|Year : 2021 | Volume
| Issue : 2 | Page : 86-95
Clinicopathological spectrum and response pattern of adolescent-onset idiopathic nephrotic syndrome: Are they different from young children?
Ranjit Ranjan Roy1, Rummana Tazia Tonny1, Romana Akbar1, Nadira Sultana1, Asif Ali2, Ashish Kumar Ray1, Shanjida Sharmim1, Abdullah Al Mamun1, Tahmina Jesmin1, Syed Saimul Huque1, Golam Muin Uddin1, Afroza Begum1
1 Department of Pediatric Nephrology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
2 Department of Pediatrics, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
|Date of Submission||10-Dec-2021|
|Date of Acceptance||22-Dec-2021|
|Date of Web Publication||28-Feb-2022|
Prof. Ranjit Ranjan Roy
Room No. 323, Block-D, Department of Pediatric Nephrology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka 1000,
Source of Support: None, Conflict of Interest: None
Background: There is a scarcity of published data regarding the clinical and pathological pattern of idiopathic nephrotic syndrome in adolescents in our country. Materials and methods: A retrospective analytical study was undertaken on 550 children with idiopathic nephrotic syndrome admitted to Bangabandhu Sheikh Mujib Medical University from January 2019 to July 2021. Data regarding clinical and laboratory parameters, current clinical status of the patients and their steroid responsiveness, complications, types of histopathological lesions, and treatment profile were retrieved from departmental automation. These parameters of the patients whose disease onset between 1 and <10 years of age (Group A) were compared to the same parameters of those with onset of disease between 10 and 18 years (Group B). Results: We found that hypertension, hematuria, and azotemia were more prevalent in childhood group than adolescent group. IFRNS was the most common disease course in Group B (56.2%) and more of them were currently on remission (80%). SRNS was more common in Group A (16.7%) and more of them were on relapse (76.16%) currently during the last follow-up. Precipitating factors such as infection and asthma were more in younger children. The rate of complication was more in childhood group in comparison to adolescent group. On renal biopsy specimen, minimal change disease (MCD) was the most common histological lesion in adolescent group (24.86%) compared to childhood group (16.16%). Adolescents (Group B) required less amount of second- and third-line immunosuppressive drugs than younger children (Group A). Conclusions: The overall clinical and histological condition was more favorable in adolescent group in comparison to childhood group in our setup. These findings necessitate larger prospective study in the future for further validation of this observation.
Keywords: Adolescent, age, better outcome, idiopathic nephrotic syndrome
|How to cite this article:|
Roy RR, Tonny RT, Akbar R, Sultana N, Ali A, Ray AK, Sharmim S, Mamun AA, Jesmin T, Huque SS, Uddin GM, Begum A. Clinicopathological spectrum and response pattern of adolescent-onset idiopathic nephrotic syndrome: Are they different from young children?. Paediatr Nephrol J Bangladesh 2021;6:86-95
|How to cite this URL:|
Roy RR, Tonny RT, Akbar R, Sultana N, Ali A, Ray AK, Sharmim S, Mamun AA, Jesmin T, Huque SS, Uddin GM, Begum A. Clinicopathological spectrum and response pattern of adolescent-onset idiopathic nephrotic syndrome: Are they different from young children?. Paediatr Nephrol J Bangladesh [serial online] 2021 [cited 2023 Jan 30];6:86-95. Available from: http://www.pnjb-online.org/text.asp?2021/6/2/86/338570
| Introduction|| |
Nephrotic syndrome (NS) is the most common kidney disease in childhood, characterized by immense proteinuria, hypoalbuminemia, edema, and hypercholesterolemia. The annual incidence of the condition has been estimated to 1.2–16.9 per 100,000 children and the prevalence varies from 12 to 16 per 100,000 children., The highest incidence has been reported in South Asian children and its considerable variation is present depending on race, geography, and ethnicity., The overall incidence of NS is less in adolescents as compared to younger children., Classification of NS can be made on the basis of etiology, clinical response to steroid therapy, pattern of relapse, and histopathology. The age at initial presentation of the disease is an important predictor of steroid responsiveness and histopathological pattern., During the past few years, striking differences have been observed in the clinical