14Chapter
Focal segmental
glomerulosclerosis
Mona N Al-Rukhaimi
Introduction
The term focal segmental glomerulosclerosis
(FSGS) implies that only a portion of the glom-
erulus (segmental) and only some of the glom-
eruli (focal) are affected. It is the most common
progressive glomerular disease in children and
is the second leading cause of end-stage renal
disease in this age group, being second only to
obstructive uropathy and hypoplastic–dysplastic
kidneys (1). It accounts for 20-25% of idiopathic
nephrotic syndrome in adults (2,3). Several re-
cent studies report up to an eight-fold increase in
the incidence of FSGS during the past 20 years
(4,5). This increase is due in part to the inclusion
of a spectrum of glomerular lesions or (variants)
under the diagnosis of primary FSGS.
Like other glomerulonephritides, FSGS could
be a primary disease or secondary to other dis-
orders. It is of prime importance to differenti-
ate between the two, since the pathogenesis and
treatment of these disorders can differ signifi-
cantly. The distinction can usually be made from
the history, the onset and degree of proteinuria
and also by electronmicroscopy.
GLOMERULAR DISEASES

Table 1. Classification of FSGS

I. Primary (idiopathic, sporadic)

II. Familial-Genetic
a.Slit diaphragm gene defects (Nephrin, Podocin, CD2-associated protein, α-Actin 4)
b. Wilm’s Tumour (WT1) gene mutations
c. Mitochondrial cytopathies (mt DNA)

III. Secondary
a.Secondary to reduced nephron mass
Oligomeganephronia

Reflux nephropathy

Renal dysplasia or agenesis

Any advanced renal disease with reduction in functioning nephrons

b.Secondary to glomerular adaptation

Diabetic nephropathy

Morbid obesity

Sickle cell disease

Type I glycogen storage disease

Severe preeclampsia

c.Secondary to hereditary nephropathies

d.Secondary to virus infection
HIV-associated.

Parvovirus B19

e.Secondary to drugs
Heroin-associated nephropathy.

