Collapsing glomerulopathy in renal allografts: A morphological pattern with diverse clinicopathologic associations

Collapsing Glomerulopathy in Renal Allografts: A Morphological Pattern With Diverse Clinicopathologic Associations Michael Barry Stokes, MB, BCh, Connie L. Davis, MD, and Charles E. Alpers, MD ● We reviewed the clinical and pathological characteristics of seven patients with collapsing glomerulopathy (CG) in renal allograft biopsy specimens. All patients underwent biopsies for graft dysfunction. Two patients had nephrotic proteinuria (protein, G3.5 g/24 h), whereas all others had only modest or insignificant proteinuria. In five of seven patients, additional pathological processes, including microvascular injury, acute rejection, recurrent diabetic nephropathy, and immune complex glomerulonephritis, were present, each of which likely contributed to graft dysfunction and proteinuria. None of the patients in this series had nephrotic syndrome solely attributable to CG. Three biopsy specimens had features consistent with chronic rejection. The development of CG in renal allograft biopsy specimens was associated with graft dysfunction and a high rate of graft loss. These findings emphasize the prognostic significance of CG in renal allografts and suggest that CG may result from diverse pathogenic mechanisms. 娀 1999 by the National Kidney Foundation, Inc. INDEX WORDS: Collapsing glomerulopathy; focal and segmental glomerulosclerosis; transplantation.

Editorial, p. 801

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OLLAPSING glomerulopathy (CG) is a variant of idiopathic focal and segmental glomerulosclerosis (FSGS) characterized by heavy proteinuria, renal insufficiency, and rapid progression to end-stage renal disease (ESRD).1,2 CG is defined pathologically by global or segmental glomerular capillary collapse, visceral epithelial cell prominence, and extensive tubulointerstitial injury, including microcystic tubular dilatation.2 The frequency of CG among individuals undergoing native kidney biopsy has increased over the last two decades.3,4 Although the cause of CG is unknown, CG shares many clinical and pathological features with human immunodeficiency virus (HIV)-associated nephropathy (HIVAN), and there may be an etiologic role for viral infections other than HIV in the pathogenesis of CG.5,6 From the Department of Pathology and Division of Nephrology, University of Washington Medical Center, Seattle, WA. Received September 18, 1998; accepted in revised form October 30, 1998. M.B.S. is supported by a Quoc Le Memorial Fellowship in Renal Pathology at the University of Washington, Seattle, WA, and a training grant award from the National Kidney Foundation, New York, NY. Address reprint requests to Michael Barry Stokes, MB, BCh, Division of Hospital Pathology, University of Washington Medical Center, Box 356100, 1959 NE Pacific St, Seattle, WA 98195-6100. E-mail: [email protected]

娀 1999 by the National Kidney Foundation, Inc. 0272-6386/99/3304-0005$3.00/0 658

Both recurrent and de novo CG have been described in renal allografts with features similar to CG in native kidneys.5,7-10 We recently identified allograft CG in several individuals who underwent biopsies for graft dysfunction, some of whom had pathological or clinical features different from idiopathic CG in native kidneys, and describe their posttransplantation course. MATERIALS AND METHODS

Case Selection In a review of all renal biopsy specimens received at the University of Washington Medical Center (Seattle, WA) between 1988 and 1998, we identified pathological findings of CG in 19 biopsy specimens from 17 individuals (11 native kidney biopsy specimens, including one from a subject who subsequently developed allograft CG, and 8 allograft biopsy specimens from 7 transplant recipients). Subjects with a history of HIV infection and/or intravenous drug use were excluded from this study to avoid inclusion of possible cases of HIVAN. No cases of CG were identified before 1990. Six biopsy specimens originated from nephrology practices outside the University Medical Center. Clinical data were obtained from standardized physician referral forms submitted with the biopsy specimens, from the patients’ charts, and from follow-up correspondence with the referring physicians.

