Predicting First-Year Relapses in Children With Nephrotic Syndrome Alexandru R. Constantinescu, Hetal B. Shah, Edward F.

Foote and Lynne S. Weiss Pediatrics 2000;105;492

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2000 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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Predicting First-Year Relapses in Children With Nephrotic Syndrome

Alexandru R. Constantinescu, MD*; Hetal B. Shah; Edward F. Foote, PharmD; and Lynne S. Weiss, MD*
ABSTRACT. Objective. More than half of the children diagnosed with nephrotic syndrome will have relapses. These can be infrequent relapses (IRs: <2 in 6 months or <3 in a year) or frequent relaspses (FRs: >2 in 6 months or >3 in a year). Patients who relapse while on alternate day steroids or within 1 month of discontinuation of steroid therapy are considered steroid-dependent (SD; J Pediatr. 1982; 101:514 518). Patients with an IR course have a better long-term prognosis, and many of them have minimal-change disease without mesangial hypercellularity or sclerosis. The purpose of our study was to identify factors at initial presentation that could predict the relapse pattern in the first year after diagnosis, without taking into consideration the histopathology found on renal biopsy. Design. We analyzed the medical records of children who were seen by us before March 1997 and followed for at least 1 year. Variables selected in the study were age, sex, race, presence or absence of hematuria, and days to remission (defined as protein-free) at the initial presentation, because they could relate to the pattern of relapses (ie, IR, FR, and SD). Results. Of 70 patients, 14 were excluded because of insufficient data. There were 38 males (67.9%) and 18 females (32.1%), giving a male:female ratio of 1.8:1. Median age at presentation was 3.25 years (range: 1.513), and 76.9% were white, 8.9% black, 7.1% Hispanic, and 7.1% other. Of all the patients, 23 were IR (41.1%), 9 were FR (16.1%), and 24 were SD (42.9%). Median days to remission were 10 (range: 2 60), on Prednisone 60 mg/M2 daily. Hematuria was present initially in 26 patients (46.4%), and absent in 30 (53.6%). Age, sex, race, and hematuria, as independent variables, were not predictors of relapses in the first year. However, using a stratified analysis based on the presence or absence of hematuria, we found that if the remission occurred within the first week of therapy, the patients without hematuria were more likely to be IR. The sensitivity and specificity of this finding were 67% and 89%, respectively, with a positive predictive value of 94%. Conclusion. We conclude that of all the presenting features, the rapidity of initial response to steroid therapy combined with the presence of hematuria, could predict future relapses and should be well documented.
From the *Department of Pediatrics, Division of Pediatric Nephrology, University of Medicine and Dentistry of New JerseyRobert Wood Johnson Medical School, New Brunswick, New Jersey; and the College of Pharmacy, Rutgers, Piscataway, New Jersey. Hetal B. Shah, PharmD, is Clinical Practice Specialist at M.D. Anderson Cancer Center, Division of Pharmacy, Houston, Texas. This study has been presented in part, in abstract form, at the 31st Annual Meeting of the American Society of Nephrology; October 2528, 1998; Philadelphia, PA. Received for publication Apr 20, 1999; accepted Apr 20, 1999. Reprint requests to (A.R.C.) 1 Robert Wood Johnson Place, CN19, New Brunswick, NJ 08903. E-mail: constaar@umdnj.edu PEDIATRICS (ISSN 0031 4005). Copyright 2000 by the American Academy of Pediatrics.

Pediatrics 2000;105:492 495; nephrotic syndrome, children, steroid therapy, hematuria.

ABBREVIATIONS. NS, nephrotic syndrome; MCD, minimalchange disease; FR, frequent relapser; SD, steroid-dependent; IR, infrequent relapser; FSGS, focal segmental glomerulosclerosis.

diopathic, noncongenital nephrotic syndrome (NS) of childhood is characterized by massive proteinuria and hypoalbuminemia, leading to edema and hypercholesterolemia. Other clinical findings, such as hematuria and hypertension, are observed in a small fraction of patients. The incidence of NS has been reported to be 2 to 7 children per 100 000 per year.13 The male:female ratio was found to be 2:1. The age at the onset is generally between 18 months and 6 years. Various histopathological findings have been reported in children with NS and 75% of cases have minimal-change disease (MCD).4 Based on the results of the International Study of Kidney Diseases in Children,5 a common practice in patients between 18 months and 6 years of age, presenting with features of Idiopathic NS, is the initiation of steroid therapy without performing an a priori kidney biopsy. Approximately 90% of children with MCD will initially respond to daily prednisone with resolution of proteinuria. The therapeutic regime used in the International Study of Kidney Diseases in Children is 60 mg/M2 for 4 weeks, followed by alternate day prednisone (40 mg/M2) for another 4 weeks. Unfortunately, the rate of relapses is high (60%75%), with a significant proportion of patients becoming frequent relapsers (FRs) or steroid-dependent (SD). Prolonged or frequent use of steroids adds morbidity, including short stature, cataracts, gastritis, osteoporosis, and other side effects of steroid therapy. A German Collaborative Study6 has suggested that if the initial period of steroid therapy is prolonged to 12 weeks, the relapse rate is lower. Several groups have determined the long-term prognosis for children with NS.710 Patients with steroid-responsive MCD had the best outcome, and those with steroid-resistant NS had the worst outcome. The purpose of our study was to identify those characteristics at the initial presentation of patients with steroid-responsive NS that could predict the disease course during the first year.
METHODS Study Characteristics
The study was conducted as a retrospective chart review of all pediatric patients with NS referred to and followed by the pedi-

