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| Year : 2010 | Volume
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| Issue : 1 | Page : 87-92 |
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| The long-term results of pediatric patients with primary focal and segmental glomerulosclerosis |
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Betul Sozeri1, Sevgi Mir1, Fatma Mutlubas1, Sait Sen2
1 Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Turkey
2 Department of Pathology, Faculty of Medicine, Ege University, Izmir, Turkey
Click here for correspondence address and email
| Date of Web Publication | 8-Jan-2010 |
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 Abstract | | |
Focal and segmental glomerulosclerosis (FSGS) is a major cause of idiopathic steroidresistant nephrotic syndrome (SRNS) and end-stage renal disease (ESRD). In this retrospective study, we report on 34 pediatric patients with FSGS who were diagnosed and treated from 1992 to 2006. The mean age at onset was 6.3 ± 4.3 years. All patients had nephrotic-range proteinuria. Microscopic hematuria was seen in three patients and hypertension was seen in 15 patients at presentation. All patients were treated with steroids (oral and/or methylprednisolone), while 23 patients received cytotoxic therapy in addition. The mean follow-up period was 8.6 ± 3.3 years at the end of which, 59% of patients achieved complete or partial remission, 20.5% continued to have active renal disease while 20.5% of the patients developed CKD. Our study suggests that most of the patients with FSGS progress to renal insufficiency. Steroid therapy increases the chances of remission and preserves renal function in patients with sporadic primary FSGS.
How to cite this article:
Sozeri B, Mir S, Mutlubas F, Sen S. The long-term results of pediatric patients with primary focal and segmental glomerulosclerosis. Saudi J Kidney Dis Transpl 2010;21:87-92 |
How to cite this URL:
Sozeri B, Mir S, Mutlubas F, Sen S. The long-term results of pediatric patients with primary focal and segmental glomerulosclerosis. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2021 Jul 24];21:87-92. Available from: https://www.sjkdt.org/text.asp?2010/21/1/87/58716 |
| Introduction | |  |
Focal and segmental glomerulosclerosis (FSGS) is a clinic-pathological entity characterized by segmental sclerosis involving glomeruli in a focal distribution, and by the presence of massive proteinuria. Primary FSGS accounts for 10% of all children presenting with the nephrotic syndrome. [1] Hematuria, hypertension and renal insufficiency are often seen at presentation, although in early stages it can be indistinguishable from minimal change disease. [2] The clinical course and prognosis of FSGS is heterogeneous in children. The reported frequency of end-stage renal disease (ESRD) in patients with FSGS ranges widely from 13 to 78% in studies with up to 20 years of follow-up. [3],[4] FSGS is primarily a histological diagnosis. [5] A group of renal pathologists re-defined these histological variants and proposed a standardized pathological classification system for FSGS, based entirely on light microscopic examination. [6] A number of studies have shown that some clinical, laboratory, and pathologic features are predictors of outcome. [7],[8],[9],[10] Primary FSGS is generally believed to carry a poor prognosis; there appears to be considerable heterogeneity in clinical features, renal histology and natural history, suggesting a diverse pathogenesis. [11]
The aim of this study was to analyze our experience in children with primary FSGS. We identified clinical and pathological features at presentation as well as outcome results of patients with sporadic primary FSGS.
| Patients and Methods | | |
The study included all children admitted to the Department of Pediatric Nephrology, Faculty of Medicine, Ege University, from January 1992 to December 2006. All the study children had biopsy-proven primary FSGS with no family history of the disease. The minimal follow-up period was 26 months. The diagnosis of primary FSGS was established by the absence of clinical evidence of systemic disease, either clinically or histologically. The data reviewed included the following: gender, age, age at onset of the nephrotic syndrome, predominant symptoms, height, weight, blood pressure, response to steroid therapy and laboratory data (urea, creatinine, 24hours proteinuria, hematuria). Blood pressure was measured according to the recommendations of the Task Force on Blood Pressure in Children. Blood pressure was standardized for age and gender using the Task Force tables and the 95 th percentile was used as the cut-off point. [12],[13]
Initially, patients were classified according to their response to the initial course of prednisone at our unit, which was administered for eight weeks, as follows: complete remission, partial remission and steroid resistant disease. At the end of the follow-up period, the patients were reclassified according to last outcome; remission (complete or partial), chronic kidney disease (CKD), and active disease.
In the treatment protocol, prednisone was started at a dose of 2 mg/kg per day (maximum daily dose 60 mg) administered orally in a single morning dose for four weeks, followed by four weeks of the same dose given every other day. After eight weeks, prednisone was progressively tapered off at the rate of 25% a week until complete discontinuation, by the end of 12 weeks. Patients who did not respond to the initial prednisone therapy were given high-dose methylprednisolone (MP) (30mg/kg/dose for six consecutive days), intravenously (i.v.). Patients who did not respond to oral prednisone and MP were given cyclophosphamide (CY) (2mg/kg for 12 weeks).
