Abstract
Abstract. The cellular lesion (CELL), seen in some patients with primary focal segmental glomerulosclerosis (FSGS), comprises proliferation, hypertrophy, and pathologic changes in the cells overlying the glomerular scar. The prognosis of the cellular lesion was retrospectively studied in 100 patients with FSGS (43 had FSGS-CELL and 57 had FSGS without the cellular lesion (classic segmental scar [CS]). Patients with the FSGS-CELL lesion were more often black and severely proteinuric and developed more end-stage renal disease (ESRD). Nephrotic patients with FSGS-CELL (n = 39) were more proteinuric at presentation than patients with FSGS-CS (n = 36). ESRD developed more frequently in patients with the FSGS-CELL (17 of 39, 44% versus 5 of 36, 14%, P = 0.005), and patients with extensive FSGS-CELL (≥ 20% glomeruli) were mainly black (94%), severely nephrotic (67%, >10 g/d), and had a poor response to treatment (23% remission). In nephrotic patients, initial serum creatinine, interstitial expansion ≥20%, and CELL independently predicted ESRD. However, the rates of remission in treated nephrotic patients with FSGS-CELL and FSGS-CS were the same (9 of 17, 53% versus 17 of 39, 52%), and patients in both groups who achieved a remission had a 5-yr survival of 100%. Steroid treatment was the only variable that predicted remission. Patients with the FSGS-CELL have an increased prevalence of ESRD, but the improved prognosis associated with remission is so significant that a therapeutic trial is warranted in all nephrotic FSGS patients, regardless of the presence of the cellular lesion.
Primary focal segmental glomerulosclerosis (FSGS) is a glomerular disease that causes proteinuria and the nephrotic syndrome in children and adults (1,2). Although patients with FSGS have a guarded prognosis and often develop renal insufficiency, some enter remission after treatment (2). The classic pathologic description of FSGS was limited to segmental glomerular scars (1), but a variety of glomerular lesions, currently included under the diagnosis of primary FSGS (3,4), have been used to stratify patients for prognosis and response to therapy. Glomerular visceral epithelial cell pathology, including proliferation, hypertrophy, vacuolization, protein resorption droplets, nuclear changes, and separation from the glomerular basement membrane, is a frequently recognized histologic feature of idiopathic FSGS (reviewed in reference (5). This pathologic lesion and changes in the underlying glomerular architecture are diagnosed as the cellular lesion of primary FSGS (5) or collapsing glomerulopathy (6). Although the nomenclature differs, the glomerular pathology of the cellular lesion and collapsing glomerulopathy is identical, and we believe that the lesion represents an early stage in the evolution of glomerular scarring in primary FSGS. However, the clinical significance fo the cellular lesion has been controversial. Detwiler et al. (7) and Valeri et al. (8) suggest that it is associated with a poor response to therapy and rapid progression to end-stage renal disease (ESRD); however, our initial experience in 81 adult patients (2,9) failed to support these conclusions.
To further define the prognosis of the cellular lesion, we obtained additional follow-up in our original patients (2,9), added patients to the study, and included an analysis of the role that the proportion of glomeruli with the cellular lesion plays in determining outcome. We present a retrospective analysis of clinical and pathologic features in 100 patients to assess whether the cellular lesion independently predicts progression to ESRD in adult patients with primary FSGS.
Materials and Methods
Study Design and Patient Selection
This study is a retrospective clinicopathologic analysis of all adult patients (≥15 yr old at presentation) with the diagnosis of primary FSGS who were seen by the Renal Pathology Service and followed by the Section of Nephrology, Department of Medicine at Rush-Presbyterian St. Luke's Medical Center, Chicago, Illinois, between 1975 and 1996. The diagnosis of primary FSGS was established if there was no pathologic evidence for a primary glomerular disease or systemic disease process that might produce secondary segmental glomerular sclerosis. The medical records were reviewed, and patients with evidence of systemic disease, other diseases associated with glomerulopathy, or a history of morbid obesity, reflux, nephrectomy, a solitary kidney, or intravenous drug abuse were excluded. Infection with HIV was excluded by clinical criteria and laboratory evaluation.
