LONG VERSUS STANDARD INITIAL STEROID THERAPY FOR CHILDREN WITH IDIOPATHIC NEPHROTIC SYNDROME

LONG VERSUS STANDARD INITIAL STEROID THERAPY FOR CHILDREN WITH IDIOPATHIC NEPHROTIC SYNDROME Mohammad Sjaifullah Noer ABSTRACT Objectives: Two regimens of steroid treatment for the first episodes of idiopathic nephrotic syndrome in children were compared to address whether a longer initial course provides superior protection against relapse without increased adverse effects. The standard regimen consisted of prednisone 60 mg/m2 or 2 mg/kg per day for 4 weeks, followed by 40 mg/m2 or 1.5 mg/kg alternate-day prednisone for 4 weeks. The long regimen consisted of daily prednisone of 60 mg/m2 or 2 mg/kg for 6 weeks, followed by alternate-day prednisone 40 mg/m2 or 1.5 mg/kg for 6 weeks. Methods: A randomized clinical trial was conducted to children with nephrotic syndrome hospitalized at Department of Child Health Dr. Soetomo Teaching Hospital Surabaya. All patients were followed one year minimally after the treatment was stopped. Results: Eighty-one children with nephrotic syndrome aged 2-15 years old were randomized into 33 children receiving long (12-week) and 48 children receiving standard (8-week) initial steroid therapy. The time to first relapse in the long regimen group and standard group was 272.28 ± 158.76 days and 238.02 ± 144.28 days, respectively (p = 0.32). The percentage of patients with no relapse in 6 and 12 months after initial prednisone withdrawal was 75.8% and 60.6% in the long regimen group and 66.7% and 54.2% in the standard group, respectively. The percentage of children with 1 relapse in 6 and 12 months after initial prednisone withdrawal was 21.2% and 21.2% in the long regimen group and 33.3% and 29.2% in the standard group, respectively. The percentage of patients with 2 relapses in 6 and 12 months was 3.0% and 12.1% in the long regimen group and 0% and 14.6% in the standard group, respectively. No significant difference showed between the two groups (p = 0.51). Conclusions: The long initial prednisone therapy may delay occurrence of the first relapses and reduced the subsequent rate of relapses compared to the standard regimen, but statistically there were no significant differences. Keywords: idiopathic nephrotic syndrome, prednisone, initial steroid therapy INTRODUCTION The annual incidence of nephrotic syndrome in children in the United States has been estimated to be 2.0 to 2.7 new cases per 100,000 children younger than 18 years of age (McEnery PT and Strife CF, 1982). The incidence of idiopathic nephrotic syndrome is six fold greater in Asian than in European children (Sharples PM, et al., 1985). In Jakarta Indonesia, Wila Wirya (Wila Wirya IGN, 1992) reported 6 new cases per 100.000 children younger than 14 years old, making it a relatively common major disease in pediatrics. In addition, even the most benign form of the nephrotic syndrome is, by nature, a recurrent disorder, so each new-onset case likely will continue to manifest disease for some time. Nephrotic syndrome is one of the most frequent reasons for referral to a pediatric nephrologist for evaluation, although its insidious onset frequently causes delay in diagnosis. Department of Child Health Airlangga University School of Medicine Dr. Soetomo Teaching Hospital, Surabaya Although it is well accepted that corticosteroids induce a complete remission in most children with new-onset idiopathic nephrotic syndrome (INS), the optimal duration of initial steroid treatment for children with this disorder is unclear. The standard approach in this study is to use the modified International Study of Kidney Disease in Children (ISKDC) 8-week regimen (International Study of Kidney Disease in Children, 1981, Niaudet P, 2004). This approach consists of 4 weeks of daily treatment with prednisone in divided doses (60 mg/m2 or 2 mg/kg per day, maximum 80 mg/day), followed by 4 weeks of alternate-day therapy (40 mg/m2 or 1.5 mg/kg qod, maximum 60 mg qod) as single morning dose. However, at least 65% of children with INS who initially respond to this regimen subsequently have a relapse, with approximately 40% of them having frequent relapses or steroid dependence (Arbeitgemeinschaft fur Padiatrische Nephrologie, 1988, Barnett HL, 1976, International Study of Kidney Disease in Children, 1979). Repeated use of corticosteroids in these patients leads to steroid toxicity, often requiring the use of potentially toxic drugs such as cyclophosphamide, chlorambucil, and cyclosporin A. Recent surveys in both North America and the United Kingdom have found considerable diversity in the Folia Medica Indonesiana 205

