17 LONGTERM OUTCOMES IN IDIOPATHIC NEPHROTIC SYNDROME FROM CHILDHOOD

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17 LONGTERM OUTCOMES IN IDIOPATHIC NEPHROTIC SYNDROME FROM CHILDHOOD
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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

¹Department of Pediatrics and Nephrology, Medical University of Warsaw

24 Marszalkowska St

00-576 Warsaw

Poland

²Department of Pediatric Nephrology, Medical University of Lublin

2 Chodzki St

20-093 Lublin

Poland

³Department of Pediatric Nephrology, Medical University of Wroclaw

213 Borowska St

50-556 Wroclaw

Poland

⁴Nephrology 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 <3^rd 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/m²vs. 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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Tags: childhood to, of childhood, syndrome, idiopathic, childhood, nephrotic, outcomes, longterm