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Clinical Transplantation


Meehan, Shane M.2,3; Pascual, Manuel4,5; Williams, Winn W.4,5; Tolkoff-Rubin, Nina4,5; Delmonico, Francis L.4,6; Cosimi, A. Benedict4,6; Colvin, Robert B.3

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Collapsing glomerulopathy (CG*) is a recently described clinicopathologic entity that is regarded as a distinct variant of focal segmental glomerulosclerosis (FSGS) (1). CG is characterized pathologically by segmental or global glomerular capillary collapse, podocyte hypertrophy and hypercellularity, and prominent tubular and interstitial injury. CG is characterized clinically by massive proteinuria and rapidly progressive renal failure. CG was initially described by Weiss et al.(2) in six patients with diffuse glomerular collapsing lesions, tubulointerstitial damage, nephrotic syndrome, and rapid progression to renal failure. A morphologically similar lesion has been described in human immunodeficiency virus (HIV) nephropathy, in which the lesion is frequently associated with the nephrotic syndrome (3). Recent studies suggest an increase in incidence of FSGS that is, in part, due to an increase in the incidence of CG since the late 1970s (4, 5). The pathogenesis of CG is unknown.

CG is known to recur in allografts (1, 6) and de novo CG has been rarely noted (6). We noted several cases in our recent renal transplant biopsies, which prompted us to review our entire experience since 1978. This report describes the pathologic and clinical features of five recent renal allografts with de novo CG.


Allograft tissues with a diagnosis of FSGS were selected from a review of all renal allograft material received from 1978 to 1996. The diagnostic pathologic criteria for CG were diffuse or focal, global or segmental glomerular capillary collapse and hypercellular podocytes, with or without periodic acid-Schiff (PAS)-positive cytoplasmic droplets. Glomerular hyaline, foam cells, adhesions to Bowman's capsule, and increased mesangial matrix were not prominent features. Fifteen to 25 sections, stained by hematoxylin and eosin and PAS, were examined by light microscopy for each tissue specimen. Histologic features were graded (ranked) as 0=none, 1+=mild, 2+=moderate, and 3+=severe. Frozen sections were examined by direct immunofluorescence for IgG, IgM, IgA, C3, fibrin/fibrinogen-related antigens, and albumin. Selected glomeruli were sampled and examined by transmission electron microscopy.

The clinical data was obtained from a review of the patients' medical records. Details recorded were age, sex, race, primary disease leading to end-stage renal failure, source of allograft, donor characteristics (age, race, sex, disease), history of risk behavior for HIV infection, severity of proteinuria, and allograft dysfunction. Immunosuppressive therapy, other medications, rejection episodes, cytomegalovirus infection, and cyclosporine toxicity were also documented. Statistical analyses were performed using the Wilcoxon ranked sum test for nonparametric data.

The number of renal allografts transplanted in the period of study was 1079. A total of 892 allograft biopsies performed during this period were distributed as follows: 1978-1982: 213; 1983-1987: 188; 1988-1992: 270; and 1993-1996 (July): 221.


Twenty-three renal allograft biopsies with FSGS were identified. Ten cases were de novo FSGS, of which five were CG and five were classical FSGS without features of CG. The remaining 13 cases were recurrent FSGS, of which 2 were recurrent CG and 11 were classical FSGS.

Frequency. The frequency of all FSGS cases (combined de novo and recurrent) was 1.4%, 1.5%, 2.2%, and 5.4%, respectively, for these periods. No allografts had CG in the period before 1993. Since 1993, 3.2% of allograft biopsies have had CG (five de novo, two recurrent) and thus the increase in frequency of FSGS is explained by the appearance of CG (Fig. 1).

Figure 1
Figure 1:
Percentage of renal allograft biopsies per 5 year period since 1978 with classical FSGS and CG. *The totals include both de novo and recurrent disease.

Histology of de novo CG in the renal allograft. Detailed histologic features of de novo CG are given in Table 1 and are contrasted with de novo classical FSGS in Table 2. Each biopsy with CG contained six or more glomeruli (range, 6-21). All biopsies had one or more glomeruli (14-100%) with segmental or global loss of capillary patency associated with swollen, markedly hypercellular podocytes in the collapsed areas. The segmental lesions demonstrated no predilection for the vascular poles or glomerular tips. The podocytes in the collapsed areas had nuclear enlargement, basophilic prominent nucleoli, and swollen cytoplasm often containing PAS-positive droplets. Parietal epithelium could be distinguished from the swollen visceral epithelium. These epithelia were, in most instances, separated from each other by Bowman's space. Globally collapsed glomeruli had a globular solidified appearance with mild to moderate increase of mesangial matrix, few remaining patent capillaries, and capped podocytes. Others had separated glomerular segments with collapsed capillaries and minimal or no increase in mesangial matrix with abundant visceral epithelial cells surrounding the collapsed segments (Fig. 2). Mesangiolysis or adhesion of glomerular tufts to Bowman's capsule was not seen.

