Primary Membranous Nephropathy

William G. Couser

Abstract
Membranous nephropathy (MN) is a unique glomerular lesion that is the most common cause of idiopathic
nephrotic syndrome in nondiabetic white adults. About 80% of cases are renal limited (primary MN, PMN) and
20% are associated with other systemic diseases or exposures (secondary MN). This review focuses only on PMN.
Most cases of PMN have circulating IgG4 autoantibody to the podocyte membrane antigen PLA2R (70%), biopsy
Division of Nephrology,
evidence PLA2R staining indicating recent immunologic disease activity despite negative serum antibody levels Department of Medicine,
(15%), or serum anti-THSD7A (3%–5%). The remaining 10% without demonstrable anti-PLA2R/THSd7A University of Washington,
antibody or antigen likely have PMN probably secondary to a different, still unidentified, anti-podocyte antibody. Seattle, Washington
Considerable clinical and experimental data now suggests these antibodies are pathogenic. Clinically, 80% of
patients with PMN present with nephrotic syndrome and 20% with non-nephrotic proteinuria. Untreated, about Correspondence: Dr.
one third undergo spontaneous remission, especially those with absent or low anti-PLA2R levels, one-third William G. Couser,
Division of
progress to ESRD over 10 years, and the remainder develop nonprogressive CKD. Proteinuria can persist for Nephrology,
months after circulating anti-PLA2R/THSD7A antibody is no longer detectable (immunologic remission). All Department of
patients with PMN should be treated with supportive care from the time of diagnosis to minimize protein Medicine, University
excretion. Patients with elevated anti-PLA2R/THSD7A levels and proteinuria >3.5 g/d at diagnosis, and those who of Washington,
Medicine, 16050
fail to reduce proteinuria to <3.5 g after 6 months of supportive care or have complications of nephrotic syndrome,
169th Avenue,
should be considered for immunosuppressive therapy. Accepted regimens include steroids/cyclophosphamide, Woodinville, WA
calcineurin inhibitors, and B cell depletion. With proper management, only 10% or less will develop ESRD over the 98072. Email: wgc@
subsequent 10 years. uw.edu
Clin J Am Soc Nephrol 12: 983–997, 2017. doi: https://doi.org/10.2215/CJN.11761116

Introduction empirically on clinical consequences of immune injury

About 20% of all cases of membranous nephropathy
(MN) are associated with other diseases or exposures
(secondary MN) that are listed in Table 1. Secondary
MN is not discussed further in this review. Primary
membranous nephropathy (PMN) is a kidney-specific,
autoimmune glomerular disease that presents with
increased protein in the urine associated with a pa-
thognomonic pattern of injury in glomeruli (Figures
1–3). Both clinical and pathogenetic aspects of the
disease have been recently reviewed elsewhere (1–8).
PMN is the commonest cause of idiopathic nephrotic
syndrome in nondiabetic adults worldwide, repre-
senting between 20% and 37% in most series and rising
to as high as 40% in adults over 60 (1,2,7). MN is rare
in children (1%–7% of biopsies) (3). Most PMN is
mediated by antibodies to the M-type phospholipase
A2 receptor (anti-PLA2R) (85%), thrombospondin type
1 domain containing 7A (THSD7A) (3%–5%), or by
other as yet unidentified mechanisms (10%) (1,2,4–8).
The recognition that PMN is an autoimmune disease
has dramatically altered both the diagnostic and ther-
apeutic approach to what was previously called idio-
pathic MN. Patients with immunologically active
disease can now be separated from those with inactive
disease and therapeutic initiatives in active disease can
be adjusted to the presence and levels of the patho-
genic antibody causing the disease rather than relying
to the glomerulus such as proteinuria or reduced GFR
(1,4–7).
Epidemiology
In the United States, the incidence of MN is
estimated at about 12/million per year with a mean
age between 50 and 60 and a 2:1 male predominance
(1–4). The incidence of ESRD due to MN in the United
States is about 1.9/million per year (1). Because only
10%–20% of patients with PMN currently progress to
ESRD, the real incidence may be as high as 20/million
per year. PMN is most common in whites followed by
Asians, blacks, and Hispanics (1,2).
Pathogenesis
Studies in the past decade have dramatically im-
proved understanding of the pathogenesis of PMN
(1,2,4–8). Current concepts derive in large part from
earlier studies carried out in the Heymann models of
MN in rats which revealed that the pathognomonic,
exclusively subepithelial deposits of IgG resulted
from in situ immune complex formation involving
megalin, a rat podocyte membrane antigen, and that
the associated proteinuria was mediated primarily by
complement through the membrane attack complex

www.cjasn.org Vol 12 June, 2017 Copyright © 2017 by the American Society of Nephrology 983
984 Clinical Journal of the American Society of Nephrology
Table 1. Recognized causes of anti-PLA2R/THSD7A–negative secondary membranous nephropathya
Cause
Infections (1,2,27,56,90)
Malignancy (20% in patients .57,
4%,57) (1,2,14–18,55,58,66)
Autoimmune diseases (1,2,4,56–58,91)
Alloimmune diseases (1,4,7,58,82)
Drugs/toxins (92)
HBV, hepatitis B; HCV, hepatitis C; CLL, chronic lymphocytic leukemia; MN, membranous nephropathy; NSAIDs, non-steroidal anti-
inflammatory drugs.
a
Most of these associations are on the basis of multiple case reports or small series. Causative roles are implied but generally not proven.
b
Common.
C5b-9 (9). The first confirmation that PMN in man involved
an analogous mechanism came from Debiec et al. in Paris
in 2002, who showed that alloimmune MN in babies of
neutral endoproteinase (NEP)–deficient mothers was me-
diated by maternal anti-NEP antibody that formed immune
complexes in situ with NEP on the podocyte membranes of
Figure 1. | Glomerulus from a patient with primary membranous
nephropathy showing the pathognomonic “spikes” of basement
membrane projecting from the outer surface of the glomerular
basement membrane (arrows) when stained with silver-methenamine
(original magnification, 340). (Provided by Dr. Charles Alpers, De-
partment of Pathology, University of Washington, Seattle, WA.)
Examples
b
HBV, HCV, HIV, parasites (filariasis, schistosomiasis, malaria),
leprosy, syphilis, hydatid disease, sarcoid
b
Solid tumors (lung 26%, prostate 15%, hematologic [plasma cell
dyscrasias, non-Hodgkin lymphoma, CLL] 14%, colon 11%),
mesothelioma, melanoma, pheochromocytoma; some benign tumors
b
SLE (class V), thyroiditis, diabetes, rheumatoid arthritis, Sjogren
syndrome, dermatomyositis, mixed connective tissue disease,
ankylosing spondylitis, retroperitoneal fibrosis, renal allografts
Anti-GBM disease, IgAN, ANCA-associated vasculitis
IgG4 disease
Membranous-like glomerulopathy with masked IgG k deposits (90)
Graft versus host disease, autologous stem cell transplants, bde novo MN
in transplants/transplant glomerulopathy
b
NSAIDs and cyclooxygenase-2 inhibitors, gold, d-penicillamine,
bucillamine, captopril, probenecid, sulindac, anti-TNFa, thiola,
trimetadione, tiopronin
Mercury, lithium, hydrocarbons, formaldehyde, benvironmental air
pollution (China)
Cationic BSA (infants)
the infant (10). In 2009, a seminal paper from Beck et al. in
Boston reported that about 70% of adult patients with PMN
have IgG4 antibodies to podocyte-expressed PLA2R that
are present in the circulation and also deposited in
glomeruli (11), a finding since confirmed, with a range of
52%–78%, by many other laboratories (1,4–8).
A second IgG4 antibody specific for THSD7A, another
podocyte membrane antigen with similar properties to
PLA2R, was later identified in a smaller number of
patients with PMN (2%–5%) (Table 2) (12). About 10%
of patients with typical PMN are negative for both
antibodies, making it probable that more autoantibodies
to podocyte antigens will be found. Dual expression of
antibodies to both PLA2R and THSD7A has been report-
ed but is rare (13).
Most statements in this review are assumed to apply to
patients with either antibody, designated in this paper as
anti-PLA2R/THSD7A, unless otherwise specified. The
only significant clinical difference identified so far is a
female predominance and a higher frequency of associ-
ated malignancies with THSD7A (14,15). THSD7A is ex-
pressed in those tumors most frequently associated with
PMN (16). Twenty percent of THSD7A-positive patients in
one series had coexistent malignancy, usually detected
within 3 months (14,17). The observation that THSD7A was
expressed in the tumor in two cases suggests one potential
mechanism for the well established association between
MN and malignancy (14,17,18). The pathogenicity of anti-
PLA2R has not yet been confirmed because PLA2R is not
expressed in rodents. However, human anti-THSD7A has
recently been shown to transfer MN with proteinuria in
mice (19).
PLA2R/THSD7A-mediated disease can also be confirmed
by the presence of PLA2R/THSD7A staining colocalized
Clin J Am Soc Nephrol 12: 983–997, June, 2017 Membranous Nephropathy, Couser 985

Figure 2. | Immunofluorescence microscopy in primary membranous nephropathy (PMN). (A) Finely granular staining for IgG, predominately
IgG4, present uniformly in a subepithelial distribution in all glomeruli in a patient with PLA2R-associated PMN (original magnification, 340)
(generously provided by Dr. Charles Alpers, Department of Pathology, University of Washington, Seattle, WA). (B) Finely granular staining for
PLA2R antigen that colocalizes with IgG4 in a patient with PMN. The presence of PLA2R indicates that anti-PLA2R antibody was present and
forming deposits in glomeruli at the time of biopsy or within the past several weeks. (original magnification, 340) (generously provided by Dr.
Charles Alpers, Department of Pathology, University of Washington, Seattle, WA). (C) Finely granular staining for the complement membrane
attack complex, C5b-9, in a patient with active PMN (original magnification, 340). Reprinted from reference 89, with permission.

