2009 Convegno Malattie Rare Barisoni [23 01]
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2009 Convegno Malattie Rare Barisoni [23 01]

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A NEW TAXONOMY FOR THE PODOCYTOPATHIES

A NEW TAXONOMY FOR THE PODOCYTOPATHIES

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2009 Convegno Malattie Rare Barisoni [23 01] 2009 Convegno Malattie Rare Barisoni [23 01] Presentation Transcript

  • A NEW TAXONOMY FOR THE PODOCYTOPATHIES Laura Barisoni Department of Pathology and Medicine, Division of Nephrology New York University
  • Old classification schemes: Proteinuria and nephrotic syndrome MCD FSGS Poor prognosis and Good prognosis and Poor Response to Response to steroid Steroid therapy Therapy
  • Nephrotic syndrome - the 80’s and 90’s • While the definition of minimal change disease did not change over the years, in the mid 80’s other patterns of glomerular damage have became part of the FSGS spectrum. • Collapsing glomerulopathy: - first description in 1978 “ malignant FSGS” - 1980’s frequent diagnosis during HIV pandemic (HIV-AN) - first described in non-HIV pts in 1986 (Weiss et al AJKD 1986) – “collapsing glomerulopathy” – new clinical-pathologic entity. - in mid 90’s became “idiopathic collapsing FSGS” • Cellular lesion: - Term used first by Schwarz and colleagues to indicate a group of lesions with endocapillary and/or extracapillary increased cellularity. - Other authors used the term cellular to indicate intracapillary cellularity only. • Tip lesion: - Howie et al described tip lesion as a well-defined and specific pathological entity with clinical similarity to MCD. (J Pathol 1984) - Tip lesions are also seen in associations with other glomerular diseases such as diabetic nephropathy or membranous glomerulopathy. View slide
  • Relatively recent classification schemes: Columbia classification - FSGS variants Perihilar NOS Tip Cellular Collapsing View slide
  • Limitations of the morphologic classification • Various morphologic entities are called “focal segmental glomerulosclerosis” regardless the presence or absence of segmental sclerosis. • Exclusive of diffuse mesangial sclerosis. • But inclusive of forms of “proliferative” forms of glomerular damage with nephrotic syndrome. • Lack of correlation with pathogenetic mechanisms and etiology. • Based on opinions – no data in the literature to justify the rational behind it.
  • Morphologic heterogeneity and clinical heterogeneity • Collapsing: – Severe proteinuria with bad prognosis – High predilection for AA • Cellular – Bad prognosis (but better than collapsing) – High predilection for AA • Tip – Severe proteinuria with good prognosis – High predilection for Caucasian • FSGS perihilar & NOS – Intermediate prognosis
  • Proteinuria and nephrotic syndrome in the 21st century • The attention of scientists, nephrologists and pathologists has been recently focused on the role of podocytes as cause of proteinuria • In the last 10 years lot of progress has been made in the understanding the biology of podocytes, how they function and how they are injured. • “Taxonomy of the podocytopathies” where morphologic diagnosis are integrated with etiology (Barisoni, Schnaper, Kopp, CJASN 2007)
  • Taxonomy The word “taxonomy” was coined by Carl Linnaeus, the 18th century Swedish scientist from the Greek roots taxis meaning arrangement or division, and nomia meaning law or method. A taxonomy is organized into multiple levels, each of which represents a taxon with one or more elements. The ideal taxonomy separates the elements of each taxon, taxa, into mutually exclusive, unambiguous, and all-encompassing categories. A good taxonomy should be simple, easy to remember and to use. Taxonomies provide classification but also a conceptual framework for analysis, discussion, and hypothesis generation.
  • Podocytopathies DEFINITION: Proteinuric diseases in which pathologic processes arise from intrinsic or extrinsic “primary” podocyte injury and where the podocyte genotype/phenotype is altered.
  • The Taxonomy of Podocytopathies Based on our current knowledge, the taxonomy of the podocytopathies is organized along two axes (taxon): • HISTOPATHOLOGY - Morphologic pattern of glomerular injury - Podocyte number • ETIOLOGY - Idiopathic - Genetic - Reactive Laura Barisoni, Jeffrey Kopp & William Schnaper C-JASN 2007
  • Podocytopathies: 4 morphologic patterns of glomerular injury Collapse of Segmental Mesangial Normal the GBM Sclerosis Sclerosis Histology CG FSGS DMS MCN
  • The Podocyte A post-mitotic cell with highly specialized structure and function specific to the glomerulus. • Regulate permselectivity • Structural support for capillary • Remodeling GBM • Endocytosis of filtered proteins • Counteract hydrostatic pressure
  • Podocyte injury = foot process effacement
  • Causes of foot process effacement 1. Impaired formation of the slit diaphragm complex 2. Abnormalities of the adhesive interaction between podocytes and GBM 3. Alterations of transcription factors 4. Abnormalities of the actin-based cytoskeleton 5. Alterations of the apical domain of podocytes 6. Mitochondria abnormalities 7. Abnormalities of cell metabolism 8. Mechanical stress 9. Viral infection 10. Acute ischemic injury 11. Toxic / metabolic effect 12. Immunologic stimuli
  • How do we translate this large variety of insults into four morphologic patterns of glomerular injury?
