RESULTS

Analysis set (data set)

Between January 1996 and January 2002, a total of 56 patients were registered at 23 centers and randomly assigned to treatment group (Group A, 29; Group B, 27). One patient was later found to be ineligible, and another patient was lost to follow-up and had no data available. These two patients were excluded from all analyses. All 10 patients enrolled at three particular centers received the regimen for Group A regardless of the assigned treatment (three patients in Group A and seven in Group B); the steering committee decided to exclude these 10 patients from all analyses except for the analysis of adverse events because these three centers were considered to violate the guidelines for good clinical practice in Japan. Therefore, this report is based on 44 patients in the intention-to-treat analysis.

A flow diagram of the patients, summarizing the numbers of patients assigned to treatment, followed up, and included in analyses, is shown in Figure 1. Data from 3 of 17 patients who discontinued the allocated treatment regimen were used as censored observations in the survival analyses: 1 (Group B) because of progression to steroid resistance and 2 because of adverse events (Group A, 1 and Group B, 1).

Figure 1.

Flow diagram of the patients. SRNS, steroid-resistant nephrotic syndrome; FRNS, frequently relapsing nephrotic syndrome.

Full figure and legend (32K)

Patient characteristics

The clinical characteristics of the patients were analyzed to confirm whether major prognostic factors were balanced between the treatment groups. The mean age of the patients was 8.5 years in Group A and 8.9 years in Group B. The demographic characteristics of the patients are shown in Table 1. Before study entry, the number of relapses/year was 3.1 in Group A and 3.6 in Group B (Table 2a, P=0.155). The demographic characteristics of the 10 patients treated at the three excluded centers are also shown in Table 2b.

Table 1 - Patient demographics.

Full table

Table 2a - Relapse rate before entry.

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Table 2b - Relapse rate before entry in 10 patients at the three excluded institutions.

Full table

As for concomitant medications, angiotensin-converting enzyme inhibitors (lisinopril or enalapril) were used in four patients in Group A and one patient in Group B. Calcium channel blockers (nifedipine or amlodipine) were used in two patients in group A and one patient in group B. No patient was prescribed HMG-CoA reductase inhibitors (statins) in either group.

CyA dosage and trough level

The mean dose of CyA required to maintain the whole-blood trough level between 80 and 100 ng/ml during the first 6 months of treatment was 5.4 mg/kg/day in Group A and 4.7 mg/kg/day in Group B (P=0.152). During the next 18 months in Group A, the mean dose of CyA required to maintain a trough level between 60 and 80 ng/ml was 4.8 mg/kg/day (Table 3a). The distribution of the median trough level of CyA during follow-up is shown according to group in Table 3b. During the first 6 months of treatment (the same in both groups), the median trough level of CyA was between 60 and 100 ng/ml in more than 60% of the patients in each group.

Table 3a - Dose of cyclosporine.

Full table

Table 3b - Median trough level of cyclosporine.

Full table

Sustained remission

The estimated relapse rate was 0.34 per year for Group A and 0.93 per year for Group B. The rate of patients with sustained remission is shown according to group in Figure 2. At month 24, the estimated sustained remission rate was significantly higher in Group A (50% ) than in Group B (15% , P=0.006). The hazard ratio for relapse was 0.37 (95% CI: 0.18–0.79, P=0.01) in Group A as compared with Group B.

Figure 2.

Proportion of patients with sustained remission among all patients.

Full figure (15K)

The sustained remission rate among patients without relapse during the first 6 months is shown in Figure 3. At month 24, the estimated sustained remission rate was 57% in Group A and 25% in Group B (P=0.060). The hazard ratio for relapse was 0.43 (95% CI: 0.17–1.09, P=0.075) in Group A as compared with Group B.

Figure 3.

Proportion of patients with sustained remission among patients who had no relapse for the first 6 months.