with IgG4 in glomerular deposits (Figure 2B) (17,20–25).
Staining persists for weeks to months after antibody
disappears (5–9,19,20). Most antibody-positive, and about
70% of antibody-negative, patients have positive PLA2R/
THSD7A staining in glomeruli, suggesting that up to
85%–90% of all cases of PMN are anti-PLA2R/THSD7A–
mediated (21) (Table 2). However, occasional anti-PLA2R–
positive, or presumed positive, patients, especially early in
the course, have been reported without staining for PLA2R
antigen in glomeruli (23–25). As summarized in Table 2,
patients presenting with PMN include those who are free of
systemic disease and are anti-PLA2R (70%) or THSD7A

Figure 3. | Electron micrograph of chronic primary membranous nephropathy showing discontinuous, electron-dense deposits representing
aggregates of PLA2R–anti-PLA2R immune complexes formed in situ along the outer surface of the glomerular capillary wall beneath a layer of
effaced podocyte foot processes (arrows). BM, basement membrane; CL, capillary lumen. Original photomicrograph generously provided
by Dr. Charles Alpers, Department of Pathology, University of Washington, Seattle, WA.
986 Clinical Journal of the American Society of Nephrology
Table 2. Interpretation of serum anti-podocyte antibody and glomerular antigen staining in primary membranous nephropathy
(4,21,23–26)
Serum Glomerular
Antibody (6) Antigen (6)
Anti-PLA2R (1) PLA2R (1)
Anti-PLA2R (2) PLA2R (1)
Anti-THSD7A (1) THSD7A (1)
Anti-THSD7A (2) THSD7A (1)
Anti-PLA2R/THSD7A (2) PLA2R/THSD7A (2)
1, positive; PMN, primary membranous nephropathy; 2, negative.
a
Patients with nephrotic syndrome due to PMN without evidence of PLA2R/THSD7A antibody or glomerular staining are presumed to
have autoimmune PMN mediated by a different, still unidentified, anti-podocyte antibody.
(3%–5%) positive, those who are anti-PLA2R/THSD7A
negative but have positive glomerular staining for PLA2R/
THSD7A (another 15%), and those without PLA2R/THSD7A
antibody or glomerular staining (10%) who may: (1) develop
detectable anti-PLA2R/THSD7A antibody later, (2) have
disease mediated by a different anti-podocyte antibody, or (3)
develop another autoimmune disease to which the MN
might be considered secondary.
Initiation of an antibody response likely precedes devel-
opment of proteinuria in PMN by weeks or months (pre-
clinical disease) (22,26) and may occur following several
etiologic events in the presence of immunogenetic risk
alleles (see below). There is one report of homology
between genes for PLA2R and the LTLENCK domain in
some gram-positive bacterial enzymes (27). Viral infections
including hepatitis B virus, hepatitis C virus, and HIV have
been reported in association with anti-PLA2R/THSD7A,
but these may represent patients who have coincidental
PMN (4–8,22) (Table 1). Other potential etiologic factors,
e.g., exposures to environmental toxins such as drugs,
mercury, formaldehyde, and air pollutants, have been
identified (Table 1) but generally the anti-PLA2R/THSD7A
status in these patients is not known. For example, a recent
report from China correlated the rising incidence of MN in
that country with increasing levels of air pollution (28).
Over time, a threshold quantity of IgG4 and C5b-9
deposition is reached in some patients that is sufficient
to cause enough podocyte injury/activation to increase
urine protein excretion and lead to nephrotic syndrome
(5–7,22,26). Just as appearance of proteinuria lags behind
initial antibody production by weeks/months, so resolu-
tion of proteinuria (clinical remission) also lags behind
antibody disappearance (immunologic remission) by
week/months. This offset between immunologic and clin-
ical remissions reflects the prolonged time required to form
sufficient deposits to cause proteinuria initially and the
time required to clear subepithelial deposits, repair podo-
cyte and capillary wall damage, and restore glomerular
permselectivity (5). Thus, proteinuria is a poor clinical
Percent of Patients Who
Diagnosis
Underwent Biopsy, %
70 PLA2R-mediated PMN
(active)
15 PLA2R-mediated PMN
(inactive)
3–5 THSD7A-mediated PMN
(active)
Unknown THSD7A-mediated PMN
(inactive)
10 Non-PLA2R/THSD7A–
mediated (pathogenesis
unknown)a
biomarker for the pathogenetic disease processes that are
targeted by current immunosuppressive therapies (IST).
C activation leading to sublytic C5b-9 attack on podo-
cytes has been established to be the primary mediator of
anti-podocyte antibody–induced cellular injury and pro-
teinuria in most studies of the Heymann rat models (5,9,29–
31). Currently available serologic and immunohistochemical
data in PMN are most consistent with complement
activation by under-glycosylated IgG4 through the man-
nose binding lectin pathway, but roles for the classic and
alternate pathways have not been entirely excluded (29–
31). In the rat models, the complement effect involves a
sublytic agonistic effect of C5b-9 insertion on the podocyte
membrane to activate several signaling pathways that lead
collectively to increased production of oxidants, proteases,
growth factors, and extracellular matrix components as
well as to slit diaphragm disruption, apoptosis, auto-
phagy, remodeling of the actin cytoskeleton, DNA damage
with cell cycle arrest, and detachment of damaged cells
(29,30). A similar role for complement in human PMN is
suggested by the facts that C3, C4d, and C5b-9 (but not
C1q) are prominent in glomerular deposits; complement
activation products are elevated in the serum (M.H. Zhao,
personal communication); and serum and urine C5b-9
seem to parallel disease activity (28–30). However, pro-
teinuria in some human PMN may also be C-independent
as suggested by some studies of the Heymann models by
Hall and colleagues (32), the transfer of anti-NEP alloim-
mune MN without complement activation (10), and an in
vivo transfer study with human anti-THSD7A where
heterologous phase proteinuria appears to precede detect-
able complement deposition (19).
Genetics of PMN
Genetic findings in PMN are reviewed in more detail
elsewhere (4–8,33–35). Familial MN is rare and usually seen
in children (3,33,34). Genome-wide association studies
(GWAS) implicate risk alleles in HLA genes, particularly
HLA–DQA1, that increase the risk for PMN three-fold in
Clin J Am Soc Nephrol 12: 983–997, June, 2017
white patients (27). GWAS studies have also identified
single nucleotide polymorphisms in noncoding regions of
the PLA2R gene (27,36–38). Homozygosity for high-risk
alleles in both HLA and PLA2R genes increases the odds
ratio for PMN almost 80-fold in white patients and ten-fold
in Chinese patients and is associated with higher levels of
antibody production, strongly suggesting interaction be-
tween HLA and PLA2R genes (36–38). Two recent GWAS
studies in Chinese patients have identified additional in-
dependent HLA risk alleles including DRB1*1501/
DRB1*0301 (37) and DRB3*02:02 (38) and suggested that
DRB1 may be more important in generating the HLA signal
than DQA1 in that population. Ninety-nine percent of
PLA2R-positive patients carry at least one of these HLA risk
alleles, and the presence of one HLA risk allele increases the
odds ratio for developing PMN almost 100-fold (35)
However, risk alleles identified so far are common in the
general population, and studies to date are also consistent
with a predisposition to autoimmunity conferred by HLA
genes and an environmental trigger rather than any unique
coding variant in PLA2R genes (33).
Structure of the PLA2R Antigen
PLA2R is a transmembrane glycoprotein member of the
mannose receptor family, which has a conserved extracellular
structure consisting of the cysteine-rich (Ricin B) domain
(Cys-R), a fibronectin II domain, and a tandem repeat of 8 C-
type lectin domains (CDLD 1–8) (1,4–7,39,40). Anti-PLA2R–
reactive epitopes are conformation-dependent and have been
identified in three domains: Cys-R, CTLD1, and CTLD7
(1,4,39,40). The potential for these different epitopes to be of
clinical significance is suggested by the finding that patients
with anti-PLA2R directed at the Cys-R epitope, which is
recognized by 100% of anti-PLA2R antibodies, may have less
severe disease and undergo more spontaneous remissions
than those with antibodies primarily reactive with the CDL1
and CDL7 domains, and that epitope spreading beyond the
Cys-R domain may confer a worse prognosis, but this
observation requires confirmation (36). The small contact
residues that bind the antibody, and would be essential to
developing specific peptide-based immunotherapies, have
not yet been identified.
Pathology
In most centers a diagnostic renal biopsy remains the
standard of care, even in anti-PLA2R/THSD7A–positive
nephrotic patients. The characteristic morphologic changes
in PMN are described elsewhere (41) and are illustrated in
Figures 1–3. By light microscopy, glomeruli may appear
entirely normal in early disease despite nephrotic-range
proteinuria. With time, changes in basement membrane,
with thickening and formation of subepithelial “spikes” of
basement membrane on the outer surface of the capillary
wall, become apparent using an extracellular matrix stain
such as silver methenamine (Figure 1). Immunofluores-
cence microscopy (Figure 2) in anti-PLA2R/THSD7A–
positive patients usually reveals diffuse, uniform, finely
granular deposits of IgG4 along the outer surfaces of all
capillary walls (Figure 2A) (41). Lesser amounts of IgG1
and IgG3 may also be seen, particularly in early disease
(21,22,26). The antigen PLA2R or THSD7A (Figure 2B)
Membranous Nephropathy, Couser 987
colocalized with IgG4 may be seen by immunofluores-
cence microscopy with appropriate antigen enhance-
ment techniques and persist for weeks to months after
serum antibody is undetectable and immune complex
formation has ceased (4–8,20–23). Complement components
including C3, C4d, and C5b-9 (Figure 2C) are also commonly
present, but not C1q (29,30,41). Although these findings
describe the typical case, they are not universal, and
occasional patients with IgG4-dominant deposits but without
detectable PLA2R/THSD7A antibody or staining have been
described (20,21).
Electron microscopy in PMN confirms the exclusively
subepithelial localization of electron-dense deposits pro-
duced by capping and shedding of immune complex
lattices formed on the podocyte membrane, which then
accumulate beneath slit pores (Figure 3). Glomerular
basement membrane thickening is seen with progression,
and the deposits are gradually incorporated within new glo-
merular basement membrane and become more electron-
lucent as they are resorbed before eventually disappearing
in patients with earlier complete remissions (41).
Additional biopsy findings that should prompt careful
search for secondary causes (Table 1) include electron-
dense deposits in subendothelial or mesangial locations;
significant mesangial or endothelial cell proliferation; cres-
cents; tubular basement membrane staining; dominant de-
position of IgG1/IgG3, IgM, IgA, or C1q; and endothelial
tubuloreticular inclusions by electron microscopy (1,2,4–
7,21,22,41). One report has described an association between
MN with intraglomerular inflammatory cell infiltrates and
cancer (18).
Clinical Manifestations
All adult patients with idiopathic nephrotic syndrome
should be screened initially for anti-PLA2R/THSD7A anti-
bodies as well as for the common causes of secondary MN
including hepatitis B and C, lupus, and sarcoid (Figure 4,
Table 1). Although the specificity of the anti-PLA2R assay
for PMN is essentially 100%, this finding has somewhat
blurred the distinction between primary and secondary
disease because some patients with secondary diseases
such as hepatitis B and C, cancer, and sarcoid have been
found to be anti-PLA2R–positive suggesting the coinciden-
tal presence of PMN in some patients with an unrelated
systemic disease rather than MN as a manifestation of, or
secondary to, the systemic disease (4–8). Observational
correlations between the anti-PLA2R/THSD7A pathogenic
mechanisms discussed above and clinical features of PMN
that now support incorporating anti-PLA2R/THSD7A into
clinical decision-making are summarized in Table 3.
The most common clinical features at onset and during
the course of PMN are presented in Table 4. The most
prominent is nephrotic syndrome and its associated man-
ifestations including various degrees of edema, hypoalbu-
minemia, and hyperlipidemia (1,2,42–45) (Table 4). About
80% of patients with PMN present with nephrotic-range
proteinuria (.3.5 g/d) and the remaining 20% have
subnephrotic proteinuria, but 61% of these latter patients
later become nephrotic, usually within the first year, and
especially if anti-PLA2R antibody is present (1,26,27,43–
45). Although the peak incidence is between ages 50 and
988 Clinical Journal of the American Society of Nephrology