approach of pediatric nephrologists to the initial therapy of children with INS (Evans JHC and Long E, 1998, Lande MB and Leonard MB, 2000). This has resulted, in part, from the publication of a number of randomized controlled trials that evaluated the effect of extending the initial course of steroid therapy from 8 weeks (standard regimen) to 12 weeks or more (long regimen) on the subsequent relapse rate in children with INS (Bagga A, et al., 1999, Ehrich JH and Brodehl J, 1993, Ksiazek J and Wyszynska T, 1995, Norero C, et al., 1996, Ueda N, et al., 1988). The long regimen according to Arbeitsgemeinshaft für Pädiatrische Nephrologie (Ehrich JH and Brodehl J, 1993), consisted of prednisone 60 mg/m2/day or 2 mg/kg/day (maximum 80 mg/day) in divided doses for 6 weeks, followed by 40 mg/m2 or 1.5 mg/kg (maximum 60 mg/qod) in single morning dose on alternate days for the next 6 weeks. The focus of this study was to evaluate whether a long initial steroid therapy in patients with INS can achieve results superior to those obtained with standard therapy without significantly increasing steroid side effects. PATIENTS AND METHODS This randomized clinical trial conducted from all children between the ages of 2 and 15 years hospitalized at the Child Health Department Dr. Soetomo Teaching Hospital Surabaya between January 1, 1997 to December 31, 2003, with first episode of INS (proteinuria > 50 mg/kg/24 hours or > 40 mg/m2 BSA/hour, hypoalbuminemia < 2.5 g/dl, edema, with or without hypercholesterolemia) (Alatas H, et al., 2005). Initial evaluation included urinalysis, chest x-ray, and measurement of blood levels of ureum, creatinine, albumin, and cholesterol. Patients having received corticosteroids or immunosuppressive agents and those showing features of an underlying systemic disease (e.g., systemic lupus erythematosus, Henoch-Schönlein purpura, amyloidosis, vasculitis, and hereditary glomerular disease) were excluded. Patients with hematuria (more than 5 red cells per high-power field of a centrifuged specimen), persistent hypertension (blood pressure more than the 95th percentile for height for age on three or more occasions) (National High Blood Pressure Education Program, 1996) were also excluded. Patients were randomized, by simple randomization, into those receiving the standard (8-week) or long (12- week) prednisone therapy. Standard therapy as a modified ISKDC regimen (International Study of Kidney Disease in Children, 1981, Niaudet P, 2004) consisted of 4 weeks of daily treatment with prednisone in divided doses (60 mg/m2 or 2 mg/kg per day, maximum 80 mg/day), followed by 4 weeks of alternate-day therapy (40 mg/m2 or 1.5 mg/kg qod, maximum 60 mg qod) as single morning dose. The long regimen according to Arbeitsgemeinshaft für Pädiatrische Nephrologie (Ehrich JH and Brodehl J, 1993), consisted of prednisone 60 mg/m2/day or 2 mg/kg/day (maximum 80 mg/day) in divided doses for 6 weeks, followed by 40 mg/m2 or 1.5 mg/kg (maximum 60 mg qod) in single morning dose on alternate days for the next 6 weeks. Informed consent was obtained from the parents. Patients were followed up regularly at pediatric nephrology outpatient clinic Dr. Soetomo Teaching Hospital Surabaya. In both groups, symptomatic and supportive treatments were instituted as required. All patients had a minimum of 1-year follow-up from completion of the initial treatment. Patients not achieving remission within 4 weeks of daily treatment or those showing non-compliance with treatment were excluded. The duration between cessation of treatment for the initial episode and the first relapse (time to first relapse) was compared in the two groups. Each