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A NEW TAXONOMY FOR THE A NEW TAXONOMY FOR THE
PODOCYTOPATHIESPODOCYTOPATHIES
Laura Barisoni
Department of Pathology andMedicine, Division of Nephrology
New York University
Old classification schemes:
Proteinuria and nephrotic syndrome
Good prognosis andResponse to steroidTherapy
Poor prognosis andPoor Response to Steroid therapy
MCD FSGS
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”- 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.
Relatively recent classification schemes:Columbia classification - FSGS variants
Perihilar NOS Tip
Cellular Collapsing
Limitations of the morphologic classification
• Various morphologic entities are called “focal segm ental glomerulosclerosis” regardless the presence or abse nce 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 an d etiology.
• Based on opinions – no data in the literature to jus tify 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)– 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 21 st century
• The attention of scientists, nephrologists and path ologists 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 fu nction and how they are injured.
• “Taxonomy of the podocytopathies” where morphologic diagnosis are integrated with etiology (Barisoni, Schnaper, Kopp, CJASN 2007)
TaxonomyTaxonomy
The word “taxonomy” was coined by Carl Linnaeus, the 18th centurySwedish scientist from the Greek rootstaxis meaning arrangement or division, andnomia meaning law or method.
A taxonomy is organized into multiple levels, each of which representsa taxon with one or more elements.a taxon with one or more elements.
The ideal taxonomy separates the elements of each taxon, taxa, intomutually 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 foranalysis, discussion, and hypothesis generation.
PodocytopathiesPodocytopathies
DEFINITION: Proteinuric diseases in which pathologicprocesses arise from intrinsic or extrinsic “primary”processes arise from intrinsic or extrinsic “primary”podocyte injury and where the podocyte genotype/phenotypeis 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 SchnaperC-JASN 2007
Podocytopathies: Podocytopathies: 4 morphologic patterns of glomerular injury4 morphologic patterns of glomerular injury
Normal Histology
Mesangial Sclerosis
Segmental Sclerosis
Collapse ofthe GBM
MCN DMSFSGS CG
The PodocyteThe 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
Causes of foot process effacementCauses of foot process effacement1. Impaired formation of the slit
diaphragm complex2. Abnormalities of the adhesive
interaction between podocytesand GBM
3. Alterations of transcription factors4. Abnormalities of the actin-based
cytoskeletoncytoskeleton5. Alterations of the apical domain of
podocytes6. Mitochondria abnormalities7. Abnormalities of cell metabolism
8. Mechanical stress9. Viral infection10. Acute ischemic injury11. Toxic / metabolic effect12. Immunologic stimuli
How do we translate this large variety of insults into four morphologic patterns of
glomerular injury?
Injured podocytes may take Injured podocytes may take distinct pathwaysdistinct pathways
Podocyte injury
Engagement of apoptotic pathways
De-differentiationAltered phenotype
Developmental arrest
Collapse
Proliferation(high)
apoptotic pathways
Cell death
No change
FSGS CG
No change in podocyte number
MCN
Mesangial sclerosis
DMS
Segmentalsclerosis
phenotype
Proliferation(low)
arrest
Minimal Change NephropathyMinimal Change Nephropathy
DEFINITIONNormal 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 nephropathyMinimal change nephropathy
• Reversible – Steroid sensitive- idiopathic
- reactive (secondary)- drug-induced (NSAID,
pamidronate, interferon, others)- dysregulation of the
immune systemimmune system- hematologic malignancy
• Irreversible - Steroid resistant- idiopathic
- genetically determined- NPHS2- DYSF
Glomerular expression of dystroglycans is reduced in MCD but not in FSGS
Regele JASN11:403-412, 2000
Normal kidney
αααα-dystroglycan ββββ-dystroglycan ββββ1-integrin
FSGS
MCD
C
IHC
sta
inin
g
DG staining in steroid sensitive and steroid resist ant MCNDG staining in steroid sensitive and steroid resist ant MCNLaura De Petris, David Thomas, Helen Liapis, Laura Barisoni
IHC
sta
inin
g
negative positive
FSGS Ctrl SR-MCN SS-MCN MCN (no f-up)
Fig 1
FOCAL SEGMENTAL FOCAL SEGMENTAL GLOMERULOSCLEROSISGLOMERULOSCLEROSISGLOMERULOSCLEROSISGLOMERULOSCLEROSIS
FSGSFSGS
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 massreduced renal mass
- medication-induced- permeability factor (?)
Idiopathic FSGSIdiopathic 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 pro tective alleles are more frequent in EA.
Segmental sclerosis large non-sclerotic glomerulus
Reactive forms: Reactive forms: HyperfiltrationHyperfiltration--mediated FSGSmediated FSGS
glomerulomegaly in pt with single kidneyglomerulomegaly in pt with single kidney
FSGS:FSGS: From podocyte hypertrophy to podocytopenia.From podocyte hypertrophy to podocytopenia.Wiggins et al JASN 2005.
