2017, 28 (4) 1286-1295; DOI: https://doi.org/10.1681/ASN.2016030342
Xiayu Li
*Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China;
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Zhangsuo Liu
†Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China;
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Li Wang
‡Department of Nephrology, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, Chengdu, China;
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Rong Wang
§Department of Nephrology, Shandong Provincial Hospital Affiliated with Shandong University, Jinan, China;
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Guohua Ding
‖Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China;
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Wei Shi
¶Nephrology Division, Guangdong General Hospital, Guangzhou, China;
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Ping Fu
**Division of Nephrology, West China Hospital of Sichuan University, Chengdu, China; and
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Yani He
††Department of Nephrology, Daping Hospital, Research Institute of Surgery, Third Military Medical University, Chongqing, China
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Genyang Cheng
†Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China;
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Shukun Wu
‡Department of Nephrology, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, Chengdu, China;
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Bing Chen
§Department of Nephrology, Shandong Provincial Hospital Affiliated with Shandong University, Jinan, China;
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Juan Du
‖Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China;
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Zhiming Ye
¶Nephrology Division, Guangdong General Hospital, Guangzhou, China;
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Ye Tao
**Division of Nephrology, West China Hospital of Sichuan University, Chengdu, China; and
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Bengang Huo
††Department of Nephrology, Daping Hospital, Research Institute of Surgery, Third Military Medical University, Chongqing, China
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Heng Li
*Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China;
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Jianghua Chen
*Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China;
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Abstract

Glucocorticoid treatment is the first choice therapy for adults with minimal change nephrotic syndrome; however, this therapy associates with many adverse effects. Tacrolimus may be an alternative to conventional glucocorticoid therapy. To investigate this possibility, we conducted a prospective, randomized, controlled trial (WHO International Clinical Trials Registry Platform: ChiCTR-TRC-11001454) in eight renal units across China. We randomized enrolled patients with adult–onset minimal change nephrotic syndrome (n=119) to receive glucocorticoid therapy or tacrolimus after intravenous methylprednisolone (0.8 mg/kg per day) for 10 days. Patients received a conventional glucocorticoid regimen or tacrolimus monotherapy, starting with 0.05 mg/kg per day (target trough whole–blood level of 4–8 ng/ml) for 16–20 weeks and subsequently tapering over approximately 18 weeks. Remission occurred in 51 of 53 (96.2%; all complete remission) glucocorticoid-treated patients and 55 of 56 (98.3%; 52 complete and three partial remission) tacrolimus-treated patients (P=0.61 for remission; P=0.68 for complete remission). The groups had similar mean time to remission (P=0.55). Relapse occurred in 49.0% and 45.5% of the glucocorticoid- and tacrolimus-treated patients, respectively (P=0.71), with similar time to relapse (P=0.86). Seven (13.7%) glucocorticoid-treated and four (7.3%) tacrolimus-treated patients suffered frequent relapse (P=0.28); five glucocorticoid-treated and two tacrolimus-treated patients became drug dependent (P=0.26). Adverse events occurred more frequently in the glucocorticoid group (128 versus 81 in the tacrolimus group). Seven adverse events in the glucocorticoid group and two adverse events in the tacrolimus group were serious. Consequently, tacrolimus monotherapy after short–term intravenous methylprednisolone is noninferior to conventional glucocorticoid treatment for adult–onset minimal change nephrotic syndrome in this cohort.

  • tacrolimus
  • monotherapy
  • adults
  • minimal change nephrotic syndrome
  • clinical trial

Minimal change nephrotic syndrome (MCNS) accounts for 10%–25% of all nephrotic syndromes affecting adults.1,2 Glucocorticoids (GCs) are the first-line therapy for adults with MCNS according to the Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines.3 Their use has affected a remission in approximately 80% of patients with MCNS.2–5 However, MCNS remains a therapeutic challenge for physicians, because 48%–76% of initially steroid–responsive patients with MCNS experience at least one relapse, whereas up to one third of patients frequently relapse or become steroid dependent, necessitating the use of a high cumulative dose of GCs.2–6 The adverse effects of long–term GC treatment include osteoporosis, infection, psychosis, cataract, hypertension, diabetes mellitus, gastrointestinal bleeding, and obesity, many of which are serious afflictions.6–9 Second– or third–line immunosuppressive agents, such as cyclophosphamide, calcineurin inhibitors (CNIs), mycophenolate mofetil, and rituximab, have been used to reduce or alleviate the adverse effects of GCs in these patients.2,3,8–11 Therefore, care must be taken to balance the risks and benefits of GCs for the treatment of adult MCNS. Ideal regimens in the treatment of adult MCNS should comprise rapid induction, longer–term sustained remission, and fewer adverse effects.