Full figure (14K)

Progression-free survival

The estimated rate of progression to FRNS was 0.14 per year in Group A and 0.42 per year in Group B. As shown in Figure 4, the progression (to FRNS)-free survival at month 24 was 75% in Group A and 56% in Group B (P=0.16). The hazard ratio for progression to FRNS was 0.48 (95% CI: 0.16–1.38, P=0.17).

Figure 4.

Progression (to FRNS)-free survival among all patients.

Full figure (14K)

Progression-free survival among patients without progression to FRNS during the first 6 months is shown in Figure 5. At month 24, the estimated progression-free survival was 78% in Group A and 59% in Group B (P=0.13). The hazard ratio for progression to FRNS was 0.43 (95% CI: 0.14–1.37, P=0.15).

Figure 5.

Progression-free survival among patients who did not progress to FRNS during the first 6 months.

Full figure (13K)

Adverse events

Adverse events are summarized in Table 4. The incidence of hypertension was 25% (6/24) in Group A and 10% (2/20) in Group B (P=0.20). Transient elevation of serum creatinine was observed in three patients (Group A, 2 and Group B, 1).

Table 4 - Adverse events.

Full table

There was one severe adverse event. Ileus of unknown origin developed at month 22 in a 10-year-old girl assigned to Group A. This event was managed conservatively and resulted in death; an autopsy was not performed. The other noteworthy events were convulsions in one patient in Group A and gastric discomfort in one patient in Group B. The patient with convulsions had progression to FRNS before the seizures occurred, but continued to receive Regimen A. Therefore, a relation of treatment to the convulsions could not be ruled out. In the patient with gastric discomfort, symptoms subsided after the withdrawal of CyA. This adverse event was, therefore, considered to be related to treatment.

Renal biopsies were performed in 35 patients (Group A, 20 and Group B, 15) at the end of the study. Mild arteriolar hyalinosis was found in 4 (20% ) of 20 patients undergoing biopsy in Group A and 1 (6.7% ) of 15 undergoing biopsy in Group B; however, no patient had striped interstitial fibrosis or tubular atrophy.

In the 10 patients at the excluded centers (all received Regimen A), there were no severe adverse effects. Elevation of alkaline phosphatase occurred in three patients, hyperuricemia in three, transient elevation of serum creatinine in one, and hypertrichosis in one. At the end of the treatment, renal biopsy was performed in four patients; none of these patients had evidence of nephrotoxicity.

Growth failure

Before CyA treatment (at study entry), the mean s.d. score for body height was - 0.70 (95% CI: - 1.17 to - 0.23) in Group A (n=24) and - 0.62 (95% CI: - 1.23 to - 0.02) in Group B (n=18). At the end of the study, the mean s.d. score for body height was - 0.10 (95% CI: - 0.54 to 0.33) in Group A (n=23) and - 0.07 (95% CI: - 0.74 to 0.60) in Group B (n=18). There was no statistically significant difference between the two groups. However, the s.d. score for height increased significantly from the start to the end of the study in both groups; Group A: +0.61 (n=23; paired t-test, P=0.0001), Group B: +0.58 (n=17, P=0.0001).

DISCUSSION

We conducted a prospective, randomized, open-label multicenter trial in children with FRNS to evaluate the efficacy and safety of 2 years of treatment with CyA.

Our results were consistently in favor of Regimen A. CyA treatment for 2 years in a dosage that maintained the trough level between 80 and 100 ng/ml from study entry to month 6 and between 60 and 80 ng/ml from months 7 to 24 (Regimen A) was more effective in terms of the duration of remission and reduction in the risk of progression to FRNS than was CyA in a fixed dose of 2.5 mg/kg/day during months 7–24 (Regimen B), the regimen approved by the Ministry of Health, Labour and Welfare (MHLW) in Japan. Although several retrospective studies have proposed each of these regimens,^{19, 25} to our knowledge this is the first multicenter, prospective, randomized trial to assess the safety and effectiveness of long-term treatment with CyA in children with FRNS. Although statistically not significant, similar results were obtained among patients without relapse or progression to FRNS during the first 6 months of treatment: Regimen A was superior to Regimen B with respect to maintaining remission and reducing the risk of progression to FRNS.