Definition of FSGS and Pathology Studies
FSGS is diagnosed when the glomerular lesion involves only a portion of some of the glomeruli with others remaining relatively uninvolved. The involved glomeruli have a scarred segment with obliteration of the glomerular architecture and capillary lumens with or without adhesions to Bowman's capsule. This describes the classic lesion of FSGS (CS), and patients whose biopsies contained only classic segmental scars are referred to as FSGS-CS. The pathology of the cellular lesion of FSGS (CELL) (5,9) is defined by hypercellularity in Bowman's space overlying a scarred or collapsed glomerulus, and the cellular lesion is either segmental or global in its intraglomerular distribution (see Tables 1 and 6). The proliferating/infiltrating cells are hypertrophic with vesicular nuclei, a prominent nucleolus, copious frequently basophilic cytoplasm with blebs, vacuoles, periodic acid-Schiff-positive resorption droplets, and focal separation from the underlying glomerular basement membrane. Patients whose biopsies contained cellular lesions are referred to as FSGS-CELL. Global sclerosis means the entire glomerular tuft is scarred, and the capillaries are obliterated without an associated cellular lesion. In Tables 1 and 6, it is apparent that cellular lesions and classic segmental scars may coexist in renal biopsies. For example, biopsies showing the cellular lesion may also contain glomeruli with classic segmental scars and/or global sclerosis.
Pathology studies: all patientsa
Pathology studies: nephrotic patientsa
On the basis of these clinical and morphologic criteria, a total of 100 adult patients with primary FSGS was identified and divided into two groups: patients in whom the glomeruli demonstrated only classic segmental scars (FSGS-CS) and those having the cellular lesion in at least one glomerulus with or without other glomeruli with classic segmental scars or global sclerosis (FSGS-CELL).
Renal biopsy tissue was divided and processed for light, fluorescence, and electron microscopy. In each case, glass slides stained with hematoxylin and eosin, Masson's trichrome, periodic acid-Schiff, and methenamine silver-periodic acid-Schiff (Jones stain) were reviewed. The average number of glomeruli examined by light microscopy per biopsy was 23 ± 17 (median 21, range 5 to 122). Histologic evaluation was performed by M.M.S., who was blinded to the clinical data pertinent to each case. In addition to establishing the diagnosis of FSGS, the following features were recorded: the number of glomeruli with classic segmental scars; the number of glomeruli with global scars; and the number of glomeruli with the cellular lesion, subdivided into segmental and global cellular lesions. Expansion of the cortical interstitium was quantified on periodic acid-Schiff-stained sections by point counting using an ocular grid.
Clinical Studies and Laboratory Examination
Demographic as well as clinical and laboratory information at the time of renal biopsy and at follow-up was obtained on each patient. Presentation was defined as the time when proteinuria was first detected. A normal serum creatinine was defined as ≤1.3 mg/dl; renal insufficiency, a creatinine >1.3 mg/dl; and ESRD was defined as a serum creatinine ≥5 mg/dl, or the need for renal replacement therapy. Patients were categorized based on the level of proteinuria at the time of biopsy. Non-nephrotic proteinuria was defined as <3.0 g/d, nephrotic-range proteinuria as ≥3.0 g/d and massive proteinuria, >10 g/d. Patients with a diastolic BP >90 mmHg or a systolic BP >140 mmHg were considered hypertensive. In patients with nephrotic proteinuria, a complete remission was defined as a urine protein of ≤0.3 g/d, and a partial remission was defined as a urine protein between 0.31 and 2.5 g/d.
Treatment
Treatment was limited to patients with FSGS and the nephrotic syndrome because historically untreated non-nephrotic patients have had an excellent prognosis (10). The decision to treat with steroids, or immunosuppressive agents, was based solely on physician discretion. However, we generally recommend a trial of steroid therapy in nephrotic patients with primary FSGS in whom renal function is reasonably well preserved (serum creatinine ≤3 mg/dl) and in whom it is not otherwise contraindicated. Although no specific therapeutic regimen was used, over the past 10 yr we have proposed a more aggressive approach to the treatment of nephrotic adults with primary FSGS (reviewed in reference (11). This comprises an initial course of prednisone given at a dose of 1 mg/kg per d (up to 80 mg) for 3 to 4 mo. In patients demonstrating a complete or partial remission (see above), the dose of prednisone is then tapered slowly over 2 to 3 mo. Patients unresponsive to the initial therapy are tapered off prednisone more rapidly, over 4 to 6 wk. To minimize potential toxicity in the elderly, we use alternate day prednisone (1 to 2 mg/kg up to 120 mg) for 4 to 5 mo.
