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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2012  |  Volume : 23  |  Issue : 3  |  Page : 513-520
A clinicopathologic study of primary focal segmental glomerulosclerosis in children


1 Department of Pediatric Nephrology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
2 Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan

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Date of Web Publication7-May-2012
 

   Abstract 

There is very little information in the literature on the treatment and prognosis of primary focal segmental glomerulosclerosis (FSGS) among children in Pakistan. This is a review of 94 children (≤16 years) with a diagnosis of primary FSGS who presented to the Sindh Institute of Urology and Transplantation between 1995 and 2008. The clinical records and original renal biopsy reports were reviewed to determine demographic, clinical, laboratory and pathologic features. Renal biopsies were studied by light microscopy, immunofluoroscence and electron microscopy. Thera­peutic regimens and response to therapy were analyzed. Majority of the children (60, 63.8%) had steroid-dependant nephrotic syndrome (SDNS) and 33 (35%) had steroid-resistant nephrotic syndrome (SRNS). Cyclosphosphamide was used in SDNS, and this produced complete remission (CR) in 25/36 (69.4%), partial response (PR) in 4/36 (11%) and no response in 7/36 (19.4%) cases. Cyclosporine was used in SRNS and some SDNS children, and showed a CR in 30 (52.6%), PR in 20 (35%) and no response in seven (12.2%) cases. Tacrolimus was used in seven (7.44%) children. CR was obtained in two (28.5%) and PR in five (71.4%) cases. Renal insufficiency developed in 12 (12.7%) children. Results from this study show that majority of the children with primary FSGS at our center could achieve high rates of sustained remission with second- and third-line immunosuppressive therapies with fairly good prognosis.

How to cite this article:
Lanewala A, Mubarak M, Kazi JI, Akhter F, Sher A, Fayyaz A, Bhatti S. A clinicopathologic study of primary focal segmental glomerulosclerosis in children. Saudi J Kidney Dis Transpl 2012;23:513-20

How to cite this URL:
Lanewala A, Mubarak M, Kazi JI, Akhter F, Sher A, Fayyaz A, Bhatti S. A clinicopathologic study of primary focal segmental glomerulosclerosis in children. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2019 Sep 21];23:513-20. Available from: http://www.sjkdt.org/text.asp?2012/23/3/513/95781

   Introduction Top


Primary focal segmental glomerulosclerosis (FSGS) is a clinicopathologic syndrome in which variable amounts of proteinuria, usually of nephrotic range, are associated with the biopsy finding of focal and segmental scarring of the glomeruli in the kidney. [1],[2],[3] First described by Rich in an autopsy series, it is now the leading cause of nephrotic syndrome (NS) in the adult population worldwide. [1],[4],[5],[6] The incidence is also on a rise in children. [7],[8],[9],[10],[11],[12],[13],[14],[15] The clinical course of patients with primary FSGS is one of progres­sive renal insufficiency leading to end-stage renal disease (ESRD) over 5-10 years in more than 50% of the cases. [16],[17],[18],[19],[20],[21] In the USA, this is currently the most common primary glomerulonephritis that leads to ESRD in both adults and children. [16] Hence, its accurate diagnosis has considerable therapeutic and prognostic impli­cations. We have earlier reported FSGS as the leading cause of idiopathic NS in adults. [6] In a survey of native renal biopsies performed at our center in nephrotic children, FSGS constituted 38.14% of all cases of NS and was second only to minimal change disease and its variants. [7]

Although its natural course has been well des­cribed, its treatment is still a matter of debate. [21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36] Steroids remain the mainstay of treatment, and the therapeutic response to steroids seems to be the best predictor of long-term outcome. [21] Because the persistence of nephrotic range proteinuria is associated with guarded prognosis and spontaneous remissions are rare, the treat­ment to be given for steroid-resistant FSGS remains controversial. [23] Many immunosuppressive agents in combination with steroids have been used in such patients with variable results, mostly from developed countries. [21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36] Detailed clinicopathologic analysis of FSGS, particularly about its treatment and prognosis, to the best of our knowledge, has not been reported from Pakistan in the international literature till date.

In this study, we report our single-center expe­rience on the clinical presentation, pathologic features, response to treatment and clinical course of children with primary FSGS.


