RENAL DATA FROM ASIA - AFRICA
|Year : 2015 | Volume
| Issue : 1 | Page : 173-181
|Focal and segmental glomerulosclerosis: Does prognosis vary with the variants?
Guditi Swarnalatha1, R Ram1, Kiran Mai Ismal2, Sharmas Vali2, Manisha Sahay2, KV Dakshinamurty1
1 Department of Nephrology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad, Andhra Pradesh, India
2 Department of Nephrology, Osmania General Hospital, Hyderabad, Andhra Pradesh, India
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|Date of Web Publication||8-Jan-2015|
| Abstract|| |
Focal and segmental glomerulosclerosis (FSGS) is a clinicopathological entity. The following five FSGS variants: Collapsing, cellular, glomerular tip, peri-hilar and not otherwise specified (NOS) are recognized, which may have prognostic value. The aim of this study was to highlight the clinical course and outcome in the different pathological variants of FSGS and to evaluate the predictive risk factors of end-stage renal disease (ESRD). It was a retrospective analysis of biopsy-proven primary FSGS patients who presented over a period of three years. The data were collected from the clinical and biopsy records of the Nephrology Unit. There were 116 patients with biopsy-proven FSGS. The frequency of occurrence of FSGS among all cases of the nephrotic syndrome seen in our unit was 35.47%. NOS was the most common pathological variant (62.2%), followed by peri-hilar (11.2%), cellular (9.4%) and glomerular tip (7.7%), and the least common variant was collapsing (4.3%). Majority of patients with collapsing, NOS and glomerular tip variants had nephrotic range proteinuria. However, the amount of proteinuria was highest in the glomerular tip and collapsing variants. A higher percentage of patients with the collapsing and cellular variants had renal failure at the time of presentation. A higher rate of tubular and interstitial changes was seen in the collapsing and cellular variants. The collapsing and cellular variants showed lower response rate and higher rates of ESRD, while the glomerular tip lesion had the highest remission rate and the lowest rate of ESRD. Poor prognostic factors for ESRD in FSGS were initial renal insufficiency, severe tubulo-interstitial change, initial nonresponsiveness to steroids and collapsing histopathological variant. Our study suggests that histopathological classification of FSGS is of paramount importance in the management and in predicting the prognosis.
|How to cite this article:|
Swarnalatha G, Ram R, Ismal KM, Vali S, Sahay M, Dakshinamurty K V. Focal and segmental glomerulosclerosis: Does prognosis vary with the variants?. Saudi J Kidney Dis Transpl 2015;26:173-81
|How to cite this URL:|
Swarnalatha G, Ram R, Ismal KM, Vali S, Sahay M, Dakshinamurty K V. Focal and segmental glomerulosclerosis: Does prognosis vary with the variants?. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2021 Mar 7];26:173-81. Available from: https://www.sjkdt.org/text.asp?2015/26/1/173/148772
| Introduction|| |
Focal and segmental glomerulosclerosis (FSGS) is not a disease entity, but rather a pattern of injury with diverse clinical and morphological features and underlying pathogenesis. The clinical course, prognosis and outcome of FSGS are heterogeneous. Recently, various morphologic variants have been defined and a classification has been proposed to better characterize the diversity of FSGS. 
There are only few studies that have looked into the pathological variants of FSGS. We tried to analyze the demographic profile, clinical course and steroid responsiveness in pathological variants of FSGS. We also looked at the predictive factors of chronic kidney disease (CKD) in FSGS.
| Materials and Methods|| |
It was a retrospective analysis of biopsyproven primary FSGS patients who presented over a period of three years from 2004 to 2007, with a minimum of one year of follow-up. The data were collected retrospectively from the clinical and biopsy records of the Nephrology Unit, Osmania Government General Hospital. The study included all children and adolescents who presented from January 2004 to May 2007 with biopsy-proven primary FSGS, the nephrotic syndrome (NS) and a minimum follow-up of one year. The information collected included gender, weight, blood pressure, response to steroid therapy, laboratory data such as urea, creatinine, 24-h urine protein excretion, hematuria, lipid profile, liver function tests and response to steroids and other immunosuppressive medications. The above data were collected at the time of presentation, at the time of biopsy, after attaining remission, at every six-month intervals and at the last followup. Exclusion criteria were onset of the NS during the first year of life, secondary causes of FSGS that included reflux nephropathy, renal hypoplasia, systemic lupus erythematosus, Henoch-Schonlein purpura, IgA nephropahy and follow-up period less than one year.