and histopathological features of adolescent-onset idiopathic NS as compared to younger children., Minimal change disease (MCD) is the commonest renal histological variety among younger children which is steroid sensitive. Adolescents are more likely to have nonminimal change disease, mainly FSGS which is mostly steroid resistant.,, The overall prognosis is excellent for steroid-responsive cases, whereas steroid resistance (SR) is an important determinants of end-stage renal disease in the future., Onset of NS during adolescent period is one of the atypical features that may obviate the need for renal biopsy to be performed.,, Other atypical features are onset of NS <1 year of age, persistent hypertension, hematuria, raised serum creatinine, hypocomplementemia, high cholesterol (>500 mg/dL), presence of extra-renal features that suggests vasculitis/ secondary cause, positive family history, anemia, very low albumin, high UTP, history of difficult to achieve remission in first attack/relapse. These atypical features are considered prognostically bad for the NS patients. Our working experience in a tertiary institution has been shown that outcomes of adolescent-onset NS patients are better than childhood-onset NS, which is contrary to current knowledge regarding older age as a bad prognostic factor. It is not well known whether the clinical and laboratory parameters, histological lesions, treatment outcome of adolescent-onset NS differ significantly from younger children with the similar disease in this part of the world. This prompted us to observe the patients with idiopathic NS in the context of two different age groups and store their data carefully to carry out this study.
The objective of the study was to compare the clinical and biochemical parameters, histological spectrum, and treatment outcome of children with idiopathic NS between earlier onset (1 and <10 years) and adolescents (10 and 18 years old).
| Materials and Methods|| |
A retrospective analysis was undertaken in the pediatric nephrology department of Bangabandhu Sheikh Mujib Medical University (BSMMU), the tertiary referral hospital in Dhaka, Bangladesh with advanced diagnostic and treatment facilities. The study was conducted from January 2019 to July 2021. It is the highest learning place with approximately 4000 resident doctors, working in 56 departments, having more than 500 faculties as well. A total of 550 children with idiopathic NS were admitted to this institution during the study period. NS was diagnosed according to KDIGO guideline 2021 (Kidney Disease Improving Global Outcome). Studied patients were divided into two groups according to age of onset of the disease. Group A comprised of children between 1 and <10 years old (childhood-onset NS) and the remaining patients between the ages 10 and 18 years old (adolescent-onset NS) comprised of Group B. Ten to nineteen years of age was designated as adolescent period by WHO. A total of 365 patients were included in Group A and 185 patients were included in Group B. A comparison between the two groups was made based on demographic factors, current clinical status (relapse or remission), precipitating factors, clinical and biochemical parameters, steroid responsiveness, complications, histological pattern, and treatment outcome during the course of the disease. Patients were categorized into four groups as per steroid responsiveness; such as infrequent relapse (IFR), frequent relapse (FR), steroid-dependent (SD) and SR. Children below one year and above 18 years, those with congenital NS, NS secondary to systemic diseases such as systematic lupus erythematosus, hepatitis B, Henoch Schonlein purpura, falciparum malaria, lymphoma, and amyloidosis were excluded from the study. Data were retrieved from departmental automation and collected by pre-tested semi-structured questionnaire.
All statistical analyses were carried out using SPSS (Statistical Package for Social Science) for Windows version 22. Chi-square test was used for categorical variables and the unpaired t test for numerical variables. Values were expressed as mean ± standard deviation. A value P < 0.05 was considered significant.
Nephrotic range proteinuria and either hypoalbuminemia (<3 g/dL) or edema.
Nephrotic range proteinuria
24-h urine protein excretion >40 mg/m2/h or spot protein to creatinine ratio >2 g/g (or 200 mg/mmol or 3 to 4+ dipstick)
Urine protein nil or trace (Up/Uc<0.2 mg/mg) for 3 consecutive early morning specimens.
