Nephrol Dial Transplant (2003) 18 [Suppl 6]: vi45–vi51

DOI: 10.1093/ndt/gfg1058

Focal segmental glomerulosclerosis in adults

J. Stewart Cameron

Renal Unit, Guy’s Hospital, King’s College, London, UK

Abstract Introduction
The lesion of focal segmental glomerulosclerosis
(FSGS) presents even greater problems of definition, The lesion of focal segmental glomerulosclerosis

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interpretation and treatment in adults than it does in (FSGS) presents even greater problems of definition,
children, to the point where the specificity and utility of interpretation and treatment in adults than it does in
the appearance can even be questioned. The histological children, to the point where the specificity and utility of
diagnosis of FSGS in adults can be interpreted only if the appearance can even be questioned. The possible
the clinical circumstances are known, but a group of pathogenesis and glomerular evolution through podo-
nephrotic patients with FSGS can be separated from a cyte damage, the details and varieties of the main
much larger group of non-specific, probably secondary histological lesion and its sub-groups, presentation
but similar lesions arising in many circumstances. This and management in children and its behaviour in allo-
group appears even so to have a diverse aetiology, the graft kidneys are dealt with in other papers in this
majority being idiopathic, but a significant minority Supplement, so I will concentrate on a general overview
showing a family history and/or mutations in genes of the appearance of FSGS and its significance as it is
relating to several intracellular or surface podocyte found in patients over the age of 15 years.
proteins, as discussed in other articles in this sym-
posium. This heterogeneity makes conclusions with
regard to prognosis and treatment difficult to draw. Focal segmental glomerulosclerosis in the past
Today, in contrast to 20 or even 10 years ago, it seems
useful to treat all adult nephrotic patients with FSGS FSGS is a glomerular appearance, which represents
using an adequate course of corticosteroids lasting at the histological aspect of a final common pathway of
least 4–6 months to establish whether they fall or not injury, and not a disease entity [1–4] as it has so often
into the 20–30% who will respond to this treatment been considered in the past. The words ‘primary’ or
with decrease or loss of proteinuria. The prognosis of ‘idiopathic’ reflect our ignorance of aetiology and
such responders (who may well suffer relapse) is pathogenesis, and as time passes they will become
relatively benign with regard to renal function, but the obsolete and unnecessary. No glomerular appearance
majority of the remainder evolve into renal failure. can ever be said to be ‘primary’: ‘cryptogenic’ is a
Their management remains a source of controversy in clumsy, but better, adjective.
the absence of a proper database of randomized trials: FSGS was first described and illustrated adequately
more prolonged (up to 24 months) use of lower-dose by Theodor Fahr in 1925 [5] in adult nephritic patients.
corticosteroids with cyclosporine for 12 months or more Even though a number of nephrotic children and adults
has support from uncontrolled studies, but cyclophos- must have died with glomeruli showing this appear-
phamide appears to be of less obvious benefit. ance, it was the paper of another pathologist, Arnold
Rich, who in 1957 clearly defined the histological lesion
Keywords: adults; focal sclerosis; focal glomerulo- in nephrotic children [6]. Rich’s paper, based on
sclerosis; FSGS; nephrotic syndrome sections of whole kidneys, was able to make the
important observation that the lesions were either
confined or most prominent in the juxta-medullary
glomeruli.
However, this paper attracted little attention at the
Correspondence and offprint requests to: Emeritus Professor
time and the important CIBA foundation meeting of
J. S. Cameron, MD, Elm Bank, Melmerby, Cumbria CA10 1HB, 1961 [7] did not mention it. Despite occasional mention
UK. Email: jstewart.cameron2@btopenworld.com in adults [8], it was only after another decade, when the