Statistical Analyses
Comparison of the clinical and laboratory characteristics among patients with cellular lesions and classic segmental scars used the Fisher exact test for categorical data (12) and the Wilcoxon rank-sum test for continuous data (13). Continuous data are reported as mean ± SD. For the analysis of length of time from biopsy to ESRD, product-limit life-table distributions were compared with the log-rank test (14). A proportional hazards regression model was used to evaluate potential clinical and laboratory predictors of progression to ESRD (14). Potential clinical and histologic predictors of remission used logistic regression analysis (15).
Results
All Patients
Pathology Studies. Histologic evaluation of all biopsies demonstrated the cellular lesion (CELL) and/or classic segmental scars (CS) in 11 ± 9% (median 9%) and global sclerosis in 20 ± 23% (median 12%) of glomeruli per biopsy. The cortical interstitial volume was 20 ± 13% (median 19%). The cellular lesion (Figure 1) was seen in 43 (43%) biopsies (FSGS-CELL) and classic segmental scars (FSGS-CS) (Figure 2) in 57 (57%) biopsies from patients with primary FSGS (Table 1). Biopsies from patients with FSGS-CS had more glomeruli with classic segmental scars than biopsies from patients with FSGS-CELL. Although the overall proportion of diseased glomeruli per biopsy (total of CS, global sclerosis, and CELL) was similar in the two groups (43 ± 13% in FSGS-CELL versus 39 ± 24% in FSGS-CS, P = NS), there appeared to be more diseased glomeruli with potentially progressive lesions (total of CS and CELL) in biopsies from patients with FSGS-CELL. The fractional cortical interstitial volume is approximately 5% in normal human kidneys (16), and although it was increased in biopsies from patients with FSGS-CELL and FSGS-CS, it was not significantly different between the two groups.
The cellular lesion. Collapse of all of the glomerular capillaries and diffuse proliferation and hypertrophy of the visceral epithelial cells. Methenamine silver-periodic acid-Schiff (Jones stain), × 185.
Classic segmental scar. Glomerulus with a parahilar segmental scar (asterisk) and an early adhesion (arrow) without changes in the overlying visceral epithelial cells. Methenamine silver-periodic acid-Schiff (Jones stain), × 185.
Clinical Characteristics at Biopsy. Clinical features at the time of biopsy for all patients are presented in Table 2. Patients with FSGS-CELL were more likely to be black and to have higher levels of proteinuria and lower serum albumin levels than patients with FSGS-CS. Virtually all patients with the cellular lesion had nephrotic-range proteinuria (91%) compared with only 63% of patients with FSGS-CS. There was a trend for patients with FSGS-CELL lesion to have a higher serum creatinine, greater prevalence of renal insufficiency, and shorter interval from clinical presentation to biopsy, but these tendencies were not significantly different.
Characteristics at biopsy: all patientsa
Outcome. The overall follow-up was longer for patients with FSGS-CS, but the duration of follow-up from the time of biopsy was not significantly different between the two groups (Table 3). The proportion of patients with FSGS-CELL progressing to ESRD was more than twice that of patients with FSGS-CS. At 5 yr, the renal survival was 45% (Figure 3) for patients with FSGS-CELL (median survival 36 mo) compared to 83% for patients with FSGS-CS (median survival 158 mo, P < 0.001).
Outcome: all patientsa
Cumulative renal survival for all patients with focal segmental glomerulosclerosis (FSGS) with classic segmental scars (FSGS-CS) and the cellular lesion of FSGS (FSGS-CELL). P < 0.001 by the log-rank test. Numbers in the table represent patients at risk at each time point.
The univariate analysis of all 100 study patients (Table 4) identified males, renal insufficiency, and level of proteinuria at the time of biopsy as clinical features predictive of progression to ESRD. The cellular lesion in any number of glomeruli (≥1%) and interstitial expansion involving more than 20% of the biopsy were the histologic features that predicted ESRD. By multivariate analysis (Table 5), male gender and renal insufficiency at biopsy remained significant clinical predictors of progressive renal disease. The cellular lesion predicted outcome, but only when combined with histologic evidence of chronic renal disease. Patients with the cellular lesion and ≥20% interstitial fibrosis were at high risk (relative risk, 27.7) for progression compared to patients with <20% interstitial fibrosis (relative risk, 2.0).
