17 LONGTERM OUTCOMES IN IDIOPATHIC NEPHROTIC SYNDROME FROM CHILDHOOD

17 long-term outcomes in idiopathic nephrotic syndrome: from childhood to adulthood piotr skrzypczyk1, małgorzata pańczyk-tomaszewska

17
LONG-TERM OUTCOMES IN IDIOPATHIC NEPHROTIC SYNDROME: FROM CHILDHOOD TO
ADULTHOOD
Piotr Skrzypczyk1, Małgorzata Pańczyk-Tomaszewska1, Maria
Roszkowska-Blaim1, Zofia Wawer1, Beata Bieniaś2, Małgorzata
Zajączkowska2, Katarzyna Kiliś-Pstrusińska3, Anna Jakubowska3, Marta
Szczepaniak4, Monika Pawlak-Bratkowska4, Marcin Tkaczyk4
1 Department of Pediatrics and Nephrology, Medical University of
Warsaw
24 Marszalkowska St
00-576 Warsaw
Poland
2 Department of Pediatric Nephrology, Medical University of Lublin
2 Chodzki St
20-093 Lublin
Poland
3 Department of Pediatric Nephrology, Medical University of Wroclaw
213 Borowska St
50-556 Wroclaw
Poland
4 Nephrology Division, Department of Pediatrics and Immunology, Polish
Mother’s Memorial Hospital-Research Institute
281/289 Rzgowska St
93-338 Lodz
Corresponding author:
Piotr Skrzypczyk, MD
Department of Pediatrics and Nephrology
Medical University of Warsaw
24 Marszalkowska St
00-576 Warsaw
Poland
Tel.: +48 502 507 822
Fax: +48 22 621 98 63
E-mail: [email protected]
Abstract:
Background: The aim of the study was to assess idiopathic nephrotic
syndrome (INS) relapse rate, co-morbidities, and social status of
adults diagnosed with INS in childhood.
Material and Methods: Age at the onset of INS, number of INS relapses
below 18 years of age, response to corticosteroids (CS), renal biopsy
findings, and immunosuppressive treatment were analyzed in 61 adults
aged 26.0±6.2 (range 18-51.5) years. On the basis of a questionnaire,
we evaluated the number and treatment of relapses above 18 years of
age, co-morbidities, age at menarche, marital status, offspring,
educational status, and occupation.
Results: Median age at the onset of INS was 3 (range 1.3-14.0) years,
median number of INS relapses at <18 years of age was 5 (1-20).
Steroid-sensitive nephrotic syndrome (SSNS) was diagnosed in 37
(60.7%) patients, steroid-dependent nephrotic syndrome SDNS in 18
(29.5%) patients, and steroid-resistant nephrotic syndrome (SRNS) in 6
(9.8%) patients. Mesangial proliferation was the most common pattern
in renal biopsy (35.7%). All patients received CS, 15 were treated
with methylprednisolone pulses, 13 with cyclophosphamide, 11 with
chlorambucil, 2 with cyclosporine, and 21 with levamisole. All
patients achieved remission and had normal renal function at the age
of 18. In adulthood, INS relapsed in 10 (16.4%) patients, including 5
(13.5%) patients with SSNS, 4 (22.2%) with SDNS, and 1 (16.7%) with
SRNS (P=0.72). Median number of relapses was 2 (range 1-11). Patients
with relapses at >18 years of age had more (P<0.005) relapses at <18
years of age. Hypertension was diagnosed in 8 (16.1%), overweight in
14 (23.0%), obesity in 3 (4.9%), and bone fractures in 12 (19.7%)
patients. Five patients had height <3rd percentile, including 4 with
INS onset at <3 years of age. One patient had growth retardation
before the treatment. No myocardial infarctions, strokes, severe
infections, and malignancies were reported. Mean age at menarche was
12.9±1.4 years, 37 (60.7%) patients were in a steady
relationship/married, 1/18 (5.6%) patients treated and 12/43 (24/7%)
patients not treated with cytostatic agents had offspring (P<0.05).
