NDT Advance Access originally published online on August 17, 2007
Nephrology Dialysis Transplantation 2008 23(1):186-192; doi:10.1093/ndt/gfm523
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Pathological variants of focal segmental glomerulosclerosis in an adult Dutch population—epidemiology and outcome
1Department of Nephrology, 2Department of Pathology and 3Department of Epidemiology and Biostatistics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Correspondence to: Jeroen K. J. Deegens, Department of Nephrology, 464, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Email: j.deegens{at}nier.umcn.nl
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Abstract |
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Background. A working group has defined five subtypes of focal segmental glomerulosclerosis (FSGS) based on light microscopic assessment (Columbia classification). Limited information is available on the prognostic and therapeutic implications of this classification in a European population. We conducted a retrospective analysis in 93 adult patients with biopsy-proven FSGS to determine the clinical features and outcome of FSGS variants.
Methods. Renal biopsy specimens of adult patients (>16 years) diagnosed with FSGS between 1980 and 2003 were reviewed according to the Columbia classification without the knowledge of clinical outcome. The medical records were reviewed for clinical data. Primary outcomes were remission rate and renal survival.
Results. The frequencies of the FSGS variants were: 32% NOS (FSGS not otherwise specified), 37% tip, 26% perihilar and 5% collapsing. Cellular FSGS was not found in the biopsies. The nephrotic syndrome was less frequent in FSGS NOS (57%) and perihilar FSGS (25%) compared to the tip variant (97%). Renal function was significantly better in patients with the tip variant compared to FSGS NOS (P < 0.05). Glomerular sclerosis and hyalinosis was most severe in patients with perihilar FSGS, intermediate in FSGS NOS and the least severe in patients with the tip variant. Patients with perihilar FSGS were less likely to receive immunosuppressive medication. Renal survival at 5 years was significantly better for patients with the tip variant (78% for tip vs 63% and 55% for FSGS NOS and perihilar FSGS; P = 0.02). Type of FSGS and serum creatinine concentration were independent predictors of renal survival. Remission rate was higher in patients with the tip variant (P = 0.1).
Conclusion. The collapsing variant was rare in our population. Renal survival and remission rates were higher in patients with the tip variant. Use of the classification scheme for FSGS may be clinically useful.
Keywords: classification; focal segmental glomerulosclerosis; nephrotic syndrome; pathology; prognosis; tip lesion
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Introduction |
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Focal segmental glomerulosclerosis (FSGS) is primarily a histological diagnosis, characterized by the presence of segmental sclerotic lesions involving some but not all glomeruli. Since the first descriptions by Fahr and Rich, several different histological variants of FSGS have been described [1–5]. A group of renal pathologists redefined these histological variants and proposed a standardized pathological classification system for FSGS based entirely on light microscopic examination [6]. This classification presumes previous exclusion of other primary glomerular diseases associated with FSGS, such as IgA nephropathy, diabetic glomerulosclerosis, membranous nephropathy and Alport's syndrome. Five histological variants were described: FSGS not otherwise specified (NOS), perihilar variant, cellular variant, tip variant and collapsing variant. The prognostic significance of this classification is still not clear. A study by Chun et al. [7] was unable to detect a significant difference in remission rate among patients with collapsing FSGS, FSGS NOS and the tip variant. In contrast, two other studies reported a lower remission rate and worse renal survival among patients with the collapsing variant compared to the tip variant and FSGS NOS [8,9]. Patients with the cellular variant had intermediate remission rates [8]. In the reported studies, 32–67% of the patients were Afro-Americans. It is questionable if the conclusions of these studies are applicable to a European population. In the present study, we analysed the characteristics and renal outcome of FSGS variants in adult Dutch patients and evaluated their predictive value compared to other known risk factors for renal failure.
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Patients and methods |
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From the pathology registry we identified all adult patients (age >16 years at biopsy) diagnosed with FSGS between 1980 and 2003 at the Radboud University Nijmegen Medical Center and affiliated hospitals. The renal biopsy specimens were reviewed by the renal pathologist (E.J.S) without knowledge of the clinical outcome. A minimum of five glomeruli in the light microscopy section was required for inclusion in the study. This number was chosen for a better comparison with previous studies by Chun et al. [7] and Thomas et al. [9]. Light microscopic assessment of glomeruli for FSGS lesions was performed in accordance with the Columbia classification system described by D'Agati et al. [6]. This classification defines five light microscopic patterns of FSGS: FSGS NOS, perihilar variant, cellular variant, tip variant and collapsing variant. Adult patients with one of the above light microscopic variants of FSGS and either negative immunofluorescence or only segmental IgM and/or C3 were considered for the study. Patients with FSGS due to other primary glomerular diseases, such as IgA nephropathy, membranous nephropathy, pauci-immune glomerulonephritis, lupus nephritis or hereditary nephritis were excluded.
