collapsing glomerulopathy: a distinct pattern of ... · collapsing glomerulopathy: a distinct...
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Collapsing glomerulopathy: a distinct pattern of glomerular injury
Laura Barisoni, MDDepartment of PathologyNew York University, NY
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Clinical features
• High prevalence in AA• Severe proteinuria• Rapid progression to renal failure• Lack of response to standard therapies
• Glomerular collapse but also sclerosis (late)• Pseudocrescent formation
Glomerular collapse but also sclerosis (late)Pseudocrescent formation
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History of Collapsing Glomerulopathy•Brown et al. Clin Nephrol 1978
first description in 1978 as “ malignant FSGS”
•Rao et al., N Engl J Med. 1984:
“Focal segmental glomerulosclerosis in 10 pts with HIV infection”
• Wiess et al., Am J Kidney Dis. 1986:
“Nephrotic syndrome, progressive irreversible renal failure, and glomerular"collapse": a new clinical-pathologic entity?” (6 pts)
• Detwiler et al., KI 1994:
“Collapsing glomerulopathy: a clinically and pathologically distinct variant of focalsegmental glomerulosclerosis.” (16 pts (13/16 AA)
• Valeri, Barisoni et al. KI 1996:
“Idiopathic collapsing focal segmental glomerulosclerosis: a clinicopathologicstudy.” (43 pts)
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Terminology
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Collapsing or cellular lesion?
• Some authors use the term “cellular lesion” toindicate a lesion characterized by hypercellularitywithin the glomerular tuft or in the urinary space.
• Columbia classification scheme:
collapsing cellular
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Collapsing FSGS or
Collapsing Glomerulopathy?
Is collapse part of the FSGS spectrum or
is part of the podocytopathy spectrum?
and
Is this distinction important?
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Sclerosis versus collapse
FSGS
CG
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Tubular microcysts
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Conclusion I
Clinical presentation and morphology indicate thatcollapsing glomerulopathy is not a form of FSGS.
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Is “collapsing” a disease or a pattern of glomerular injury?
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Incidence of collapsing pattern of injury at NYU (2003-2005)
Idiopathic: 16 + 4 with severe AIN = 20
HIV-associated: 4 + 4 collapse and other GN = 8
PVB19: = 1
Mesangial deposits: 4 unknown + 3 C1q + 2 lupus-like
+ 3 IgA + 2 Hep C associated MPGN = 16
MGN: = 1
Diabetes: = 3
TMA: 4 post Tx + 2 native kidney = 6
GBM abnormalities: = 5
Familial: 2 families + 2 pts with fam. history = 5
Total 65 / 869 (7.3%)
Collapse is a pattern of glomerular injury
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CG: etiology and clinical associations• Idiopathic• Genetic
• Syndromic - action myoclonus renal failure• Non-Syndormic - CoQ2 NP
• Reactive• Virus associated
- HIV- parvovirus B19- CMV
• Infections - filariasis- leishmania- TB
• Autoimmune - Still’s disease- lupus like- RA - mixed connective tissue
• Malignancy (myeloma, AML)• Medications - pamidronate
- interferon- valproic acid
• Vascular insult - TMA• Permeability factor
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Why only some patients develop collapsing glomerulopathy?
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Genetic susceptibility
• Human: MYH9 is also a major-effect risk gene for CG.MYH9 risk alleles are more frequent in AA. MYH9protective alleles are more frequent in EA.(Kopp et al. Nat Genet. 2008)
• Mice: Accelerated development of collapsingglomerulopathy in mice congenic for the HIVAN1locus.A gene on chromosome 3A1-A3 increasessusceptibility to HIVAN, resulting in early onset andrapid progression of kidney disease.(Chang et al KI 2009)
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CollapsingGlomerulopathy
Medications
Activation of the immune
system
Specificgenetic
mutations
Ischemicinsult
Dysregulation of mitochondrial
activity
Environmental factorsInfections
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Conclusion II
Collapsing glomerulopathy is a parrtern of glomerularinjury that can occur in association with variousetiologic factors.
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Which is the underlying mechanism of pseudocrescent formation and
collapse of the basement membranes?
