EDITORIAL
Focal Segmental Glomerulosclerosis:
Does Histology Predict Outcome?
Shaheera Shakeel Malik and Muhammed Mubarak
Focal and Segmental Glomerulosclerosis (FSGS) is not
a single disease entity; rather, it represents a
morphologic ideogram of a spectrum of pathologic
disorders involving the kidney, either as a primary
process or secondary to some systemic disorders.1 It is
one of the predominant morphologic insignia presenting
with Nephrotic Syndrome (NS) in both adults and
children. It accounted for 39.87% and 38.14% of
nephrotic adult and pediatric patients in previously
reported studies.2,3 FSGS is one of the leading causes
of End-Stage Renal Disease (ESRD) in both adult and
pediatric patients worldwide.4,5 The correct recognition
and proper categorization of the histological spectrum of
this lesion is of considerable help for better management
and prediction of the outcome.
The framework for classification of FSGS is diverse,
reflecting the heterogeneity of the disease. It may be
classified on the basis of etiology.6 The other foundation,
commonly employed to classify the disease, is on the
basis of morphological features as detected on renal
biopsies. These provide a suitable benchmark for
rendering uniform and reproducible diagnostic criteria.7-9
The Columbia classification is a working proposal put
forward by a collaborative panel of expert renal
pathologists in 2000.7 This classification schema is
based on an algorithmic approach towards an attempt to
unify the descriptive terminologies for the histological
variants of FSGS. This schema empowers renal
pathologists to arrive not only at the best possible
morphologic diagnosis but also guides nephrologists to
consign appropriate management and speculate
probable outcome of the disease.7-9
This hierarchical classification elaborates rigorously
defined diagnostic criteria for each of the five subtypes
of FSGS. Furthermore, these defining hallmark features
may be observed in primary as well as secondary FSGS.
However, the noteworthy ultrastructural foot process
effacement responsible for this podocytopathy has not
been addressed.1 Soon after the promulgation of
Department of Histopathology, Sindh Institute of Urology and
Transplantation (SIUT), Karachi.
Correspondence: Prof. Dr. Muhammed Mubarak, Professor of
Pathology, Department of Histopathology, Sindh Institute of
Urology and Transplantation, Karachi-74200.
E-mail: [email protected]
Received: July 30, 2015; Accepted: October 27, 2015.
Columbia classification of FSGS, several retrospective
as well as prospective studies from around the world
elucidated the significance and clinical relevance of this
dynamic classification. Despite the above mentioned
shortcoming, the prognostic and therapeutic utility of this
schema has been widely acknowledged.1,7-10
The authors have previously reported the relative
frequencies of these five variants among both adult and
pediatric nephrotics at our center. 8,9 There is a
remarkable variation in relative frequencies of these
variants as reported from various parts of the world. To
illustrate the point, the prevalence of FSGS, Not
Otherwise Specified (NOS) variant, varies from 42% to
77%.1-7 It is the predominant lesion among all the five
variants in most of the studies from different ethnic and
geographic areas. The possible reason for this may be
the evolution of any of the other four variants which may
ultimately result into this histological pattern.10 NOS
variant was found in 76.6% of adult nephrotic patients.
The second most common variant among our adult
nephrotic population was collapsing variant, accounting
for 12% of cases.8 This variant is markedly notorious in
its clinical course and progression towards ESRD,
probably due to severe tubulointerstitial damage
associated with this unique glomerular lesion. This
component is not a part of the defining criteria as per
Columbia classification, but it reflects the morphologic
signature of clinical course and progression of the
disease.9,10 Indeed, at the molecular level, the
collapsing variant is characterized by a lack of podocyte
maturity markers, and re-expression of immaturity
markers, particularly in the collapsed region.11 This
molecular insight might help in future to develop novel
therapies against these podocyte differentiation
markers.
The third variant following the collapsing was tip variant,
accounting for 9.8% in our series.8 The reported
frequency of this variant also varies from 13% to 17%.1-8
The defining criteria of this variant have curious
restrictions and need exclusion of other variants. Some
authors even suggest that the tip lesion is simply a
glomerular response to heavy proteinuria which may be
observed in minimal change nephropathy, FSGS or in
diabetic nephropathy.1,12 However, it has been observed
that glomerular tip lesion, either defined by original
definition or by Columbia classification, follows more
favorable clinical course in terms of excellent response
to steroid therapy.7,12
Journal of the College of Physicians and Surgeons Pakistan 2015, Vol. 25 (12): 849-850
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Shaheera Shakeel Malik and Muhammed Mubarak
The next variant is perihilar variant which, like the tip
variant, is defined topographically and requires
exclusion of all other variants.7 Its frequency varies from
26% to 43%. We have found a frequency of 1.1% in our
series.8 This variant is more commonly associated with
forms secondary to hyperfiltration, nephron loss or
glomerular hypertension and often accompanied by
glomerulomegaly. The clinical course is slowly
progressive and will lead to ESRD within few years.
Last, but not the least, is the cellular variant, which is
remarkable in its novel defining features. The relative
frequency varies from 1% to 3% in different series.7 We
have reported 0.5% in this study.8 It is not clear as to
whether the low frequency of this lesion is due to real
rarity of this entity or due to difficulty in categorizing this
lesion accurately. There is remarkable overlap in
histological features of cellular and collapsing variants,
so the latter variant should be excluded carefully.
Unfortunately the clinical implications of cellular variant
are not very clear due to very limited number of cases in
the majority of studies. However, one of the studies with
largest number of cellular variants reported by Stokes
et al. observed no statistically significant difference in
clinical course and progression of disease with the NOS
variant.13
Much more important than the above glomerular
changes from the prognostic point of view are the
changes in the tubulointerstitial compartment.1-5 These
can be both acute and chronic in nature and determine
the ultimate outcome of the disease. It is important to
quantify changes in this compartment in the pathology
report. Vascular changes also become important, as the
disease progresses, and result in additional ischemic
damage to the kidney parenchyma.1-5,7
In conclusion, the histological variants of FSGS are the
morphologic signatures of the heterogeneous nature of
the disease. An accurate identification and exact
categorization of these histological variants, though
difficult at times, are helpful in delineating the clinical
course and prediction of progression of disease. As the
understanding of the pathogenesis of disease is rapidly
expanding, further detailed insight garnered through
ultrastructural and novel molecular studies of these
850
histological subtypes will help guide nephropathologists
and nephrologists in tailoring optimal treatment strategies.
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Journal of the College of Physicians and Surgeons Pakistan 2015, Vol. 25 (12): 849-850