The theory that T and/or B cell–mediated events result in the production of a yet to be identified circulating factor that harms glomerular cells, causing MCNS, is well documented.12,13 In addition, the roles of two podocyte proteins (i.e., CD80 and angiopoietin-like protein 4) have been explored in MCNS.13–15 Tacrolimus (TAC) is a stronger suppressor of the immune system, most notably of T cells, than cyclosporin and differs in the nature of its cytokine suppression. This may explain its differential effect on proteinuria in nephrotic syndromes, particularly MCNS.16 Interestingly, recent findings showed that the additional effect of TAC on proteinuria was a result of the stabilization of the actin cytoskeleton or reduction of angiopoietin-like protein 4 levels in podocytes.17,18 These results suggest that the antiproteinuric effect of TAC is independent of its immunosuppressive effect and instead, results from a direct effect on podocytes, indicating its potential application in the treatment of MCNS. Several previous studies have reported the use of TAC for the treatment of refractory MCNS in adult and pediatric patients.10,19–22 A controlled trial suggested that TAC might be a promising alternative to cyclosporin because of its lower risk of relapse and lack of cosmetic adverse effects.21 We have previously published a case series with TAC as the preferred CNI for the treatment of adults with steroid-dependent and steroid-resistant MCNS, showing that TAC was a more effective and safe treatment alternative for such patients.19,20 In addition, our group recently found that TAC might be a potential rescue therapy of adult patients with MCNS irresponsive to a steroid (or a steroid combined with another immunosuppressive drug) treatment or who developed reversible acute renal failure.23,24

Despite these promising results, further research is warranted to determine if TAC monotherapy has fewer adverse effects than observed for steroid therapy to successfully replace steroids as the primary course of therapy for patients with MCNS. This multicenter, randomized trial tested this hypothesis by comparing a new strategy of short–term intravenous methylprednisolone followed by TAC monotherapy with conventional GC treatment in adult patients with MCNS.

Results

Patients

One hundred nineteen adult patients admitted between September 28, 2011 and May 10, 2013 at eight clinical centers were randomly enrolled into the trial (Figure 1). Fifty-six and sixty-three patients were assigned to the GC group and the TAC group, respectively. The baseline characteristics of the two groups were similar (Table 1). One hundred nine patients (53 in the GC group and 56 in the TAC group) completed at least 12 weeks of therapy and were included in the subsequent evaluation of efficacy. One hundred patients (47 in the GC group and 53 in the TAC group) completed at least 24 weeks of therapy. One patient from each group discontinued treatment due to serious adverse events (AEs)—severe abdominal cavity infection in the GC group and reversible acute nephrotoxicity in the TAC group.

Figure 1.
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Figure 1.

Flow chart of study populations, including the number of patients who were assessed for eligibility, underwent randomization, and completed the study treatment. Of 162 patients assessed for eligibility, 43 patients were withdrawn, 119 patients were randomly enrolled in GC group (n=56) or TAC group (n=63). One hundred patients (47 in the GC and 53 in the TAC group) completed at least 24 weeks of therapy.

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Table 1.

Baseline characteristics of participants

A second renal biopsy was performed in some patients because of no remission, partial remission, or relapses (five and four in the GC and TAC groups, respectively), resulting in a modification of the initial histopathologic pattern in four patients (two each in the GC and TAC groups) from minimal change nephropathy to FSGS.

The mean dose of TAC administered was 2.8±1.3 mg/d (corresponding to 0.05±0.02 mg/kg per day) during the first 20 weeks of treatment and 2.2±1.7 mg/d (corresponding to 0.04±0.03 mg/kg per day) during the following 16 weeks.

Primary Outcomes

Efficacy

The treatment efficacy was evaluated on the basis of the outcome of patients who completed at least 12 weeks of therapy. The study was designed as a noninferiority trial to determine whether the difference in the remission (either complete or partial remission) rates between the GC and TAC groups was not >9.5%. The remission rates were 96.2% (51 of 53) and 98.3% (55 of 56) in the GC and TAC groups, respectively (P=0.61), and could be evaluated with a 95% confidence interval (95% CI) for difference (95% CI, −6% to 10%) in noninferiority of the TAC group. Complete remission was experienced by 51 of 53 patients (96.2%) in the GC group and 52 of 56 patients (92.9%) in the TAC group (P=0.68) (Figure 2). The mean time to remission was similar in the GC (2.7±2.3; range =0.6–12.6 weeks) and TAC (2.6±2.6; range =0.9–16.0 weeks) groups (P=0.55). Patients who showed no remission because of persistent severe proteinuria (two in the GC group and one in the TAC group) were recommended to receive the exchange protocol. One of these two patients in the GC group achieved complete remission after switching to the TAC protocol; the other patient exhibited resistance to both TAC and combined TAC and GC therapy and was rediagnosed with FSGS after repeat renal biopsy. The one patient with exhibiting resistance to TAC showed no response after switching to the GC protocol.

Figure 2.
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Figure 2.

Percentage of patients who achieved complete remission (CR) and partial remission (PR) during the 36 weeks of therapy. The treatment efficacy was evaluated on the basis of the outcome of patients who completed at least 12 weeks of therapy. The remission rate was 96.2% (51 out of 53 patients) and 98.3% (55 out of 56 patients) in the GC and TAC group, respectively (P=0.61). Complete remission was experienced by 51 out of 53 patients (96.2%) in the GC group and 52 out of 56 patients (92.9%) in the TAC group (P=0.68). Three patients (2 in the GC group and 1 in the TAC group) showed no remission. G, GC group; T, TAC group.

Changes in the Proteinuria and Serum Albumin Levels

Figure 3 shows the proteinuria and serum albumin levels of the patients before the start and at the regular checkups after the start of GC and TAC treatments. No significant differences were observed in mean proteinuria during therapy between the two groups (P>0.05). The differences in the mean serum albumin levels between the two groups during the treatment period were not statistically significant (P>0.05).

Figure 3.
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Figure 3.

Changes in proteinuria and serum albumin levels at baseline and during the 36 weeks of therapy. (A) Proteinuria and (B) serum albumin before therapy (week 0) and during the 36 weeks of therapy. No significant differences between the two groups were observed in mean proteinuria and serum albumin levels before therapy and during the 36 weeks of therapy (P>0.05).