Pamidronate

38

Patients with primary FSGS typically present
with acute onset nephrotic syndrome (periph-
eral oedema, hypoalbuminaemia and nephrotic
range proteinuria), whereas slowly increasing
proteinuria and renal insufficiency over time are
characteristics of the secondary disorders. The
proteinuria in the secondary form is often non-
nephrotic and even when excretion exceeds 3-4
G/day, low serum level of albumin and oedema
are unusual.
The electronmicroscopic findings are also dif-
ferent in the two conditions. Primary FSGS is
associated with diffuse foot process fusion while
in the secondary form, these abnormalities tend
to be focal and largely limited to the sclerotic
areas (2). However, this has been challenged in
the recent years.
Causes
Focal segmental glomerulosclerosis can be clas-
sified according to aeitology as shown on table 1.
Pathogenesis
Idiopathic FSGS
The aetiology of idiopathic FSGS is unknown
but pathologic studies have implicated podocyte
injury (6). The podocytes (so called because of
their characteristic interdigitating foot processes)
are highly specialized epithelial cells that cover
the outer surface of the basement membrane of
the glomerular capillary wall responsible for ul-
trafiltration. In many acquired and inherited ne-
phropathies, disruption of the glomerular filter
is associated with extensive leakage of plasma
proteins and a diffuse effacement of the podo-
cyte foot processes as detected by electronmi-
croscopy. This effacement of podocyte foot pro-
39
FOCAL SEGMENTAL GLOMERULOSCLEROSIS
cesses suggests a key role for podocyte either as
a target of glomerular permeability factor or as
the site of alteration of a structural component
of the foot processes.
The study of renal allografts has provided insight
into the pathogenesis of renal diseases. The re-
currence of nephrotic syndrome within minutes
after removal of arterial clamps in patients with
idiopathic FSGS who undergo kidney transplan-
tation, suggests the presence of a circulating
factor(s) that alters glomerular permeability to
macromolecules. The recurrence occurs in 20-
40% of patients receiving a first transplant, lead-
ing to graft failure in half of them and in 80% of
those receiving a second transplant after a first
recurrence (12). Savin, Sharma and colleagues
have described a permeability factor initially of
100 – 120 KD (7, 8) and later purified to 30-50
KD (9) in the serum of approximately 30% of
patients with FSGS and in adult steroid-resistant
nephrotic syndrome. The presence of this circu-
lating factor underlies the rationale for plasma-
phoresis in the treatment of recurrent FSGS in
the allograft (10,11).
Fogo et al (13), have linked the pathogenesis
of primary FSGS to clinical and experimental
glomerular hypertrophy by demonstrating that
in children and adults with FSGS, the mean
glomerular area is significantly greater than in
similar patients with minimal change glomeru-
lonephritis or in age-matched controls. They
also demonstrated that glomerular hypertrophy
precedes the lesion of FSGS in patients with an
initial diagnosis of minimal change glomerulo-
nephritis who had a deteriorating course and a
subsequent biopsy demonstrating FSGS. This
suggests a role of glomerular hypertrophy in the
pathogenesis of primary FSGS.
GLOMERULAR DISEASES
Familial FSGS
Developments in molecular biology have en-
abled investigators to study genetic disorders
by a (reverse genetics approach) or (positional
cloning) in which the genetic disorder is initially
linked to a chromosome marker. Subsequently,
mapping of the genes may be followed by iden-
tification of the gene itself, the mutations re-
sponsible for the disorder and finally the gene
product.
A number of forms of familial FSGS are a result
of genetic mutations of various membrane pro-
teins expressed by the podocyte that are impor-
tant in protein trafficking. Mutations of Nephrin
(NPHS1 gene), Podocin (NPHS2 gene), Actinin 4
(ACTN4 gene) and CD2-associated protein as
well as mutations of the Wilm’s tumour gene
(WT1), all have been associated with the devel-
opment of focal segmental glomerulosclerosis.
Mutation of the NPHS2 gene found in chromo-
some 1q are inherited in an autosomal recessive
fashion (14) and mutations of ACTN4 gene are
inherited in an autosomal dominant fashion and
are linked to chromosome 19 q (15). Winn and
colleagues (16, 17), identified a point mutation
in the TRPC6 (Transient Receptor Potential Cat-
ionic Channel 6) on chromosome 11q in a large
New Zealand family. In addition, mitochondrial
cytopathies due to mitochondrial DNA mutation
(mt DNA) have been associated with FSGS as
in MELAS syndrome (mitochondrial encepha-
lopathy, lactic acidosis and stroke-like episode)
(18). A new locus for linkage to FSGS in Af-
rican Americans has been identified by Geno-
vese and associates. This locus is within 60kb
of MYH9 gene on chromosome 22 which might
explain why African Americans have approxi-
mately four times the risk of FSGS compared
with European Americans (19).
40
These familial forms of FSGS are associated
with steroid resistance and with progression to
end-stage renal disease. However, unlike the
sporadic forms of FSGS associated with the per-
meability factor, these inherited forms of FSGS
do not recur after renal transplantation. Thus
the pathogenesis of FSGS in patients with the
familial form can differ significantly from that
of patients with the sporadic form. While in the
former there is structural alteration in the podo-
cyte, there is a circulating factor that damages
podocytes in the latter. It is of interest that spo-
radic forms of FSGS secondary to mutation in
NPHS2 gene are now being recognized (20,21).
Thus when available, genetic screening for these
various mutations will become an integral part
in the evaluation of patients with FSGS. Besides
better classification of the disease entity, identi-
fication of NPHS2 mutation may save some of
these patients from unnecessary steroid treat-
ment and also permit the prediction of absence
of disease recurrence after kidney transplanta-
tion.
Secondary FSGS
Reduced number of functioning nephrons or in-
creased functional stress on an initially normal
nephron population will result in compensating
intraglomerular hypertension and hypertrophy
in the remaining glomeruli that will initially
tend to maintain the total GFR. Over a period
of years, however, (hypertensive) injury may
lead to focal glomerulosclerosis. Glomerular
cell proliferation, macrophage infiltration and
the progressive accumulation of extracellular
matrix components, all may contribute to the
development of the sclerotic lesion (22). The
release of transforming growth factor b (TGF-
β) from platelets and from the glomerular cells
may play an important role in progressive renal
injury. TGF-β is a cytokine that stimulates ex-

