Summary
Background and objectives Collapsing glomerulopathy is a podocytopathy with segmental or global wrinkling and collapse of capillary walls and overlying epithelial cell proliferation. Idiopathic collapsing glomerulopathy is a distinct clinicopathologic entity with significant proteinuria, poor response to immunosuppressive therapy, and rapid progression to renal failure. Collapsing glomerulopathy is associated with viral infections, autoimmune disease, and drugs. This work presents the largest group of collapsing glomerulopathy in patients with SLE.
Design, setting, participants, & measurements Clinicopathological features were retrospectively studied in 19 patients with SLE (16 patients) or SLE-like (3 patients) disease with collapsing glomerulopathy.
Results Initially, 95% of patients had nephrotic syndrome with proteinuria of 3–12 g per 24 hours, creatinine levels of 0.6–9.6 mg/dl, positive lupus serologies, and normal complement levels in 63%. Segmental and/or global collapsing glomerulopathy was seen in 11%–77% of glomeruli. Tubular atrophy with focal microcystic changes and interstitial fibrosis was seen in 35% of patients. Minimal glomerular mesangial deposits were noted in 63% of patients, and extensive foot process effacement was seen in 82% of patients. Initial treatment was with pulse/oral steroids. Follow-up from 13 patients revealed that 7 patients progressed to ESRD at the time of biopsy up to 21 months later, 1 patient returned to normal creatinine (1.1 mg/dl) without proteinuria, and 5 patients had creatinine of 1.2–3.6 mg/dl with proteinuria of 0.37–4 g per 24 hours.
Conclusions Collapsing glomerulopathy may be seen in SLE patients presenting with massive proteinuria with or without lupus nephritis, which may have prognostic significance.
Introduction
Collapsing glomerulopathy (CG) has become an increasingly recognized pattern of glomerular injury with a rapid clinical course including massive proteinuria and relative resistance to standard treatment. The pathologic appearance is characterized by global or segmental collapse of the glomerular capillary tuft, with wrinkling and retraction of the capillary walls overlaid by epithelial cell proliferation in the Bowman space that is frequently accompanied by tubulointerstitial disease (1–3). CG is regarded as a podocytopathy, it is predominantly seen in the primary form in patients of African descent, and it has been associated with numerous etiologies, including viral infections (HIV, cytomegalovirus, Parvovirus B19, and hepatitis C virus), drugs (pamidronate and all forms of IFN), and anecdotally, autoimmune diseases (SLE and mixed connective tissue disease) (4,5). The trigger for the development of CG has been elusive, but an underlying immune-mediated mechanism has been postulated in most cases.
Podocytes have a characteristic phenotype in the adult glomerulus, expressing transcription factor Wilms’ tumor protein 1 (WT-1) as well as podocyte proteins podocin, synaptopodin, podocalyxin, nephrin, and glomerular epithelial protein 1 (6). According to the dysregulated podocyte phenotype theory, in CG, the affected podocytes lose markers of differentiation (WT-1, glomerular epithelial protein 1, synaptopodin, and podocalyxin) and assume a proliferative dedifferentiated state that is positive for Ki-67 and paired box gene 2 (7). However, the renopoietic hypothesis suggests that the lack of maturity markers is because of the absence of podocytes and participation of progenitor cells migrating from the Bowman capsule to form the proliferative lesions in the urinary space (pseudocrescents) (7,8).
Anecdotal CG in autoimmune diseases including SLE, SLE-like disease, and mixed connective tissue disease has been previously reported (1,2,9–18). The aim of this study is to report an analysis of the clinicopathologic findings and the possible association of renal lesions with CG in the setting of SLE and lupus-like disease and review the literature of the reported cases.
Materials and Methods
Native renal biopsies, processed using standard techniques for light, immunofluorescence, and electron microscopy, from 2003 to 2010 were reviewed from patients with history of SLE or SLE-like disease and a diagnosis of CG. SLE-like disease was defined as having multiple lupus criteria suggesting but not meeting the total of four criteria required for American Rheumatology Association (ARA) diagnosis of SLE (19). Demographic, clinical, laboratory, and serologic findings were obtained. The diagnosis of CG was made using the Columbia Classification criteria for the collapsing variant of FSGS (3), which are based on light microscopy showing at least one glomerulus with global or segmental collapse of the capillary tuft, wrinkling of the glomerular basement membrane, and hyperplasia and/or hypertrophy of the overlying epithelial cells usually containing intracytoplasmic protein droplets and vacuolization (3). The light, immunofluorescence, and electron microscopic findings are summarized.