Secondary Outcomes

Relapses

The incidence of relapse in both treatment groups is presented in Table 2. Among those patients who experienced remission, 26 of 51 (51.0%; GC) and 30 of 55 (54.5%; TAC) patients who underwent remission sustained the remission successfully (P=0.71). The mean time to relapse was similar between the GC (24.2±15.4; range =4.0–55.0 weeks) and the TAC (23.3±16.9; range =1.5–54.0 weeks) groups (P=0.86). The Kaplan–Meier curves show the probability of first relapse at different time points between the GC and TAC groups (P=0.81; log rank test) (Figure 4). Frequent relapses were observed in seven (13.7%; GC) and four (7.3%; TAC) patients (P=0.28), whereas five and two patients in the GC and TAC groups, respectively, became drug dependent (P=0.26). There were five late nonresponders (three in the GC group and two in the TAC group).

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Table 2.

The incidence of relapses in GC and TAC groups

Figure 4.
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Figure 4.

The incidence of the first relapse in the GC and TAC groups. Kaplan-Meier curves show the probability of the event (first relapse) at different time points between the GC and TAC groups (P=0.81 by long rank test). Point 0 represents onset of remission.

Renal Function

Four (7.1%) patients in the GC group and three (4.8%) in the TAC group suffered AKI. One patient in the TAC group developed exacerbated AKI, with an increase in serum creatinine (SCr) levels from 75 μmol/L before TAC therapy to 156 μmol/L after 1 week of therapy; the SCr decreased from 156 to 76 μmol/L after TAC treatment was discontinued for 1 week. The other patients in both groups suffered AKI because of a rapid decrease in the serum albumin levels during the relapse period. The changes in the SCr and eGFR levels during the treatment period and the final follow-up period are presented in Figure 5. The SCr and eGFR levels did not differ significantly between the GC and TAC groups (P>0.05). Repeat renal biopsies were performed in four patients after initiation of TAC. No evidence of TAC nephrotoxicity was observed in the sections obtained from patients.

Figure 5.
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Figure 5.

Changes in SCr and eGFR levels at baseline, during the periods of therapy and follow-up. SCr (A) and eGFR (B) before therapy (week 0), during the periods of therapy and follow-up. The SCr and eGFR levels before therapy, during the periods of therapy and follow-up did not differ significantly between the GC and TAC groups (P>0.05).

Changes in Metabolic Indices and Quality of Life

The changes in metabolic indices during therapy with GC or TAC are presented in Supplemental Table 1. New–onset overweight characteristics (body mass index of 25 to approximately 29.9 kg/m2) were observed in six (10.7%; GC) and zero (TAC) patients (P=0.01). New–onset glucose intolerance was observed in six (10.7%; GC) and four (6.4%; TAC) patients, and new–onset diabetes mellitus was observed in three patients of the GC group. Dyslipidemia after the 12-week therapy was still observed in 11 (19.6%; GC) patients and three (4.8%; TAC) patients who required statin therapy. New-onset hyperuricemia was observed in six (10.7%; GC) patients and 11 (17.5%; TAC) patients, of whom nine showed reversal after cessation of TAC therapy. New-onset hypertension occurred in ten (17.9%; GC) patients versus four (6.4%; TAC) patients who required antihypertensive medication.

Eight dimensions of the 36-item short form health survey (SF-36; physical functioning, mental health, physical role, bodily pain, general health, vitality, social functioning, and emotional role) were similar among the patients of the GC and TAC groups at all time points.

AEs

Two hundred nine AEs (128 and 81 in patients in the GC and TAC groups, respectively) were recorded in 92 patients (49, GC; 43, TAC) (Table 3); of these, nine (seven and two in the GC and TAC groups, respectively) were deemed as serious AEs that needed hospital treatment. The most common AEs observed in the two groups were infections, hepatotoxicity, gastrointestinal symptoms, and new-onset hypertension. The patients in the GC group had some additional AEs, including metabolic disorders, osteoporosis, Cushing syndrome, purple stripes, and acne; those in the TAC group also had reversible hyperuricemia.

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Table 3.

AEs and serious AEs for GC and TAC therapy

Discussion

This study suggests that TAC monotherapy after short–term intravenous methylprednisolone is noninferior to conventional steroid therapy in inducing remission. A similar percentage of patients in the GC (96.2%) and TAC (98.3%) groups showed remission (complete or partial), with 96.2% (GC) and 92.9% (TAC) of the patients experiencing complete remission. Previous studies showed that GC therapy resulted in remission in approximately 80% of adults with MCNS, with 50% of the patients responding by 4 weeks, and 10%–25% of the patients requiring 12–16 weeks of therapy.2,4,5 However, the majority (over 90%) of the patients in this trial had attained remission by 4 weeks, and the mean time to remission was similar between the two groups. The optimal dose, trough level, and duration of TAC therapy remain unknown, because they are solely on the basis of case series reports.19–21 In this trial, we found that a mean TAC dose of 0.05 mg/kg per day, with trough levels ranging from 4 to 8 ng/ml, was sufficient to induce remission in the majority of the patients with MCNS.