tracellular matrix production, inhibits matrix
degradation and facilitates the adhesion of in-
flammatory cells to the matrix; each of these
changes can promote the development of glo-
merulosclerosis (23).
The risk of developing glomerulosclerosis fol-
lowing nephron loss, is dose dependant with
loss of more than 50% of nephron mass usually
being required in adults (24). Renal transplant
donors showed no loss of glomerular filtration
rate or increase in the incidence of proteinuria
or hypertension when compared to their nondo-
nating siblings (25). However, unilateral renal
agenesis is associated with an increased inci-
dence of secondary FSGS, suggesting that the
loss of 50% of renal mass beginning at birth is
sufficient to induce haemodynamically-medi-
ated glomerular injury (26). Merlet-Benichou
(27, 28) found reduced number of glomeruli and
larger glomerular volumes in newborn rats ex-
posed to toxins in utero and in infants born with
small placentas and low birth weights. Hence,
glomerulomegaly could be an important predis-
posing factor to glomerulosclerosis (29,30).
The pathogenesis of HIV and heroin-associated
nephropathy is not well known but viral pro-
teins themselves might be toxic to podocytes
or tubular cells or might induce renal cells to
release cytokines that initiate FSGS (31,32). In
heroin-associated nephropathy, it has been pro-
posed that podocyte injury may be induced by
exogenous toxins admixed with the heroin. This
was supported by the observation that heroin
nephropathy has largely disappeared in large
urban centres at a time when the purity of street
heroin increased markedly (33). An alternative
explanation for the disappearance of heroin
nephropathy is that drug abusers have become
HIV positive and either die earlier or develop
41
FOCAL SEGMENTAL GLOMERULOSCLEROSIS
HIV nephropathy.
Pathogenesis
Light Microscopy
The characteristic (classic) lesion of FSGS
(2,34) (Fig 1), is an area of solidification in-
volving one segment of glomerular tuft usually
occurring in the perihilar region in continuity
with the vascular pole. A variable number of
glomeruli may show such lesions and early in
the course of the disease, the lesions are more
commonly seen in juxtamedullary glomeruli.
The sclerotic lesion shows collapse and wrin-
kling of capillary walls and obliteration of the
capillary lumens. There may also be an area of
adhesion to Bowman’s capsule. Adjacent podo-
cytes often appear prominent and may contain
eosinophilic protein droplets. In some sclerotic
areas there is eosinophilic material within cap-
illary loops, known as hyalinosis lesion. Foam
cells are commonly seen in the area of sclerosis.
Uninvolved glomerular segments appear normal
or show mild mesangial hypercellularity. Even-
tually the segmental sclerosis may progress to
global obsolescence.
There are variations on this typical appearance.
In the cellular variant (Fig 2), there is endocap-
illary as well as extracapillary hypercellularity
usually in a focal segmental distribution, which
can be easily confused with focal proliferative
glomerulonephritis by the inexperienced ob-
server. In the extracapillary space, the swol-
len and hyperplastic visceral epithelial cells
form a (pseudocrescent) without attachment to
Bowman’s capsule or continuity with the pa-
rietal epithelium. Unlike a true crescent, these
extracapillary proliferations consist by and large
of poorly cohesive visceral cells, often rich in
protein resorption droplets without the cell spin-
GLOMERULAR DISEASES

Fig 1. Classic lesion; the lesion of segmental sclerosis is discrete and located at the vascular tip.

Fig 2. Cellular variant; segmental endocapillary as well as extracapillary hypercellularity.

42
 FOCAL SEGMENTAL GLOMERULOSCLEROSIS

dling or pericellular matrix that characterize true
crescents of parietal epithelial origin.
It has been observed by some, that patients with
the cellular form are more likely to have a more
severe proteinuria and nephrotic syndrome than
those without cellular lesions and also to have a
shorter time course from clinical onset of renal
disease to biopsy.
The collapsing variant (Fig 3), is particularly
associated with HIV infection but may also be
seen in the absence of any identifiable infection.
It is characterized by marked wrinkling and col-
lapse of glomerular capillaries, which in some
glomeruli may be global rather than segmental;
visceral epithelial cell swelling is often very
marked.
In some cases of FSGS, the segmental lesions
occur exclusively at the tubular pole of glom-
erulus (tip lesion) (Fig 4) suggesting a better re-
sponse to steroids and a more favourable prog-
nosis.
The tubules show focal atrophy associated with
interstitial fibrosis proportionate to the severity
of the glomerulosclerosis. The presence of such
scarring in a biopsy from a patient with ne-
phrotic syndrome and apparently normal glom-
eruli should prompt a careful search for seg-
mental sclerosis. Collection of foam cells may
be present in the interstitium. In the collapsing
variant, particularly when associated with HIV
infection, there may be marked tubular damage
with cystic dilatations and tubulointerstitial in-
flammation.
The Columbia classification proposed by
D’Agati and her colleagues comprises five cat-

Fig 3. Collapsing variant glomerulosclerosis with few open loops in the sclerotic area . The degree
of collapse can be appreciated by the openness of the Bowman’s space. Vacuolization and the
crowding of the glomerular epithelial cells can be seen.

43
GLOMERULAR DISEASES

Fig 4. Glomerular tip lesion. The glomerulus shows a segmental sclerosing lesion confined to the
tubular pole or (tip). The tubular portion can be identified as that portion of the urinary space from
where the proximal tubule originates.

egories based on assessment on glomerular light number as in minimal change nephropathy.

microscopic alteration. Here, the pathologist
will begin by diagnosing or excluding collaps-
ing variant, then tip variant, then cellular vari-
ant, then perihilar variant and finally FSGS not
otherwise specified (NOS) (35).
2. Podocyte injury and depletion as in FSGS
3. Podocyte injury with low proliferation as in
diffuse mesengial sclerosis
4. Podocyte injury with high proliferation as in
collapsing glomerulopathy

Another new taxonomy for primary nephrotic
disease based on podocyte abnormalities was
postulated by Barisoni and associates. They
classified podocytopathies along two dimen-
sions that are histopathology which includes
podocyte phenotype and glomerular morphol-
ogy and aetiology. Accordingly, this will result
in four different glomerular morphologies:
1. Podocyte injury with no change in podocyte
This proposed taxonomy still needs to be tested
and developed to enhance its clinical use (36).
Immunohistochemistry
The sclerotic area stains for IgM and C3 but the
uninvolved glomerular segments are negative
(Fig 5). Focal and segmental staining for IgM
and C3 may precede recognizable changes by
light microscopy.