Urine protein 3+ or more (Urinary protein to creatinine ratio >2 mg/mg) for three consecutive early morning specimens, having been in remission previously.
Infrequent relapsing NS
<2 relapses per 6 months within 6 months of disease onset or <4 relapses per 12 months in any subsequent 12-month period
Frequent relapsing NS
>2 relapses per 6 months within 6 months of disease onset or >4 relapses per 12 months in any subsequent 12- month period
Two consecutive relapses when on alternate day steroids, or within 14 days of its discontinuation.
Lack of complete remission despite therapy with daily prednisolone at a dose of 2 mg/kg (or 60 mg/m2) for 4–6 weeks with or without additional therapy with 3 doses of IV methylprednisolone.,
Adolescent age was defined as 10–19 years according to WHO.
| Results|| |
A total of 550 children and adolescents aged from 1 year to 18 years hospitalized for idiopathic NS during the study period were included. Among them, 365 patients were 1–10 years (Group A), and 185 patients were more than 10 years (Group B). The mean age of presentation in Group A was 7.16 ± 4.29 years, and Group B was 13.51 ± 1.34 years [Table 1]. In Group B more children were from low-income family (Group A = 48.5% and Group B = 51.4%) (P = 0.003). Other demographic variables, that is, gender distribution, residence, and immunization status, had no significant difference between the two groups [Table 1].
|Table 1: Comparison of demographic characteristics among childhood and adolescent-onset nephrotic syndrome patients|
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In the last clinical follow-up, a higher number of patients were in relapse in Group A (n = 278, 76.16%), whereas in Group B, a higher number of patients (n = 148, 80%) were in remission. Total number of relapses since onset and in the last year was more in Group A (P < 0.001). The mean days required to achieve remission following first attack were 20.41 ± 5.52 days in Group A (P < 0.001) [Table 2].
|Table 2: Clinical status in last follow-up in childhood and adolescent-onset NS|
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Most common precipitating factors were Asthma and URTI both in Group A and Group B. Asthma and URTI were significantly higher in Group A than in Group B (P < 0.001) [Figure 1].
|Figure 1: Precipitating factors for relapse between childhood and adolescent-onset nephrotic syndrome|
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At the time of disease onset, frequency of hypertension, hematuria, leg swelling, ascites and scrotal/labial swelling were significantly higher in Group A (P < 0.001) [Table 3].
|Table 3: Clinical and laboratory parameters at the time of disease onset between childhood and adolescent-onset NS|
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Initial mean serum albumin level was 1.66 ± 0.44 mg/dL and 1.84 ± 0.23 mg/dL in Group A and Group B, respectively, which is statistically significant (P < 0.001) [Figure 2].
|Figure 2: Serum albumin level at the time of disease onset between childhood and adolescent-onset NS|
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There was no difference in mean serum cholesterol level between two groups at the onset of disease [Figure 3]. Mean serum calcium level in Group A (6.41 ± 1.04) was significantly lower than Group B (8.40 ± 1.19) [Figure 4].
|Figure 3: Serum cholesterol level at the time of disease onset between childhood and adolescent-onset NS|
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|Figure 4: Serum calcium level at the time of disease onset between childhood and adolescent-onset NS|
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At first presentation 24-h UTP was significantly higher in Group A (3.76 ± 0.90 gm/day) in comparison to Group B (2.31 ± 1.02) (P < 0.001) [Figure 5]. But scatter diagram shows very weak positive correlation between age of onset and 24-h UTP level (r = 0.069) [Figure 6].
|Figure 5: 24-h urinary total protein at the time of disease onset between childhood and adolescent-onset NS|
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|Figure 6: Correlation between age of onset of disease and 24-h UTP at presentation|
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Estimated GFR shows very weak negative correlation with the age of onset of disease (r = –0.079) [Figure 7].