Relapse rates in adults with MCNS are high. Case series data show that 48%–76% of the patients experience at least one relapse after steroid-induced remission, which is often accompanied by frequent relapses or steroid dependence.4–6,25,26 Furthermore, in previous studies, the relapse group showed a significantly higher frequency of steroid AEs, such as cataract and osteoporosis, compared with the nonrelapse group.6,7,26 Steroid-sparing agents, such as cyclophosphamide, CNIs, and mycophenolate mofetil, are recommended to avoid steroid dependence.3 A recent trial indicated the efficacy of rituximab in childhood–onset nephrotic syndrome, complicated frequent relapses, and steroid dependence.11 In our previous study, we showed that steroid–dependent/steroid–resistant adult patients with MCNS undergoing TAC therapy experienced relapse rates of approximately 40%–50%.20,21 This trial showed the occurrence of relapse in 49.0% and 45.5% of the patients treated with GC and TAC, respectively; frequent relapses also occurred at similar rates in both groups (13.7% versus 7.3%, respectively). Because of the high relapse rate observed using this particular treatment regimen, future research is warranted to evaluate whether extending the duration of TAC therapy would result in fewer patients with relapse.

AKI in the presence of MCNS has been well documented and typically occurs in 25%–30% of the adult patients.5,27 Waldman et al.5 retrospectively examined 95 adults with MCNS, 25.2% of who met the criteria for AKI during initial presentation or relapse. In this trial, AKI was observed in 7.1% (GC) and 4.8% (TAC) of the patients, and the most common cause of AKI was relapse with a rapid decrease in serum albumin levels. Indeed, AKI in MCNS could be consistent with a sudden decreasing in serum albumin levels and severe plasma volume depletion.5,24,27 Additionally, acute nephrotoxicity is a concern, because TAC is a CNI.28 To reduce the risk of acute CNI nephrotoxicity in this study, a short–term intravenous methylprednisolone infusion before TAC treatment was administered, and patients with SCr levels >133 μmol/L and/or AKI were excluded. Furthermore, long-term use of a CNI is associated with chronic nephrotoxicity.28,29 The SCr and eGFR levels remained stable in all patients of this study after TAC or GC therapy. These favorable results may be attributed to our use of a relatively low TAC dosage and short treatment course. There is no evidence of chronic CNI nephrotoxicity on the basis of repeat renal biopsies of TAC-treated patients. However, the repeat renal biopsies were acquired from only four patients who underwent short–term follow-up periods.

In this trial, changes in metabolic indices and disorders, such as dyslipidemia, glucose intolerance or diabetes mellitus, hyperuricemia, and being overweight, during the treatment with GC and TAC were assessed. Interestingly, a greater number of patients in the GC group developed metabolic disorders (characteristics of being overweight, dyslipidemia, and glucose intolerance or new–onset diabetes mellitus). Previous studies have reinforced the association between metabolic disorders and all-cause mortality.30–33 TAC therapy has been reported to cause new–onset diabetes mellitus and hyperuricemia more often in kidney transplant recipients.34,35 Here, the number of patients with new-onset hyperuricemia was higher in the TAC group; however, in the majority of the patients, this was reversed after TAC discontinuation.

The incidence of overall AEs tended to be more frequent in the GC group compared with that in the TAC group. No significant differences in the onset of infections, hepatotoxicity, and gastrointestinal symptoms were observed between the two groups. However, osteoporosis, new-onset hypertension, and symptoms affecting the skin, muscles, and joints occurred more frequently in patients who received GC therapy.

There are some limitations to our study. First, the number of participants included was relatively small. However, this limitation does not diminish the importance of our findings, because the data used for the design of treatments for initial MCNS in adults are limited to case reports and case series. Second, the follow-up period was relatively short. We plan to follow these patients for a longer period of time to assess relapse occurrence, renal function, and AEs.

In conclusion, the results of our trial suggest that TAC monotherapy after short–term intravenous methylprednisolone is noninferior to conventional GC treatment for adult-onset MCNS. This conclusion is on the basis of the similar remission and relapse rates observed in both treatment groups. Metabolic disorders occurred more frequently in the patients of the GC group. In addition, patients in the GC group had a higher number of AEs. Therefore, TAC monotherapy after short–term intravenous methylprednisolone could be considered an alternative to conventional GC therapy for adult-onset MCNS. In future studies, it would be worthwhile to investigate if this novel treatment regimen could be used as the initial therapeutic course for MCNS in adults and children.

Concise Methods

Study Design

In this prospective, open label, multicenter, randomized, controlled trial, we compared a TAC monotherapy regimen after short–term intravenous methylprednisolone with conventional GC treatment for adult-onset MCNS. The study protocol was registered at the Chinese Clinical Trial Registration of the World Health Organization International Clinical Trials Registry Platform (no. ChiCTR-TRC-11001454). Detailed information is available at http://www.chictr.org.cn/. The trial was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained from the research ethics committees of all participating hospitals. All patients provided informed consent.

Participants

In this trial, patients were recruited from eight nephrology centers across China. The inclusion criteria were as follows: age 18–65 years old; renal biopsy–verified diagnosis of minimal change nephropathy (examined using light microscopy, immunofluorescence, and electron microscopy); new–onset nephrotic syndrome (proteinuria >3.5 g/d and serum albumin <30 g/L); initial SCr level of <133 μmol/L; and urine volume of >600 ml/d (or >1000 ml/d after the use of diuretic drugs). Patients with the following conditions were excluded: secondary minimal change disease, AKI, hepatitis B or C infection, diabetes mellitus, a history of pancreatitis or gastrointestinal ulcer, a history of congenital or acquired immunodeficiency, or previous treatment with corticosteroids or other immunosuppressants (e.g., cyclophosphamide, CNIs, or mycophenolate mofetil).