Elementary education was reported by 4 (6.6%), secondary education by
32 (52.5%), and higher education by 25 (40.9%) patients, and 34
(55.7%) patients were professionally active. None of 6 patients with
SRNS developed end-stage renal disease.
Conclusions: 1. High number of INS relapses in childhood is a risk
factor for recurrences in adulthood. 2. INS relapses in childhood do
not preclude active professional life in adulthood.
Key words: nephrotic syndrome – children – outcomes – health status –
social status
Running title: Long-Term Outcome In Idiopathic Nephrotic Syndrome
Introduction
The incidence of idiopathic nephrotic syndrome (INS) in childhood is
estimated at 2-7/100 000 children below 16 years of age but the
recurrent nature of the disease increases its prevalence to 16/100 000
children [1]. In approximately 10% of children, the disease is
steroid-resistant, with 50% of them progressing to end-stage renal
disease (ESRD) during long-term follow-up [2]. Long-term outcomes in
children with INS are considered good but reliable data regarding
adult patients are scarce [3-5]. Prolonged treatment with
corticosteroids (CS) and cytotoxic agents is associated with numerous
adverse effects, as is concomitant hyperlipidemia [6, 7]. Moreover,
INS like every chronic disease has a negative effect on the social
life of patients and their families [8]. The purpose of the study was
to assess long-term outcomes in adult patients treated for INS in
childhood.
Material and methods
We studied long term-outcomes in 61 adults (26 males, 35 females; mean
age 26.0±6.2 years, range 18-51.5 years) who were treated for INS in
childhood in 4 nephrology centers in Poland in 1970-2010. Based on
medical records from childhood (age <18 years) the following data were
analyzed: age at onset of INS, number of INS relapses, response to CS,
renal biopsy findings, and immunosuppressive treatment. Data on the
outcomes in patients during adulthood (age ≥18 years) were collected
using a questionnaire that included the following items: number and
treatment of INS relapses, presence of arterial hypertension and
patient age at the time of this diagnosis, body mass index (BMI),
adverse cardiovascular events (myocardial infarction, stroke), severe
infections, malignancies, fractures (including their circumstances),
age at menarche, marital status, number of children, age at first
delivery, education and occupation, and nephrological care.
The diagnosis of nephrotic syndrome was based on proteinuria >50
mg/kg/24h, hypoalbuminemia (<2.5 g/dL), hyperlipidemia, and edema.
Relapse of INS was defined as a recurrence of nephrotic range
proteinuria, most commonly with recurrence of edema, and remission as
0 to trace proteinuria in urinalysis or 24-hour urinary collection for
3 consecutive days. Based on the response to CS, the disease was
categorized as steroid-sensitive nephrotic syndrome (SSNS), defined as
remission of nephrotic syndrome within 8 weeks of CS therapy;
steroid-dependent nephrotic syndrome (SDNS), defined as nephrotic
syndrome with 2 consecutive relapses during, or within 14 days of
ceasing CS therapy; and steroid-resistant nephrotic syndrome (SRNS),
defined as no remission of nephrotic syndrome despite 8 weeks of CS
therapy [9]. Overweight in adult patients was defined as BMI > 25 kg/m2,
and obesity as BMI > 30 kg/m2 [10].
The initial bout of nephrotic syndrome was treated with 60 mg/m2/24h
or 2 mg/kg/24h (not more than 60 mg/24h) of prednisone for 4-6 weeks,
with the same dose subsequently used every 48 hours for 4 weeks, then
gradually tapered for a total treatment duration of 3 months (in
1970-1995) or 6 months (after 1995). Relapses were treated using the
same protocol as the initial episode. Indications for renal biopsy
were: age at onset >10 years or <1 year, steroid dependency or
resistance, persistent microscopic hematuria, renal dysfunction, and
intended treatment with cyclosporine A (CsA). Indications for
alternative immunosuppressive treatment included SRNS and severe side
effects of CS therapy. Methylprednisolone pulses (MPP) were given
intravenously in the dose of 15-30 mg/kg/pulse for 3 consecutive days
and then on alternate days until remission, up to 12 pulses. CsA was
introduced in 1993 and started at 5 mg/kg/24h with subsequent dosing
modified to achieve predose blood level (C0) of 100-150 ng/mL, and
further reduction to the lowest dose required to maintain the
remission. Alkylating agents were administered orally, including
cyclophosphamide (CYP) 2 mg/kg/24h to cumulative doses of 168
mg/kg/therapy in boys, 200 mg/kg/therapy in girls; and chlorambucil
(CHL) 0.2 mg/kg/24h to a cumulative dose of 10 mg/kg/therapy.
