review
org
Membranous nephropathy: integrating basic
science into improved clinical management
Daniel C. Cattran1 and Paul E. Brenchley2
1
Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; and 2Renal Research Labs, Institute of
Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom
Idiopathic membranous nephropathy (INM) remains a
common cause of the nephrotic syndrome in adults.
The autoimmune nature of IMN was clearly delineated in
2009 with the identification of the glomerular-deposited
IgG to be a podocyte receptor, phospholipase A2 receptor
(PLA2R) in 70% to 75% of cases. This anti-PLA2R
autoantibody, predominantly the IgG4 subclass, has
been quantitated in serum using an enzyme-linked
immunosorbent assay and has been used to aid diagnosis
and monitor response to immunosuppressive therapy.
In 2014, a second autoantigen, thrombospondin type 1
domain–containing 7A (THSD7A), was identified.
Immunostaining of biopsy specimens has further detected
either PLA2R or THSD7A antigen in the deposited
immune complexes in 5% to 10% of cases autoantibody
seronegative at the time of biopsy. Therefore, the term
IMN should now be superseded by the term primary or
autoimmune MN (AMN) (anti-PLA2R or anti-THSD7A
positive) classifying w80% to 90% of cases previously
designated IMN. Cases of secondary MN associated with
other diseases show much lower association with these
autoantibodies, but their true incidence in secondary
cases still needs to be defined. How knowledge of the
autoimmune mechanism and the sequential measurement
of these autoantibodies is likely to change the clinical
management and trajectory of AMN by more precisely
defining its diagnosis, prognosis, and treatment is
discussed. Their application early in the disease course to
new and old therapies will provide additional precision to
AMN management. We also review innovative therapeutic
approaches on the horizon that are expected to lead to our
ultimate goal of improved patient care in A(I)MN.
Kidney International (2017) 91, 566–574; http://dx.doi.org/10.1016/
j.kint.2016.09.048
KEYWORDS: glomerulonephritis; membranous nephropathy; nephrotic
syndrome; proteinuria; renal pathology
Copyright ª 2016, International Society of Nephrology. Published by
Elsevier Inc. All rights reserved.
Correspondence: Daniel C. Cattran, Toronto General Research Institute,
University Health Network, 585 University Avenue, Toronto, Ontario Canada
M5G 2N2. E-mail: daniel.cattran@uhn.ca
Received 7 June 2016; revised 26 August 2016; accepted 8 September
2016; published online 5 January 2017
566
www.kidney-international.
I
diopathic membranous nephropathy (IMN) remains one
of the most common causes of nephrotic syndrome in
adults and one of the leading known causes of end-stage
renal disease.1,2 Reported variation in incidence may reflect
specific country/physician indication for kidney biopsy but
could as well be real differences related to the population’s so-
cioeconomics, ethnicity, or environment.3 What does seem
likely, given the advances in the both the understanding of
the autoimmune nature of the disease and improvements in
conservative management as well as more specific therapeutic
options, is that the natural IMN history, classically the rule of
thirds (one third spontaneous remission, one third persistent
proteinuria and one third progressive renal failure), has
altered.4,5
Although the incident biopsy rate of IMN in the North
American population has changed little, as evidenced by data
over the past 30 years from the Toronto Glomerulonephritis
Registry, despite widened population ethnicity (Table 1),6
there has also been minimal change in numbers from the
dominant Caucasian population served by the Mayo Clinic7
and the Scottish Renal Association, Renal Biopsy Registry.8
In all instances, IMN remains near the top of the list of the
most common incident GN variants.5,9,10 What has changed
is that the average age at presentation has increased by
approximately 2 decades and when combined with the global
issue of obesity, increases the risks of our current therapeutic
options and brings into focus the need for more precise
management tools and more specific therapies now poten-
tially offered by our new understanding of the nature of the
pathobiology of the disease.
The new biology of autoimmune disease
Discovery of the specific autoimmune mechanism and
autoantigen phospholipase A2 receptor. IgG antibody has
been associated with the glomerular lesion of IMN since the
1960s, but the autoimmune nature of the antibody specificity
was not determined until 2009 with the identification of
phospholipase A2 receptor (PLA2R) on podocytes as the
target antigen in >70% of cases.11 Sera from IMN patients
with active disease was found to contain a circulating auto-
antibody, predominantly of the IgG4 subclass, that reacted by
Western blotting on high molecular protein bands only on
unreduced sodium dodecylsulfate gels. Analysis of relevant
protein bands by mass spectrometry identified PLA2R as the
target antigen. The PLA2R gene had previously been cloned12
but in the context of studies on the PLA2 enzyme not MN.
