Nephrology Self-Assessment Program - Vol 21, No 5, December 2022
Article
Primary Nephrotic Syndrome
Landan Zand, MD and Fernando C. Fervenza, MD, PhD, FASN
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
Learning Objectives
1. To review recent evidence on the diagnosis and treatment of
minimal change disease
2. To determine the role of genetic testing in a patient with an
FSGS lesion
3. To discuss updates on the significance of recently discovered
antigens in the diagnosis and treatment of membranous
nephropathy
4. To describe updates in the diagnosis and management of
maladaptive FSGS
5. To discuss the efficacy of treatment options in managing
patients with membranous nephropathy
Introduction
Nephrotic syndrome (NS) is defined as persistent proteinuria of
$3.5 g/d (in adults) or $40 mg/h per m2 (in children) in combi-
nation with hypoalbuminemia (,3.5 g/dl) (if measured by bromo-
cresol green method) or ,3.0 g/dl (if measured by bromocresol
purple or immunonephelometric methods) (1,2). Other features of
NS include edema (most commonly peripheral, but could present
with ascites or pleural effusion), hyperlipidemia, and a hypercoagul-
able state. These additional features are not required to make a
diagnosis of NS but are commonly present. Urine studies typically
show lipiduria, fatty casts, and oval fat bodies. Hypoalbuminemia
is essential for diagnosis of NS, and in the absence of hypoalbumi-
nemia the proteinuria is instead referred to as nephrotic-range
proteinuria (1). This is a crucial differentiation because nephrotic-
range proteinuria in patients without edema or hypoalbuminemia is
more likely to be due to secondary FSGS (e.g., resulting from adap-
tive changes such as glomerular hyperfiltration, obesity). NS arises
as a result of glomerular disease primarily characterized by podocyte
damage, and it can be due to primary podocytopathies or it can be
secondary to conditions such as diabetes or amyloidosis. In this
section we will discuss the three main primary causes of NS, includ-
ing minimal change disease (MCD), FSGS, and membranous
nephropathy (MN).
MCD
MCD is a primary podocytopathy that mainly affects children
(90%) and less commonly adults (10%). A renal biopsy specimen
Copyright # 2022 by the American Society of Nephrology
337
typically shows minimal or no changes on light microscopy, and
immunofluorescence is either negative or shows scant immunoglob-
ulin deposition. The hallmark of the disease is presence of diffuse
foot process effacement on electron microscopy (EM). In older
adults with heavy proteinuria, acute tubular necrosis is commonly
present on light microscopy (3). The majority of the cases of MCD
are idiopathic (primary). In secondary forms, MCD has been associ-
ated with drugs, neoplasms (primarily hematologic malignancies),
infections, and allergies (4). In this section we will focus on
primary/idiopathic MCD.
Pathogenesis
Both T and B cells have been suggested to play a role in the patho-
genesis of MCD (5). The main proposed mechanism has been
secretion of permeability factor(s) that damages podocytes. This per-
meability factor, however, has remained elusive until recently. Previ-
ously suggested circulating factors included a vascular permeability
factor that mimics hemopexin (6–9), angiopoietin-like-4 secreted by
the podocyte (10), or cytokines such as IL-8 and IL-13 (11–13),
but none of these candidates were shown to be specific to patients
with MCD and were present in patients with NS from other
diseases (14,15). More recently in a landmark paper, Watts et al.
showed that nephrin autoantibodies are indeed the circulating factor
that results in diffuse podocytopathy in a subset of patients with
MCD (16–18). In this study they evaluated the sera of 62 patients
with noncongenital and biopsy-proven MCD at the time of active
disease and showed that 18 of the 62 (29%) patients had circulating
nephrin autoantibodies. The authors showed that the nephrin auto-
antibody levels either decreased significantly or were absent after
treatment and once patients entered partial remission or complete
remission, suggesting that indeed the nephrin autoantibodies play a
role in the pathogenesis of the disease. The patients with positive
nephrin antibodies were also noted to have evidence of fine punctate
IgG staining on immunofluorescence and colocalization of IgG
with nephrin on confocal microscopy. The authors proposed that it
is through this in situ binding of anti-nephrin IgG to nephrin that
the integrity of the slit diaphragm is disrupted and podocytopathy
and proteinuria ensues.
Therapies
Corticosteroids. Corticosteroids are historically considered first-line
therapy for treatment of MCD in both adult and children. The cor-
ticosteroids commonly used include prednisone or prednisolone,
given as either daily dosing or alternate-day dosing. The optimal
duration of therapy with corticosteroid is not known. Several ran-
domized trials in children suggest that a shorter duration of therapy
may be as effective as longer therapy without increasing the risk of
relapse (19–21). However, a 2019 randomized controlled trial
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(RCT) of 237 children aged 1–14 years with steroid-sensitive NS
comparing extended prednisolone treatment (16 weeks) with stan-
dard prednisolone treatment (8 weeks) found similar efficacy and
rates of relapse but reported that extended prednisolone treatment
was more cost effective (owing to less primary care and hospital vis-
its) and was associated with better quality of life (21). This study,
however, was not able to assess long-term side effects associated with
corticosteroid therapy. There is less robust evidence available in
adults. Traditionally, patients are treated for $3 months, with retro-
spective studies suggesting more patients enter remission with longer
duration of therapy (22). In adults, alternate-day corticosteroid ther-
apy shows no differences in remissions, time to remission, relapse
rate, or time to relapse compared with daily-treated patients (23).
An RCT is required to evaluate short- versus long-term cortico-
steroid therapy in adults with MCD. Given the concerns regarding
complications related to a prolonged course of steroids in patients
with MCD, there has been a growing shift toward using steroid-
sparing agents such as calcineurin inhibitors (CNIs) as first-line ther-
apy, as discussed below.
CNIs. Cyclosporine and tacrolimus have been used successfully in
treating patients with steroid-dependent or frequently relapsing MCD
in adults (24–27). The goal of CNIs is to minimize repeated expo-
sures to corticosteroids because relapses are common, with one-third
of patients having more than one relapse (23). However, many
patients will experience significant toxicity from the corticosteroids
related to the first prolonged exposure, especially those with underly-
ing obesity or diabetes mellitus. As a result, newer trials have evaluated
use of tacrolimus as first-line therapy. In an RCT of adult-onset
MCD, 119 patients were treated with 10 days of intravenous methyl-
prednisolone, followed by treatment with tacrolimus or prednisone
for 16–20 weeks with taper over 18 weeks. Tacrolimus was noninfer-
ior to prednisone, with similar rates of remission and sustained remis-
sion and similar rates of relapse and time to relapse (28). Adverse
events and serious adverse events were more common in the predni-
sone group (28). Another recent multicenter RCT from the United
Kingdom enrolled 50 patients with de novo MCD and compared a
steroid-free protocol of tacrolimus with prednisolone therapy. Earlier
remissions were seen in prednisolone-treated patients, with a higher
remission rate at 4 weeks and nonsignificantly greater remission rate at
8 weeks (84% in prednisolone group versus 68% in the tacrolimus
group) but with similar rates of complete remission at 16 and 26 weeks
in both groups. Both groups had similar rates of relapses during the
follow-up period and very similar rates of adverse events (29). The
overall number of patients in this trial was small and it is likely that
the study was underpowered to detect a difference between the two
groups. Taken together, these two trials suggest that tacrolimus may
be used as a first-line agent and certainly should be considered in
patients who are at higher risk of complications from corticosteroids.