All biopsies were stained with hematoxylin- eosin, PAS and Masson's trichrome for light microscopy evaluation and with fluorescent antibodies against IgG, IgM, IgA and C3 for direct immunofluorescence analysis. Biopsy specimens were reclassified according to the new pathological classification. Pathological data collected were histological type of FSGS, percentage of global and segmental sclerosis, presence of mesangial hypercellularity and severity of tubulo-interstitial changes. Immunosuppressive drug(s) received by FSGS patients were also recorded.
| Statistical Analysis|| |
The Medcalc statistical analysis software was used for statistical analysis. All values were presented as mean ± standard deviation. Statistical significance was assumed at P < 0.05. Univariate and multivariate analyses were used to predict the risk factors.
| Results|| |
One-hundred and sixteen patients were diagnosed to have FSGS. The total number of patients with the NS who presented during the above-mentioned period was 327. Hence, the frequency of FSGS was 35.47% of all cases of NS. [Table 1] shows the age and sex distribution of the FSGS patients. The average age at presentation of FSGS patients was 24.28 ± 19.3 years, ranging from 2 to 74 years. There were 38 females (32.76%) and 78 males (67.27%). The most common age-group at presentation was 11-30 years.
|Table 1: Age and sex distribution of patients with focal and segmental glomerulosclerosis.|
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When pathological variants were considered according to age-group [Table 2], not otherwise specified (NOS) was seen in the younger age-group (17.7 ± 12.1 years), which was not statistically significant. NOS was the most common pathological variant, seen in 78 patients (62.2%), followed by peri-hilar in 13 patients (11.2%), cellular in 11 patients (9.4%) and glomerular tip in nine patients (7.7%), and the least common variant was collapsing, seen in five patients (4.3%). Majority of patients with collapsing variety (80%), NOS (82.0%) and glomerular tip variant (77.7%) had nephrotic range proteinuria at presentation. However, the amount of proteinuria was highest in the glomerular tip variant (11.93 ± 1.6 g), followed by the collapsing variety (9.43 ± 1.7 g), which were statistically significant when compared with the cellular variant (P 2 -0.01 and P 1 -0.03, respectively). Also, the serum albumin levels were lowest in the glomerular tip variant (1.2 ± 0.9) and collapsing variant (1.45 ± 1.1), and were statistically significant (P 2 - 0.024 and P 1 -0.015, respectively) [Table 3]. A significantly higher percentage of patients with the collapsing and cellular variants of FSGS had renal failure at the time of presentation when compared with the glomerular tip and peri-hilar variants (P 2 -0.036 and P 3 - 0.023, respectively). However, severe degree of renal failure was seen only in the collapsing variant (P 1 -0.042). The frequency of hypertension was equal in all pathological variants of FSGS.
|Table 2: Age distribution versus pathological variants of focal and segmental glomerulosclerosis.|
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|Table 3: Baseline clinical characteristics of various pathological variants among patients with focal and segmental glomerulosclerosis.|
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[Table 4] shows the glomerular changes in various pathological variants of FSGS. Significantly higher percentage of patients with the collapsing variant (60%, P1 -value 0.0023) had glomerular sclerosis when compared with the other variants. A significantly higher frequency of capsular adhesions was seen in the peri-hilar variant (46.15%, P 3 - 0.045) and increased mesangial cellularity was seen in the cellular variant (63.6%) when compared with the glomerular tip and NOS lesions (P 2 0.008 and P 4 0.02, respectively). A higher rate of tubular and interstital changes was seen in the collapsing variant [Table 5] (P 1 0.004).