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DC Cattran and PE Brenchley: Membranous nephropathy
Table 1 | Trends in Toronto Glomerulonephritis Registry: 1975–2015a
1975–1979 1980–1984 1985–1989 1990–1994
MN 134 172 171 164
MPGN 99 67 33 46
FSGS 141 164 163 239
IGA 129 215 227 262
LUPUS 170 191 143 174
Vasculitis 29 66 76 93
FSGS, focal segmental glomerulosclerosis; IGA, IgA nephropathy; MN, membranous nephropathy; MPGN, membranoproliferative glomerulonephritis; N/A, not available.
a
In 5-year blocks (4-year block, 2012–2015).
Genetics of idiopathic (A)MN. Initially, IMN was associated
with human leukocyte antigen (HLA) DR,13 then, with the
advent of molecular typing, DQA1.14 The first DQA1 in IMN
reported in 2011 confirmed DQA1 and identified PLA2R as
the second gene with strong interaction between these 2
genes, supporting genetic susceptibility in a high percentage
of previously defined IMN.15 Sequencing of the PLA2R gene
in 100 IMN cases identified no amino acid changes in the
structure specific to MN.16 A recent combined approach
using a denser single nucleotide polymorphism dataset based
on the 1000 Genomes Project of genotype imputation,
genome-wide association study, and human leukocyte antigen
imputation investigated the genetic IMN risk variants in a
more comprehensive way17 but found no other significant
loci linked to IMN and no sex-specific links to explain the
male predominance. Evidence from both lines of investigation
of antibody specificity and genome-wide association study
confirms PLA2R as the major autoimmune antigen in IMN.
The nature of PLA2R. The antigen PLA2R belongs to the
mannose receptor structural family consisting of the mannose
receptor, DEC205, Endo180, and FcRY.18 The main function
of the human receptor remains undefined. It is assumed to be
a receptor for human PLA2 based on structural homology to
rodent and rabbit homologues that show high affinity binding
for their homologous PLA2 ligands.19 However, there is no
published evidence of direct binding of human PLA2 by
human PLA2R. Indeed, there is evidence that human sPLA2-1B
and sPLA2-IIA do not bind human PLA2R.20 The true ligand
may be a rare PLA2 species or even another protein.
PLA2R, like its family member FcRY, displays a pH-
induced structural change in shape, but there is no evidence
that it is important for autoantibody binding.21 Other
members of the mannose receptor family bind type IV
collagen, but the evidence of PLA2R doing so is controver-
sial.22,23 The Manchester model of PLA2R, accurate to 20 Å,
shows a compact N-terminal ring formed by the ricin domain
with a C-terminal tail of CTLD4-8 domains.24 The dominant
epitope recognized by anti-PLA2R is present in the
N-terminal ricin domain. The synthetic peptide containing a
linear sequence and disulfide-linked ring retains the ability to
interact with the autoantibody with high affinity. The affinity
of anti-PLA2R antibodies to the ricin epitope is very high at
1
10-10M, which has possible implications for clinical
interpretation of anti-PLA2R positivity status. Some patients
who are low producers of antibody may appear to be
Kidney International (2017) 91, 566–574
review
1995–1999 2000–2004 2005–2011 2012–2015a Total
129 138 230 168 1306
37 22 34 N/A 329
311 318 338 288 1962
309 299 349 286 2076
136 130 262 N/A 1206
76 87 152 N/A 579
seronegative until the antibody has saturated the PLA2R
binding sites on podocytes and only then become seroposi-
tive. In practical terms, the high affinity of anti-PLA2R means
that PLA2R tissue positivity (PLA2R antigen in the glomer-
ular basement membrane immune complexes) can account
for 80% to 90% of cases, including those showing low or even
absent seropositivity.25
Two other domains in PLA2R, namely, CTLD1 and
CTLD7, have been identified as targets for some anti-PLA2R
antibodies,26 but these seem to appear only consequent to the
development of autoantibodies to the dominant ricin epitope
and are likely to represent epitope spreading as the immune
response to PLA2R matures over time. Although autoanti-
bodies to the N-C3 fragment27 probably describe those to the
ricin and CTLD1 domains, this must be tested in much larger
prospective studies as must the clinical utility of antidomain
epitopes in characterizing the maturity of the immune
response to PLA2R.