ß 2003 European Renal Association–European Dialysis and Transplant Association

vi46 J. S. Cameron
pathologists of the International Study of Kidney that scarring, immunoglobulin-positive proliferative
Disease in Children (ISKDC), Jack Churg, Renée glomerulonephritis or immunoglobulin-negative vas-
Habib and Richard White reported on renal biopsies culitis, could later give rise to an identical appearance
taken from 1966 to 1969 and pointed out the presence [11], although some such patients were distinguishable
of this type of lesion in a significant proportion of on immunohistology by the presence of (for example)
childhood nephrotics [9,10]. IgA; however, in many others immunohistology was
The initial impetus, during the 1970s, was to negative.
emphasize the differences between FSGS and minimal The lesion of FSGS can be found superimposed in
change in nephrotic patients, as it became obvious that glomeruli showing widespread pathology. Alport’s
the prognosis of FSGS was in general poorer, and a syndrome and membranous nephropathy are two
complete or partial response to corticosteroids less particular examples, but almost any type of pathology
frequent. Later in the 1980s, however, discussion swung could be complicated in its chronic course by lesions
back to emphasizing the many similarities between which, although clearly secondary to identifiable
patients with the two appearances, prompted by the processes, seemed morphologically identical to so-
fact that one appearance could evolve into the other in called ‘primary’ or ‘isolated’ FSGS [1–4,12,13]. Few of
serial biopsies. Observations on recurrence in allograft these patients, however, showed a nephrotic syndrome.
kidneys (discussed in this symposium by Newstead) These considerations apply much more to adult
further emphasized the unitary hypothesis, suggesting a patients whose histology is classified as FSGS,
common (but as yet undefined) pathogenetic mecha- compared with children in whom the majority are
nism at work in both situations. nephrotic and show no associated or prior pathology.

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Although proportionately most common in older The wider the range of patients with minor urinary
children, it rapidly became obvious that this glomerular abnormalities who are submitted to a renal biopsy, the
appearance could be found in nephrotic patients at any wider the spectrum of changes and the lower the
age, accounting for 5–15% of cases at almost all age proportion of patients with classical, so-called ‘pri-
groups (Table 1). Thus, it is an important underlying mary’ disease in a nephrotic setting, and the higher
pathology in the adult-onset nephrotic syndrome. An proportion of others, will be found. These others will
early observation was that, although the lesions visible often show one the supposed causes of ‘secondary’
on light microscopy might be focal and segmental, FSGS [1–4,12,13], a topic discussed by Mallick in this
diffuse simplification of foot processes (usually called symposium (Table 2). Thus, it is impossible to give a
‘fusion’ at that time as seen in cross section of useful estimate of the percentage of biopsies with FSGS
transmission electron microscopy) was present in all in adults, because this figure depends too much upon
glomeruli and unaffected portions of affected glomer- local biopsy policy, and in particular policy with regard
uli, at least in apparently ‘primary’ forms of the disease. to patients with minor proteinuria, with or without
This may not, however, be true in renoprival and haematuria and hypertension.
‘secondary’ forms of FSGS. Finally, in adults particularly, the problem of focal
and segmental lesions in renoprival settings arises. Loss
of one kidney or greater, or advancing destruction of
‘Focal segmental glomerulosclerosis’ in the kidney in settings seemingly as remote as polycystic
adults today kidney disease, can be accompanied by the appearance
of similar lesions, which have their analogy in the
FSGS lesions found in rats subjected to sub-total
Histology in a clinical setting
nephrectomy [14,15]. The possible pathogenetic impli-
It remains obvious (but is often neglected) that without cations of these observations are discussed elsewhere in
information on the clinical setting of the histological this symposium.
appearance, the significance of a finding of FSGS Recently, Howie et al. [16], based on work in animals
cannot be interpreted in detail. Thus, in adults, by Grond et al. in 1981 [17] as well as their
identical focal and segmental scarring with hyalinosis observations on human biopsies showing FSGS,
can be found in patients with proteinuria of minor suggested that the detailed distribution of this type of
dimensions (0.5–1.5 g/24 h), often hypertensive, whose FSGS differs from that of ‘primary’ FSGS. They noted
prognosis was good even in the absence of any that the glomeruli have a larger cross-sectional area
treatment [1–4]. Also, we have known for a long time and the lesion is almost always perihilar, never at the