Univariate analysis of predictors of ESRDa
Multivariate analysis of ESRD in FSGS
Nephrotic Patients
Pathology Studies. Biopsies from nephrotic patients with FSGS-CS had more glomeruli with classic segmental scars than biopsies from nephrotic patients with FSGS-CELL (Table 6), but the percentage of glomeruli with global sclerosis was similar. Although the proportions of diseased glomeruli per biopsy (total of CS, global sclerosis, and CELL) were similar in the two groups (44 ± 24% in FSGS-CELL versus 36 ± 24% in FSGS-CS, P = NS), the proportion of potentially progressive lesions (CS and CELL) appeared to be greater in biopsies from patients with the cellular lesion. Eighteen (46%) biopsies with the cellular lesion had cellular lesions in more than 20% of the glomeruli (39 ± 16%, median 33%): The cortical interstitial volume was not significantly different between patients with <20% and ≥20% cellular lesions.
Clinical Characteristics at Biopsy. Nephrotic patients with FSGS-CELL had significantly more proteinuria and hypoalbuminemia than patients with FSGS-CS (Table 7). Even though the serum creatinine levels at biopsy were not significantly different, the proportion of patients with renal insufficiency tended to be greater in patients with cellular lesions. Among nephrotic patients, black race was no longer predominant in patients with FSGS-CELL.
Characteristics at biopsy: nephrotic patientsa
Outcome. The duration of clinical follow-up tended to be longer in nephrotic patients with FSGS-CS but was not significantly different from patients with FSGS-CELL (Table 8). Nonetheless, the prevalence of ESRD in patients with FSGS-CELL was more than three times greater than in patients with FSGS-CS. The overall renal survival (Figure 4) was worse for nephrotic patients with FSGS-CELL (median survival 36 mo, P < 0.01) in whom the 5-yr survival was 47% compared to 76% for patients with FSGS-CS.
Outcome: nephrotic patientsa
Cumulative renal survival for all nephrotic patients with FSGS-CS and FSGS-CELL. P < 0.0001 by the log-rank test. Numbers in the table represent patients at risk at each time point.
Steroid therapy was provided in 56% (42 of 75) of nephrotic patients. They received high-dose prednisone therapy (60 mg/d) for 2.34 ± 1.49 mo, mean ± SD (median 2.00), and the total therapeutic course including the steroid taper was 8.07 ± 10.01 mo, mean ± SD (median 5.50 mo). Although a higher proportion of patients with FSGS-CELL received treatment, the difference was not significantly different. In addition, highdose prednisone therapy (1.99 ± 1.20 mo [median 2.00] versus 2.60 ± 1.65 [median 1.90]) and total therapeutic course (10.38 ± 14.89 mo [median 5.60] versus 6.43 ± 3.65 [median 5.30]) were not significantly different in patients with FSGS-CS and FSGS-CELL. Only three patients with FSGS-CS and four patients with FSGS-CELL received cyclo-phosphamide as initial therapy in addition to steroids, and this number was too small to analyze. More than 50% of treated patients entered a remission, and there was no difference in response to therapy between patients with FSGS-CELL and FSGS-CS (53% and 52%). However, in the subset of patients with FSGS-CELL ≥20% (94% were black and 67% had >10 g/24 h of proteinuria) only 23% of those treated entered a remission (data not shown). Only a few untreated nephrotic patients experienced spontaneous remissions in each group. The course for patients with both FSGS-CELL and FSGS-CS who achieved a remission was excellent with 5-yr renal survivals of 100% (data not shown). This outcome was comparable to the 5-yr renal survival of 92% observed in the 25 25 non-nephrotic patients (four with the FSGS-CELL and 20 with FSGS-CS). The prognosis for nephrotic patients who did not respond to therapy was grim (Figure 5), and this was especially true for patients with FSGS-CELL who had a 5-yr renal survival of only 16% (versus 69% for patients with FSGS-CS). The renal survival was not significantly different between nonresponsive patients with ≥20% and <20% FSGS-CELL (median survival 21 versus 12 mo, P = NS). Univariate analysis in nephrotic patients (Table 4) identified renal insufficiency and the level of protein excretion at biopsy as clinical variables associated with an increased risk of progression to ESRD. Race was not predictive of ESRD. Among the morphologic features evaluated, global glomerular sclerosis, the cellular lesion, and interstitial fibrosis ≥20% significantly increased the relative risk of ESRD. In contrast to these findings, treatment and/or remission of proteinuria significantly decreased the risk of progression to ESRD.
