Cellular Focal Segmental Glomerulosclerosis: A
Controversial Pathological Entity. Its Pathogenesis and
Therapeutic Basis
Jorge
Humberto Mukdsi
Jorge Humberto Mukdsi, Electron Microscopy Center, School of
Medicine, National Unversity of C¨®rdoba. Haya de la Torre - E. Barros.
University Campus, C¨®rdoba, Argentina
Correspondence to: Jorge Humberto Mukdsi, Electron Microscopy
Center, School of Medicine, National Unversity of C¨®rdoba. Haya de la Torre -
E. Barros. University Campus, C¨®rdoba, Argentina.
Email: mukdsijorge@gmail.com
Telephone: +54-351-4333021 Fax: +54-351-4333021
Received: March 30,
2015
Revised: June 21, 2015
Accepted: June 23, 2015
Published online: June 26, 2015
ABSTRACT
Cellular FSGS
variant was described in 1980 and it was incorporated in diagnostic algorithm
of Columbia Classification in 2004. This type of FSGS must show several
diagnostic pathological criteria. This review highlights the key features of
FSGS cellular variant in relation to histopathological changes, the
differential diagnosis and discusses about pathogenesis and therapeutic
advances. Although FSGS cellular variant is a recognized category in Columbia
Classification it is remained as a controversial renal pathology, and it is
observation open the possibility to consider other pathological diagnosis.
© 2015 ACT. All
rights reserved.
Key words: FSGS; Cellular variant; Electron microscopy;
Immunfluorescens
Mukdsi JH. Cellular Focal
Segmental Glomerulosclerosis: A Controversial Pathological Entity. Its
Pathogenesis and Therapeutic Basis. Journal of
Nephrology Research 2015; 1(1): 30-33 Available from: URL:
http://www.ghrnet.org/index.php/jnr/article/view/1154
History of
Cellular FSGS Variant
In 1925, Fahr provided the first description of focal
and segmental glomerular hyalinization and capillary degeneration being
considerate as degenerative changes of glomeruli in patients with lipoid
nephrosis[1]. Other authors began to report progressive renal
disease in nephrotic patients coinciding with progressive glomerular sclerosis
and increased interstitial scarring. In the mid-1980s other similar glomerular
diseases became part of the FSGS spectrum, including collapsing, cellular, and
tip lesions. The recognition in this study of the heterogeneity of clinical
presentation, degree of proteinuria, and morphology has been a critical step in
the history of FSGS, although it had created some controversy among pathologists.
The cellular lesion was described by Schwartz and Lewis[2] and
included a group of glomerular lesions characterized by hypercellularity. After
that, some authors accepted and used the term cellular lesion for all forms of
severe nephritic syndrome with increased cellularity, whereas others made a
distinction between those with extracapillary proliferation and collapse versus
those with endocapillary proliferation; the term collapsing FSGS was used for
the former, and the term cellular lesion was restricted to the latter. In 2004
an editorial on the pathologic classification of FSGS was published and
standardized approach in diagnosis of the FSGS[3].
Columbia¡¯s
classification of FSGS
It comprises five histological classes of FSGS: NOS (not otherwise
specified), perihilar FSGS (PHG); the tip lesion (GTL); cellular FSGS (CELL);
and collapsing FSGS (COLL). The main objective for this classification is to
afford uniform definitions, and to establish distinct classes of FSGS. Columbia
classification has a hierarchy five classes, and the collapsing lesion is the
overriding consideration when other forms of FSGS are present and therefore the
cellular, tip, hilar, and NOS lesions are of descending importance in
determining the diagnosis (Figure 1). Moreover the cellular and collapsing
lesions are considered separate entities and finally, the variants are not
specific for primary FSGS, and the growing number of causes of secondary FSGS
makes a purely morphologic classification with mutually exclusive categories
less pressing: a pathogenetic classification, based on etiologic and molecular
insights, is more likely to lead to therapeutic advances[4].
Ultimately, a
morphologic classification of FSGS is useful if it provides therapeutic and
prognostic guidance or pathogenic insights. A critical point is the prognostic
and therapeutic utility of this classification, largely because studies that
have assessed the clinical relevance of the histologic variants of primary FSGS
in nephrotic patients are few and conflicting[5].