Figure 4. | Antibody-guided diagnosis and treatment algorithm for primary membranous nephropathy (PMN). Patients who undergo biopsies
for proteinuria of uncertain cause who have MN should initially be classified as anti-PLA2R/THSD7A–positive (active disease) or negative (Table
2). Patients who are antibody-negative should have the absence of a PLA2R/THSD7A-related mechanism further excluded by the absence of
PLA2R/THSD7A staining in glomeruli and usually the dominance of IgG1–3 in the biopsy sample. Most of these latter patients have secondary
MN and require other tests to identify the cause. They are treated with supportive care and therapy for their underlying systemic disease. Patients
who are negative for anti-PLA2R/THSD7A in the serum but have PLA2R or THSD7A antigen staining in the biopsy sample, and usually
predominately IgG4 deposition in glomeruli, have inactive anti-PLA2R/THSD7A–mediated PMN and should be treated with supportive care
while monitoring anti-PLA2R levels for 4–6 months. They would be considered for ISTonly if anti-PLA2R becomes positive or proteinuria.3.5 g/
d persists after 6 months of supportive care. Patients with elevated anti-PLA2R levels (with positive PLA2R staining and [usually] predominantly
IgG4 in the biopsy sample) and proteinuria ,3.5 g/d have active anti-PLA2R/THSD7A–mediated PMN but would receive supportive care with
monthly anti-PLA2R monitoring because most of these patients will undergo spontaneous remission. If patients have, or develop, elevated anti-
PLA2R levels and .3.5 g/d of proteinuria they have active, anti-PLA2R/THSD7A–mediated PMN and would be considered for immediate IST. IST
options would be selected on the basis of characteristics of individual patients with dose and duration of therapy (Table 6) guided by regular
monitoring of anti-PLA2R levels. About 10% of patients with anti-PLA2R/THSD7A–negative antibody and glomerular staining have PMN
presumably mediated by a different anti-podocyte antibody rather than secondary MN and would be treated with traditional restrictive care
(4,52,53). Occasional patients with negative anti-PLA2R antibody but dominant IgG4 in the biopsy sample have also been reported and should
be monitored for later development of positive circulating anti-PLA2R antibody. ANA, anti-nuclear antibody; HBV, hepatitis B; HCV, hepatitis C;
IST, immunosuppressive therapy; MN, membranous nephropathy. Modified from other schemas in references 1 and 4, with permission.

60, 23% or more are over 60 (2,43–45). Renal function is
normal at presentation in .90% (2,42–45) (Table 4).
Spontaneous remissions occur in about 32% in an average
of 14 months and up to 62% by 5 years, and occur more
commonly in patients with low anti-PLA2R/THSD7A
levels (46–48). Anti-PLA2R/THSD7A levels generally cor-
relate with proteinuria, clinical course, and outcomes
(Table 3) (4–8,22,46–51).
The clinical consequences of PMN can be considered as
both short and long term. In the short term, they include
Clin J Am Soc Nephrol 12: 983–997, June, 2017 Membranous Nephropathy, Couser 989

Table 3. Clinical and translational correlates of circulating levels of anti-PLA2Ra

70%–80% of patients with PMN have anti-PLA2R/THSD7A antibody (4–6,11)

Anti-PLA2R antibody is about 80% sensitive and 100% specific for PMN (although rare patients with sarcoid, HBV, HCV,
HIV, and cancer have been reported) (4,7,8,20,22)
Anti-PLA2R antibody can be present for many months before proteinuria appears (22,26)
In non-nephrotic patients, low, or declining, anti-PLA2R levels predict spontaneous remission and high levels predict
progression to nephrotic syndrome (47,48,51)
Anti-PLA2R–negative patients can become positive later (4,47,48)
High antibody levels (before and after treatment) correlate with proteinuria, response to therapy, and (after therapy)
long-term outcomes (4–8,50,51,70,71)
Patients with higher antibody levels require more prolonged immunosuppression to achieve remission rates comparable
to those with lower levels (63,70)
Expansion of the specificity of anti-PLA2R antibody to include additional epitopes (epitope spreading) correlates with a
worse prognosis (36)
Patients with IgG4 antibody directed only at the cysteine-rich epitope of PLA2R have a higher rate of spontaneous
remission (36)
Anti-PLA2R levels go down in remission and return with relapse (4–8,47,48)
Elevated anti-PLA2R levels after treatment predict relapse (5–8,47,48)
Elevated anti-PLA2R levels at the time of transplantation predict recurrence (especially if DQA1a05:01/05 positive)
(71,83–85)
Disappearance of anti-PLA2R antibodies (immunologic remission) precedes renal remission (disappearance of
proteinuria) by weeks to months (5–8)
Patients previously positive for anti-PLA2R/THSD7A who become negative will exhibit positive glomerular staining for
weeks to months (5–8,13,20,21)
.50% of cases of pediatric PMN are PLA2R-positive (3)

PMN, primary membranous nephropathy; HBV, hepatitis B; HCV, hepatitis C.

a
Although established in only a few cases, most of these associations are likely similar in anti-THSDA–mediated PMN.

complications of nephrotic syndrome such as development
of thrombotic and thromboembolic events that are pro-
portional to the degree of hypoalbuminemia and increase
significantly below albumin levels of about 2.8 g/L (1,2,42,
52–54) (Table 4). There is also an increased risk of infection,
due primarily to urinary loss of Igs, and of cardiovascular
disease (42,49). An association with malignancies is well
documented (55). Cancer may be seen within 3 years in up
to 20% of patients over 60 and may be more common in the
anti-THSD7A group where up to 20% have had a malig-
nancy detected within 3 months (14–16).
The most feared long-term consequence of MN is
progressive loss of renal function as occurs in 60% of
untreated patients with about 35% eventually develop-
ing ESRD within 10 years (1,2,4,44–46). Patients
who never become nephrotic virtually never progress
(1,2,4,43–45). Other established risk factors for progres-
sion include age, male sex, decreased GFR on presenta-
tion, increased excretion of some low molecular weight
markers such as b 2 microglobulin, persistent elevation of
anti-PLA2R levels after therapy, C3 staining in the biopsy
sample, and increased urinary excretion of C3dg and C5b-9
(1,2,43–45).
Treatment
Selection of patients for IST
Traditional approaches to treatment of PMN begin with
supportive care alone and withhold IST until the patient
meets certain criteria that predict progression (restrictive
therapy). Supportive care should be initiated in all patients
at the time of diagnosis and continued for the course of
the disease. It includes careful BP control, angiotensin-
converting enzyme inhibitor/angiotensin receptor blocker
therapy to minimize proteinuria and enhance chances of
a spontaneous remission, statins for hyperlipidemia, salt
restriction and diuretics to control edema, and a low
protein diet allowing for replacement of urinary protein
losses (1,2,4,56–60) Some patients are also anticoagulated if
serum albumin is ,2.5 g/L in the presence of other risk
factors and a favorable risk/benefit ratio as defined by
online calculators (54).
Current criteria for adding IST to supportive care (SC)
are based on either evidence of progressive loss of GFR
(usually .50% increase in serum creatinine or a level
.1.5 mg/dl) or proteinuria refractory to 6 months of SC
as defined by the Toronto risk score (56). The latter
approach divides patients after 6 months of supportive
care into three categories: low risk (,4 g/d, stable GFR),
moderate risk (4–8 g/d with stable GFR), or high risk
(. 8 g/d, ,50% decrease from baseline or .30% decline in
GFR since baseline) categories. Initiation of IST is recom-
mended in most patients in the moderate- and high-risk
categories unless factors that reduce the chance of a good
response are present, such as GFR,30 ml/min, serum
creatinine .3.5 mg/dl, small fibrotic kidneys, or an abun-
dance (.50%) of sclerotic glomeruli. Other situations that
would dictate early initiation of IST would include pro-
teinuria.10 g/d or failure to reduce proteinuria below 8 g/d
after 3 months, complications of nephrotic syndrome such as
990 Clinical Journal of the American Society of Nephrology