Pathological Analysis Renal biopsy tissue was processed for light microscopy, immunofluorescence microscopy, and electron microscopy by standard techniques as previously described.11 For light microscopy, tissue sections were stained with Jone’s methenamine silver stain, periodic acid–Schiff, and hematoxylin and eosin. CG was defined pathologically by segmental or global glomerulosclerosis with collapse or retraction of glomerular capillaries, prominence of visceral epithelial cells (caused by hyperplasia and/or hypertrophy), often with prominent cytoplasmic periodic acid–Schiff–positive droplets, but without appreciable increase of mesangial matrix,

American Journal of Kidney Diseases, Vol 33, No 4 (April), 1999: pp 658-666

COLLAPSING GLOMERULOPATHY IN ALLOGRAFTS

Fig 1. Case 3: Glomerulus showing features of global capillary collapse and prominence of visceral epithelial cells. (Jones’ silver methenamine silver stain counterstained with hematoxylin and eosin; original magnification ⴛ200.)

tuft adhesions to Bowman’s capsules, or accumulations of intracapillary hyaline material (Fig 1). Epithelial cell accumulation was distinguished from cellular crescent formation by the identification of Bowman’s space external to the cell accumulation, absence of intercellular matrix, and lack of spindled-cell morphological characteristics. All cases containing at least one glomerulus with features of global capillary collapse, as previously defined, were included; no other selection criteria were used. Glomeruli showing segmental or global obliteration of capillary lumina with adhesions to Bowman’s capsules, expansion of the intracapillary region by mesangial matrix, prominent foam cells, and accumulations of hyaline material were categorized as segmental sclerosis, non-CG type (Fig 2).

Fig 2. Case 3: Glomerulus showing features of segmental glomerulosclerosis, noncollapsing type. (Jones’ silver methenamine silver stain counterstained with hematoxylin and eosin; original magnification ⴛ200.)

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Some sclerotic glomeruli of non-CG type showed variable, usually mild, prominence of visceral epithelial cells. Interstitial fibrosis, interstitial inflammation, and tubular atrophy were each graded semiquantitatively on a scale of 0 to 3⫹ (involving ⬍5%, 5% to 25%, 25% to 75%, or ⬎75% of the cortical area, respectively). The presence or absence of intratubular mononuclear cells and multinucleated cells resembling macrophages was noted. For allografts, cellular (interstitial) rejection was identified by mononuclear inflammatory cell infiltrates in the interstitium with leukocyte infiltration of nonatrophic tubular segments (tubulitis) and was graded as mild, moderate, or severe, based on the extent of cortical involvement. Interstitial inflammation confined to areas of interstitial fibrosis and tubular atrophy was classified as of uncertain significance not clearly related to rejection.12 Acute vascular rejection was identified by subendothelial or transmural inflammatory cell infiltration of arterial walls, with or without fibrinoid necrosis.13 Intimal sclerosis in muscular arteries (arcuate-sized and proximal interlobular arteries) was defined by the presence of a neointima. Cyclosporine/tacrolimus arteriolopathy was diagnosed by the presence of hyaline lesions on the adventitial surface of arterioles. Hyaline lesions located predominantly in subendothelial locations of small arteries and arterioles were categorized separately and graded semiquantitatively 0 to 3⫹ (absent, mild, moderate, or severe). The number of glomeruli examined per case by immunofluorescence microscopy ranged from one to seven. The intensity of staining with immune reactants in mesangial areas and peripheral capillary walls was graded 0, ⫾, or 1 to 3⫹ (no staining, equivocal, weak, moderate, or strong). Immune-type electrondense deposits identified by electron microscopic examination were classified by their distribution in mesangial, paramesangial, subendothelial, or subepithelial locations.

RESULTS

The clinical characteristics of seven patients with allograft CG are listed in Table 1. There were five men and two women, with an average age of 37.6 years (range, 23 to 55 years). Five patients were white, one was black, and one was Hispanic (non-black). The causes of ESRD leading to transplantation included diabetes mellitus (two cases), membranous nephropathy (two cases), CG (one case), and lupus nephritis (one case). One patient, a 38-year-old white man, developed progressive renal insufficiency after radiotherapy and chemotherapy for a testicular tumor 10 years previously, but lacked a specific pathological diagnosis. One patient (no. 6) received a pancreas allograft several years previously, but this had failed and the patient had insulin-dependent diabetes for at least 2 years before undergoing a renal allograft biopsy. All seven transplant recipients underwent renal biopsies for evaluation of graft dysfunction (mean serum creatinine level, 5.14 mg/dL; range, 3.4 to

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STOKES, DAVIS, AND ALPERS Table 1. Clinical Data of Patients With Collapsing Glomerulopathy in Renal Allografts Patient No.