Renal biopsies
For light microscopy, pieces of kidneys were fixed in Bouin's solution overnight at room temperature, dehydrated and embedded in Paraplast. Two micrometer-thick sections were stained with periodic acid Schiff and methenamine silver. For immunofluorescence, kidney fragments were snap frozen in liquid nitrogen, and 2 µm cryostat sections were incubated with fluorescein-labelled antisera directed to human IgG, IgM, IgA, C1q, C3, 
, 
and fibrinogen. Electron microscopic examination was performed on small pieces of kidneys fixed in glutaraldehyde.
Glomerular cross sections were arbitrarily assessed for the extent of sclerosis and hyalinosis, and called normal, mild, moderate or severe.
Clinical data
Medical records were reviewed for clinical data at presentation, at biopsy and at 3-month intervals thereafter. The following data were collected: age, sex, weight, blood pressure, level of protein excretion, serum creatinine concentration, serum albumin concentration, serum cholesterol concentration, use of immunosuppressive therapy and antihypertensive medication, initiation of dialysis and death. In addition, the medical records were reviewed for diseases associated with secondary FSGS: morbid obesity, renal dysplasia, solitary kidney, reflux nephropathy, infections (HIV, parvovirus B19), medication (pamidronate, lithium, interferon-
) or intravenous drug abuse, family history of renal disease and sickle cell anaemia.
Definitions
Presentation was defined as the time when proteinuria was first detected. Renal failure was defined as a sustained increase of the serum creatinine concentration of >50% from baseline (renal biopsy), or development of end-stage renal disease (ESRD). ESRD was defined as a serum creatinine concentration of >450 µmol/l or the need for renal replacement therapy or kidney transplantation. Nephrotic syndrome was defined as proteinuria of 
3 g/day in association with serum albumin concentration of 
30 g/l. Patients treated with antihypertensive drugs or with a systolic blood pressure >140 mmHg or a diastolic blood pressure >90 mmHg were considered hypertensive. A complete remission (CR) was defined as proteinuria <0.3 g/24 h with a stable serum creatinine concentration (<50% increase from baseline) and a partial remission (PR) was defined as proteinuria between 0.3 g/24 h and 2.0 g/24 h with at least 50% reduction in proteinuria from baseline and a stable serum creatinine concentration. A relapse was defined as a proteinuria >3 g/24 h after prior reduction of the proteinuria to less than 2.0 g/24 h
Statistical analysis
Values are given as means ± SD or median (range) when appropriate. Differences in continuous data were analysed with use of the Kruskal–Wallis test, followed by Dunn's post hoc rank test in the case of more groups. Fisher's exact test was used for differences in categorical data. Renal survival and remission rates for the different FSGS variants were estimated with Kaplan–Meier statistics. The log-rank test was used for comparison of the Kaplan–Meier curves. The univariable Cox proportional-hazards model was used to select variables associated with renal survival or attainment of a remission. The following variables were tested: serum creatinine concentration, serum albumin concentration, serum cholesterol concentration, proteinuria and mean arterial blood pressure all measured at biopsy, sex, age and type of FSGS. As for strongly skewed variables the high values may have a disproportionate influence on the outcome of the analysis, the log transformation was used to reduce their impact. In order to identify independent predictive parameters, the multivariable proportional-hazards model was used in a forward stepwise fashion, with P < 0.05 for inclusion of variables. Due to the low number of patients, data for the collapsing variant are presented but not included in the statistical comparison among variants. Throughout, a two-sided P-value <0.05 was considered as the level of statistical significance.
The analysis was performed using SPSS 14.0 for Windows (SPSS Inc., Cambridge, MA, USA). Multiple comparison procedures (Dunn's method) was performed using GraphPad InStat version 3.00 for Windows 95, GraphPad Software, San Diego, CA, USA.