Levamisole (LEV) was administered in patients with frequent relapses
or SDNS in the dose of 2.5 mg/kg/24h during the first month, followed
by 2.5 mg/kg/48h or 2.5 mg/kg twice a week. In approximately 10% of
the patients, treatment was individualized with departures from the
above protocol due to severe medication side effects or a
severe/atypical course of the disease.
Follow-up was defined for all patients as the period from the onset of
the disease to completion of the questionnaire and ranged from 6.0 to
38.0 (mean 21.5±6.4) years.
Patients were divided into 4 subgroups based on their current age:
18-20 years (n=12), >20-25 years (n=19), >25-30 years (n=18), and >30
years (n=12).
The study was approved by the Bioethics Committee at the Medical
University of Warsaw and all participants gave their informed consent
prior to their inclusion into the study.
Statistical analyses were performed using the Statistica 9.0 software
(Statsoft). Variable distribution was analyzed using the Shapiro-Wilk
test. Normally distributed variables were presented as mean values
with standard deviation and compared using the Student t test for
independent groups and the ANOVA test. Non-normally distributed
variables were presented as median values with range and compared
using the Mann Whitney U test and the Kruskal-Wallis analysis of
variance. Differences in the frequency of analyzed variables between
two groups were analyzed using the chi-square test or the Fisher exact
test when appropriate. P value of less than 0.05 was considered
statistically significant.
Results
In the study group of 61 patients, median age of the onset of INS was
3.0 years (range 1.33-14.0 years), and median number of INS relapses
in childhood was 5 (range 1-20). SSNS was diagnosed in 37 patients
(60.7%), SDNS in 18 patients (29.5%) and SRNS in 6 patients (9.8%). At
the time of current evaluation, mean age in these groups was 26.9±7.1
(range 18.0-51.5), 24.5±4.5 (range 18.9-34.0), and 24.6±4.5 (range
18.5-32.4) years, respectively (P=0.35). Duration of follow-up in the
SSNS group ranged from 6 to 38 years (mean 21.4±7.40 years), in the
SDNS group from 15.5 to 32.7 years (mean 21.7±4.8 years), and in the
SRNS group from 13.4 to 29.8 years (mean 21.4±5.3 years) (P=0.88).
Renal biopsies were performed in childhood in 28 patients (45.6%),
with the following morphological patterns found: minimal change in 10
patients (35.7%), mesangial proliferation in 17 patients (60.7%), and
focal and segmental glomerulosclerosis in one patient (3.6%). All
patients were initially treated with oral CS. Patients with frequently
relapsing SSNS were also treated with MPP (n=4, 10.8%), LEV (n=6,
16.2%), CHL (n=3, 8.1%), and CYP (n=2, 5.4%); SDNS patients were
treated with MPP (n=8, 44.4%), LEV (n=15, 25.0%), CYP (n=6, 33.3%),
CHL (n=5, 27.8%), and CsA (n=2, 11.1%); and SRNS patients were treated
with MPP (n=3, 50.0%), CYP (n=5, 83.3%), and CHL (n=3, 50.0%). All
patients achieved complete remission in childhood and had normal renal
function at the age of 18.
In adulthood, INS relapses were observed in 10 patients (16.4%; median
number of relapses: 2, range 1-11). Table 1 shows clinical
characteristics of patients with or without INS relapses in adulthood.