Age (yr)/ race/sex HIV/HCV Native kidney disease Time of biopsy (mos posttransplantation) Immunosuppression regimen Indication for biopsy

1

2

3

4

5

6

7

34/H/M

55/W/M

23/B/M

38/W/M

34/W/M

51/W/F

28/W/F

⫺/⫹ Diabetes

⫺/⫹ MN

⫺/⫺ CG

⫺/⫺ Unknown

⫺/⫺ MN

⫺/⫺ Diabetes

⫺/⫺ SLE

48

132

18

21

72

144

84

C, P

C, P, A

C, P

C, P, M

C, P, M

C, P, A

C, P

Acute graft Acute graft Chronic graft Chronic graft Acute graft Chronic graft Chronic graft dysfunction dysfunction, dysfunction dysfunction dysfunction dysfunction dysfunction nephrotic syndrome 4.5 5.4 4.9 4.4 9.4 3.4 4.0 (neg) 8.19 (neg) (⫹1) (⫹1) (⫹3) 3.5

SCr (mg/dL) UP (g/24 h; dipstick analysis) Hypertension ⫺ Follow-up Lost (mos postbiopsy) Outcome HD

⫹ 16

⫹ 3

HD

⫺ 3

⫹ 3

⫺ 4

⫹ 3

HD

HD

HD

Abbreviations: H, Hispanic; W, white; B, black; C, cyclosporine; CG, collapsing glomerulopathy; P, prednisone; A, azathioprine; M, mycophenolate mofetil; SCr, serum creatinine; UP, urinary protein excretion; HIV, human immunodeficiency virus; HCV, hepatitis C virus; MN, membranous nephropathy; HD, hemodialysis; SLE, systemic lupus erythematosus; neg, negative; ⫺, absent; ⫹, present; mos, months.

9.4 mg/dL) that developed acutely (days to weeks) in three individuals and more gradually (months) in the others. The mean time from transplantation to biopsy was 74.1 months (range, 18 to 144 months). One patient (no. 2) had nephrotic syndrome (proteinuria of 8.19 g/d, edema, and hypoalbuminemia). One other patient (no. 7) had nephrotic-range urinary protein excretion, and one patient had 3⫹ proteinuria by dipstick analysis (quantified at 620 mg/dL); neither of these two individuals had other features of nephrotic syndrome. Two patients had 1⫹ dipstick proteinuria and two patients had no proteinuria by dipstick analysis. Four patients had hypertension, which was long standing (ranging from months to years) in all cases and was controlled using a combination of beta-adrenergic receptor antagonists, calcium channel blockers, and/or thiazide diuretics. None had clinical signs of malignant hypertension. None had clini-

cal or radiological evidence of urinary reflux. Two individuals had systemic prodromal symptoms before biopsy; one patient had a 2-week history of myalgia, fatigue, and dry cough, and the other had flu-like symptoms after a recent trip abroad. Immunosuppressive therapy consisted of cyclosporine and prednisone (n ⫽ 7) with mycophenolate mofetil (n ⫽ 2) or azathioprine (n ⫽ 2). Serological tests for HIV infection were negative in all. Two patients had hepatitis C viral infection identified by serum enzyme-linked immunosorbent assay for circulating antibodies, but the time of infection could not be determined. Test results for circulating cryoglobulins and serum complement levels were normal in the one patient (no. 2) who was tested. One patient, a black man, presented with nephrotic syndrome and renal insufficiency when he was 18 years of age. Review of the native renal biopsy specimen confirmed the diagnosis of CG. This patient underwent living related