relapse was treated with prednisone 2 mg/kg daily until one week after proteinuria not detected anymore, and then continued with 1.5 mg/kg on alternate days for 4 weeks (International Study of Kidney Disease in Children, 1982). The number of relapse at 6 and 12 months of follow-up were recorded. Cushingoid face and other steroid side effects, including increased appetite, cataracts, emotional lability, glycosuria, hirsutism, obesity, hypertension, and striae, were evaluated as present, absent, or unknown. The following definitions were used in data collection and analysis. Remission of nephrotic syndome is defined as disappearance of proteinuria on boiling test (Wallach J, 1986) (i.e., negative or trace). Relapse of nephrotic syndrome is defined as recurrence of proteinuria requiring the reinstitution of daily prednisone therapy. The two groups were first compared on all measured characteristics, to evaluate whether the process of case identification might have resulted in different reference populations. Statistical analysis was performed using chi-squared, and t-test. RESULTS Of 101 patients with the first episode of INS, were randomized to receive the standard (8-week) regimen or the long (12-week) regimen. Patients were later excluded due to steroid resistance (n=6) or poor compliance (n=14). Eighty-one children with nephrotic Folia Medica Indonesiana 206

syndrome aged 2-15 years old were randomized into 33 children receiving the long (12-week) regimen and 48 children receiving the standard (8-week) regimen. Patient characteristics (Table 1) The initial characteristics of patients in the two groups were similar with regard to sex, age, weight, blood pressure, serum albumin, serum cholesterol, ureum, and creatinine. Table 1. Characteristics of the long and standard regimen groups Characteristics long 12-week group (n=33) standard 8-week group (n=48) p Sex boys 20 30 girls 13 18 total 33 48 0.86 Age (years) 7.12 ± 3.14 6.13 ± 2.91 0.15 Body weight (kg) 20.9 ± 6.4 19.6 ± 6.2 0.36 Blood pressure: systolic 115.12 ± 9.29 111.52 ± 8.95 0.08 diastolic 75.02 ± 7.46 72.53 ± 6.39 0.11 Albumin (g/dl) 1.74 ± 0.49 1.80 ± 0.54 0.59 Cholesterol (mg/dl) 500.47 ± 151.96 477.21 ± 112.30 0.43 Ureum (mg/dl) 23.05 ± 21.15 21.62 ± 18.02 0.75 Creatinine (mg/dl) 0.76 ± 0.30 0.72 ± 0.27 0.50 Note: There were no significant differences between the two groups Efficacy of long and standard prednisone regimen (Table 2) The mean duration of follow-up was similar in the two groups (13.3 ± 4.7 months in the long regimen group and 13.8 ± 5.5 months in the standard regimen group, p = 0.69). The remission after prednisone started were 15.18 ± 7.41 days in the long regimen group and 13.44 ± 6.28 days in the standard regimen group (p = 0.25). The time to first relapse was longer in the long regimen group (mean 272.28 ± 158.76 days) than the standard regimen group (mean 238.02 ± 144.28 days). There was no significant difference between the two groups (p = 0.32). The percentage of patients with no relapse 6 and 12 months after initial prednisone withdrawal was 75.8% and 66.7% in the long regimen group and 66.7% and 56.2% in the standard regimen group, respectively. Within 1 year of stopping steroid therapy, 11 of 33 patients (33.3%) who received the long regimen and 22 of 48 patients (43.8%) who received the standard regimen relapsed. Most of these patients relapsed in the first 6 months, 8 of 11 (73%) in the long regimen group and 16 of 22 (73%) in the standard regimen group. The differences were, however, statistically not significant. The percentage of children with 1 relapse in 6 and 12 months after initial prednisone withdrawal was 21.2% and 21.2% in the long regimen group and 33.3% and 29.2% in the standard regimen group, respectively. The percentage of patients with 2 relapses in 6 and 12 months was 3.0% and 12.1% in the long regimen group and 0% and 14.6% in the standard group, respectively. No significant difference showed between the two groups (p = 0.51). The mean of total cumulative prednisone dose received for the initial therapy and in the next 12 months in the long regimen group (3,012.2 mg) was significantly higher than standard group (2,087.1 mg) (p = 0.002). Folia Medica Indonesiana 207