Table 4. Clinical manifestations of primary membranous nephropathy at presentation and during the course of the disease
(1,2,42,43,56,58)

Clinical Manifestations Initially During Course Comments

Nephrotic syndrome
Proteinuria.3.5 g/d 60% 75% Anti-PLA2R antibody predicts
later development of
nephrotic syndrome
Edema 60% 75% Less severe than minimal
change nephrotic syndrome
or primary FGS
Hypoalbuminuria 60% 75% Inversely related to
proteinuria
Hyperlipidemia 50% 65% Inversely related to serum
albumin levels, associated
with cardiovascular disease
Thromboemboli ,1% 7% Risk increases with serum
albumin ,2.8 g/dl
Hematuria 50% 60% Red blood cell casts rare
Reduced GFR 20% 40% Seen only in nephrotic patients
ESRD NA 10%–20% (treated) to Requires .10 yr follow-up if
33% (untreated) ESRD is used as a clinical
end point in studies of
therapy
Hypertension 30% Up to 50% Usually associated with
progression
Risk alleles HLA-DQR1; PLA2R1 Presence of risk alleles for both
HLA and PLA2R raises the
risk for PMN up to 79-fold
Anti-PLA2R antibody 70%–80% 85% May be present before
proteinuria and resolve
weeks to months before
proteinuria resolves
Anti-THS7DA antibody 2%–7% ? Similar to anti-PLA2R, but
may be associated with more
extrarenal cancer
Associated with cancer 10% overall, 20% age .57 PMN usually follows cancer
diagnosis, anti-PLA2R
usually negative, issue of
causality versus coincidence
still unresolved

FGS, focal glomerular sclerosis; NA, not applicable; PMN, primary membranous nephropathy.

thromboembolic events, anasarca due to severe hypoalbumi-
nemia, or unexplained loss of GFR.
Definitions of terms conventionally used to classify
responses to therapy of PMN are presented in Table 5
(4,52,53). Goals of therapy would be complete or partial
remission. Thompson et al. have recently presented evi-
dence supporting the validity of considering complete and
partial remissions of proteinuria in PMN as surrogate
markers of good outcomes and consequently as valid goals
of therapy or end points for therapeutic trials (43).
For decades, clinicians have treated PMN with nephrotic
syndrome with potentially toxic IST using the above
proteinuria/GFR-based guidelines, because there was no
way to distinguish patients with immunologically active
disease from those with inactive disease who have persis-
tent proteinuria despite immunologic remission. Table 6
provides an overview of IST regimens of established benefit
in preserving renal function in PMN.
Figure 4, and the legend to Figure 4, outline a different
approach to IST applicable to all patients with protein-
uria.3.5 g/d, normal or stable GFR and active disease,
defined as ongoing glomerular immune deposit formation
indicated by elevated circulating levels of anti-PLA2R/
THSD7A. Based on the data reviewed above, such patients
have active immunologic disease and should be consid-
ered for immediate IST without waiting 6 months on
supportive care alone as prescribed by restrictive therapy
protocols. Although much remains to be learned about
translating anti-PLA2R/THSD7A levels into predictive
clinical algorithms, patients with anti-PLA2R levels in
the highest tertile have only a 4% chance of undergoing
spontaneous immunologic remission while being treated
with SC alone (47,48,50,51,59,60). Informed consent should
always be obtained before IST is initiated.
Both supportive care and IST should continue with antibody
monitoring every 1–2 months until anti-PLA2R/THSD7A
Clin J Am Soc Nephrol 12: 983–997, June, 2017
Table 5. Definitions of clinical responses in primary
membranous nephropathy (4,56–58)a
Clinical Response Definition
Complete remission Proteinuria ,0.3 g/d
Partial remission .50% reduction from baseline
and between 0.3 and 3.5 g/d
With stable GFRb
No remission ,50% reduction or .3.5 g/d
Relapse Recurrence of .3.5 g/d after
remission
ESRD GFR,15 ml/min or
requirement for dialysis/
transplant
a
Measurements of proteinuria for clinical decision-making
should be done on 24-hr collections. Overnight or random
samples can be used for monitoring.
b
Decline of ,15%.
levels become undetectable (or fall below some as yet
undefined level below which progression is unlikely),
recognizing that a response in proteinuria (clinical re-
mission) may only occur several weeks to months after an
immunologic remission is achieved (4,6,7). Considering the
current high cost of anti-PLA2R assays, obtaining levels at
the time of diagnosis and when a clinical decision point is
reached (e.g., after 6 months of IST) would be acceptable if
cost to the patient is a limiting factor. However, monitor-
ing levels initially every 1–2 months may justify shorter
courses of therapy and better predict remissions and
relapses. In most anti-PLA2R/THSD7A–positive patients,
circulating antibody disappears after 4–6 months of IST,
which should then be tapered and discontinued even if
some proteinuria persists (4,6,56–60). If antibody levels
persist but show a downward trajectory after 4–6 months,
the IST regimen can be maintained until antibody disap-
pears (immunologic remission). If no substantial reduction
in antibody levels is seen after 4–6 months or GFR falls
(.30% increase in serum creatinine on two determinations)
and nephrotic-range proteinuria persists at .50% of baseline,
changing to an alternate IST regimen would be justified
(Figure 4).
In the 10% of patients with PMN who are PLA2R/
THSD7A antibody– and glomerular antigen–negative, and
therefore have uncertain immunologic activity, initiation
of IST should follow the current restrictive proteinuria or
GFR-based guidelines outlined above (56,57) (Figure 4).
Clinical outcomes using these restrictive therapy protocols
have been equivalent to earlier results achieved by initi-
ating IST in all patients with PMN at the time of diagnosis
while sparing about 50% of patients with PMN the toxic
effects of IST (61). However, using the current recommen-
dations of 6 months of SC alone, nephrotic syndrome
resolves more slowly, patients are exposed to the nephrotic
state for longer periods of time and therefore are at greater
risk for developing complications of nephrotic syndrome
such as thromboembolic disease (Table 4), and some
nephrons will inevitably be damaged or destroyed while
waiting for a spontaneous remission to occur (4–6).
Membranous Nephropathy, Couser 991
The quantitative ELISA assay for PLA2R (Euroimmune
AG, Luebeck, Germany), or the recently developed cell-
based ALBIA assay (Mitogen Advanced Diagnostics Lab-
oratory, Calgary, Canada) should be used for monitoring
antibody levels (4–7). As we move more toward antibody-
guided therapy, it is essential that measurements be
standardized between commercial laboratories and that
the threshold antibody level below which IST does not
provide sufficient benefit to offset potential risks be de-
fined. In the ELISA assay, levels .20 RU/ml are considered
positive, and available data indicates a relationship be-
tween anti-PLA2R levels and clinical outcomes with pa-
tients in the lowest tertile frequently undergoing
spontaneous remission and levels in the highest tertile
associated with progression and rarely (,5%) with spon-
taneous remission (4,47,50,51).
IST regimens in PMN
Table 6 presents an overview of the IST regimens of
established benefit in PMN. Current data do not permit an
evidence-based choice between these IST protocols on the
basis of differences in their efficacy in suppressing anti-
PLA2R/THSD7A production. The three most utilized regi-
mens (cyclophosphamide/steroids, calcineurin inhibitors
[CNIs]/steroids, and rituximab) appear similar in their
effect on anti-PLA2R levels (1,4,59–63). Small studies have
shown that a combination of a CNI and rituximab was more
effective in suppressing antibody than cyclophosphamide/
steroids (63), that cyclophosphamide/steroids was more
effective than mycophenolate mofetil (MMF) (64), and that
tacrolimus (TAC) and cyclophosphamide/steroids were of
similar efficacy (62). However, each of these studies is small
and short-term. All three regimens lead to marked reductions
in circulating antibody in most patients within 3–4 months,
followed by disappearance of antibody within 6–9 months,
and remission of proteinuria in 12–24 months in .80% of
patients (4,63). Thus, IST prolonged for 6 months may not be
necessary in all patients, whereas longer courses might be
required in others.
Most current therapeutic guidelines, on the basis of older
randomized controlled trials (RCTs), recommend initiating
IST in patients with proteinuria resistant to supportive care
after 6 months utilizing a modified Ponticelli regimen of 6
months of alternating pulse steroids and cyclophosphamide
(56–60,65). This leads to remissions of proteinuria in about
50%–60% of patients at 1 year and 70%–80% at 2–3 years,
versus about 30% of controls treated with supportive care
only (2,56–60,65). Development of ESRD 10 years later is
reduced from 30%–40% to 10% or less when all patients with
PMN are treated at the time of diagnosis with alkylating
agents/steroids (65). Proteinuric relapses, seen in about 25%
of patients, are not predicted by any clinical parameter, but
usually follow the return of anti- PLA2R/THSD7A antibody
and are treated by repeating the same therapy that induced
the initial remission (1,2,56–60). A course of cyclophospha-
mide should be repeated only once because cumulative
doses .36 g are associated with an increased incidence of
malignancy (55), although increased incidence ratios for
malignancy have been reported in PMN at all levels of
cumulative cyclophosphamide dose (66). Advantages of the
Ponticelli regimen include the well established efficacy,
992 Clinical Journal of the American Society of Nephrology