Other target antigens. In 2014, a second autoantigen,
thrombospondin type 1 domain–containing 7A (THSD7A),
was described in A(I)MN accounting for perhaps 5% of
cases.28 Initially, it was reported that patients are either
seropositive for anti-PLA2R or anti-THSD7A but not for
both antigens, but a few cases of dual antibody positivity on
renal biopsy staining have recently been identified.29 The
genetic susceptibility to anti-THSD7A MN has not yet been
determined, but the very strong association of HLA DQA1
pathologic allele in biopsy-proven A(I)MN suggests a com-
mon HLA gene in anti-PLA2R and anti-THSD7A MN, but in
the latter, single nucleotide polymorphisms in THSD7A
versus PLA2R will be the marker of involvement. That 10%
to 20% of A(I)MN cases are anti-PLA2R and anti-THSD7A
seronegative raises the possibility that other autoantigen-
autoantibody systems may exist. Cytoplasmic antigens
(e.g., alpha enolase, aldose reductase, and superoxide dis-
mutase) have been proposed as candidates30,31 but have not
been widely confirmed.
The interaction of complement and autoantibodies
The role of complement in inducing proteinuria in experi-
mental MN models has long been clear,32,33 and in human
studies, urinary C5b-9 complexes appeared as a possible
biomarker of disease activity.34–37 Recently, there have been
new insights that support a potentially significant role in
human IMN but are currently based on complement
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interaction with anti-GBM antibodies and not with the
A(I)MN-associated autoantibodies.38
Although immunostaining for C3 and C5b-9 is universal
on A(I)MN biopsy specimens, the precise pathway of com-
plement activation and its relative contribution to the clinical
phenotype after autoimmune system activation is unclear. In
general, the classic pathway, marked by C1q deposition, is
more closely associated with cases of secondary MN than A(I)
MN. Some evidence of involvement of mannose-binding
protein suggested that the lectin pathway may be
involved.38,39 Some A(I)MN patients have a genetic and
functional deficiency in this pathway, and in these cases, the
alternate pathway is the likely functional one activated.40
Although anti-PLA2R has been shown to affect podocytes
in vitro,24 currently there is no evidence that anti-PLA2R
alone can induce proteinuria in vivo. However, it has been
shown that passive transfer of human anti-THSD7A into mice
(which constitutively express THSD7A on podocytes) initiates
the histopathologic pattern of MN with induction of pro-
teinuria at 3 days in the absence of complement activation.41
Currently, however, we have no evidence of how anti-PLA2R
and anti-THSD7A autoantibodies interact with the comple-
ment system, but understanding this link could be vital to
improving our understanding of the mechanism driving
variable levels of proteinuria and clinical outcomes in patient
subgroups.
Histopathology of A(I)MN versus secondary MN
A long list of secondary causes has recently been reviewed.4
Features associated with secondary MN include mesangial
and endocapillary deposits, tubuloreticular inclusions, and
immunofluorescence demonstrating full-house Ig deposition
(G,M,A) as well as additional complement components
such as C1q. Increased inflammatory cells have been reported
with underlying malignancy, but the overlap of any or all of
these findings with AMN (PLA2R associated) remains a
concern.42
The most significant recent advance in diagnostic histo-
pathology of MN is the enhanced expression of the PLA2R or
THSD7A antigen enriched with Ig subclass IgG4 in the same
distribution pattern as IgG.43 This staining pattern needs
careful differentiation from the variable podocyte cell body
staining of PLA2R and THSD7A in most cases, and although
an important addition to the pathology armamentarium,
recent studies have introduced a note of caution with a sig-
nificant variability in staining related to both ethnicity and
age.44,45 In a recent meta-analysis of 19 studies and >1100
cases focused on the diagnostic accuracy of glomerular
staining in primary versus secondary MN, a sensitivity of 0.78
and a specificity of 0.84 with an area under the curve receiver-
operating characteristic of 0.84 was determined.46 The posi-
tive glomerular staining of PLA2R in presumed secondary
cases (although a dual diagnosis is also possible) has been
seen in sarcoidosis, viral infections, and malignancy.42,44,46–48
This underlines the need to continue to apply clinical acumen
to these advances in diagnostic methodology in the evaluation
568
DC Cattran and PE Brenchley: Membranous nephropathy
of any patient with MN given that management within this
differential diagnosis is widely divergent. A combined analysis
of the type of antigen (PLA2R, THSD7A), antibody subclass
(IgG4/G1 ratio), and dominant complement pathway com-
ponents (classic, alternate, lectin) in a large series of primary
and secondary MN biopsy specimens to assess whether the
pattern of immunostaining of these immune reactants can
differentiate primary from secondary MN is still lacking.