Table 1
Table 1:
Histology of de novo collapsing glomerulopathy
Table 2
Table 2:
Comparative histology of de novo CG and FSGS
Figure 2
Figure 2:
De novo CG in a renal allograft with segmental collapse of the glomerular tuft and prominent, hypercellular visceral epithelium (PAS,×400).

The juxta-glomerular apparatus was prominent in three biopsies (cases 1, 2, and 3) of allografts in diabetic recipients who had moderate to severe hyaline arteriolosclerosis with lumenal narrowing. Two of these allografts (cases 1 and 2) were obtained from the same donor, who was a 53-year-old hypertensive man. Moderate to severe large arterial intimal fibrosis was seen in three of five cases. Diffuse interstitial fibrosis, involving more than 50% of the cortex with accompanying tubular atrophy, was present in four cases, and the fifth case had patchy fibrosis with approximately 5% tubular atrophy. One sample had mononuclear infiltrates in >50% of the cortex with multiple foci of tubulitis, sufficient for the diagnosis of acute cellular rejection. Four other samples had mononuclear infiltrates in 2-10% of the cortex with only rare foci of tubulitis.

The light microscopic features of tissue specimens from five patients with classical de novo FSGS (without features of CG) are presented inTable 2. These glomeruli had conspicuous adhesions to Bowman's capsule, and capillary loop hyaline accumulation was prominent in foci with a loss of capillary patency. PAS-positive cytoplasmic droplets were present in the podocytes of only one case. Moderate hyaline arteriolosclerosis was present in one case, and arterial intimal fibrosis and lumenal narrowing were evident in three cases. Interstitial fibrosis with tubular atrophy involved >50% of the cortex in one case and 5-40% in four cases. Two de novo FSGS diagnosed 23 and 30 months after transplantation had prominent adhesions of the sclerosed segments and hyaline accumulation and were thus distinguishable from the CG lesions.

Immunofluorescence. The five specimens with CG revealed focal broad irregular staining in the involved glomerular segments for IgM and C3 in four cases. Two cases had evidence of immune complex deposition. One case had diffuse granular deposits of IgG, IgM, and C3 along the glomerular basement membrane in a pattern typical of membranous nephropathy, which was recurrent. The other had diffuse granular staining for IgM (most intense), IgG, IgA, and C3 in the mesangium and segmentally along the capillary loops consistent with an immune complex glomerulopathy (the primary disease was IgA nephropathy). The classical FSGS cases had segmental broad staining of the sclerotic segments for IgM and C3. Other stains (IgG, IgA, fibrin) were negative. One case had diffuse segmental granular deposits of IgG and C3 along the capillary loops.

Electron microscopy. The five CG cases demonstrated podocyte microvillous changes, segmental to global effacement of the foot processes with condensation of intermediate filaments in effaced areas and cytoplasmic swelling. Many podocytes had cytoplasmic vesicles containing electron dense or lucent material. The podocytes were separated segmentally from the GBM in two cases with laminated new basement formation. The GBM was segmentally wrinkled and had focal areas of duplication with cytoplasmic debris admixed with fibrils of the newly formed basement membrane and foci of cellular interposition in four of five cases. The endothelial cells had reactive changes, many exhibiting loss of the fenestrae in collapsed glomerular capillaries. Dense deposits were present in two cases. One had subepithelial and mesangial deposits indicative of recurrent membranous nephropathy (case 4). One had diffuse mesangial and segmental subendothelial deposits and tubuloreticular structures in endothelial cells (case 5).

Three of the de novo classical FSGS cases had glomeruli examined by electron microscopy and demonstrated wrinkling and segmental duplication of the glomerular basement membrane and extensive effacement of the foot processes. The case with granular IgG by immunofluorescence had segmental scattered subepithelial electron dense deposits indicative of de novo membranous nephropathy.