Table 1. Percentage of all nephrotic patients with FSGS

Children Adults

Age 0–15 15–19 20–30 30–40 40–50 50–60 >60 years

% FSGS 7 19 18 11 27 16 2

0–15 years: data from 521 unselected childhood onset nephrotic syndromes from ISKDC patients, predominantly Caucasian and Japanese.
Adults: data from 506 nephrotic patients seen at Guy’s Hospital 1964–1984, predominantly Caucasian.
FSGS in adults vi47
Table 2. Nephrotic adults: distribution of different lesions by race example, Schwartz et al. [19] noted an average of
21 ± 14% glomeruli apparently affected in limited
Race n MCD FSGS Memb MCGN number of sections from biopsies of 81 adult-onset
patients. That this simple approach is inadequate is
‘White’ 170 20 23 36 6 (%) clear from several studies. In ‘primary’ FSGS, Fogo
‘Black’ 121 14 57 24 2 (%) et al. [20] noted that lesions were more widely
Data of Korbet, 1994 [22], Rydel et al., 1995 [23]. The weakness of distributed in adults (31.5 ± 6.8%) than children
any definition of racial origin is well known. (11.7 ± 5.7%), but also that on examination of serial
sections the number involved rose to 48 ± 6.6% and
23.2 ± 7.4, respectively. Remuzzi and colleagues [18]
‘tip’ of the glomerulus, and can be distinguished in the performed an even more extensive study on four sub-
absence of clinical data. They noted this appearance in total nephrectomy kidneys involving three-dimensional
11 of 130 patients, five of whom had single kidneys reconstructions: in single sections, 51% were of
three were biopsies from the larger of asymmetric glomeruli which were globally sclerosed, 12% segmen-
kidneys. These suggestions, however, are not in accord tally sclerosed and 37% normal, whilst these figures
with the data of Remuzzi et al. [18] discussed below. were 51, 42 and 8% normal on serial sectioning.
These authors noted in a very detailed examination of Finally, Fuiano et al. [21] showed that in 14 biopsies
four kidneys, exposed previously to subtotal nephrect- from adults, although 31.5% of 182 glomeruli had
omy that up to eight separate areas of glomerulo- sclerotic glomeruli, this figure rose to 71.8% on serial
sclerosis might be present in a single glomerulus. They sectioning, and in the 57 glomeruli for which the whole

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also observed that the majority of glomeruli showed glomerulus was available, to 81.7%. Thus, the ‘focal’
more than one segmental lesion and that there was no nature of the lesion is exaggerated greatly by sampling
correlation between glomerular size and sclerosis. errors contingent on their segmental nature. Perhaps
Again the jury remains out as to the significance of we should drop the ‘focal’ from the name of this
these observations. appearance, and call it simply ‘segmental sclerosis’.
Thus, the concept of FSGS in adults today, centres
around the clinical identification of so-called ‘primary’ FSGS and the minimal change lesion
forms, related to minimal changes and dominated by
profuse proteinuria and its consequences, and the What can we make of all this today? Clearly the focal
separation of a variety of ‘secondary’ forms, in which sclerosing lesion seen in circumstances outside the
associated conditions can be identified and which apparently primary nephrotic syndrome forms a
presumably relate to the cause of the change which may different group of patients from those with minimal
have a variety of clinical presentations. changes. Nevertheless, they must share some final
common expression of injury to generate a lesion,
which is morphologically the same as that in ‘primary’
FSGS. The continuing question centres on whether, in
a setting of the nephrotic syndrome, minimal change
The histological sub-types of FSGS lesions and FSGS represent two aspects, more or less
severe, of the same pathogenetic mechanism. This
The characteristics of the various sub-types of FSGS in mechanism concerns the presence of a circulating
adults have been reviewed by myself and others in the substance yet to be fully identified, which is discussed in
past, and are discussed by Howie elsewhere in this detail elsewhere in this symposium.
symposium, so that here I will mention them only Three important pieces of clinical evidence support
briefly, although they are of great interest and the identity of the two appearances [2]. The first is
importance. The major problem is to know whether the repeated description of occasional patients with
these sub-types—‘cellular’, ‘tip’ or ‘collapsing’—have initially and indubitably corticosteroid-sensitive dis-
useful meaning either in terms of understanding the ease and minimal change on histology, who evolve to
pathogenesis, or in predicting outcome or response to show FSGS on biopsy, develop corticosteroid resis-
treatment of FSGS [19]. Here, despite evidence for the tance, end-stage renal failure—and even on occasion
contrary view, I will discuss adults with ‘primary’ FSGS recurrent disease in their transplant, as in one of our
as though they are a homogenous group, regardless of own cases. On the other hand, intense immunosup-
which sub-type of FSGS they may demonstrate. pression can on occasion (see below) push even
patients with renal functional impairment and FSGS
into remission, contrary to what was formerly believed.
Finally, proteinuria can recur in kidneys grafted into
Definition of FSGS
patients with FSGS, with the subsequent appearance
We must also consider the broad definition of FSGS. of FSGS lesions only after months of proteinuria.
By implication, this means that in single section However, some current data do not support the idea
preparations, the lesion is focal in distribution and of identity between FSGS and the minimal change
segmental in nature, and that the frequency of the lesion. In particular, studies of families of patients with
lesions can be assessed by doing glomerular counts. For FSGS and with minimal change lesions reveal linkages
vi48 J. S. Cameron
with as yet ill-defined genetic loci (see note added in filtration rate (GFR) measurements depends upon the
proof), which are different in patients with the two severity of the nephrotic syndrome and the duration of
appearances. This is difficult to reconcile with the disease before investigation, but is frequently reduced
unitary hypothesis, and suggests that nephrotic FSGS, (20–25%).
just like other forms, is but one of a group of Only during the past 10 years or so has it been
appearances, which resemble each other but are not realized that FSGS shows a remarkable racial
identical. Only when the pathogenesis can be described predominance. This is particularly so in adult
more accurately at various levels of precipitating nephrotics, with almost two-thirds of Afro-American
factors, genetic background and mediation of injury adults with a nephrotic syndrome showing the FSGS
is this question likely to be settled. lesion [25,26] (Table 4). This is true also for one-third or
more of Afro-American nephrotic children. It has been
suggested in addition that the frequency with which the
Clinical features of FSGS in adults lesion is now seen in nephrotic patients has increased,
particularly in adults [27,28] but also in children.
The clinical features of FSGS in adults have been However, all these reports have emerged from the
described in only a few hundred patients in numerous United States, and it is not clear whether these findings
series over several decades (Table 3) [1,2,22–24] and the are true also of European countries. Certainly there has
tiny size of this database needs to be remembered. been no increase in the apparent incidence of FSGS in
Proteinuria is almost invariable, of dimensions, which our own data, in which the proportion of adult
will induce a nephrotic syndrome in a proportion of nephrotics with the appearances of FSGS in their renal