Table 6. Summary of the most common IST protocols for treating patients with primary membranous nephropathy (56–60,93)

IST Regimen Drug, Dose Comments

Cytotoxic drugs KDIGO first choice

Modified Ponticelli Months 1, 3, 5: 1 g methylprednisolone Monitor Uprotein and WBC weekly
iv on days 1, 2, and 3 followed by oral 38, then every 2 mo; daily oral
prednisone, 0.5 mg/kg daily for 27 d prednisone and
cyclophosphamide may have
similar efficacy. Increased risk of
malignancy above 36 g
Months 2, 4, 6: 2.0–2.5 mg/kg oral Relapse rate 20%–30%
cyclophosphamide daily
Dutch protocol Months 1, 3, 5: 1 g MP days 1–3 followed Same as above
by oral prednisone, 0.5–1.0 mg/kg for
6 mo, then taper
Oral cyclophosphamide, 1.5–2.0 mg/kg
daily for 12 mo
CNIs KDIGO second choice
Cyclosporin 3.5–5.0 mg/kg daily in divided doses Used in patients resistant to cytotoxic
adjusted to level of 120–200 mg/L for drugs but can be used as initial
12–18 mo and tapered therapy. Taper slowly
Prednisone 5–10 mg/kg daily or alt days Discontinue at 6 mo if no response
Relapse rate 40%–50%
Tacrolimus 0.05–0.075 mg/kg daily in two divided Same as above
doses adjusted to level of 3–5 mg/L for
12–18 mo and taper slowly
Prednisone 5–10 mg/kg per day daily or Preferable in young women
alt days
B cell depletion Used for patients resistant to
cytotoxic drugs or CNIs
Utility as initial therapy not yet
established by RCTs
Rituximab 375 mg/kg weekly times 4 Follow CD20 counts and repeat dose
375 mg/kg once and follow CD20 if counts rise before remission in
counts proteinuria or relapse occurs
1000 mg on days 1 and 15
ACTH
Tetracosactrin 1 mg IM every 2 wk for 6–12 mo
(Synacthen)
(synthetic)
Corticotropin 80 U IM every 2 wk for 6–12 mo
(ACTHAR) (purified)

IST, immunosuppressive therapy; KDIGO, Kidney Disease Improving Global Outcomes; WBC, white blood cells; MP, methylpred-
nisolone; CNI, calcineurin inhibitor; alt, alternate; RCT, randomized controlled trial; ACTH, adrenocorticotrophic hormone; IM,
intramuscular.

