The treatment of relapsing primary nephrotic syndrome in children

The treatment of relapsing primary nephrotic syndrome in children first-author †E-mail:yaping_wang163@163.com †E-mail:yaping_wang163@163.com yaping_wang163@163.com Affiliated Children’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China Affiliated Children’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China Objective: 2 To explore better therapy and reduce the rate of re-relapse of primary nephritic syndrome in children who had been treated with corticosteroids but relapsed. Methods: 2 Eighty relapsers were enrolled from Jan. 1994 to Apr. 2000, who were randomly divided into two groups. The treatment group ( n =39) had been treated with tripterysium glucosides for three months, with the control group ( n =41) members were treated with cyclophosphmide (CTX) by intermission intravenous pulse, with total dose of CTX not being more than 150 mg/kg. Prednisone, meanwhile, was given to both groups. The total treatment period of prednisone was prolonged by 12–18 months. Results: 2 After following up for 3–7 years, the re-relapse rates of both groups were observed. The re-relapse rate of the treatment group was 28.2% to 29.3% in the CTX-controlled group. The re-relapse rates between two groups were almost similar, and with no observed significant difference ( P > 0.05). The side effect of tripterysium glucosides was less than that of CTX. Conclusion: 2 For the treatment of relapsing nephritic syndrome in children, the combination of tripterysium glucosides and prolonged corticosteroid therapy is as effective as the regimen of CTX plus prolonged use of prednisone. Primary nephrotic syndrome Relapse Tripterysium glucosides Prednisone INTRODUCTION 1 Primary nephrotic syndrome is the most common renal disease in children. Most children with nephrotic syndrome respond to corticosteroids (Hodson et al., 2000 2000 ). However, 71.2% of children experience a relapsing course with recurrent episodes of edema and proteinuria within two years after 6~9 months treatment of corticosteroids (Yang, 2000 2000 ). The relapse of primary nephrotic syndrome in children after treatment and remission is a common phenomenon. In order to reduce the re-relapse, from January 1994 to April 2000 we adopted different schemes to research treatment. Tripterysium glucosides was produced by abstracting from the wood core part of tripterysium, a Chinese medicine celastraceace plant. It has been proved that tripterysium glucosides have anti-inflammatory and immunosuppressive effects. Tripterysium glucosides may have effect by suppressing the production of interleukin-2 and its receptor effect, inducing activated lymphocytes apoptosis, interfering with the lymphocytes cell cycle, decreasing lymphocytes proliferation, and suppressing the activation of nuclear factor-kappa B (Liu et al., 1999 1999 ; Qiu and Kao, 2003 2003 ). We compared the effects of tripterysium glucosides plus prolonged use of prednisone with that of CTX plus prolonged use of prednisone. Now we report the outcome as follows. PATIENTS AND METHODS 1 Eighty cases in the research met the criteria of the Association Group of Science and Research of the National Children’s Nephropathy in 1981. The so called relapse means: the proteinuria was changed from negative to positive, there were signs of ++ for three times in one week, or the amount of protenuria is equal to or greater than 50 mg/kg in 24 h. The frequent relapse means: the times of relapse in half a year are equal to or more than 2, or the times of relapse in one year are equal to or greater than 3. In clinical practice, we often classify primary nephrotic syndrome into clinical simple type and nephritic type. The clinical simple type means that the patients have four features including proteinuria (urinary protein excretion greater than 50 mg/(kg·d)), hyperlipidemia, hypoalbuminemia and edema. The nephritic type means that the patients have one of the follow situations, besides the above four features: (1) hematuria (more than 10 red blood cells per high power field in centrifuged urine three times within two weeks); (2) hypertention (except for the influence of prednisone); (3) increased serum levels of creatinine and urea nitrogen (except for hypovolemia); (4) hypocomplementemia 3. The patients were randomly divided into two groups. One group is the treatment group. In this group, there were 39 cases: male 31 cases, female 8 cases. The age was from 1 to 13 years old. The mean age was 4.99 years old. There were 35 cases of the clinical simple type, 4 cases of the nephritic type; 29 cases of non-frequent relapse type, and 10 cases of frequent relapse type. The other group was the control group. In this group, there were 41 cases: male 33 cases, female 8 cases. The age was from 1.5 to 12 years old. The mean age was about 4.37 years old. There were 32 cases of the clinical simple type, 9 cases of the nephritic type; 23 cases of non-frequent relapse type, and 18 cases of frequent relapse type (Table 1 1 ). Groups Cases Male/female Mean age (year) Clinical simple type Nephritic type Non-frequent relapse Frequent relapse Renal biopsy Tripterysium group 39 31/8 4.9 35 4 29 10 7 CTX group 41 33/8 4.4 32 9 23 18 8 Total 80 67 13 52 28 15 Fifteen cases of frequent relapse were renal biopsied, in which 7 cases were included in the treatment group, 8 cases in the control group. The histopathologic changes showed that there were 6 cases of minimal change, 4 cases of mesangial proliferative glomerulonephritis from minor to medium level, one case of IgA nephropathy, 3 cases of IgM nephropathy, one case of focal segmental glomerulosclerosis. Sufficient dose (1.5–2.0 mg/(kg·d), not to exceed 60 mg/d) of prednisone was given to both groups. When remission occurred within 4 to 8 weeks of therapy, the dose of prednisone was decreased. At the first time, one third of total dose was deducted, and it was given in each morning for 3–4 weeks. Then 5 mg was deducted every other day every two weeks, and the dose of prednisone was gradually changed to alternate-day doses in the morning. About 2–3 months were needed in this period. After the above period, the