  • Injured podocytes may take distinct pathways Podocyte injury Altered Engagement of Developmental De-differentiation phenotype apoptotic pathways arrest Proliferation Proliferation No change in Cell death (high) (low) podocyte number Segmental Mesangial No change Collapse sclerosis sclerosis MCN FSGS DMS CG
  • MINIMAL CHANGE NEPHROPATHY
  • Minimal Change Nephropathy DEFINITION Normal histology. Extensive foot process effacement, but preserved number of podocytes. ETIOLOGY AND CLINICAL ASSOCIATION • Idiopathic • Inherited - Non-Syndromic (NPHS1, NPHS2) - Syndromic (DYSF) • Reactive - drug-induced (NSAID, pamidronate, interferon, others) - dysregulation of the immune system - hematologic malignancy
  • Minimal change nephropathy • Reversible – Steroid sensitive - idiopathic - reactive (secondary) - drug-induced (NSAID, pamidronate, interferon, others) - dysregulation of the immune system - hematologic malignancy • Irreversible - Steroid resistant - idiopathic - genetically determined - NPHS2 - DYSF
  • Can pathologists discriminate between steroid sensitive and steroid-resistant MCN?
  • Glomerular expression of dystroglycans is reduced in MCD but not in FSGS Regele JASN11:403-412, 2000 β-dystroglycan α-dystroglycan β1-integrin Normal kidney FSGS MCD
  • DG staining in steroid sensitive and steroid resistant MCN Laura De Petris, David Thomas, Helen Liapis, Laura Barisoni IHC staining C Fig 1 negative positive SR-MCN SS-MCN MCN (no f-up) FSGS Ctrl
  • a b Podocin: control Podocin: steroid-resistant MCN d c
  • FOCAL SEGMENTAL GLOMERULOSCLEROSIS
  • FSGS DEFINITION Segmental solidification of the tuft accompanied by sinechiae. Hyalinosis and foam cells can also be present. Low number of podocytes (podocytopenia). ETIOLOGY AND CLINICAL ASSOCIATION • Idiopathic • Inherited - syndromic - non-syndromic • Reactive - hyperfiltration-mediated normal renal mass reduced renal mass - medication-induced - permeability factor (?)
  • Idiopathic FSGS Is idiopathic really idiopathic? MYH9 is a major-effect risk gene for FSGS. (Kopp et al. Nat Genet. 2008) MYH9 risk alleles are more frequent in AA. MYH9 protective alleles are more frequent in EA.
  • Reactive forms: Hyperfiltration- Hyperfiltration-mediated FSGS glomerulomegaly in pt with single kidney Segmental sclerosis large non-sclerotic glomerulus
  • Which is the relationship between glomerulomegaly and FSGS?
  • FSGS: From podocyte hypertrophy to podocytopenia. Wiggins et al JASN 2005. In response to increased glomerular volume, podocytes undergo hypertrophy though 5 stages. •Stage 1, normal podocyte; •Stage 2, non-stressed hypertrophy; •Stage 3, quot;adaptivequot; hypertrophy: changes in synthesis of structural components but maintenance of normal function; •Stage 4, quot;de-compensatedquot; hypertrophy - reduced production of proteins necessary for normal podocyte function. - widened foot processes and decreased filter efficiency (proteinuria); •Stage 5, podocyte numbers decrease. Dr Kriz’s model
  • Genetic forms of FSGS • Associated with other organ abnormalities (syndromic): – Freiser Syndrome (WT-1). – Nail-patella syndrome (LMX1B) – Renal-coloboma syndrome with oligomeganephronia (PAX2) – Alport’s disease (COL4A3, A4, A5) – Metabolic disorders (GLA – Fabry’s) – Mitochondriopathies (mtDNA tRNALeu and tRNATyr,CoQ2 NP, CoQ6 NP) • Limited to the kidney (non-syndromic): - NPHS1 – nephrin – autosomal recessive - NPHS2 – podocin – autosomal recessive ε - NPHS3 – phospholipase Cε1 – autosomal recessive - CD2AP – susceptibility to FSGS - MYH9 – susceptibility to FSGS - ACTN4 – α-actinin-4 - autosomal dominant - TRPC6 – Transient Receptor Potential channel 6 - autosomal dominant - WT1 – sporadic/isolated FSGS
  • DIFFUSE MESANGIAL SCLEROSIS
  • DMS DEFINITION: Diffuse increase of mesangial matrix accompanied by mild proliferation of hypertrophic podocytes. ETIOLOGY: • Idiopathic • Genetic - Non-syndromic - WT1 - NPHS1 - NPHS2 - NPHS3 - COQ6 - Syndromic - LAMB2 (Pierson S.) - WT-1 (Denys-Drash S.)