Complete remission was defined as proteinuria < 0.3 g/day and clinical remission of the nephrotic syndrome. Partial response was defined as urinary protein excretion of > 0.3 g/day and < 1 g/day or, a 50% reduction of initial proteinuria. Steroid resistant disease and active disease were defined as persistent urinary protein excretion of > 1 g/day with serum biochemical alterations of the nephrotic syndrome such as hypoalbuminemia and hyperlipidemia. Chronic kidney disease was defined based on estimated glomerular filtration rate (eGFR) (Schwartz formula): Stage-1 (renal injury) was defined as eGFR of > 90 mL/min per 1.73 m 2 ; Stage-2 (mild), eGFR of 60-89 mL/min per 1.73 m 2 ; Stage-3 (moderate), eGFR 30-59 mL/min per 1.73 m 2 ; Stage-4 (severe), eGFR of 15-29 mL/min per 1.73 m 2 ; Stage5 (ESRD), eGFR of < 15 mL/min per 1.73 m 2 .
Histopathological analysis
The review of histopathological features was performed by an independent renal histopathologist who was blinded to the clinical details and outcome of these patients. All biopsies were stained with hematoxylin-eosin, PAS, and Masson's trichrome for light microscopic evaluation, and with fluorescent antibodies agonist immunoglobulin (Ig) G, IgM, IgA, and C3 for direct immunofluorescence analysis. Light microscopic assessment of glomeruli for FSGS lesions was performed in accordance with the Columbia classification system described by D'Agati et al. [7],[8],[9],[10] This classification has defined five light microscopic patterns of FSGS: FSGS not otherwise specified (NOS), perihilar variant, cellular variant, tip variant and collapsing variant. The perihilar variant is defined as perihilar hyalinosis and sclerosis involving the majority of glomeruli with segmental sclerosis. [7] The collapsing variant is defined by the presence of at least one glomerulus with implosive tuft collapse and overlying visceral epithelial cell hypertrophy and hyperplasia. [14] The tip variant is defined by the presence of at least one segmental lesion, and the cellular variant shows segmental endocapillary hypercellularity. [15] FSGS not otherwise specified (NOS) does not meet defining criteria for any other variant.
| Statistical Analysis | | |
SPSS (version 11.0 for Windows) was used for statistical analysis. Continuous data were described as medians and ranges. Categorical variables were expressed as percentages. Variables were analyzed by chi-square (Pearson) and Fisher's exact tests and relative risks were calculated. A P value of less than 0.05 was considered to be significant.
| Results | | |
Thirty-four patients met the inclusion criteria for the study. They included 23 males (67.6%) and 11 females (32.4%). The mean age at onset was 6.3 ± 4.3 years (range 1 to 15.5). All patients had nephrotic-range proteinuria. Microscopic hematuria was detected in 3/34 patients (10%), while hypertension was noted in 15/34 patients (44.1%) at initial presentation. Six patients (18%) had elevated serum creatinine at diagnosis. In this cohort, the frequency of FSGS variants on renal biopsy included: cellular in 3% (n=1), collapsing in 9% (n=3), perihilar in 9% (n=3), tip lesion in 9% (n=3) and NOS variant in 70% (n=24). The mean follow-up duration was 8.6 years (SD 3.3, range 26 months to 14 years). Twenty-nine patients (85.2%) were followed-up for more than five years and 18 (52.9%), for more than 10 years. The demographics, clinical features and biopsy findings of the study subjects are shown in [Table 1].
All patients began therapy with steroids. Five of the 34 patients (14.7%) achieved complete remission with the initial course of prednisone (2 mg/kg/day). In this group, four patients had NOS variant and one had cellular variant of FSGS. Sixteen patients (47%) had partial remission. In this group, 10 patients had NOS variant, three had tip variant, two had collapsing variant and one patient had perihilar variant of FSGS. Thirteen patients (38.2%) were steroid resistant after the initial course of prednisone. Of them 10 had NOS variant, two had perihilar variant one had collapsing variant of FSGS.
Twenty-nine patients, in whom remission was not achieved with initial steroid therapy, were given MP. Six of these patients achieved remission following this, while 23 had to be given CY in addition to MP. The results of therapy are shown in [Figure 1]. Nineteen patients (55.8%) developed sustained hypertension and needed therapy with antihypertensive drugs.
At the end of the follow-up period, 20/34 patients (59%) achieved remission (5 with oral prednisone, 6 with MP, and 9 with MP plus CY), while seven patients (20.5%) each developed CKD and active renal disease. There was an association between initial response to steroid therapy and the condition of patients at the end of the follow-up period.
| Discussion | | |
In the present study, we examined the characteristics and outcome in children with sporadic primary FSGS. We excluded patients who had secondary or familial FSGS.