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Results |
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A search of the pathology registry identified 116 patients with a diagnosis of FSGS. Twenty-three patients were not included in the study due to missing slides or less than five glomeruli in the renal biopsy. Baseline characteristics of the remaining 93 patients are shown in Table 1. The majority of the patients were native Dutch. There were no Afro-American patients. One patient was Indonesian, two patients were Indian and one patient was Turkish. In this cohort, the frequencies of the FSGS variants were: 32% NOS, 37% tip, 26% perihilar and 5% collapsing. Notably, the cellular variant was not observed. Renal function was significantly better in patients with the tip variant compared to FSGS NOS (P < 0.05). Significantly, more patients with the tip variant presented with nephrotic syndrome compared with patients with FSGS NOS and perihilar FSGS (P < 0.01). Nephrotic syndrome was also more common in patients with FSGS NOS compared to perihilar FSGS (p < 0.05). A secondary cause was identified in eight patients. Four patients with FSGS NOS and two patients with perihilar FSGS had a solitary kidney. Reflux nephropathy was present in one patient with perihilar FSGS and one patient with the tip variant was diagnosed with a thymoma. There were no cases of HIV.
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Pathology
The median number of glomeruli for evaluation by light microscopy was 12 (range 5–62). The number of glomeruli was significantly higher in patients with the tip variant (16, range 5–62) compared with patients with perihilar FSGS (11, range 5–35; P = 0.01). The median number of glomeruli in patients with FSGS NOS was 12 (range 5–60) and 20 (5–28) for patients with collapsing FSGS. Glomerular sclerosis and hyalinosis was most severe in patients with perihilar FSGS, intermediate in FSGS NOS and the least severe in patients with the tip variant (P < 0.001, perihilar vs the tip variant and FSGS NOS and P < 0.01, tip variant vs FSGS NOS). Electron microscopic examination was available for 51 patients. These patients were equally distributed among the four groups. Significantly more patients with the tip variant (90%) showed diffuse foot process fusion compared with patients with FSGS NOS (50%; P = 0.01) and perihilar FSGS (27%; P < 0.001). Diffuse foot process fusion was present in 67% of the patients with collapsing FSGS.
Treatment
Seventy-five patients (81%) were treated with an ACE inhibitor or an angiotensin receptor blocker. A total of 40 patients (43%) received immunosuppressive therapy (Table 2). There was a significantly greater use of immunosuppressive medication in patients with the tip variant and FSGS NOS compared with patients with perihilar FSGS (P < 0.001 and P = 0.018, respectively). Patients treated with immunosuppressive medication had significantly more proteinuria, a lower serum albumin concentration and a higher serum cholesterol concentration (Table 3). The initial course of immunosuppressive therapy consisted of prednisone alone (n = 24) or prednisone and cyclophosphamide (n = 15). One patient was treated with prednisone and azathioprine due to severe side-effects shortly after initiation of treatment with cyclophosphamide. Patients received high-dose prednisone (1 mg/kg/day) for a median of 2.3 months (range 0.4–8.6 months). The total duration of prednisone treatment was 5.6 months (range 1.3–55.3 months). Cyclophosphamide was administered orally in a dose of 1.5–2 mg/kg/day for a median of 3 months (range 2–12 months). The duration of immunosuppressive therapy was not significantly different among the groups.
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Remission and renal survival
Remission rate at 5 years was 44% (Table 2). Patients with the tip variant had the highest remission rate compared with patients with FSGS NOS and perihilar FSGS (P = 0.2 and P = 0.04, respectively); however, the overall difference between the three variants did not reach the level of statistical significance (P = 0.1; Table 2). A spontaneous remission occurred more often in patients with the tip variant compared with patients with FSGS NOS or perihilar FSGS (P < 0.01; Table 2). Two patients with collapsing FSGS also had a spontaneous remission. At the end of follow-up a remission was attained by 12 patients (6 CR/6 PR) with FSGS NOS, 18 patients (15 CR/3 PR) with the tip variant, 5 patients (3 CR/2 PR) with perihilar FSGS and 2 (2 CR) patients with collapsing FSGS.
The overall renal survival was 66 and 54% at 5 and 10 years, respectively. Patients with the tip variant had a significantly better renal survival compared with FSGS NOS and perihilar FSGS (P = 0.02; Table 2 and Figure 1). Renal survival at 5 and 10 years of patients attaining a remission was 100% for all variants.