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patients, which varies with numbers of non-nephrotic biopsy remains 20% from the 1970s up to the end of
patients biopsied, but is usually 60% at onset and the century. It is very difficult to be sure about the
may be as high as 80–90% with time. Secondary forms current proportion of FSGS in nephrotic children,
of FSGS rather rarely present with a full nephrotic because far from all nephrotic children are biopsied and
syndrome, even if in the presence of quite heavy because today it is almost standard practice between
proteinuria they become hypoalbuminaemic. HIV- the ages of 1 and 6 or even 10 years only to biopsy those
positive patients are an exception to these statements, who fail to show an initial favourable response to
however. In primary FSGS, macroscopic haematuria is treatment with corticosteroids, or who suffer a sub-
very rare, but microscopic haematuria usual and sequent troublesome course.
hypertension common. Renal function as judged by Some patients with apparently primary FSGS have
plasma creatinine concentration or, better, glomerular other family members affected [29]. The pattern of
inheritance is probably both autosomal dominant and
autosomal recessive in different families, but this has
not been established with certainty. Linkages with
Table 3. A classification of FSGS loci on chromosomes 11 and 19 have been reported,
suggesting heterogeneity of inheritance.
1. ‘Primary’ (idiopathic) FSGS, including: Numerous studies have attempted to correlate
Collapsing glomerulopathy clinical and histological features with outcome so that
Cellular variant
Glomerular tip lesion prognosis and treatment can be better informed [21–
2. FSGS with reduced renal mass and glomerulomegaly 24,29–31]. Clinically, the over-riding feature is whether
Reflux nephropathy or not proteinuria becomes normal, almost always in
Dysplasia association with treatment. Patients in whom this
Oligomeganephronia
Morbid obesity
happens, even if they relapse repeatedly, almost always
Failing allografts do well. The only other features that have prognostic
Renovascular disease, etc. value are renal function at the time of investigation
3. Secondary FSGS and the amount of proteinuria. Age, sex, race and
Alport’s syndrome hypertension do not seem to affect prognosis. In renal
Membranous nephropathy
Sickle cell disease biopsy specimens—as in almost all forms of so-called
Pre-eclampsia ‘glomerular’ diseases—the major prognostic factor is
Diabetes, etc.
HIV-associated FSGS
Heroin-associated FSGS
Table 4. Clinical features of adult-onset patients with FSGS
4. Associated with inherited disorders and anomalies
Alport syndrome
Mitochondrial cytopathies %
Charcot-Marie-Tooth disease
Down’s syndrome Male sex 62
Etc. Nephrotic syndrome 68
5. Scarred proliferative disease Hypertension 43
IgA nephropathy Haematuria 45
Henoch–Schonlein purpura Renal impairment 24
Lupus nephritis
Post-streptococcal nephritis, etc.
Analysis of 492 patients in the literature from Korbet et al. [22].
FSGS in adults vi49
the presence and extent of tubulo-interstitial damage. Table 5. Outcome in relation to response to treatment in adult
We have not been able to confirm in our own data any patients with FSGS
correlation between the site of the glomerular lesions
Response to treatment Proportion entering renal failure
and prognosis [2].
This issue of whether the site of injury within the n %
glomerulus is associated with prognosis is controver-
sial, and I have reviewed the evidence as I see it Complete response 2 of 278 3
previously [2]. Since then, no new data have arrived to Partial response 8 of 32 25
allow me to change my position that site of the FSGS No response 73 of 132 60
lesion has no influence on outcome. Total 83 of 242 30

From an analysis of the literature by Korbet et al. [24].