Cumulative renal survival for nephrotic patients with FSGS-CS and FSGS-CELL who did not achieve a remission. P < 0.0001 by the log-rank test. Numbers in the table represent patients at risk at each time point.
Multivariate analysis of nephrotic patients (Table 5) demonstrated creatinine >1.3 mg/dl as the only independent clinical predictor of progression to ESRD. Interstitial fibrosis ≥20% and the cellular lesion were the only histologic features independently predictive of ESRD in nephrotic patients. A significant decrease in the risk of ESRD was associated with steroid treatment. The risk of ESRD was substantially less in patients achieving a remission (relative risk 0.03, P = 0.001), but this could only be demonstrated when the serum creatinine was omitted from the multivariate model.
Multivariate logistic regression analysis (data not shown) of clinical and histologic factors that might predict a remission in nephrotic patients found steroid treatment as the only covariate independently predictive of a remission (relative risk 10.6, P = 0.001). Factors predictive of decreased relative risk of remission were male gender (relative risk 0.23, P = 0.012) and ≥20% cellular lesions (relative risk 0.03, P = 0.002).
Discussion
We describe two classes of patients with primary FSGS that are distinguished by the presence or absence of the cellular lesion and differences in clinical features and prognosis. The levels of protein excretion at presentation and progression to ESRD were greater in patients with any amount of glomerular involvement by the cellular lesion, but we focused on nephrotic patients because nephrotic-range proteinuria is an independent predictor of outcome in FSGS (10) and because non-nephrotic patients with FSGS are rarely treated. We confirmed that renal survival is excellent in nephrotic patients with FSGS who achieve a remission of proteinuria (reviewed in reference (17). In addition, the present study further supports a role for therapy by showing that remissions associated with steroid treatment are equally likely in nephrotic patients with the cellular lesion and those with only classic segmental scars. Thus, a therapeutic response favorably affects outcome in primary FSGS patients with nephrotic-range proteinuria independent of the presence of the cellular lesion.
The cellular lesion is a descriptive diagnosis that encompasses the proliferative/infiltrative cellular changes seen in Bowman's space in some renal biopsies that fall within the morphologic and clinical spectrum of FSGS (5), and in our opinion, the cellular lesion is identical to the descriptions and illustrations of collapsing glomerulopathy (6). In this study, the cellular lesion predicted the outcome of ESRD, a result that is in accord with the findings of Detwiler et al. (7) and Valeri et al. (8) in collapsing glomerulopathy. We extended these observations by stratifying patients with the cellular lesion according to the proportion of glomerular involvement and demonstrated that patients with biopsies showing <20% and ≥20% cellular lesions have different clinical features and prognoses. Patients with FSGS-CELL ≥20% are almost exclusively black, have more severe proteinuria, and are less responsive to treatment than either patients with FSGS-CELL <20% or FSGS-CS, and the increased prevalence of ESRD observed in patients with FSGS-CELL can be attributed to the adverse natural history of the patients with FSGS-CELL ≥20%. Thus, the cellular lesion, when it is widely distributed among the glomeruli in a renal biopsy, has adverse implications for prognosis and therapeutic response. Because spontaneous remission of FSGS is unusual (2), it is likely that the remissions seen in the treated patients are induced by therapy, although this has never been tested, prospectively. The physician should not fall into the “slough of despond” when confronted by the cellular lesion in the renal biopsy of a nephrotic patient. Although pessimism is justified when the cellular lesion is widespread, the present experience demonstrates that a majority of patients with more focal cellular lesions (FSGS-CELL ≤20%) and even some patients with extensive glomerular involvement by cellular lesions (FSGS-CELL >20%) will respond to treatment as well as patients with FSGS-CS.