Mycophenolate Mofetil. Mycophenolate salts are available as either
mycophenolate mofetil (MMF) or enteric-coated mycophenolate
sodium. Limited data are available for their use in MCD. Thus far,
MMF has been used as a second- or third-line agent for the treatment
of patients with frequently relapsing disease. In children with fre-
quently relapsing NS, MMF was inferior to cyclosporine, with more
relapses occurring in patients treated with MMF during the first
year (but not the second year) (30). A more recent Chinese study
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comparing MMF with cyclosporine in children with frequently
relapsing NS showed similar results, with lower rates of remission
and more relapses in MMF-treated patients (31). When compared
with levamisole in children with frequently relapsing NS, MMF
showed equivalent efficacy, with similar rates of remission and
relapse (32). However, both treatments reduced exposure to corti-
costeroids by 30%–45% (32).
Data for the use of MMF in adult patients with MCD is sparse.
A 2018 open-label RCT enrolled 119 adults with new-onset MCD
and compared high-dose prednisone (1 mg/kg per day) with low-
dose prednisone (0.5 mg/kg per day) with enteric-coated mycophe-
nolate sodium (720 mg twice daily) as first-line therapy over a
24-week period. The primary outcome was complete remission at 4
weeks, which was achieved in approximately 60% of patients in
either arm. Both treatment arms had similar rates of complete remis-
sion at 24 weeks, and rates of relapse and adverse events did not
differ between groups. This study suggests a potential role for myco-
phenolate to reduce exposure to corticosteroids (33).
Rituximab. Over the past two decades since the first report of
successful treatment of a patient with steroid-dependent NS with
rituximab, there has been growing evidence from observational
studies and clinical trials (comparing rituximab with steroids or
placebo) that rituximab is efficacious for the treatment of patients
with steroid-dependent NS or frequently relapsing NS in children
(34–38). A large, randomized trial published in 2018 included
120 children with steroid-dependent NS, and compared rituximab
(375 mg/m2 3 2) with prednisolone for 4 weeks versus tacrolimus
(0.2 mg/kg per day) with tapering alternate-day prednisolone,
stopped by 6 months in those without relapse. In this study,
a course of rituximab was more effective than tacrolimus in
maintaining remission, with relapse-free survival of 90% versus
63% during 12 months of follow-up (odds ratio, 5.21; 95%
confidence interval [CI], 1.93 to 14.07). Median time to relapse
was 40 weeks in the rituximab-treated patients versus 29 weeks
in the tacrolimus-treated group. In addition, mean cumulative
corticosteroid dose was significantly lower in rituximab-treated
patients (39).
Several dosing regimens for rituximab have been used in chil-
dren, and two retrospective observational studies have reported on
outcomes with an immunosuppressive protocol. Lower-dose rituxi-
mab (100 mg/m2 or 375 mg/m2 3 1) in the absence of mainte-
nance immunosuppression has been associated with a higher rate of
relapse (hazard ratio for relapse, 1.55–4.98). Higher-dose rituximab
(375 mg/m2 3 2 or a cumulative dose of 750–1500 mg/m2)
resulted in sustained remission, with relapse-free survival up to
14 months in one series (40,41). However, those given lower-dose
rituximab with maintenance immunosuppression (defined as co-
treatment with steroids, CNIs, or mycophenolate) had similar
relapse-free survival to those treated with high-dose rituximab alone
(41). Prior studies in children with NS who are dependent on CNI
and prednisone therapy have shown that the addition of rituximab
allows for lowering of CNI and prednisone doses without increasing
rate of relapse, both short-term and long-term (42,43). However, a
prior RCT of 31 children with resistant NS demonstrated that addi-
tion of rituximab provides no additional benefit in children who are
resistant to prednisone and CNI therapy (44).
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An ongoing trial is comparing rituximab with a newer anti-
CD20 agent (ofatumumab) in children with steroid-dependent NS
on stable doses of prednisone and CNI therapy (NCT02394119)
(45). Fewer data are available in adults, but observational data and
evidence from several small trials suggest that rituximab is similarly
effective in children, in maintaining remission and reducing the
requirement for maintenance immunosuppression in both new-
onset MCD and frequently relapsing NS (37,46–48).
Adrenocorticotropic Hormone. Adrenocorticotropic hormone
(ACTH) was widely used in the 1950s for treatment of patients
with NS. This was later replaced by corticosteroids. Over the past
decade, there has been renewed interest in ACTH on the basis of
case series and systemic reviews suggesting a potential role for
ACTH in treatment of MCD despite scarce data (49,50). A recent
randomized trial compared 6 months of ACTH therapy with con-
trol, with a crossover design (from control arm to ACTH arm in
case of relapse) in children with NS (51). The study was ended early
because of the high rate of relapse in the ACTH arm (93%), sug-
gesting ACTH was ineffective in maintaining remission (51). There
are no randomized trials available in adults. At this point there are
not enough data to support use of ACTH in patients with MCD,
especially in children.
Outcomes
Children with MCD typically have a good long-term outcome, and
progression to ESKD is rare. Steroid responsiveness is the best pre-
dictor of outcome in these patients. The FSGS lesion is commonly
identified on repeated biopsy specimens from patients who do not
respond to steroids. Even though long-term renal outcome is favor-
able in children with MCD, those with frequently relapsing disease
requiring repeated courses of corticosteroids experience complica-
tions related to the corticosteroids, including osteoporosis, obesity,
and hypertension.
In adults with MCD, the outcome is less favorable (52).
Overall, 50% of patients respond to steroids and do not have
recurrence of the disease, but close to 30% of patients have fre-
quently relapsing disease. In addition, concomitant AKI related to
acute tubular necrosis in adults is common and is associated with
increased time to remission after steroid therapy. Similarly, as in
children, response to immunosuppression is the best predictor of
outcome in adults with MCD. Repeated biopsy in steroid-
unresponsive patients may be indicated, and not uncommonly an
FSGS lesion is identified. Genetic testing should be considered in
patients who do not respond to steroids, and this is discussed in
greater detail below.
4 Circulating nephrin autoantibody is the cause of
podocytopathy in about 30% of the patients with
MCD and the antibody titers decrease significantly
as patients enter remission.
4 One hypothesis is that in situ binding of anti-
nephrin IgG disrupts the integrity of the slit
diaphragm causing the podocytopathy.
339
FSGS
FSGS, often incorrectly abbreviated as focal sclerosis, is a lesion
identified on light microscopy with diverse causes and pathogenici-
ties that are linked by podocyte injury and depletion (53). FSGS is
not a disease entity but rather a pattern of injury. It is not uncom-
mon to find FSGS lesions in patients with other glomerulonephriti-
des such as lupus nephritis or ANCA-associated vasculitis, which
reflects postinflammatory scarring of a proliferative or necrotizing
lesion.
