Collapsing Glomerulopathy

Collapsing Glomerulopathy

A. Brad Farris, III, MD

In collapsing glomerulopathy, glomerular capillary loops are not well defined image, and a rim of crowded, reactive podocytes is present image.

Podocyte proliferation in collapsing glomerulopathy can resemble a cellular crescent image. However, the cells are more rounded than the more spindle-shaped parietal epithelial cells typically seen in a crescent.



  • Collapsing glomerulopathy (CG)

  • Focal segmental glomerulosclerosis (FSGS)


  • Primary FSGS, collapsing variant

  • Idiopathic collapsing FSGS


  • “Podocytopathy” defined pathologically by prominent capillary loop collapse, podocyte hypercellularity, and proliferation

    • Many different causes of collapsing podocyte phenotype

    • Target not limited to podocytes: Proximal tubular cells proliferate, and tubules are dilated


Many Causes

  • Idiopathic (usual)

  • Infection

  • Drugs

  • Vascular disease

  • Autoimmune disease

  • Malignancy

  • Genetic disorders

Idiopathic (Primary)

  • Cause unknown

    • Circulating permeability factor suspected but has limited experimental evidence

  • Genetic factors may contribute

    • Prevalent APOL1 in blacks has strong association with HIV-associated nephropathy and FSGS (and possibly with idiopathic CG)

      • Closely linked to MYH9 E1 haplotype (nonmuscle myosin heavy chain IIA)

Podocyte Proliferation

  • CG is thought to be disorder resulting from podocyte proliferation and dedifferentiation

    • Normally, podocytes have low rate of turnover

      • WT-1 transcription factor inhibits proliferation

      • Podocytes in CG characteristically lose expression of WT-1 and increase expression of proteins involved in cell division (e.g., Ki-67)

  • Because of this, authors argue that CG may not be a form of FSGS since other forms of FSGS are considered to be due to loss of podocytes (podocytopenia)

    • FSGS consists of sclerosis (segmental solidification) of glomerulus and adhesions to Bowman capsule

    • In contrast, CG consists of pseudocrescent collapse of tuft with increased numbers of podocytes with few adhesions

    • CG also does not respond to typical therapies used for FSGS, suggesting different pathogenesis

Mitochondrial Dysfunction

  • Mitochondrial phenyltransferase-like protein mutations have been identified in kd/kd mice and associated with CG

  • May be involved in damage induced by some bisphosphonates



  • Ethnicity

    • Blacks are disproportionately affected (20-50x)


  • Proteinuria, nephrotic range

  • Nephrotic syndrome

    • Hypoalbuminemia

    • Hypercholesterolemia

  • Renal dysfunction

    • Elevated serum creatinine at presentation, higher than FSGS controls


  • Drugs

    • None effective

    • Steroid therapy may be used, but disease may be refractory

    • Retinoic acid derivatives and inhibitors of cyclin-dependent kinesis may inhibit or reverse CG

      • Inhibits proliferation and promotes differentiation


  • Rapid progression to renal failure (6 months) is usual course of idiopathic CG, more rapid than other types of FSGS

    • Described as “malignant” FSGS variant when initially recognized in 1978 by Brown and colleagues

  • Other causes of CG also typically have rapid loss of renal function although improvement can occur with recovery from or removal of etiologic agent


Histologic Features

  • Glomeruli

    • At least 1 glomerulus with global or segmental collapse and overlying podocyte hyperplasia and hypertrophy, according to Columbia Working Proposal

      • This is lowest possible threshold and has led to marked increase in diagnosis of CG

    • Podocytes with hypertrophy and hyperplasia

      • Urinary space may be filled with podocytes, forming pseudocrescents

      • Enlarged nuclei with open, vesicular chromatin and frequent nucleoli

      • Binucleate forms may be seen

      • Mitotic figures may rarely be seen

      • Protein resorption droplets may be seen in pseudocrescent podocytes

    • Glomerular basement membranes are wrinkled in areas of collapse

      • PAS and Jones methenamine silver stains are useful in highlighting basement membrane collapse

    • Mesangial and intracapillary matrix are not appreciably increased

  • Tubules

    • Tubular microcysts (in 40% of cases)

      • Proximal tubules dilated with proteinaceous casts, sometimes with “peripheral scalloping”

      • Proliferation of tubular cells

      • Enlarged hyperchromatic nuclei, mitotic figures, nucleoli, and focal apoptosis

    • Tubular atrophy/injury

      • Tubular epithelial simplification and flattening

    • Tubulitis can be present, often composed of neutrophilic tubulitis

  • Interstitium

    • Inflammation

      • Interstitial mononuclear inflammation can be prominent

    • Edema

  • Arteries/arterioles

    • Renal vessels may have changes of thrombotic microangiopathy if etiology involves TMA



  • IgM and C3 with segmental or global deposits in collapsed segments with less common deposits of C1q

  • IgG, IgA, and albumin in visceral epithelial protein resorption droplets

  • Tubules have epithelial protein resorption droplets containing plasma proteins (IgG, IgA, C3, albumin, and others)

Electron Microscopy

  • Podocyte hypertrophy overlying areas of collapse

    • Foot processes are extensively effaced

    • Contain electron-dense protein resorption droplets, electron-lucent transport vesicles, and increased numbers of organelles, including prominent rough endoplasmic reticulum

    • Podocytes detached from glomerular basement membrane with interposition of newly formed extracellular matrix

