EDITORIALS
Pathologic Classification of Focal Segmental Glomerulosclerosis:
A Working Proposal
I N 1957, ARNOLD RICH1 described segmen-
tal sclerosis involving juxtamedullary glo-
meruli in autopsy specimens of children dying of
nephrotic syndrome caused by apparent lipoid
nephrosis. He hypothesized that the development
of glomerulosclerosis accounted for the progres-
sion to renal failure seen in a subset of children
with idiopathic nephrotic syndrome. However, it
was not until the 1970s, in a report by the
International Study of Kidney Diseases in Chil-
dren, that focal segmental glomerulosclerosis
(FSGS) emerged as a separate clinicopathologic
entity distinguished from minimal change dis-
ease by its greater steroid resistance and progres-
sion to renal failure.2
During the past 4 decades, concepts of FSGS
have been refined in more detailed clinicopatho-
logic studies from numerous centers. FSGS is
defined as a clinicopathologic syndrome manifest-
ing with proteinuria, usually of nephrotic range,
associated with lesions of focal and segmental
glomerular sclerosis and foot-process efface-
ment.3,4 Early in the disease process, the pattern
of glomerular sclerosis is focal, involving a sub-
set of glomeruli, and segmental, involving a
portion of the glomerular tuft. As the disease
progresses, a more diffuse and global pattern of
sclerosis evolves. Alterations of the podocyte
constitute the major ultrastructural findings.
The approach to a diagnosis of FSGS is prob-
lematic because morphological features are non-
specific and can occur in a variety of other
conditions or superimposed on other glomerular
processes.5,6 Primary (or idiopathic) FSGS must
be differentiated from secondary forms with rec-
ognized etiologic associations, including genetic
mutations in podocyte-associated proteins (such
as -actinin-4, podocin, Wilms tumor [WT]-1
protein, and integrin),7-10 viruses (such as hu-
man immunodeficiency virus [HIV] type 1 and
parvovirus B19),11,12 and drug toxicities (such as
Received August 13, 2003; accepted in revised form
October 14, 2003.
2004 by the National Kidney Foundation, Inc.
0272-6386/04/4302-0013$30.00/0
doi:10.1053/j.ajkd.2003.10.024
368 American Journal of Kidney Diseases, Vol 43, No 2 (February), 2004: pp 368-382
heroin, interferon, lithium, and pamidronate)13-16
(Table 1). In addition, primary FSGS must be
distinguished from the large group of secondary
FSGS caused by structural-functional adapta-
tions mediated by intrarenal vasodilatation, in-
creased glomerular capillary pressures and plasma
flow rates, and other maladaptive processes6
(Table 1). Such maladaptive glomerular alterations
can arise through a reduction in the number of
functioning nephrons (such as after unilateral renal
agenesis, surgical ablation, oligomeganephronia, or
any advanced primary renal disease) or by mecha-
nisms that place hemodynamic stress on an initially
normal nephron population (as in morbid obesity,
cyanotic congenital heart disease, and sickle cell
anemia).6 Finally, primary and secondary forms of
FSGS also must be differentiated from the nonspe-
cific pattern of focal and segmental glomerular
scarring that can follow a variety of inflammatory,
proliferative, thrombotic, and hereditary condi-
tions, such as chronic glomerulonephritis, Alports
syndrome, and mitochondrial cytopathies.6,17-19
During the past 20 years, a growing number of
publications have addressed the morphological het-
erogeneity of primary and secondary FSGS.5,6,20
However, a standardized approach to the subclas-
sification of disease is lacking. The time has
come to consider subclassifying FSGS based on
morphological features, although there is consid-
erable controversy surrounding the significance
and definition of these variants. Precedents for a
consensus-based morphological approach to the
subclassification of renal disease can be found in
the World Health Organization (WHO) classifica-
tion of lupus nephritis,21 the Chapel Hill nomen-
clature of systemic vasculitides,22 and the Banff
working classification of renal transplant pathol-
ogy.23 As in the latter conditions, the pathologic
spectrum of FSGS is sufficiently complex that
there is a compelling need for a consensus classi-
fication based on a synthesis of the literature and
the knowledge of experts. The classification pre-
sented here is a working proposal predicated on a
large body of peer-reviewed literature. It at-
tempts to define more precisely and codify exist-
EDITORIAL 369

Table 1. Etiologic Classification of FSGS lularity may be seen, including endocapillary

