A NEW TAXONOMY FOR THE PODOCYTOPATHIES · 2009. 3. 29. · Hyalinosis and foam cells can also be present. Low ... • Idiopathic • Inherited - syndromic - non-syndromic • Reactive

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

Podocyte injury = foot process effacementPodocyte injury = foot process effacement

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 MINIMAL CHANGE NEPHROPATHYNEPHROPATHYNEPHROPATHYNEPHROPATHY

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

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

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

ba

Podocin: control Podocin: steroid-resistant MCN

c d

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

Which is the relationship between glomerulomegaly

and FSGS?

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

DIFFUSE MESANGIAL DIFFUSE MESANGIAL SCLEROSISSCLEROSISSCLEROSISSCLEROSIS

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

COLLAPSING COLLAPSING GLOMERULOPATHYGLOMERULOPATHYGLOMERULOPATHYGLOMERULOPATHY

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 idiopathic and HIV-associated CG dedifferentiated podocytes have a

dysregulated phenotype

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

Podocyte phenotype in human idiopathic and HIV-associated CG

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