   Materials and Methods Top


This is a retrospective review of 94 consecu­tive children (≤16 years) with the diagnosis of biopsy-proven primary FSGS who presented to the Pediatric Nephrology Department of Sindh Institute of Urology and Transplantation (SIUT) between July 1995 and June 2008 and who had at least 6 months of follow-up. Patients with secondary FSGS with known causes were ex­cluded. The clinical records and original biopsy reports were reviewed to determine the pa­tients' age, sex, presence of hypertension, level of protein excretion, serum creatinine, total protein and serum albumin and presence of hematuria at the time of presentation. All children presented with NS and underwent percuta­neous renal biopsies under real-time ultrasound guidance. Informed consent was obtained from parents prior to undertaking the biopsy. Renal biopsy specimens were examined and classified according to standard criteria. [1] In three cases, biopsies were performed to exclude cyclosporine toxicity during the course of the study. These were not included and only first biopsies were included in the study for analysis of histopathologic features.

Hypertension was defined as blood pressure readings exceeding the 95th percentiles for sys­tolic or diastolic blood pressure for age and gender. Renal insufficiency was diagnosed when the estimated glomerular filtration rate was less than 60 mL/min and the ESRD was defined by the need for dialysis therapy. [17]

Standard therapeutic regimens and response to therapy definitions were used. [20],[32] The patients were treated with prednisone, 2.0 mg/kg body weight per day, in divided doses for six weeks, followed by single dose on alternate days for six additional weeks, which was then gradually discontinued over three months. Remission was defined as the absence of proteinuria (complete) or reduction of proteinuria to non-nephrotic levels without edema (partial) and resistance as the persistence of nephrotic range proteinuria during the four weeks of daily treatment. Re­lapse was defined as recurrence of the nephrotic range proteinuria and edema while tapering the dose of steroids or on stopping steroid treat­ment. The response to prednisone was classified as: steroid sensitive - complete or partial remis­sion of proteinuria during the steroid therapy persisting for at least 12 weeks after therapy and steroid dependent - two relapses of proteinuria within 14 days after stopping or during alternate-day steroid therapy.

Children with steroid-dependent nephrotic syn­drome (SDNS) either received a daily oral dose of 2-3 mg cyclophosphamide/kg body weight for 12 weeks, concurrently with prednisone in a dose of 1 mg/kg body weight/day or were main­tained on prolonged low-dose steroids to con­trol proteinuria. All cases of steroid-resistant nephrotic syndrome (SRNS) and those who failed or relapsed following treatment with cyclophosphamide were given cyclosporine in a dose of 5 mg/kg/day in two divided doses in combination with 1 mg/kg of steroids on alternate days for three months with a slow but complete with­drawal of steroids. Cyclosporine was then con­tinued for two years if no side-effects were noted. The clinical course and final outcome of each patient were evaluated at the last follow-up.

Pathologic study

Renal biopsies were evaluated by light micros­copy (LM), immunoflourescence (IF) and elec­tron microscopy (EM) as described in detail in our previous studies. [6],[7]

Light microscopy (LM)

For LM, routinely, 10 serial sections were cut and stained by hematoxylin and eosin (H&E), trichrome, periodic acid Schiff (PAS) and Gomori's methanamine silver (GMS) stain. The total number of glomeruli examined by LM was recorded, along with the number of glomeruli with global and segmental glomerular sclerosis. FSGS was defined according to established criteria. [1],[2],[3] A representative glomerular lesion is shown in [Figure 1]. Established criteria were used to grade the degree of tubular atrophy and inters­titial fibrosis. [37] Mild tubular atrophy was defined as atrophic changes involving less than 25% of the cortical tubules, moderate as 26-50% [Figure 2] and severe as >50% of cortical tubules.
Figure 1: Photomicrograph showing one glomerulus showing segmental scarring (arrow) and adhesion formation with Bowman's capsule (silver stain, ×200).

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Figure 2: Photomicrograph showing moderate degree of tubular atrophy and interstitial scarring (silver stain, ×200).

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Immunoflourescence (IF)

Tissue specimens for IF were stained by the direct method using FITC-conjugated antisera mono-specific for IgG, IgA, IgM, C3 and C1q (Dako, Glostrup, Denmark), as detailed in our earlier reports. [6],[7] IF findings on the biopsy spe­cimens were obtained from the original biopsy reports.

Electron microscopy (EM)

Tissue samples for EM were processed accor­ding to presently established techniques. [6],[7] Briefly, EM tissue was fixed in 4% glutaraldehyde, post-fixed in 1% osmium tetroxide at 0.02 M Sorenson phosphate buffer at pH 7.4, processed for electron microscopy and embed­ded in Eponate resin. Ultrathin sections (100 nm) were cut on Leica ultramicrotome. Sections were stained on copper 300-mesh girds with uranyl acetate and lead citrate and examined with a JEM 1200 EX II electron microscope. EM findings were obtained from the original biopsy reports.


