Pulse cyclophosphamide therapy in frequently relapsing nephrotic syndrome

Sanjeev Gulati1,, Saurabh Pokhariyal1, Raj Kumar Sharma1, Ravi Elhence1, Vijay Kher1, Chander Mohan Pandey2 and Amit Gupta1

1 Department of Nephrology and 2 Department of Biostatistics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, India



   Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. The treatment of frequently relapsing (FR) and steroid-dependent (SD) idiopathic nephrotic syndrome (INS) with oral cyclophosphamide (OCP) poses problems of compliance, side-effects and infections.

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



   Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Idiopathic nephrotic syndrome (INS) in children is steroid sensitive in the majority of children. However, a significant number (40–50%) of these will have a relapsing course [1,2] and will either be frequent relapsers (FR) with or without steroid dependence. The various options available for treatment of these patients include corticosteroids, levamisole, oral cyclophosphamide (OCP), chlorambucil, mechlorethamine and cyclosporin. Of these, OCP is the most effective form of therapy [3]. However, the use of OCP is complicated by attendant side effects. This is especially true in children in whom there is an increased risk of infection, particularly measles and chicken pox, which run a more fulminant course during treatment with OCP [4]. Drug compliance in these patients can pose a major problem.

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.



   Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
The study group comprised of 51 consecutive children who fulfilled the following inclusion criteria: (i) age group 1–16 years; (ii) frequent relapsers (i.e. two or more relapses in a 6-month period following cessation of steroid therapy or steroid dependence (SD), or at least two consecutive relapses during a period of steroid tapering or within 2 weeks of stopping steroid therapy); (iii) presence of at least two of the following features of steroid toxicity—hypertension, growth suppression, gross cushingoid appearance, cataract, diabetes, glaucoma or psychosis; (iv) no history of previous use of cytotoxic drugs. Patients had been categorized as either frequently relapsing or SD INS after receiving standard therapy with oral prednisolone [1,10]. The qualifying period for the diagnosis of FR or SD was the 6 months preceding the enrolment into the study. None of the children in the SD group had previously received long-term alternate day steroids. Of the 29 children in the SD group, 11 had relapsed within 2 weeks of stoppage of prednisolone while 18 relapsed on prednisolone therapy. The steroid threshold in these children was 0.96±0.15 mg/kg/alternate day. A kidney biopsy was performed prior to cyclophosphamide therapy in those patients for whom consent was available. However, this was not a prerequisite for enrolment into the study protocol. The patients were given oral prednisolone 60 mg/m2/day for 2 weeks or until they had been in remission for 3 days, and they were then given 40 mg/m2 on alternate days for 4 weeks tapering off over the next 4 weeks. IVCP was started in a dose of 500 mg/m2/month for 6 months after achieving a steroid-induced remission. The drug was dissolved in 300 ml of 5% dextrose and infused over 3 h in a supervised day care setting. None of these patients were administered MESNA.

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 syndrome—proteinuria, 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 {chi}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 Kaplan–Meiyer 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.



   Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
A total of 51 children with either FR or SD INS were prospectively recruited into the study. Of these 22 were FR and 29 were SD. The demographic data, histopathology, outcome and duration of follow up in the two groups were similar (Table 1Go). The mean age at onset of NS was 4±3.2 years and there were 42 boys and nine girls.


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Table 1. Demographic, clinical, histopathology and outcome in FR and SD

 
In the FR group, 15 (67.5%) patients achieved a prolonged remission, four (18%) improved and became IFR, while another three (13.6%) patients remained FR despite IVCP therapy. In the SD group, 12 (41%) patients achieved a prolonged remission, nine (31%) improved to IFR status, five (17%) turned FR, and three (10%) remained SD despite IVCP. After a mean follow up of 27±21 months after the last dose of IVCP, of the 51 patients, 27 (51%) achieved sustained remission, 13 (25%) became IFR, eight (16%) were FR while three (6%) remained SD. The number of children in the FR group who achieved a sustained remission (15/22) was similar to that in the SD group (12/29) (P=0.19). The serum creatinine levels before (0.74±0.03 mg/dl) and after IVCP (0.78±0.9 mg/dl) therapy were similar. The serum albumin levels (23±1.6 g/l before therapy vs 34±2 g/l after therapy) and the serum protein levels (49.7±2.2 g/l before therapy vs 58.5±3.6 g/l after therapy) were significantly higher after IVCP therapy (P<0.001) compared with those before IVCP. The maximum duration of proteinuria-free days post IVCP (mean 1256±167 days) was also significantly higher compared with those before the start of treatment (mean 19.90±3.5) (P<0.00001). The duration of proteinuria-free days after IVCP in frequent relapsers and SD patients (mean 1385±221 and 988±181 days respectively) was not significantly different (P=0.69) (Figure 1Go).



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Fig. 1. Cumulative remission (proteinuria-free days) in frequent relapsers and steroid dependent subgroups.

 
Renal biopsy was performed on 30 patients, of whom 17 had minimal change disease and 13 had focal segmental glomerulosclerosis (FSGS). On analysing the response of these patients as per histopathology, we observed that the children in the MCD group had mean proteinuria-free days post IVCP of 1391±280 days, whereas in the FSGS group the mean duration was 818±173 days. The 21 patients without biopsy had mean proteinuria-free days of 589±116 days after IVCP. The differences were not statistically significant (P=0.45). Children younger than 6 years at onset were compared with patients older than 6 years at onset. The mean proteinuria-free days in these groups post IVCP were 1189±186 and 859±178 respectively, and the difference was not statistically significant (P=0.25). The response to IVCP was also compared between boys and girls. In boys a mean of 1003±145 proteinuria-free days was observed as against a mean of 1720±274 in girls (P=0.29). The overall cumulative sustained remission was 49% at 5 years in the study group. Children in the SD group had actuarial cumulative sustained remission of 38% at 5 years, while 49% of those in FR group had sustained remission at 5 years (Figure 1Go).