Table 2. Effect of long versus standard steroid therapy on course of nephrotic syndrome long 12-week group (n=33) standard 8-week group (n=48) p Duration of follow-up (months) 13.3 ± 4.7 13.8 ± 5.5 0.69 Remission after prednison started (days) 15.18 ± 7.41 13.44 ± 6.28 0.25 Time to first relapse (days) 272.28 ± 158.76 238.02 ± 144.28 0.32 Relapses in 6 months No relapse 75.8% 66.7% 1 relapse 21.2% 33.3% 2 relapses 3.0% 0% Total relapses 24.2% 33.3% Relapses in 12 months 0.51 No relapse 66.7% 56.2% 1 relapse 21.2% 29.2% 2 relapses 12.1% 14.6% Total relapses 33.3% 43.8% Total cumulative prednisone (mg) 3.012.2 ± 1.572.9 2.087.1 ± 977.0 0.002 Table 3. Frequency of adverse events Adverse events Long 12-week group (n=33) Standard 8-week group (n=48) N % N % Increased appetite 29/33 87.8% 40/48 83.0% Hirsutism 25/33 75.7% 32/48 66.7% Obesity 22/33 66.7% 30/48 62.5% Cushingoid face 14/33 42.4% 19/47 40.4% Emotional lability 5/33 15.2% 5/48 10.4% Increased blood pressure 1/33 3.0% 1/47 2.1% p > 0.01 Side effects from prednisone (Table 3) Steroid side effects observed more frequently in the long regimen including increased appetite, hirsutism, obesity, cushingoid face, emotional lability, and increased blood pressure but there were no statistically significant differences. None of the patients showed striae, glycosuria, or cataracts. DISCUSSIONS Since 1967, the International Study of Kidney Disease in Children has been conducting multicentre, prospective trials in children with the nephrotic syndrome (International Study of Kidney Disease in Children, 1979). Treatment with a standard initial prednisone regimen was found to be satisfactorily in terms of the subsequent course and lack of toxicity in approximately half of over 300 children with minimal change histology treated between 1967 and 1973 (Barnett HL, 1976). The regimen used by most nephrologists over the past 30 years has been that introduced by the International Study of Kidney Disease in Children (ISKDC), or a modification of it (Alatas H, et al., 2005, Barnett HL, 1976, Haycock G, 2003). The ISKDC regimen consists of prednisone, 60 mg/m2/day (or 2 mg/kg/day) with a maximum of 80 mg/day in Folia Medica Indonesiana 208

divided doses for 4 weeks, followed by 40 mg/m2/day (or 1.5 mg/kg/day) with a maximum of 60 mg/day in divided doses on 3 consecutive days per week for 4 weeks (International Study of Kidney Disease in Children, 1981). The Arbeitsgemeinschaft für Pädiatrische Nephrologie (APN) showed that an alternate-day regimen (40 mg/m2 or 1.5 mg/kg qod for 4 weeks) after initial daily therapy resulted in a significantly lower number of patients with relapses and fewer relapses per patients (Arbeitsgemeinschaft fur Padiatrische Nephrologie, 1979). It also showed that on alternate days, prednisone could be given in a single dose rather than in divided doses. Leisti and Koskimies (Leisti S and Koskimies O, 1983) later showed that the steroid-induced adrenal suppression positively correlated with the rate of subsequent relapse. Therefore the Arbeitsgemeinschaft für Pädiatrische Nephrologie (APN) conducted a study in which a short prednisone course of 4 weeks (2 weeks daily and 2 weeks alternate day) for the initial attack was compared with a standard regimen (Arbeitgemeinschaft fur Padiatrische Nephrologie, 1988). The short regimen led to shorter periods of remissions and higher relapse rates than the standard treatment. Subsequently APN compared, in a randomized trial, a long 12-week prednisone course (6 weeks daily and 6 weeks alternate-day) with the standard 8-week therapy (Ehrich JH and Brodehl J, 1993) and showed that prolonged initial treatment lead to prolonged duration of initial remission and reduced relapse rates. Other workers have also examined the effect of duration of steroid therapy on the course of INS. Some of these studies were not prospective and randomized. Ksiazek and Wyszynska (Ksiazek J and Wyszynska T, 1995) randomly assigned 184 children with INS to 2, 3, and 6 months' treatment with prednisone. The results were comparable in