Frequency of IFRNS was higher in Group B (P < 0.001), whereas FRNS was higher in Group A (P < 0.001). Steroid-resistant cases were more common in Group A than in Group B (P < 0.001) [Figure 8].
|Figure 8: Steroid responsiveness and relapse rate in childhood and adolescent-onset nephrotic syndrome|
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The complications during treatment are shown in [Figure 9]. It depicts that pneumonia, pharyngo-tonsillitis, peritonitis, UTI, failure to thrive, hypocalcemic convulsion were significantly higher in Group A in comparison to Group B. Cellulitis and tuberculosis showed no significant statistical difference between the two groups [Figure 9].
|Figure 9: Comparison of complications during disease period between childhood and adolescent-onset NS patients|
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Renal biopsy was carried out in 122 patients. The distribution of renal pathology is shown in [Figure 10]. The histopathologic findings were MCD in 16.16% of children, FSGS in 12.93% children, MesPGN in 12.93% children, IgA nephropathy in 8.7% children, and IgM nephropathy in 6.03% children in Group A, whereas in Group B, MCD was found 24.86% children, FSGS in 4.32% children, MesPGN in 5.6% children, IgA nephropathy in 2.6% children and IgM nephropathy in 1.62% children. FSGS, MesPGN, IgA nephropathy, and IgM nephropathy were significantly higher in Group A than in Group B. Most common histology in Group B was MCD (P = 0.019) [Figure 10].
|Figure 10: Comparison of histological diagnosis between childhood and adolescent NS patient who had undergone renal biopsy at the time of disease onset|
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[Figure 11] shows that Levamisole, Cyclophosphamide, CNI and Azathioprine were used more in Group A (P < 0.001). There was no significant difference in the use of MMF between the two groups [Figure 11].
|Figure 11: Comparison of medication between childhood and adolescent-onset NS|
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| Discussion|| |
The etiologies, histopathologic features, and response patterns of glomerular disorders vary according to the age group.,, This study provides information for the first time in this country about the clinicopathological spectrum of idiopathic NS in the adolescent age group. To the best of our knowledge, this is the largest study that possesses a sample size of 550 patients of INS and comparing clinical, laboratory, histological parameters as well as treatment outcome of adolescent-onset group (Group A) with earlier onset of similar disease (Group B). Computerized database of our center is a rich source of data for a study of INS among an ethnically homogenous population. Recent epidemiological studies had shown that incidence and prognosis of NS among children differ by race, ethnicity, and geographic area.,,
Idiopathic NS is the most common form of childhood NS, characterized by immense proteinuria, hypoalbuminemia, generalized edema, and hypercholesterolemia., Histopathologically, the condition is defined as a podocytopathy responsible for loss or altered function of podocyte that results in massive proteinuria. The peak age of onset of INS is 2–8 years with a male predominance., Previously it had been noted that the incidence is higher in children with low socioeconomic status as poverty increases the risk of infection., Infection, allergy may immediately trigger the onset of the disease or causing its relapse.
Clinically, a nephrotic child usually presents with a history of progressive edema, initially involving periorbital area, more noticeable in the morning. A history of antecedent infection, more commonly upper respiratory tract infection may be present. Mild diarrhea, abdominal pain, frothy urine are not uncommon.,
Evaluation of a nephrotic child has been done by a thorough history and physical examination as well as limited laboratory screening such as urinalysis and blood biochemistry. Kidney biopsy is not routinely required in children with INS unless indicated.,,
Corticosteroid is the cornerstone of treatment for children with INS., Steroid responsiveness is the best therapeutic guide for this condition and also an important predictor of long-term outcome.,, Vast majority of the patients are steroid responsive (approximately 85%–90%), termed as steroid-sensitive nephrotic syndrome (SSNS). Among the SSNS cases, approximately 50% show FRs or steroid dependence.,,, Approximately 10%–15% cases are steroid resistant.,
In our study, 278/365 in Group A and 37/185 in Group B were on relapse. Currently, remission was maintained in 87/365 patients in Group A and 148/185 in Group B. Thereby remission status was more in case of adolescent group during the last follow-up. Precipitating factors such as infection, asthma episodes were more in childhood group than adolescent. Younger children are more prone to infection and approximately 80% of all asthmatic children have been reported prior to 6 years of age. Two-third of childhood asthma improves through their teen years. This is the reason for higher prevalence of infection and asthma in younger children, causing more relapse of this group.