including reduction in ESRD, lower relapse rate (25%), and
considerable experience with its use (4,59,60,62). Disad-
vantages include a relatively high adverse event rate (25%)
that includes infection, need for close monitoring of
hematologic parameters, infertility, and later malignancy
(56,57,62,66).
CNIs (cyclosporin [CSA] or tacrolimus [TAC]), used
either as monotherapy or combined with low-dose steroids,
which is thought to improve response and reduce nephro-
toxicity, have also been shown to decrease proteinuria,
reduce the rate of loss of renal function, and decrease anti-
PLA2R levels in PMN (1,2,4,56–60). In the United States,
many clinicians prefer to initiate therapy with CNIs to avoid
the more severe adverse events associated with alkylating
agents and higher doses of steroids. Most studies show
about equal efficacy between TAC and CSA (1,4,56–60).
Advantages of CNIs include the lower incidence of in-
fection and malignancy compared with cytotoxic drugs
and the efficacy of monotherapy if steroids are not used
(1,56,58). Disadvantages include long-term nephrotoxicity
with consequent need to closely monitor drug levels,
increased incidence of hypertension and diabetes, espe-
cially with TAC, and some recent concerns about whether
CNIs are effective at all in preventing ESRD in the long
term (67). The relapse rate with CNIs (40%–50%) is also
higher than with cyclophosphamide (25%) but may di-
minish with longer periods of therapy (1,59,60), and some
have advocated using low-dose CSA as maintenance
therapy to reduce or prevent relapses. CNIs have been
shown to not only reduce anti-PLA2R levels (62,63) but also to
Clin J Am Soc Nephrol 12: 983–997, June, 2017
have a direct effect to stabilize the podocyte actin cytoskeleton,
which reduces protein filtration (68). CNIs induce partial or
complete remissions in up to 80% of cases of PMN within 12
months and could be employed if cyclophosphamide/steroid
treatment fails, previous cumulative doses of cyclo-
phosphamide approach 36 g, there is inability to tolerate
cytotoxic drugs, or issues such as osteoporosis
or preservation of fertility are present (1,56–60). However,
CNIs have not yet been established by proper RCTs to
reduce the long-term development of ESRD, although a
strong case can be made that complete and partial
remissions of proteinuria can serve as surrogate markers
of failure to progress to ESRD in PMN (44). The limited
data comparing cytotoxic drug therapy directly to CNIs
suggests they have similar short-term clinical efficacy
(1,44,56–60). However, in one recent RCT, the response
to CNIs was not different from the response to SC alone
(67). An excellent initial response rate to CNIs (80%) has
been reported in some patients who failed the Ponticelli
regimen and, conversely, some patients who have failed
CNIs may respond to the Ponticelli regimen (59,60,69).
MMF monotherapy has not been established to be
effective in PMN (64). In one study only 44% of patients
receiving MMF were in remission at 23 months versus
75% in the cyclophosphamide group (63).
B cell depletion using the anti-CD19/20 monoclonal
rituximab as monotherapy has recently emerged as a less
toxic approach, with efficacy equivalent to cytotoxic drugs
and CNIs but with a significantly lower adverse event rate
(58,70–72). Rituximab was initially given weekly for 4
weeks as doses of 375 mg/M2 intravenously (iv) or, more
recently, as two iv doses of 1000 mg, or 375 mg/m2, 15
days apart (71). Rituximab, 375 mg/M2 as a single dose
repeated only when B cell counts return (B cell–driven
therapy), has also been established to reduce anti-PLA2R
antibody levels and to induce remission of proteinuria in
about 64% of patients in a mean of 7 months, but that
figure increases over 3–4 years and the safety profile is
better than that of cyclophosphamide or CNIs (1,70–72).
Also, similar effects on proteinuria have been reported in
PLA2R/THSD7A antibody–negative patients, suggesting
that these patients too may have an antibody-mediated
disease (71). Advantages of B cell–driven therapy include
the freedom from steroids, low adverse event rate, ability to
monitor B cell levels to assess efficacy and predict remission
and relapse, and modest cost when only a single dose is given
(71). Disadvantages include the lack of confirmation that
early reductions in proteinuria predict a lower incidence of
ESRD (with the caveat mentioned above that remissions of
proteinuria in PMN may be acceptable surrogate markers for
ESRD in PMN [44]). The response rate closely parallels CD
19/20 B cell counts and anti-PLA2R levels, and seems similar
in patients treated initially and those in whom rituximab
was used later as rescue therapy (70–72). The relapse rate in
rituximab responders is about 30%, associated with return
of circulating B cells and anti-PLA2R antibody, and relapse
can sometimes be associated with development of anti-
rituximab antibodies (72). Most patients who relapse respond
to another dose (70–72). A recent RCT (Evaluate Rituximab
Treatment for Idiopathic Membranous Nephropathy Study)
comparing supportive care alone to supportive care plus
rituximab, 375 mg/M2 iv on days 0 and 8 in patients with
Membranous Nephropathy, Couser 993
persistent nephrotic syndrome after 6 months of supportive
care, demonstrated much greater efficacy of rituximab in
reducing anti-PLA2R levels (56% versus 4% at 3 months,
P,0.05) and more complete and partial remissions of pro-
teinuria at a mean of 17 months in the rituximab group (65%
versus 34%, P,0.01), with short-term adverse event rates
similar to those in the group receiving SC alone (72). Analysis
of the cost of therapy over the course of the disease using a
Markov decision analysis model suggests it is lower than the
cost of cyclophosphamide/steroids (73). Thus, experience to
date supports considering rituximab monotherapy as a third
option for induction therapy, as well as a popular choice for
maintenance or rescue therapy (71).
Adrenocorticotrophic hormone monotherapy, usually
given as 1 mg twice a week for a year (Table 6), has also
been shown in one small randomized controlled study to
reduce anti-PLA2R levels and produce results (.80%
remission at 6 months) equivalent to cyclophosphamide/
steroids, with minimal adverse events (Table 6) (74–75).
However, another study comparing the two using histor-
ical controls favored cyclophosphamide (75). The cost of
adrenocorticotrophic hormone is very high, and its place
in the therapeutic armamentarium for PMN remains to be
established (76).
Another treatment option is to utilize combinations of
drugs in lower doses (multidrug therapy), usually ritux-
imab plus a cytotoxic drug or CNI to retain efficacy and
reduce adverse events, especially those due to steroids.
For example, a recent observational study using rituximab
with low-dose cyclophosphamide and an accelerated taper
of steroids reported a 100% remission rate over a mean
follow-up of 37 months (77). Another, using a combination
of rituximab and CSA, achieved remissions in 92% and
antibody depletion in 100% in 9 months (78), and a
combination of rituximab and plasma exchange showed
promise in a third small study (79). These studies all require
confirmation, and RCTs comparing these approaches to
conventional IST reviewed above are necessary before
multidrug therapy can be recommended as an established
approach to initial therapy in PMN.
Transplantation in PMN
Renal transplantation is effective in the 10%–20% of
patients who do reach ESRD from PMN (1,4,75–78). In anti-
PLA2R–positive patients, subepithelial deposits can ap-
pear in the allograft within 6 days (70,80,81). As deposits
increase, clinical recurrence (proteinuria) is seen within 13–
15 months in about 40%–50% of allografts and can diminish
allograft survival (70,80–85). The recurrence rate of sub-
epithelial deposits in patients positive for anti-PLA2R
antibodies at the time of transplantation may approach
90% (70,80,81). Delaying transplantation until anti-PLA2R/
THSD7A is no longer detectable seems advisable unless
there are clinical reasons for greater urgency. Anti-PLA2R–
negative de novo MN is also a common cause of transplant
nephrotic syndrome, affecting about 2% of all renal trans-
plant recipients whose original disease was not MN, and is
about equal in frequency to recurrent MN in patients with
PMN (82–85). In these patients, IgG1 deposits often pre-
dominate, anti-PLA2R/THSD7A is negative, and the
mechanism(s) involved are not yet known, although the
994 Clinical Journal of the American Society of Nephrology
lesion is believed to be related to graft rejection (82). Anti-
PLA2R positivity has a sensitivity of 83% and specificity of
.90% in differentiating between recurrent and de novo MN
in transplants (78–80,84).
Because patients with recurrent subepithelial deposits
do not all go on to manifest clinical recurrence, treatment
for recurrent MN is usually considered only when protein
excretion reproducibly exceeds 1 g/d in patients with PMN
or 4 g/d in patients with de novo MN (82–85). However, an
approach analogous to the one recommended above for
PMN in native kidneys would suggest initiating additional
IST in patients with PMN with elevated anti-PLA2R/
THSD7A levels and nephrotic-range proteinuria post-
transplant. Based entirely on observational data, rituximab
is usually added to regular immunosuppressive protocols,
which often already include CNIs (70,82–84). The doses
employed have ranged from one dose of 200 mg to the older
375 mg/M2 given four times at weekly intervals with
monitoring of CD20 counts. Because these patients are
being treated early and are already on IST for the trans-
plant, lower doses are probably preferable. Use of pretrans-
plant rituximab has been attempted in antibody-positive
patients, and may have been effective in preventing re-
currence in some patients with a history of recurrent PMN
in previous allografts (84). In patients receiving CNIs and
resistant to rituximab, cyclophosphamide, 2 mg/kg per
day, is usually employed after other antimetabolites such as
MMF or azathioprine are discontinued (78,82–84).
Gaps and Shortfalls in Current Therapy
Despite the numerous translational observations that
have already been made (Table 3), many questions remain
unanswered (86). Some of the more clinically relevant ones
include: What is the best way to measure anti-PLA2R,
and, in the future, anti-THSD7A, antibody? How do
antibody levels translate into risk of progression and are
there levels below which IST is not worthwhile? If therapy
is antibody-directed, will this achieve better clinical out-