44

Electronmicroscopy
The most significant feature in idiopathic FSGS,
is extensive fusion of the foot process of viscer-
al epithelial cells over nonsclerotic, otherwise,
normal appearing lobules. These cells may also
show vacuolation and protein resorption drop-
lets as well as focal detachment from the base-
ment membrane (Fig 6). In the secondary form
of the disease, foot process loss may be much
less widespread and is confined mainly to areas
of sclerosis while in HIV infection, the presence
of cytoplasmic tubuloreticular structure is quite
characteristic.
Management
Since spontaneous remission is rare, the prog-
nosis of untreated patients with focal segmental
glomerulosclerosis is poor. The degree of pro-
teinuria at presentation is an important prog-
Fig 5. Immunohistology demonstrates entrapment of IgM and C3 in zones of sclerosis.
45
FOCAL SEGMENTAL GLOMERULOSCLEROSIS
nostic factor. The presence of nephrotic range
proteinuria predicts outcome in primary FSGS
with 50% of patients reaching end-stage renal
disease within 5-10 years. Patients with massive
proteinuria (>10 G/day) have an even more ma-
lignant course, with essentially all progressing
to ESRD within 5 years. This is in contrast to
patients with nonnephrotic range proteinuria in
whom the 10-year renal survival exceeds 80%
(37-40).
An additional clinical feature of prognostic sig-
nificance is the serum creatinine at presentation.
Patients with a plasma creatinine of >1.3 mg/dl
manifest a significantly poorer renal survival
than do those whose serum creatinine is < 1.3
mg/dl (39, 40).
As with other forms of glomerulonephritis, his-
tological abnormalities found outside the glom-
GLOMERULAR DISEASES

Fig 6. Electronmicrograph; shows a relatively normal capillary wall to the left with effacement of
foot processes and to the right, a zone of sclerosis with some electron-dense material (that would
correspond to hyalinosis by light microscopy) and lipid vaculation.

erulus are a significant prognostic factor. With
FSGS, the presence of interstitial fibrosis at the
time of presentation uniformly predicts poorer
renal survival (41,42).
The prognosis of FSGS also varies with the re-
sponse to therapy. Those patients who undergo
partial or complete remission have a much lower
risk of developing renal failure. Renal survival
is over 90% at 10 years in responders; compa-
rable values in treatment of nonresponders at 5
and 10 years are 50-60% and 25-40% respec-
tively (39-42).
The remission of proteinuria, either spontaneous
or following treatment usually heralds a favour-
able renal outcome (43). Patients who remain in
remission for more than 10 years have an excel-
lent prognosis and are unlikely to relapse sub-
sequently (44). Any form of treatment able to
achieve a remission is thus likely to prevent not
only the consequences of nephrotic syndrome
but also the development of progressive renal
failure.
The various treatments available are: (45, 46,
47).
Corticosteroids
The response to corticosteroids can be divided
into two eras, that before 1980 when the re-
sponse was < 20% and that after 1980 when
more than 80% of studies have reported com-
plete remission rates in excess of 30% with the

