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DOI: 10.1542/peds.105.3.4922000;105;492-495Pediatrics

Alexandru R. Constantinescu, Hetal B. Shah, Edward F. Foote and Lynne S. WeissPredicting First-Year Relapses in Children With Nephrotic Syndrome

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atric nephrologists at Robert Wood Johnson Medical School, forwhom at least 12 months of follow-up were completed. Beforedata collection, exemption from review was obtained from Rut-gers University and University of Medicine and Dentistry of New

Jersey institutional review boards.

Exclusion Criteria

Patients for whom there were incomplete data from the initialpresentation or who were followed up for 12 months wereexcluded from analysis. The steroid-resistant patients were alsoexcluded.

VariablesThe medical records of patients diagnosed with NS were ana-

lyzed and the following information was noted from the initialpresentation: gender, race, age, hematuria (presence of at least 5red blood cells per high power field), steroid regimes, days toremission, duration of therapy, and the pattern of relapses in thefirst year after diagnosis.

Data Analysis

Initial analysis was made using Epi-Info program, version 6.0(Centers for Disease Control and Prevention, Atlanta, GA). Tofurther assess the relative contribution of multiple factors thataffect the determination whether a patient will be an infrequentrelapser (IR), FR, or SD, a logistic regression analysis was per-formed using the SAS program (SAS Institute, Cary, NC). The

dependent variable was the patient type (IR, FR, or SD). Theindependent variables were age at presentation, race, sex, hema-turia, and days to remission. A 2 analysis was performed todetermine significant relationship between the variables and thetherapeutic outcome. Statistical significance was defined by a Pvalue of.05.

RESULTS

Patient Characteristics

Of 70 patients diagnosed before March 1997, andfollowed up for at least 1 year, 14 were excluded

based on the above criteria (4 because of a lack ofadequate follow-up time, 8 because of insufficientdata at initial presentation, and 2 who were steroid

nonresponsive). Of the remaining 56 patients, 38(67.9%) were males, 18 (32.1%) were females, givinga male:female ratio of 1.8:1. The mean age at presen-tation was 4.37 .4 years, with a range of 1.5 to 13years. 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

Initial steroid therapy was 60 mg/M2 in divideddaily doses, for at least 4 weeks, followed by equalnumber of weeks of alternate day therapy, in thedose of 40 mg/M2. The majority of patients were on

4 weeks of daily steroids followed by 4 weeks ofalternate day therapy. If there was no response totherapy after 4 weeks, patients underwent a kidney

biopsy. The 2 patients who were steroid-resistantwere excluded from the data analysis. A total of 13other patients were biopsied because of late nonre-sponse at varying intervals after the initial presenta-tion and are included in the study; 8 had MCD, 1 hadimmunoglobulin A nephropathy, and 4 had focalsegmental glomerulosclerosis (FSGS). The result ofthe biopsy did not have an influence on the currentdata analysis.

The number of treatment days until the patientsurine became protein-free (or days to remission) was

noted in all patients. It took an average of 13.9 1.6days to achieve remission, ranging from 2 to 60 days.In the first year after initial presentation, there were23 patients with IR (41.1%), 9 with FR (16.1%), and 24who were SD (42.9%). Because of the small numberof FR in the first year, the SD and FR groups wereanalyzed together, compared with the IR group.

The age distribution of patients in each group is inFig 1. In the group of patients younger than 3 yearsof age, there were twice as many FR SD patients,compared with the IR group, a difference not seen inolder patients. However, there was no direct influ-ence of age on the relapse pattern (P .45).

The distribution according to the rapidity of re-sponse (days to remission) in both groups can beseen in the Fig 2. There was no correlation betweenthe age of patients and the number of days to remis-sion (r .04), regardless of sex (P .95 for femalesandP .82 for males), or relapse pattern (P .98 forSD, P .99 for FR, and P .84 for IR). However, itseemed that there may be other factors identifiable inthe patients who responded within 1 week, com-pared with those who required a longer treatmentperiod. The other characteristic noted at the onset

was hematuria.

Hematuria

At presentation, 26 patients had hematuria (46.4%;7 with gross hematuria and 19 with microscopichematuria), and 30 patients did not have hematuria(53.6%). The presence of hematuria both gross andmicroscopic did not correlate with the number ofdays to remission or to the relapse pattern (Fishersexact test;P 1.0; Fig 3). Among those patients withgross hematuria, 3 had an SD course, and 4 had an IRcourse. However, among the patients without hema-turia at presentation, the number of days to remis-

sion correlated well with the relapse pattern. Patientswho 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

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

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correction; P .004, with an odds ratio of 25; Fig 4).The sensitivity and specificity of this finding were67% and 89%, respectively, with a positive predictive

value of 94%.In the group without hematuria, 1 patient had anSD course and responded in 4 days and was later

biopsied because of late nonresponse. This patientwas found to have FSGS. The risk of FSGS in ourgroup of steroid-responsive patients was 8.9%, with13% among the IR and 3% among the SD patients.However, we do not know the exact prevalence ofFSGS in this sample, because not all patients were

biopsied.