In the absence of an underlying GN, FSGS is broadly catego-
rized into three groups to differentiate between the underlying path-
ophysiologic changes that result in the formation of the segmental
scar. Primary (also known as idiopathic) FSGS is a lesion whose
underlying cause has not yet been identified, but indirect evidence
suggests a potential role for permeability factor(s) that cause diffuse
podocyte damage. Secondary FSGS can be due to toxins or drugs
(e.g., pamidronate) (54) or virus (e.g., HIV) (55), which result in dif-
fuse podocyte damage. Secondary FSGS can also be the result of
hyperfiltration, either through structural adaptation of the glomeruli
to nephron loss (e.g., after partial nephrectomy) or through increased
demand on existing nephrons (e.g., obesity) (56–58). More recently,
the class of genetic FSGS has been included under secondary FSGS
to reflect patients who have mutations either in podocyte genes or
glomerular basement membrane (GBM) collagen genes and who
present with lesions of FSGS. Still, despite extensive evaluation, a
significant number of patients have a cause that is not identified and
these patients are classified as FSGS on undetermined cause (59,60).
Understanding the underlying pathophysiology is essential
because it has significant implications on how to treat the patient.
Podocyte Injury and Death
Podocytes are a key player in the pathogenesis of FSGS because they
play a central role in maintaining the integrity of the filtration bar-
rier. Damage to the podocyte is central to the development and pro-
gression of disease. The initial podocyte injury leads to a variety of
morphologic changes in the podocyte, the most prominent of which
is foot process effacement (61). If injury is sustained or more severe,
it results in podocyte apoptosis and detachment. For example, Yes-
associated protein has been shown to be an inhibitor of podocyte
apoptosis, and in animal models its suppression results in podocyte
apoptosis, proteinuric kidney disease, and the development of histo-
logic features of FSGS (62,63). After podocyte loss, the denuded
GBM comes into contact with the parietal epithelial cell, resulting
in scar formation (64). Parietal epithelial cells may act as a progeni-
tor and replace the lost podocytes (65). There may, however, be a
critical threshold of podocyte depletion, after which repair may not
be possible and progression of the disease may be inevitable (66).
A variety of different mechanisms can result in podocyte injury
and death. In primary FSGS, a soluble factor(s) results in diffuse
podocyte damage. Proposed candidates have included soluble
urokinase-type plasminogen activator receptor, cardiotrophin-like
cytokine-1, and CD40 antibodies, but none have proved to be spe-
cific (67–70). In secondary FSGS, the mismatch between glomerular
demand and glomerular capacity results in glomerular hypertension
and increased fluid shear stress on the podocytes, which in turn
results in podocyte loss and development of segmental scars (58).
Genetic forms of FSGS (familial or sporadic) result from mutations
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in genes encoding proteins that are essential for maintenance of
podocyte cytoskeleton, foot processes, slit diaphragm, or interaction
between the podocyte and the basement membrane (71).
Importance of Renal Biopsy in Classification of FSGS
FSGS is diagnosed when at least one glomerulus in a biopsy sample
shows the typical appearance of a segmental increase in glomerular
matrix with obliteration of glomerular capillaries and scar formation
(72). Thorough evaluation of a biopsy sample by light microscopy
and EM is required to accurately classify primary versus secondary
FSGS, and exclude other causes of an FSGS lesion (73). A classi-
fication system on the basis of light microscopic appearance has
been proposed, whereby five morphologic patterns have been identi-
fied: FSGS not otherwise specified, tip, perihilar, cellular, and col-
lapsing variants (72,74,75). However, light microscopic appearance
alone cannot differentiate between primary, secondary, and genetic
FSGS (74).
An important consideration in the evaluation of a kidney
biopsy sample showing FSGS, in any of its light microscopic var-
iants, is the degree of foot process effacement on EM examination
(53). The degree of foot process effacement is determined primarily
by the nature of the pathogenic process affecting the podocyte (76).
Patients with primary FSGS show diffuse foot process effacement,
whereas foot processes are relatively preserved in cases of secondary
FSGS, with little overlap between the two (77). Thus, the degree of
foot process effacement by EM is a crucial clue to distinguishing pri-
mary from secondary forms of FSGS, with some exceptions, such as
cases of “collapsing” FSGS secondary to HIV, IFN, or pamidronate
therapy that are characterized by widespread foot process effacement
on EM. However, appearance on light microscopy or EM cannot
reliably distinguish a genetic cause from a primary form of FSGS
(see below).
Primary FSGS
Primary, or idiopathic, FSGS is a primary podocytopathy that
results from circulating factor(s) that cause diffuse podocyte damage.
The underlying pathophysiology resembles that of MCD, and
although MCD and primary FSGS are commonly considered to be
two separate diseases, some have proposed that they are different his-
tologic manifestations of the same disease process (78). Inasmuch as
the disease is the result of diffuse podocyte damage, the onset tends
to be sudden, and patients present clinically with NS ($3.5 g/d of
proteinuria in association with hypoalbuminemia ,3.5 g/dl). Histo-
logically, light microscopy reveals FSGS lesions but, more impor-
tantly, EM shows diffuse foot process effacement (.80%) (74,79).
It is important to note that the diagnosis of presumed primary
FSGS in not a pathologic diagnosis but a clinical-pathologic one,
necessitating careful evaluation of the clinical, laboratory, and kidney
biopsy findings (80). It is a diagnosis of exclusion, and distinction
between primary and secondary FSGS is not always obvious. Failure
to accurately identify the cause of FSGS can result in patients with
secondary or genetic forms of FSGS undergoing unnecessary immu-
nosuppressive therapy. Until a specific biomarker is identified, a
detailed and comprehensive evaluation of the native kidney biopsy
specimen, including EM examination, together with the clinical and
laboratory findings, provides the best chance of approaching the cor-
rect diagnosis.
Nephrology Self-Assessment Program - Vol 21, No 5, December 2022
Treatment. The goal of therapy in patients with primary FSGS is to
induce remission (either complete or partial) as it has been associated
with improved long-term outcome. Historically, the majority of the
drug trials in primary FSGS have suffered from the fundamental flaw
of enrolling a heterogeneous group of patients comprising not just
patients with primary FSGS but also those with secondary or genetic
causes (59,80). This has resulted in many negative trials and inability
to interpret the data. Despite these limitations, there is no doubt that
in patients with presumed primary FSGS, immunosuppression is
required. In general, angiotensin-converting enzyme inhibitors and
angiotensin receptor blockers are recommended, but alone they are
inadequate to treat patients with primary FSGS.
Corticosteroids. Historically, corticosteroids have been the first-
line therapy for patients with primary FSGS. Prolonged courses
($16 weeks) of high-dose steroids (1 mg/kg) may be required to
achieve remission. Up to 30% of patients will have a relapse after
tapering or stopping corticosteroids, and a second course of steroids
may not be as effective (81). If patients do not respond to steroids
after 16 weeks of therapy, second-line therapy such as CNIs should
be considered. A recent study suggests that proteinuria response at 8
weeks is an excellent predictor of the overall response to immuno-
suppressive therapy (82). This was a retrospective cohort study
including 51 patients (mean age 47 years) treated with corticoster-
oids for a median of 17 weeks. Ten patients achieved a partial
response at 8 weeks with a total of 18% and 35% achieving com-
plete response and partial response, respectively. A decrease of
.20% predicted remission.