FSGS Cellular Variant
Clinical
Features
Schwartz and Lewis[2] reported that 18 of 20 patients with
the called cellular lesion had protein excretion at or above 3.0 g per day
compared with only 19/39 patients with FSGS without the cellular lesion, and
this was reflected in a higher protein excretion. In addition, the time from
onset of proteinuria to renal biopsy was significantly shorter in patients with
the cellular lesion suggesting that more fulminant symptoms prompted earlier
biopsy. In other studies the cellular lesion is more frequent in African
Americans when nephrotic and nonnephrotic patients with FSGS are included, but
in patients with nephrotic range proteinuria, the difference is no longer
significant. When we consider the Columbia classification cellular variant is
the least frequent, representing 3% of the case[6]. If the criteria of the
Columbia classification are applied to a pediatric population with a high
prevalence of African Americans, the ratio between the different variants
changes, increasing the percentage of cellular type (32%). Moreover, patients
with FSGS cellular variant showed an intermediate rate of remission between
COLL and GTL variant (44.5% vs 13.2% and 65.3%, respectively). CELL FSGS
as well as COLL FSGS, and GTL share clinical presenting features of heavier
proteinuria, more frequent nephrotic syndrome, and shorter duration of symptoms
compared to FSGS NOS, suggesting that these three morphologic variants reflect
acute glomerular injury, or possibly a response to heavy proteinuria.
Pathological
Findings
In relation to Columbia classification of FSGS the diagnosis of
cellular variant is required the presence of endocapillary hypercellularity
(foam cells, endothelial cells, macrophage, neutrophils, lymphocytes) involving
¡Ý25% of the tuft and causing occlusion of the capillary lumen/lumina in
at least 1 glomeruli. Also, there may be pyknotic or karyorrhectic debris.
Furthermore, neither hyalinosis nor segmental scleroses are required features.
However, endocapillary hypercellularity involving the tip domain rules out the
cellular variant, as endocapillary hypercellularity may characterize lesions in
tip variant. There are several problems with this definition of the cellular
lesion. Cellular variant could be include cases of unsampled tip or collapsing
lesion, underscoring the importance of adequate sampling[7].
Increased mesangial cellularity was seen in the cellular variant (63.6%) when
compared with the glomerular tip and NOS lesions[5]. Many cases have
podocytes swollen and crowded, sometime forming pseudocrescents.
Immunofluorescence (IF) only demonstrates focal and segmental deposits of IgM
and C3 At ultraestructural level cellular variant shows severe and diffuse foot
process effacement with segmental occlusion of capillary lumen with foam cells
and hyaline. The basement glomerular membrane does not exhibit any
ultrastructural change (Figure 2).
Some authors
question the existence of a separate CELL variant, and claim it is merely a
form of the COL variant[8]. Others agree that both variants are very
difficult to distinguish histologically, if not impossible[9]. No
clear clinical or prognostic differences between the two have been demonstrated
by some authors, but common pathophysiological pathways affecting cell cycle
regulatory proteins have been established[8-9].
Laboratory
findings
Majority of patients with collapsing variety (80%), NOS (82.0%) and GTL
variant (77.7%) had nephrotic range proteinuria at presentation. However, the
amount of proteinuria was highest in the glomerular tip variant (11.93¡À1.6 g),
followed by the collapsing variety (9.43¡À1.7 g), which were statistically
significant when compared with the CELL variant. A significantly higher
percentage of patients with the collapsing and cellular variants of FSGS had
renal failure at the time of presentation when compared with the GTL and PHG
variants. However, severe degree of renal failure was seen only in the
collapsing variant. The frequency of hypertension was equal in all pathological
variants of FSGS[5].
Differential
Diagnosis
As we can deduce from its definition and described microscopic
features, lesions may be histologically very similar to focal and segmental
proliferative glomerulonephritis, such as lupus nephritis, IgA nephropathy, or
pauci immune focal crescentic glomerulonephritis. It is essential in these
cases a rigorous examination and analysis of IF, other histological features,
clinical manifestations, and, in some cases, electron microscopy[10].