Randomization and Treatment Procedures

After the confirmation of eligibility, the patients were randomly assigned (1:1) to one of two groups (according to a random number label): (1) GC group: short–term intravenous methylprednisolone followed by a conventional tapering oral prednisone regimen or (2) TAC group: short–term intravenous methylprednisolone followed by TAC monotherapy. The minimization method was applied using a computer-generated sequence.

All patients received an intravenous methylprednisolone (0.8 mg/kg per day) infusion for 10 consecutive days at hospital admission. In the GC group, patients subsequently received oral prednisone at 1 mg/kg per day (maximum 80 mg/d) for 6–8 weeks according to the treatment response. This dose was subsequently reduced by 5 mg every week to 30 mg on alternate days and maintained for 8 weeks followed by tapering of the dose over approximately 12 weeks until complete withdrawal. In the TAC group, TAC therapy was initiated on the eighth day, with an initial oral dose of 0.05 mg/kg per day (that was divided into two doses administered over a 12-hour interval). The TAC dosage was adjusted to a target trough whole–blood level of 4–8 ng/ml and maintained for 16–20 weeks according to the treatment response. Subsequently, the dose was tapered to achieve a target trough level of 2–5 ng/ml over approximately 18 weeks until complete withdrawal. The treatment course for both groups was 36 weeks. The treatment was prolonged by 8 weeks for patients who underwent partial remission after 12 weeks of therapy. Patients who showed no remission after 12 weeks of therapy with GC or TAC were recommended to withdraw from the trial and undertake the other treatment trial (TAC monotherapy or conventional GC therapy). Patients who relapsed during the therapy were treated with a second cycle of GC or TAC therapy. Patients who relapsed twice were recommended to withdraw from the study.

The dose of angiotensin–converting enzyme inhibitors or angiotensin II receptor blockers used by the respective patients was maintained for the duration of therapy. If required, additional antihypertensive drugs were administered to achieve adequate BP control. Statins were administered to those patients who still had dyslipidemia after 12 weeks of therapy.

Definitions and Outcome Measures

Complete remission was defined as a decrease in proteinuria to ≤0.3 g/d. Partial remission was defined as a decrease in proteinuria to <3.5 g/d but >0.3 g/d. The persistence of nephrotic proteinuria after 12 weeks of treatment with prednisone (1.0 mg/kg per day) or oral TAC (with a trough whole–blood level of 4–8 ng/ml) was considered to be no remission (treatment resistance). The time to remission was defined as the time from the initiation of the therapy to the day when remission (complete or partial remission) was observed. Relapse was defined as an increase in proteinuria to ≥3.5 g/d in patients who underwent partial or complete remission. Time to relapse was defined as the time from initiation of remission to the day when the first relapse occurred. Frequent relapse was defined as two or more relapses within 6 months of the initial response or four or more relapses in any 12-month period, and patients with two consecutive relapses during steroid (or TAC) therapy or within 14 days of ceasing therapy were considered to be drug (steroid or TAC) dependent. Late nonresponder was defined as no response to the second period of steroid or TAC therapy after relapsing during tapering or discontinuation of steroid or TAC therapy. AKI was defined as an increase in SCr to >50% above baseline or >26.4 μmol/L during 48 hours according to KDIGO guidelines.

The primary outcome measures were the cumulative numbers of patients who experienced complete remission or partial remission. Secondary outcome measures were determined using the following variables: relapse, time to remission, time to relapse, changes in the SCr and eGFR levels, AKI, metabolic disorders (being overweight, glucose intolerance, diabetes mellitus, dyslipidemia, and hyperuricemia), AEs, and serious AEs.

Follow-Up

In this trial, the follow-up duration was 64 weeks after therapy. Follow-ups were performed weekly for the first 4 weeks, every 4 weeks for the subsequent 36 weeks, and every 8 weeks thereafter. During each visit, the patients underwent anthropometric measurements (body weight and standing height) and BP measurements. Complete blood count, proteinuria, blood glucose, SCr, serum uric acid, lipid profile, albumin, alanine aminotransferase, and aspartate aminotransferase levels were determined. The trough TAC level was measured every week until stable followed by measurements every 4 weeks. The body mass index (weight in kilograms divided by the square of the height in meters) was measured, and the questionnaire SF-36 and bone mineral density measurement (with dual energy x-ray absorptiometry) were performed at the baseline and every 12 weeks.

Sample Size

TAC therapy was hypothesized to be noninferior to GC therapy in achieving remission. On the basis of the results of previous studies and our observations that the remission rates of GC and TAC therapy in adult-onset MCNS were 80% and 90%, respectively,2–5,19,20 a sample size of 54 patients in each group (total of 108 patients) was required to determine that TAC therapy was not >9.5% inferior to GC therapy with a type 1 error probability of 2.5% and a power of 80% according to the formulas by Gart and Nam.36 Allowing for an expected dropout rate of 10%, we aimed at enrolling 120 patients.

Statistical Analyses

All efficacy analyses were on the basis of the intention-to-treat principle, comparing groups according to the randomly assigned treatment. For the primary efficacy analysis for noninferiority, we carried out a per-protocol analysis, which included patients who received protocol treatments as scheduled. Noninferiority was assessed by estimating the two–sided 95% CI for the difference in remission rates between the GC and TAC groups using the method by Gart and Nam36 and verifying that the lower limit of the 95% CI was not lower than −9.5%. The 9.5% margin was on the basis of clinical adjustment.