CNIs. CNIs are typically used as second-line therapy for treat-
ment of patients who are resistant to corticosteroids (83,84). CNIs
should also be considered as first-line therapy in patients who have
contraindications to using corticosteroids, such as those with obesity,
diabetes mellitus, or osteoporosis (85). The effectiveness of CNIs is
partly due to immunosuppressive effects but may also partly relate
to their stabilization of the actin cytoskeleton in podocytes (86).
Nephrotoxicity related to CNIs remains a concern, especially in
those with impaired renal function (84,87,88). Voclosporin, a new
CNI agent, was under investigation as first-line therapy in treating
patients with primary FSGS but the trial was ended early because of
difficulty with recruitment.
Anti-CD20 Therapy. Rituximab has been shown to be effective
in the treatment of children and adults with FSGS who are
steroid responsive but remain steroid dependent or who experience
frequent relapse (37,48,88). Addition of rituximab to existing
immunosuppression has been associated with increased rates of
remission, reductions in relapse rates, and reduced need for addi-
tional immunosuppression, in retrospective and observational stud-
ies (39,46,87,89). Its use in patients with steroid-resistant FSGS is
less clear (89–91).
Newer anti-CD20 agents such as obinutuzumab have been
shown to be effective in the treatment of patients with other paren-
chymal diseases such as lupus nephritis and those with MN resis-
tant to rituximab therapy (92,93). Its use in treatment of patients
with treatment-dependent or -resistant primary FSGS is currently
under investigation in a prospective single arm clinical trial
(NCT04983888).
Other. Data regarding use of MMF in patients with primary
FSGS are less robust. MMF is likely inferior to CNI therapy but
may be used in combination with low-dose steroids for treatment of
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patients who have impaired renal function and are unable to take
CNIs (94). In very small case series, ACTH has been shown to
lower proteinuria in some patients with steroid-resistant FSGS
(95,96). A clinical trial evaluating the role of ACTH in treatment-
resistant FSGS (NCT02633046) has been completed but results on
the efficacy of the drug have not yet been published.
Sparsentan is a combination agent, comprising an endothelin
type A receptor antagonist and the angiotensin receptor blocker
irbesartan. Its use was studied in a phase 2 trial of sparsentan dose
escalation in patients with primary FSGS, where the primary end
point was change in proteinuria from baseline to week 8 (97).
Endothelin type A receptor antagonists have been shown to reduce
proteinuria in rodent models of FSGS, and they may augment the
effect of inhibitors of the renin-angiotensin system. The study
enrolled 109 patients across three dosing arms (36 treated with
irbesartan and 73 treated with varying doses of sparsentan). Signifi-
cantly greater reductions in proteinuria were observed in pooled
sparsentan-treated versus irbesartan-treated patients (244.8%; 95%
CI, 252.7% to 235.7% versus 218.5%; 95% CI, 235.6% to
1.7%). However, it should be pointed out that even though the
study aimed to enroll patients with primary FSGS, the inclusion
criteria were such that patients with secondary and genetic forms of
FSGS were also included. The main benefit was seen in patients
without NS; therefore, the results may not apply to patients with
primary FSGS.
Secondary FSGS
Adaptive secondary FSGS is due to glomerular capillary hyperten-
sion and hyperfiltration as a result of mismatch between glomerular
load and glomerular capacity. Patients with secondary FSGS (in the
absence of a virus or drug) present less acutely and without features
of NS. The proteinuria may be nephrotic or subnephrotic but is
typically associated with a normal serum albumin (.3.5 g/dl). His-
tologically, light microscopy shows an FSGS lesion, but EM reveals
mild-to-moderate foot process effacement (,80%) (72,74).
Treatment. Treatment is focused on mitigating factors that increase
glomerular demand, including weight loss, tight BP control, and
treatment of sleep apnea. Renin-angiotensin-aldosterone system
(RAAS) blockade with either an angiotensin-converting enzyme
inhibitor or an angiotensin receptor blocker is strongly recom-
mended to lower proteinuria and control BP. The protective effect
of RAAS blockade is partly mediated by vasodilation of efferent
arterioles and lowering intraglomerular hypertension. More recently,
interest has grown in evaluating the role of sodium-glucose cotran-
sporter 2 (SGLT-2) inhibitors in further lowering glomerular hyper-
tension. Their proposed mechanism of action is via increased
sodium delivery to the macula densa, which, through tubuloglomer-
ular feedback, results in afferent arteriolar vasoconstriction and
reduction in intraglomerular hypertension. They have been shown
to reduce proteinuria and delay progression of kidney disease in
both diabetic and nondiabetic patients (75,98). The DAPA-CKD
trial randomized 4304 patients with eGFR between 25 and 75
ml/min per 1.73 m2 and albumin-creatinine ratio between 200 and
5000 mg/g to receiving dapagliflozin 10 mg daily versus placebo.
Subgroup analysis was performed on 104 patients with biopsy-
proven FSGS (45 receiving dapagliflozin and 59 receiving placebo).
341
The type of FSGS was not clarified in this study but the median
albumin-creatinine ratio in the cohort was 1248 (range, 749–2211)
mg/g, suggesting that the majority of patients either had secondary
or genetic FSGS (99). The primary outcome was composite of
sustained eGFR decline of 40% or death because of kidney or
cardiovascular causes. There was higher rate of primary outcome in
placebo (21%) compared with dapagliflozin (11.3%) but this did
not reach statistical significance (hazard ratio, 0.46; 95% CI, 0.17 to
1.24) likely because of the small number of patients in this subgroup
of patients. Additional studies in larger cohorts are needed to evalu-
ate the efficacy of SGLT-2 inhibitors in this population.
Genetic FSGS
Genetic FSGS refers to monogenic forms of FSGS in which genes
encoding proteins expressed on either the podocyte or the GBM
are mutated. The clinical presentation of patients with genetic
FSGS can vary widely, which makes it difficult for clinicians to
select the patients who would benefit from testing. Patients can
present with NS, nephrotic-range proteinuria, or subnephrotic pro-
teinuria, and the degree of foot process effacement on EM can be
variable (71,72). However, full-blown NS in adults with genetic
forms of FSGS is uncommon. In some cases, extrarenal features
may be present, and the FSGS may be part of a syndromic disease,
but in the majority of the patients extrarenal manifestations are
uncommon. Genetic FSGS more commonly affects the pediatric
population, but up to 14% of adult cases are due to genetic muta-
tions (100). Several retrospective studies have identified significant
rates of gene mutations (#30%) in patients with steroid-resistant
NS despite clinical presentation and histologic findings that mimic
primary FSGS (101–103). Conversely, genetic testing in a small
subgroup of patients with steroid-sensitive NS failed to reveal any
gene mutations (100). Therefore, adults who appear to have pri-
mary FSGS but do not respond to therapy should be tested for a
genetic cause of FSGS. Other groups that may benefit from genetic
testing are those who appear to have secondary FSGS in the
absence of an obvious cause (e.g., no evidence of reduced nephron
mass or obesity) and those who cannot be easily categorized into
primary or secondary FSGS (undetermined FSGS) when there is a
mismatch between their clinical presentations and the degree of
foot process effacement on biopsy (72,104) (Figure 1). In a recent
prospective study of 49 consecutive patients with an FSGS lesion
who underwent genetic testing, patients with undetermined FSGS
had the highest rate of positivity (87.5%, 7 of 8) followed by
patients with secondary FSGS without an identifiable cause
(61.5%, 8 of 13). Genetic testing may also be indicated in patients
younger than 18 years of age, those with a family history of FSGS,
and those with syndromic forms of FSGS.