|Table 4: Pathological features of focal and segmental glomerulosclerosis; glomerular changes.|
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|Table 5: Pathological features of focal and segmental glomerulosclerosis; tubulo-interstitial changes.|
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A significant percentage of patients with the glomerular tip variant (66.6%, P 2 -0.025) were steroid responsive when compared with the cellular and collapsing variants, as shown in [Table 6]. None of the patients with the collapsing variant was steroid responsive, while those with the peri-hilar and NOS variants were intermediate. A significantly higher percentage of patients with the cellular variant were steroid non-responsive (63.63%, P 2 0.03); they had to be treated with other immunosuppressive drugs like cyclophosphamide (72.72%), cyclosporine (27.27%) and mycophenolate mofetil (9.90%). A higher percentage of patients with the collapsing and peri-hilar variants progressed to ESRD; however, only the collapsing variant (60%, P 1 -0.034) reached statistical significance.
|Table 6: Response of pathological variants of focal and segmental glomerulosclerosis to immunosuppressive drugs.|
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On univariate analysis, the significant risk factors for progression to ESRD were renal insufficiency at presentation, severe tubulointerstitial changes and initial steroid non-responsiveness. Nephrotic range prioteinuria was not a risk factor for progression to ESRD. Among the pathological variants of FSGS, the collapsing variant was a significant risk factor for ESRD [Table 7].
| Discussion|| |
Primary FSGS is a clinic-pathologic entity defined by the presence of proteinuria, often in the nephrotic range, and by segmental glomerular scars involving some, but not all, glomeruli.  Several publications have suggested that the prevalence of idiopathic FSGS in adults is increasing. , In a series of 1368 renal biopsies from patients over 60 years of age, FSGS was present in 5.4% of the patients with the NS.  In our series of 327 patients with the NS during the study period, FSGS was present in 116 patients (35.47%).
Since the first descriptions by Fahr and Rich, several different histological variants of FSGS have been described. ,,,, A group of renal pathologists redefined these histological variants and proposed a standardized pathological classification system for FSGS, based entirely on light microscopic examination. 
In a study by Thomas et al,  the frequencies of FSGS variants were: Cellular, 3%; collapsing, 11%; tip lesion, 17%, peri-hilar, 26% and NOS, 42%. Collapsing FSGS affected younger and, more often, black patients. In another study of 225 patients with idiopathic FSGS, 22 patients had the cellular variant, 56 had the collapsing variant, 60 had the glomerular tip lesion and 87 had the NOS.  In a retrospective analysis, 87 adult nephrotic patients with biopsy-proven primary FSGS were categorized on the basis of histologic criteria into those with a classic scar (36 patients 41%), the cellular or collapsing lesion (40 patients - 46%) or the tip lesion (11 patients 13%). 
Paik et al  reported that the most common pathologic variant in their Asian pediatric population was the NOS variant. In our study, the frequency of pathological variants was: NOS, 62.2%; peri-hilar, 11.2%; cellular, 9.4%; glomerular tip, 7.7% and collapsing, 4.3%.
In a study of pathological variants in childhood primary FSGS, the NOS variant was more commonly observed than either the cellular or the collapsing variant as in adult FSGS.  In contrast, the tip variant was the most frequent variant in a series by Deegens et al,  seen in 37% of their patients. Cellular FSGS was not found in the biopsies. This was explained by the difference in composition of the study populations as there were no AfroAmerican patients in that series.
The clinical features at presentation of our study patients were not very different from other series. Korbet et al  compiled data for 459 children with FSGS and showed that there was a predominance of males (56%), the NS (88%) and hematuria (54%), and that 28% of patients present with hypertension. In our series also there was a preponderance of males (67.27%) and 75.8% of patients presented with the NS; however, 76.78% of our patients had hypertension.
The presentation of patients with primary FSGS can differ among the histologic variants. Thomas et al  in their study found that at presentation, collapsing FSGS and tip lesion FSGS usually had severe NS with mean 24-h protein excretion of 10.0 and 9.7 g/day, respectively, whereas peri-hilar FSGS and FSGS NOS had less proteinuria with mean 24-h protein excretion of 4.4 and 5.5 g/day, respectively. Deegens et al  also showed that renal function was significantly better in patients with the tip variant compared with NOS (P < 0.05). Significantly more patients with the tip variant presented with the NS compared with patients with the NOS and peri-hilar variants (P < 0.01). The NS was more common in patients with NOS compared with peri-hilar FSGS (P < 0.05). Similarly, the present study also showed that the NS was more common in the collapsing and glomerular tip variants of FSGS.