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atric nephrologists at Robert Wood Johnson Medical School, for whom at least 12 months of follow-up were completed. Before data collection, exemption from review was obtained from Rutgers University and University of Medicine and Dentistry of New Jersey institutional review boards.

Exclusion Criteria
Patients for whom there were incomplete data from the initial presentation or who were followed up for 12 months were excluded from analysis. The steroid-resistant patients were also excluded.

Variables
The medical records of patients diagnosed with NS were analyzed and the following information was noted from the initial presentation: gender, race, age, hematuria (presence of at least 5 red blood cells per high power field), steroid regimes, days to remission, duration of therapy, and the pattern of relapses in the first year after diagnosis.

Data Analysis
Initial analysis was made using Epi-Info program, version 6.0 (Centers for Disease Control and Prevention, Atlanta, GA). To further assess the relative contribution of multiple factors that affect the determination whether a patient will be an infrequent relapser (IR), FR, or SD, a logistic regression analysis was performed using the SAS program (SAS Institute, Cary, NC). The dependent variable was the patient type (IR, FR, or SD). The independent variables were age at presentation, race, sex, hematuria, and days to remission. A 2 analysis was performed to determine significant relationship between the variables and the therapeutic outcome. Statistical significance was defined by a P value of .05.

noted in all patients. It took an average of 13.9 1.6 days to achieve remission, ranging from 2 to 60 days. In the first year after initial presentation, there were 23 patients with IR (41.1%), 9 with FR (16.1%), and 24 who were SD (42.9%). Because of the small number of FR in the first year, the SD and FR groups were analyzed together, compared with the IR group. The age distribution of patients in each group is in Fig 1. In the group of patients younger than 3 years of age, there were twice as many FR SD patients, compared with the IR group, a difference not seen in older patients. However, there was no direct influence of age on the relapse pattern (P .45). The distribution according to the rapidity of response (days to remission) in both groups can be seen in the Fig 2. There was no correlation between the age of patients and the number of days to remission (r .04), regardless of sex (P .95 for females and P .82 for males), or relapse pattern (P .98 for SD, P .99 for FR, and P .84 for IR). However, it seemed that there may be other factors identifiable in the patients who responded within 1 week, compared with those who required a longer treatment period. The other characteristic noted at the onset was hematuria.
Hematuria

RESULTS Patient Characteristics

Of 70 patients diagnosed before March 1997, and followed up for at least 1 year, 14 were excluded based on the above criteria (4 because of a lack of adequate follow-up time, 8 because of insufficient data at initial presentation, and 2 who were steroid nonresponsive). Of the remaining 56 patients, 38 (67.9%) were males, 18 (32.1%) were females, giving a male:female ratio of 1.8:1. The mean age at presentation was 4.37 .4 years, with a range of 1.5 to 13 years. The racial/ethnic distribution was as follows: 43 whites (76.9%), 5 blacks (8.9%), 4 Hispanics (7.1%), and 4 others (7.1%).
Disease Course

At presentation, 26 patients had hematuria (46.4%; 7 with gross hematuria and 19 with microscopic hematuria), and 30 patients did not have hematuria (53.6%). The presence of hematuria both gross and microscopic did not correlate with the number of days to remission or to the relapse pattern (Fishers exact test; P 1.0; Fig 3). Among those patients with gross hematuria, 3 had an SD course, and 4 had an IR course. However, among the patients without hematuria at presentation, the number of days to remission correlated well with the relapse pattern. Patients who responded within 7 days had an IR course, whereas those with a delayed response (7 days) had a FR or SD course (Fishers exact test, with Yates

Initial steroid therapy was 60 mg/M2 in divided daily doses, for at least 4 weeks, followed by equal number of weeks of alternate day therapy, in the dose of 40 mg/M2. The majority of patients were on 4 weeks of daily steroids followed by 4 weeks of alternate day therapy. If there was no response to therapy after 4 weeks, patients underwent a kidney biopsy. The 2 patients who were steroid-resistant were excluded from the data analysis. A total of 13 other patients were biopsied because of late nonresponse at varying intervals after the initial presentation and are included in the study; 8 had MCD, 1 had immunoglobulin A nephropathy, and 4 had focal segmental glomerulosclerosis (FSGS). The result of the biopsy did not have an influence on the current data analysis. The number of treatment days until the patients urine became protein-free (or days to remission) was

Fig 1. Age distribution. There were 23 patients with IRs and 33 patients with FRs and SD. There was no difference between the groups (P .45).