Presenting features
The most common presentation of A(I)MN is nephrotic range
proteinuria.49–51 This is often associated with other features of
the nephrotic syndrome, but this complex of signs and
symptoms are nonspecific to this condition and overlap with
many other primary and secondary glomerular disorders.
Beyond the classic kidney pathology, the finding of circulating
autoantibody against the PLA2R antigen has provided sub-
stantial strength to the diagnostic platform of A(I)MN.48,52
Confounding the classic clinical picture is the 25% to 30%
of A(I)MN patients who present with low-level, subnephrotic
range proteinuria.53–55 They are usually asymptomatic and
follow a different natural history. Forty percent will not
progress and will have a high rate of spontaneous remission,
and conservative management is all that is required. However,
in the other 60%, nephrotic range proteinuria will develop,
most within 2 years of presentation. This accelerates the rate
of progression by w4-fold and equivalent to those whose
initial presentation is with nephrotic syndrome. Clinical
predictors of outcome in this group are few: female sex and
those with initial proteinuria <2 g/day.53 This is another
scenario in which measurement of PLA2R autoantigen/
autoantibody system is likely to be important. Certainly the
sensitivity and specificity of tissue staining in this cohort
seems to be the same as those who present with full-blown
nephrosis, but they more commonly have low-titer PLA2R
antibody. Data here are still scanty, but recently in a small
retrospective cohort of 33 nonnephrotic patients, the authors
showed by multivariate analysis that those positive for PLA2R
antibodies at entry (48% of the cohort) were more likely to
progress to nephrotic syndrome 13 of 16 (81%) than PLA2R-
negative patients, 5 of 17 (29%) (hazard ratio: 3.66, 95% CI
1.39–9.64). The PLA2R-positive patients were more likely to
have received immunosuppression (IS) therapy and were
more likely to show signs of deteriorating function by the end
of follow-up compared with the negative patients, but the
numbers were small and follow-up too short to assess hard
outcomes.56
Certainly an unusual feature of the A(I)MN patient
remains the 25% to 35% spontaneous remission rate, much
higher than other primary GNs. A substantial improvement
in the accuracy of predicting those more likely to progress is
made by a watch-and-wait policy, monitoring 24-hour urine
protein and creatinine clearance for at least 6 months versus
using the presenting nephrotic level proteinuria.57,58 More
recent data support this approach but also indicate that
spontaneous remission occurs even with presenting
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DC Cattran and PE Brenchley: Membranous nephropathy
proteinuria values >12 g/day.59 However, there are 2 impor-
tant caveats to this; the higher the presenting proteinuria is,
the lower the spontaneous remission rate is and the longer it
takes to reach this point. In their >12-g/day cohort, there was
only a 22% spontaneous remission rate, and the time to
remission averaged 21 months. These authors, however, did
observe that a 50% reduction in proteinuria in the first year,
regardless of the initial level, was associated with a signifi-
cantly higher subsequent spontaneous remission. This prin-
ciple of observation before the introduction of IS has been
extended by some groups to include patients with impair-
ment of the estimated glomerular filtration rate (GFR). These
authors delayed the introduction of IS until a decrease in the
GFR is noted and found remission rates equal to earlier
introduction of IS.60 The uptake of this approach has been
somewhat muted given the concern that the functional
changes in the GFR may significantly underestimate the
irreversible structural damage.61,62
The capacity to estimate circulating PLA2R antibody has
also added substantially to this component of AMN man-
agement. Higher antibody levels have been associated with a
poor prognosis and/or a marker of patients unlikely to be
responsive to therapy.63 Whether the initial antibody level
represents a truly unresponsive patient versus a slower
responder is unknown. The latter is suggested in this paper
where, although remission was achieved more quickly in
those starting with the lowest versus highest antibody titer, by
24 months the cumulative percentage in remission was equal.