The study by Chung et al  compared three FSGS variants, but only two of the variants were defined using the Columbia working proposal criteria. The level of proteinuria, the proportion of patients with proteinuria >10 g/d and the degree of hypo-albuminemia were significantly greater in patients with the cellular lesion compared with patients with the classic scar. Patients with the tip lesion had more severe hypo-albuminemia than patients with the classic scar, but the severity of proteinuria was not significantly different. In a study by Douglas et al,  majority (81.8%) of patients with the cellular variant presented with the NS. The presenting features of patients with the NOS variant were as follows: 55.6%, NS; 38.9%, fixed proteinuria; and 5.6% isolated hematuria. Similarly, cellular FSGS, collapsing FSGS and glomerular tip lesion share presenting features of heavy proteinuria, more frequent NS and shorter duration of symptoms compared with FSGS NOS, suggesting that these three morphologic variants reflect acute glomerular injury or possibly a response to heavy proteinuria.  Kyung Hoon Paik et al  reported that patients with the cellular variant more commonly presented with the NS compared with patients with the collapsing or NOS variants.
The peri-hilar variant is often associated with secondary forms of FSGS, especially due to maladaptive responses that follow loss of functioning nephrons, hyper-filtration or increased glomerular pressure.  Typically, these patients present with nephrotic range proteinuria without a full pledged NS. Serum albumin concentration usually remains normal even though proteinuria exceeds 3 g/24h. 
Stokes et al  showed that the cellular and glomerular tip variants showed very similar pathologic findings, including percentage of global sclerosis, percentage of segmental lesions, tubulo-interstitial scarring, arteriosclerosis score and percentage of foot process effacement. The collapsing variant showed the highest degree of pathologic injury, including tubulo-interstitial scarring. Deegens et al  reported that glomerular sclerosis and hyalinosis were most severe in patients with perihilar FSGS, intermediate in FSGS NOS and least severe in patients with the tip variant. However, in another study, the degree of interstitial fibrosis and glomerulosclerosis was not different among their three groups of patients.  In our series, the percentage of glomerulosclerosis was severe in collapsing FSGS and tubulo-interstitial changes were severe in the collapsing and cellular variants.
There is some dispute regarding the predictive value of the pathological variants. Schwartz et al  demonstrated that the pathologic variant had no predictive value for long-term outcome. Similarly, the Southwest Pediatric Nephrology Study group  showed that the pathologic variant had no definitive predictive value for renal function. Chun et al  concluded that there was no significant difference in the response to steroid treatment among the three groups; classic scar, cellular and tip lesions, with a remission rate of >50% in all patients who received steroid therapy.
In a recent report by Dijkaman et al,  in a case of recurrent FSGS, the segmental lesions were classified initially as collapsing FSGS because of the findings of areas of capillary collapse and epithelial hyperplasia. However, on serial sectioning of the involved glomeruli, lesions containing contiguous foci with different pathological appearances were seen, suggesting that the histological variants represented different stages in the evolution of glomerular lesions rather than independent lesions.  This may explain why we did not see any differences in the prognosis among pathological variants.
In contrast, recent studies suggest that the occurrence of the "tip lesion" variant of FSGS identifies a group of patients with a better prognosis. , In the initial study of Howie and Brewer,  all 16 patients who were treated with steroids showed reduction of proteinuria and only one untreated patient developed progressive renal impairment, suggesting a favorable prognosis. In the studies of Schwartz et al  and Morita et al,  three of four patients with initial biopsy findings of pure glomerular tip lesion had complete remission and stable renal function, and one had normal renal function and minimal proteinuria following steroid therapy. Other groups, on the other hand, reported no prognostic significance for "tip lesions" , or peripheral lesions , compared with idiopathic FSGS. The collapsing variant was noted by several groups to have more severe renal insufficiency at presentation, more severe markers of the NS and a more rapidly progressive course to renal failure than the non-collapsing forms. , Thomas et al  showed that the collapsing variant had a low complete remission rate (14%) and low three-year renal survival (33%), whereas the tip lesion had the highest complete remission rate (50%) and the best three-year renal survival (76%).