INS relapses above 18 years of age were most commonly observed in
patients with SDNS (4/18; 22.2%) and SRNS (1/6; 16.7%), and they were
least common in the SSNS group (5/37; 13.5%), although these rates did
not differ significantly (P=0.72). INS relapses in adulthood were
treated with CS in all patients, with MPP in 5 patients (50.0%), with
CYP in 3 patients (30.0%), and with CHL in one patient (10.0%).
Patients with INS relapses in adulthood also had significantly more
relapses in childhood (P<0.005).
In the overall study group, arterial hypertension was diagnosed in 8
of 61 patients (16.1%), including 5 males and 3 females (mean age
28.0±11.5 years, range 15.0-49.0 years). Among these, hypertension was
diagnosed in 2 patients (25.0%) in childhood at the age of 15 and 17
years, respectively, and in 6 patients (75.0%) in adulthood at the age
ranging from 21 to 49 years (mean 32.0±10.3 years). Among 6 patients
with hypertension diagnosed de novo at the age of ≥18 years, relapses
of nephrotic syndrome in adulthood were noted in 3 patients (50.0%)
and their number was significantly higher compared to patients without
hypertension (median: 10.0, range 3-11, vs. median: 2.0, range 1-2;
P<0.05).
In the study group of 61 patients, BMI ranged from 16.6 to 33.2 kg/m2
(mean 23.2±3.8 kg/m2). Fourteen patients (23.0%) were found to be
overweight (11 men and 3 women), and 3 patients (4.9%) were obese (2
men, 1 woman) with BMI values of 30.7, 33.2, and 32.7 kg/m2,
respectively. BMI was significantly higher in males than in females
(25.2±3.5 kg/m2 vs. 21.7±3.4 kg/m2, P<0.0005), and overweight and
obesity were also significantly more common among men than women
(13/26 or 50.0% vs. 4/35 or 11.4%, P<0.005). No significant
differences in BMI were found between patients with or without INS
relapses in adulthood (22.3±3.8 vs. 23.4±3.9 kg/m2, P=0.41). BMI also
did not differ significantly between SSNS, SDNS and SRNS patients
(P=0.88). Mean BMI was higher in hypertensive patients but this
difference was not significant (25.7±4.1 vs. 22.8±3.7 kg/m2, P=0.10).
Five (8.2%) adult patients were short-statured, including four with
initially normal growth rate and INS onset at the age of <3 years with
1-8 (median: 3) INS relapses in childhood. One patient with SNSS and
INS onset at the age of 6 years was already growth-retarded before
immunosuppressive treatment.
No cases of myocardial infarction, stroke, severe infection or
malignancy were found the studied patients. Twelve of 61 patients
(19.7%) suffered a bone fracture, including one case that might be
related to osteoporosis (spontaneous metatarsal fracture).
In the 35 analyzed women, age at menarche ranged from 11.0 to 17.0
years (mean 12.9±1.4 years). Thirty seven of 61 patients (60.7%) were
in a steady relationship or married. Cytostatic agents were
administered in childhood to 17 patients (27.9%), including 11 males
and 6 females. Three of them (2 males, 1 female) received another
course of cytostatic drug treatment in adulthood due to INS relapses;
only one female patient was treated with CYP solely as an adult. Mean
age at the time of current evaluation did not differ between 18
patients treated and 43 patients not treated with cytostatic drugs
(25.3±4.7 vs. 26.3±6.8 years, P=0.54). Among women treated with
alkylating agents in the prepubertal period (n=6), age at menarche did
not differ from that in the remaining women (12.5±1.3 vs. 13.0±1.5
years, P=0.44). Among 18 patients treated with cytostatic drugs, only
one man (5.6%) conceived a child, compared to 12 of 43 patients
(24.7%) who did not receive cytostatic drugs (P<0.05).