In response to increased glomerular volume, podocyt es undergo hypertrophy though 5 stages.
•Stage 1, normal podocyte;
•Stage 2, non-stressed hypertrophy;
•Stage 3, "adaptive" hypertrophy: changes in synthesis of st ructural components but maintenance of normal function; but maintenance of normal function;
•Stage 4, "de-compensated" hypertrophy- reduced production of proteins necessary for normal podocyte function. - widened foot processes and decreased filter effici ency (proteinuria);
•Stage 5, podocyte numbers decrease.
Dr Kriz’s model
Genetic forms of FSGSGenetic forms of FSGS
• Associated with other organ abnormalities (syndromi c):– Freiser Syndrome (WT-1).– Nail-patella syndrome (LMX1B)– Renal-coloboma syndrome with oligomeganephronia (PA X2)– Alport’s disease (COL4A3, A4, A5)– Metabolic disorders (GLA – Fabry’s)– Mitochondriopathies (mtDNA tRNA Leu and tRNATyr,CoQ2 NP, CoQ6 NP)– Mitochondriopathies (mtDNA tRNA and tRNA ,CoQ2 NP, CoQ6 NP)
• Limited to the kidney (non-syndromic):- NPHS1 – nephrin – autosomal recessive- NPHS2 – podocin – autosomal recessive- NPHS3 – phospholipase C εεεε1 – autosomal recessive- CD2AP – susceptibility to FSGS - MYH9 – susceptibility to FSGS- ACTN4 – αααα-actinin-4 - autosomal dominant - TRPC6 – Transient Receptor Potential channel 6 - aut osomal dominant - WT1 – sporadic/isolated FSGS
DMS
DEFINITION:Diffuse increase of mesangial matrix accompanied by mild proliferation of hypertrophic podocytes.
ETIOLOGY:• Idiopathic• Idiopathic• Genetic
- Non-syndromic- WT1 - NPHS1 - NPHS2- NPHS3- COQ6
- Syndromic- LAMB2 (Pierson S.)- WT-1 (Denys-Drash S.)
•Reduced or dysfunctional expression of WT-1, a podocyte tra nscription factor.
•Increased expression of growth-promoting molecules (Pax- 2, Ki-67).
•Podocyte entry into the cell cycle.
•Preservation of other podocyte markers (nephrin, synaptop odin, a-actinin-4).
WTWT--1 associated DMS1 associated DMS
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 whi ch rapidly evolves into sclerosis.
•Low proliferative and apoptotic index has been demo nstrated in the DMS phase.
(Kuusniemi KI 2006) (Patrakka KI 2000)
NPHS3-PLCE1
Chromosome 10q23.32-q24.1 = phospholipase C εεεε1.
Truncating mutations non-truncating missense mutations
Developmental arrest
DMS
early onset of severe NS and rapid progression to renal failure.
Of Note: 2 pts responded to steroid and Cyclosporin A.
Podocytopenia
FSGS
Later onset of NS and slower progression to renal failure.
Hinkes et al. Nat Genetic 2006
CG Definition: GBM collapse and CG Definition: GBM collapse and pseudocrescent formationpseudocrescent formation
HIV
CG: etiology and clinical associationsCG: etiology and clinical associations• Idiopathic• Genetic
• Syndromic - action myoclonus renal failure
• Non-Syndormic - CoQ2 NP
• Reactive• Virus associated
- HIV- parvovirus B19- CMV- 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 proliferateEarly phase Late phase
Degree of dedifferentiation is variable among different subcategories of CG
HIV - CG
Non collapsed glomeruli Collapsed glomeruli
Pamidronate-associated CG
TMA-Associated CG
Barisoni, Thomas et al. ASN 2004
In inherited CG (COQ2In inherited CG (COQ2--NP)NP)podocyte phenotype is dedifferentiated podocyte phenotype is dedifferentiated
but not dysregulatedbut not dysregulated
WT1Synpo Ki67
TAXONOMY OF PODOCYTOPATHIESidiopathic genetic reactive
MCN Idiopathic•Steroid-sensitive•Steroid-resistant
Non-syndromic•NPHS1•NPHS2
Syndromic•DYSF
Clinical association(immunologic stimuli, Tumors)
Medications(NSAID,gold, penicillamine, lithium, IF, pamidronate)
FSGS Idiopathic•Steroid-sensitive•Steroid-resistant
Non-syndromicITGB4, NPSH2, NPHS3, NPHS1 + NPHS2, COQ2, MHY9, ACTN4, CD2AP, TRCP6, WT-1
Syndromic
Post-adaptive•nephron mass•Initially normal nephron mass
Medications SyndromicMtDNA, WT1, PAX2, COQ6, COL4,GLA, LMBX1
(tacrolimus, lithium, IF, pamidronate)
DMS Idiopathic Non-syndromicWT1, NPHS1, NPSH2, NPHS3, LAMB2,
SyndromicWT1, LAMB2, COQ6,
CG Idiopathic Non-syndromicCOQ2MHY9
SyndromicSCARB
Infections (viruses, TB, others)
Clinical association•Autoimmune, TMA, tumors
Medications (IF, pamidronate, valproic acid)
� MCN, FSGS, DMS and CG are pattern of glomerular damage where t he commondenominator is podocyte injury and therefore they should be grouped under theumbrella of podocytopathies.