Clinical features of CG(Table 3). The recipients with CG were 31-66 years old; four were men and one was a woman. Two were white, two were African-American, and one was Hispanic. The primary diseases leading to end-stage renal failure were insulin-dependent diabetes mellitus (three patients), membranous nephropathy (one patient), and IgA nephropathy (one patient); all received cadaveric allografts. All of the patients had significant proteinuria (1.8-11.8 g/24 hr) and progressive decline in allograft function; three had nephrotic syndrome. The time from transplantation to diagnosis ranged from 6 to 25 months. All of the patients received standard triple immunosuppression with cyclosporine, prednisone, and azathioprine. All were entered in a randomized clinical trial of anti-intercellular adhesion molecule (ICAM) monoclonal antibody therapy, which was received by four (patients 1, 3, 4, and 5) at a dose of 60 mg intravenously on day 1 and 40 mg intravenously daily from days 2 through 6 after transplantation. Three had previous acute cellular rejection episodes treated with intravenous methylprednisolone (three pulses, 500 mg each); in two cases, OKT3 therapy was given. All patients and donors were negative for HIV infection before transplantation. Two patients were retested at the time of biopsy diagnosis and were negative.

Table 3
Table 3:
Clinical features of de novo collapsing glomerulopathya

Patients have been followed up from 6 to 30 months since the diagnosis of CG. All five patients have developed end-stage allograft failure within 24 months due to CG. Symptoms of HIV infection have not been detected in any of the patients.

No specific donor characteristics (age, sex, race, or cause of death) distinguished the CG from the de novo FSGS group. However, cases 1 and 2 received kidney transplants from the same donor, which suggested the possibility of transmission of donor disease. Biopsies of these allografts less than 1 month after transplantation revealed no evidence of CG, thus it is improbable that the CG was transmitted from the donor, unless in a latent state. The contralateral donor kidneys of cases 3, 4, and 5 have excellent function and CG has not been detected.

The de novo classical FSGS cases presented between 23 months and 10 years after transplantation, with progressive decline in renal function as the indication for biopsy. None presented with the nephrotic syndrome but all had proteinuria (1+ to 3+; 24-hr was not performed). Three patients received standard triple immunosuppression (cyclosporine, prednisone, and azathioprine) and two patients received prednisone and azathioprine only. At follow-up, three patients (cases 2, 3, and 5) had died within 1 year (two of myocardial infarction and one of sepsis). One allograft with de novo membranous nephropathy progressed to end-stage allograft failure with nephrotic syndrome and was removed 3 months after the biopsy. The remaining allograft was lost because of rejection 1 year after the diagnosis of FSGS.

The median time to diagnosis was significantly different between the CG and FSGS groups (17 vs. 96 months, P=0.016). There were no differences in numbers of rejection episodes, immunosuppressive therapy (apart from anti-ICAM, as above), or episodes of delayed graft function between the groups, although the small numbers do not permit adequate analysis of these variables.


This report describes the occurrence of CG in renal allografts as a de novo phenomenon. The five de novo CG cases presented 6 to 25 months after transplantation with proteinuria, ranging from 1.8 to 11.8 g/24 hr, and had rapidly progressive allograft impairment. De novo CG lacked the scarring pattern of de novo FSGS and showed no predilection for inner or outer cortical glomeruli. Arterial intimal fibrosis and hyaline arteriolosclerosis were present in four of the five cases, and two of these received cadaveric allografts from the same donor, who had mild hyaline arteriolosclerosis. On biopsy 25 months later, the arteriolar changes had progressed and were associated with CG and interstitial fibrosis. However, it is notable that the contralateral donor kidneys of the other three CG cases have not demonstrated any evidence of CG.

All of the patients with CG received cyclosporine and had prominent hyaline arteriolosclerosis, raising the possibility of a role for cyclosporine toxicity in the genesis of CG. Cyclosporine-related FSGS has been described in allografts, arising 1.5-3 years after transplantation, associated with arteriolopathy (7). Glomerular capillary collapse and segmental sclerosis have also been described at autopsy in native kidneys of heart and bone marrow transplant recipients treated with cyclosporine(8). Morozumi et al. (9) described focal and segmental glomerulosclerosis with glomerular capillary microthrombi, prominent podocytes, and hyaline arteriolosclerosis in biopsies obtained 6-53 months after transplantation in patients receiving cyclosporine. Four of five patients had proteinuria and all but one had stable graft function on follow-up 12 months later, in contrast to the rapid and irreversible decline of allograft function in five of five patients reported here.