Immunohistochemical stains on paraffin-embedded sections in 14 of 19 cases were performed using the Bond Max Autostainer (Leica Microsystems, IL) to further characterize the glomerular lesions. The primary antibodies used were against Ki-67 (clone MIB-1; Dako), mouse monoclonal antibody against β-dystroglycan (1:50 dilution, clone 43DAG1/8D5; NovoCastra), mouse monoclonal antibody against synaptopodin (1:10 dilution, clone G1D4; Progen Biotechnik), rabbit anti-human podocin (20 μg/ml dilution, clone PODO 11-A, Alpha Diagnostics), and polyclonal antiserum against WT-1 (C19; Santa Cruz Biotechnology). The sections were deparaffinized, and endogenous peroxidase was inactivated. Antigen retrieval was accomplished using the Bond Epitope Retrieval Solution 2 at 99–100°C for 20 minutes (Leica Microsystems). The sections were then incubated sequentially with the primary antibody for 25 minutes, the post-primary antibody for 15 minutes, and the polymer for 25 minutes, ending with colorimetric development with diaminobenzidine for 10 minutes (Bond Polymer Define Detection; Leica Microsystems).
This study was approved by the Institutional Review Board of Weill Cornell Medical College, New York. Patient informed consent was not required by the Institutional Review Board, because the study was a retrospective review of clinical and archived pathologic material only.
Results
Clinical and laboratory characteristics from the 19 patients are listed in Table 1. The patients ranged in age from 16 to 65 years old, and they were predominantly of African descent (17 of 19 patients; 89%) and female (male to female ratio is 4:15). SLE or lupus nephritis was diagnosed before the onset of CG in 11 patients (1–20 years before CG presentation), whereas a simultaneous first-time diagnosis of SLE along with CG occurred in 8 patients. At the time of renal biopsy, 16 of 19 patients had active lupus or lupus-like disease by clinical symptoms, including rash (4), arthritis (6), mucositis (2), antinuclear antibody (ANA) positive with or without double-stranded DNA (dsDNA) (13), and hypocomplementemia (8). The median serum Cr and BUN at presentation were elevated (3.0 mg/dl, interquartile range [IQR]=3.3 mg/dl and 31.5 mg/dl, IQR=22 mg/dl, respectively). The proteinuria ranged from 0.3 to 12 g per 24 hours, with a median of 6 g per 24 hours (IQR=5.6 g per 24 hours). All patients but one (case #19) had nephrotic range proteinuria at presentation. Complement levels were within the normal range in 10 cases; median C3 was 76 mg/dl (IQR=103 mg/dl, range=27–164), and median C4 was 11.8 mg/dl (IQR=33 mg/dl, range=8–61). ANA was positive in 14 of 15 (93%) patients. The remaining four patients had previously diagnosed SLE and did not have a current ANA titer on record. Anti-dsDNA was positive in 12 of 15 (80%) tested patients. All patients were HIV-negative. hepatitis C virus (n=11) and Parvovirus (n=7) serologies were negative in patients tested.
Clinical and laboratory findings at the time of biopsy
The pathologic findings are listed in Table 2. At least one glomerulus in each biopsy displayed either segmental or global collapse accompanied by epithelial proliferation (Figure 1, A and B). Global collapse was seen in up to a maximum of 65% of glomeruli per biopsy (mean=21.1%). Segmental collapse was present in 0%–48% of glomeruli per biopsy. However, 68% had a focal distribution (involvement of <50% of glomeruli). Global glomerulosclerosis was present in 11 of 19 biopsies, ranging from 0% to 57% of the total glomeruli. Acute tubular injury was seen in 11 of 19 cases, ranging from focal to extensive. Tubular atrophy and interstitial fibrosis varied from <5% to 90% of the renal cortical areas, and tubular microcyst formation was observed in 7 of 19 patients (Figure 1, C and D); 6 of 19 cases disclosed moderate arterio- and arteriolosclerosis, and the rest of the cases had no significant to mild vascular changes, with the exception of antiphospholipid-associated thrombotic microangiopathy in one case (case #16). No evidence of lupus vasculitis or vasculopathy was noted. Morphologic changes of lupus nephritis (LN) were present in seven cases, ranging from mesangial hypercellularity in four cases to focal endocapillary proliferation in one case, which corresponded to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classes II and III LN (Figure 2, A and B). One case had capillary wall thickening with diffuse subendothelial deposits without endocapillary proliferation (ISN/RPS class IV LN) (Figure 2C). Two cases displayed small external capillary wall spike formation, which is seen best by Jones methenamine silver staining, corresponding to ISN/RPS class V LN (Figure 2D). No necrosis or crescent formation was seen in any of the biopsies.