Primary (idiopathic) FSGS
Secondary FSGS
1. Familial/genetic
A. Mutations in -actinin 4
B. Mutations in podocin
C. Mutations in WT-1
D. Mutations in integrin
2. Virus-associated
A. HIV-1 (HIV-associated nephropathy)
B. Parvovirus B19
3. Drug-induced
A. Heroin (heroin nephropathy)
B. Interferon-
C. Lithium
D. Pamidronate
4. Mediated by adaptive structural-functional responses
A. Reduced renal mass
Oligomeganephronia
Unilateral renal agenesis
Renal dysplasia
Reflux nephropathy
Sequela to cortical necrosis
Surgical renal ablation
Chronic allograft nephropathy
Any advanced renal disease with reduction in
functioning nephrons
B. Initially normal renal mass
Hypertension
Atheroemboli or other acute vaso-occlusive
processes
Obesity
Cyanotic congenital heart disease
Sickle cell anemia
ing concepts to provide a standardized approach
to the morphological subclassification of FSGS.
HISTORIC APPROACH TO HISTOLOGICAL
SUBCLASSIFICATION OF FSGS
Primary and secondary FSGS include a num-
ber of morphological subtypes that may have
different prognostic and therapeutic implica-
tions. Historically, the early descriptions of Rich1
depicted discrete segmental scars with hyalino-
sis, predominantly affecting juxtamedullary glo-
meruli. In the early 1980s, the pathologic hetero-
geneity of FSGS was increasingly appreciated.
The lesions of FSGS differed in both their topo-
graphic location within the glomerular tuft and
the quality of endocapillary and extracapillary
alterations.
Schwartz and Lewis24 were the first to draw
attention to the cellular lesion of FSGS, in
which endocapillary and extracapillary hypercel-
foam cells, infiltrating leukocytes, and pyknotic
cellular debris. They noted that cellular features
correlated with a shorter time course from onset
of clinical disease to renal biopsy, suggesting
that they represent an early stage in the develop-
ment of the segmental scars.24 Although these
investigators were the first to coin the term
cellular FSGS, observations on this lesion were
made as early as 1970 by Churg et al2 and 1975
by Velosa et al.25
After the emergence and recognition of HIV-
associated nephropathy as a collapsing form of
FSGS in the 1980s,11 there was increasing aware-
ness that similar histological lesions existed in
some patients with primary FSGS, although these
cases lacked endothelial tubuloreticular inclu-
sions at the ultrastructural level.26-28 The relation-
ship of this collapsing lesion to the previously
described cellular lesion has been a point of
contention, and clearly, overlap exists between
these forms with respect to the extracapillary
cellularity caused by podocyte hyperplasia. Cases
of primary FSGS with collapsing features were
noted by several groups to be more prevalent in
African Americans and to have more severe
renal insufficiency at presentation, more severe
markers of nephrotic syndrome, and a more
rapidly progressive course to renal failure than
noncollapsing forms.27,28
The importance of the location of segmental
lesions with respect to the perihilar and periph-
eral segments also has been debated. Perihilar
lesions have been reported to be more common
in adults versus children29 and in secondary
forms mediated by glomerular hyperfiltration/
hypertension, such as obesity-related glomeru-
lopathy30,31 and hypertensive nephrosclerosis with
proteinuria.32 It has been hypothesized that the
predisposition for sclerosis to occur in the peri-
hilar segment may relate to greater filtration
pressures in the more proximal portions of the
glomerular capillary bed.5
Lesions arising in the periphery at the tubular
pole have been termed tip lesions by Howie
and Brewer.33 Evidence from several groups sug-
gests that cases of tip lesion may have a clinical
course more like that of minimal change disease,
with greater likelihood of steroid responsivity
and more favorable outcome.34,35 It is possible
that this lesion arises through physical stress
370 DAGATI ET AL

Table 2. Glossary of Terms

Adhesion: continuity of collagenous matrix between the glomerular tuft and Bowmans capsule
Collapse: implosive glomerular capillary wall collapse with wrinkling of glomerular basement membranes causing
obliteration of the capillary lumen/lumina, without increase in intracapillary matrix or cells
Confluence of podocytes with parietal or tubular epithelial cells at the tubular lumen or neck: direct cellular contact of
podocytes with the parietal epithelial cells or tubular epithelial cells at the tubular lumen or neck
Endocapillary hypercellularity: occlusion of glomerular capillaries by absolute increase in the number of intraluminal cells,
which can include foam cells, endothelial cells, macrophages, and other leukocytes, sometimes associated with
hyalinosis, karyorrhexis, and rarely fibrin, often producing an expansile lesion
Focal: involving some, but not all, glomeruli
Global: affecting the entire glomerular tuft
Glomerulomegaly: glomerular tuft larger than that in age-matched controls (by measurement, glomerular area 1.5
normal)
Hyaline: glassy smooth eosinophilic accumulation of proteinaceous material
Mesangial hypercellularity: 3 mesangial cells surrounded by mesangial matrix in an intact glomerular segment in 3-m
thick sections
Perihilar: segmental involvement contiguous with the glomerular hilus
Podocyte hyperplasia: increased number of podocytes, often with crowding and multilayering; unlike true crescents, these
lesions typically lack cell spindling, pericellular matrix, extracapillary fibrin, or continuity with parietal epithelial cells
Podocyte hypertrophy: increased size of the podocyte with or without intracytoplasmic protein resorption droplets,
vacuoles, nuclear enlargement and vesiculation, and prominent nucleoli
Sclerosis: increased glomerular extracellular matrix with obliteration of the glomerular capillary lumen/lumina
Segmental: 100% glomerular tuft involvement with some residual patent glomerular capillaries
Tip domain: outer 25% of the tuft next to the origin of the proximal tubule (the tubular pole must be identified)
Tuft: the glomerular globe, not including Bowmans capsule or Bowmans space