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renal transplantation, complicated by an episode of acute cellular rejection (without vascular rejection) that responded to therapy with polyclonal antithymocyte globulin. One year posttransplantation, the patient developed severe hypertension, dipstick proteinuria (1⫹), and a progressive increase in serum creatinine level that led to an allograft biopsy 18 months posttransplantation. Dipstick urinalysis at the time of biopsy disclosed no evidence of proteinuria. One other transplant recipient (no. 7) also had a history of acute rejection, which was treated successfully with OKT3. Pathological findings are listed in Table 2. Two biopsy specimens, separated by an interval of approximately 1 month, were examined from one individual (no. 2A and 2B). The average number of glomeruli examined per biopsy specimen was 18 (range, 4 to 33 glomeruli). All biopsy specimens showed globally collapsed glomerular capillaries (6% to 29% of nonglobally

sclerosed glomeruli) with adjacent visceral epithelial cell prominence (Fig 1). Of note, in four cases, the diagnosis of CG was made on the basis of findings in one or two glomeruli only, emphasizing the focal distribution of this lesion. In two cases, there were also some glomeruli in which capillary collapse was evident only in some segments of the tuft, whereas other segments maintained a normal architectural appearance. Six biopsy specimens also contained globally or segmentally sclerotic glomeruli without features of collapse (Fig 2). In one biopsy specimen (no. 2B), three of five nonsclerotic glomeruli (without features of collapse) showed prominent intracapillary leukocytes and foci of possible endothelial cell necrosis. Features of mesangial hypercellularity, mesangial cell interposition in peripheral capillary walls, and silver positive spike formation in peripheral capillary walls were not identified in this case. In one biopsy specimen (no. 6), many nonsclerotic glomeruli showed

Table 2. Pathological Findings in Patients With CG in Renal Allografts Patient No.

1

Light microscopy No. of glomeruli Global collapse (%) Segmental collapse (%) Global sclerosis (%) Segmental sclerosis (%) Transplant GN Other glomerular injury Interstitial fibrosis/atrophy Interstitial rejection Vascular rejection Hyalinosis Intimal sclerosis Previous allograft biopsy findings Immunofluorescence microscopy Electron microscopy

4 25 25 – – – – 2⫹ – – 2⫹ 3⫹r – 2⫹ IgM, C3 nd

2 (a)*

33 25† – 50 – – TMA 2⫹ – – 3⫹ 3⫹

nd nd

2 (b)*

17 20† – 50 – – ICGN 2⫹ – – 3⫹ 3⫹r see (a) 3⫹ IgG, C3, diffuse EVEC, EDD

3

4

19 20† – 10 5 – – 3⫹ – – – ns ACR

15 20† 10† 33 12

3⫹ IgM, C3 EVEC

1-2⫹ IgM, C3 nd

– – 2⫹ – – 2⫹c ns –

5

16 6 – – – – – 1⫹ 2⫹ – 1⫹ ns NER nd FVEC

6

7

12 29† – 42 – – DN 2⫹ – – 2⫹ 2⫹r –

7 20† – 40 30 – – 2⫹ – – 2⫹ ns ACR

–

–

nd

nd

NOTE. See text for definitions of corresponding semiquantitative scores. Abbreviations: Transplant GN, transplant glomerulopathy; ICGN, immune complex glomerulonephritis; DN, diabetic nephropathy; c, cyclosporine arteriolopathy; TMA, thrombotic microangiopathy; ACR, acute cellular rejection; NER, no evidence of rejection; EDD, capillary wall immune-type electron-dense deposits; EVEC, extensive effacement of foot processes; FVEC, focal effacement of foot processes; ⫺, negative or not found; nd, not done; ns, no muscular arteries sampled; r, concentric intimal hyperplasia. *Patient no. 2 had biopsy specimens (a) and (b) submitted 1 month apart. †Percent of nonglobally sclerotic glomeruli.

