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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2010  |  Volume : 21  |  Issue : 1  |  Page : 87-92
The long-term results of pediatric patients with primary focal and segmental glomerulosclerosis


1 Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Turkey
2 Department of Pathology, Faculty of Medicine, Ege University, Izmir, Turkey

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Date of Web Publication8-Jan-2010
 

   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 2014 Jul 25];21:87-92. Available from: http://www.sjkdt.org/text.asp?2010/21/1/87/58716

   Introduction Top


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 Top


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 Top


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 Top


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 Top


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.

 
   References Top

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Correspondence Address:
Betul Sozeri
Department of Pediatrics, Faculty of Medicine, Ege University, Izmir
Turkey
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