placed on the paratubular segment of the tuft in
the setting of severe nephrotic syndrome by the
flux of protein-rich filtrate toward the tubular
pole, and a role for glomerular prolapse as a
precursor to tip lesion formation has been pro-
posed.36 The existence of tip lesions in a variety
of glomerular diseases manifesting proteinuria
(such as immunoglobulin A [IgA] nephropathy,
membranous glomerulopathy, and diabetic ne-
phropathy) would support this contention.37 The
potential reversibility of the tip lesion and how
this lesion should be viewed within the minimal
change diseaseFSGS spectrum remain to be
defined.
WORKING GROUP METHODS
The histological subclassification of FSGS has
been hampered by lack of conformity in the
definition of the variants and lack of agreement
about the pathologic terminology and usage. To
achieve uniformity in the approach to the patho-
logic classification of FSGS, an international
group of renal pathologists with mutual interest
in FSGS convened at Columbia University, New
York, NY, from November 4 to 5, 2000. The
goals of the meeting were to define terms and
formulate a classification of the histological vari-
ants of FSGS on which to base future clinical-
pathologic studies. First, cases from each of the
participating centers illustrating the broad scope
of morphological presentations of FSGS were
reviewed using a multiheaded microscope. After
extensive discussion of the morphological char-
acteristics of the lesions, a set of histological
terms was defined (Table 2). Once a consensus
on the meaning and proper usage of these descrip-
tive terms was reached, a working classification
of the variants of FSGS was formulated (Tables 3
and 4). After the consensus meeting in New
York, the participants collected a spectrum of
FSGS biopsy specimens from their respective
practices (42 specimens total) and circulated
them among each other to evaluate the applicabil-
ity of the definitions and classification. There
was agreement among participating pathologists
on the application and usage of the proposed
classification.
PROPOSAL
Recommendations for Tissue Processing and
Interpretation of Immunofluorescence and Electron
Microscopy
We recommend that renal biopsy specimens
be processed by a skilled technologist, cut at 3
EDITORIAL 371

Table 3. Morphological Classification of FSGS

Variant Inclusion Criteria Exclusion Criteria

FSGS (NOS) At least 1 glomerulus with segmental increase in matrix Exclude perihilar, cellular,
obliterating the capillary lumina tip, and collapsing variants
There may be segmental glomerular capillary wall
collapse without overlying podocyte hyperplasia
Perihilar At least 1 glomerulus with perihilar hyalinosis, with or Exclude cellular, tip, and
variant without sclerosis collapsing variants
50% of glomeruli with segmental lesions must have
perihilar sclerosis and/or hyalinosis
Cellular At least 1 glomerulus with segmental endocapillary Exclude tip and collapsing
variant hypercellularity occluding lumina, with or without variants
foam cells and karyorrhexis
Tip variant At least 1 segmental lesion involving the tip domain Exclude collapsing variant
(outer 25% of tuft next to origin of proximal tubule) Exclude any perihilar
The tubular pole must be identified in the defining lesion sclerosis
The lesion must have either an adhesion or confluence
of podocytes with parietal or tubular cells at the
tubular lumen or neck
The tip lesion may be cellular or sclerosing
Collapsing At least 1 glomerulus with segmental or global collapse None
variant and overlying podocyte hypertrophy and hyperplasia

m or less, optimally studied by at least 15 serial
sections, and stained with hematoxylin and eosin
(H&E), periodic acidSchiff (PAS), Masson
trichrome, and Jones methenaminesilver (JMS).
H&E will provide an excellent assessment of the
glomerular cellularity, podocyte alterations, and
presence of foam cells or infiltrating leukocytes.
Areas of sclerosis will be highlighted as blue,
and areas of hyalinosis as red or orange, by
Masson trichrome stain. PAS and JMS stains
show the state of the glomerular basement mem-
brane and delineate areas of collapse and solidifi-
cation by matrix material. Serial sections will
provide a thorough sampling of the tissue and
allow tracking of particular lesions through dif-
ferent levels of the paraffin block to assess their
relationship to the vascular and tubular poles.
Complete workup of the biopsy specimen re-
quires immunofluorescence and electron micros-
copy. Integration of immunofluorescence and
ultrastructural findings with light microscopy
and clinical history will allow differentiation of
primary and secondary forms of FSGS from the
nonspecific pattern of segmental sclerosis that
can occur in other primary glomerular diseases
(such as the chronic scarred phase of IgA nephrop-
athy, pauci-immune glomerulonephritis, lupus
nephritis, or hereditary nephritis).
By immunofluorescence, FSGS typically
shows focal and segmental granular deposition
of IgM, C3, and, more variably, C1 in the distri-
bution of the segmental glomerular sclerosis and
hyalinosis. More generalized weak mesangial
deposition of IgM and C3 also may be present.
Staining for albumin and some immunoglobulins
(particularly IgA, as well as IgG) may be found
within the podocytes, corresponding to intracyto-
plasmic protein resorption droplets. Similarly,
intracytoplasmic staining for albumin, immuno-
globulins, and, sometimes, C3 may be found in
proximal tubules, reflecting protein resorption.
Substantial (ie, numerous or 1 intensity) glo-
merular deposits of IgG or IgA in mesangial,
subendothelial, or subepithelial locations are in-
compatible with a diagnosis of FSGS.
By electron microscopy, the lesions of segmen-
tal sclerosis show wrinkling and retraction of
glomerular basement membrane and accumula-
tion of inframembranous hyaline, with resulting
narrowing or occlusion of the glomerular capil-
lary lumina. Hyaline deposits are electron dense
and may contain curvilinear membranous par-
ticles or entrapped electron-lucent lipid globules.
Endocapillary foam cells appear as large intracap-
illary cells containing abundant electron-lucent
vacuoles. Sparse small electron densities may be
identified in the mesangium. However, the pres-
ence of sizeable or regular electron-dense depos-
its in the subendothelial or subepithelial location
372 DAGATI ET AL

Table 4. Morphological Features of Histological Variants of FSGS

Location
of Distribution
Defining of Defining Podocyte Hypertrophy/ Mesangial Arteriolar
Variant Lesions Lesions Defining Features Hyaline Adhesion Hyperplasia Glomerulomegaly Hypercellularity Hyalinosis