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Pathogenesis of CG:from podocyte injury to pseudocrescent formation
The dysregulated podocyte
Podocytes are injured
They dedifferentiate and dysregulate their phenotype
Dedifferentiated podocytes can re-enter the cell cycle and
proliferate
Pseudocrescent formation
The exuberant renopoietic system
Podocytes are injured
They undergo apoptosis/death
CD24+CD133+ cells migrate from the Bowman’s capsule
Exuberant proliferation
Pseudocrescent formation
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Hypothesis #1
The dysregulated podocyte phenotype
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In collapsing glomerulopathy podocytes resemble immature precursorsNormal CG
FSGS
Barisoni and Kopp 2002
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Differently from other podocytopathies, in CG podocytes are de-differentiated
Barisoni, Mundel et al. JASN 1999
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In idiopathic and HIV-associated CG dedifferentiated podocytes have a
dysregulated phenotype
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In CG de-differentiated podocytes re-enter the cell cycle and proliferate
p57 Ki-67 Ki-67
Barisoni et al. KI 2000
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Loss of synaptopodin expression precedes glomerular damage in HIV-CG
NAK MCD HIV-CG
Barisoni et al. JASN 1999, 10: 51-61
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Inheritable CoQ2 NP:
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In CoQ2-associated CG podocyte phenotype is dedifferentiated but not dysregulated
Ki67 WT1
Synpo podocin CK
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Hypothesis #2
The renopoietic system
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Copyright ©2009 American Society of Nephrology
Ronconi, E. et al. J Am Soc Nephrol 2009;20:322-332
Hierarchical distribution of CD133+CD24+PDX- and CD133+CD24+PDX+ cells within human glomeruli
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Exuberant proliferation of CD24+CD133+
resident progenitor cells is the cause of pseudocrescent formation
Smeets et al, JASN 2009
Copyright ©2009 American Society of Nephrology
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Conclusion III
Collapsing glomerulopathy is a proliferative podocytopathy
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Amelioration of nephropathy in mice expressing HIV-1 genes by the cyclin-dependent kinase inhibitor flavopiridol(Nelson et al. Journal of Antimicrobial Chemotherapy 2003)
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Conclusions
• CG is a proliferative disease, different from otherpodocytopathies, histologically defined by glomerularcollapse and pseudocrescent formation .
• Both intrinsic cell damage and reactive mechanism of injurymay play a role in podocyte injury, provided a predisposinggenetic background.
• Pseudocrescents may be the result of exuberantproliferation of dedifferentiated podocytes or of renopoieticresident cells, or both.
• Recognition of the unique etiologies and pathogeneticmechanism for CG should guide therapeutic intervention.
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Classification of CG
Idiopathic forms
Genetic forms Reactive forms
• Idiopathic CG • Non-SyndromicCOQ2
• SyndromicAction myoclonus-renalfailure (SCARB2)
• InfectionViruses (HIV-1, parvovirus B19, CMV)Others (Loa loa filiariasis, visceralleishmaniasis, Mycobacteriumtuberculosis*)
• Disease associationsAdult Still’s disease, thrombotic
microangiopathy, multiple myeloma
• MedicationInterferon-alpha, pamidronate
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Pamidronate-associated CG
TMA-Associated CG
Non collapsed glomeruli Collapsed glomeruli
In “reactive” forms of CG podocyte phenotype is preserved in non-affected glomeruli.
Barisoni, Thomas et al. ASN 2004
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The kd/kd mouse is a model of spontaneous CGBarisoni, Madaio, Eraso, Gasser, and Nelson. JASN 2005
The susceptibility gene has been mapped on chromosome 10 and encodes a prenyltransferase-like mitochondrial protein (PLMP) (Dell et al. Mamm Genome 2000)
Dysmorphic mitochondria
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Collapsing glomerulopathy:Three pathogenetic variant
IDIOPATHIC INHERITED REACTIVE
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Expression of podocyte maturity markers in podocytopathies
MCNS FSGS CG
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Podocyte de-differentiation and dys-regulation lead to proliferation
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Viruses and podocyte injury
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Bruggeman JCI 1999
Barisoni, KI 2000
HIV-1 expression in renal epithelial cells or selectively in podocytes alone leads to CG
Zhong et al. KI 2005
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Human renal glomerular and tubular epithelial cells contain HIV-1 mRNA
and DNA
Bruggeman et al. JASN 2000
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Association of parvovirus B19 infection with collapsing glomerulopathy
Moudgil et al KI 2001
PVB19 DNA was detected in renal biopsies of 78.3% ofpatients with idiopathic CG by PCR, and localized to theepithelial cells and podocytes by in situ hybridization.
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Genetic forms of CG
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Mitochondrial activity is reduced in renal parenchyma
COX
SDH
Control CoQ2 NP