Indian Pediatrics 2000;37: 141-148
Intravenous pulse cyclophosphamide_a new regime for steroid resistant focal segmental glomerulosclerosis
Sanjeev Gulati and Vijay Kher
From the Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical
Sciences, Lucknow 226 014, India.
Objective: A prospective study was conducted to evaluate the role of intravenous pulse cyclophosphamide (IVCP) infusions in the management of children with steroid resistant (SR) idiopathic focal segmental glomerulosclerosis (FSGS). Methods: The study group comprised of 20 consecutive children with idiopathic nephrotic syndrome secondary to FSGS who were SR. All of them were subjected to standard baseline investigations. They were started on monthly infusions of IVCP in a dose of 500-750 mg/m2. Adjunctive prednisolone was given in a dose of 60mg/m2/day for 4 weeks followed by 40 mg/m2/alternate day for another 4 weeks and tapered off over next 4 weeks. Results: The study group comprised of 15 boys and 5 girls with mean age of onset of disease of 5.5±3.5 years. Two of these children had chronic renal insufficiency prior to starting therapy. At the end of the study, after a mean duration of disease (since onset of NS) of 77±55 months, all 20 children had normal renal functions. After a mean follow up post IVCP therapy of 21.2±13.4 months, 13 of the 20 children (65%) had attained a complete remission. Of these, 10 children were infrequent relapsers, 2 frequent relapsers and 1 steroid dependent. The mean duration of remission following last dose of IVCP in these children was 12.5±11.9 months. Of the 7 children who continued to be proteinuric, 3 became edema free and have not required any albumin infusion or diuretics. One other died due to peritonitis 2 years after the last dose of IVCP. The mean total protein and serum albumin levels following the IVCP infusion were significantly higher than those prior to therapy (6.5±1.0 mg/dl Vs 5.0±0.8) (p=0.0004) and (3.5±0.7g/dl Vs 2.3±0.7) (p = 0.000007) respectively. The serum creatinine levels following IVCP therapy (0.8±0.2 mg/dl) were significantly lower than those prior to treatment (1.0±0.6 mg/dl) (p=0.02). The only side effects that were observed were transient nausea and vomiting during infusion (n=2) and alopecia (n=1). None of the children developed leukopenia or hemorrhagic cystitis. Conclusion: IVCP infusions appear to be safe, effective and economical therapeutic modality in steroid resistant children with idiopathic FSGS.
Key words: Cyclophosphamide, Focal segmental glomerulosclerosis, Nephrotic syndrome, Steroid resistant.
This paper was awarded the S.T. Achar Gold Medal at the National Conference of Indian Academy of Pediatrics held in Jaipur in February 1999.
Idiopathic nephrotic syndrome (INS) is the commonest glomerular disease in children(1). Focal segmental glomerulosclerosis (FSGS) accounts for 10% of children with INS(2,3). However, recent studies have shown increasing prevalence of this entity(4,5). In contrast to minimal change disease (MCD), 75-80% of patients with FSGS are steroid resistant (SR) and majority of them slowly progress to end stage renal disease(6,7). It is also the most common cause of serious recurrent disease after renal transplantation in children(8). The dismal prognosis has prompted efforts to develop alternative treatment regimens with variable results(9-16). We have previously demonstrated that intravenous pulse cyclophosphamide (IVCP) is effective in SR MCD(17). Hence we conducted a prospective study to evaluate the role of monthly intravenous cyclophosphamide (IVCP) infusion in the management of children with INS secondary to FSGS and resistant to steroid therapy.
Patients and Methods
Since 1990 we have diagnosed INS in 400 children and they are on our regular follow up. The diagnosis of nephrotic syndrome in these children was based on the ISKDC criteria for proteinuria (>40 mg/m2/day), hypoalbuminemia (<25 g/L), edema and hypercholesterolemia (>250 mg/dl)(18). After informed consent, kidney biopsy was performed in the following situations: (i) age of onset of nephrotic syndrome <1 year or >8 years, (ii) no response to 4 weeks course of prednisolone therapy, (iii) frequent relapsers and steroid dependent children prior to cytotoxic therapy, and (iv) children with unusual clinical features (hypertension/gross hematuria) and abnormal renal functions(19). Renal biopsy was evaluated by light and immunoflourescent microscopy. These children were treated with standard prednisolone therapy(20,21). Based on the response, these children were further cate-gorized on follow up into frequent relapsers (FR), steroid dependent (SD), infrequent relapsers (IFR), initial non responders (INR) and subsequent non responders (SNR)(18).