  • WT-1 associated DMS WT- •Reduced or dysfunctional expression of WT-1, a podocyte transcription factor. •Increased expression of growth-promoting molecules (Pax-2, Ki-67). •Podocyte entry into the cell cycle. •Preservation of other podocyte markers (nephrin, synaptopodin, a-actinin-4).
  • CNS Finnish type •Massive proteinuria in utero and NS at birth. •Rapid progression to renal failure probably due to presence of atubular glomeruli. •Patients first have DMS with mild proliferation which rapidly evolves into sclerosis. •Low proliferative and apoptotic index has been demonstrated in the DMS phase. (Patrakka KI 2000) (Kuusniemi KI 2006)
  • NPHS3-PLCE1 ε Chromosome 10q23.32-q24.1 = phospholipase Cε1. non-truncating missense Truncating mutations mutations Podocytopenia Developmental arrest FSGS DMS Later onset of NS and slower early onset of severe NS and progression to renal failure. rapid progression to renal failure. Of Note: 2 pts responded to steroid and Cyclosporin A. Hinkes et al. Nat Genetic 2006
  • COLLAPSING GLOMERULOPATHY
  • CG Definition: GBM collapse and pseudocrescent formation HIV
  • 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 (?)
  • CG is a proliferative disease: Dedifferentiated podocytes re-enter the cell cycle and proliferate Early phase Late phase
  • Degree of dedifferentiation is variable among different subcategories of CG Non collapsed glomeruli Collapsed glomeruli HIV - CG Pamidronate- associated CG TMA- Associated CG Barisoni, Thomas et al. ASN 2004
  • In idiopathic and HIV-associated CG dedifferentiated podocytes have a dysregulated phenotype
  • In inherited CG (COQ2-NP) (COQ2- podocyte phenotype is dedifferentiated but not dysregulated Synpo Ki67 WT1
  • TAXONOMY OF PODOCYTOPATHIES idiopathic genetic reactive Idiopathic Non-syndromic Clinical association MCN •Steroid-sensitive •NPHS1 (immunologic stimuli, Tumors) •Steroid-resistant •NPHS2 Medications Syndromic (NSAID,gold, penicillamine, lithium, •DYSF IF, pamidronate) Idiopathic Non-syndromic Post-adaptive FSGS •Steroid-sensitive ITGB4, NPSH2, NPHS3, NPHS1 + •nephron mass NPHS2, COQ2, MHY9, ACTN4, •Steroid-resistant •Initially normal nephron mass CD2AP, TRCP6, WT-1 Medications Syndromic (tacrolimus, lithium, IF, pamidronate) MtDNA, WT1, PAX2, COQ6, COL4,GLA, LMBX1 Idiopathic Non-syndromic DMS WT1, NPHS1, NPSH2, NPHS3, LAMB2, Syndromic WT1, LAMB2, COQ6, Idiopathic Non-syndromic Infections CG COQ2 (viruses, TB, others) MHY9 Clinical association Syndromic •Autoimmune, TMA, tumors SCARB Medications (IF, pamidronate, valproic acid)
  • Conclusions MCN, FSGS, DMS and CG are pattern of glomerular damage where the common denominator is podocyte injury and therefore they should be grouped under the umbrella of podocytopathies. Morphologic classifications alone are insufficient to capture the complexity and heterogeneity of diseases presenting with NS. - multiple specific disease processes can present with indistinguishable histopatholology - a specific monogenetic disorder can present with more than one form of histopathologic pattern of glomerular damage. We propose that the final diagnosis of the podocytopathies should occur in 3 steps: a. clinical evaluation b. morphologic evaluation c. additional clinical tests, such as genetic or serology for evidence of infections, or others, when indicated. It is expected that in the future other variables (proteomics, transcriptomics) will be added to the present criteria to better define each category and their prognosis. The taxonomy should serve as a base structure to classify diseases and guide therapeutic approach.