comes or fewer adverse events in patients with active
disease compared with current restrictive therapy regi-
mens? Is it important for prognosis or treatment to know
the pathogenic epitopes and molecular configurations of
the PLA2R peptides against which antibodies in individual
patients are directed? Does a biopsy contribute to im-
proved outcomes in typical anti-PLA2R/THSD7A–positive
PMN with nephrotic syndrome? If a patient has apparent
secondary MN with another systemic disease, but also has
elevated anti-PLA2R/THSD7A antibody or positive glomer-
ular staining, should such a patient be treated for PMN? If
a biopsy is done in antibody-negative patients, is positive
glomerular staining for IgG4 and PLA2R/THSD7A suffi-
cient to establish anti-PLA2R/THSD7A–related PMN and
exclude secondary causes?
Can multidrug therapy protocols combining currently
available drugs reduce adverse events without sacrificing
efficacy as has been done in lupus nephritis? Can outcomes
be further improved if complement inhibitors are added to
current IST protocols, especially during the interval of
active disease between initiation of IST and disappearance
of the antibody? Can routine maintenance therapy reduce
relapses and the need for retreatment?
New Therapies on the Horizon
Current knowledge of the roles of autoantibody IgG and
complement in the pathogenesis of PMN make better B
cell–depleting agents and complement inhibitors of par-
ticular interest. New therapeutic approaches to suppress
antibody production or interfere with antibody-induced
podocyte injury include improved B cell–depleting agents,
B cell depletion targeted specifically to anti-PLA2R re-
active cells, and suppressors of B cell activation. A recent
pilot study of belimumab, an inhibitor of B cell activation,
in 11 anti-PLA2R–positive patients reported a 90% re-
duction in anti-PLA2R levels and a (delayed) 70% re-
duction in proteinuria in patients receiving monthly iv
doses of the drug over a period of 28 weeks (87). Other
approaches under development include antibody traps or
decoys and efforts to directly protect the podocyte itself
from consequences of immune injury such as endoplasmic
reticulum stress, autophagy, and oxidant injury (88).
Pending identification of PLA2R peptides that neutralize
antibody, peptide-blocking agents will likely also be de-
veloped. Although one trial of the C5 inhibitor eculizumab
was negative in PMN, adequate complement -inhibiting
doses were not used, and other trials with newer comple-
ment inhibitors, including oral agents, recombinant com-
plement regulatory proteins, small molecules, new
monoclonal antibodies, small interfering RNA agents,
and approaches that upregulate natural complement in-
hibitors, are in progress or under development (31).
Disclosures
None.
References
1. Cattran DC, Brenchley PE: Membranous nephropathy: Integrating
basic science into improved clinical management. Kidney Int 91:
566–574, 2017
2. Salant DJ, Cattran DC: Membranous nephropathy. Chapter 20. In:
Comprehensive Clinical Nephrology, 5th Ed., edited by Floege J,
Johnson RJ, Feehally J, St. Louis, MI, Saunders, an imprint of
Elsevier Inc., 2015, pp 239–251
3. Kumar V, Ramachandran R, Kumar A, Nada R, Suri D, Gupta A,
Kohli HS, Gupta KL, Jha V: Antibodies to m-type phospholipase
A2 receptor in children with idiopathic membranous nephrop-
athy. Nephrology (Carlton) 20: 572–575, 2015
4. De Vriese AS, Glassock RJ, Nath KA, Sethi S, Fervenza FC: A
proposal for a serology-based approach to membranous ne-
phropathy. J Am Soc Nephrol 28: 421–430, 2016
5. Francis JM, Beck LH Jr., Salant DJ: Membranous nephropathy: A
journey from bench to bedside. Am J Kidney Dis 68: 138–147, 2016
6. Debiec H, Ronco P: Immune response against autoantigen
PLA2R is not gambling: Implications for pathophysiology, prog-
nosis and therapy. J Am Soc Nephrol 27: 1275–1277, 2016
7. Ronco P, Debiec H: Pathophysiological advances in membranous
nephropathy: Time for a shift in patient’s care. Lancet 385: 1983–
1992, 2015
8. Sinico RA, Mezzina N, Trezzi B, Ghiggeri GM, Radice A: Im-
munology of membranous nephropathy: From animal models to
humans. Clin Exp Immunol 183: 157–165, 2016
9. Kerjaschki D: Pathomechanisms and molecular basis of mem-
branous glomerulopathy. Lancet 364: 1194–1196, 2004
10. Debiec H, Guigonis V, Mougenot B, Decobert F, Haymann JP,
Bensman A, Deschênes G, Ronco PM: Antenatal membranous
glomerulonephritis due to anti-neutral endopeptidase antibodies.
N Engl J Med 346: 2053–2060, 2002
11. Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW,
Cummins TD, Klein JB, Salant DJ: M-type phospholipase A2 re-
ceptor as target antigen in idiopathic membranous nephropathy.
N Engl J Med 361: 11–21, 2009
Clin J Am Soc Nephrol 12: 983–997, June, 2017
12. Tomas NM, Beck LH Jr, Meyer-Schwesinger C, Seitz-Polski B, Ma
H, Zahner G, Dolla G, Hoxha E, Helmchen U, Dabert-Gay AS,
Debayle D, Merchant M, Klein J, Salant DJ, Stahl RA, Lambeau G:
Thrombospondin type-1 domain-containing 7A in idiopathic
membranous nephropathy. N Engl J Med 371: 2277–2287, 2014
13. Larsen CP, Cossey LN, Beck LH: THSD7A staining of membranous
glomerulopathy in clinical practice reveals cases with dual au-
toantibody positivity. Mod Pathol 29: 421–426, 2016
14. Hoxha E, Wiech T, Stahl PR, Zahner G, Tomas NM, Meyer-
Schwesinger C, Wenzel U, Janneck M, Steinmetz OM, Panzer U,
Harendza S, Stahl RA: A mechanism for cancer-associated
membranous nephropathy. N Engl J Med 374: 1995–1996, 2016
15. Timmermans SA, Ayalon R, van Paassen P, Beck LH Jr, van Rie H,
Wirtz JJ, Verseput GH, Frenken LA, Salant DJ, Cohen Tervaert JW;
Limburg Renal Registry: Anti-phospholipase A2 receptor anti-
bodies and malignancy in membranous nephropathy. Am J Kid-
ney Dis 62: 1223–1225, 2013
16. Stahl PR, Hoxha E, Wiech T, Schröder C, Simon R, Stahl RA:
THSD7A expression in human cancer. Genes Chromosomes
Cancer 56: 314–327, 2017
17. Hoxha E, Beck LH Jr, Wiech T, Tomas NM, Probst C, Mindorf S,
Meyer-Schwesinger C, Zahner G, Stahl PR, Schöpper R, Panzer
U, Harendza S, Helmchen U, Salant DJ, Stahl RA: An indirect
immunofluorescence method facilitates detection of throm-
bospondin type 1 domain-containing 7A-specific antibodies in
membranous nephropathy. J Am Soc Nephrol 28: 520–531,
2017
18. Lefaucheur C, Stengel B, Nochy D, Martel P, Hill GS, Jacquot C,
Rossert J; GN-PROGRESS Study Group: Membranous ne-
phropathy and cancer: Epidemiologic evidence and determi-
nants of high-risk cancer association. Kidney Int 70: 1510–1517,
2006
19. Tomas NM, Hoxha E, Reinicke AT, Fester L, Helmchen U, Gerth J,
Bachmann F, Budde K, Koch-Nolte F, Zahner G, Rune G, Lambeau
G, Meyer-Schwesinger C, Stahl RA: Autoantibodies against
thrombospondin type 1 domain-containing 7A induce mem-
branous nephropathy. J Clin Invest 126: 2519–2532, 2016
20. Larsen CP, Messias NC, Silva FG, Messias E, Walker PD: De-
termination of primary versus secondary membranous glomer-
ulopathy utilizing phospholipase A2 receptor staining in renal
biopsies. Mod Pathol 26: 709–715, 2013
21. Dong HR, Wang YY, Cheng XH, Wang GQ, Sun LJ, Cheng H, Chen
YP. Retrospective study of phospholipase A2 receptor and IgG
subclasses in glomerular deposits in chinese patients with
membranous nephropathy. PLoS One. 11: e0156263, 2016
22. Beck LH Jr, Salant DJ: Membranous nephropathy: Recent travels
and new roads ahead. Kidney Int 77: 765–770, 2010
23. Svobodova B, Honsova E, Ronco P, Tesar V, Debiec H: Kidney
biopsy is a sensitive tool for retrospective diagnosis of PLA2R-
related membranous nephropathy. Nephrol Dial Transplant 28:
1839–1844, 2013
24. Debiec H, Ronco P: PLA2R autoantibodies and PLA2R glomer-
ular deposits in membranous nephropathy. N Engl J Med 364:
689–690, 2011
25. Ryan MS, Satoskar AA, Nadasdy GM, Brodsky SV, Hemminger JA,
Nadasdy T: Phospholipase A2 receptor staining is absent in many
kidney biopsies with early-stage membranous glomerulone-
phritis. Kidney Int 89: 1402–1403, 2016
26. Guerry MJ, Vanhille P, Ronco P, Debiec H: Serum anti-PLA2R
antibodies may be present before clinical manifestations of
membranous nephropathy. Kidney Int 89: 1399, 2016
27. Stanescu HC, Arcos-Burgos M, Medlar A, Bockenhauer D,
Kottgen A, Dragomirescu L, Voinescu C, Patel N, Pearce K,
Hubank M, Stephens HA, Laundy V, Padmanabhan S, Zawadzka
A, Hofstra JM, Coenen MJ, den Heijer M, Kiemeney LA, Bacq-
Daian D, Stengel B, Powis SH, Brenchley P, Feehally J, Rees AJ,
Debiec H, Wetzels JF, Ronco P, Mathieson PW, Kleta R: Risk
HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous
nephropathy. N Engl J Med 364: 616–626, 2011
28. Xu X, Wang G, Chen N, Lu T, Nie S, Xu G, Zhang P, Luo Y, Wang Y,
Wang X, Schwartz J, Geng J, Hou FF: Long-term exposure to air
pollution and increased risk of membranous nephropathy in
china. J Am Soc Nephrol 27: 3739–3746, 2016
29. Ma H, Sandor DG, Beck LH Jr.: The role of complement in
membranous nephropathy. Semin Nephrol 33: 531–542, 2013
Membranous Nephropathy, Couser 995
30. Takano T, Elimam H, Cybulsky AV: Complement-mediated cel-
lular injury. Semin Nephrol 33: 586–601, 2013
31. Reddy YN, Siedlecki AM, Francis JM: Breaking down the com-
plement system: a review and update on novel therapies. Curr
Opin Nephrol Hypertens 26: 123–128, 2017
32. Spicer ST, Tran GT, Killingsworth MC, Carter N, Power DA, Paizis
K, Boyd R, Hodgkinson SJ, Hall BM: Induction of passive Hey-
mann nephritis in complement component 6-deficient PVG rats. J
Immunol 179: 172–178, 2007
33. Salant DJ: Genetic variants in membranous nephropathy:
Perhaps a perfect storm rather than a straightforward con-
formeropathy? J Am Soc Nephrol 24: 525–528, 2013
34. Bomback AS, Gharavi AG: Can genetics risk-stratify patients with
membranous nephropathy? J Am Soc Nephrol 24: 1190–1192,
2013
35. Lv J, Hou W, Zhou X, Liu G, Zhou F, Zhao N, Hou P, Zhao M,
Zhang H: Interaction between PLA2R1 and HLA-DQA1 variants
associates with anti-PLA2R antibodies and membranous ne-
phropathy. J Am Soc Nephrol 24: 1323–1329, 2013
36. Seitz-Polski B, Dolla G, Payré C, Girard CA, Polidori J, Zorzi K,
Birgy-Barelli E, Jullien P, Courivaud C, Krummel T, Benzaken S,
Bernard G, Burtey S, Mariat C, Esnault VL, Lambeau G: Epitope
spreading of autoantibody response to PLA2R1 is associates with
poor prognosis in membranous nephropathy. J Am Soc Nephrol
27: 1517–1533, 2016
37. Cui Z, Xie LJ, Chen FJ, Pei ZY, Zhang LJ, Qu Z, Huang J, Gu QH,
Zhang YM, Wang X, Wang F, Meng LQ, Liu G, Zhou XJ, Zhu L, Lv
JC, Liu F, Zhang H, Liao YH, Lai LH, Ronco P, Zhao MH. MHC
Class II risk alleles and amino acid residues in idiopathic