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diffuse mesangial expansion, predominantly caused by increased matrix, that focally had a nodular configuration. These findings were associated with capillary microaneurysm formation, accumulations of hyaline, and severe arteriolar hyalinosis, consistent with diabetic nephropathy. No biopsy specimen showed other light microscopic features of transplant glomerulopathy, such as splitting of peripheral capillary walls. All biopsy specimens showed variable, generally moderate, interstitial fibrosis and tubular atrophy associated with patchy interstitial mononuclear inflammatory cell infiltrates, but without clearcut tubulitis. Only one biopsy specimen (no. 5) showed features diagnostic of acute cellular (interstitial) rejection. In no case was the degree of tubular injury disproportionate to the degree of accompanying interstitial fibrosis or interstitial inflammation. In particular, features of microcystic tubular dilatation, epithelial simplification, nuclear atypia, and mitoses were not identified. Intraluminal mononuclear and small syncitia of cells with indistinct cell borders that possibly contained multinucleated cells were identified in six biopsy specimens (from five patients). Focally, these cells could be seen making contact with the luminal surface of tubular epithelial cells. Many of these cells had abundant cytoplasm that frequently contained lipid inclusion droplets. These cells were focally numerous, but there was no discernible correlation between the presence of such cells and the degree of accompanying tubular epithelial cell injury. Concentric intimal sclerosis of muscular arteries was present in three of four biopsy specimens in which these arteries were sampled; muscular arteries were not well sampled in the other three biopsies. Arteriolar hyalinosis was present in six biopsy specimens (from five patients); in five cases, this was moderate to severe. One biopsy specimen (no. 4) had features characteristic of cyclosporine arteriolopathy. No biopsy specimen showed other features of cyclosporine toxicity, such as striped interstitial fibrosis or isometric vacuolization of tubular epithelia. Viral inclusions were not identified in glomeruli or other parenchymal structures in any case. Immunofluorescence microscopy showed focal, segmental, predominantly mesangial glomerular staining for immunoglobulin M (IgM) and C3 in three cases, and widespread granular

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capillary wall staining for IgG and C3 in one biopsy specimen (no. 2B; Fig 3). No detectable glomerular deposits were identified in two cases, and no glomeruli were identified in cryosections of the remaining biopsy specimens. Electron microscopy was performed in all three cases in which diagnostic tissue was available; thick sections showed no glomeruli in three cases, and no tissue was submitted for ultrastructural studies in one case. One biopsy specimen (no. 2B) showed numerous immune-type electron densities in peripheral capillary walls in subendothelial and subepithelial locations, corresponding to the deposits of IgG and C3 identified by immunofluorescence microscopy (Fig 4). Endothelial cell tubuloreticular inclusions were not identified in this or any other case. Visceral epithelial cell foot processes were extensively effaced in two cases and focally effaced in one case. The biopsy specimen (no. 2B) with evidence of immune complex deposition showed an unusual combination of glomerular histological features that precluded classification by standard diagnostic schema. This patient had a native kidney diagnosis of membranous nephropathy, but diagnostic material from the native renal biopsy was not available for review. A previous biopsy performed 1 month earlier (no. 2A) showed light microscopic features of CG with

Fig 3. Case 2B: Electron microscopy shows immune-type electron-dense deposits in peripheral capillary walls in subendothelial (arrows), subepithelial, and intramembranous locations (arrowheads), corresponding to the immune complex deposits identified by immunofluorescence microscopy. (Original magnification ⴛ3,200.)

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663

hepatitis C–associated glomerular disease, such as cryoglobulinemia and hypocomplementemia, at the time of biopsy. Follow-Up Five patients returned to dialysis at the time of biopsy or shortly thereafter (at 0, 3, 3, 3, and 4 months). One of these patients was subsequently lost to follow-up. The other two patients had persistent elevated serum creatinine levels (4.0 and 3.6 mg/dL) at last follow-up (3 and 16 months, respectively). The same immunosuppressive regimen was maintained in both these individuals, with a reduction in cyclosporine dose in patient no. 4, in whom the biopsy specimen showed features of cyclosporine arteriolopathy. Fig 4. Case 2B: Direct immunofluorescence microscopy for IgG showing fine granular capillary wall staining for IgG. (Original magnification ⴛ250.)

additional findings of thrombotic microangiopathy. Diagnostic tissues for immunofluorescence microscopy and electron microscopy were not submitted for this case for this earlier biopsy. Although it was not possible to entirely exclude recurrent immune complex glomerulonephritis (ICGN) in this case, the likelihood of recurrent disease presenting 11 years after transplantation appears remote. It is difficult to assess a possible pathogenic role for hepatitis C viral infection in this case given the uncertainty about the time of infection and the lack of other typical features of