With this degree of overlap and with the discovery of 2
autoantibodies, anti-PLA2R and anti-THSD7A (and likeli-
hood of at least another antigen specificity) with 3 known
domain-restricted epitopes in PLA2R and at least 2 in
THSD7A (P.E Brenchley, personal communication, May
2016), variations in subclass composition (and likely differ-
ential ability to activate complement), we need to map these
antibody properties against the clinical phenotypes in pro-
spective studies to determine whether they can explain more
of the clinical diversity of treatment response and outcome.
Outcome of A(I)MN disease
Surrogate endpoints. Patients with persistent high-grade
proteinuria have a cumulative incidence of end-stage kidney
disease or chronic kidney disease of between 50% and 75%
within 10 years.64,65 It is this long lag time between pro-
teinuria changes and the approved regulatory indicators of
progression, doubling of serum creatinine, or end-stage kid-
ney disease that drives the search for early sensitive and
specific biomarker(s) of those who will progress to chronic
kidney disease. This is critical because the impact of treatment
on these very delayed outcomes makes proving efficacy,
especially with the high relapse rate post-treatment, very
difficult.66 Complete remission of proteinuria in MN is
known to be associated with excellent long-term kidney
survival67,68 but was not accepted by health regulatory
agencies until a recent review concluded that complete
remission could be used as an surrogate outcome measure in
Kidney International (2017) 91, 566–574
review
treatment trials.69 Also on their review, they indicated partial
remission was also associated with an improved outcome, but
the data were weaker and less secure than with complete
remission. They suggested that partial remission could be
considered an endpoint provided that there were post-
marketing trials. A paper using a new to nephrology ana-
lytic approach demonstrates a clear relationship between the
duration of remission, either partial or complete, and
improved kidney survival.70 These authors found that
regardless of age, baseline GFR, spontaneous or drug-induced
remission, each landmark analysis from 3 to 24 months was
associated with a reduction in hard endpoints and prolonged
kidney survival. Additional early valid surrogate indicators
have been advocated including specific molecular weight
urinary proteins, but more recent data suggest that they add
little to the known prognostic biomarkers of proteinuria and
creatinine changes.70 This is an important niche where the
presence and/or the change in titer of circulating levels of
PLA2R or THSD7A autoantibody could be an additional
surrogate.63,71,72 This is premised on the theory that there is
an initial immunologic phase in AMN pathobiology related to
the autoantibody that temporally precedes the clinical
phenotype of kidney injury and proteinuria.73 This pattern of
decreasing antibody titer, preceding sometimes by months
improvement in proteinuria, was first reported in a retro-
spective analysis of a rituximab pilot study in IMN.74 Similar
findings using other IS agents have subsequently been pub-
lished.63,71 The absolute reduction in titer that would allow
alteration of IS therapy and the variability in timing between
immunologic and clinical remission remains to be deter-
mined, but this is an area ripe for further investigation.75,76
The introduction of these surrogate markers, if broadly
accepted, would result in a more reasonable duration in the
design of A(I)MN randomized, controlled trials (RCTs). This,
in turn, would accelerate interest in new therapies/clinical
trials by both the pharmaceutical industry and peer-review
agencies, a much needed change in A(I)MN.77
Complications of A(I)MN: new data. Although it is the
clinical presentation and not the histologic pattern that dic-
tates complications of IMN, we currently do not know
whether anti-PLA2R or anti-THSD7A status/specificities/
levels influence these complications. We do know that high-
grade proteinuria with severe hypoalbuminemia and
decreased renal function is associated with significant and
often severe complications and in combination are indicators
for early institution of IS. A recent A(I)MN study found an
8% incidence of thromboembolic events with a hazard ratio
of 22 referenced to an IgA population.78 These events
occurred early, a median of 3.8 months post-presentation and
were highly correlated with serum albumin level.79 An algo-
rithm allowing a risk-to-benefit ratio of prophylactically oral
anticoagulants has subsequently been developed80 (also
available at www.UNC kidney center.orgyGN tools-team).