Elementary education was reported by 4 patients (6.6%), secondary
education by 32 patients (52.5%), and higher education by 25 patients
(40.9%). In addition, 12 of 32 patients (37.5%) reporting secondary
education were studying at the higher education level at the time of
current evaluation. Thirty four (55.7%) patients were professionally
active, including 23 patients (67.6%) reporting higher education which
translated to as much as 92.0% of patients with higher education
(23/25) being professionally active. We did not fin any differences
between patients with elementary, secondary, or higher education, and
between professionally active or nonactive patients in regard to the
age at the onset of INS, number of relapses below 18 years of age,
response to CS therapy, and the rate and number of relapses at ≥18
years years of age.
Eight of the evaluated patients (13.1%) were under care of
nephrologists, and relapses of INS in adulthood were found in 7 of
them (87.5%). Three of 10 patients (30.0%) with INS relapses at ≥18
years of age were not under nephrological care at the time of current
evaluation.
When we compared age groups of 18-20, >20-25, >25-30, and >30 years,
no significant differences were found in regard to age at the onset of
INS, number of relapses in childhood and response to CS therapy.
Patients aged >30 years had more relapses in adulthood than all other
age groups, but this difference was significant only for patients aged
>25-30 years (median: 10, range 3-11, vs. median: 2, range 1-2,
P<0.05). Additionally, patients aged >30 years had significantly
(P<0.05) more hypertension, higher mean BMI, and more fractures
compared to younger age groups. Among 37 adults categorized as having
SSNS in childhood, we also found no differences in the relapse rate
between various age groups.
Among 6 patients with SRNS due to mesangial proliferative
glomerulonephritis, 10 relapses at ≥18 years of age were noted in a
single patient with 12 bouts of the disease in childhood. None of SRNS
patients required renal replacement therapy. One male patient with
SDNS and no relapses in adulthood died at the age of 29 due to alcohol
abuse.
Discussion
Despite a tendency for recurrences, prognosis in INS is considered to
be good, especially in case of steroid sensitivity, and the disease
usually subsides after sexual maturity is achieved [3]. In contrast,
SRNS may be associated with unfavorable outcomes, leading to ESRD
sometimes as early as in childhood [2].
Our findings indicate that patients with a more severe course of the
disease in childhood (i.e., with a high number of relapses) are prone
to have INS relapses as adults, which is consistent with the results
of other studies [3, 4]. In our study cohort, relapses were found in
13.5% of SSNS patients. Studies from the 1980s showed that no more
than 10% of children with SSNS have a relapse in adulthood [11, 12]
but more recent data indicate a higher relapse rate [3, 5, 13], up to
42% in a study by Fakhouri et al. [4]. In our study population, the
proportion of older SSNS patients (> 30 years) with a relapse did not
differ from that among younger patients.
SRNS is a disease with poor renal outcomes and no optimal therapeutic
strategy. In the multicenter international French-Belgian-Swiss study
that included 78 patients with SRNS, renal replacement therapy was
initiated by 5 years in 25% of patients, by 10 years in 42% of
patients, and by 15 years in 47% of patients [2]. Risk factors for
progression to ESRD include renal function impairment at the onset of
nephrotic syndrome, poor response to treatment [14], and disease onset
above 10 years of age [2]. None of our 6 patients with SRNS, aged 18.5
to 32.4 years, developed ESRD.
Arterial hypertension was found in 13.1% patients and was more common
among men and in older patients. Similarly to the general population
[25], patients with hypertension had higher BMI compared to
normotensives, but this difference was not significant. Prevalence of
hypertension in our study group was much higher than in Polish general
population at a comparable age. In the Polish NATPOL III PLUS study,
hypertension was found in approximately 7.2% of people aged 18-39
years and was more common among men (11%) than women (3.4%) [15]. Our
results suggest that nephrotic syndrome may increase the risk of
arterial hypertension during long-term follow-up.
Obesity is one of the possible side effects of long-term CS therapy.
Overweight and obesity were found in approximately 1/5 of our
patients. A similar proportion of overweight and obese patients (19%)
was found in adults with SSNS in childhood who were studied by Rueth
et al. In that group, BMI did not correlate with cumulative CS dose.