DISCUSSION

Idiopathic CG, defined in biopsy studies of native kidneys, is characterized by preceding or concurrent systemic illness, a predilection for black populations, severe proteinuria, and a high rate of progression to ESRD.1,2,4 Both recurrent and de novo CG with features similar to these have been described in allograft recipients (Table 3), usually presenting within 25 months after transplantation.5,7-9 The mean time until diagnosis of allograft CG of 74 months in this study indicates that CG may also be a late complication of renal transplantation. None of these seven individuals had nephrotic syndrome that was clearly related to CG, distinct from the usual

Table 3. Selected Findings of Published Cases of CG in Renal Allografts

No. of Cases

Months Post-tx to Diagnosis of CG

Urinary Protein (g/24 h)

5 7 8

1 de novo 1 recurrent 7 de novo, 3 recurrent

2 6 1-48

NS 14.0 ‘‘all had NS, worsening renal function, or both’’

9

5 de novo

6 15 17 25 25 4

11.8 7.6 9.5 1.8 5.3 8.9

Reference

10

1 recurrent

Outcome

Other Findings

ESRD n/a 8 ESRD

B19 infection

ESRD ESRD ESRD ESRD ESRD ESRD

Recurrent MN ICGN ACR

Abbreviations: NS, nephrotic syndrome; ICGN, immune complex glomerulonephritis; n/a, not available; ESRD, end-stage renal disease; MN, membranous nephropathy; ACR, acute cellular rejection; B19, human parvovirus B19 infection; tx, transplantation.

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presentation of CG in native kidneys. Several biopsy specimens showed additional pathological findings that probably contributed to graft dysfunction and subsequent graft loss. These findings extend the clinicopathologic associations of CG in renal allografts and suggest that this pattern of glomerular injury may result from diverse pathogenic mechanisms. Previous reports of allograft CG have shown similarities with idiopathic CG in native kidneys, namely the frequent occurrence of nephrotic syndrome and rapid progression to ESRD.5,7-10 We present evidence of greater clinical and pathological heterogeneity in allograft CG than has previously been recognized. The lack of significant proteinuria in several of the cases described here might be related to the closeness of monitoring of renal function in transplant recipients, leading to renal biopsy before proteinuria has time to develop. Alternatively, there may be a role for immunosuppressive drugs in modulating the clinical expression of CG in these individuals. Interestingly, one patient (no. 3) with clinical and pathological features of typical idiopathic CG in his native kidney subsequently developed allograft CG, leading to graft loss, in the absence of significant proteinuria. The cause and pathogenesis of idiopathic CG are unknown. The many clinical and pathological similarities with HIVAN suggest a possible role for viral infection in some cases. Recently, Moudgil et al6 identified human parvovirus B19 DNA in the kidney tissue of individuals with CG and reported the development of CG in one allograft recipient with active B19 infection.5 Two patients with allograft CG in our study had prodromal symptoms suggestive of a recently acquired infection, but none had other clinical features suggestive of B19 infection, such as hypoplastic anemia, and diagnostic testing for this infection was therefore not performed. Meehan et al9 noted the high frequency of vascular abnormalities in CG and the morphological similarities to other forms of ischemic glomerular injury and proposed that CG may be a peculiar response to direct glomerular injury from ischemia. Five cases in our study had features of moderate to severe microvascular injury that may have been related, in individual cases, to thrombotic microangiopathy, cyclosporine toxicity, and recurrent diabetic injury. Although it is