DISCUSSION

The results of our initial analysis suggested thatthe earliest predictor of a relapsing course could be

the number of days it took the patient to enter remis-sion, after initial treatment with prednisone. Therewas a tendency for patients who took longer to re-spond to be FRs or SD. However, this was significantonly among patients without hematuria, becausethose with hematuria had similar chances of being IRor FR/SD. This is an important finding, suggestingthat the first day when the patients urine becomesprotein-free, along with the presence (or absence) ofhematuria can be predictors of future relapses, atleast in the first year.

The male:female ratio in our group of patients was

1.8:1, consistent with epidemiologic findings inwhich NS is twice as prevalent in males.1,2 The usualage of onset in the literature is between 18 monthsand 6 years of age. The mean age of our patients was4.37 .4 years. A majority of our patients werewhites (76.9% vs 5.9% blacks), representative of thereferral pattern in our area. It has been suggestedthat there is an increased incidence of NS in blackpatients.2 However, there are no data in the literatureaddressing racial differences among pediatric pa-tients with NS. A majority of patients will respondwithin the first 3 weeks from the initiation of steroidtherapy, and smaller percentages will respond in the

subsequent weeks of therapy. Consistent with thattrend, our study had a mean number of days toremission of 13.9 1.6. It appears from the aboveanalysis that our patient population had characteris-tics similar to those reported in the literature.

Data from the literature indicate that 40% of re-lapsers are represented by FR and SD patients.1,11

Our data suggest that nearly 60% of the patients arerepresented by FR and SD. It is possible that ourpatient population may have a different steroid-re-sponse distribution in the subsequent years, but thiswas beyond the scope of this analysis.

Our study is unique because it investigated thelikelihood of being a FR or SD patient from the initial

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

Fig 3. Relapse pattern in patients with hematuria, based on theirresponse to steroid therapy. A total of 10 patients had an IRpattern, 4 responded within 1 week, 6 responded in7 days. Also,there were 16 patients with FR or SD pattern, of whom 6 re-sponded within 1 week, and 10 in 7 days (P 1.0).

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

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clinical and laboratory findings. No previous studyanalyzed the rapidity of response to oral steroidtherapy as a predictive feature. Most previous stud-ies have examined the long-term prognosis of pa-tients who have already been identified as FR orSD710 or of those only with MCD12 or with a mildinitial attack.13 Cornfield and Schwartz14 reportedthat the older the patient at the onset, the worse theprognosis, but most of their patients had glomerulo-nephritis, a histopathological finding associated withpoor response to steroids. Other studies15,16 have con-cluded that there was no statistically significant re-lationship between relapses and age at onset, gender,or hematuria. Therefore, it may have been the his-topathological finding rather than the age at onsetthat predicted a worse prognosis.

The incidence of hematuria in our patient popula-tion was higher (46.4%) than that reported by othercenters (30%). We could not yet determine the rea-son for this discrepancy, because we did not perform

biopsies in these patients at the initial presentation.However, the presence of gross or microscopic he-maturia alone did not have predictive value. Theabsence of hematuria, by itself, seemed at the initial

analysis to suggest an IR course but was not statis-tically significant. When we stratified the patientswithout hematuria based on the number of days toremission, we found that those who respond within1 week have a greater chance of having fewer re-lapses in the first year.

One of the most difficult problems in the care ofchildren with NS remains the occurrence of relapses,despite initial response to steroids. Because the ulti-mate prognosis is quite good for most patients, ef-forts should be directed toward minimizing the com-plications of steroid and/or cytotoxic agents. Thepredictive factors identified in this study may be

helpful in that regard. This would alert physicianscaring for these patients to monitor them closer andwould allow them to counsel appropriately the pa-tients and their caretakers. Consequently, being able

to identify patients who are more likely to have anFR or SD course may allow a better management,and treatment protocols may be developed accord-ing to the initial presentation and response.

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DOI: 10.1542/peds.105.3.4922000;105;492-495Pediatrics

Alexandru R. Constantinescu, Hetal B. Shah, Edward F. Foote and Lynne S. WeissPredicting First-Year Relapses in Children With Nephrotic Syndrome

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