Current
Treatment and Prognosis
Furthermore, it remains to be determined if endocapillary proliferation
is associated with disease activity and progression in FSGS. In addition, in a
work from Columbia University, the authors state: ¡°cellular variant may include
cases of unsampled tip or collapsing lesion¡±. It has been proposed that
hypercellular lesions would be frequently observed in patients with severe
clinical manifestations, such as observed in collapsing lesions. Implications
for cellular variant diagnosis are unknown as so few patients are registered in
most series reported.
Stokes et
al[11] have reported ¡°intermediate rates of remission and
end-stage renal disease compared to collapsing and tip lesion¡±, and there was
not statistical differences with NOS variant. From this study it can be support
the view that CELL and COLL FSGS are not equivalent and validates an approach
to pathologic classification that distinguishes between COLL, CELL, and tip
lesion variants of FSGS.
Predictors of
end-stage renal disease (ESRD) for all FSGS patients included initial serum
creatinine, % global sclerosis, % COLL lesions, chronic tubule-interstitial
injury score, and lack of remission response. CELL variant showed intermediate
rates of remission (44.5%) and ESRD (27.8%) compared to COLL and tip lesion[11].
FSGS is not a
disease but a lesion initially affecting the podocyte. Various factors may
induce 'secondary' FSGS, including defects in molecules that contribute to the
podocyte slit diaphragm permselectivity to albumin. They do not represent
indications for immunosuppression and require symptomatic treatment only,
comprising angiotensin 2 and endothelin antagonists. Primary (idiopathic) FSGS
is possibly but not certainly of immunologic origin, owing to an elusive
glomerular permeability factor (GPF), explaining relapse on a renal transplant
and justifying an immunosuppressive treatment. The best prognostic feature of
primary nephrotic FSGS is its response to corticosteroids. Alkylating agents
are mostly ineffective in steroid-resistant forms. An association of
corticosteroids and cyclosporine A (CsA) remains the mainstay of treatment,
with a good tolerability when CsA dosage is low. A definite advantage of
tacrolimus on CsA has not yet been established. Sirolimus appears ineffective
and potentially harmful. Azathioprine is not indicated. A number of mostly
uncontrolled trials indicate that mycophenolate mofetil might find an
adjunctive place in the treatment. Plasmapheresis is of no avail outside the
special case of relapse in a transplanted kidney. Immunoabsorption of the GPF
has not led to practical treatment options. Anecdotal reports on rituximab are
as yet too few to determine whether this monoclonal anti-CD20 antibody will
find a place in the treatment of primary FSGS[12].
A
significantly higher percentage of patients with the cellular variant were
steroid non-responsive (63.63%); they had to be treated with other
immunosuppressive drugs like cyclophosphamide (72.72%), cyclosporine (27.27%)
and mycophenolate mofetil (9.90%)[5]. Perhaps the strongest argument for
distinguishing CELL from COLL lesions is that many cases of apparent CELL
proved to be undersampled GTL after examining additional (deeper) tissue
sections and applying stringent criteria to define FSGS variants[13].
Pathogenesis
The pathogenesis clasical FSGS has not been fully elucidated; however,
data from molecular studies of familial cases in the last two decades suggest
that FSGS is a defect of the podocyte[14]. Evidence from animal
models and in vitro studies suggests that injury inherent within or directed to
the podocyte is a central pathogenetic factor. Disruption of signaling from any
of the podocyte's specialized membrane domains, including slit diaphragm,
apical and basal membranes, or originating at the level of the actin
cytoskeleton, may promote the characteristic response of foot process
effacement. Irreversible podocyte stress leading to podocyte depletion through
apoptosis or detachment is a critical mechanism in most forms of FSGS[15].
The pahogenesis of primary CELL is unknown but a key role for podocyte
injury is evidenced by the findings of diffuse foot process effacement and
glomerular epithelial cell hypertrophy/hyperplasia in most cases. All forms of
FSGS share podocyte damage and depletion as central mediators. In the renal
allograft, recurrent FSGS often has CELL or COLL features, and this has been
linked to the presence of a circulating permeability factor in some cases.