Clinical observations suggest that glomerular visceral epithelial cell injury is the initiating event in the pathogenesis of primary FSGS. The most convincing evidence supporting the evolution from the cellular lesion to glomerular scarring is seen in serial biopsies from renal transplant recipients who develop recurrent FSGS: Early onset of massive proteinuria coincides with minimal light microscopic changes, while ultrastructural pathology is limited to foot process effacement. With time the cellular lesion develops, but classic segmental scars are only seen in renal biopsies taken late in the clinical course (18). Additionally, the cellular lesion is frequently present in renal biopsies taken from patients near to the onset of the nephrotic syndrome (5,8). In contrast, classic segmental scars dominate the pathology later in the course suggesting that the cellular lesion heals with the formation of a classic segmental scar.
The relationship between the extent of the cellular lesion and ESRD demonstrates that involvement of a larger proportion of glomeruli (≥20%) is usually associated with a therapeutically unresponsive and progressive form of FSGS. Because patients with FSGS-CELL ≥20% frequently have other glomeruli with either global sclerosis or classic segmental scars, the presence of the cellular lesion in many other glomeruli indicates the potential to develop further scarring and progression to renal insufficiency. In contrast, FSGS is less aggressive in patients with FSGS-CELL <20% and FSGS-CS, and irreversible damage is usually restricted to diseased glomeruli. These observations suggest that there is a critical proportion of glomerular involvement by the cellular lesion that favors progressive glomerular disease. However, it is also possible that different distributions of the cellular lesion represent discrete diseases with different etiologies.
The cellular lesion is presumed to arise from glomerular visceral epithelial cells, but the markers that characterize the mature epithelial cell are not present in the cellular lesion (19,20). Therefore, the presumptive origin of the cellular lesion is based on its morphology, including the location in the urinary space outside the glomerular basement membrane and transitions observed between glomerular visceral epithelial cells and the cellular lesion (20). Proliferation is the definitive morphologic feature of the cellular lesion, as demonstrated by increased cells in Bowman's space, the presence of mitotic figures (5), and the cell cycle marker, Ki-67 (20), but the degree of proliferation is difficult to reconcile with the limited regenerative capacity of mature glomerular visceral epithelial cells (21). The mechanism of this anomalous proliferation may be related to the demonstrated loss of WT1 protein from the glomerular visceral epithelial cells (20). WT1 is a zinc finger, tumor suppressor factor normally expressed in mature podocytes, and it is critical in normal renal development. Loss of WT1 may allow the expression of factors (21,22) that result in proliferation. The pathogenesis of glomerular scarring following loss of WT1 is unknown, but it is noteworthy that abnormalities in the WT1 gene have been demonstrated in several forms of the congenital nephrotic syndrome (22), suggesting that loss of WT1 expression leads to progressive glomerular sclerosis in these inherited diseases. It is not known whether WT1 expression is lost in limited forms of the cellular lesion with a favorable response to treatment and a relatively good prognosis. However, widespread loss of WT1 expression is associated with a poor renal prognosis whether the loss is the result of a point mutation in the Denys-Drash syndrome (22), a viral infection in HIV-associated nephropathy, or unknown causes in collapsing glomerulopathy (20).
The pathologic finding of the cellular lesion in a nephrotic patient with primary FSGS portends an adverse outcome, but in our experience these patients are as likely to have a therapeutic response as nephrotic patients with FSGS-CS. In contrast, extensive glomerular involvement by the cellular lesion portends a poor prognosis that is due to the adverse outcome seen in patients with the FSGS-CELL >20%. Given the lack of response of the widely distributed form of the cellular lesion (>20%) to current therapy, we recommend that it be included in the stratification of patients with FSGS for therapeutic trials. Despite the negative prognostic connotation of the cellular lesion, the favorable outcome associated with a remission of proteinuria strongly supports therapeutic intervention in nephrotic patients with primary FSGS regardless of the presence of the cellular lesion.
Acknowledgments
Acknowledgment
We thank Dr. Edmund J. Lewis for his critical review of the manuscript.
Footnotes
American Society of Nephrology
This work was presented in part at the 30th annual meeting of the American Society of Nephrology, San Antonio, TX, and has been published in abstract form (J Am Soc Nephrol 8: 98A, 1997).
- © 1999 American Society of Nephrology
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