1. FSGS Anywhere Segmental Segmental increase in / / / / / /

(NOS) matrix obliterating
capillary lumina
(also segmental
collapse without
overlying podocyte
hyperplasia)
Exclude 2,3,4, and 5
2. FSGS Perihilar Segmental At least 1 glomerulus / / / / / /
perihilar with perihilar
variant hyalinosis /
sclerosis
50% of glomeruli
with segmental
lesions must have
perihilar sclerosis
and/or hyalinosis
Exclude 3,4, and 5
3. FSGS Anywhere Segmental At least 1 glomerulus / / / / / /
cellular with segmental
variant endocapillary
hypercellularity
occluding lumina,
/ foam cells,
/ karyorrhexis
Exclude 4 and 5
4. FSGS At tip Segmental At least 1 segmental / / / / / /
tip variant domain lesion involving tip
domain (outer 25%
of tuft next to origin
of proximal tubule)
The tubular pole must
be identified
Lesion must have
either an adhesion
or confluence of
podocytes with
parietal or tubular
cells at the tubular
lumen or neck
Lesions can be
sclerosing (in 25%
of tuft) or cellular (in
50% of tuft)
No perihilar sclerosis
Exclude 5
5. FSGS Anywhere Segmental At least 1 glomerulus / / / Often with / / /
collapsing or global with collapse and droplets/vacuoles
variant overlying podocyte
hypertrophy and
hyperplasia

NOTE. Plus () and minus () indicate the range of possible findings in all the involved glomeruli of a given biopsy
specimen with the most frequent finding to the left and the least frequent finding to the right of the virgule.

of nonsclerotic capillaries is incompatible with a mulation of lamellated neomembrane material is

diagnosis of FSGS.
Directly overlying the lesions of segmental
sclerosis, there usually is complete effacement of
foot processes, accompanied by podocyte alter-
ations that include hypertrophy, increased or-
ganellar content, and focal microvillous transfor-
mation. This microvillous appearance is caused
by the formation of slender cellular projections
resembling villi along the surface of podocytes
facing the urinary space. The hypertrophied podo-
cytes show rounded cell bodies that adhere
smoothly to the glomerular basement membrane,
with frequent loss of primary processes. There
may be detachment of podocytes from the scle-
rosing segment. In these areas, intervening accu-
often observed between the naked glomerular
basement membrane and retracted podocyte cell
body. The major ultrastructural finding involving
nonsclerotic glomerular capillaries is foot-pro-
cess effacement, which may vary from mild to
severe. In areas of foot-process effacement, there
usually is loss of recognizable slit diaphragms
and mat-like condensations of cytoskeletal fila-
ments oriented parallel to the glomerular base-
ment membrane. Thus, although the lesions of
FSGS are focal and segmental at the light micro-
scopic level, podocyte alterations are relatively
diffuse and global at the electron microscopic
level. Glomerular basement membranes of non-
sclerotic capillaries usually are normal in thick-
EDITORIAL
ness and texture. Extensive thinning or lamella-
tion of glomerular basement membranes (typical
of disorders of collagen IV) should be excluded.
Proposed Classification of Histological Variants of
FSGS
General Approach
The morphological categorization outlined next
encompasses the spectrum of primary FSGS, as
well as secondary forms. This schema presumes
previous exclusion of focal and segmental scle-
rosing conditions caused by glomerular scarring
in the course of other primary glomerular dis-
eases (such as chronic glomerulonephritis, dia-
betic glomerulosclerosis, membranous glomeru-
lopathy, and Alports syndrome) by integration
of light microscopy, immunofluorescence micros-
copy, electron microscopy, and clinical findings.
Table 2 provides a glossary of pertinent histo-
logical terms. Five main light microscopic pat-
terns of FSGS have been defined, including FSGS
not otherwise specified (NOS), perihilar variant,
cellular variant, tip variant, and collapsing vari-
ant (Tables 3 and 4). Although the appearance of
the glomerular tuft differs in these forms, all
share the common feature of podocyte alter-
ations at the ultrastructural, and often the light
microscopic, level (including podocyte hypertro-
phy and derangements in foot-process architec-
ture).
Formulating and applying a classification of
FSGS is a particular challenge because several
types of glomerular morphological lesions may
coexist in a renal biopsy specimen. We aimed to
devise a classification that would encompass the
spectrum of possible pathologic patterns using
categories that are mutually exclusive and, as
much as possible, nonoverlapping. Therefore, in
addition to inclusion criteria, we used a hierarchi-
cal system of exclusion for classification (Table
3). By this method, FSGS (NOS) requires exclu-
sion of all 4 of the other forms (perihilar, cellular,
tip, and collapsing). The perihilar variant, in
turn, requires exclusion of cellular, tip, and col-
lapsing variants. The cellular variant requires
exclusion of the tip and collapsing variants. The
former exclusion criteria are derived from the
fact that tip lesions, defined by their juxtatubular
location, may show either cellular or sclerosing
features. The tip variant requires exclusion of the
collapsing variant. In addition, the presence of
373
any glomerulus with perihilar sclerosis rules out
the tip variant. Finally, the presence of collapsing
sclerosis involving 1 or more glomeruli trumps
all the other categories. By this approach, a
biopsy specimen of FSGS can be assigned to a
histological subcategory based on its dominant
morphological features despite considerable in-
terglomerular heterogeneity.
The classification proposed is based entirely
on an assessment of glomerular light micro-
scopic features, but requires immunofluores-
cence and electron microscopic examination to
exclude other causes of sclerosis (discussed pre-
viously). The classification requires assessment
of both the location and quality of the segmental
lesion. After specific variants are excluded, inclu-
sion criteria for a given category can be either the
presence of a single defining lesion (in the case
of tip, cellular, and collapsing categories) or the
percentage of segmental lesions with the defin-
ing characteristic (in the case of the perihilar
variant).
At the present time, it is unclear whether these
morphological variants reflect pathogenetic dif-
ferences or are the consequence of different
severities of podocyte (or other) injury or differ-
ent stages or rates of histopathologic evolution.
Our aim is that the proposed classification will
provide a framework to address these questions
in future clinicopathologic studies.
Specific Categories
FSGS (NOS). This category requires that all
other categories (FSGS perihilar variant, FSGS
cellular variant, FSGS tip variant, and FSGS
collapsing variant) be excluded. It is defined by
focal and segmental consolidation of the tuft by
increased extracellular matrix, obliterating the
glomerular capillary lumen/lumina (Fig 1A to
C). There may be segmental glomerular capillary
wall collapse without overlying podocyte hyper-
plasia. Lesions of sclerosis are typically discrete
and can affect perihilar and/or peripheral seg-
ments. Any number of glomeruli can be affected
by segmental sclerosis, with or without associ-
ated global sclerosis. Foam cells may be en-
trapped in sclerotic lesions. Most cases have
little, if any, podocyte hypertrophy or hyperpla-
sia. However, there is no restriction on the de-
gree of podocyte hypertrophy or hyperplasia,
provided these podocyte alterations do not affect
374 DAGATI ET AL