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difficult to attribute a pathogenic role to ischemic injury alone in individual cases of allograft CG, given the fact that similar vascular injuries are common in renal allograft biopsy samples and CG is not, these findings support a key role for ischemic injury in the pathogenesis of CG. Further support for a role for ischemia comes from studies of FSGS complicating large-vessel arterial disease. In a study of 24 patients with (native) renal biopsy findings of cholesterol atheroembolic disease, Greenberg et al14 identified FSGS in 15 patients, 10 of whom showed the cellular variant of FSGS (a glomerular lesion that morphologically resembles and may not always be distinguishable from CG15). The clinical presentation in patients with renal atheroembolic disease who had the cellular variant of FSGS was dominated by nephrotic proteinuria, followed by a slow progressive decline in renal function, distinct from the classic presentation of acute renal failure caused by massive cholesterol embolism. The pathogenesis of FSGS (and CG) in these cases might be related to ischemia or hyperfiltration injury in remnant glomeruli not affected by acute ischemic events.14 Idiopathic CG in native kidneys is frequently accompanied by the more usual, noncollapsing FSGS,4 supporting the interpretation that idiopathic CG may be a variant of primary FSGS. The cases described here extend this observation and suggest that CG in allografts may be a variant of secondary forms of FSGS. Regardless of the exact pathogenic mechanism involved in individual cases, these findings support the observation that CG may have broader clinicopathologic associations than has been previously recognized and strongly suggests a possible pathogenic role for ischemic injury in some cases of CG. A recently described, novel observation is the presence of intratubular cells expressing phenotypic markers of macrophages in CG and other glomerular diseases.16,17 The origin of these cells is unclear. They may be derived from the transformation of visceral epithelial cells that lose the usual phenotypic markers of podocyte differentiation and acquire macrophage-like characteristics, perhaps under the influence of a locally released humoral factor in glomerular disease states, and are subsequently shed into tubular lumina.16 This finding correlates with other indices of glomerular injury, such as the presence of

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crescents and the degree of hematuria, suggesting a possible pathogenic role in renal injury.17 The location of these cells, focally in contact with tubular epithelium, may indicate a role in mediating the tubulointerstitial injury that is probably largely responsible for the renal insufficiency and progression to renal failure in these individuals. We were unable to detect an association with the severity of tubulointerstitial injury in this small sample. Additional studies, including larger numbers of cases of CG (and other glomerular diseases) are required to determine the pathological significance of this finding. Graft dysfunction in some of the cases of allograft CG presented here could be related, at least in part, to concurrent pathological processes, including acute rejection, recurrent diabetic nephropathy, and ICGN. Although most reported cases of allograft CG have lacked evidence for recent or concurrent acute rejection (see Table 3), the possibility that allograft CG might be a manifestation of chronic rejection in some cases cannot be entirely excluded. We identified features typically associated with chronic graft failure (concentric intimal hyperplasia of medium-sized arteries) in three of four biopsy specimens that contained an adequate sample of artery. FSGS in allografts, associated with nephrotic syndrome, may be a manifestation or a consequence of rejection episodes.18,19 However, it may be difficult to assess the relative contribution of several possible causes of FSGS in renal allografts, including recurrent glomerular disease, reduction in renal mass, and hypertension. Immune complex deposition, identified in one biopsy specimen, is not a typical feature of idiopathic CG, although this association has been previously described.9,20 In one series of de novo allograft CG,9 two of five patients had ICGN, suggesting that this association may not be rare. The pathogenesis of ICGN in our patient could not be determined, and it was not possible to evaluate the respective contributions of ICGN and CG to the clinical presentation of nephrotic syndrome. We have also encountered three patients with CG in native kidneys (data not shown) in whom earlier biopsies showed ICGN (IgA nephropathy, membranous nephropathy, and lupus nephritis, World Health Organization class IV). The pathogenic relation of CG and ICGN in these cases is unclear; in particular, it is not