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Fig 2. Days to remission. There was a lack of correlation between the age of the patients and the number of days to remission (r .04) within each group of relapse pattern (P .98 for SD, P .99 for FR, and P .84 for IR).

Fig 4. Relapse pattern in patients without hematuria, based on their response to steroid therapy. Of the 13 patients with IR, 8 responded within 1 week, the remaining 5 responded in 7 days. Also, 17 patients had a FR or SD pattern, and only 1 responded within 1 week, 16 responding in 7 days (* indicates P .004; odds ratio: 25).

Fig 3. Relapse pattern in patients with hematuria, based on their response to steroid therapy. A total of 10 patients had an IR pattern, 4 responded within 1 week, 6 responded in 7 days. Also, there were 16 patients with FR or SD pattern, of whom 6 responded within 1 week, and 10 in 7 days (P 1.0).

correction; P .004, with an odds ratio of 25; Fig 4). The sensitivity and specificity of this finding were 67% and 89%, respectively, with a positive predictive value of 94%. In the group without hematuria, 1 patient had an SD course and responded in 4 days and was later biopsied because of late nonresponse. This patient was found to have FSGS. The risk of FSGS in our group of steroid-responsive patients was 8.9%, with 13% among the IR and 3% among the SD patients. However, we do not know the exact prevalence of FSGS in this sample, because not all patients were biopsied.
DISCUSSION

The results of our initial analysis suggested that the earliest predictor of a relapsing course could be
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the number of days it took the patient to enter remission, after initial treatment with prednisone. There was a tendency for patients who took longer to respond to be FRs or SD. However, this was significant only among patients without hematuria, because those with hematuria had similar chances of being IR or FR/SD. This is an important finding, suggesting that the first day when the patients urine becomes protein-free, along with the presence (or absence) of hematuria can be predictors of future relapses, at least in the first year. The male:female ratio in our group of patients was 1.8:1, consistent with epidemiologic findings in which NS is twice as prevalent in males.1,2 The usual age of onset in the literature is between 18 months and 6 years of age. The mean age of our patients was 4.37 .4 years. A majority of our patients were whites (76.9% vs 5.9% blacks), representative of the referral pattern in our area. It has been suggested that there is an increased incidence of NS in black patients.2 However, there are no data in the literature addressing racial differences among pediatric patients with NS. A majority of patients will respond within the first 3 weeks from the initiation of steroid therapy, and smaller percentages will respond in the subsequent weeks of therapy. Consistent with that trend, our study had a mean number of days to remission of 13.9 1.6. It appears from the above analysis that our patient population had characteristics similar to those reported in the literature. Data from the literature indicate that 40% of relapsers are represented by FR and SD patients.1,11 Our data suggest that nearly 60% of the patients are represented by FR and SD. It is possible that our patient population may have a different steroid-response distribution in the subsequent years, but this was beyond the scope of this analysis. Our study is unique because it investigated the likelihood of being a FR or SD patient from the initial

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clinical and laboratory findings. No previous study analyzed the rapidity of response to oral steroid therapy as a predictive feature. Most previous studies have examined the long-term prognosis of patients who have already been identified as FR or SD710 or of those only with MCD12 or with a mild initial attack.13 Cornfield and Schwartz14 reported that the older the patient at the onset, the worse the prognosis, but most of their patients had glomerulonephritis, a histopathological finding associated with poor response to steroids. Other studies15,16 have concluded that there was no statistically significant relationship between relapses and age at onset, gender, or hematuria. Therefore, it may have been the histopathological finding rather than the age at onset that predicted a worse prognosis. The incidence of hematuria in our patient population was higher (46.4%) than that reported by other centers (30%). We could not yet determine the reason for this discrepancy, because we did not perform biopsies in these patients at the initial presentation. However, the presence of gross or microscopic hematuria alone did not have predictive value. The absence of hematuria, by itself, seemed at the initial analysis to suggest an IR course but was not statistically significant. When we stratified the patients without hematuria based on the number of days to remission, we found that those who respond within 1 week have a greater chance of having fewer relapses in the first year. One of the most difficult problems in the care of children with NS remains the occurrence of relapses, despite initial response to steroids. Because the ultimate prognosis is quite good for most patients, efforts should be directed toward minimizing the complications of steroid and/or cytotoxic agents. The predictive factors identified in this study may be helpful in that regard. This would alert physicians caring for these patients to monitor them closer and would allow them to counsel appropriately the patients and their caretakers. Consequently, being able

to identify patients who are more likely to have an FR or SD course may allow a better management, and treatment protocols may be developed according to the initial presentation and response.
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Predicting First-Year Relapses in Children With Nephrotic Syndrome Alexandru R. Constantinescu, Hetal B. Shah, Edward F. Foote and Lynne S. Weiss Pediatrics 2000;105;492
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2000 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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