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Predictors of remission and renal survival
On univariable analysis, a remission was predicted by a lower serum creatinine concentration, a lower serum albumin concentration and a higher serum cholesterol concentration (Table 4). Type of FSGS, proteinuria at renal biopsy and immunosuppressive therapy did not predict a remission. On multivariable analysis, only serum albumin concentration (P = 0.03) predicted a remission (Table 4).
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On univariable analysis, renal survival was predicted by a lower serum creatinine concentration, a lower serum albumin concentration, a higher serum cholesterol concentration and type of FSGS (tip variant; Table 5). Proteinuria at renal biopsy and immunosuppressive therapy did not predict renal survival. On multivariable analysis both serum creatinine concentration (P = 0.02) and type of FSGS (tip variant; P = 0.03) predicted renal survival (Table 5).
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Discussion |
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In the present study, we examined the characteristics and outcome of FSGS variants in an adult West-European population. In our population collapsing FSGS was rare. This is in agreement with other studies showing that 54–91% of patients with collapsing FSGS were Afro-Americans [5,7,9]. In a more detailed study of 42 patients with non-HIV collapsing FSGS only five patients were of European descent and three were hepatitis C positive after intravenous drug abuse [10]. Thus, collapsing FSGS is rare in our population, and the small number of patients precludes firm conclusions on prognosis and outcome. We also did not observe the cellular variant. There is some dispute if the cellular variant is a separate entity. Some authors do not discriminate between the cellular and collapsing variant [7]. Furthermore, careful analysis of biopsies with the cellular lesion often results in reclassification into the tip and collapsing lesion [8]. In two studies by Thomas et al. [9] and Stokes et al. [8], the prevalence of the cellular variant was only 3–4.5%. In view of these low percentages it is not unexpected that we did not observe the cellular lesion in our study population.
The tip variant was the most frequent variant in our study. This finding is somewhat in contrast to literature data reporting a lower prevalence of the tip variant compared to FSGS NOS [8,9]. Most likely, this reflects the difference in composition of the study populations. In contrast to previous reports, there were no Afro-American patients in our study. Alternatively, this series, like most others, relies on the diagnosis of FSGS given contemporaneously with biopsies, almost always by different pathologists. Therefore, it is likely that not all biopsies were classified as FSGS and may be missed, especially in the case of the tip variant, which may have been diagnosed as minimal change disease (MCD). This may also be part of the explanation of differences in outcome between reported series. Patients with the tip variant more often presented with nephrotic syndrome, had better renal function and less histological damage compared with patients with FSGS NOS and perihilar FSGS. These findings are in agreement with literature data [8,9,11].
The perihilar variant is often associated with secondary forms of FSGS, especially due to maladaptive responses that follow loss of functioning nephrons, hyperfiltration or increased glomerular pressure [12]. Typically, these patients present with nephrotic range proteinuria without a full nephrotic syndrome. Serum albumin concentration usually remains normal even though proteinuria exceeds 3 g/24h [13]. Most patients with perihilar FSGS in our study also presented without nephrotic syndrome. Nevertheless, an identifiable secondary cause was rare in our patients with perihilar FSGS. Admittedly, this conclusion is not unexpected since in patients with a readily identifiable cause of secondary FSGS, a renal biopsy is not done. Nearly all patients included in the study underwent examination by ultrasound or intravenous pyelogram, which makes it unlikely that secondary causes due to a reduced renal mass, e.g. renal agenesis or dysplasia, were missed. Alternatively, long-standing hypertension, a known cause of secondary FSGS, may have been present in our patients with the perihilar variant. Most patients with perihilar FSGS indeed had a history of hypertension before presentation to our centre or one of the affiliated hospitals. However, due to the retrospective nature of the study, it was not possible to establish the duration and severity of hypertension in these patients. Most patients with perihilar FSGS did not receive immunosuppressive therapy. This is likely due to the low number of patients with nephrotic syndrome. Although data on the use of immunosuppressive therapy in non-nephrotic patients are lacking, currently most authors would advise against immunosuppressive therapy in these patients [14]. In addition, Praga et al. [13] showed that patients with secondary FSGS due to maladaptive responses are usually characterized by a normal serum albumin concentration even though proteinuria is in the nephrotic range. Therefore, most treating physicians did not use immunosuppressive medication in patients with perihilar FSGS. Prognosis of patients with perihilar FSGS is comparable to FSGS NOS. After 10 years renal function remains stable in 
50% of the patients.