Renal pathologic findings
Glomerular and tubulointerstitial findings in collapsing glomerulopathy in the setting of SLE. Pathologic features of segmental (A) and/or global (B) collapsing glomerulopathy with capillary wrinkling and retraction and epithelial cell proliferation containing prominent protein resorption droplets. Tubular microcysts and chronic interstitial disease (C) and tubular epithelial cell injury (D) were also seen. A, Jones methenamine silver; B, Jones methenamine silver; C, Periodic acid-Schiff; D, hematoxylin & eosin. Original magnification, ×600 in A; ×400 in B; ×200 in C; ×200 in D.
Lupus glomerulonephritis was present in 8 of 19 cases. (A) Mesangial (class II) in four cases. (B) Focal proliferative (class III) in one case. (C) Diffuse lupus nephritis (class IV) in one case with diffuse subendothelial deposits detected by electron microscopy. (D) Membranous (class V) in two cases. Small capillary wall spikes are indicated by the white arrow. A, periodic acid-Schiff; B, periodic acid-Schiff; C, Jones methenamine silver; D, Jones methenamine silver. Original magnification, ×400 in A; ×600 in B; ×600 in C; ×600 in D.
There was positive immunofluorescence staining for immune deposits in 84% of the cases (16 of 19 cases) (Figure 3, A and B). Where present, the deposits were commonly trace to 1+ in mesangial locations for various combinations of immunoglobulins, complement components (C3, C1q), and κ- and λ-light chains. Glomerular immune complex deposits were found by electron microscopy in eight cases: four cases with mesangial deposits (Figure 3C), two cases with subendothelial deposits, and two cases with subepithelial deposits. The foot processes were affected in all cases, ranging from 10% (two cases) to 100% effacement (Figure 3D). Four cases displayed endothelial cell tubuloreticular inclusions.
Immunoflourescence and electron microscopic findings. Glomeruli in 16 of 19 cases displayed immune complex deposits by immunofluorescence (A; anti-IgG). The remaining cases were negative by immunofluorescence (B; anti-IgG). Mainly mesangial (eight cases) lupus nephritis with mesangial electron-dense deposits (C; electron microscopy) were seen. Eleven cases showed only wrinkling and retraction of the glomerular basement membranes without immune complex deposits by electron microscopy (D). Original magnification, ×400 in A; ×400 in B; ×6000 in C; ×6000 in D.
Immunohistochemical stains for podocyte proteins have been documented in idiopathic CG and HIV-associated nephropathy (HIVAN) but not CG associated with autoimmune disease (20). Previous reports indicate widespread loss of synaptopodin and WT-1 markers in viral and idiopathic related CG with less dysregulation and dedifferentiation in reactive and genetic cases (20). In this study, WT-1 staining was preserved in 9 of 14 cases (64%), with loss of synaptopodin and podocin in the collapsed segments in 10 of 12 (83%) cases and 8 of 10 (80%) cases, respectively (Figure 4, A–C and Table 2). β-Dystroglycan was absent in 7 of 11 (63%) cases in the collapsed areas (Figure 4D). Ki-67 proliferation marker showed nuclear positivity in proliferating glomerular epithelial cells overlying the collapse in all cases tested (13) (Figure 4E).
Immunohistochemical staining for podocyte antigens and Ki-67 labeling in collapsed glomeruli. The glomeruli with collapsing lesions largely displayed preservation for Wilms’ tumor protein 1 staining (A), with decrease or loss in the collapsed regions for synaptopodin (B) and podocin (C). Anchoring protein β-dystroglycan was lost or attenuated in the collapsed regions (D). Proliferation marker (Ki-67) was positive in epithelial cell nuclei in all cases (E). Original magnification, ×600 (immunohistochemistry).
Follow-up data were available for 13 patients from 2 months to 3.5 years (Table 3); 7 of 13 (54%) patients progressed to ESRD from the time of biopsy to 21 months after presentation despite treatment. One case (8) was rebiopsied at 10 months for rapidly rising Cr to 11 mg/dl and showed persistent collapsing features and increased interstitial fibrosis with microcystic changes; this case was in ESRD. A second case with partial response (14) was rebiopsied at 1 year for persistent proteinuria (5–6 g) and showed increased segmental and global glomerulosclerosis with partial foot process effacement (40%) and advancing interstitial fibrosis. The treatment was most typically comprised of pulse dose steroids (12 of 13 cases); six cases received additional mycophenolate mofetil, one case received intravenous Igs, one case received azathioprine, and two cases received plaquenil. Of the six patients who did not progress to ESRD, one patient achieved return to normal Cr, and four patients had Cr levels between 1.2 and 3.6 mg/dl at last follow-up. In those patients with partial response, treatment consisted of high-dose, long-term oral steroids ranging from 60 to 100 mg/d for 2–6 months. The partial and complete responders had fewer collapsing lesions (31% versus 42%), less global glomerulosclerosis (8% versus 22%), and less interstitial fibrosis (28% versus 49%). In addition, a better response was seen in patients with concomitant LN. Four of six responders had LN, whereas only one of seven of those cases progressing to ESRD had LN (case #17).