Fig 1. FSGS (NOS) and FSGS perihilar variant. (A) FSGS (NOS). A low-power view shows segmental lesions of
sclerosis in all 4 glomeruli pictured. Lesions of sclerosis are characterized by increased matrix, causing obliteration of
the capillary lumina. Distribution of lesions within the tuft is variable, affecting both peripheral and perihilar segments. In
some glomeruli, the location of the sclerosis cannot be ascertained because of the plane of section. (JMS; original
magnification 100.) (B) FSGS (NOS). High-power view of a glomerulus shows a discrete segmental lesion of sclerosis
with wrinkling and collapse of glomerular basement membranes (stained blue) and hyaline deposits (stained red).
Overlying the wrinkled capillaries, there is detachment of podocytes, which form a cap, with intervening deposition of
looser neomembrane that is weakly trichrome-blue positive. Although the capped podocytes appear hypertrophied,
there is no podocyte hyperplasia. (Masson trichrome; original magnification 400.) (C) FSGS (NOS). There is segmental
obliteration of the glomerular tuft by increased matrix and hyaline material. Sclerosed segments form adhesions to
Bowmans capsule. There is no obvious podocyte hypertrophy or hyperplasia. The location of the sclerotic lesion within
the glomerular tuft cannot be determined because neither the tubular nor the vascular pole are represented in the plane
of section. (PAS; original magnification 250.) (D) FSGS perihilar variant. On low-power examination, 1 of the 3 glomeruli
pictured contains a discrete lesion of segmental sclerosis affecting the vascular pole region. The lesion shows both
increased matrix (sclerosis) and hyalinosis. There is adhesion of the sclerotic segment to Bowmans capsule in the
vascular pole region. Perihilar lesions were identified in more than 50% of glomeruli with segmental sclerosis. Both the
glomerulus with segmental sclerosis and the 2 nonsclerotic glomeruli are hypertrophied in this patient with morbid
obesity. (PAS; original magnification 100.) (E) FSGS perihilar variant. High-power view of the perihilar lesion in (D)
shows both the increased matrix (sclerosis) and glassy hyalinosis deposited in the vascular pole segment of the tuft,
identified by the incoming arteriole and macula densa. There is no obvious podocyte hypertrophy or hyperplasia. (PAS;
original magnification 250.) (F) FSGS perihilar variant. A very early lesion illustrates the mild increase in matrix and
hyaline surrounding the glomerular hilus. There also is hyalinosis of the adjacent preglomerular arteriole. The
glomerulus is hypertrophied in this patient with a solitary functioning kidney. (PAS; original magnification 250.)
EDITORIAL 375

Fig 2. FSGS cellular variant. (A) The defining glomerulus in this patient with primary FSGS shows segmental
endocapillary hypercellularity. Involved segments are engorged with endocapillary cells, including some infiltrating
mononuclear leukocytes. (H&E; original magnification 250.) (B) In the cellular variant, silver stain shows
expansion of the involved segments by endocapillary cells (not matrix), including foam cells and some karyorrhec-
tic leukocytes. No glomerular capillary wall collapse is seen. There is hypertrophy and hyperplasia of the overlying
podocytes. (JMS; original magnification 400.) (C) This example of the cellular lesion shows numerous endocapil-
lary leukocytes, mimicking a segmental endocapillary proliferative glomerulonephritis. There is hypertrophy and
hyperplasia of overlying podocytes. Adjacent glomerular segments have mild mesangial hypercellularity. (H&E;
original magnification 400.) (D) High-power view of a cellular lesion shows karyorrhectic nuclear debris, admixed
with foam cells and hyaline material. Overlying podocytes are hyperplastic. (H&E; original magnification 600.) (E)
Electron micrograph of the cellular lesion shows engorgement of the glomerular capillary lumen by foam cells and
infiltrating mononuclear cells. There is mild inframembranous hyalinosis. No collapse or rupture of the glomerular
basement membrane is seen. There is overlying podocyte hypertrophy and complete foot-process effacement with
loss of primary processes. (Original magnification 2,500.) (F) Electron micrograph shows more pronounced
dilatation of the glomerular capillary by endocapillary cells, including many lipid-laden foam cells. Foot processes
are completely effaced, with loss of primary processes and detachment of podocytes from the glomerular basement
membrane. (Original magnification 2,500.)
376 DAGATI ET AL