All data were expressed as the mean±SD or median (interquartile range) for continuous variables and percentage for categorical variables. The differences in normally distributed continuous variables between two groups were compared using the two–tailed independent sample paired t test. A paired t test was performed to compare two means obtained at different times during the therapy. Nonparametric variables obtained at different times were compared using the Wilcoxon signed rank test, and categorical variables were compared by Fisher exact or chi-squared test. The probability of the first relapse between two groups was estimated by the Kaplan–Meier method, and survival curves were compared with log rank tests. A P value <0.05 was considered statistically significant. All statistical analyses were performed using the SAS software, version 9.2.

Disclosures

None.

Acknowledgments

We thank Dr. Huiping Wang for reviewing the renal biopsies of the patients and Dr. Xiuyang Li (College of Medicine, Zhejiang University) for reviewing the statistical analyses. Dr. Rong Lv, Fei Han, Qun Li, Xuelin He, Rending Wang, and Wenhan Peng were in charge of patient care and follow-up.

This trial was supported, in part, by National Nature Science Foundation of China grants 2011BAI10B07, 2012CR517603, and 2012AA02A512.

The funding source had no role in the design of the study, data collection, data analysis, data interpretation, or writing of the manuscript.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

  • This article contains supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2016030342/-/DCSupplemental.