Initial treatment and follow-up data
Discussion
Herein, we report a cohort of patients presenting with SLE or SLE-like disease, nephrotic syndrome, or nephrotic range proteinuria and renal insufficiency, with an active lupus flare (16 of 19 patients; 84%) and biopsy-proven CG. Underlying immune complex-mediated LN was also noted in 8 of 19 cases, which ranged from mesangial (class II) in four cases, focal proliferative (class III) in one case, and diffuse proliferative (class IV) in one case to membranous (class V) in two cases; 11 of the patients had SLE from 1 to 20 years before the diagnosis of CG, whereas eight patients had simultaneous new diagnosis of SLE and onset of CG. In the majority of cases, treatment was initiated with high doses of steroids for prolonged periods, with 6 of 13 cases achieving complete (1 case) or partial (5 case) remission.
This report represents, to our knowledge, the largest collection of cases with biopsy-proven CG in the setting of SLE or SLE-like disease with clinicopathological data and follow-up information. Our findings are similar to previous anecdotal case reports (Table 4) (9–13,15–18). Overall, 13 patients with ARA criteria meeting SLE and 9 other SLE-like patients have been reported as well as 5 additional patients presenting with isolated positive serology for ANA but lacking other SLE symptoms, a finding of unclear significance (1,2,9–18,21). In both the present and previously reported cases, the patients are predominantly female and of African descent with nephrotic range proteinuria, positive ANA, and relatively poor response to treatment. In larger studies of CG (1,2,21), eight additional cases of SLE, SLE-like, or mixed connective tissue disease were briefly described without specific clinical or outcome data available. All these patients had positive ANA, four patients had positive dsDNA, one patient had hypocomplementemia, and one patient had endothelial tubuloreticular inclusions on electron microscopy. A series of podocytopathy in SLE also contained two patients with CG and SLE, one of which progressed to ESRD and died secondary to sepsis (14).
Literature review of collapsing glomerulopathy in lupus or lupus-like conditions
Follow-up information was provided in eight of the reported cases: four cases had partial remission, two cases had a complete remission, and two cases led to no response or death during therapy (9–12,15–18). Only 25% progression to ESRD or death in this group is a surprising finding, and it may be related to a shorter follow-up period or less-stringent criteria for the diagnosis of CG. In fact, all previously reported cases of remission had either diffuse proliferative LN (5) or thrombotic microangiopathy in the biopsy, which may confuse the diagnosis.
CG has been associated with a variety of etiologies, including the well-recognized glomerular and tubulointerstitial lesions in HIV infection or Parvovirus B19 (22–24). CG is also described secondary to certain medications, including Pamidronate (25), and with all forms of IFN (α, β, and γ) therapy (5).
One common theme to both HIVAN and the various etiologies of HIV-negative CG seems to be a perturbation of the immune system, whether triggered by an infectious agent or an endogenous autoimmune T cell regulatory disruption (26). A T cell cytokine-mediated process modified by genetic influences has been proposed as one of the underlying mechanisms inducing SLE (27). T cells are abnormal in SLE, expressing lower levels of CD3ζ and IL2 and having a diminished cytotoxic activity, a lower proportion of T regulatory cells, and a faster homing response to chemokines such as CXCL12 (28). In addition, patients with SLE have previously been reported to develop proteinuric podocytopathic renal disease in the form of FSGS (29,30) or minimal change disease, which some have suggested to result from mainly T cell activation (31,32). Although the pathophysiology of the podocyte injury in SLE is not entirely clear, an immune-mediated pathway through an antibody- or T cell-mediated process is a possible mechanism in the setting of a genetically susceptible patient population.