Traditionally, testing for a few of the most common mutations
was carried out by Sanger sequencing. However, with the growing
recognition of genes that can cause genetic FSGS (now .50 genes)
the preferred method has moved to next-generation sequencing,
which allows sequencing of a large number of genes. Whole exome
sequencing is a technique in which the exome (part of the DNA
that encodes proteins) is sequenced with the goal of finding patho-
genic mutations. This method has been successfully used to identify
mutations in patients with FSGS and CKD of unknown cause
(102,103,105,106).
342
To date, the majority of genes that have been associated with
genetic FSGS are those encoding proteins involved in the mainte-
nance of podocyte cytoskeleton, slit diaphragm, and foot processes.
There is increasing evidence that patients with FSGS lesions com-
monly have mutations in genes encoding type IV collagen
(COL4A3, COL4A4, COL4A5) in the absence of any evidence of
abnormality in the GBM (105–109). In a recent study, 193 indivi-
duals who were identified either by having biopsy-proven FSGS or
by the presence of proteinuria and a family member with FSGS
were examined for abnormalities in 109 genes associated with
FSGS, GBM abnormalities, and congenital abnormalities of the kid-
neys and urinary tract. Genetic abnormalities were identified in
11% of cases, of which 55% were identified in genes encoding type
IV collagen, and 40% in podocyte genes. In this series, abnormali-
ties of COL4A3, COL4A4, and COL4A5 were the commonest
monogenetic cause of FSGS in adults (107). Therefore, these genes
should be considered for testing in evaluating a patient for genetic
FSGS.
There are currently no specific treatments available for
patients with genetic forms of FSGS. Response to immunosup-
pression is suboptimal and should be avoided (110). Focus should
be on conservative measures, including weight and BP control in
addition to use of RAAS blockade if BP allows. SGLT-2 inhibitors
may also provide benefit in these patient but more studies are
needed.
MN
MN is a pattern of injury the hallmark of which is the presence of
immune complexes in the subepithelial region of the glomeruli.
Traditionally, MN has been divided into primary and secondary
Figure 1. Opinion-based approach to genetic testing in adult-onset FSGS. Note that viral- and drug-associated forms of FSGS are usually
excluded by clinical and serologic evaluation. EM, electron microscopy; FPE, foot process effacement. Reprinted from ref. 72, with permission.
Nephrology Self-Assessment Program - Vol 21, No 5, December 2022
forms with secondary forms seen in association with other diseases
such as sarcoidosis, malignancy, systemic autoimmune diseases
such as SLE, hepatitis B, and drugs. There is now growing recog-
nition that both primary and secondary MN are due to circulating
autoantibodies against specific antigens on the podocyte surface or
associated with overexpression of a specific antigen (reviewed in
Hoxha et al.) (111). Therefore, a target antigen-based approach
has been proposed for the classification of MN (112) rather than
categorizing the disease as primary versus secondary. Antigens that
are more commonly seen in the absence of an associated disease
include M-type phospholipase A2 receptor 1 (PLA2R), thrombos-
pondin type 1 domain-containing 7A (THSD7A), neural EGF-
like 1 protein (NELL-1), semaphorin 3B (Sema3B), protocadherin
PCDH7 (PCDH7), and serine protease high-temperature require-
ment A1 (HTRA1) (113–118). There are likely other antigens on
the podocyte surface with associated autoantibodies that cause
MN that are yet to be identified. Other antigens seen commonly
in association with other diseases including lupus and post bone
marrow transplantation include exostosin 1 and 2 (EXT1/EXT2)
(119), neural cell adhesion molecule 1 (NCAM-1) (120,121), and
protocadherin FAT1 (FAT1).
Anti-PLA2R Serology for Diagnosis, Prognosis,
and Management
The diagnosis of MN is on the basis of the renal biopsy findings of
an MN lesion with the associated typical immune complex deposits.
PLA2R-associated MN can be diagnosed for a renal biopsy specimen
showing staining of the PLA2R antigen in the deposits. This can be
done either by immunofluorescence or by immunoperoxidase stain-
ing on paraffin-embedded kidney tissue that has undergone pronase
Nephrology Self-Assessment Program - Vol 21, No 5, December 2022
digestion (122). In cases of PLA2R-associated MN, the staining is
intense along the glomerular capillary walls, whereas in negative cases
the staining is either absent or faint (minimal “blush”) (122). Given
the specificity of anti-PLA2R antibodies in patients with MN, the
data suggest that a kidney biopsy could be safely deferred in patients
with positive anti-PLA2R antibodies who have preserved renal func-
tion (eGFR .60 ml/min) and no evidence of secondary MN or dia-
betes. (123). These results were further confirmed in a validation
cohort in which 101 patients with biopsy-proven MN and positive
PLA2R antibodies were evaluated. Of the 79 patients with an eGFR
$60 ml/min per 1.73 m2, addition of kidney biopsy did not change
the diagnosis or the management in any of the patients (124).
PLA2R antibody has been shown to be highly specific for the
diagnosis of MN and has not been detected in other glomerular dis-
eases or healthy control individuals. However, there are a handful of
reports of patients with secondary MN who have positive PLA2R anti-
bodies. It is possible that some of these cases are not true secondary
but rather represent patients with PLA2R-associated MN who happen
to have a secondary disease as well. This is supported by reports of
cases that did not enter remission despite treatment of the secondary
cause or cases that entered spontaneous remission without treatment
of the secondary cause (125). Patients with secondary MN who most
commonly have been found to have positive PLA2R antibodies
include those with hepatitis B, hepatitis C, and sarcoidosis (126–128).
In a study of 39 patients with hepatitis B–associated MN, 25 patients
had positive PLA2R staining on kidney biopsy specimens (128). The
authors showed that the hepatitis B antigen colocalized along the glo-
merular capillary loop, which suggests that hepatitis B may trigger
an immune response to PLA2R antigen in these patients (128).
The mechanism by which this may occur remains unknown.
A variety of different assays have been developed over the past
decade to detect anti-PLA2R antibodies. The ELISA (Euroimmun,
L€ubeck, Germany) is the most commonly used commercial assay
that allows quantitative assessment of the anti-PLA2R antibody.
However, it is not as sensitive as other assays. The cell-based indirect
immunofluorescence assay (Euroimmun) is sensitive and may be use-
ful in detecting low levels of anti-PLA2R antibodies, but it does not
allow for quantitative assessment, and its use is not as widespread.