The management of nephrotic syndrome in children depends to a large extent on the response to corticosteroids and the frequency of relapses. Patients whose disease is refractory to corticosteroids have a rather poor prognosis and respond differently to CyA than patients with steroid-sensitive disease.^{2, 12, 26} Most patients with steroid-sensitive nephrotic syndrome have a good prognosis.^{1, 27} In such patients, adverse effects of therapy are a major concern that may negatively affect the general condition and disease status of patients. Some patients with FRNS have severe adverse reactions to corticosteroids and may particularly benefit from immunosuppressants with steroid-sparing effects.^{5, 6, 23}

Cyclosporine is widely used to treat FRNS in children; however, the optimal dosage and duration of treatment remain controversial. Nephrotoxicity is the most important adverse effect of CyA.^{12, 22} Typical CyA-induced chronic nephrotoxicity is characterized by arteriolopathy and striped interstitial fibrosis with tubular atrophy.^{17, 28} Hamahira et al.⁹ showed that arteriolopathy resolved 6–19 months after the withdrawal of CyA, whereas interstitial fibrosis and tubular atrophy did not. These findings suggested that the dose of CyA should be carefully adjusted to avoid the development of CyA-induced tubulointerstitial changes in children with FRNS. One previous study showed that 2 years of treatment with CyA in a dose that maintained the trough level at 100 ng/ml caused tubulointerstitial changes in 7 of 13 patients.⁸ Iijima et al.⁷ reported that the risk factors for CyA-induced tubulointerstitial lesions included a duration of treatment exceeding 24 months and the presence of heavy proteinuria for more than 30 days during treatment. On the other hand, several studies assessing the value of short-term treatment with CyA demonstrated an insufficient response.^{10, 11, 29, 30} To better define the optimal dosage, we compared the safety and effectiveness of two dosage regimens given for 2 years. Regimen A was found to be an effective and, as discussed below, relatively safe treatment for children with FRNS.

We also evaluated the effect of CyA treatment on growth. Growth failure is a particularly important problem for children, with profound effects on their quality of life. The mean s.d. score for height and the change from the baseline value were evaluated in each group. Our results indicate that CyA has a beneficial effect on growth: height approached the mean value of Japanese healthy children after CyA treatment in both groups. This result is consistent with the findings of a meta-analysis of similar cohorts of patients.³¹ Improved height is attributable to the decreased exposure to corticosteroids enabled by the administration of CyA.

In general, Regimen A appeared to be as well tolerated as Regimen B in terms of safety. Frequent adverse events were hypertension, hypertrichosis, elevation of serum alkaline phosphatase levels (>1000 IU/l), elevation of urinary ₂-microglobulin levels (>500 g/l), and hyperuricemia (>8 mg per 100 ml). Mild nephrotoxicity associated with mild arteriolar hyalinosis was found in four patients in Group A and one in Group B. Among these adverse effects, hypertension, elevation of urinary ₂-microglobulin, and nephrotoxicity were slightly but not significantly more frequent in Group A. High trough levels may increase the risk of these adverse events, and hypertension and nephrotoxicity might have been related. Careful observation and management of blood pressure and renal function are thus required in patients who receive Regimen A. Fortunately, no severe pathological changes of the kidney, such as interstitial fibrosis and tubular atrophy, were detected in either group. As stated above, the pathological changes of the kidney in our series are expected to resolve with time. As for the death associated with ileus in Group A, the precise cause is unclear because an autopsy was not performed. To our knowledge, however, a direct link between CyA and severe ileus has not been reported previously; the development of ileus thus appears to be an incidental finding.