  • Specific genetic mutations Medications Podocyte Dysregulation Activation of Proliferation of mitochondrial the immune activity system CG Ischemic insult Environmental Infections factors
  • Conclusions MCN, FSGS, DMS and CG are pattern of glomerular injury rather than single entities. The common denominator is podocyte injury and therefore they should be grouped under the umbrella of podocytopathies. We propose that final diagnosis of the podocytopathies should occur in 3 steps: a. clinical evaluation b. morphologic evaluation c. additional clinical tests, such as genetic or serology for evidence of infections, or others, when indicated. It is expected that in the future other variables (proteomics, transcriptomics) will be added to the present criteria to better define each category, their prognosis and identify the potential response to specific therapy (personalized medicine).
  • α-actinine - 4 - associated FSGS • Adult onset of FSGS • Variable degree of foot process effacement. • Rapid degradation and “second hit theory” Kaplan, Nat Gen 2000
  • Podocin (NPHS2) Childhood onset of steroid resistant NS Boute et al Nat Gen 2000 • Onset between 3 months and 5 years of age • Familial and sporadic forms - variable pathological findings • Clinical course similar to idiopathic FSGS • Resistant to steroid therapy • Progresses to ESRD • Most of mutations are clustered in N-terminal domain Adult onset of steroid resistant NS Tsukaguchi et al., JASN 2000 • Adolescent and adult-onset familial FSGS locus located on Chromosome 1q25-31. • Most of mutations are clustered in C-terminal domain • Rapid progression to renal failure
  • The Podocyte A post-mitotic cell with highly specialized structure and function specific to the glomerulus. • Regulate permselectivity • Structural support for capillary • Remodeling GBM • Endocytosis of filtered proteins • Counteract hydrostatic pressure
  • Podocyte phenotype in human idiopathic and HIV-associated CG
  • Summary • MCN, FSGS, DMS and CG are pattern of glomerular injury rather than single entities. The common denominator is podocyte injury and therefore they should be grouped under the umbrella of podocytopathies. • The common denominator is podocyte injury and therefore they should be grouped under the umbrella of podocytopathies. • Each morphologic category is associated with (or the result of) a specific pathway that injured podocyte may take, from altered phenotype and no change in number, to podocytopenia, or proliferation, when developmental arrest or dedifferentiation occur. • Criteria for the classification of podocytopathies should include, in addition to morphologic analysis, clinical associations and podocyte phenotype.
  • Specific genetic mutations Medications Dysregulation Activation of of mitochondrial the immune Collapsing activity system glomerulopathy Ischemic insult Environmental Infections factors
  • In inherited CG (COQ2-NP) (COQ2- Podocyte phenotype is not dysregulated Ki67 Synpo WT1
  • Nephrotic syndrome – historical background • Historically nephrotic syndrome was at first associated with the term “lipoid nephrosis” a renal disease where glomeruli have minimal lesions. In the early 20th century, the histologic features of FSGS were first • described as degenerative changes of glomeruli in lipoid nephrosis. (Fahr T. “Pathologische Anatomie des morbus brightii” Berlin: Springer; 1925). It was not until the mid 20th century that it was reported there was a • different clinical course between patients with NS and minimal glomerular changes versus those with juxtamedullary glomerular hyaline or sclerosing lesions without cellular proliferation. (Rich A. “A hitherto underscribed vulnerability of the juxtamedullary glomeruli in lipoid nephrosis” Bull Johns Hopkins Hosp. 1957). • Other authors began to report progressive renal disease in nephrotic patients coinciding with progressive glomerular sclerosis and increased interstitial scarring. (Hayslett JP Kl et al “Progression of quot;lipoid nephrosisquot; to renal insuffienciency” N Engl J Med. 1969)
  • THE TAXONOMY OF PODOCYTEPATHIES Based on our current knowledge, the taxonomy of the podocytopathies is organized along two axes (taxon): • HISTOPATHOLOGY - Morphologic pattern of glomerular injury - Podocyte number • ETIOLOGY - Idiopathic - Genetic - Reactive Laura Barisoni, Jeffrey Kopp & William Schnaper C-JASN 2007
  • Minimal change nephropathy • Reversible – Steroid sensitive - idiopathic - reactive (secondary) - drug-induced (NSAID, pamidronate, interferon, others) - dysregulation of the immune system - hematologic malignancy • Irreversible - Steroid resistant - idiopathic - genetically determined - NPHS2 - DYSF