patients receiving treatment for 2 or 3 months. Therapy for 6 months was associated with a higher proportion of children in sustained remission and reduced relapse rates during 2 years' follow-up. These findings were similar to those of Ueda et al. (Ueda N, et al., 1988) who also showed that 6 months' treatment with prednisone led to a significant reduction in the proportion of patients who relapsed. Recently the Chilean Cooperative Group (Norero C, et al., 1996) reported the results of 8- or 12-week prednisone treatment in 96 patients with the first episode of INS. Over an 18-month follow-up, there were no differences in the duration of remission and relapse rates in the two groups. In a recent meta-analysis, Hodson et al. (Hodson EM, et al., 2000) reported that the combined results from these studies allowed a recommendation that the initial treatment of children with INS should be for at least 3 months. Long initial steroid therapy in this present study led to a longer duration of initial remission; the proportion of children in sustained remission at 6, and 12 months was higher in the long regimen than the standard group (Table 2). There is a marked variation, in the literature, with regard to the proportion of children achieving sustained remission following initial steroid therapy. The 8-week standard regimen is reported to be associated with sustained remission in 36.4%-55.2% of patients at 6 months, and 27.3%-44.8% of patients at 12 months' follow-up (Arbeitgemeinschaft fur Padiatrische Nephrologie, 1988, Ehrich JH and Brodehl J, 1993, Ksiazek J and Wyszynska T, 1995, Ueda N, et al., 1988). In the present study these proportions were increased at 66.7% and 56.2%, respectively. The higher proportion of our patients of each group showed that they responded better to steroid therapy. The histopathology and clinical characteristics of children with idiopathic nephrotic syndrome at Surabaya is similar to that reported from other countries (Noer MS, 2004). The reasons for sustained remission in a higher proportion of our patients following standard 8-week initial steroid therapy are not clear, but ethnic patterns may play a role, as McKinney PA, et al. (McKinney PA, et al., 2001) reported that over the 12-year study period incidence rates of steroid sensitive nephrotic syndrome, south Asian children displayed significantly higher rates than non-south Asians (p<0.01). In this study the relapse rate tended to be lower in the long regimen group compared with the standard group (24.2% vs. 33.3% at 6 months and 33.3% vs. 43.8% at 12 months, respectively), but the difference does not reach statistical significance (p = 0.51). Steroid side effects as worried by many experts observed minimally in this study. In this present study some common adverse events due to steroid therapy (increased appetite, hirsutism, obesity, cushingoid face, emotional lability, and increased blood pressure) were observed. The results of adverse events in our study are very similar to those reported by Bagga A, et al.(bagga A, et al., 1999), and Lande MB, et al. (Lande MB, et al., 2003). Steroid side effects observed more frequently in the long regimen, however, there were no statistically significant differences between the two groups. The absence of a relapse within the first 6 months is considered a reliable predictor of a favorable course of INS (International Study of Kidney Disease in Children, 1981, International Study of Kidney Disease in Children, 1982, Ksiazek J and Wyszynska T, 1995, Tarshish P, et al., 1997). Our results suggest that prolongation of the initial steroid therapy may delay occurrence of the first relapse. Such a strategy may be Folia Medica Indonesiana 209