The risk of developing ESRD in idiopathic FSGS can be predicted at the time of diagnosis. Heavy proteinuria, either at the time of biopsy or, more particularly, following treatment, predicts a poor long-term outcome. Other features that increase the risk for progressive renal disease include elevated serum creatinine at the time of diagnosis, presence of hypertension, age at the time of diagnosis and male gender. ,, One series suggests that if a patient with primary FSGS fails to respond to initial therapy (most often steroid-based), the likelihood of renal death was as great as if the patient received no treatment at all.  Similarly, our study showed that initial renal insufficiency, presence of severe tubulo-interstitial changes and initial steroid non-responsiveness were the risk factors for progressive renal disease. However, heavy proteinuria was not a risk factor. One recent study in pediatric FSGS showed that there was no difference in renal survival on the basis of histologic variants. 
Collapsing FSGS had worse one-year (74%) and three-year (33%) renal survival compared with the other variants (overall cohort renal survival at one and three years: 86% and 67%, respectively).  Renal survival at five years was significantly better for patients with the tip variant (78% for tip vs 63% and 55% for NOS and peri-hilar FSGS). The type of FSGS and serum creatinine concentration were independent predictors of renal survival. We observed differences in renal survival on the basis of histological variant, with a much higher percentage of patients with the collapsing variant reaching stages 3 to 5 CKD compared with the cellular or NOS variants.
| Conclusion|| |
As FSGS has a diverse clinical course, morphological lesions, underlying pathogenesis and heterogeneous outcome, prognosis varies in different patients. The collapsing variant has least remission rates and highest rate of ESRD. The glomerular tip variant has highest remission rates and lowest rate of ESRD. Cellular and NOS showed intermediate rates. Initial renal insufficiency, initial steroid non-responsiveness, tubulo-interstitial changes and collapsing variant were risk factors for progresssion to ESRD.
| References|| |
D'Agati VD, Fogo AB, Bruijn JA, Jennette JC. Pathologic classification of focal segmental glomerulosclerosis: A working proposal. Am J Kidney Dis 2004;43:368-82.
Korbet SM. Primary focal segmental glomerulosclerosis. J Am Soc Nephrol 1998;9:1333-40.
Davison AM, Johnston PA. Glomerulonephritis in the elderly. Nephrol Dial Transplant 1966;11 Suppl 9:34-7.
Haas M, Spargo BH, Coventry S. Increasing incidence of focal-segmental glomerulosclerosis among adult nephropathies: A 20-year renal biopsy study. Am J Kidney Dis 1995;26:740-50.
Fahr T. Pathologische Anatomie des Morbus Brightii. In: Henke F, Lubarsch O, eds. Handbuch der Speziellen Pathologischen Anatomie und Histologie. Vol. 6. Berlin: Springer; 1925. p. 156-472.
Rich A. A hitherto undescribed vulnerability of the juxtamedullary glomeruli in lipoid nephrosis. Bull Johns Hopkins Hosp 1957;100:173-86.
Howie A, Brewer D. The glomerular tip lesion: A previously undescribed type of focal segmental glomerular abnormality. J Pathol 1984;142:205-20.
Detwiler R, Falk R, Hogan S, Jennette J. Collapsing glomerulopathy: A clinical and pathologic distinct variant of focal segmental glomerulosclerosis. Kidney Int 1994;45:1416-24.
Schwartz M, Evans J, Bain R, Korbet S. Focal segmental glomerulosclerosis: Prognostic implications of the cellular lesion. J Am Soc Nephrol 1999;10:1900-7.
Thomas DB, Franceschini N, Hogan SL, et al. Clinical and pathologic characteristics of focal segmental glomerulosclerosis pathologic variants. Kidney Int 2006;69:920-6.
Stokes MB, Valeri AM, Markowitz GS, D'Agati VD. Cellular focal segmental glomerulosclerosis: Clinical and pathologic features Kidney Int 2006;70:1783-92.
