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.


TERMINOLOGY


Abbreviations



  • Collapsing glomerulopathy (CG)


  • Focal segmental glomerulosclerosis (FSGS)


Synonyms



  • Primary FSGS, collapsing variant


  • Idiopathic collapsing FSGS


Definitions



  • “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


ETIOLOGY/PATHOGENESIS


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


CLINICAL ISSUES


Epidemiology



  • Ethnicity



    • Blacks are disproportionately affected (20-50x)


Presentation



  • Proteinuria, nephrotic range


  • Nephrotic syndrome



    • Hypoalbuminemia


    • Hypercholesterolemia


  • Renal dysfunction




    • Elevated serum creatinine at presentation, higher than FSGS controls


Treatment



  • 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


Prognosis



  • 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


MICROSCOPIC PATHOLOGY


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


ANCILLARY TESTS


Immunofluorescence



  • 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


Immunohistochemistry



  • 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


DIFFERENTIAL DIAGNOSIS


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



SELECTED REFERENCES

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






Tables

















































































































Pathogenetic Classification of Collapsing Glomerulopathy


Category


Cause


Comments


Idiopathic


Possible circulating factor


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


Infection



HIV


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



Parvovirus B19


Viral antigen in podocytes



Leishmaniasis



Loa loa



Filariasis



Tuberculosis



Cytomegalovirus



Campylobacter enteritis



Drugs



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


Vascular



Thrombotic microangiopathy



Atheroemboli


Autoimmune disease



Guillain-Barré syndrome



Systemic lupus erythematosus and lupus-like syndromes



Mixed connective tissue disease



Still disease


Malignancy



Leukemia/lymphoma


Genetic



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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