46

majority being >40%. The most obvious differ-
ence that could explain the above finding was
the total duration of therapy and the duration of
high dose initial therapy. The duration of ther-
apy in the studies that yielded a poor response
rate was < 2 months compared to an average of
5-9 months in studies achieving high remission
rates. In most studies achieving > 30% complete
remission rates, a period of high dose steroids
(1mg/kg/day up to 80 mg) was maintained for
2-3 months before tapering. However, some pa-
tients do not tolerate these agents and a number
of responders show a relapse of the nephrotic
syndrome needing further treatment, which ex-
poses them to steroid-related toxicity. For others
who are resistant to steroids or have contraindi-
cation due to obesity or family history of diabe-
tes, an alternative therapy must be tried.
Alternative therapy to steroids
a. Calcineurin inhibitors (cyclosporine / tacro-
limus).
Most experience with calcineurin inhibitors has
been done with cyclosporine. Ponticelli and
Passerini, by reviewing the data in the literature
with noncontrolled studies, found that 39% of
children and 21% of adults could enter complete
remission of proteinuria under cyclosporine and
most patients who responded did so within 3
months of beginning therapy. Most respond-
ers had early relapses when cyclosporine was
stopped abruptly, while some patients main-
tained complete remission if cyclosporine was
given long term and was then tapered off very
gradually.
It was also found that those patients who were
given cyclosporine alone had lower chances of
complete or partial remission than patients giv-
en cyclosporine along with small doses of corti-
costeroids. One of the concerns with the use of
47
FOCAL SEGMENTAL GLOMERULOSCLEROSIS
cyclosporine is its nephrotoxicity. Multivariate
analysis by Meyrier et al identified three predic-
tive factors of cyclosporine toxicity, an abnormal
baseline serum creatinine level, high percentage
of sclerotic glomeruli at initial biopsy and an
initial dosage of cyclosporine greater than 5.5
mg/kg/day. The recommendation therefore is
to limit the use of cyclosporine to patients with
normal renal function without diffuse glomeru-
losclerosis or interstitial fibrosis at biopsy and at
doses lower than 5 mg/kg/day. Continuous mon-
itoring of serum creatinine and blood pressure
should be maintained. If plasma creatinine in-
creases by 30%, cyclosporine should be stopped
for a minimum of one month and resumed only
after plasma creatinine returns to normal or to
values not higher than 10% over baseline.
Tacrolimus has also been used in patients with
focal sclerosis but the experience with it is lim-
ited. McCauley in 1993 reported the result of ta-
crolimus in 4 children who had failed to respond
to steroid and cyclosporine agents. One entered
complete remission of proteinuria and in the
other three children the reduction of proteinuria
was more than 50%. However, tacrolimus in-
duced a rapid increase in serum creatinine level
and attempts to stop the drug were followed by
relapses of the nephrotic syndrome (48). Segar-
ra and coworkers in Spain in 2000 reported the
result of tacrolimus plus steroids in 25 patients;
treatment was given for 6 months. 40% entered
complete remission, 8% partial remission and
76% of responders relapsed after stopping ta-
crolimus (49).
b. Alkylating agents (cyclophosphamide/ chlo-
rambucil)
A course of cytotoxic therapy with cyclophos-
phamide 2 mg/kg/day or chlorambucil 0.1 to 0.2
mg/kg/day for 2-3 months, often in combination
GLOMERULAR DISEASES
with prednisolone leads to reestablishment of
remission in steroid-dependant patients in more
than 70% of cases. A much lower response of
only 10% is encountered in steroid-resistant pa-
tients.
A regimen by Mendoza et al consisting of cyclo-
phosphamide or chlorambucil in combination
with intravenous pulses of methylprednisolone
and oral corticosteroids has been reported to
obtain good results in steroid-resistant children
(50).
c. Sirolimus
Sirolimus is a novel immunosuppressive agent
that blocks cystokine-dependent T-cell prolifera-
tion. Tumlin and others (51) treated prospective-
ly 21 patients with steroid-resistant FSGS with 6
months course of oral sirolimus and found that
sirolimus induced complete or partial remission
and stabilized renal function in 57% of patients.
However, in another study by Cho ME and oth-
ers (52), 6 patients were enrolled to receive siro-
limus for 1 year. Sirolimus therapy was stopped
prematurely concluding that sirolimus may be
associated with nephrotoxicity especially in pa-
tients with prolonged disease duration and prior
cyclosporine therapy.
d. Purine synthesis inhibitor (azathioprine / my-
cophenolate)
There is insufficient information supporting their
beneficial effect in patients with FSGS. Recent
data suggests a steroid sparing role for myco-
phenolate, although these results will need con-
firmation in a larger prospective controlled trial.
The results of the National Institute of Health
FSGS-CT trial which commpares CsA with my-
cophenolate and dexamethasone are awaited.
e. Aphoresis – immunoadsorption
Plasmaphoresis or immunoadsorption by remov-
48
ing a circulating plasma factor has been found to
be effective in treating patients with FSGS ei-
ther in a native kidney or following recurrence
in a grafted kidney. Lipophoresis (removal of
low density lipoprotein) has also been tried in
Japan with good results.
f. Monoclonal antibodies (Rituximab, Adalim-
umab)
Further studies are needed to confirm their ef-
ficacy.
g. Pefloxacin
Given in a dose of 200-400 mg twice a day for
4-8 weeks, pefloxacin acts as an immunomodu-
lator and can reduce proteinuria in children with
steroid-resistant or dependant FSGS.
h. Vitamin E
Being an antioxidant, vitamin E in a dose of
200 iu twice a day given for 3 months can re-
duce proteinuria in children with FSGS.
i. Galactose
Galactose may block the binding site or change
the configuration of the free soluble factor pre-
venting it from binding to the podocyte as pos-
tulated by Savin and colleagues (53). Therefore,
oral galactose has been used as a treatment for
recurrent FSGS in two patients so far and result-
ed positively in reducing their proteinuria. How-
ever, larger studies are needed to assess the role
and side effects of this novel approach (54).
Conservative therapy
Control of blood pressure and the use of angio-
tensin converting enzyme inhibitors (ACEI) and
angiotensin II receptor blockers (ARBs) reduce
proteinuria and the rate of decline in glomeru-
lar filtration rate by as much as 50% in patients
with primary glomerulonephritis including
 FOCAL SEGMENTAL GLOMERULOSCLEROSIS