On comparison of various clinical and biochemical features, hypertension, hematuria and azotemia were more common in earlier onset (Group A) compared to adolescent-onset (Group B). Previous one study found that children beyond 8 years of age with INS have higher incidence of microscopic hematuria, hypertension, and risk of progression to CKD in long term follow-up. Zsuzsanna et al. found serum creatinine was significantly higher in adolescent-onset group compared to childhood-onset group which is contrary to our study. Mubarak et al. found no significant difference in clinical and laboratory parameters among the young children <12 years and adolescent INS. In our study, younger children had more edema resulting from severe proteinuria and hypoalbuminemia compared to adolescent group. Patients with younger age of onset had higher prevalence of active disease for longer period. This resulted in more complication rate such as infection, steroid toxicity and growth failure in childhood group (Group A) in comparison to adolescent group (Group B). The commonest infection-related complication in our study was pneumonia. In childhood NS, the most common type of infection is URTI, followed by pneumonia, UTI and peritonitis. Previously it has been reported that children with INS are more infection prone due to defective cellular and humeral immunity, loss of IgG, properdin and complement through urine, presence of edema and ascitic fluid which acts as a culture media for bacteria, skin breakage through which organism can be invaded, steroid and other immunosuppressive drugs, splenic hypoperfusion.
Regarding steroid responsiveness, 3.8% of patients of adolescent-onset group (Group B) had SR compared to 16.7% of earlier onset group (Group A). Other studies showed an increase in primary SR in later decade which is different from our findings. The older the age of onset, the worse the prognosis. Chang et al. found a statistically significant relationship between older age at onset and progression to ESRD.
IFRNS was the most common clinical course of our adolescent group. On the contrary, FR was more common in childhood group. SR was also more in this group. Patients with frequent relapsing and steroid-resistant NS are at higher risk of complications due to intercurrent illness and toxicity of steroid as well as other immunosuppressive drugs.
It has been observed that the pathology of glomerular diseases in adolescent differs significantly from younger children with INS., In a sentinel data published by ISKDC, 60% patients of >12 years of age had non-MCD. Mubarak et al. noted MCD in 51% of nephrotic child in <12 years and 28.9% in adolescent patients. FSGS was the most prevalent histological findings in adolescent-onset INS (36.4%). The reduction of MCD and higher frequency of FSGS as age increases have been noted in other studies as well., The comparison of histopathological profile of different studies including this study is shown in [Table 4].
Baqi et al. also reported FSGS as the most common pathological variety in adolescent-onset INS due to ethnic differences as it is more prevalent in African American population. Hogg et al. and Takada et al. noted a different scenario. MCD was the predominant lesion in biopsied specimen of adolescent group, a finding similar to ours. Gulati et al. found a significant higher frequency of MPGN and lower frequency of MCD in the case of INS of adolescent group than childhood group. [Table 5] shows the histopathological profile of adolescent-onset idiopathic NS of previous studies and gives an overview of comparison with this study.
|Table 5: Histopathological profile of adolescent-onset idiopathic nephrotic syndrome and comparison with previous study|
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In our study, we observed that most of the adolescent with INS required less number of second- and third-line immunosuppressants in comparison to younger children. Pradhan et al. found MCD as the most common underlying cause of adolescent-onset NS, followed by FSGS like ours and most of the cases responded to a combination of prednisolone with either second- or third-line immunosuppressive drug (23%).
There are some limitations of our study. This is a retrospective study. Interobserver variation was not a consideration while reporting biopsied specimen. Electron microscope-based histological diagnosis could not be included. At the same time strength of the study is larger sample size and eagle-eye supervision of the authors.
| Conclusion|| |
In our study, we found that the clinical, biochemical, histological, and treatment response were more favorable for adolescent-onset INS than those of the earlier onset. Randomized controlled study is required for further validation of this observation. Better prognosis of adolescent-onset INS may open a new horizon in the field of research of pediatric nephrology.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]