   Statistical Analysis Top


Data are reported as means ± SD or as pro­portions. All statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS), version 10.0.


   Results Top


Patient characteristics

The patient characteristics are shown in [Table 1]. A total of 94 children satisfied the study criteria and were entered into the study. Of these, 60 (63.8%) were males and 34 (36.2%) were females, with a male to female ratio of 1.76:1. Their age (mean ± SD) was 8.27 ± 3.99 years, with a range of 1-16 years.
Table 1: Patient characteristics.

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Clinical and laboratory findings on presentation

All children by inclusion criteria had nephrotic range proteinuria. Microscopic hematuria was found in 17 (18%) children. Mean red blood cell count per microliter was 106.47 ± 110.5 on urinary dipstick testing. Mean serum albumin was 1.92 ± 0.78 gm/dL (range 0.00-2.5 g/dL). Mean serum creatinine was 0.49 ± 0.42 mg/100 mL (range 0.06-1.7 mg/100 mL). Only eight children (8.5%) had a positive family history of renal disease in first-degree relatives. Fifty-five (58.5%) children were normotensive at the time of presentation, while 39 (41.5%) exhibited va­riable degrees of hypertension.

Pathological findings

The main histopathologic findings in renal biopsies from 94 children are given in [Table 2]. Tubular atrophy and interstitial scarring paral­leled each other and were graded together. IF study showed negative results in majority of the cases (63/94, 67.02%), while focal to diffuse mesangial positivity of IgM was noted in 31 (32.98%) cases, half of these (15/31, 48.39%) associated with C3 deposition.
Table 2: Histopathologic characteristics of biopsies in 94 children with primary FSGS.

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EM done in all cases showed diffuse efface­ment of foot processes with focal detachment of podocytes from glomerular basement membrane. No electron-dense deposits were observed thus ruling out secondary FSGS.

Treatment responses and follow-up

All children had been initially treated with steroids except one who was subjected to biopsy directly. Majority of the children (60, 63.8%) showed a steroid-dependent pattern, 33 (35%) were steroid resistant and one case was not primarily treated with steroids. Renal biopsy was performed at this stage before further treatment with immunosuppressant agents. Cyclophosphamide was used in 36/60 (60%) SDNS chil­dren in combination with steroids in a dose of 1 mg/kg body weight on alternate days. Cyclosporine was administered to 57 (60.6%) chil­dren. Of these, 19 (33.3%) also received cyclophosphamide, while 38 (66.6%) did not receive this drug prior to cyclosporine. Of the later, 33 children had an SRNS pattern and five had SDNS response in whom cyclosporine was used as second-line therapy because of logistic reasons. All seven (19.4%) cases with no res­ponse to cyclophosphamide received cyclosporine, three (8.3%) with partial remission (PR) to cyclophosphamide and nine (25%) children with complete remission(CR) to cyclophosphamide, but with a later relapse, also received cyclosporine. Tacrolimus was used in seven (7.44%) children only. The response rates to different therapeutic agents are summarized in [Table 3]. All children with response are in remission till the end of this study.
Table 3: Response rates to steroids and immunosuppressant drugs of 94 children with primary FSGS.

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In this group of children, the follow-up period (mean ± SD) was 33.1 ± 24.38 months (range 6- 121 months). Renal insufficiency developed in 12 (12.7%) children. Of these, three are on maintenance hemodialysis and nine are not yet on dialysis. All these children had normal renal function at the time of presentation.


   Discussion Top


Although the clinicopathologic features of FSGS have been well characterized in nume­rous studies in the last four decades since its first description by Rich in 1957, its manage­ment is still a matter of debate. [1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20] No detailed clinicopathologic analysis of this entity, parti­cularly its treatment and prognosis in children, is available in the international literature from Pakistan. We herein review our experience in one of the largest series of pediatric FSGS with regard to clinical presentation, laboratory and histopathologic features, treatment responses and short-term outcome. Although this is a single-center-based study, our study population spans the whole country. Uniform clinical and pathologic criteria for diagnosis of FSGS and its management have been used. Thus, we be­lieve that our study results are fairly accurately representative of the clinical course and out­come of primary FSGS in children from this country.