Protocol violations are an important concern of the present study. Seven patients at the three centers who were assigned to Group B received the regimen for Group A (Regimen A), that is, from month 7 onward the dose of CyA was adjusted to maintain the trough level between 60 and 80 ng/ml, instead of using a fixed dose of 2.5 mg/kg. The steering committee decided that additional patients would not be enrolled at these centers. The reason for these violations was that the physicians in charge at these three centers had assumed that Regimen A was more effective than Regimen B, irrespective of potential adverse effects. Thus, the steering committee finally decided to exclude these ineligible centers, and the 10 patients were excluded from all analyses except for those of adverse effects. Because these protocol violations were unrelated to disease severity and the disease severity of the 10 excluded patients was similar to that of the patients analyzed (Table 2a and 2b), comparability of the treatment groups was considered to be maintained.

Another limitation is that all of our patients received Sandimmune, the older formulation of CyA. Whether our results can be extrapolated to patients who receive the newer formulation of CyA, Neoral (Novartis), must be carefully considered. Several studies have compared efficacy and safety between Sandimmune and Neoral in children with nephrotic syndrome¹⁶ and renal-transplant recipients.^{32, 33, 34} Neoral has consistently been shown to be more effective, without compromising safety. To confirm the efficacy and safety of Neoral administered according to Regimen A, we are currently conducting a multicenter prospective trial.

The trough level monitoring (C0) was used to titrate the dosage of CyA in this trial. For the recipients of kidney transplants, C2 monitoring (C2) has been shown to be a more superior strategy compared with C0 in the prevention of acute rejection.^{35, 36} Preliminary data obtained from the ongoing trial of Neoral mentioned above indicate that C2 as well as C0 correlate with clinical response. Thus, in Japan another new multicenter clinical trial supported by the MHLW, entitled 'Cyclosporine C2 monitoring for frequent-relapsing nephrotic syndrome in children: A randomized controlled trial' is now being conducted to evaluate the efficacy and safety of C2 of CyA in children with FRNS.

In conclusion, our results suggest that treatment with CyA for 2 years in a dosage that maintains the trough level between 80 and 100 ng/ml for the first 6 months and 60 and 80 ng/ml for the next 18 months is an effective and relatively safe treatment for children with FRNS. With this regimen, approximately half of these patients can be expected not to have relapse during treatment, without the most critical adverse effect of CyA, that is, interstitial changes of the kidney. The Sandimmune formulation of CyA was used in the trial, and Neoral is now being evaluated in a subsequent trial.

MATERIALS AND METHODS

Patients

Patients with FRNS who were younger than 18 years were eligible for enrollment. The criteria for and definitions of nephrotic syndrome, remission, and relapse were in accordance with the International Study of Kidney Disease in Children.⁴ FRNS was defined as two or more relapses of nephrotic syndrome within 6 months of the initial episode, three or more relapses within any 6-month period, or four or more relapses within any 12-month period. Exclusion criteria consisted of the following: previous treatment with CyA, renal insufficiency (creatinine clearance of 60 ml per min per 1.73 m²), active infections, secondary nephrotic syndrome, and pregnancy. The study was performed in accordance with the ethical standards laid down in the Declaration of Helsinki Principles, and informed consent was obtained from all patients.

Study design

Patients were assigned to either Group A or B with the use of a randomization list prepared by the steering committee. The total duration of treatment was 24 months (Figure 6). For the first 6 months of treatment, both groups received CyA (Sandimmune) in a dose that maintained the whole-blood trough level between 80 and 100 ng/ml. During months 7–24, Group A received CyA in a dose producing a whole-blood trough level between 60 and 80 ng/ml (Regimen A), and Group B received CyA in a fixed dosage of 2.5 mg/kg/day (Regimen B), the dose used in previous study of children with FRNS¹⁰ and approved by the MHLW in Japan. After 2 years of treatment, all patients were scheduled to undergo renal biopsy, and the dose of CyA was tapered by 0.5–1.0 mg/kg/day every week. The concomitant use of drugs other than corticosteroids and immunosuppressants was not restricted. Antihypertensive drugs, including angiotensin-converting enzyme inhibitors, were also permitted.

Figure 6.

Protocol of the trial. CyA, cyclosporine.