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.



   Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In this study, IVCP was found to be an effective therapy for children with INS who were either FR or SD. The patients receiving IVCP had a significant increase in proteinuria-free days, despite lower total cumulative dose than is usually administered with OCP, and they had minimal side-effects.

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 1–3 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.



   Acknowledgments
 
This paper was accepted for oral presentation at the 36th ERA-EDTA congress held in Madrid in September 1999.



   Notes
 
Correspondence and offprint requests to: Dr Sanjeev Gulati, Assistant Professor, Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, India. Email: sgulati{at}sgpgi.ac.in Back



   References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Gulati S, Kher V, Sharma RK, Gupta A. Steroid response pattern in Indian children with nephrotic syndrome. Acta Paed Scand1994; 83: 530–533
  2. Barnett HL, Nash MA, Edelmann Jr CM, Bernstein J. Minimal change nephrotic syndrome, diffuse mesangial hypercellularity and focal glomerular sclerosis. In: Paediatric Kidney Disease. Little, Brown and Co., Boston, 1992; 1267–1291
  3. Takeda A, Hiroaki O, Fumio N, Hidetomo M. Long term effects of immunosuppressants in steroid dependant nephrotic syndrome. Pediatr Nephrol1998; 12: 746–750[ISI][Medline]
  4. Trompeter RS. Minimal change nephrotic syndrome and cyclophosphamide. Arch Dis Child1986; 61: 727–729[ISI][Medline]
  5. Valeri A, Radhakrishnan J, Estes D et al. Intravenous pulse cyclophosphamide treatment of lupus nephritis: a prospective five year study. Clin Nephrol1994; 42: 71–78[ISI][Medline]
  6. Austin HA, Klippel JH, Balow JE et al. Therapy of lupus nephritis. Controlled trial of prednisolone and cytotoxic drugs. N Engl J Med1986; 314: 614–619[Abstract]
  7. Martin F, Lanwerys B, Lefbuze C, Devogelair JP, Houssian FA. Side effects of intravenous cyclophosphamide pulse therapy. Lupus1997; 6: 254–257[ISI][Medline]
  8. Haubitz M, Ehlerding C, Kamino A, Koch KM, Brunkhorst R. Reduced gonadal toxicity after IV cyclophosphamide administration in patients with non malignant disease. Clin Nephrol1988; 49: 19–23
  9. Elhence R, Gulati S, Kher V, Gupta A, Sharma RK. Intravenous pulse cyclophosphamide—a new regime for steroid resistant minimal change nephrotic syndrome. Pediatr Nephrol1994; 8: 1–3[ISI][Medline]
  10. Gulati S, Kher V, Elhence R, Kumar P, Sharma RK, Gupta A. Treatment of nephrotic syndrome. Indian Paediatr1994; 31: 165–170
  11. Garin EH, Pryor ND, Fennel RS, Richard GA. Pattern of response to prednisolone in idiopathic minimal lesion nephrotic syndrome as a criterion in selecting patients for cyclophosphamide therapy. Am J Dis Child1998; 142: 985–988
  12. Srivastava RN, Agarwal RK, Chowdhary VP, Moudgil A, Bhuyan UN, Sunderram KL. Cyclophosphamide therapy in frequently relapsing nephrotic syndrome with and without steroid dependance. Int J Paed Neph1987; 6: 245–250
  13. Arbeitsgemeinschaft für Pädiatrische Nephrologie. Treatment of steroid dependent nephrotic syndrome: comparison of 8 weeks with 12 week course. Arch Dis Child1987; 62: 1102–1106[Abstract]
  14. Ueda N, Kuno K, Ito S. Eight and twelve week courses of cyclophosphamide in nephrotic syndrome. Arch Dis Child1990; 65: 1147–1150[Abstract]
  15. Kashtan C, Melvin T, Kim Y. Long term follow up of patients with steroid dependent minimal change nephrotic syndrome. Clin Nephrol1988; 29: 79–85[ISI][Medline]
  16. Shohet I, Meyerovitch J, Aladjem M, Boichis H. Cyclophosphamide in treatment of minimal change nephrotic syndrome. Eur J Paediatr1988; 147: 239–241[ISI][Medline]
  17. Broyer M, Meyrier A, Niaudet P, Habib R. Minimal change and focal glomerular sclerosis. In: Davison AM, Cameron JS, Grunfeld JP, Kerr DNS, Ritz E, Winerals CG (eds). Oxford Textbook of Clinical Nephrology. Oxford University Press, Oxford, 1998; 493–535
  18. Kala UK, Rennert WP, Jacob D, Goestsch S, Verhaart S. Pulse cyclophosphamide for steroid resistant FSGS. Paed Nephrol1999; 13: 113–116
  19. Gandhi R, Thomas C. Cyclophosphamide pulse therapy in frequently relapsing nephrotic syndrome. Nephron1990; 55: 444[ISI][Medline]
  20. Jones BF. Cyclophosphamide pulse therapy in frequently relapsing nephrotic syndrome. Nephron1993; 63: 472[ISI][Medline]
Received for publication: 9. 8.00
Revision received 22. 5.01.