1 Department of Nephrology and 2 Department of Biostatistics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, India
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Abstract |
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Methods. We prospectively evaluated the usefulness of intravenous cyclophosphamide (IVCP) in children with steroid sensitive INS who were frequent relapsers or steroid dependent. Fifty-one children were included in the study of whom 22 were FR and 29 were SD. IVCP was administered in a dose of 500 mg/m2/month for 6 months after achieving a steroid-induced remission. The response to IVCP was evaluated in terms of remission, change in the steroid response status of the patient, duration of remission (i.e. proteinuria-free days), side effects and compliance with therapy.
Results. The proteinuria-free days (mean 19.9±3.5 before IVCP therapy vs 1256±167 days after IVCP therapy) (P<0.00001), and serum albumin levels (23±1.6 g/l before IVCP therapy vs 34±2 g/l after IVCP therapy) (P<0.001) were significantly higher following IVCP therapy. The cumulative remission rate in the study group was 49% at 5 years and was comparable to that achieved with oral cyclophosphamide at a 40% lower cumulative dose.
Conclusions. We conclude that IVCP is a safe and effective therapeutic modality in children with INS who are FR and SD. Its efficacy is comparable to the results obtained with oral cyclophosphamide based on historical comparisons with previous studies.
Keywords: cyclophosphamide; frequent relapses; nephrotic syndrome
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Introduction |
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Intravenous cyclophosphamide (IVCP) has been extensively used in lupus nephritis and various vasculitic disorders and has been shown to be an effective form of therapy with significantly fewer side-effects than OCP [68]. We have previously demonstrated a beneficial role of IVCP in steroid-resistant minimal change disease (MCD), with minimal side-effects [9]. Hence, we decided to prospectively evaluate its usefulness in children with steroid sensitive INS who were frequent relapsers with or without steroid dependence.
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Patients and methods |
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The children were followed up monthly for the first 6 months and thereafter once every 3 months. On each visit the child was evaluated clinically for evidence of disease activity and complications. In addition, the following investigations were carried out: urine albumin and creatinine in a spot sample, serum protein, albumin, creatinine, haemoglobin, and total leukocyte count. The children were monitored for infections, leukopenia and alopecia. In the presence of infections or leukopenia, the next dose of IVCP was delayed until complete normalization of counts or recovery from infection.
Evaluation of response to IVCP
The response to IVCP was evaluated in terms of remission, change in the steroid response status of the patient, duration of remission (i.e. proteinuria-free days), side-effects and compliance with therapy.
The maximum number of proteinuria-free days prior to IVCP was compared with the duration of sustained proteinuria-free days post therapy. The proteinuria-free days refer to the maximum number of proteinuria-free days (longest remission) in the 6 months prior to enrolment into the study. The proteinuria-free period post IVCP was calculated from the time of completion of IVCP protocol to the occurrence of first relapse. The following case definitions were used: (i) remission (i.e. a reduction in urinary albumin excretion by 0 to trace dipstix reading or spot urine albumin/creatinine ratio<0.2 for at least 3 consecutive days); (ii) relapse (i.e. 3+ albuminuria by dipstix for 3 consecutive days or recurrence of nephrotic syndromeproteinuria, oedema, hypoalbuminaemia). The outcome was classified as: (i) sustained remission (i.e. 6 or more months of remission); (ii) infrequent relapses (i.e. one relapse over a period of 6 months); (iii) frequent relapses; (iv) steroid dependent.
Statistical analysis
Difference in various parameters before and after treatment and between the two groups was compared using the 2-square test and the paired Student's t-test. The cumulative sustained remission was derived on the basis of proteinuria-free days. The impact of other determinants such as gender, age at onset, age at treatment, histopathology, steroid response category on cumulative remission, was analysed using KaplanMeiyer survival analysis for each factor separately. The log rank test was used for testing the difference between sustained remission duration. The analysis was carried out using SPSS statistical software (SPSS Inc., Chicago, IL, USA, 1998). All values are in mean±SE.
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Results |
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The incidence of side-effects was minimal, with 5% of the patients developing nausea and vomiting during infusion of CP. This too subsided with prophylactic antiemetic therapy with metoclopramide. Alopecia was seen in four patients and reversed on completion of therapy. Leukopenia was seen in only two patients and was transient. The next dose of IVCP was given after the counts normalized. One child developed pneumonitis 3 weeks after the 3rd dose of IVCP. At that time he was not having prednisone therapy. He was managed with i.v. co-amoxclav for 7 days followed by oral therapy for another 7 days, after which he recovered clinically. Another child developed chickenpox. In both of these children the next dose of cyclophosphamide was delayed until they had completely recovered. None of the patients discontinued therapy due to side effects. Haemorrhagic cystitis was not observed in any of our patients.