The study group comprised of 20 consecutive children who were analyzed prospectively and who fulfilled the following inclusion criteria: (i) age at onset of 1-16 years, (ii) evidence of steroid resistance, i.e., persistent heavy proteinuria (>40mg/m2/h) despite 8 weeks of standard prednisolone therapy (60mg/m2/od ´ 4 weeks, 40mg/m2/ad ´ 4 weeks); (iii) hypoalbuminemia (<2.5g/dl), (iv) evidence of FSGS on renal biopsy [presence of at least one glomerulus demonstrating a segmental area of loop collapse and sclerosis(1)], (v) absence of clinical or laboratory evidence of other systemic disease or anatomic disorders, (vi) HbsAg and HIV seronegativity. The biopsies were scored semiquantitatively as per standard methodology described previously. The severity of glomerular changes was assessed by calculating the percentage of glomeruli with segmental sclerosis. The other histological changes (mesangial matrix, mesangial cellularity, interstitial fibrosis, interstitial infiltration, tubular atrophy and blood vessel involvement) were each scored on a semiquantitative scoring system as follows: 0 = no change, 1 = focal changes, 2 = mild involvement, 3 = moderate and 4 = severe changes(22). Of these 20 children, 6 were initial nonresponders and 14 subsequent nonresponders. An informed consent was taken and they were started on monthly infusions of IVCP in a dose of 500 mg/m2 for three months. IVCP was administered as an infusion in 300 ml of 5% dextrose over 3-4 hours in a day care setting. Adjunctive prednisolone was given in a dose of 60 mg/m2/day for 4 weeks followed by 40 mg/m2/alternate day for 4 weeks and then tapered off over next 4 weeks. If the proteinuria persisted at the end of 3 months and the infusions were well tolerated, the dose of IVCP was increased to 750 mg/m2/month for the next 3 months and a repeat course of prednisolone given. These 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 estimation in spot sample, serum protein, albumin, creatinine, hemoglobin and total leukocyte count. The children were monitored for the leukopenia, infections and other side effects. In presence of infection or leukopenia, the next dose was delayed till there was complete normalization of counts or recovery from infection. The outcome was analyzed in terms of complete remission (protein free or urine spot albumin/creatinine <0.2 and increase in serum albumin >3.5 g/dl), remission (persistent proteinuria but edema free with increase in serum albumin >2.5 g/dl) and non-response (persistence of proteinuria and edema and serum albumin <2.5 g/dl)(1,9).
The results were analyzed for statistical significance using the paired student's t-test. The mean significance histopathological scores in patients who responded were compared with those who showed partial or no response using the analysis of variance (ANOVA).
The study group comprised of 20 children (15 boys) with mean age of onset of disease 5.5±3.5 years. Prior to starting therapy 2 of these 20 children had chronic renal insufficiency, while the other 8 had normal renal functions. At the end of the study period after a mean duration of disease of 77±55 months, all 20 children had normal renal function (serum creatinine of 0.77±0.25 mg/dl). Thirteen of the 20 children (65%) had attained a complete remission. Of the 6 children who were INR, 3 attained a complete remission while 10 of the 14 children who were SNR achieved a complete remission. Of the 2 children with renal dysfunction prior to onset (Case 1 and Case 7), one achieved a complete remission and the other a partial remission (Table I).
Table I__Summary of Patient Profile
MEAN+_SD (5.5+_3.5) (4.2+_18.7) (2.3+_0.7) (14.6+_18.7) (1+_0.6) (3.5+_0.7) (11.2+_3.7) (0.8+_0.2) (21.2+_13.4)
In the 14 children who were SNR, the mean time between initial response and secondary steroid resistance was 5.5±4.8 yr. There was no significant difference in the mean histopathological scores in the group of patients who showed a complete response as compared to those who had a partial/no response (Table II).
Table II__ Correlaton of Clinical Response with Renal Histopathology
The mean time to achieve a complete remission in these 13 children was 2.4±1.9 months. After a mean follow up post IVCP therapy of 21.2±13.2 months, 10 children were IFR, 2 had become FR and 1 steroid dependent. The mean duration of remission following last dose of IVCP in these children was 12.5±11.9 months. Post IVCP relapses were treated with standard prednisolone therapy as per APN proto-col(21,22). Of the 7 children who continued to be proteinuric, 3 had achieved a partial remission, i.e., became edema free with increase in serum albumin and not requiring any albumin infusion or antiproteinuric drugs. One child died due to septicemia and peritonitis 2 years after the last dose of IVCP. At last follow up, the children in the study group had significantly higher total protein (6.5 ±1.0 mg/dl versus 5.0±0.8) (p = 0.0004) and serum albumin levels (3.5 ± 0.7g/dl versus 2.3±0.7) (p = 0.00007) and significantly lower serum creatinine levels (0.8±0.2 mg/dl versus 1.0±0.6) (p = 0.02) as compared to the pre-IVCP values, respectively. The only side effects observed were transient nausea and vomiting during IVCP infusion in 2 children and alopecia in one. None of the children developed leukopenia or hemorrhagic cystitis.