� Morphologic classifications alone are insufficient to cap ture the complexity andheterogeneity 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 s hould occur in 3steps :
Conclusions
steps :a. clinical evaluationb. morphologic evaluationc. additional clinical tests, such as genetic or serology fo r evidence of infections,
or others, when indicated.
� It is expected that in the future other variables (proteomic s, transcriptomics) willbe added to the present criteria to better define each catego ry and theirprognosis.
� The taxonomy should serve as a base structure to classify dis eases and guidetherapeutic approach.
PodocyteProliferation
Medications
Activation of
Specificgenetic
mutations
Dysregulation of mitochondrial Proliferation
CG
Activation of the immune
system
Ischemicinsult
of mitochondrial activity
Environmental factors
Infections
� MCN, FSGS, DMS and CG are pattern of glomerular injury rather thansingle entities. The common denominator is podocyte injury andtherefore they should be grouped under the umbrella ofpodocytopathies.
� We propose that final diagnosis of the podocytopathies shou ld occur in3 steps:
a. clinical evaluationb. morphologic evaluation
Conclusions
b. morphologic evaluationc. additional clinical tests, such as genetic or serology fo r evidence of
infections, or others, when indicated.
� It is expected that in the future other variables (proteomic s,transcriptomics) will be added to the present criteria to be tter defineeach category, their prognosis and identify the potential r esponse tospecific therapy (personalized medicine).
αααααααα--actinine actinine -- 4 4 -- associated FSGSassociated FSGS• Adult onset of FSGS • Variable degree of foot process effacement.• Rapid degradation and “second hit theory”
Kaplan, Nat Gen 2000
Podocin (NPHS2)Podocin (NPHS2)
Childhood onset of steroid resistant NSBoute 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• Most of mutations are clustered in N -terminal domain
Adult onset of steroid resistant NSTsukaguchi et al., JASN 2000
• Adolescent and adult-onset familial FSGS locus loca ted on Chromosome 1q25-31.
• Most of mutations are clustered in C-terminal domai n
• Rapid progression to renal failure
The PodocyteThe 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
Summary
• MCN, FSGS, DMS and CG are pattern of glomerular injury ratherthan single entities. The common denominator is podocyte in juryand therefore they should be grouped under the umbrella ofpodocytopathies.
• The common denominator is podocyte injury and therefore the yshould be grouped under the umbrella of podocytopathies.
• Each morphologic category is associated with (or the result of) aspecific pathway that injured podocyte may take, from alter edphenotype and no change in number, to podocytopenia, orproliferation, when developmental arrest or dedifferenti ation occur.
• Criteria for the classification of podocytopathies should include, inaddition to morphologic analysis, clinical associations a ndpodocyte phenotype.
Medications
Activation of
Specificgenetic
mutations
Dysregulation of mitochondrial
Collapsingglomerulopathy
Activation of the immune
system
Ischemicinsult
of mitochondrial activity
Environmental factors
Infections
In inherited CG (COQ2In inherited CG (COQ2--NP)NP)Podocyte phenotype is not dysregulatedPodocyte phenotype is not dysregulated
Ki67
WT1Synpo
Nephrotic syndrome – historical background
• Historically nephrotic syndrome was at first associated wi th the term“lipoid nephrosis” a renal disease where glomeruli have minimal lesions.
• In the early 20 th century, the histologic features of FSGS were firstdescribed as degenerative changes of glomeruli in lipoid ne phrosis.(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• It was not until the mid 20th century that it was reported there was adifferent clinical course between patients with NS and mini mal glomerularchanges versus those with juxtamedullary glomerular hyali ne orsclerosing lesions without cellular proliferation .(Rich A. “A hitherto underscribed vulnerability of the juxtamedullary glomeruli in lipoidnephrosis” Bull Johns Hopkins Hosp. 1957).
• Other authors began to report progressive renal disease in n ephroticpatients coinciding with progressive glomerular sclerosi s and increasedinterstitial scarring.(Hayslett JP Kl et al “Progression of "lipoid nephrosis" to renal insuffienciency” N Engl JMed. 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 SchnaperC-JASN 2007
Minimal change nephropathyMinimal change nephropathy
• Reversible – Steroid sensitive- idiopathic
- reactive (secondary)- drug-induced (NSAID,
pamidronate, interferon, others)- dysregulation of the
immune systemimmune system- hematologic malignancy
• Irreversible - Steroid resistant- idiopathic
- genetically determined- NPHS2- DYSF