This document discusses a new taxonomy for classifying podocytopathies, diseases involving injury to podocytes. It proposes organizing podocytopathies based on their histopathology (morphological pattern of glomerular injury and podocyte number) and etiology (idiopathic, genetic, reactive). Four main morphological patterns are described: minimal change nephropathy (MCN), focal segmental glomerulosclerosis (FSGS), diffuse mesangial sclerosis (DMS), and collapsing glomerulopathy (CG). Each pattern is defined and their etiologies and clinical associations are discussed. The taxonomy aims to integrate morphological diagnoses with etiology based on current understanding of podocyte biology and
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1. A NEW TAXONOMY FOR THE
PODOCYTOPATHIES
Laura Barisoni
Department of Pathology and
Medicine, Division of Nephrology
New York University
2. Old classification schemes:
Proteinuria and
nephrotic syndrome
MCD FSGS
Poor prognosis and
Good prognosis and
Poor Response to
Response to steroid
Steroid therapy
Therapy
3. 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.
5. 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.
6. 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
7. 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)
8. 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.
10. 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
12. 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
14. 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
15. How do we translate this large
variety of insults into four
morphologic patterns of
glomerular injury?
16. 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
18. 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
21. 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
22. 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
23. a b
Podocin: control Podocin: steroid-resistant MCN
d
c
25. 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 (?)
26. 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.
27. Reactive forms:
Hyperfiltration-
Hyperfiltration-mediated FSGS
glomerulomegaly in pt with single kidney
Segmental sclerosis large non-sclerotic glomerulus
28. Which is the relationship
between glomerulomegaly
and FSGS?
29. 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
32. 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.)
33. 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).
34. 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)
35. 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
39. CG is a proliferative disease:
Dedifferentiated podocytes re-enter the
cell cycle and proliferate
Early phase Late phase
40. 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
41. In idiopathic and HIV-associated CG
dedifferentiated podocytes have a
dysregulated phenotype
42. In inherited CG (COQ2-NP)
(COQ2-
podocyte phenotype is dedifferentiated
but not dysregulated
Synpo Ki67 WT1
44. 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.
45.
46. Specific
genetic
mutations
Medications
Podocyte Dysregulation
Activation of Proliferation of mitochondrial
the immune activity
system
CG
Ischemic
insult
Environmental
Infections
factors
47. 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).
48. 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
49. 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
50. 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
53. 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.
54. Specific
genetic
mutations
Medications
Dysregulation
Activation of of mitochondrial
the immune Collapsing activity
system glomerulopathy
Ischemic
insult
Environmental
Infections
factors
55. In inherited CG (COQ2-NP)
(COQ2-
Podocyte phenotype is not dysregulated
Ki67
Synpo WT1
56. 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)
57. 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