However, the nature of this factor and its role in CELL in the native kidney
has not been determined. The segmental lesions in CELL show variable features
of endocapillary hypercellularity related to accumulation of inflammatory
cells. Similar findings are seen in GTL and some case of COLL, all of which are
associated with heavy proteinuria, as well as in other human and experimental
diseases characterized by proteinuria, suggesting that the intracapillary
hypercellularity might represent a localized inflammatory response to high
transcapillary flux of a protein- and lipid-rich filtrate. Of note, the lack of
correlation of CELL and GTL with serum cholesterol levels argues against
hypercholesterolemia per se being a major pathogenetic factor in the
morphogenesis of these lesions, although the role of other lipids is unknown.
Recent
research has led to suggesting that FSGS is not a T-cell-driven autoimmune
glomerulopathy. Thus, treatments considered as etiologic, including
glucocorticoids and calcineurin inhibitors, are in fact endowed with a mode of
action on podocytes that suggests that drugs used such as immunosuppressors
also might be considered as antiproteinuric agents[16].
Experimental
toxin models have advanced our understanding of the threshold and dynamics of
podocyte injury. Following initial podocyte depletion, spreading fields of
podocyte injury through secondary mediators appear to be important in
generating the segmental pathologic lesions. Proliferating glomerular
epithelial cells are common in FSGS, although there are conflicting views about
their identity. Evidence suggests potential contributions by mature parietal
epithelial cells, facultative stem cells and podocyte[17].
Glomerular IgM
and C3 deposits frequently accompany idiopathic FSGS and secondary
glomerulosclerosis, but it is unknown whether IgM activates complement,
possibly contributing to the pathogenesis of these diseases. We hypothesized
that IgM natural antibody binds to neoepitopes exposed in the glomerulus after
nonimmune insults, triggering activation of the complement system and further
injury. We examined the effects of depleting B cells, using three different
strategies, on adriamycin-induced glomerulosclerosis. First, we treated
wild-type mice with an anti-murine CD20 antibody, which depletes B cells,
before disease induction. Second, we evaluated adriamycin-induced glomerulosclerosis
in Jh mice, a strain that lacks mature B cells. Third, we locally depleted
peritoneal B cells via hypotonic shock before disease induction. All three
strategies reduced deposition of IgM in the glomerulus after administration of
adriamycin and attenuated the development of albuminuria. Furthermore, we found
that glomerular IgM and C3 were detectable in a subset of patients with FSGS;
C3 was present as an activation fragment and colocalized with glomerular IgM,
suggesting that glomerular IgM may have bound a cognate ligand. Taken together,
these results suggest that IgM activates the complement system within the
glomerulus in an animal model of glomerulosclerosis. Strategies that reduce IgM
natural antibody or that prevent complement activation may slow the progression
of glomerulosclerosis[18].
The
pathogenesis of primary CELL is unknown but a key role for podocyte injury is
evidenced by the findings of diffuse foot process effacement and glomerular
epithelial cell hypertrophy/hyperplasia in most cases. In the renal allograft,
recurrent FSGS often has CELL or COLL features and this has been linked to the
presence of a circulating permeability factor in some cases. However, the
nature of this factor and its role in CELL in the native kidney has not been
determined. The segmental lesions in CELL show variable features of
endocapillary hypercellularity related to accumulation of inflammatory cells
(mostly foamy macrophages, with or without neutrophils and other mononuclear
cells). suggesting that the intracapillary hypercellularity might represent a
localized inflammatory response to high transcapillary flux of a protein- and
lipid-rich filtrate. Of note, the lack of correlation of CELL and GTL with
serum cholesterol levels argues against hypercholesterolemia per se being a
major pathogenetic factor in the morphogenesis of these lesions, although the
role of other lipids is unknown.
Conclusion
In concordance with Stokes et al[19] I believe it is
important to recognize CELL as a distinct morphologic lesion (defined by
segmental expansion of the glomerular tuft with endocapillary hypercellularity,
without features of COLL or GTL.
CONFLICT OF INTERESTS
The author declare no conflict of interest.