Treatment of FSGS in adults

greater the rate of response. The response seems likely
In the absence of any real understanding of the to be more frequent in those with normal renal
pathogenetic background, treatment of FSGS in adults function, but this point has never been tested
was—and remains—empiric. Again, the tiny database adequately.
and paucity of controlled trials must be remembered If there is no response, what to do next remains
when making and assessing any statements about the controversial. No controlled clinical trials of cyclophos-

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treatment of FSGS [32–34]. This topic is reviewed in phamide have ever been conducted in adults with
this Supplement by Filler and Meyrier. However, a few FSGS, but likely benefit seems low; the only trial, in
brief remarks are in order here. children, showed no benefit. However, Ponticelli and
Obviously a first step is to identify patients with colleagues [36] have made a strong plea for longer and
a ‘secondary’ form of FSGS (see Mallick, this stronger primary treatment in adult patients, with
Supplement), as they may need different management. corticosteroids alone with or without cytotoxic agents.
Here, we are concerned only with so-called ‘primary’ Similar and more numerous pleas have been made in
FSGS in adults. Treatment may then be graded the treatment of children with FSGS also (see Cochat,
according to the presence or absence of adverse this Supplement). Unfortunately it is not clear which
prognostic features. Thus, it is probably not worthwhile patients might benefit from additional cytotoxic agents,
treating patients aggressively who have only 0.5–2.0 and in the Italian data the outcome was similar to that
g/24 h proteinuria, as the analyses discussed above using corticosteroids alone.
suggest that the great majority of such patients will do Thus, one option after 6 months treatment using
well and will not develop renal failure even on corticosteroids without response is to continue the
prolonged follow-up. It is with the remainder suffering treatment for up to 2 years in lower dosages. One
more profuse and persistent proteinuria that we are problem is that the Italian database consists only of
concerned. Many of these patients will have reduced patients with a normal or near normal plasma
renal function and tubulo-interstitial damage in their creatinine. This makes comparison with previous data
renal biopsy. difficult, as it is impossible to derive from these
Today in my view it seems worthwhile to treat all accounts what the relationship between renal function
adult-onset nephrotic patients showing FSGS in their and apparent response to treatment may have been.
biopsies using corticosteroids. In the past, inadequate Nevertheless, within this restricted group of those with
courses were often used [35], frequently of only 8 normal/near normal renal function, 50% achieved
weeks duration, because the majority of children with remission after 3 years treatment, and a further 20%
minimal change will respond within this time. partial remission [36].
Unfortunately it took a long time to realize that this In contrast there is now a considerable quantity of
was not true in adults, even with only minimal changes uncontrolled data [35], and one small controlled trial
present, and that a minimum of 16 weeks treatment reviewed in detail by Meyrier in this Supplement, which
is necessary to establish ‘resistance’ to corticosteroid suggests that cyclosporine does confer major benefit
therapy. Thus, today a minimum of 4 months cor- in ‘corticosteroid-resistant’ patients [37]. In 49 such
ticosteroids (preferably 6 months) is suggested, not only patients, 70% of those randomized to prednisolone
because of possible benefit from loss or major plus cyclosporine went into complete (9%) or partial
diminution of proteinuria in as many as 30% of (61%) remission, compared with only 4% of those
patients, but also because of the prognostic value that continuing to take prednisolone plus placebo. The
even failure to achieve benefit can bring (see above). effect on progression of renal failure was, however, less
The data (Table 5) include studies with different dramatic: a quarter of the treated group and half of the
dosages and duration of corticosteroid treatment, placebo group suffered a halving of renal function
which makes evaluation difficult. There is a suggestion during 4 years. The weakness of this study is that
from the data in aggregate, recently emphasized by ‘steroid resistance’ was defined by only a minimum of 8
Ponticelli and colleagues [36], that the greater the weeks (mean 14 weeks) treatment, which certainly
intensity and duration of immunosuppression, the means that some ultimately steroid-responsive patients
vi50 J. S. Cameron
will have been included. Also, all patients with a 6. Rich AR. A hitherto undescribed vulnerability of the
creatinine clearance <42 ml/min/1.73 m2 were excluded. juxtaglomerular glomeruli in lipoid nephrosis. Bull Johns
Hopkins Hosp 1957; 100: 173–186
Nevertheless, if after 6 months treatment with cortico-
7. Wolstenholme GEW, Cameron MP (eds). Renal Biopsy.
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