Some investigators suggest that both should be used simultaneously
for the initial diagnosis (123). Addressable laser bead immunoassay
(Mitogen Advanced Diagnostics Laboratory, Calgary, Canada) is the
most sensitive and quantitative assay available, but it is not commer-
cially in use (129).
Antibody titers have been helpful in predicting patients who
would enter spontaneous remission and those who would respond to
therapy. Low levels of antibody titer have been associated with high
rates of spontaneous remission (130,131), whereas high levels are asso-
ciated with progressive loss of renal function (131–133). The associa-
tion between baseline PLA2R antibody titers and proteinuria is less
clear, and this may be due to the lag between detection of antibodies
in the blood and the development of proteinuria. Indeed, in a large
retrospective study using Department of Defense repository samples,
anti-PLA2R antibodies were detected at a median of 274 days (inter-
quartile range, 71–821 days) before a diagnosis of MN on the basis of
renal biopsy (134). In a subset of these patients, PLA2R antibodies
were also found to predate the onset of nonnephrotic-range protein-
uria. Declining levels of PLA2R over time are shown to be the best
predictor of response and have the best prognostic value (135,136).
343
PLA2R1 is a transmembrane receptor that has a large extracel-
lular domain with three distinct regions, including a cysteine-rich
domain (CysR), a fibronectin type II domain (FNII), and eight dis-
tinct C-type lectin domains (CTLD1–8) (137). The most com-
monly recognized epitope by the PLA2R antibody is the CysR
region, but over time the antibodies may recognize other epitopes,
including CTLD1 and CTLD7. The phenomenon whereby new
epitopes (typically within the same molecule) are recognized by the
immune system is known as epitope spreading. In patients with
PLA2R-associated MN, epitope spreading was suggested to portend
a poor prognosis (137,138). However, in a prospective study of
150 patients with newly diagnosed PLA2R-associated MN, the
authors elegantly showed that detection of a specific epitope was
predominantly dependent on the PLA2R antibody level, and it was
the antibody level (rather than the epitope recognition) that pre-
dicted renal outcome and response to therapy (139). In other words,
it was the PLA2R antibody level that determined how many
additional epitopes on the PLA2R antigen it would bind to; by
diluting the PLA2R antibody titers, the antibody was no longer
able to recognize the less common epitopes such as CTLD1 or
CTLD7. These authors also identified another epitope (CTLD8),
which had been previously described, that the antibody could
recognize (139).
Monitoring PLA2R antibody levels over time is of great value
when treating patients with PLA2R-associated MN. A decline in
PLA2R antibody level over time is highly predictive that the patient
will enter remission (140–142). Therefore, a serology-based approach
when treating patients with PLA2R-associated MN has been sug-
gested (Figure 2) (143). In patients treated with immunosuppression
who show a rapid decline in PLA2R antibody within the first
6 months, and the antibody eventually disappears, immunosuppres-
sion could be safely discontinued. On the other hand, if the patient
does not show any appreciable decline in PLA2R antibody within the
first 6 months, a different immunosuppressive agent should be con-
sidered (143). Disappearance of PLA2R antibody (known as immu-
nologic remission) precedes improvement in proteinuria (clinical
remission). In patients who have reached immunologic remission but
continue to have proteinuria, additional immunosuppression is not
recommended but rather patience to allow for repair and remodeling
of the basement membrane to occur. In these patients the use of a
SLGT-2 inhibitor can be considered.
Other Serology
THSD7A. THSD7A is another target antigen on the podocyte sur-
face that is responsible for the development of MN. Antibodies to
THSD7A are present in 10% of MN patients who are PLA2R nega-
tive, accounting for 3% of cases of MN overall (114). The PLA2R
antibody and the THSD7A antibody were originally thought to be
mutually exclusive; however, since the publication of the original
study, a handful of cases with dual positivity have been reported
(144). The method of antibody detection in original reports was
Western blot, which is not commercially feasible. An indirect immu-
nofluorescence assay has been developed but is not as commonly
available commercially. Similar to PLA2R antibody, THSD7A anti-
body, detected by ELISA (Euroimmun), is helpful in both the diag-
nosis and the treatment of patients, and antibody titers over time
could be used to monitor disease activity (143). A notable difference
344 Nephrology Self-Assessment Program - Vol 21, No 5, December 2022

Figure 2. Prognostic algorithm. Although the temporal relationship between PLA2R antibody (Ab) levels and disease activity is well established,
a time lag of several months between immunologic and clinical response should be taken into account. Measurement of PLA2R Ab may obviate
the need for a “wait and see” period of 6 months, as recommended by the Kidney Disease: Improving Global Outcomes guidelines, and allow
more rapid treatment decisions. Serial PLA2R Ab measurements may guide the decision to start immunosuppression (IS). Patients with initial
high PLA2R Ab titers should be followed monthly, whereas those with moderate to low PLA2R Abs should be re-evaluated every two months.
This recommendation does not apply to patients with rapidly declining renal function, in whom prompt initiation of IS may be warranted.
PLA2R Ab ELISA (Euroimmun): low, 14–86 U/ml; moderate, 87–204 U/ml; and high, $204 U/ml. SCreat, serum creatinine. Reprinted
from ref. 143, with permission.

between PLA2R-positive and THSD7A-positive patients with MN
is the high rate of malignancy in patients with THSD7A positivity.
In the largest series of THSD7A cases, eight of the 40 patients were
found to have an underlying malignancy within 3 months of diagnosis
of MN (145). Therefore, in patients with THSD7A-associated MN, a
search for an underlying malignancy is highly recommended.
NELL-1. NELL-1 is one of the two antigens most recently recog-
nized as a cause of MN (115). NELL-1 was identified through laser
microdissection of the glomeruli, followed by mass spectrometry. In
evaluating a total of 210 PLA2R-negative MN patients, 34 (16%)
were found to be NELL-1 positive (115). Therefore, NELL-
1–associated MN is the second most common form of primary
MN. In this cohort, immunohistochemistry was also performed,
which confirmed NELL-1 positivity. Patients with NELL-1–
associated MN are older (average age, 63 years), with no sex predilec-
tion. The most common IgG identified was IgG1, but IgG2, IgG3,
and IgG4 were also present in some cases. This is in contrast to
patients with PLA2R-associated MN, in whom the IgG is typically
IgG4. Anti–NELL-1 antibody was identified in a subset of these
patients, and in patients in whom longitudinal sera was available, a
reduction in NELL-1 antibody preceded clinical remission. It is there-
fore likely that the concept of immunologic remission and serial
monitoring of antibody levels also applies to patients with NELL-
1–associated MN. Antibody testing for NELL-1, however, is currently
not available commercially. It should also be noted that of the
34 patients with NELL-1–associated MN, four (12%) had underlying
malignancy. As such, patients who are positive for anti–NELL-1 anti-
bodies in the biopsy specimen need to be evaluated for underly-
ing malignancy.