As corticosteroids are the mainstay of treat­ment, and the therapeutic response to steroids seems to be the best predictor of long-term out­come and prognosis, we initially treated all our pediatric NS cases with steroids. [17] A classifica­tion of NS according to response to steroid the­rapy showed a majority of children in this cohort to be SDNS (60/94, i.e. 63.8%), while 33/94 (35%) showed SRNS pattern. A some­what similar steroid response pattern has been observed in a study of FSGS in Egypt involving 106 nephrotic children. [22] The prolonged admi­nistration of steroids in SDNS exposes children to risk of steroid toxicity, such as osteoporosis, growth retardation, cataract, diabetes and psychoemotional problems. Thus, numerous immunosuppressive agents have been used in combina­tion with steroids to increase the response rates and to obviate steroid toxicity. Different thera­peutic regimens and protocols are used in diffe­rent centers from around the world. [21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36] These combination therapies have produced variable remission rates, which are usually much lower than those achieved in initially steroid-respon­sive children. [23] A review of the literature shows that treatment of pediatric steroid-dependent FSGS with cyclophosphamide is associated with CR in 51%, PR in 23% and no response in 26%. [20] We obtained a higher CR rate (69.4%) with this drug, with an additional 11.1% sho­wing PR. No response was seen in 19.4% cases. In the Egyptian study, 16.4% of SDNS children responded to this drug and resistance was noted in 31.1% of the cases. [22] The study from Brazil reported a CR of 26.7% and PR of 20%, with a cumulative response of 46.7% using a com­bination of cyclophosphamide and steroids. [23] Our results are however concordant with the results obtained (67%) in the study utilizing cyclophosphamide for 12 weeks. [24] The reasons for high CR rate with cyclophosphamide in our children are not clear, but may partly be due to the fact that we used cyclophosphamide only in FSGS children with SDNS, as was used in the previous studies with high remission rates. [20],[24] Other investigators have used this drug in both SDNS and SRNS children, or they did not classify the patients before starting this drug. [23] Some investigators have suggested that the most important factor in the treatment of SDNS patients is the duration and the cumulative dose. [25] We used the drug for a three-month duration, which has been associated with a high remission rate. [20],[24] Moreover, majority of our FSGS patients had little or mild tubular atrophy and interstitial fibrosis at the time of biopsy. This may partly be responsible for the very high response rate in this cohort. Nine of the 25 patients (36%) with CR to cyclophosphamide relapsed and were treated with cyclosporine, while the remaining 16 patients (64%) are in sustained remission till last follow-up.

Cyclosporine is another effective immunosup-pressive agent that was first used in the treat­ment of idiopathic nephrotic syndrome (INS) in 1986. [26],[27],[28],[29],[30],[31],[32],[33],[34],[35] This is the only drug with docu­mented efficacy for steroid-resistant FSGS in controlled clinical trials in both adults and children. [31] The variability in response rates re­ported with this drug may partly be due to lack of the standardized dosing and duration criteria. Recently, an international workshop was con­vened to address this issue and to undertake a multidisciplinary, expert review of the clinical data currently available on cyclosporine therapy in INS. [32] We used cyclosporine in children with SRNS and those cases of SDNS that either did not respond to cyclophosphamide or relapsed after stopping this drug. The response to cyclosporine showed a CR in majority of the cases (30, 52.6%), while 20 (35%) cases showed PR, and no response was seen in seven (12.2%) cases. Our CR rate with this third-line immunosuppressant (52.6%) is similar to 51% reported by Korbet [20] but higher as compared with 44.4% attained in the Egyptian study of FSGS SRNS. [22] A much higher remission rate of 87% in SRNS children was however reported in a study from the US. [35]

Tacrolimus was used in seven (7.44%) cases of cyclosporine-resistant FSGS. CR was ob­tained with this drug in two (28.5%) and PR in five (71.4%) cases. All these are in remission till the end of this study. This newer and more potent calcineurin inhibitor has not undergone a controlled clinical trial for the treatment of FSGS, but there are anecdotal reports of res­ponses in patients with NS, some of whom had FSGS. [36] One retrospective study of 16 children with various forms of treatment-resistant NS, including 13 with FSGS, documented reduction in urinary protein excretion in 13 while on therapy and subsequent relapse in three of the 13. This drug is also associated with the pro­blem of high relapse rate on drug withdrawal similar to cyclosporine. [36]

Renal insufficiency developed in 12 (12.7%) children. The reported frequency of ESRD in children ranges widely from 13% to 78% in studies with up to 20 years of follow-up. [17] The low rate of progression to renal failure observed in this report may partly be due to the very high sustained remission rates achieved with immunosuppressive agents in our children and the relatively short follow-up period.

In conclusion, results from this study show that majority of our children with primary FSGS achieve very high sustained remission rates with immunosuppressive therapies and, conse­quently, exhibit an excellent prognosis.

 
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Correspondence Address:
Ali Lanewala
Assistant Professor, Pediatric Nephrology Department, Sindh Institute of Urology and Transplantation, Civil Hospital, Karachi
Pakistan
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