dose of prednisone was about 0.5–1.0 mg/kg every other day, which was given in 6 months or longer period of time. The total treatment period was about 12–18 months. Tripterysium glucosides were added in the treatment group, 1 mg/kg each day. The total dose each day was not be over 30 mg, which was given orally 2 or 3 times. The total treatment period was about 3 months. Tripterysium glucosides were used for 10 cases in the initial treatment period, for 29 cases in the last 3 months before completion of the prednisone treatment when two kinds of medicines were simultaneously not used anymore. The dose of prednisone for the control group was the same as that of the treatment group, and cyclophosphamide (CTX) was applied by intermission intravenous pulse, at dose 10 mg/kg each day, with 0.9% normal saline being added in the vein injection given for two days as treatment and repeated each 2–4 weeks. About 7 treatment periods in average were needed, with the total dose of CTX not being more than 150 mg/kg within 3–6 months. Comparisons between the two groups were analyzed. Statistical analysis was performed using χ 2 -test and Fisher-exact probabilities. Differences were considered significant at P < 0.05. RESULTS 1 The relapse of both groups: after following up for 3–7 years, mean of about 4.9 years. There were 11 relapse cases (about 28.2% re-relapse rate) in the treatment group, in which there were 7 cases of non-frequent relapse, 4 cases of frequent relapse. There were 12 relapse cases (about 29.3% re-relapse rate) in the control group, in which there were 7 cases of non-frequent relapse, 5 cases of frequent relapse. The re-relapse rates between the two groups were almost similar, with no significant difference observed ( P > 0.05) (Table 2 2 ). χ 2 =0.011; P > 0.05 Group Cases Re-relapse No-relapse Re-relapse rate Tripterysium group 39 11 28 28.2% CTX group 41 12 29 29.3% Total 80 23 57 The numbers of children who relapsed 6 months after the end of therapy comprised 3 cases in the treatment group, one case in the CTX group. By 12 months there were 3 relapse cases in the treatment group, 2 cases in the CTX group. By 24 months there were 3 relapse cases in the treatment group, 4 cases in the CTX group. There were 2 cases in the treatment group who relapsed after ceasing therapy 2~4 years, 5 cases in the CTX group (Table 3 3 ). Group Cases <6 months 6–12 months 12–24 months 2–4 years Tripterysium group 11 3 3 3 2 CTX group 12 1 2 4 5 Total 23 4 5 7 7 Regarding the side effects of the medicine: there was one case rising GTP in the treatment group, one case of transient leukocytopenia. They were all back to normal after stopping the medicine. As for the control group, there was one case of rising of GTP, 3 cases of transient leukocytopenia, 11 cases of alopecia to different extent, 6 cases of the reaction of gastrointestinal tract. The above situation was changed to normal after stopping the medicine. The long-term side effect should be observed during further follow up. DISCUSSION 1 The relapse of primary nephrotic syndrome in children may result in the change of histopathologic type, which would cause difficulty in the treatment, and even affect children’s future (Yap et al., 2001 2001 ). Many factors may cause the relapse of primary nephrotic syndrome, including too short steroid treatment period, rapid tapering off the dose of prednisone, infections, etc. The most important factor is too short prednisone treatment period, so we adopted prolonged prednisone treatment plus tripterysium glucosides therapy. The prolonged period during which 0.5~1.0 mg/kg prednisone was given on alternate days for about six months or longer. This therapy strengthened the treatment effect of prednisone, but the adverse effect of prednisone did not increase. Some patients had tripterysium glucosides added to their medication for three months during the initial prednisone treatment period, but most patients received it during the last three months of prednisone therapy. Children who are steroid sensitive and have relapsing nephrotic syndrome are more likely relapse during withdrawal of prednisone or after the end of prednisone treatment, so during the last three months of predinsone therapy we added tripterysiun glucosides in order to strengthen the treatment and reduce the re-relapse. Currently it is commonly thought that combining with CTX, especially intravenous intermission pulse treatment can certainly reduce the relapse of the illness (Mendoia and Tune, 1995 1995 ; Takcda et al., 2001 2001 ). With the same treatment scheme of prednisone, the writers added tripterysium glucosides and compared the results with the CTX-controlled group. After following up for 3~7 years, the re-relapse rate of the treatment group was 28.2%, 29.3% in the CTX-controlled group. The total re-relapse rates between two groups were almost similar, and there were no significant differences ( P > 0.05). In addition, in this study we observed the re-relapse numbers of children who had relapsed by 6, 12, 24 months or longer period after the end of therapy. The result suggested that CTX-controlled patients have more stable long-term remission compared with tripterysium glucosides group. In this randomized CTX-controlled clinical study, the numbers of two groups were not equivalent because two patients of the treatment group were lost from the follow-up. This study’s results suggested that the effect of intermission intravenous pulse CTX plus prednisone on the frequent relapse nephrotic syndrome may be better than that of tripterysium glucosides plus prednisone. Further observation is needed. In conclusion, for the treatment of relapsing nephrotic syndrome in children, the combination of tripterysium glucosides and prolonged corticosteroid therapy is as effective as a regimen of CTX plus prolonged use of prednisone. 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Risk factors for steroid dependency in children with idiopathic nephrotic syndrome 10.1631/jzus.2005.B0682 2004-07-05 2004-10-17 2005-06-23 2022-01-05 Copyright © 2005, Journal of Zhejiang University Science 2005 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 07 6B