These authors also documented a higher risk of cardiovas-
cular events in these IMN patients including strokes,
myocardial infarctions, and peripheral artery events. These
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had independent associations with the expected factors of age
and previous cardiovascular events, but uniquely, the severity
of proteinuria.81
Approach to treatment
It is recommended that conservative therapy be instituted at
the earliest phase of A(I)MN. These studies were all done
before the recognition of the new autoantibody/antigen sys-
tems, but there is no reason to think, given their 90% to 95%
involvement in IMN, that these results will be much different
with these agents today, but this is being look at in ongoing
studies. In low risk of progression patients with low-level
proteinuria, <4 g/day, and well-preserved renal function,
this may potentially eliminate the need for subsequent IS
therapy.4,82 The use of renin-angiotensin system blockade,
augmented by diuretics for edema and a low-sodium diet,
remains at the core of management.4 Failure to adhere to
sodium restriction can significantly mute the benefits of
conservative treatment even if the immunologic injury has
dissipated.82 The approach to, and duration of, conservative
management remains as set out in the recent KDIGO GN
guidelines. In addition to the decision of when and what IS to
use, there is the vexing question of when to stop. The GN
guidelines suggest that a creatinine >300 mmol/L level (or
estimated GFR <30) plus an ultrasound showing small and
echogenic kidneys indicate irreversible kidney damage and
insufficient parenchyma to warrant the risks of therapy. A
marker of immunologic inactivity such as a PLA2R-positive
patient becoming negative would further support the argu-
ment for not starting (or stopping) IS therapy.
Specific IS regimens
Alkylating agent and steroids. The highest level of evi-
dence, IA recommended in the GN guidelines, is for the
Ponticelli regimen, a 6-month cycling of an alkylating agent
with corticosteroids.4,65,83 Adverse events are common,
however, and a recent study found a 23% occurrence rate of
adrenal insufficiency related to the abrupt discontinuation of
the steroids in this protocol.84 This is an additional caution,
especially in the elderly patient, a relevant point given the
increasing age at presentation of the A(I)MN patient. An
alternative regimen is combining cyclophosphamide for 6 to
12 months with prednisone with an option for delaying
introduction of treatment until renal dysfunction is demon-
strated.60 There are 2 important caveats to this approach: an
awareness that the delay in the proteinuria nadir can be 12 to
18 months following treatment and the substantial cancer risk
with alkylating therapy, with the most recent data indicating a
tripling of its incidence compared with the nonexposed
population.85
Calcineurin inhibitors. The only other level I treatment
recommendation in the GN guidelines was for calcineurin
inhibitors in IMN patients who refused/failed cyclophos-
phamide/steroid therapy or had contraindications to this
approach. RCTs have demonstrated reductions in proteinuria
570
DC Cattran and PE Brenchley: Membranous nephropathy
similar in degree to the above regimens but an earlier and
higher elapse rate.86,87
The most recent RCT in IMN was restricted to patients
with rapid progressive decrease of >20% in EGFR within
2 years of entry. In the intention-to-treat analysis only, the
alkylating/steroid regimens showed benefit when compared
with a calcineurin inhibitor group (cyclosporine) or placebo,
but overall patient survival was not different in any of the
arms. There was a substantial serious adverse event (AE) rate
in all groups, highest in the chlorambucil/steroid group.88
Fortunately, this is a rare MN phenotype, as illustrated by
the decade required to recruit their sample.
Rituximab. All currently recommended regimens have a
25% to 30% primary failure rate. Rituximab efficacy in
observational studies has indicated a similar or even higher
short-term success rate associated with reduced AEs.89–91
Dose exposure has varied from 375 mg/m2 weekly for
4 weeks to 1 g every 15 days
2 to a single 1-g i.v. dose, all
with similar response rates. Like the alkylating agents, the
nadir of proteinuria often occurs months beyond the treat-
ment exposure. Short-term AEs have been low with the
exception of infusion reactions in 10% to 15% of patients
with other AEs varying in their frequency and intensity, but
given that it is IS, infectious complications are to be expected,
and an increased incidence of late malignancies a possibility.