Sema3B. Sema3B was identified in 11 cases of PLA2R-negative
MN. Sema3B localized as granular deposits along the GBM by
immunohistochemistry (116). In four of 11 cases, kidney biopsy
specimens also showed tubular basement membrane deposits of
IgG. In five patients, Western blot analysis showed reactivity to
reduced Sema3B in four of four patients with active disease and no
reactivity in one patient in clinical remission. Eight (73%) of the
11 cases of Sema3B–associated MN were pediatric cases, and in five
patients the disease started at or below the age of 2 years. This
suggests that Sema3B–associated MN appears to be a distinct type
of MN more commonly seen in pediatric patients. Sema3B–asso-
ciated MN has been shown to recur post kidney transplantation in
association with positive anti–Sema3B antibodies confirming that
anti–Sema3B plays a role in the pathogenesis of this disease and
levels should be monitored peritransplantation (146).
PCDH7. PCDH7 was detected via mass spectrometry in ten patients
out of 175 patients with negative PLA2R, THSD7A, NELL-1,
Sema3B, and EXT1/EXT2 (5.7%) from the Mayo Clinic cohort.
Majority of patients were men (70%) with an average age of
61.2610.4 years with baseline creatinine of 1.3 mg/dl and 24-hour
urinary protein of 4.2 g/24 h. One notable finding of the kidney
biopsy in these patients was the absence of C3 staining in six of ten
Nephrology Self-Assessment Program - Vol 21, No 5, December 2022
patients and only 11 staining in the remaining four patients, suggest-
ing lack of complement activation in this subtype of MN. The
IgG subtype was a combination of IgG1 through 4. An additional
four patients were identified from the Belgian and French cohort
and taken together the prevalence of PCDH7-associated MN is
estimated to be about 1.6%–2% of the biopsies with MN. Of the
14 patients, six patients had associated autoimmune disease, sar-
coidosis, and underlying malignancy (117). Sera of six patients
with PCDH7-associated MN showed presence of anti-PCDH7
autoantibodies.
EXT1/EXT2. EXT1/EXT2 are another set of novel antigens that
have been identified in patients with MN (119). Similar to NELL-1,
the antigens were initially identified on mass spectrometry, and immu-
nohistochemistry later confirmed staining for EXT1/EXT2. Of the
224 PLA2R-negative cases of MN, 26 (11.6%) had staining for
EXT1/EXT2 by immunohistochemistry. These patients are younger
(mean age, 35.7 years) and are predominantly female (80.8%). They
typically have preserved renal function, with a mean creatinine of 1.0
mg/dl and average proteinuria of 5.9 g/24 h. In addition, 70% of the
patients had evidence of an underlying autoimmune disease with posi-
tive serology. Indeed, 34.6% of the patients had an underlying diagno-
sis of SLE. When biopsy specimens that were consistent with class V
lupus nephritis were specifically evaluated, eight out of 18 (44%) had
positive staining for EXT1/EXT2. In the validation cohort in this
study, in the evaluation of patients who were PLA2R and THSD7A
negative without evidence of class V lupus nephritis, three of 16
patients had staining for EXT1/EXT2. However, on further review all
three patients had evidence of underlying autoimmune disease, and
two patients later received diagnoses of SLE. In addition, many of the
biopsy specimens had features of secondary MN on histologic analysis,
including staining for C1q, mesangial deposits, and subendothelial
deposits in addition to tubuloreticular inclusions. Therefore,
EXT1/EXT2 are proteins that are overexpressed in the secondary form
of MN in association with underlying autoimmune disease, most com-
monly lupus. In this study, antibodies to EXT1/EXT2 could not be
identified. The absence of antibodies to EXT1/EXT2 in this study
does not rule out the possibility that such an antibody exists, but it also
raises the possibility that EXT1/EXT2 may not be the target antigens
themselves. Additional studies are required to further elucidate this.
In a more recent study of the 374 biopsies with membranous lupus
nephritis, 122 (32.6%) were positive for EXT1/EXT2 and the rest were
negative. Patients with EXT1/EXT2-positive lupus MN were younger
with lower serum creatinine, higher proteinuria, and less chronicity on
biopsy and had much lower rate of progression to ESKD compared
with those with EXT1/EXT2 negative membranous lupus nephritis
(147). These data show that patients with EXT1/EXT2 have favorable
prognosis and perhaps a period of monitoring should be highly consid-
ered in this population before proceeding with immunosuppressive
therapy. A recent study in 165 patients with class V lupus nephritis con-
firmed that patients who were positive for EXT1/EXT2 had lower
scores for activity index and lower chronicity tubular and atrophy scores
compared with patients that were EXT1/EXT2 negative (148).
NCAM-1. NCAM-1 is another antigen that is found to be overex-
pressed in patients with membranous lupus nephritis (121). Of 212
patients with membranous lupus 14 patients (6.6%) were NCAM-1
positive. In this same cohort 15.8% were EXT1/EXT2 positive.
345
Similar to EXT1/EXT2, patients were predominantly female (70%)
with an average age of 34612 years with baseline creatinine of
1.3560.88 mg/dl with an average proteinuria of 6.769.5 g/24 h and
serum albumin of 2.260.78 g/dl. Twenty-five percent of patients had
concomitant proliferative features associated with class III and IV
lupus nephritis. Anti–NCAM-1 antibody was identified in two
patients with available sera and was absent in patients with
EXT1/EXT2 MN, suggesting presence of anti–NCAM-1 antibodies
in a subset of lupus patients.
FAT1. MN can be a complication in patients who undergo hemato-
poietic stem cell transplantation (HSCT) and develop graft versus
host disease. The antigen in this subset of patients has remained
unknown until recently when FAT1 was identified to be the puta-
tive antigen (120). In this study, a total of 14 patients with FAT1-
associated MN were identified, all of whom had undergone HSCT.
MN occurred 2.460.8 years after HSCT, predominantly in men
(64%), with mean serum creatinine of 1.460.5 mg/dl and protein-
uria of 7.6 g/24 h at time of diagnosis. FAT1 antibody was identi-
fied in serum of one patient who underwent testing.
Treatment
All patients with MN should initially be given supportive therapy
aiming to reduce proteinuria. This should include dietary sodium
restriction to ,2 g/d, low-protein diet (0.8–1 g/kg per day), and BP
control aiming at a systolic BP ,130 mm Hg if tolerated.
Since the recognition of PLA2R as the primary antigen in pri-
mary MN and the advent of serial PLA2R antibody measurement,
the approach to treating patients with PLA2R-associated MN has
evolved over time. The goal of therapy now is to induce immuno-
logic remission, which corresponds to disappearance of the PLA2R
antibody (60). Clinical remission (corresponding to improvement
in proteinuria) typically follows 6 to 24 months after immuno-
logic remission has been achieved (149). In patients who do not
have antibodies detectable at the time of diagnosis, the traditional
approach of monitoring serum albumin and urinary protein is
recommended.
Before deciding whether or not to treat a patient with MN, it is
important to risk stratify because many patients may enter spontane-
ous remission without the need for immunosuppressive therapy.