FSGS and should be part of the therapeutic ap-

proach in these patients. Several measures have
been proven to be effective in enhancing anti-
proteinuric effect of ACE inhibitors. These in-
clude control of volume excess by dietary sodi-
um restriction and/or diuretics as well as dietary
protein restriction.

Future therapy
Podocyte stem cells originating from the glo-
merular parietal epithelial cells and deoxysper-
gualin which is a potent immune suppressive
medication known to block T and B lymphocyte
differentiation are under research as promising
therapy for FSGS.

49
GLOMERULAR DISEASES

50

Reference
1. Warady BA, Hebert D, Sullivan K, Alex-
ander SR and Tejani A: Renal transplantation,
chronic dialysis and chronic renal insufficiency
in children and adolescents. The 1995 Annual
Report of the North American Paediatric Renal
Transplant Co-operative study. Paediat Nephrol
11:49-64,1997.
2. D’Agati V; The many mask of focal seg-
mental glomerulosclerosis kidney Int 46: 1223-
1241, 1994.
3. Korbet SM, Schwartz MM, Lewis EJ: Prima-
ry Focal Segmental Glomerulosclerosis: Clini-
cal course and response to therapy. Am J Kidney
Dis 23: 773-783, 1994.
4. Valeri A, Radhakrishnan J, Nash M, Appel
GB, D’Agati V: Focal Segmental Glomerulo-
sclerosis: A 20 year Epidemiological Perspec-
tive. J Am Soc Nephrol 5: 347, 1994.
5. Haas M, Spargo BH, Coventry S: Increasing
Incidence of focal segmental glomerulosclero-
sis among adult nephropathies: A 20 year renal
biopsy study, Am J Kidney Dis 26: 740-750
1995.
6. Kriz W, Elger M, Nagata M, Kretzler M,
Uiker S, Koeppen – Hagemam I, Tenschert S,
Lemley K. The role of podocytes in the develop-
ment of glomerular sclerosis. Kidney int suppl
1994; 45:564-72.
7. Dantal J, Soulillou JP. Relapse of focal seg-
mental glomerulosclerosis after kidney trans-
plantation. Adv Nephrol Necker Hosp 1996;
25:91-106.
51
FOCAL SEGMENTAL GLOMERULOSCLEROSIS
8. Savin VJ, Chonko AM, Sharma R, Sharma
M, Gunwar S: Factor present in serum of patient
with minimal change nephrotic syndrome or fo-
cal sclerosing glomerulopathy causes an imme-
diate increase in glomerular protein permeabil-
ity in vitro. J Am Soc Nephrol 2: 791, 1991.
9. Sharma M, Sharma R, Gunwar S, Vincenti
F, Antero M, Savin V: Partial Purification and
characterization of a circular protein that in-
creases albumin permeability in human focal
segmental glomerulosclerosis J Am Soc Nephrol
3:751, 1992.
10. Sharma M., Sharma R, McCarthy E.T, Savin
V. The FSGS Factor: Enrichment and in vivo
effect of activity from Focal Segmental Glo-
merulosclerosis Plasma. J Am Soc Nephrol 10:
552-561 1999.
11. Artero M, Biava C, Amend W, Tomlanovich
S, Vincenti F: Recurrent focal glomerulosclero-
sis: Natural history and response to therapy. Am
J Med 92:375-383, 1992.
12. Mowry J, Marik J, Cohen A, Hogg R, Sah-
ney S, Ettenger R: Treatment of recurrent focal
segmental glomerulosclerosis with high dose
cyclosporine A and plasmapheresis. Transplant
Proc 25: 1345-1346, 1993.
13. Fogo A, Hawkins EP, Berry PL, Glick AD,
Chiang ML, MacDonnell RC, Ichikawa I: Glo-
merular Hypertrophy in Minimal Change Dis-
ease Predicts Subsequent Progression to Focal
Glomerular Sclerosis. Kidney Int 38: 115-123,
1990.
14. Boute N, Gribouval O, Roselli S, Benessy
F, Lee H, Fuchshuber A, Dahan K, Gubler MC,
Niaudt P, Antignac C. NPHS2, encoding the
GLOMERULAR DISEASES
glomerular protein podocin, is mutated in auto-
somal recessive steroid-resistant nephrotic syn-
drome. Nat Genet 2000 Apr; 24(4): 349- 54.
15. Mathis BJ, Kim SH, Calabrese K, Haas M,
Seidman JG, Seidman CE, Pollack MR. A Lo-
cus for Inherited focal segmental glomerulo-
sclerosis maps to chromosome 1q q13. Kidney
Int 1998; 53:282-286.
16. Winn MP, Colon PJ, Lynn KL, Howell DN,
Slotterbeck BD, Smith AH, Graham FL, Bembe
ML, Quarles LD, Pericak – Vance MA, Vance
JM: Linkage of a Gene Causing FSGS to Chro-
mosome 11 and further evidence of Genetic het-
erogeneity. Genomics 58:113-1200, 1999.
17. Winn MP, Conlon PJ, Lynn KL, Farrington
MK, Creazzo T, Hawkins AF, Daskalakis N,
Kwan SY, Ebersviller S, Burchette JL, Pericak-
Vance MA, Howell DN, Vance JM, Rosenberg
PB. A Mutation in the TRPC6 Cation Channel
Causes Familial Focal Segmental Glomerulo-
sclerosis. Science, 2005.
18. Goto Y, Nonaka I, Horai S. A mutation in
the tRNA (Leu) [UUR] gene associated with the
MELAS subgroup of mitochondrial encephalo-
myopathies. Nature 1990; 348:651.
19. A risk of allele for focal segmental glo-
merulosclerosis in African Americans is located
within a region containing APOLI and MYH9
20. Winn MP: Not all in the family: Mutations
of Podocin in sporadic steroid-resistant nephrot-
ic syndrome. J AM Soc Nephrol 13:577-579,
2002.
21. Karle SM, Utez B, Ronner V, Glaeser L.
Heidebrandt F, Fauchshuber A. Novel Mutations
52
in NPHS2. Detected in Both Familial and Spo-
radic Steroid Resistant Nephrotic Syndrome. J
AM Soc Nephrology 13: 388-393, 2002.
22. Floege J, Alpers CE, Burns MW, Pritzl P,
Gordon K, Couser WG, Johnson RJ. Glomeru-
lar cells extracellular matrix accumulation and
the development of glomerulosclerosis in the
remnant kidney model. Lab invest 1992; Apr,
66(4): 485-97.
23. Sharma K. Ziyadeh FN. The emerging role
of transforming growth factor – b in kidney dis-
eases. Am J Physiol 1994; 266: F 829-42.
24. Novick AC, Gephardt G, Guz B, Steinmuller
D, Tubbs RR. Long-term follow-up after partial
removal of solitary kidney. N Eng J Med 1991
Oct 10; 325 (15): 1058-62.
25. Najarian JC, Chavers BM, McHugh LE,
Matas AJ. 20 years or More Follow-up of Liv-
ing Kidney Donors. Lancet 1992; 340: 807.
26. Argueso LR, Ritchey ML, Boyle ET, Milli-
ner DS, Bergstralh EJ, Kramer SA. Prognosis of
patients with unilateral renal agenesis. Paediatr
Nephrol 1992; 6: 412-6.
27. Merlet- Benichou C, Leroy B, Gilbert T, Le-
lievre – Pegorier M: Retard de croissance intra-
uterine et deficit en nephron. Medicine/Sciences
9: 777-780, 1993.
28.Gilbert T, Lelievre – Pegorier M, Melet
– Benichou C: Long term effects of mild oligo-
nephronia induced in utero by gentamicin in the
rat. Paediatr Res 30: 450-456, 1991.
29. Zatz R, Fujihara CK; Glomerular Hypertro-
phy and Progressive Glomerulonephropathy. Is
there a Definite Pathogenetic Correlation? Kid-
ney Int 45 (Suppl 45): S27-S29, 1994.