In view of the prominent arterial and arteriolar narrowing, glomerular capillary collapse and wrinkling of the glomerular basement membrane, it is tempting to ascribe a role for ischemia in the pathogenesis of this process. Fourteen of 16 patients (87.5%) with CG affecting the native kidney had sclerotic changes in arteries and arterioles, ranging from mild to severe(1). Arteriosclerosis was identified in 27 of 43 cases(63%) in another study of CG (4). Mild arterio- and arteriolosclerosis was described in HIV nephropathy with CG(3). It is of interest that a morphologically identical glomerular lesion, termed the cellular variant of FSGS, has recently been reported in native kidneys with cholesterol atheroembolic disease(10). It seems that this distinctive lesion was present in areas of ischemic glomerular collapse. These studies, together with our observations, suggest that CG may be a peculiar response to direct glomerular injury from ischemia, possibly aggravated by cyclosporine administration.

It is evident, however, that arterio- and arteriolosclerosis are much more prevalent than CG, and therefore other factors, as yet undetermined, play a pathogenetic role in the development of this lesion. The most striking glomerular abnormality in this study was hypercellularity of the visceral epithelium evident in all of the CG cases. There was evidence of podocyte injury with cytoplasmic swelling, foot process effacement, and microvilli, by electron microscopy. Kidney biopsies taken soon after the onset of FSGS showed hypercellularity of the visceral epithelium in the native kidney(11) and in recurrent FSGS in renal allografts(12, 13). This occurs with minimal morphologic evidence of glomerular injury and suggests that primary injury of the podocyte may be important in the pathogenesis of FSGS. Cytoskeletal injury, redistribution of integrins, and loss of cell-matrix adhesion in areas of podocyte hypercellularity have been described in recurrent FSGS(14). Thus, it is possible that podocyte injury with cytoskeletal disruption results in the loss of a supporting framework for the capillary loops, and when combined with ischemia, may have additive effects in the genesis of capillary collapse.

Because of the morphologic similarity of CG to the glomerulopathy of HIV nephropathy, careful exclusion of HIV was indicated. All of the patients were serologically negative and none had known risk behavior for HIV infection. None of the four patients for whom there is available follow-up, have developed HIV infection. Notably, all of the cases presented since 1993. Allograft biopsies with FSGS obtained between 1978 and 1993 were carefully reviewed and no examples of CG were identified. Hence, nonrecognition of a newly described entity does not explain the lack of occurrence of this lesion in allografts before 1993. Although this is a small case series, the number of cases of CG identified since 1993 has exceeded that of de novo classical FSGS in allografts. This suggests a new etiologic agent. Four of five patients received anti-ICAM induction therapy, raising the possibility that this monoclonal antibody contributed to the development of the glomerulopathy. However, patient 1 received anti-ICAM and patient 2 did not, yet both received kidneys from the same donor and presented at the same time after transplantation, indicating that the anti-ICAM monoclonal antibody could not be solely responsible for this glomerulopathy. In addition, one of us has observed two further examples of this lesion in renal allografts that occurred in patients who never received anti-ICAM. Other possible contributing factors are (i) an infectious agent or (ii) the use of older donors. The possibility that combinations of these factors contributed to the development of these glomerular abnormalities is not excluded and requires further study.

The presence of CG with immune complex deposits in two of our cases with recurrent immune complex disease in the allograft indicates that CG may be associated with other forms of glomerulonephritis. One of these cases had prominent endothelial tubuloreticular structures and the patient was HIV negative on initiation of hemodialysis 2 years after biopsy. Their significance, if any, in this context is unknown. One study identified intraendothelial tubuloreticular structures in 36% of allograft biopsies(15). A form of CG and concomitant immune complex deposition has also been described in the native kidney of an HIV-negative patient with membranous nephropathy and tubuloreticular structures in endothelial cells (16).

Two recipients were African American, of whom one had end-stage renal failure due to diabetic nephropathy and one had membranous nephropathy, which recurred in the graft. African Americans account for 7% of allograft recipients in the population studied. Two of five (40%) of the de novo CG patients were African American, a proportion that may be exaggerated due to the small numbers in this study. Others have noted black racial predominance in patients with CG. Whether this reflects differences in proportions of African Americans in the patient populations studied is uncertain(1, 6).