    • Multiple layers of newly formed GBM between podocyte and original GBM

    • Actin cytoskeleton is disrupted, making cytoplasm appear open and pale

    • Podocytes become cuboidal

  • Glomerular basement membrane

    • Wrinkled GBM in areas of collapse

    • GBM not appreciably thickened

    • Absent electron-dense deposits except for small, rare paramesangial deposits

  • Glomerular endothelium

    • Absent tubuloreticular inclusions in all forms except for HIV-associated CG, interferon-mediated forms, and lupus-associated forms


  • Ki-67 (MIB-1), a proliferation marker, is positive in podocytes, indicating that they are engaged in proliferation

    • Normal podocytes have no or rare Ki-67(+) podocytes (< 1/glomerulus)

  • Podocyte differentiation markers are lost (e.g., WT-1, synaptopodin, podocin, podocalyxin, glomerular epithelial protein 1 [GLEPP1], C3b receptor, and CALLA [CD10]), suggesting that dedifferentiation plays a role in CG


FSGS, Cellular Variant

  • CG lacks endocapillary hypercellularity seen in FSGS, cellular variant

  • Some authors consider cellular variant or “cellular lesion” to be same entity as CG

    • However, Columbia working proposal for FSGS classification (D’Agati et al) specifies that endocapillary hypercellularity is more evident in “cellular variant”

    • Endocapillary cells may even appear decreased in CG

FSGS, Not Otherwise Specified (NOS)

  • Podocyte proliferation and hypercellularity absent

  • CG typically has less hyalinosis and adhesions to BC

  • Segmental and global sclerosis of usual type can be seen together with collapsing lesions, but collapsing features are considered to trump others and force classification to CG

Crescentic Glomerulonephritis

  • Crescent cells generally do not have prominent reabsorption droplets

  • Hypertrophic podocytes of CG do not have spindled morphology of true crescents

  • True crescents also contain fibrin and matrix material not seen in pseudocrescents of CG

  • Necrotizing lesions in capillary tuft and glomerular basement membrane breaks

HIV-associated Nephropathy

  • Prominent tubuloreticular structures in endothelial cells

  • May have mitochondrial abnormalities in tubules due to HAART

CG Related to Other Diseases

  • Evidence of thrombotic microangiopathy

  • Cholesterol emboli

  • Underlying glomerular disease

    • Lupus nephritis


1. Lasagni L et al: Glomerular epithelial stem cells: the good, the bad, and the ugly. J Am Soc Nephrol. 21(10):1612-9, 2010

2. Winkler CA et al: Genetics of focal segmental glomerulosclerosis and human immunodeficiency virus-associated collapsing glomerulopathy: the role of MYH9 genetic variation. Semin Nephrol. 30(2):111-25, 2010

3. Albaqumi M et al: Current views on collapsing glomerulopathy. J Am Soc Nephrol. 19(7):1276-81, 2008

4. Kopp JB et al: MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet. 40(10):1175-84, 2008

5. Albaqumi M et al: Collapsing glomerulopathy. J Am Soc Nephrol. 17(10):2854-63, 2006

6. D’Agati VD et al: Atlas of Nontumor Pathology: Non-neoplastic Kidney Diseases. Washington, DC: American Registry of Pathology, 2005

7. D’Agati VD et al: Pathologic classification of focal segmental glomerulosclerosis: a working proposal. Am J Kidney Dis. 43(2):368-82, 2004

8. Moudgil A et al: Association of parvovirus B19 infection with idiopathic collapsing glomerulopathy. Kidney Int. 59(6):2126-33, 2001

9. Valeri A et al: Idiopathic collapsing focal segmental glomerulosclerosis: a clinicopathologic study. Kidney Int. 50(5):1734-46, 1996

10. Carbone L et al: Course and prognosis of human immunodeficiency virus-associated nephropathy. Am J Med. 87(4):389-95, 1989

11. Weiss MA et al: Nephrotic syndrome, progressive irreversible renal failure, and glomerular “collapse”: a new clinicopathologic entity? Am J Kidney Dis. 7(1):20-8, 1986

12. Brown CB et al: Focal segmental glomerulosclerosis with rapid decline in renal function (“malignant FSGS”). Clin Nephrol. 10(2):51-61, 1978

13. Cameron JS et al: The long-term prognosis of patients with focal segmental glomerulosclerosis. Clin Nephrol. 10(6):213-8, 1978


Pathogenetic Classification of Collapsing Glomerulopathy





Possible circulating factor

Most common form, higher frequency in blacks; possibly associated with APOL1 variant



Widespread recognition in 1980s in HIV-associated nephropathy; higher frequency in blacks; associated with APOL1 variant

Parvovirus B19

Viral antigen in podocytes


Loa loa




Campylobacter enteritis


IV drug abuse (e.g., heroin)

Often associated with HIV

Bisphosphonates (e.g., pamidronate)

Interferons-α and -β

Valproic acid

Calcineurin inhibitors

May originate through thrombotic microangiopathy-like state


Thrombotic microangiopathy


Autoimmune disease

Guillain-Barré syndrome

Systemic lupus erythematosus and lupus-like syndromes

Mixed connective tissue disease

Still disease




CoQ2 nephropathy (co-enzyme Q2)

Described in Europeans

Mandibuloacral dysplasia (zinc metalloproteinase, ZMPSTE24)

Metalloproteinase is involved in post-translational cleavage of carboxy-terminal residues of farnesylated prelamin A

Action-myoclonus renal failure (SCARB2)

Myoclonic epilepsy associated with renal failure and preserved cognitive function

HIV-associated nephropathy, FSGS, and focal global glomerulosclerosis (hypertensive glomerular disease)

Associated with APOL1 variant that promotes resistance to trypanosomiasis

Familial CG

Unknown genes

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Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Collapsing Glomerulopathy

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