The tip variant was associated with the highest remission rate (57%). The remission rate compares very well to previous studies reporting remission rates varying between 53% and 59% [7,9,11]. Notably, a large proportion of patients with the tip variant in the present study attained a spontaneous remission. Stokes et al. [11] demonstrated that the presenting features and outcome of the tip variant more closely resembled MCD [11]. Although patients with MCD usually receive immunosuppressive therapy, up to 50% of the patients with MCD can attain spontaneous remission after a prolonged period [15,16]. We have published our experience in patients with primary FSGS. Spontaneous remissions occurred relatively frequently in a subgroup of patients that more closely resembled MCD, i.e. a more selective proteinuria and few sclerotic lesions [17]. Howie et al. [18] reported similar results in a group of patients presenting with only tip lesions. Some patients behaved as though they had MCD. Half the patients did not progress even though some may not have been treated or had received similar treatment as those who progressed. Our results and those of Howie suggest that some patients with the tip lesion may not need immunosuppressive therapy to attain a remission.
Admittedly, in multivariable analysis the tip variant did not predict attainment of a remission. This is probably related to a relatively low number of patients. A low serum albumin concentration was an independent predictor of a remission. However, inclusion of serum albumin as a variable may not be justified since clinical decisions may have depended on the actual serum albumin concentration. Although the differences in remission rate can be disputed, our study clearly showed a renal survival advantage for patients with the tip variant compared with patients with FSGS NOS and perihilar FSGS. The better renal survival of the tip variant only became apparent after 5 years of follow-up. This explains why Thomas et al. [9] were unable to show a renal survival benefit in patients with the tip variant, in spite of a higher remission rate. In their study, follow-up ended after four years. The tip variant was an independent predictor of renal survival. Only serum creatinine concentration at biopsy predicted renal survival better. In agreement with a previous study by Chun et al.[7], the overall renal survival in our patients attaining a remission was good irrespective of the type of FSGS. Therefore, the difference in renal survival, especially between the tip variant and FSGS NOS, is most likely explained by a better prognosis in patients with the tip variant who did not attain a remission. Half of these patients did not progress to renal failure compared with only 22% of patients with FSGS NOS. Our results support the concept of Howie, who suggested that the tip variant may be a manifestation of two diseases, i.e. MCD and FSGS [18]. In some patients with MCD, tip lesions may occur, however, these patients do not progress to sclerosis or renal failure [3]. On the other hand, tip lesions may occur early in the course of classical nephrotic FSGS, and these patients can progress to renal failure [19]. The existence of two forms of FSGS may also explain the different results reported in studies by Stokes and Chun [7,11]. In the study by Stokes et al. [11], of eight patients with the tip variant who did not attain a remission, only one progressed to ESRD. In contrast, Chun et al. [7] reported a poor prognosis in patients with the tip variant not attaining a remission.
Patients with the tip variant of FSGS present more often with a nephrotic syndrome, a better renal function and less histological damage. Patients with the tip variant have a better prognosis, and can attain a remission without treatment. Our data demonstrate the clinical usefulness of the FSGS classification.
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Acknowledgements |
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J.K.J.D is supported by a grant from the Dutch Kidney Foundation (PV 02). We thank Dr J. J. Beutler, Dr A. Hollander, Dr J.L.J. Jansen and Dr M.I. Koolen, Jeroen Bosch Hospital, ‘s-Hertogenbosch; Dr F.H. Bosch, Dr L.J.M. Reichert and Dr K.J. Parlevliet, Rijnstate Hospital, Arnhem; Dr M.A.G.J. ten Dam and Dr M.M.J. Schuurmans, Canisius Wilhelmina Hospital, Nijmegen; Dr G.W. Feith and Dr M. den Hartog, Hospital Gelderse Vallei, Ede; Dr A.W.L. van den Wall Bake and Dr P.G.G. Gerlag, Maxima Medical Centrum, Veldhoven, for their participation in this study.
Conflict of interest statement. None declared.
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References |
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Accepted in revised form: 6. 7.07
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