30. Fogo A: Internephron Heterogeneity of
Growth Factors and Sclerosis. Kidney Int 45
(Suppl 45): S24-26, 1994.
31. Kopp JB, Mclune BK, Notkins AL, Sporn
MB, Klotman PE: Increased Expression of
Transforming Growth Factor Beta (TGF-B)
in HIV- Transgenic Mouse Kidney. J Am Soc
Nephrol 3: 600, 1992.
32. Kimmel PL, Bodi I, Abraham A, Philips
TM: Increased Renal Tissue Cytokines in Hu-
man HIV Nephropathy. J Am Soc Nephrol 4:
279, 1993.
33. Friedman EA, Rao TK, Disappearance of
Uremia due to Heroin-Associated Nephropathy.
Am J Kidney Dis 1995; 25: 689.
34. Schwartz MM, Korbet SM. Primary Focal
Segmental Glomerulosclerosis: Pathology, His-
tological Variants, and Pathogenesis. Am J Kid-
ney Dis Vol 22, No 6, 1993:874-883.
35. D’ Agati VD, Fogo AB, Bruijn JA, Jennette
JC. Pathologic classification of Focal Segmental
Glomerulosclerosis: A Working Proposal, Am J
Kidney Dis. 43:368-382, Feb 2004
36. A proposed taxonomy for the podocytopa-
thies: A reassessment of the primary nephrotic
diseases
37. Velosa JA, Holley KE, Torres VE, Offord
KP: Significance of Proteinuria on the Outcome
of Renal Function in Patients with FSGS. Mayo
Clin Proc 58: 568-577, 1983.
38. Korbet SM, Schwartz MM, Lewis EJ. The
Prognosis of Focal Segmental Glomerular Scle-
rosis of Adulthood. Medicine (Baltimore) 65:
53
FOCAL SEGMENTAL GLOMERULOSCLEROSIS
304-311, 1986.
39. Rydel JJ, Korbet SM, Borok RZ, Schwartz
MM; Focal segmental glomerular sclerosis in
adult: Presentation, Course and Response to
Treatment. Am J kidney Dis 25: 534-542, 1995.
40. Brown CB, Cameron JS, Turner DR, Cantler
C, Ogg CS, Williams DG. Focal segmental glo-
merulosclerosis with rapid decline in renal func-
tion (“malignant FSGS”). Clin Nephrol 10(2):
51-61, 1978
41. Wehrmann M, Bohle A, Held H, Schumm G,
Kendziorra H, Pressler H. Long-term Prognosis
of Focal Sclerosing Glomerulonephritis. An
analysis of 250 cases with particular regards to
tubulointerstitial changes. Clin Nephrol 1990;
33:115.
42. Chitalia VC, Wells JE, Robson RA, Searle
M, Lynn KL. Predicting Renal Survival in Pri-
mary Focal Glomerulosclerosis from the time of
presentation. Kidney Int 1999, 56: 2236.
43. Korbet SM. Clinical Picture and Outcome
of Primary Focal Segmental Glomerulosclero-
sis. Nephrol Dial Transplant 1999; 14 (Suppl.3):
68-73.
44. Mongeau JG, Robitaille PO, Clermont MJ,
Merouani A, Russo P. Focal Segmental Glomer-
ulosclerosis (FSG) 20 years Later. From Toddler
to Grown up. Clin Nephrol 4:1-6, 1993.
45. Passerini P, Ponticelli C. Treatment of Fo-
cal Segmental Glomerulosclerosis. Curr Opin
Nephrol Hypertens. 2001 Mar; 10 (2): 189-93.
Review.
46. Korbet SM; Treatment of Primary focal seg-
mental glomerulosclerosis. Kidney Int 62;
2301-2310, 2002.
GLOMERULAR DISEASES