Idiopathic nephrotic syndrome has an incidence of 2 per 100,000 children per year with a cumulative prevalence of 16 per 100,000 children(19). Although similar data from our country are not available, a study done in United Kingdom revealed that this was 6 times more common in Asians(23). The treatment of SR FSGS continues to pose a therapeutic challenge. If not aggressively treated it is likely to progress to end stage renal failure. A number of therapeutic regiments have been tried with variable results (Table III).
Table III__Therapeutic Protocols Tried in Children with Sterod Resistant FSGS
In the present study IVCP infusions were found to be beneficial with a complete response rate of 65%. Another three children have had a partial remission and remain edema free despite persistent proteinuria. The prognostic significance of partial remission has been demonstrated previously(9). If these are also included, the response rate increases to 80% after a mean follow up post IVCP of 21.2±13.2 month. Of the 13 children who achieved a complete remission 10 were classified as infrequent relapsers, 2 frequent relapsers and one was steroid dependent. Further, after a mean duration of disease of 77±55 months, all 20 children continued to have normal renal functions.
The efficacy of other cytotoxic agents like azathioprine and vincristine has been considered to be poor(24). There are no known reports with chlorambucil. Cyclosporine (CsA) therapy has been found to have a success rate of 30-35% in inducing a partial or complete remission in most series(1,13). However, there is a recent report of a success rate of 80% when used in combination with intravenous methylpre-dnisolone infusion(15). But these children tend to become CsA dependent. Moreover this drug is expensive and remains beyond the reach of the vast majority of our patient population. The risk of nephrotoxicity is much higher in FSGS than MCD and in steroid resistant patients as compared to steroid dependent(1). One of the 4 children biopsied did show evidence of nephrotoxicity on histopathology(15). The other regimen of a combination of oral cyclophos-phamide and intravenous methylpred-nisolone infusion has been reported to have a success rate of 66%. However, this is an extremely aggressive and prolonged therapy over two years and is not without its attendant cost and steroid side effects(12). Our results are comparable to the intravenous methylpre-dnisolone but with much shorter duration of treatment (6 months), at a fraction of the total cost and with minimal side effects. Experience in lupus nephritis has shown that when compared with lower dose daily protocol, IVCP is associated with a lower incidence of cancer, gonadotoxicity, bladder toxicity and chronic bone marrow suppression(25). There is conflicting data regarding the role of cyclophosphamide in SR FSGS. While the ISKDC study failed to demonstrate any benefit of oral cyclophosphamide, there are other studies that suggest a beneficial role(9-11). However, this trial used oral cyclophosphamide with alternate day steroids. Our steroid regimen was more intensive. Moreover in a previous study it has been demonstrated that IVCP is more effective than oral cyclophosphamide in steroid resistant MCD(16). There have also been other reports that IVCP can change the natural course of steroid resistant INS(26). A single high dose infusion has been shown to prevent the development of immune complex nephritis in mice despite repeated antigen stimulation(27). Moreover even in studies involving methyl-prednisolone therapy, the failure rate varied from 18%-100% and there was a direct relation-ship between the percentage of children given a cytotoxic agent and the percentage of success-ful outcomes(1). Recently, there has been a preliminary report of its beneficial effect in a small series of 10 patients, in a study conducted over a similar period of time as this study(28).
In our study we observed that complete remission with cyclophosphamide was higher in children who were SNR (71.4%) as com- pared to those who were INR (50%). Children with late resistance to steroids have been found to respond better to cyclophosphamide(28,29). Thus, our study suggests that the prognosis is better in those who have late resistance and are subsequent non responders. As these children did not have a biopsy at the onset of NS, it would be difficult to speculate whether they initially had MCD and subse-quently developed FSGS or had FSGS to begin with. There was no correlation of the response to IVCP with the histiopathological changes. It is concluded that IVCP may be a safe, effective and economical therapeutic modality in the management of children with steroid resistant idiopathic FSGS.
This study was carried out during the tenure of the author (SG) as a Senior Research Associate which was supported by the Council of Scientific and Industrial Research. The author also wishes to acknowledge the generous help and guidance of the faculty members, residents and nursing staff of the department in carrying out this study.
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