How does the autoimmune injury occurring in SLE contribute to podocyte injury, and are they necessarily related to one another? In our patients, the time of onset of CG seems to indicate that active lupus disease was associated with the development of CG, which was supported by serologic and clinical parameters. Humoral factors may play a role in inducing podocyte injury, which was shown in the work by Avila-Casado et al. (33); rats injected with serum from patients with CG developed proteinuria, whereas rats injected with FSGS or normal human serum did not. Other mouse models have shown that an antibody-induced glomerular injury produced a CG-like pattern in three different strains of transgenic mice (34–36). A circulating factor has been postulated to play a role in podocyte injury in FSGS not otherwise specified in the form of high soluble urokinase receptor (37). In a recent report by El Karoui et al. (38), IgA nephropathy was associated with podocyte injury representing all variants of FSGS, including the collapsing variant. The work by El Karoui et al. (38) concluded that immunologic injury may be responsible for the epithelial injury seen in immune complex-mediated glomerular disease. Development of antiphospholipid antibodies and subsequent thrombotic microangiopathy may also play a role in some lupus patients by causing podocyte ischemia to contribute to epithelial injury (particularly case #16 in our study).
Whether by a T cell-mediated or humoral process, the podocytes (all cases) and the tubular epithelial cells (12 cases) seem to be affected with a change in functional, morphologic, and immunophenotypic features. By immunohistochemistry, the glomerular epithelial cells show a proliferative (100% of cases with +Ki-67 labeling) and dedifferentiated phenotype, displaying loss of synaptopodin and podocin localized mainly in the areas of CG in 83% and 80% of cases tested, respectively, whereas WT-1 preservation is seen in 64% of the cases. The pattern of staining for synaptopodin and podocin is consistent with other nonlupus-related cases of idiopathic CG or HIVAN (20), but WT-1 preservation seems to be unique to an autoimmune etiology, because idiopathic cases of CG typically also show a loss of WT-1 (20). WT-1 positivity in CG cases with SLE was also noted in one other reported case (18).
Because the majority of patients with both HIVAN and idiopathic CG are of African descent, there is an increased probability of a genetic susceptibility to developing this type of proliferative podocyte disease (1,2,21,39–44). The work by Freedman et al. (45) found a 5.4-fold increase in ESRD among HIV-negative first- and second-degree relatives of patients with known HIVAN, strengthening the notion of a genetically encoded susceptibility to kidney injury. Studies by Kopp et al. (46) and subsequently, Genovese et al. (47) found an association of FSGS and nondiabetic kidney disease in African-Americans with the MYH9 and closely positioned APOL1 genes on chromosome 22.
SLE occurs in African-American women four times more frequently than Caucasians (48). CG is also highly associated with an African lineage (1,2,21). Our study also shows that there is both a strong African and female preponderance, which may suggest a coincidental association between the two diseases in a patient population that is at a higher risk of developing both conditions. At all institutions included in the study, biopsies of SLE patients are more frequently from women than men. Previous studies of nonlupus nephritides developing in patients with SLE have shown that the association with SLE and podocyte injury, including minimal change disease and FSGS, has been far higher in patients with SLE (1.6% and 1.7%, respectively) than in the general population (<0.01%), suggesting a noncoincidental link (10,14,30). The multifactorial interplay between ethnic background, presence of SLE, and development of CG in these patients is not currently known, and the main aim of this multicenter study is to bring this rare disease process to the attention of clinicians and pathologists as yet another renal lesion in SLE patients that may require a different management.
Owing to the rarity of this disease, the study has a few limitations. This study is the largest to date on CG in SLE, which required the collective efforts of five large renal biopsy centers to amass the 19 total cases. Sampling bias may be present based on the tertiary centers involved. The retrospective and small series comprised a heterogeneous group of patients with uncontrolled comorbidities, who received varying treatment regimens and had inconsistent follow-up periods.
In summary, SLE patients with massive proteinuria and rapidly progressive renal failure may have renal injury not related to classic immune complex-mediated LN but as a result of a podocytopathy, such as CG. The emerging association between CG and SLE should be recognized for additional characterization. Therefore, kidney biopsy is useful for the definitive diagnosis and findings of prognostic value in these patients.
Disclosures
None.
Acknowledgments
The authors thank Drs. Satish Arora, James Chevalier, Vanita Jassal, Odler Jeanlouie, Valerie Johnson, Joshua Kaplan, Kyriakos Kirou, Kameswari Lakshmi, C. Bruce Murdock, James Najarian, Kotresha Neelakantappa, Chike Okechukwu, Rodolfo Ortiz, Eduardo Perelstein, Alluru Reddi, Nathan Thompson, Kevin Vitting, Joseph Weisstuch, and Joan Wither for providing the clinical information.
This study was presented in part at the American Society of Nephrology Renal Week, November 16–21, 2010, Denver, Colorado.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
See related editorial, “Collapsing Glomerulopathy in Systemic Lupus Erythematosus: An Extreme Form of Lupus Podocytopathy?,” on pages 878–880.
- Received November 18, 2011.
- Accepted March 6, 2012.
- Copyright © 2012 by the American Society of Nephrology
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