47. C.D. Pusey (ed): The Treatment of Glomer- 54. De Smet E, Rioux JP, Ammann H, Deziel
ulonephritis 1998. Development in Nephrology, C, Querin S (2009) FSGS permeability factor-
Volume 40. associated nephrotic syndrome: remission after
oral galactose therapy. Nephrol Dial Transplant
48. McCauley J; Shapiro R; Ellis D; Igdal H; 24:2938-2940
Tzakis A; Starzl TE. Pilot trial of FK 506 in
the management of steroid-resistant nephrotic
syndrome. Nephrol Dial Transplant 1993;8(11):
1286-90.

49. Segarra A; Vila J; Pou L; Majo J; Arbos A; .

Quiles T; Piela LL. Combined therapy of tacro-
limus and corticosteroids in cyclosporine-resis-
tant or-dependent idiopathic focal glomerulo-
sclerosis: a preliminary uncontrolled study with
prospective follow-up. Nephrol Dial Transplant
2002 Apr;17(4):655-62

50. Mendoza SA, Reznik VM, Griswold WR,

Krensky AM, Yorgin PD, Tune BM. Treatment
of steroid-resistant focal segmental glomeru-
losclerosis with pulse methylprednisolone and
alkylating agents. Pediatr Nephrol 1990; 4(4):
303-7.

51. Tumlin JA, Miller D, Near M, Selvaraj S,

Hennigar R, Guasch A, A Prospective, Open-
Label Trial of Sirolimus in the Treatment of
Focal Segmental Glomerulosclerosis. Am. Soc.
Nephrol. 1:109-116, 2006

52. Cho ME, Hurley JK, Kopp JB, Sirolimus

therapy of focal segmental glomerulosclerosis
is associated with nephrotoxicity. Am J Kidney
Dis. 2007 Feb; 49 (2): 310-7.

53. Savin VJ, McCarthy ET, Sharma R, Charba

D, Sharma M, (2008) Galactose binds to focal
segmental glomerulosclerosis permeability fac-
tor and inhibits its activity. Transl Res 151:288-
292

54
 FOCAL SEGMENTAL GLOMERULOSCLEROSIS

55