The risk of progression should be determined on the basis of clinical
and immunologic parameters. Patients are considered to be at low
risk of progression if they have normal or stable eGFR over the pre-
ceding 6 months with proteinuria ,4 g/24 h with either negative
PLA2R or low PLA2R antibody levels (,50 RU/ml) that are decreas-
ing by $25%. These patients do not require immunosuppressive
therapy and should be treated conservatively with good BP control,
RAAS blockade, statin therapy, and modification of dietary protein
intake. Renal function, serum albumin, and 24-hour proteinuria
should be monitored every 6 months. Patients at moderate risk of
progression are those who have normal or stable eGFR over the
preceding 6 months; however, proteinuria is between 4 and 8 g/24 h
(in the absence of life-threatening NS; e.g., complications such as a
thromboembolic event), with moderately elevated PLA2R levels
(.50 RU/ml but ,150 RU/ml) that are stable over a span of
6 months. These patients may need to be treated depending on how
they progress over time. For example, if the proteinuria increases,
346
eGFR declines, or PLA2R titer rises, then the patients should be trea-
ted. Options include rituximab or cyclic cyclophosphamide plus glu-
cocorticoids. Alternative treatment includes CNIs (discussed below).
Patients who are at high risk of progression should be treated without
any additional observation period. These patients include those
who have a decline in their eGFR $25% related to the MN, have
.8 g/24 h of proteinuria, have life-threatening NS, or have PLA2R
antibodies that are elevated ($150 RU/ml) and are not declining
.25% within a 1- to 2-month interval. These patients require
immunosuppressive therapy. Recent trials suggest that rituximab may
be equally effective, with more remission durability (discussed below).
Historically, alkylating agents (e.g., cyclophosphamide or chlor-
ambucil) in combination with corticosteroids have been shown to
be effective in the treatment of patients with MN (150,151). The
significant toxicities associated with alkylating agents constitute a
major concern. However, in patients presenting with an already low
GFR or deteriorating kidney function, a course of cyclophospha-
mide combined with prednisone may be considered. Alternatively,
CNIs have been shown to be effective in treating patients with MN.
Both tacrolimus and cyclosporine have been used either as mono-
therapy or in combination with corticosteroids, with good results
(152–156). The major limitation with the use of CNIs is the high
rate of relapse after discontinuation of therapy (155,157), which
results in long-term use of CNIs in such patients and can in turn
lead to nephrotoxicity.
Over the past decade, rituximab has emerged as the most prom-
ising therapy in patients with MN. Since the initial report of suc-
cessful treatment of MN patients with rituximab, several additional
prospective trials have emerged and have confirmed the effectiveness
of rituximab (149,158–160). This was ultimately followed by Mem-
branous Nephropathy Trial of Rituximab (MENTOR), a random-
ized, open-label, noninferiority trial comparing rituximab with
cyclosporine therapy. This study enrolled 130 patients with MN, at
moderate risk of progression, with at least 5 g/d of proteinuria and
eGFR .40 ml/min per 1.73 m2. Patients were randomized to receive
either rituximab 1 g for two doses (a second identical course of rituxi-
mab was given to patients that had .25% decrease in proteinuria at
6 months) or cyclosporine 3.5 mg/kg for 12 months. Rituximab was
noninferior to cyclosporine in inducing remission at 12 months but
was superior to cyclosporine in maintaining proteinuria remission at
24 months. The rates of complete and partial remission at 24 months
differed widely, with remission in 60% of rituximab-treated versus
20% of cyclosporine-treated patients (161). Among patients who expe-
rienced complete or partial remission, those who received cyclosporine
had lower creatinine clearance at 24 months (87 ml/min per 1.73 m2)
compared with those who received rituximab (100 ml/min per
1.73 m2), despite having not taken cyclosporine for 12 months
(161). This highlights the fact that the effect of CNIs on renal func-
tion can be long lasting even after discontinuation of therapy. Given
these results, the upcoming Kidney Disease: Improving Global Out-
comes guidelines recommend rituximab as first-line therapy (60).
Whether rituximab or cyclophosphamide is more efficacious in
treating patients with MN has been a subject of ongoing debate in
the nephrology community. There are currently two trials that have
compared cyclophosphamide in combination with prednisone to
rituximab (162,163). First was the STARMEN trial in which
86 patients were randomized to receive either methylprednisolone
on months 1, 3, and 5 and cyclophosphamide on months 2, 4, and
Nephrology Self-Assessment Program - Vol 21, No 5, December 2022
6 or oral tacrolimus for 6 months (and then taper over 3 months)
and 1 g of rituximab on month 6. The primary outcome was rate of
complete or partial remission at 24 months. In the cyclophosphamide
group, 60% achieved complete remission at 24 months versus 26% in
the tacrolimus/rituximab group (relative risk, 2.36; 95% CI, 1.34 to
4.16). Patients also achieved remission faster in the cyclophosphamide
group. This study, however, is not a direct comparison of rituximab
with cyclophosphamide as patients were given rituximab 6 months
into the trial while receiving a CNI which is known to be inferior
to rituximab and subsequently received a low dose of rituximab (only
1 g) with no redosing at 6 months, and no information was available
as to whether patients were adequately B cell depleted. In fact, results
of the study can be explained by a lag in anti-PLA2R antibody decline
in the tacrolimus during the first 6 months versus a faster decrease in
anti-PLA2R antibody decline in the cyclophosphamide arm.
Another trial was the RI-CYCLO trial in which 74 patients were
randomized to receive 6 months of cyclophosphamide alternating
with corticosteroids versus two doses of rituximab (1 g each) given on
day 1 and day 15. The primary outcome was probability of complete
or partial remission at 12 months. There were few partial and com-
plete remissions at 12 months in patients receiving rituximab com-
pared with cyclophosphamide, but this was not statistically significant.
At 24 months there were similar rates of complete and partial remis-
sions in the rituximab (85%) and cyclophosphamide (81%) groups.
This rate of complete remission and partial remission remained similar
at 36 months. There were similar rates of adverse events in both
groups during the study period with infusion-related reactions more
common in the rituximab group and leukopenia and infectious com-
plications more common in the cyclophosphamide group. Based on
this trial, rituximab and cyclophosphamide combined with corticoster-
oids had a similar safety and efficacy profile.
4 Although the STARMEN trial showed increased
remission with methylprednisolone/cyclophospha-
mide compared with tacrolimus and low-dose
rituximab, the late administration and low dose of
rituximab render the trial an inconclusive compari-
son between cyclophosphamide and rituximab.
4 The RI-CYCLO trial showed comparable remission
at 24 and 36 months in patients treated with
cyclophosphamide versus rituximab.
Finally, in patients who become sensitized to rituximab (a chime-
ric type I anti-CD20 agent), a fully humanized type I anti-CD20
drug such as ofatumumab has been used successfully (164). Despite
the effectiveness of rituximab in inducing remission in patients with
MN, up to 30% of patients do not achieve remission. A case series
from Mayo Clinic reported on three patients with PLA2R-positive
MN who did not respond to rituximab. Obinutuzumab is a type II
anti-CD20 agent, which leads to more potent B cell depletion and
may have a greater effect on memory B cells than rituximab. After
treatment with obinutuzumab, two patients experienced complete
remission and one patient partial remission. This suggests that obinu-
tuzumab may be an alternative for patients who do not experience
Nephrology Self-Assessment Program - Vol 21, No 5, December 2022
clinical or immunologic remission with rituximab (93,165). There is
currently an ongoing trial comparing the safety and efficacy of obinu-
tuzumab with tacrolimus therapy (NCT04629248).
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