Fig 3. FSGS tip variant. (A) Low-power view shows a segmental lesion involving the tip domain at the origin of
the tubular pole. The vascular pole is not visible in this plane of section. (PAS; original magnification 250.) (B)
High-power view of the lesion in A shows the involved segment to contain endocapillary foam cells and form an
adhesion to Bowmans capsule at the mouth of the proximal tubule. There is capping of the overlying podocytes,
which become confluent with the adjacent tubular epithelium. (PAS; original magnification 600.) (C) Low-power
view shows the portion of the glomerular tuft involving the tip domain to be expanded by a segmental lesion with
cellular features located at the tubular pole. (PAS; original magnification 250.) (D) High-power view of the tip lesion
in C shows endocapillary foam cells admixed with a few leukocytes. There is a small adhesion of the tuft to
Bowmans capsule at the tubular pole. Overlying podocytes appear confluent with the adjacent tubular epithelial
cells. (PAS; original magnification 600.) (E) Opposite the vascular pole, the origin of the proximal tubule is visible.
In this area, there is an early tip lesion with inframembranous hyalinosis, a few endocapillary foam cells, and
confluence of swollen podocytes with the tubular epithelium. (PAS; original magnification 250.) (F) In this
glomerulus, the tip lesion appears to herniate into the tubular lumen and forms a capsular adhesion. (PAS; original
magnification 250.) (G) High-power view of a tip lesion shows its cellular character, with endocapillary foam cells.
There is adhesion to the origin of the tubular pole, with capping of the overlying podocytes and confluence with the
adjacent tubular epithelium. (H&E; original magnification 600.) (H) This tip lesion has cellular features and forms
an adhesion to Bowmans capsule at the origin of the proximal tubule. The segment of the tuft containing the tip
lesion appears to be detached from the remainder of the tuft because of the plane of section. (PAS; original
magnification 250.) (I) In this example, the tip lesion has sclerosing, rather than cellular, features. There is
segmental sclerosis involving the tip domain at the origin of the proximal tubule, with adhesion to Bowmans
capsule and capping of the overlying podocytes. Brush border identifies the tubular epithelial cells. (PAS; original
magnification 250.)
EDITORIAL
Fig 3. (continued)
collapsed capillaries. Podocyte hypertrophy may
produce the appearance of podocyte capping
over the sclerosed segment. Hyalinosis and adhe-
sions are common, but not required, features.
Mesangial hypercellularity, glomerulomegaly,38
and arteriolar hyalinosis may occur.
This is the most common form of FSGS. All 4
variants described next may evolve into this
pattern in the course of disease progression and
increasing chronicity.
FSGS perihilar variant. This category re-
quires that the cellular variant, tip variant, and
collapsing variant of FSGS be excluded. Defin-
ing criteria include both of the following: (1)
there must be at least 1 glomerulus with perihilar
hyalinosis, with or without sclerosis; and (2)
more than 50% of glomeruli with segmental
lesions must have perihilar sclerosis and/or hya-
linosis (Fig 1D to F). Glomerulomegaly and
adhesions are common. There is often arteriolar
hyalinosis, sometimes in continuity with hyalino-
sis in the perihilar segment. Foam cells may be
entrapped in the sclerotic lesions. Podocyte hy-
pertrophy and hyperplasia may be present, as in
FSGS (NOS), but typically are less frequent than
377
in the other variants discussed next. Mesangial
hypercellularity usually is absent. Other glo-
meruli may show lesions of segmental and/or
global glomerulosclerosis, as described for FSGS
(NOS).
This variant of FSGS may occur in primary
FSGS. It also is common in patients with second-
ary forms of FSGS mediated by an adaptive
response to nephron loss or glomerular hyperten-
sion (eg, in association with obesity, cyanotic
congenital heart disease, reflux nephropathy, re-
nal agenesis, dysplasia, oligomeganephronia, or
any advanced renal disease with reduced number
of functioning nephrons).
FSGS cellular variant. This category re-
quires that the tip variant and collapsing variant
be excluded. It is defined by the presence of at
least 1 glomerulus with endocapillary hypercellu-
larity involving at least 25% of the tuft and
causing occlusion of the capillary lumen/lumina
(Fig 2). Any segment (perihilar and/or periph-
eral) may be affected. The lesions of endocapil-
lary hypercellularity may be expansile, causing
engorgement of the glomerular capillary(ies).
Endocapillary cells typically include foam cells,
378 DAGATI ET AL