important in developing countries where frequent infections often induce early relapses. Patients should, however, be observed closely for signs of steroid toxicity. CONCLUSIONS The long regimen prednisone therapy may delay occurence of the first relapse and reduce the subsequent rate of relapse compared to standard regimen, but statistically there were no significant differences. Steroid side effects observed minimally in this study, however, there were no statistically significant differences between the two group despite the total cumulative prednisone doses were significantly different. REFERENCES Alatas H, Tambunan T, Trihono PP, and Pardede SO, 2005. Konsensus tata laksana sindrom nefrotik idiopatik pada anak. Jakarta: UK Nefrologi Ikatan Dokter Anak Indonesia, pp. 1-20 Arbeitgemeinschaft fur Padiatrische Nephrologie, 1988. Short versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children. Lancet 1, pp. 380-83. Arbeitsgemeinschaft fur Padiatrische Nephrologie, 1979. Alternate-day vs. intermittent prednisone in frequently relapsing nephrotic syndrome. Lancet 1, pp. 401-3. Bagga A, Hari P, and Srivastava RN, 1999. Prolonged versus standard prednisolone therapy for initial episode of nephrotic syndrome. Pediatr Nephrol 13, pp. 824-7. Ehrich JH, and Brodehl J, 1993. Long versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children. Arbeitsgemeinschaft fur Padiatrische Nephrologie. Eur J Pediatr 152, pp. 357-61. Evans JHC, and Long E, 1998. A national audit of nephrotic syndrome: the initial course of prednisone and outcome. Pediatr Nephrol 12, pp. C154. Haycock G, 2003. The child with idiopathic nephrotic syndrome. In: Webb NJA, and Postlethwaite RJ (ed). Clnical Paediatric Nephrology. Oxford: Oxford University Press, pp. 341-66. Hodson EM, Knight JF, Willis NS, and Craig JC, 2000. Corticosteroid therapy in nephrotic syndrome: a metaanalysis of randomised controlled trials. Arch Dis Child 83, pp. 45-51. International Study of Kidney Disease in Children, 1979. Nephrotic syndrome in children: A randomized trial comparing two prednisone regimens in steroidresponsive patients who relapse early. Report of the International Study of Kidney Disease in Children. J Pediatr 95, pp. 239-43. International Study of Kidney Disease in Children, 1981. The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. J Pediatr 98, pp. 561-4. International Study of Kidney Disease in Children, 1982. Early identification of frequent relapsers among children with minimal change nephrotic syndrome. J Pediatr 101, pp. 514-8. Ksiazek J, and Wyszynska T, 1995. Short versus long initial prednisone treatment in steroid-sensitive nephrotic syndrome in children. Acta Paediatr 84, pp. 889-93. Lande MB, Gullion C, Hogg RJ, Gauthier B, Shah B, Leonard MB, Bonilla-Felix M, Nash M, Roy III S, Strife CF, and Arbus G, 2003. Long versus standard initial steroid therapy for children with the nephrotic syndrome. A report from the Southwest Pediatric Nephrology Study Group. Pediatr Nephrol 18, pp. 342-6. Lande MB, and Leonard MB, 2000. Variability among pediatric nephrologists in the initial therapy of nephrotic syndrome. Pediatr Nephrol 14, pp. 766-9. Leisti S, and Koskimies O, 1983. Risk of relapse in steroid-sensitive nephrotic syndrome: effect of stage of post-prednisone adrenocortical suppression. J Pediatr 103, pp. 553-7. McEnery PT, and Strife CF, 1982. Nephrotic syndrome in childhood. Management and treatment in patients with minimal change disease, mesangial proliferation, or focal glomerulosclerosis. Pediatr Clin North Am 29, pp. 875-94. McKinney PA, Feltbower RG, Brocklebank JT, and Fitzpatrick MM, 2001. Time trends and ethnic patterns of childhood nephrotic syndrome in Yorkshire, UK. Pediatr Nephrol 16, pp. 1040-4. National High Blood Pressure Education Program, 1996. Working group on hypertension control in children and adolescents. Update on the 1987 task force report on high blood pressure in children and adolescents. Pediatrics 98, pp. 649-58. Niaudet P, 2004. Steroid-sensitive idiopathic nephrotic syndrome in children. In: Avner ED, Harmone WE, and Niaudet P (ed). Pediatric Nephrology. Philadelphia: Lippincot Williams & Wilkins, pp. 543-56. Noer MS, 2004. Histopathology and clinical characteristics of primary nephrotic syndrome at time of diagnosis at Soetomo Hospital Surabaya. Pediatr Nephrol 19, pp. C81. Norero C, Delucchi A, Lagos E, and Rosati P, 1996. Initial therapy of primary nephrotic syndrome in children: evaluation in a period of 18 months of two Folia Medica Indonesiana 210

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