De novo FSGS has been described in allografts with the onset of proteinuria between 4 months and 2 years after transplantation (17) without features of CG. The glomerular morphology was characterized by the presence of hyaline, segmental adhesions to Bowman's capsule, wrinkling and splitting of the glomerular basement membrane, and mesangial expansion. These changes were most striking in the outer cortical glomeruli and were associated with “obliterative arteriopathy” (17). Progressive decline in allograft function was also observed, however, most of the early graft losses were due to acute rejection and not to progressive FSGS. Two of our de novo FSGS cases also presented 23 and 30 months after transplantation and the other three cases presented more than 5 years after transplantation. It is evident that these lesions are clinically and histologically distinct from de novo CG.

In conclusion, CG can occur as a de novo disease in the renal allograft and has a poor prognosis. Significant arterial and arteriolar narrowing suggests that glomerular ischemia, possibly aggravated by cyclosporine, may be important in the development of this form of glomerular injury. Therefore, although the origin and the pathogenesis of the lesion are uncertain, its recognition in allograft biopsies is important, as it is a lesion with a high risk for rapid progression to graft failure.

Acknowledgments. The authors thank Mary Lin Farrell and Cheryl Nason for their help in the preparation of the manuscript.


1. Detwiler RK, Falk R, Hogan S, Jennette JC. Collapsing glomerulopathy: a clinically and pathologically distinct variant of focal segmental glomerulosclerosis. Kidney Int 1994; 45: 1416.
2. Weiss M, Daquioag E, Margolin E, Pollak V. Nephrotic syndrome, progressive irreversible renal failure and glomerular“collapse”: a new clinicopathologic entity? Am J Kidney Dis 1986; 7: 20.
3. D'Agati V, Suh J, Carbone L, Cheng J, Appel G. Pathology of HIV-associated nephropathy. Kidney Int 1989; 35: 1358.
4. Valeri A, Barisoni L, Appel G, Seigle R, D'Agati V. Idiopathic collapsing focal segmental glomerulosclerosis: a clinicopathologic study. Kidney Int 1996; 50: 1734.
5. Haas M, Spargo B, Coventry S. Increasing incidence of focal-segmental glomerulosclerosis among adult nephropathies: a 20 year renal biopsy study. Am J Kidney Dis 1995; 26: 740.
6. Detwiler RK, Hogan S, Falk R, Jennette JC. Collapsing glomerulopathy in renal transplant patients: recurrence and de novo occurrence. J Am Soc Nephrol 1996; 7: 1331A.
7. Takeda A, Morozumi K, Uchida K, et al. Is cyclosporine-associated glomerulopathy a new glomerular lesion in renal allografts using CyA? Transplant Proc 1993; 25: 515.
8. Nizze H, Mihatsch M, Zollinger H, et al. Cyclosporine-associated nephropathy in patients with heart and bone marrow transplants. Clin Nephrol 1988; 30: 248.
9. Morozumi K, Yoshida A, Suganuma T, et al. Morphological analysis of glomerular lesions in renal transplants immunosuppressed with cyclosporine A (CYA): has CYA induced a new transplant glomerular lesion? Transplant Proc 1989; 21: 282.
10. Greenberg A, Bastacky S, Iqbal A, Borochovitz D, Johnson J. Focal segmental glomerulosclerosis associated with nephrotic syndrome in cholesterol atheroembolism: clinicopathologic correlations. Am J Kidney Dis 1997; 29: 334.
11. Schwartz M, Lewis E. Focal segmental glomerular sclerosis: the cellular lesion. Kidney Int 1985; 28: 968.
12. Verani R, Hawkins E. Recurrent focal segmental glomerular sclerosis. Am J Nephrol 1986; 6: 263.
13. Korbet S, Schwartz M, Lewis E. Recurrent nephrotic syndrome in renal allografts. Am J Kidney Dis 1988; 11: 270.
14. Kemeny E, Mihatsch M, Durmuller U, Gudat F. Podocytes lose their adhesive phenotype in focal segmental glomerulosclerosis. Clin Nephrol 1995; 43: 71.
15. Bariety J, Richer D, Appay M, Grossette J, Callard P. Frequency of intraendothelial “virus-like” particles: an electron microscopic study of 376 human renal biopsies. J Clin Pathol 1973; 26: 21.
16. Shimamura T, Walker J. A collapsing form of glomerulopathy. Pathol Int 1995; 45: 520.
17. Cheigh J, Mouradian J, Soliman M, et al. Focal segmental glomerulosclerosis in renal allografts. Am J Kidney Dis 1983; 2: 449.
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