Fig 4.
EDITORIAL 379

macrophages, and endothelial cells. Other leuko-
cytes, such as neutrophils and lymphocytes, also
may be present. Endocapillary cells occasionally
manifest apoptosis, producing pyknotic or kary-
orrhectic debris. Inframembranous hyaline may
be present; however, neither hyalinosis nor seg-
mental sclerosis are required features. Endocapil-
lary fibrin occasionally is identified, but without
associated rupture of the glomerular basement
membrane. Podocyte hypertrophy and hyperpla-
sia are typically identified overlying these le-
sions, but are not required features. Adhesions
may or may not be present. Glomerulomegaly
and mesangial hypercellularity are uncommon.
Other glomeruli may contain lesions of segmen-
tal and/or global glomerulosclerosis as described
for FSGS (NOS).
FSGS tip variant. This category requires that
the collapsing variant be excluded. It is defined
by the presence of at least 1 segmental lesion
involving the tip domain (ie, the outer 25% of the
tuft next to the origin of the proximal tubule)
with either adhesion between the tuft and Bow-
mans capsule at the tubular lumen or neck, or
confluence of podocytes with parietal or tubular
epithelial cells at the tubular lumen or neck (Fig
3). The proximal tubular pole must be identified
in the defining glomerulus. In some cases, the
affected segment appears to herniate into the
tubular lumen. Segmental lesions may be charac-
terized by either endocapillary hypercellularity
(involving 50% of the tuft) or sclerosis (involv-
ing 25% of the tuft). Foam cells are common.
Hyalinosis is variable. There often is podocyte
hypertrophy/hyperplasia overlying the involved
segment. Mesangial hypercellularity, glomerulo-
megaly, and arteriolar hyalinosis are variable
findings. Although initially peripheral, these le-
sions may evolve more centrally. Other glo-
meruli may show segmental sclerosis or endocap-
illary hypercellularity in the periphery, but not
involving the tip, or in a portion of the tuft that
cannot be identified as tip or perihilar. However,
the presence of segmental sclerosis or endocapil-
lary hypercellularity in a perihilar location in any
glomerulus rules out the tip variant of FSGS.
Global sclerosis may be present.
FSGS collapsing variant. This category pre-
empts all the other variants. It is defined by at
least 1 glomerulus with collapse and overlying
podocyte hypertrophy and hyperplasia (Fig 4).
The number of glomeruli with defining lesions is
highly variable. Collapsing lesions may be seg-
mental or global. Both peripheral and/or peri-
hilar segments may be involved. The hypertro-
phied and hyperplastic podocytes typically crowd
the urinary space and often contain intracytoplas-
mic protein droplets and vacuoles. Adhesions
and hyalinosis are unusual, at least in the early
stages. Mesangial hypercellularity, glomerulo-
megaly, and arteriolar hyalinosis are uncommon.
Other glomeruli may contain segmental lesions
of any category (usual sclerosis, endocapillary
hypercellularity, lesions at the tip domain) and/or
global sclerosis.
DISCUSSION
We propose that 5 morphological variants of
FSGS can be defined by histological criteria,
based entirely on assessment of glomerular light
microscopic alterations. These criteria encom-
pass the spectrum of primary FSGS, as well as