  • Copyright © 2017 by the American Society of Nephrology

References

  1. ↵
    1. Bargman JM
    : Management of minimal lesion glomerulonephritis: Evidence-based recommendations. Kidney Int Suppl 70: S3–S16, 1999pmid:10369190
    OpenUrlPubMed
  2. ↵
    1. Hogan J,
    2. Radhakrishnan J
    : The treatment of minimal change disease in adults. J Am Soc Nephrol 24: 702–711, 2013pmid:23431071
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephrits Work Group
    : KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl 2: 139–274, 2012
    OpenUrlCrossRef
  4. ↵
    1. Szeto CC,
    2. Lai FM,
    3. Chow KM,
    4. Kwan BC,
    5. Kwong VW,
    6. Leung CB,
    7. Li PK
    : Long-term outcome of biopsy-proven minimal change nephropathy in Chinese adults. Am J Kidney Dis 65: 710–718, 2015pmid:25465164
    OpenUrlCrossRefPubMed
  5. ↵
    1. Waldman M,
    2. Crew RJ,
    3. Valeri A,
    4. Busch J,
    5. Stokes B,
    6. Markowitz G,
    7. D’Agati V,
    8. Appel G
    : Adult minimal-change disease: Clinical characteristics, treatment, and outcomes. Clin J Am Soc Nephrol 2: 445–453, 2007pmid:17699450
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Shinzawa M,
    2. Yamamoto R,
    3. Nagasawa Y,
    4. Oseto S,
    5. Mori D,
    6. Tomida K,
    7. Hayashi T,
    8. Izumi M,
    9. Fukunaga M,
    10. Yamauchi A,
    11. Tsubakihara Y,
    12. Isaka Y
    : Comparison of methylprednisolone plus prednisolone with prednisolone alone as initial treatment in adult-onset minimal change disease: A retrospective cohort study. Clin J Am Soc Nephrol 9: 1040–1048, 2014pmid:24721890
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Eguchi A,
    2. Takei T,
    3. Yoshida T,
    4. Tsuchiya K,
    5. Nitta K
    : Combined cyclosporine and prednisolone therapy in adult patients with the first relapse of minimal-change nephrotic syndrome. Nephrol Dial Transplant 25: 124–129, 2010pmid:19740915
    OpenUrlCrossRefPubMed
  8. ↵
    1. Bruchfeld A,
    2. Benedek S,
    3. Hilderman M,
    4. Medin C,
    5. Snaedal-Jonsdottir S,
    6. Korkeila M
    : Rituximab for minimal change disease in adults: Long-term follow-up. Nephrol Dial Transplant 29: 851–856, 2014pmid:24121763
    OpenUrlCrossRefPubMed
  9. ↵
    1. Fujiwara A,
    2. Hirawa N,
    3. Kobayashi Y,
    4. Yatsu K,
    5. Katsumata M,
    6. Ehara Y,
    7. Okuyama Y,
    8. Yutoh J,
    9. Kaneda T,
    10. Fujita M,
    11. Yamamoto Y,
    12. Saka S,
    13. Toya Y,
    14. Yasuda G,
    15. Umemura S
    : Efficacy of cyclosporine combination therapy for new-onset minimal change nephrotic syndrome in adults. Clin Exp Nephrol 19: 240–246, 2015pmid:24771147
    OpenUrlCrossRefPubMed
  10. ↵
    1. Gulati A,
    2. Sinha A,
    3. Gupta A,
    4. Kanitkar M,
    5. Sreenivas V,
    6. Sharma J,
    7. Mantan M,
    8. Agarwal I,
    9. Dinda AK,
    10. Hari P,
    11. Bagga A
    : Treatment with tacrolimus and prednisolone is preferable to intravenous cyclophosphamide as the initial therapy for children with steroid-resistant nephrotic syndrome. Kidney Int 82: 1130–1135, 2012pmid:22763815
    OpenUrlCrossRefPubMed
  11. ↵
    1. Iijima K,
    2. Sako M,
    3. Nozu K,
    4. Mori R,
    5. Tuchida N,
    6. Kamei K,
    7. Miura K,
    8. Aya K,
    9. Nakanishi K,
    10. Ohtomo Y,
    11. Takahashi S,
    12. Tanaka R,
    13. Kaito H,
    14. Nakamura H,
    15. Ishikura K,
    16. Ito S,
    17. Ohashi Y; Rituximab for Childhood-onset Refractory Nephrotic Syndrome (RCRNS) Study Group
    : Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: A multicentre, double-blind, randomised, placebo-controlled trial. Lancet 384: 1273–1281, 2014pmid:24965823
    OpenUrlCrossRefPubMed
  12. ↵
    1. Araya C,
    2. Diaz L,
    3. Wasserfall C,
    4. Atkinson M,
    5. Mu W,
    6. Johnson R,
    7. Garin E
    : T regulatory cell function in idiopathic minimal lesion nephrotic syndrome. Pediatr Nephrol 24: 1691–1698, 2009pmid:19495805
    OpenUrlCrossRefPubMed
  13. ↵
    1. Wei C,
    2. Reiser J
    : Minimal change disease as a modifiable podocyte paracrine disorder. Nephrol Dial Transplant 26: 1776–1777, 2011pmid:21414975
    OpenUrlCrossRefPubMed
    1. Clement LC,
    2. Avila-Casado C,
    3. Macé C,
    4. Soria E,
    5. Bakker WW,
    6. Kersten S,
    7. Chugh SS
    : Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. Nat Med 17: 117–122, 2011pmid:21151138
    OpenUrlCrossRefPubMed
  14. ↵
    1. Macé C,
    2. Chugh SS
    : Nephrotic syndrome: Components, connections, and angiopoietin-like 4-related therapeutics. J Am Soc Nephrol 25: 2393–2398, 2014pmid:24854282
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Budde K,
    2. Fritsche L,
    3. Neumayer HH
    : Differing proteinuria control with cyclosporin and tacrolimus. Lancet 349: 330, 1997pmid:9024386
    OpenUrlCrossRefPubMed
  16. ↵
    1. Li JS,
    2. Chen X,
    3. Peng L,
    4. Wei SY,
    5. Zhao SL,
    6. Diao TT,
    7. He YX,
    8. Liu F,
    9. Wei QJ,
    10. Zhang QF,
    11. Li B
    : Angiopoietin-Like-4, a potential target of tacrolimus, predicts earlier podocyte injury in minimal change disease. PLoS One 10: e0137049, 2015pmid:26352670
    OpenUrlCrossRefPubMed
  17. ↵
    1. Liao R,
    2. Liu Q,
    3. Zheng Z,
    4. Fan J,
    5. Peng W,
    6. Kong Q,
    7. He H,
    8. Yang S,
    9. Chen W,
    10. Tang X,
    11. Yu X
    : Tacrolimus protects podocytes from injury in lupus nephritis partly by stabilizing the cytoskeleton and inhibiting podocyte apoptosis. PLoS One 10: e0132724, 2015pmid:26161538
    OpenUrlCrossRefPubMed
  18. ↵
    1. Li H,
    2. Shi X,
    3. Shen H,
    4. Li X,
    5. Wang H,
    6. Li H,
    7. Xu G,
    8. Chen J
    : Tacrolimus versus intravenous pulse cyclophosphamide therapy in Chinese adults with steroid-resistant idiopathic minimal change nephropathy: A multicenter, open-label, nonrandomized cohort trial. Clin Ther 34: 1112–1120, 2012pmid:22503105