Chun MJ, Korbet SM, Schwartz MM, Lewis EJ. Focal segmental glomerulosclerosis in nephrotic adults: Presentation, prognosis, and response to therapy of the histologic variants. J Am Soc Nephrol 2004;15:2169-77.
Paik KH, Lee BH, Cho HY, et al. Primary focal segmental glomerulosclerosis in children: Clinical course and prognosis. Pediatr Nephrol 2007;22:389-95.
Silverstein DM, Craver R. Presenting features and short-term outcome according to pathologic variant in childhood primary focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 2007;2:700-7.
Deegens JK, Steenbergen EJ, Borm GF, Wetzels JF. Pathological variants of focal segmental glomerulosclerosis in an adult Dutch population-epidemiology and outcome. Nephrol Dial Transplant 2008;23:86-192.
Korbet SM, Schwartz MM, Lewis EJ. Primary focal segmental glomerulosclerosis: Clinical course and response to therapy. Am J Kidney Dis 1994;23:773-83.
Praga M, Morales E, Herrero JC, et al. Absence of hypoalbuminemia despite massive proteinuria in focal segmental glomerulosclerosis secondary to hyperfiltration. Am J Kidney Dis 1999;33:52-8.
Schwartz MM, Korbet SM, Rydell J, Borok R, Genchi R. Primary focal segmental glomerulosclerosis in adults: Prognostic value of histologic variants. Am J Kidney Dis 1995;25:845-52.
Southwest Pediatric Nephrology Study Group: Focal segmental glomerulosclerosis in children with idiopathic nephritic syndrome. A report of the Southwest Pediatric Nephrology Study Group. Kidney Int 1985;27:442-9.
Schwartz MM. The blind men and the elephant. Kidney Int 2005;68:1894-5.
Stokes MB, Markowitz GS, Lin J, Valeri AM, D'Agati VD. Glomerular tip lesion: A distinct entity within the minimal change disease/focal segmental glomerulosclerosis spectrum. Kidney Int 2004;65:1690-702.
Howie AJ, Pankhurst T, Sarioglu S, Turhan N, Adu D. Evolution of nephrotic associated focal segmental glomerulosclerosis and relation to the glomerular tip lesion. Kidney Int 2005;67:987-1001.
Morita M, White RH, Coad NA, Raafat F. The clinical significance of the glomerular location of segmental lesions in focal segmental glomerulosclerosis. Clin Nephrol 1990;33:211-9.
Rydel JI, Korbet SM, Borok RZ, Schwartz MM. Focal segmental glomerular sclerosis in adults: Presentation, course, and response to treatment. Am J Kidney Dis 1995;25:534-42.
Shiiki H, Nishino T, Uyama H, et al. Clinical and morphological predictors of renal outcome in adult patients with focal and segmental glomerulosclerosis (FSGS). Clin Nephrol 1996;46:362-8.
Detwiler RK, Falk RJ, Hogan SL, Jennette JC. Collapsing glomerulopathy: A clinically and pathologically distinct variant of focal segmental glomerulosclerosis. Kidney Int 1994;45:1416-24.
Valeri A, Barisoni L, Appel GB, Seigle R, D'Agati V. Idiopathic collapsing focal segmental glomerulosclerosis: A clinicopathologic study. Kidney Int 1996;50:1734-46.
Banfi G, Moriggi M, Sabadini E, Fellin G, D'Amico G, Ponticelli C. The impact of prolonged immunosuppression on the outcome of idiopathic focal segmental glomerulosclerosis with nephrotic syndrome in adults: A collaborative retrospective study. Clin Nephrol 1991;36:53-9.
Cameron JS. Focal segmental glomerulosclerosis in adults. Nephrol Dial Transplant 2003;18 Suppl 6:vi45-51.
Abrantes MM, Cardoso LS, Lima EM, et al. Clinical course of 110 children and adolescents with primary focal segmental glomerulosclerosis. Pediatr Nephrol 2006;21:482-9.
Dr. Guditi Swarnalatha
Department of Nephrology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad - 500 082, Andhra Pradesh
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]
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