REFERENCES
1
Fahr T. Pathologische Anatomie des
morbus brightii.1925.Vol 156. Berlin, Germany:Springer
2
Schwartz MM, Lewis EJ. Focal segmental
glomerular sclerosis: the cellular lesion. Kidney Int 1985; 28: 968-974
3
D¡¯Agati VD, Fogo AB, Bruijn JA, Jennette
JC. Pathologic classification of focal segmental glomerulosclerosis: a working
proposal. Am J Kidney Dis 2004; 43: 368-382
4
Hogan J, Radhakrishnan J. The treatment
of idiopathic focal segmental glomerulosclerosis in adults. Adv Chronic Kidney
Dis 2014;21: 434-441
5
Swarnalatha G, Ram R, Ismal KM, Vali S,
Sahay M, Dakshinamurty KV. Focal and segmental glomerulosclerosis: does
prognosis vary with the variants?. Saudi J Kidney Dis
Transpl 2015;26: 173-181
6
Thomas DB, Franceschini N, Hogan SL, Ten
Holder S, Jennette CE, Falk RJ, Jennette JC. Clinical and pathologic
characteristics of focal segmental glomerulosclerosis pathologic variants.
Kidney Int 2006 Mar; 69: 920-926
7
Taneda S, Honda K, Uchida K, Nitta K,
Yumura W, Oda H, Nagata M. Histological heterogeneity of glomerular segmental
lesions in focal segmental glomerulosclerosis. Int Urol Nephrol 2012; 44:
183-196
8
Noël LH. Morphological features of
primary focal and segmental glomerulosclerosis. Nephrol Dial Transplant 1999;
3: 53-57
9
D'Agati VD, Alster JM, Jennette JC,
Thomas DB, Pullman J, Savino DA, Cohen AH, Gipson DS, Gassman JJ, Radeva MK,
Moxey-Mims MM, Friedman AL, Kaskel FJ, Trachtman H, Alpers CE, Fogo AB, Greene
TH, Nast CC. Association of histologic variants in FSGS clinical trial with
presenting features and outcomes. Clin J Am Soc Nephrol 2013;8:399-406
10
Thomas DB. Focal segmental
glomerulosclerosis: a morphologic diagnosis in evolution. Arch Pathol Lab Med
2009;133:217-223
11
Stokes MB, Valeri AM, Markowitz GS,
D'Agati VD. Cellular focal segmental glomerulosclerosis: Clinical and
pathologic features. Kidney Int 2006; 70: 1783-1792
12
Meyrier A. An update on the treatment
options for focal segmental glomerulosclerosis. Expert Opin Pharmacother 2009;
10:615-628
13
Malaga-Dieguez L, Bouhassira D, Gipson
D, Trachtman H. Novel Therapies for FSGS: Preclinical and Clinical Studies. Adv
Chronic Kidney Dis 2015;22:e1-e6
14
Gbadegesin R, Lavin P, Foreman J, Winn
M. Pathogenesis and therapy of focal segmental glomerulosclerosis: an update.
Pediatr Nephrol 2011 26: 1001-1015
15
D'Agati VD The
spectrum of focal segmental glomerulosclerosis: new insights. Curr Opin Nephrol
Hypertens 2008; 17: 271-281
16
Meyrier A. Focal and segmental
glomerulosclerosis: multiple pathways are involved. Semin Nephrol 2011;31:
326-332
17
D'Agati VD. Pathophysiology of focal
segmental glomerulosclerosis: new developments. Curr Opin Nephrol Hypertens
2012 Mar 1. [Epub ahead of print]
18
Strassheim D, Renner B, Panzer S, Fuquay
R, Kulik L, Ljubanović D, Holers VM, Thurman JM. IgM contributes to glomerular
injury in FSGS. J Am Soc Nephrol 2013; 24: 393-406
19
Stokes MB, D'Agati VD. Morphologic
variants of focal segmental glomerulosclerosis and their significance. Adv
Chronic Kidney Dis 2014;21: 400-407
Peer reviewer: Jens Cordes, Ltd. Oberarzt,
Klinik f¨¹r Urologie, UKSH Campus L¨¹beck, Ratzeburger Allee 160, 23538 L¨¹beck,
Germany
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