There has been only 1 RCT trial published to date, but others
are ongoing: Gemritux is the published RCT that compares
conservative therapy with rituximab dosed at 375 mg/m2 on
days 1 and 8 in patients with nephrotic-range proteinuria
(clinical trials.gov identifier NCT01508468); the other ones
are the MENTOR trial in IMN patients with persistent pro-
teinuria >5 g/day comparing cyclosporine monotherapy
for 12 months with rituximab dosed at 1 g on days 1 and
15 repeated at 6 months92 (clinical trials.gov identifier
NCT01180036), and STARMEN, comparing corticosteroids
and cyclophosphamide for 6 months with 6 months of
tacrolimus followed by a single dose of rituximab (clinical
trials.gov identifier: NCT01955187).93 The first published
RCT, Gemritux, indicated a remission rate in controls of 21%
versus 35% in the rituximab cohort at 6 months (P ¼ not
significant), but during the follow-up observation period, this
increased to 34% and 65%, respectively (P < 0.01). Similar AE
rates were reported in both arms and changes in PLA2R titer
paralleled proteinuria responsiveness.94 A pilot study using the
combination of rituximab and cyclosporine, with the latter
tapered after 6 months but repeat rituximab infusion at
that point, is also ongoing (ClinicalTrials.gov identifier:
NCT00977977). PLA2R antibody monitoring is included in all
these protocols and will potentially provide answers
to questions posed earlier related to the capacity of the antibody
titer change to predict treatment responsiveness and outcome.
Adrenocorticotropic hormone. The natural adrenocortico-
tropic hormone (ACTH) gel was one of the first “modern”
empirical therapies for nephrotic syndrome.95 A synthetic
variant of ACTH was tested in a small RCT in comparison
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DC Cattran and PE Brenchley: Membranous nephropathy review

with the corticosteroids/alkylating agent regimen a decade
ago.96 Efficacy was similar in both arms with 80% of patients
having significant proteinuria reduction. Only relatively
minor side effects were reported in the ACTH cohort,
although a small number of patients showed an unusual
bronzing of the skin. The latter is intriguing given the
potential that this agent may act through the melanocyte or
melanocyte receptor recently found on the surface of the
podocyte.97,98 A more recent nonrandomized study using this
synthetic agent found a lower response rate and an incidence
of AEs approaching 95%, prompting these authors to suggest
that this agent not be used in IMN.99,100 In contrast, a recent
dose escalation study using the natural ACTH gel, a more full-
length molecule, found a significant reduction in proteinuria
proportionate to drug exposure in the majority of IMN
patients with an acceptable AE profile also accompanied by a
parallel reduction in PLA2R levels.101 An RCT testing this
agent versus placebo in patients at high risk of progression is
in progress (ClinicalTrials.gov identifier: NCT01386554). An
algorithm integrating monitoring tools and therapeutics is
given in Figure 1.
New and novel approaches to therapy. Current treatment
strategies all have a significant nonresponsive cohort and a
high relapse rate post-treatment. These issues have stimulated
the search not only for new therapies but have introduced the
concept that A(I)MN is a chronic condition that requires
maintenance therapy. Suggested new approaches to treatment
include initially combining multiple medications in an
induction phase using an alkylating agent (with or without
steroids) or rituximab followed by a maintenance therapy
with a less potent agent like azathioprine or mycophenolate
mofetil. Another routine could be initial rituximab given
frequently or at a higher dose followed by a maintenance
phase at a reduced dose/frequency similar to ongoing
vasculitis studies.102
New therapies in trial include combining an angiotensin
receptor blocker with a Chinese herbal medication, Qing-
ReMoShen granules. These authors will also study potential
mechanisms including the capacity of the herbal agent to
modulate T-cell function (ClinicalTrials.gov indicator:
NCT01845688). Renewed interest in older therapies include
the anti-C5 inhibitor eculizumab in A(I)MN despite an early
failed RCT that showed no difference in proteinuria versus
placebo over 16 weeks.100,103 Now that it is possible to
monitor both anti-PLA2R and C5b-9 in serum, tissue, and
urine, revisiting the effect of C5 blockade, especially in
combination with IS, has merit.
New therapies are likely to exploit knowledge of the
dominant early epitope in PLA2R. This offers the possibility
of developing specific and rapid anti-PLA2R removal through
the use of immunoadsorption columns. Currently there is at
least a suggestion that the addition of plasma exchange to IS
may help to deplete antibody.104 If successful, we could
contemplate limiting IS exposure proportionate to antibody
level reductions.
Future new therapeutic modalities theoretically could
include tolerogenic peptides identified from PLA2R (T-cell
peptides) that are presented on class II receptors to T cells.