Earlier studies have shown that there is male predominance and majority of the patients with FSGS present with the nephrotic syndrome, mi croscopic hematuria and hypertension. [11],[14],[15] In this cohort, 67.6% of the patients were male. The clinical features at presentation of our patients were similar to other studies. All patients presented with the nephrotic syndrome. Three patients (10%) had microscopic hematuria, six (18%) had elevated serum creatinine and 15 (44.1%) had hypertension, in addition. In our study, age at onset ranged from 1-15 years (median 5) and most of the patients were older than five years (60%). Data from other series have shown that the mean age at onset is about six years. [11],[15]
FSGS is primarily a histological diagnosis, characterized by the presence of segmental sclerotic lesions involving some, but not all glomeruli. The classification for primary FSGS has been reported by D' Agati V, et al. [6] They noticed the NOS variant in 42%, the perihilar variant in 26%, the tip lesion in 17%, the collapsing lesion in 11%, and the cellular variant in 3% of the patients. The NOS variant was the most frequent variant in our study (70%). This finding is similar to other published data which have reported a higher prevalence of the NOS variant. [7],[16] The collapsing, tip and perihilar variants were seen in equal frequency in our cohort (9% each). We observed the cellular variant in 3% of the patients although there is some dispute whether the cellular variant is a separate entity.
Several studies have shown that the clinical characteristics and renal outcomes of patients with FSGS vary according to the histological variant. [7],[8],[9] The degree of proteinuria and poor prognosis was highest in the collapsing variant. [7],[17],[18] In our series, three patients had the collapsing variant, all of whom presented with the nephrotic syndrome; two of them had active disease at the end of the study. The patients with the tip variant of FSGS usually have better renal survival. [5],[13] We had three patients with tip variant all of whom achieved remission with prednisone therapy. Patients with perihilar FSGS had the lowest frequency of the nephrotic syndrome (55%) and the highest frequency of hypertension (80%). [19] The patients with the NOS variety of FSGS tended to have clinical and pathologic parameters that were intermediate with respect to the spectrum of findings in the other distinctive variants, although this group was more similar to the perihilar FSGS group. [19] Previously studies have shown that the tip and NOS variants of FSGS have benign course and a better response to steroid therapy compared to other variants. [7],[19] Analogously, 14 of 24 patients with the NOS variants and all patients with the tip variant achieved complete or partial remission with initial steroid therapy in our study.
Most children with the nephrotic syndrome achieved remission with daily corticosteroid therapy and had normal renal function over the long-term. [20] Primary FSGS appears to be less responsive to steroids than minimal change disease. [21] The initial response to corticosteroids in patients with primary FSGS has been considered to be poor and only about 20-25% of them achieved complete remission of proteinuria. [11],[22] A number of studies have shown that the rate of complete remission ranges from 050% while partial response is seen in 10-60% of the patients. [15],[23],[24] In the majority of studies published, the response rate has been less than 30%. [26]
Treatment has been directed against immunological abnormalities in patients with steroid resistant nephrotic syndrome using long-term steroid therapy, alkylating agents (cyclophosphamide) or calcineurin inhibitors (cyclosporine, mycophenolate). A controlled trial failed to demonstrate any efficacy of oral cyclophosphamide therapy in inducing remission in FSGS when compared to placebo therapy. [24],[25] However, another study demonstrated that a single course of oral cyclophosphamide induced remission in 43.1% of patients with FSGS when used as the first cytotoxic agent and thus, supports the use of cyclophosphamide in steroid resistant FSGS. [25] In our study, 23 patients were treated with cyclophosphamide, nine of them (26%) achieved remission at the end of the study. Repeated courses of cyclophosphamide therapy have adverse effects such as malignancy and gonadal toxicity. [11],[25] Therefore, the intensity of cyclophosphamide therapy should be carefully balanced. [11] The results of our study supports the use of cyclophosphamide in steroid resistant FSGS.
The patients with the nephrotic syndrome have five-year renal survival rates of 60 to 90%, and 10-year renal survival rates of 30 to 50%. [15],[27],[28] Untreated FSGS often follows a progressive course to ESRD. Previously, studies have shown that the outcome is variable and progression to renal insufficiency occurs in 25 to 62 % of patients with FSGS. [10],[28] Massive proteinuria, especially if unresponsive to treatment, is associated with an even worse prognosis, with most patients progressing to ESRD within five years. [27] In this study, seven patients (20.5%) developed ESRD after the onset of the nephrotic syndrome.
In conclusion, our findings suggest that corticosteroid therapy increases the chances of a remission and preserves renal function in patients with sporadic primary FSGS. We are conscious of the limitations associated with the retrospective design of our study and further studies on larger numbers of patients are recommended.
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Correspondence Address:
Betul Sozeri
Department of Pediatrics, Faculty of Medicine, Ege University, Izmir
Turkey
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PMID: 20061699 
[Figure 1]
[Table 1] |
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