Due to a retrospective nature of our study, we were not able to
provide reliable estimates of the cumulative CS dose. Similarly to our
study group, patients with or without relapses in adulthood and with
varying response to CS who were evaluated by Rueth et al. did not
differ in BMI [3]. When comparing findings in our cohort with
published data for Polish general population, we found very similar
proportions of overweight and obese patients. In the Polish NATPOL III
PLUS study, obesity/overweight were found in 24% of people aged 18-39
years, more frequently among men (34%) than women (14%) [15], which
may suggest that nephrotic syndrome in childhood does not increase
risk of overweight and obesity during long-term follow-up.
In our study group, we found no generalized infections and no
cardiovascular events also among patients older than 30 years of age.
Our results are similar to those reported by other authors who also
noted a low rate of extrarenal morbidity [3, 5, 6, 16, 17].
Alkylating agents have been used for many years in frequently
relapsing SSNS and SDNS, although recent analyses show a rather
disappointing long-term efficacy of these drugs [18]. Hodgkin disease,
brain tumors and leukemia were observed in patients treated with
cytostatic drugs in childhood due to nephrotic syndrome [6, 19, 20]
but such adverse effects were not found in our patients. It is well
known that cytostatic drugs may have a negative effect on fertility,
and this risk is higher in males [21] and with higher cumulative doses
[22]. For example, in the above mentioned study by Rueth et al., only
8% of the patients treated with cytostatic agents in childhood were
found to have offspring [3]. Silva et al. found spermatogram
abnormalities in all males with lupus nephritis who received CYP [23].
In contrast, Kyrieleis et al. found no correlation between the
cumulative dose of CYP and the risk of sperm abnormalities in 8 adult
men with nephrotic syndrome in childhood, and six of them were
considered able to father children based on semen quality [5]. In our
study group, treatment with alkylating agents seemed to have a
negative effect on fertility, as only one patient with a history of
cytotoxic therapy was found to have offspring.
Our findings regarding the distribution of educational status are
particularly interesting, as higher education was reported by as many
as 40.9% of our patients, with additional 19.7% of patients currently
being enrolled in higher education. According to the 2010 Polish
Statistical Yearbook, the proportion of people with higher education
in general population in Poland was much lower at 19.2% [24]. One
explanation may be that children with chronic disease have limited
prospects to do manual labors and thus are indirectly forced to
improve their educational status.
At the time of evaluation, only 13.1% of patients in our cohort were
under nephrological care. We believe that patients with a history of
nephrotic syndrome require periodical urine and renal function tests,
as well as blood pressure measurements.
Conclusions:
1. High number of INS relapses in childhood is a risk factor for
recurrences in adulthood.
2. INS relapses in childhood do not preclude active professional life
in adulthood.
Conflict of interest statement:
The authors declare that they do not have any conflicts of interest
and that the results presented in this paper have not been published
previously in whole or part, except in abstract form.
Table 1
Selected clinical parameters in patients with or without relapses of
nephrotic syndrome in adulthood.
Parameter
Nephrotic syndrome in adulthood
P
Relapse
No relapse
Patients (n, %)
10 (16.4%)
51 (83.6%)
<0.0005
Males/females (n/n)
5/5
30/21
NS
Current age [years]
28.2±5.1
25.6±6.4
NS
Nephrotic syndrome in childhood
Age at the disease onset [years]
2.6 (1.3-13.5)
3.1 (1.5-14.0)
NS
Response to CS (n, %)
5 (50.0%)
4 (40.0%)
1 (10.0%)
32 (62.7%)
14 (27.5%)
5 (9.8%)
NS
NS
NS
SSNS
SDNS
SRNS
n=37 (60.7%)
n=18 (29.5%)
n=6 (9.8%)
Number of nephrotic syndrome relapses in childhood
10 (4-20)
4 (1-16)
<0.005
CS, corticosteroids; n, number of patients; NS, nonsignificant; SDNS,
steroid-dependent nephrotic syndrome; SRNS, steroid-resistant
nephrotic syndrome; SSNS, steroid-sensitive nephrotic syndrome.
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