Stable soluble T-cell peptides could be developed and used to
tolerize T cells and/or enhance Treg cells to downregulate the

MN TREATMENT ALGORITHM

Mild UPro Moderate UPro Heavy UPro

<4 g/day (≥4 <8 d/day) ≥8 g/day
RFTs normal RFTs normal + RFTs
+ low PLA2R * + mid PLA2R * + high PLA2R *

BP ≤125/75 BP ≤125/75 BP ≤125/75

ACEi/ARB ACEi /ARB Diet ACEi/ARB
Monitor Monitor 6/12 Monitor < 3/12

* if +, monitor and consider **Persistent **Persistent ≥8 g/day

PLA2R titer change ≥4 g/day + RFTs
** risk reduction strategies
*** consider risk/benefit
Cytotoxic + steroids
# other options, see text
or *** CNI
CNI or
or ***Cytotoxic + steroids
Rituximab
or
ACTH# ***Rituximab
Figure 1 | Membranous treatment algorithm. ACEi, angiotensin-converting enzyme inhibitor; ACTH, adrenocorticotropic hormone; ARB,
angiotensin receptor blocker; BP, blood pressure; CNI, calcineurin inhibitor; MN, membranous nephropathy; RFT, renal function tests.

Kidney International (2017) 91, 566–574 571

review
anti-PLA2R response. This mechanism could be an underlying
regulatory process that occurs in spontaneous remission.105
Integration of new biology with clinical medicine
In the development of new approaches and therapies, the
monitoring of PLA2R and THSD7A antigen/antibody systems
and others yet to be discovered will be central. Early results
regardless of the IS used have indicated that a reduction in
antibody titer is associated with improving proteinuria.
Whether this evidence is sufficiently strong to warrant alter-
ations in IS therapy is being tested in prospective studies.92,93
The rapid escalation of the importance of these autoanti-
bodies underscores the need for an international standard of
their measurement to allow valid comparison across all
studies/trials/assays. Given that there is now a recognized
dominant epitope in the ricin domain and minor epitopes in
CTLD1 and CTLD7, an international anti-PLA2R (and anti-
THSD7A) standard preparation should represent this
mixture of epitopes. Otherwise there is potential for under-
reading of anti-PLA2R antibody levels, especially given the
potential for a long-running mature antibody response being
enriched in anti-CTLD7 specificity.
Western blotting was originally used to define the nature of
both PLA2R and THSD7A autoantigens and is exquisitely
sensitive but does not provide the simplicity and ease of use
required for clinical testing. Enzyme-linked immunosorbent
assays have been described for detecting anti-PLA2R72 and
offer the advantage of quantitation, rapidity, and simplicity of
assay with the ability to handle large numbers of samples.
Currently there is no commercially available assay for anti-
THSD7A antibodies.
Many questions remain related to this autoimmune
pathology.
 Why do MN patients make an antibody to self-proteins
PLA2R or THSD7A which they have tolerated for most of
their life?
 What is the environmental trigger that stimulates the im-
mune response to PLA2R or THSD7A in genetically sus-
ceptible individuals?
 Do anti-PLA2R and anti-THSD7A autoantibodies associate
with phenotypically different subsets of MN patients?
 Why is the autoimmune disease only apparent in the kidney
when PLA2R is expressed on cells in other organs?
 How does intrinsic immune regulation of anti-PLA2R and
antiTHSD7A occur in spontaneous remission?
The development of a multiunit, multicountry consortium
focused on in-depth exploration of the pathobiology of GN is
providing a milieu necessary to successfully address these
fundamental questions in A(I)MN. The prototype is the
Nephrotic Syndrome Study Network106 with a prime objec-
tive of developing a molecular-based taxonomy that will
facilitate not only more accurate diagnostic tests but also
provide new insights into the pathways of injury and repair.
These are additional absolute requirements for advancing our
goal to prevent or cure A(I)MN and fulfill our ultimate
objective of improving the care of our patients.
572
DC Cattran and PE Brenchley: Membranous nephropathy
DISCLOSURE
All the authors declared no competing interests.
ACKNOWLEDGMENTS
DCC is supported in part by the National Institutes of Health, project
grant UM1DK100846-02, and project grant 2U54KD083912-06. PEB is
supported financially by Medical Research Council Project grant MR/
J010847/1, Kidney Research UK grants RP56/2012 and RP31/2015, EU
Framework 7 Programme Grant 305608 “EURenOmics,” and by
Central Manchester Foundation Trust through the Manchester
Academic Healthcare Science Centre (MAHSC) (186/200).
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