4
Fig 4. FSGS collapsing variant. (A) A low-power view shows 4 glomeruli, all of which have global collapse of the
tuft and podocyte hypertrophy and hyperplasia. There are associated tubular degenerative changes. (JMS; original
magnification 100.) (B) On high-power view, the lesion of collapsing sclerosis shows global occlusion of capillary
lumina by implosive collapse of glomerular basement membranes. There is no appreciable increase in intracapillary
cells or matrix. Overlying podocytes form a cellular corona over the collapsed tuft. Some of the enlarged podocytes
appear binucleated and have lost their cohesion to the tuft. (JMS; original magnification 400.) (C) An example of
global collapse of the glomerular tuft with marked overlying podocyte hyperplasia, forming a pseudocrescent that
fills the urinary space. An apoptotic podocyte has detached from the tuft and is passing into the tubular pole. (JMS;
original magnification 400.) (D) Hyperplastic podocytes contain numerous intracytoplasmic protein resorption
droplets, which appear red with trichrome stain. The collapsed tuft, shown in blue, has no patent capillary lumina.
(Masson trichrome; original magnification 400.) (E) Hyperplastic podocytes form several layers of cells over the
collapsed tuft. Some of the swollen podocytes contain intracytoplasmic vacuoles. Podocyte nuclei have a vesicular
chromatin pattern with prominent nucleoli. (JMS; original magnification 400.) (F) A segmental lesion of collapsing
sclerosis spares more than half the tuft. Collapsed capillaries have prominent overlying podocyte hypertrophy and
hyperplasia, with abundant trichrome-red intracytoplasmic protein resorption droplets. (Masson trichrome; original
magnification 400.) (G) By electron microscopy, the collapsed loop has folded glomerular basement membranes,
with complete effacement of foot processes. Overlying podocytes are detached from the glomerular basement
membrane with intervening layering of neomembrane material. (Original magnification 2,500.)
380
secondary forms. However, focal and segmental
glomerular scarring following other primary glo-
merular diseases (eg, immune-complex glomeru-
lonephritis and hereditary nephritis) should be
ruled out by immunofluorescence and electron
microscopy. According to this schema, FSGS
(NOS) constitutes the generic most common
lesion of FSGS. The synonyms classic FSGS or
FSGS of the usual type have been applied in the
past. This category requires that other morpho-
logical categories (perihilar, cellular, tip, and
collapsing variants) be excluded. Evidence from
repeat biopsies suggests that other variants may
evolve into the FSGS (NOS) pattern in the course
of disease progression.
The perihilar variant requires that the cellular
variant, tip variant, and collapsing variant be
excluded. Introduction of the perihilar cat-
egory was based on the recognition that some
forms of FSGS have lesions predominantly origi-
nating at the glomerular hilus, accompanied by
perihilar hyalinosis. In our groups experience,
there was empirical appreciation that FSGS bi-
opsy specimens showing a predominance of peri-
hilar lesions, especially when accompanied by
glomerulomegaly, often represent secondary
forms of FSGS mediated by glomerular hyperten-
sion or other adaptation after loss of renal mass,
as supported by the literature.31,32 Although peri-
hilar lesions may be seen in both primary and
secondary FSGS, the introduction of this cat-
egory may help the pathologist identify forms of
FSGS more likely to be secondary to structural-
functional adaptations to loss of renal mass or
glomerular hypertension, to be confirmed by
other supporting clinical and pathologic features.
By the exclusion criteria proposed, a biopsy with
greater than 50% of segmental lesions showing
perihilar sclerosis and hyalinosis with a single tip
lesion would be classified as perihilar variant
because the presence of any perihilar sclerosis
excludes tip variant. However, a biopsy speci-
men with only 20% of segmental lesions show-
ing perihilar sclerosis and hyalinosis and with
several tip lesions would be classified as FSGS
(NOS) because it does not meet defining criteria
for either perihilar variant (requirement of at
least 50% of segmental lesions to be perihilar) or
tip variant (no perihilar sclerosis permitted).
A diagnosis of cellular FSGS requires that tip
and collapsing variants be excluded. The exclu-
DAGATI ET AL
sion of tip variant is based on the observation
that most tip lesions are cellular in nature.33,39
The tip variant of FSGS is defined by the pres-
ence of at least 1 glomerulus with a segmental
lesion of cellular or sclerosing nature involving
the tip domain. The designation of tip lesion
requires that the collapsing variant be excluded.
Moreover, the presence of any glomerulus with a
segmental lesion in the perihilar location rules
out the tip variant, in keeping with the peripheral
phenotype of this variant.39
We propose that the designation of collapsing
variant (also known as collapsing glomerulopa-
thy) be applied to cases of FSGS in which at least
1 glomerulus shows segmental or global oblitera-
tion of the glomerular capillary lumina by wrin-
kling and collapse of glomerular basement mem-
branes in association with hypertrophy and
hyperplasia of the overlying podocytes. The col-
lapsing lesion involving a single glomerulus is
considered significant, such that the presence of
any glomerular collapse with the requisite associ-
ated podocyte hyperplasia preempts the other
morphological categories of FSGS. This pattern
has been described in some patients with primary
FSGS,26-28 as well as in HIV-associated nephrop-
athy,11 parvovirus B19 infection,12 and pamidr-
onate toxicity.16 It also has been reported in some
secondary forms of FSGS, such as chronic allo-
graft nephropathy with chronic transplant arteri-
opathy (in which the zonal distribution of glomer-
ular lesions suggests a vascular or hemodynamic
basis),40 atheroembolism,41 acute vaso-occlusive
events, and other rare associations.
The approach to classification of FSGS can
now designate a morphological category (listed
in Tables 3 and 4) and, when possible, an etio-
logic category (listed in Table 1). The 2 classifi-
cation systems are not mutually exclusive, but
can be applied together to a particular biopsy
specimen. This approach is analogous to the
manner in which glomerulonephritis is described
by a morphological pattern (mesangial prolifera-
tive, endocapillary proliferative, extracapillary
proliferative) and an etiologic modifier (consis-
tent with IgA nephropathy, lupus nephritis, anti
glomerular basement membrane nephritis, and
so on). Similarly, after complete workup, it may
be ascertained that a biopsy specimen manifest-
ing FSGS collapsing variant represents primary
FSGS, HIV-associated nephropathy, or pamidr-
EDITORIAL
onate toxicity, for example. On clinical correla-
tion, a biopsy specimen showing FSGS perihilar
variant may prove to be primary FSGS or be
secondary to obesity, renal agenesis, or reflux
nephropathy, among others. Morphological clas-
sification according to Tables 3 and 4 does not
eliminate the need to identify secondary causes
of FSGS. As the morphological classification is
applied routinely, it may facilitate the identifica-
tion of new etiologic associations that typically
manifest a particular pattern of sclerosis, in the
same way that appreciation of the collapsing
variant aided the morphological identification of
HIV-associated nephropathy in the 1980s14 and
pamidronate toxicity in recent years.29
Subclassifications of disease on morphologi-
cal grounds are valid only if they carry meaning-
ful clinical or pathogenetic implications. It re-
mains to be determined how the different
morphologic subtypes of FSGS may reflect dif-
ferences in etiology, pathogenesis, prognosis, or
optimal therapy. It is possible that different severi-
ties or types of podocyte injury will be identified
in the various subcategories of FSGS, with differ-
ent implications for patient prognosis and man-
agement. We hope the proposed pathologic
schema will allow studies to be devised that
address these issues using standardized and repro-
ducible terminology. As a working classification
analogous to the Banff classification of renal
transplant pathology or the WHO classification
of lupus nephritis, this proposal provides a tem-
plate for future iterations as our understanding of
pathogenesis and clinical relevance evolve.
ACKNOWLEDGMENT
The authors thank Dr Adrian Spitzer for his help in the
organization of the consensus conference and the Kidney
and Urology Foundation of America for its generous sup-
port. A summary of the consensus classification was pre-
sented in a recent review article.42
Vivette D. DAgati, MD
Department of Pathology
Columbia University
College of Physicians and Surgeons
New York, NY
Agnes B. Fogo, MD
Department of Pathology
Vanderbilt University
Nashville, TN
381
Jan A. Bruijn, MD
Department of Pathology
Leiden University Medical Center
Leiden, The Netherlands
J. Charles Jennette, MD
Department of Pathology
University of North Carolina at Chapel Hill
Chapel Hill, NC
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