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Discussion |
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MCD, mesangial proliferative glomerulonephritis (MesPGN) and FSGS account for the majority of children with idiopathic nephrotic syndrome. Such children are also treated by a common protocol for steroids and cyclophosphamide [2]. Hence we included children with MCD and FSGS in our study, including children with idiopathic nephrotic syndrome who were steroid sensitive without a prior biopsy. In the FR group, 65% of the children attained a prolonged remission which is comparable to that in previous studies. Further, another 17.5% of the children improved their steroid response status and became IFR. If these children are included, the response rate increases to 82.5%. In the SD category 43% of the children attained prolonged remission while another 25% improved their steroid category and became infrequent relapsers with an overall response rate of 68%. We studied steroid sensitive patients who were frequent relapsers or SD immediately prior to their enrolment into the study. There is always a possibility of spontaneous remission. It is possible that they may have become IFR and the effect erroneously attributed to the drug administered. It is extremely unusual for patients who are FR or SD to have a sustained remission spontaneously.
OCP has long been the preferred therapy for children who frequently relapse, with or without SD INS, who develop steroid toxicity. The average response rate in various studies in SD has ranged from 28 to 75% for SD children and from 24 to 70% in FR at 13 years [1116]. Srivastava et al. [12] observed an overall prolonged remission rate of 61% in their study. They concluded that a higher age at OCP therapy and remission of 6 months were predictors of a better response and SD children had a poorer outcome. The APN study compared 8 weeks of OCP with 12 weeks of OCP in SD children with INS [13]. Children treated with 12 weeks of OCP had significantly higher rates of sustained remission (75%). In contrast Ueda et al. [14] found that the relapse-free rate of patients treated for 8 weeks (25%) was similar to those treated with OCP for 12 weeks (24%) at 5 years after stopping the treatment [3]. Similarly, Kashtan et al. [15] have reported OCP to be effective therapy for children who are FR or SD. Shohet et al. [16] reported a higher response to OCP in the FR group. Although 89% of children showed an initial response rate, sustained remissions were observed in only 37.5% of children. Further, some of the children in this study received prolonged and repeated courses of steroid and cyclophosphamide. This could be due to the fact that a second course of OCP results in a more sustained remission. Moreover, this study included children with MCD only which has a much better long-term response to cyclophosphamide as compared to MesPGN and FSGS [17]. The actuarial cumulative sustained remission in our study of 38% at 5 years in the SD group and 49% at 5 years in the FR group are comparable with those observed with previous studies [1116]. In our study too, children in the MCD group had a longer remission than the FSGS group, although the difference was not significant. This was possibly because of the small number of patients in each group. Our results are comparable to that in most other studies. All the previous studies have evaluated children with MCD. In contrast, our study included patients with NS due to non-MCD lesions.
In steroid-resistant NS, IVCP has been shown to be more effective in inducing remission at a lower total cumulative dose and with fewer side effects [9,18]. There are only anecdotal reports of its use in children with INS who are FR or SD [19,20]. However, the role of IVCP in lupus nephritis is well documented. Valeri et al. [5] evaluated the clinical efficacy, toxicity and effects on renal morphology of IVCP in severe lupus nephritis. The side-effects were minimal with no serious infections and only mild alopecia and amennorrhoea. There was no case of haemorrhagic cystitis or development of malignancy at 5 years of follow up. Similarly Austin et al. [6] found IVCP to be less gonadotoxic, carcinogenic and myelosuppressive then OCP in lupus nephritis. Also, recently it has been conclusively proven that IVCP has significantly less gonadal toxicity compared with OCP in a rat model as well as in patients with non-malignant diseases [8].
Thus, in our study, the overall response rate of 49% was comparable to that reported previously. Furthermore the response was observed at 40% lesser cumulative dose as compared to OCP [8,9]. The infusions were well tolerated and were administered in a day care setting. In only two children was the next dose of IVCP delayed because infections occurred. As the infusions were administered in a supervised day care setting, the possibility of non-compliance which might occur with daily OCP is also negated. Hence we conclude that IVCP is a safe and effective therapeutic modality in children with INS who are frequent relapsers, with or without SD.
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Acknowledgments |
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Notes |
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References |
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