    OpenUrlCrossRefPubMed
  19. ↵
    1. Li X,
    2. Li H,
    3. Chen J,
    4. He Q,
    5. Lv R,
    6. Lin W,
    7. Li Q,
    8. He X,
    9. Qu L,
    10. Suya W
    : Tacrolimus as a steroid-sparing agent for adults with steroid-dependent minimal change nephrotic syndrome. Nephrol Dial Transplant 23: 1919–1925, 2008pmid:17911091
    OpenUrlCrossRefPubMed
  20. ↵
    1. Choudhry S,
    2. Bagga A,
    3. Hari P,
    4. Sharma S,
    5. Kalaivani M,
    6. Dinda A
    : Efficacy and safety of tacrolimus versus cyclosporine in children with steroid-resistant nephrotic syndrome: A randomized controlled trial. Am J Kidney Dis 53: 760–769, 2009pmid:19268410
    OpenUrlCrossRefPubMed
  21. ↵
    1. Roberti I,
    2. Vyas S
    : Long-term outcome of children with steroid-resistant nephrotic syndrome treated with tacrolimus. Pediatr Nephrol 25: 1117–1124, 2010pmid:20217433
    OpenUrlCrossRefPubMed
  22. ↵
    1. Li X,
    2. Li H,
    3. Ye H,
    4. Li Q,
    5. He X,
    6. Zhang X,
    7. Chen Y,
    8. Han F,
    9. He Q,
    10. Wang H,
    11. Chen J
    : Tacrolimus therapy in adults with steroid- and cyclophosphamide-resistant nephrotic syndrome and normal or mildly reduced GFR. Am J Kidney Dis 54: 51–58, 2009pmid:19406543
    OpenUrlCrossRefPubMed
  23. ↵
    1. Li X,
    2. Xu N,
    3. Li H,
    4. Han F,
    5. Wang R,
    6. He Q,
    7. He X,
    8. Chen J
    : Tacrolimus as rescue therapy for adult-onset refractory minimal change nephrotic syndrome with reversible acute renal failure. Nephrol Dial Transplant 28: 2306–2312, 2013pmid:23787554
    OpenUrlCrossRefPubMed
  24. ↵
    1. Tse KC,
    2. Lam MF,
    3. Yip PS,
    4. Li FK,
    5. Choy BY,
    6. Lai KN,
    7. Chan TM
    : Idiopathic minimal change nephrotic syndrome in older adults: Steroid responsiveness and pattern of relapses. Nephrol Dial Transplant 18: 1316–1320, 2003pmid:12808168
    OpenUrlCrossRefPubMed
  25. ↵
    1. Takei T,
    2. Koike M,
    3. Suzuki K,
    4. Shirota S,
    5. Itabashi M,
    6. Ohtsubo S,
    7. Sugiura H,
    8. Suzuki K,
    9. Kojima C,
    10. Takahashi M,
    11. Ino J,
    12. Ogawa T,
    13. Uchida K,
    14. Tsuchiya K,
    15. Yumura W,
    16. Nitta K
    : The characteristics of relapse in adult-onset minimal-change nephrotic syndrome. Clin Exp Nephrol 11: 214–217, 2007pmid:17891348
    OpenUrlCrossRefPubMed
  26. ↵
    1. Jennette JC,
    2. Falk RJ
    : Adult minimal change glomerulopathy with acute renal failure. Am J Kidney Dis 16: 432–437, 1990pmid:2239933
    OpenUrlCrossRefPubMed
  27. ↵
    1. Naesens M,
    2. Kuypers DR,
    3. Sarwal M
    : Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 4: 481–508, 2009pmid:19218475
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Morgan C,
    2. Sis B,
    3. Pinsk M,
    4. Yiu V
    : Renal interstitial fibrosis in children treated with FK506 for nephrotic syndrome. Nephrol Dial Transplant 26: 2860–2865, 2011pmid:21303962
    OpenUrlCrossRefPubMed
  29. ↵
    1. Kramer CK,
    2. Zinman B,
    3. Retnakaran R
    : Are metabolically healthy overweight and obesity benign conditions?: A systematic review and meta-analysis. Ann Intern Med 159: 758–769, 2013pmid:24297192
    OpenUrlCrossRefPubMed
    1. Flegal KM,
    2. Kit BK,
    3. Orpana H,
    4. Graubard BI
    : Association of all-cause mortality with overweight and obesity using standard body mass index categories: A systematic review and meta-analysis. JAMA 309: 71–82, 2013pmid:23280227
    OpenUrlCrossRefPubMed
    1. Wu CY,
    2. Chou YC,
    3. Huang N,
    4. Chou YJ,
    5. Hu HY,
    6. Li CP
    : Association of body mass index with all-cause and cardiovascular disease mortality in the elderly. PLoS One 9: e102589, 2014pmid:25014070
    OpenUrlCrossRefPubMed
  30. ↵
    1. Zhou B,
    2. Wu Y,
    3. Yang J,
    4. Li Y,
    5. Zhang H,
    6. Zhao L
    : Overweight is an independent risk factor for cardiovascular disease in Chinese populations. Obes Rev 3: 147–156, 2002pmid:12164466
    OpenUrlCrossRefPubMed
  31. ↵
    1. Batista F,
    2. Auyanet I,
    3. Torregrosa JV,
    4. Oppenheimer F
    : Long-term follow-up after conversion from tacrolimus to cyclosporin in renal transplant patients with new-onset diabetes mellitus after transplantation. Transplant Proc 44: 2582–2584, 2012pmid:23146461
    OpenUrlCrossRefPubMed
  32. ↵
    1. Kanbay M,
    2. Akcay A,
    3. Huddam B,
    4. Usluogullari CA,
    5. Arat Z,
    6. Ozdemir FN,
    7. Haberal M
    : Influence of cyclosporine and tacrolimus on serum uric acid levels in stable kidney transplant recipients. Transplant Proc 37: 3119–3120, 2005pmid:16213325
    OpenUrlCrossRefPubMed
  33. ↵
    1. Gart JJ,
    2. Nam JM
    : Approximate interval estimation of the difference in binomial parameters: Correction for skewness and extension to multiple tables. Biometrics 46: 637–643, 1990pmid:2242407
    OpenUrlCrossRefPubMed
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Journal of the American Society of Nephrology: 28 (4)
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Tacrolimus Monotherapy after Intravenous Methylprednisolone in Adults with Minimal Change Nephrotic Syndrome
Xiayu Li, Zhangsuo Liu, Li Wang, Rong Wang, Guohua Ding, Wei Shi, Ping Fu, Yani He, Genyang Cheng, Shukun Wu, Bing Chen, Juan Du, Zhiming Ye, Ye Tao, Bengang Huo, Heng Li, Jianghua Chen
JASN Apr 2017, 28 (4) 1286-1295; DOI: 10.1681/ASN.2016030342

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Tacrolimus Monotherapy after Intravenous Methylprednisolone in Adults with Minimal Change Nephrotic Syndrome
Xiayu Li, Zhangsuo Liu, Li Wang, Rong Wang, Guohua Ding, Wei Shi, Ping Fu, Yani He, Genyang Cheng, Shukun Wu, Bing Chen, Juan Du, Zhiming Ye, Ye Tao, Bengang Huo, Heng Li, Jianghua Chen
JASN Apr 2017, 28 (4) 1286-1295; DOI: 10.1681/ASN.2016030342
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