Full figure and legend (41K)

We estimated that a sample size of 90 (Group A, 45 and Group B, 45) followed for 2 years would permit the detection of a hazard ratio of 0.46 at a significance level of 0.05 and a power of 0.80. During the study, a new formulation of CyA, that is, Neoral (Novartis), was approved by the MHLW, and the steering committee decided to terminate patient recruitment. A total of 56 patients (Group A, 29 and Group B, 27) gave informed consent and were enrolled.

Corticosteroid treatment for relapses

To treat initial episodes of nephrotic syndrome, patients received 2 mg/kg/day of prednisolone in three divided doses (maximum dose 80 mg/day) for 4 weeks and were then given a single dose of 1.3 mg/kg of prednisolone in the morning on alternate days for 4 weeks. Patients who had relapses of nephrosis during the study period received 2 mg/kg/day of prednisolone in three divided doses (maximum dose 80 mg/day) for 4 weeks, followed by a single dose of 2 mg/kg of prednisolone administered in the morning on alternate days for 2 weeks, 1 mg/kg on alternate days for 2 weeks, and 0.5 mg/kg on alternate days for 2 weeks. No patient received maintenance therapy with corticosteroids. Patients who had FRNS during follow-up received off-protocol therapy, left to the discretion of their physicians.

Pretreatment evaluation and follow-up

The patient's characteristics (including age, sex, and the results of blood tests) were first recorded at baseline. Blood analysis (complete blood cell count, blood chemistry, and CyA trough level) and urine tests (urinalysis, quantitative proteinuria, and urinary ₂-microglobulin) were performed monthly for patients in both groups during follow-up. Abnormal laboratory findings and adverse events were reported to the steering committee. The trough level of CyA was measured monthly by monoclonal radioimmunoassay.

Statistical analysis

The primary end point was the proportion of patients who had sustained remission until the first relapse. The secondary end point was progression-free survival, using the period until the development of FRNS. Survival curves were estimated by the Kaplan–Meier method and were compared using the log-rank test. Since both groups received the same treatment regimen for the first 6 months, the proportion of sustained remission and progression (to FRNS)-free survival were calculated in patients without relapse or progression to FRNS for the first 6 months for secondary analysis. In these analyses, patients without an event were censored at the date of the last follow-up. The hazard ratio of the relapse rate and the rate of progression (to FRNS) were estimated by Cox regression analysis.

A two-sided significance level of 0.05 was used for analysis of the primary end point. All statistical analyses were performed with the use of the software package SAS for Windows, release 8.02 (SAS Institute Inc., Cary, NC, USA).

Registration

This study has been registered in a public trials registry, UMIN (the University Hospital Medical Information Network, ID C000000014, http://www.umin.ac.jp/ctr/index.htm).

DISCLOSURE

There is no conflict of interest to disclose.

Notes

Japanese Study Group of Renal Disease in Children:

Araki Y (Hokkaido), Awazu M (Tokyo), Furuse A (Kumamoto), Hamasaki Y (Tokyo), Hatae K (Fukuoka), Hataya H (Tokyo), Hiramatsu M (Oita), Hiramoto R (Chiba), Kaku Y (Fukuoka), Kameda A (Hyogo), Kamezaki K (Fukuoka), Kamitsuji H (Nara), Kitagawa K (Osaka), Kosaka T (Tokyo), Maeda E (Gunma), Matsuyama T (Tokyo), Minato T (Hyogo), Miyamoto H (Hyogo), Nishino M (Osaka), Sako M (Wakayama), Sato T (Saga), Suehiro F (Hyogo), Suzuki T (Tokyo), Tamura K (Ibaraki), Tanaka R (Hyogo), Tanaka Y (Tokyo), and Yamaoka K (Osaka).

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Acknowledgments

We are grateful to Professor Yasuo Ohashi (Department of Biostatistics, School of Public Health, the University of Tokyo) and Mr Takashi Ando (Medical Toukei Co. Ltd) for helpful advice on the data set and statistical analyses. This study was supported in part by the Kidney Foundation, Japan.