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possible to exclude the possibility of concurrent but independent injury processes. Nonetheless, these cases provide further evidence that CG may be a nonspecific consequence of severe glomerular injury resulting from diverse pathogenic pathways. Consideration of the clinical and pathological data presented here has led us to favor the interpretation that CG is a pathological marker of severe glomerular injury that may be related to diverse pathogenic mechanisms. CG in renal allografts may have a different clinical profile that includes, but is not restricted to, the distinct clinicopathologic entity of CG as it has been defined in biopsy studies of native kidneys.2,4 Regardless of the pathogenic mechanisms involved, the histopathological finding of CG in allograft kidneys, analogous to native kidneys, portends a poor renal outcome with frequent graft loss. REFERENCES 1. Weiss MA, Daquioag E, Margolin EG, Pollak VE: Nephrotic syndrome, progressive irreversible renal failure, and glomerular ‘‘collapse’’: A new clinicopathologic entity? Am J Kidney Dis 7:20-28, 1986 2. Detwiler RK, Falk RJ, Hogan SL, Jennette JC: Collapsing glomerulopathy: A clinically and pathologically distinct variant of focal segmental glomerulosclerosis. Kidney Int 45:1416-1424, 1994 3. 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 26: 740-750, 1995 4. Valeri A, Barisoni L, Appel GB, Seigle R, D’Agati V: Idiopathic collapsing focal segmental glomerulosclerosis: A clinicopathologic study. Kidney Int 50:1734-1746, 1996 5. Moudgil A, Shidban H, Nast CC, Bagga A, Aswad S, Graham SL, Mendez R, Jordan SC: Parvovirus B19 infection–related complications in renal transplant recipients: Treatment with intravenous immunoglobulin. Transplantation 64: 1847-1850, 1997 6. Moudgil A, Nast CC, Wei L, Toyoda M, Cohen AH, Jordan SC: Detection of parvovirus B19 DNA in renal biopsies of patients with idiopathic collapsing glomerulopathy. J Am Soc Nephrol 8:94, 1997 (abstr) 7. Clarkson MR, O’Meara YM, Murphy B, Rennke HG, Brady HR: Collapsing glomerulopathy—Recurrence in a renal allograft. Nephrol Dial Transplant 13:503-506, 1998 8. Detwiler RK, Falk RJ, Jennette JC: Collapsing glomerulopathy in renal transplant patients: Recurrence and de novo occurence. J Am Soc Nephrol 17:1331, 1996 (abstr) 9. Meehan SM, Pascual M, Williams WW, Tolkoff-Rubin N, Delmonico FL, Cosimi AB, Colvin RB: De novo collapsing glomerulopathy in renal allografts. Transplantation 65: 1192-1197, 1998 10. Toth CM, Pascual M, Williams WW Jr, Delmonico

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FL, Cosimi AB, Colvin RB, Tolkoff-Rubin N: Recurrent collapsing glomerulopathy. Transplantation 65:1009-1010, 1998 11. Alpers CE, Marchioro TL, Johnson RJ: Monoclonal immunoglobulin deposition disease in a renal allograft: Probable recurrent disease in a patient without myeloma. Am J Kidney Dis 13:418-423, 1989 12. Colvin RB: The renal allograft biopsy. Kidney Int 50:1069-1082, 1996 13. Nickeleit V, Vamvakas EC, Pascual M, Poletti BJ, Colvin RB: The prognostic significance of specific arterial lesions in acute renal allograft rejection. J Am Soc Nephrol 9:1301-1308, 1998 14. Greenberg A, Bastacky SI, Iqbal A, Borochovitz D, Johnson JP: Focal segmental glomerulosclerosis associated with nephrotic syndrome in cholesterol atheroembolism: Clinicopathological correlations. Am J Kidney Dis 29:334344, 1997 15. D’Agati V: The many masks of focal segmental glomerulosclerosis. Kidney Int 46:1223-1241, 1994

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16. Bariety J, Nochy D, Mandet C, Jacquot C, Glotz D, Meyrier A: Podocytes undergo phenotypic changes and express macrophagic-associated markers in idiopathic collapsing glomerulopathy. Kidney Int 53:918-925, 1998 17. Oda T, Hotta O, Taguma Y, Kitamura H, Sugai H, Onodera S, Horigome I, Suzuki K, Shouji Y, Furuta T, Chiba S, Yoshizawa N, Nagura H: Clinicopathological significance of intratubular giant macrophages in progressive glomerulonephritis. Kidney Int 53:1190-1200, 1998 18. Ettenger RB, Heuser ET, Malekzadeh MH, Pennisi AJ, Uittenbogaart CH, Fine RN: Focal glomerulosclerosis in renal allografts: Association with the nephrotic syndrome and chronic rejection. Am J Dis Child 131:1347-1352, 1977 19. Cheigh JS, Mouradian J, Susin M, Stubenbord WT, Tapia L, Riggio RR, Stenzel KH, Rubin AL: Kidney transplant nephrotic syndrome: Relationship between allograft histopathology and natural course. Kidney Int 18:358-365, 1980 20. Shimamura T, Walker J: A collapsing form of glomerulopathy. Pathol Int 45:520-523, 1995