membranous nephropathy. J Am Soc Nephrol 28: 1642–1650,
2017
38. Le WB, Shi JS, Zhang T, Liu L, Qin HZ, Liang S, Zhang YW, Zheng
CX, Jiang S, Qin WS, Zhang HT, Liu ZH. DRB1*15:01 and HLA-
DRB3*02:02 in -related membranous nephropathy. J Am Soc
Nephrol 28: 1642–1650, 2017
39. Kao L, Lam V, Waldman M, Glassock RJ, Zhu Q: Identification
of the immunodominant epitope region in phospholipase A2
receptor-mediating autoantibody binding in idiopathic mem-
branous nephropathy. J Am Soc Nephrol 26: 291–301, 2015
40. Fresquet M, Jowitt TA, Gummadova J, Collins R, O’Cualain R,
McKenzie EA, Lennon R, Brenchley PE: Identification of a major
epitope recognized by PLA2R autoantibodies in primary mem-
branous nephropathy. J Am Soc Nephrol 26: 302–313, 2015
41. Fogo AB, Lusco MA, Najafian B, Alpers CE: AJKD atlas of renal
pathology: Membranous nephropathy. Am J Kidney Dis 66: e15–
e17, 2015
42. Barbour S, Reich H, Cattran D: Short-term complications of
membranous nephropathy. Contrib Nephrol 181: 143–151, 2013
43. Ponticelli C, Glassock RJ: Glomerular diseases: Membranous
nephropathy–a modern view. Clin J Am Soc Nephrol 9: 609–616,
2014
44. Thompson A, Cattran DC, Blank M, Nachman PH: Complete and
partial remission as surrogate end points in membranous ne-
phropathy. J Am Soc Nephrol 26: 2930–2937, 2015
45. Hladunewich MA, Troyanov S, Calafati J, Cattran DC; Metro-
politan Toronto Glomerulonephritis Registry: The natural history
of the non-nephrotic membranous nephropathy patient. Clin J Am
Soc Nephrol 4: 1417–1422, 2009
46. Polanco N, Gutiérrez E, Covarsı́ A, Ariza F, Carre~no A, Vigil A,
Baltar J, Fernández-Fresnedo G, Martı́n C, Pons S, Lorenbnvzo D,
Bernis C, Arrizabalaga P, Fernández-Juárez G, Barrio V, Sierra M,
Castellanos I, Espinosa M, Rivera F, Oliet A, Fernández-Vega F,
Praga M; Grupo de Estudio de las Enfermedades Glomerulares de
la Sociedad Espa~ nola de Nefrologı́a: Spontaneous remission of
nephrotic syndrome in idiopathic membranous nephropathy. J
Am Soc Nephrol 21: 697–704, 2010
47. Hofstra JM, Beck LH Jr, Beck DM, Wetzels JF, Salant DJ: Anti-
phospholipase A2 receptor antibodies correlate with clinical
status in idiopathic membranous nephropathy. Clin J Am Soc
Nephrol 6: 1286–1291, 2011
48. Hoxha E, Harendza S, Pinnschmidt H, Panzer U, Stahl RA: PLA2R
antibody levels and clinical outcome in patients with membra-
nous nephropathy and non-nephrotic range proteinuria under
treatment with inhibitors of the renin-angiotensin system. PLoS
One 9: e110681, 2014
996 Clinical Journal of the American Society of Nephrology
49. Lee T, Derebail VK, Kshirsagar AV, Chung Y, Fine JP, Mahoney S,
Poulton CJ, Lionaki S, Hogan SL, Falk RJ, Cattran DC,
Hladunewich M, Reich HN, Nachman PH: Patients with primary
membranous nephropathy are at high risk of cardiovascular
events. Kidney Int 89: 1111–1118, 2016
50. Radice A, Trezzi B, Maggiore U, Pregnolato F, Stellato T,
Napodano P, Rolla D, Pesce G, D’Amico M, Santoro D, Londrino
F, Ravera F, Ortisi G, Sinico RA: Clinical usefulness of autoanti-
bodies to M-type phospholipase A2 receptor (PLA2R) for moni-
toring disease activity in PMN. Autoimmun Rev 15: 146–154,
2016
51. Kanigicherla D, Gummadova J, McKenzie EA, Roberts SA, Harris S,
Nikam M, Poulton K, McWilliam L, Short CD, Venning M, Brenchley
PE: Anti-PLA2R antibodies measured by ELISA predict long-term
outcome in a prevalent population of patients with idiopathic
membranous nephropathy. Kidney Int 83: 940–948, 2013
52. Li SJ, Guo JZ, Zuo K, Zhang J, Wu Y, Zhou CS, Lu GM, Liu ZH:
Thromboembolic complications in membranous nephropathy
patients with nephrotic syndrome-a prospective study. Thromb
Res 130: 501–505, 2012
53. Rankin AJ, McQuarrie EP, Fox JG, Geddes CC, MacKinnon B;
Scottish Renal Biopsy Registry: Venous thromboembolism in
primary nephrotic syndrome - Is the risk high enough to justify
prophylactic anticoagulation? Nephron 135: 39–45, 2017
54. Lee T, Biddle AK, Lionaki S, Derebail VK, Barbour SJ, Tannous S,
Hladunewich MA, Hu Y, Poulton CJ, Mahoney SL, Charles
Jennette J, Hogan SL, Falk RJ, Cattran DC, Reich HN, Nachman
PH: Personalized prophylactic anticoagulation decision analysis
in patients with membranous nephropathy. Kidney Int 85: 1412–
1420, 2014
55. Leeaphorn N, Kue-A-Pai P, Thamcharoen N, Ungprasert P, Stokes
MB, Knight EL: Prevalence of cancer in membranous nephrop-
athy: A systematic review and meta-analysis of observational
studies. Am J Nephrol 40: 29–35, 2014
56. Kidney Disease Improving Global Outcomes (KDIGO) Glomer-
ulonephritis Work Group: KDIGO clinical practice guideline for
glomerulonephritis. Kidney Int Suppl 2: 139–274, 2012
57. Cybulsky AV, Walsh M, Knoll G, Hladunewich M, Bargman J,
Reich H, Humar A, Samuel S, Bitzan M, Zappitelli M, Dart A,
Mammen C, Pinsk M, Muirhead N: Canadian Society of Ne-
phrology Commentary on the 2012 KDIGO clinical practice
guideline for glomerulonephritis: Management of glomerulone-
phritis in adults. Am J Kidney Dis 63: 363–377, 2014
58. Cattran D, Brenchley P: Membranous nephropathy: thinking
through the therapeutic options. Nephrol Dial Transplant
32(suppl_1): i22–i29, 2017
59. Tran THJ, J Hughes G, Greenfeld C, Pham JT: Overview of current
and alternative therapies for idiopathic membranous nephropa-
thy. Pharmacotherapy 35: 396–411, 2015
60. van de Logt AE, Hofstra JM, Wetzels JF: Pharmacological treat-
ment of primary membranous nephropathy in 2016. Expert Rev
Clin Pharmacol 16: 1–16, 2016
61. van den Brand JA, van Dijk PR, Hofstra JM, Wetzels JF: Long-
term outcomes in idiopathic membranous nephropathy using a
restrictive treatment strategy. J Am Soc Nephrol 25: 150–158,
2014
62. Ramachandran R, Hn HK, Kumar V, Nada R, Yadav AK, Goyal A,
Kumar V, Rathi M, Jha V, Gupta KL, Sakhuja V, Kohli HS: Tacro-
limus combined with corticosteroids versus Modified Ponticelli
regimen in treatment of idiopathic membranous nephropathy:
Randomized control trial. Nephrology (Carlton) 21: 139–146,
2016
63. Bech AP, Hofstra JM, Brenchley PE, Wetzels JF: Association of
anti-PLA2R antibodies with outcomes after immunosuppressive
therapy in idiopathic membranous nephropathy. Clin J Am Soc
Nephrol 9: 1386–1392, 2014
64. Dussol B, Morange S, Burtey S, Indreies M, Cassuto E, Mourad G,
Villar E, Pouteil-Noble C, Karaaslan H, Sichez H, Lasseur C,
Delmas Y, Nogier MB, Fathallah M, Loundou A, Mayor V, Berland
Y: Mycophenolate mofetil monotherapy in membranous ne-
phropathy: A 1-year randomized controlled trial. Am J Kidney Dis
52: 699–705, 2008
65. Hofstra JM, Wetzels JFM: Alkylating agents in membranous ne-
phropathy: Efficacy proven beyond doubt. Nephrol Dial Trans-
plant 25: 1760–1766, 2010
66. Khan S, Bolton WK: Balancing cancer risk and efficacy of using
cyclophosphamide to treat idiopathic membranous nephropathy.
Clin J Am Soc Nephrol 9: 1001–1004, 2014
67. Howman A, Chapman TL, Langdon MM, Ferguson C, Adu D,
Feehally J, Gaskin GJ, Jayne DR, O’Donoghue D, Boulton-Jones
M, Mathieson PW: Immunosuppression for progressive mem-
branous nephropathy: A UK randomised controlled trial. Lancet
381: 744–751, 2013
68. Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S,
Delfgaauw J, Chang JM, Choi HY, Campbell KN, Kim K, Reiser J,
Mundel P: The actin cytoskeleton of kidney podocytes is a direct
target of the antiproteinuric effect of cyclosporine A. Nat Med 14:
931–938, 2008
69. Ramachandran R, Kumar V, Jha V: Cyclical cyclophosphamide
and steroids is effective in resistant or relapsing nephrotic syn-
drome due to M-type phospholipase A2 receptor-related mem-
branous nephropathy after tacrolimus therapy. Kidney Int 89:
1401–1402, 2016
70. Ruggenenti P, Debiec H, Ruggiero B, Chianca A, Pellé T, Gaspari F,
Suardi F, Gagliardini E, Orisio S, Benigni A, Ronco P, Remuzzi G:
Anti-phospholipase A2 receptor antibody titer predicts post-
rituximab outcome of membranous nephropathy. J Am Soc
Nephrol 26: 2545–2558, 2015
71. Cravedi P, Remuzzi G, Ruggenenti P: Rituximab in primary
membranous nephropathy: First-line therapy, why not? Nephron
Clin Pract 128: 261–269, 2014
72. Dahan K, Debiec H, Plaisier E, Cachanado M, Rousseau A,
Wakselman L, Michel PA, Mihout F, Dussol B, Matignon M,
Mousson C, Simon T, Ronco P; GEMRITUX Study Group: Rit-
uximab for severe membranous nephropathy: A 6-month trial
with extended follow-up. J Am Soc Nephrol 28: 348–358, 2017
73. Hamilton P, Kanigicherla DAK, Venning M, Brenchley PE, Meads
DM: Rituximab versus the modified Ponticelli regime in the
treatment of primary membranous nephropathy: A health eco-
nomic model. J Am Soc Nephrol 27: 776a, 2016
74. Ponticelli C, Passerini P, Salvadori M, Manno C, Viola BF, Pasquali
S, Mandolfo S, Messa P: A randomized pilot trial comparing
methylprednisolone plus a cytotoxic agent versus synthetic ad-
renocorticotropic hormone in idiopathic membranous ne-
phropathy. Am J Kidney Dis 47: 233–240, 2006
75. van de Logt AE, Beerenhout CH, Brink HS, van de Kerkhof JJ,
Wetzels JF, Hofstra JM. Synthetic ACTH in high risk patients with
idiopathic membranous nephropathy: A prospective, open label
cohort study. PLoS One 10: e0142033, 2015
76. Kittanamongkolchai W, Cheungpasitporn W, Zand L: Efficacy and
safety of adrenocorticotropic hormone treatment in glomerular
diseases: A systematic review and meta-analysis. Clin Kidney J 9:
387–396, 2016
77. Cortazar FB, Leaf DE, Owens CT, Laliberte K, Pendergraft 3rd WF,
Niles JL: Combination therapy with rituximab, low-dose cyclo-
phosphamide, and prednisone for idiopathic membranous ne-
phropathy: A case series. BMC Nephrol 18: 44, 2017
78. Waldman M, Beck LH Jr, Braun M, Wilkins K, Balow JE, Austin 3rd
HA: Membranous nephropathy: Pilot study of a novel regimen
combining cyclosporine and Rituximab. Kidney Int Rep 1: 73–84,
2016
79. Müller-Deile J, Schiffer L, Hiss M, Haller H, Schiffer M: A new
rescue regimen with plasma exchange and rituximab in high-risk
membranous glomerulonephritis. Eur J Clin Invest 45: 1260–
1269, 2015
80. Kattah A, Ayalon R, Beck LH Jr, Sethi S, Sandor DG, Cosio FG,
Gandhi MJ, Lorenz EC, Salant DJ, Fervenza FC: Anti-phospholipase
A2 receptor antibodies in recurrent membranous nephropathy. Am J
Transplant 15: 1349–1359, 2015
81. Dabade TS, Grande JP, Norby SM, Fervenza FC, Cosio FG: Re-
current idiopathic membranous nephropathy after kidney
transplantation: A surveillance biopsy study. Am J Transplant 8:
1318–1322, 2008
82. PonticelliC,MoroniG,GlassockRJ:Denovoglomerulardiseasesafter
renal transplantation. Clin J Am Soc Nephrol 9: 1479–1487, 2014
83. Filippone EJ, Farber JL: Membranous nephropathy in the kidney
allograft. Clin Transplant 30: 1394–1402, 2016
84. Cosio FG, Cattran DC: Recent advances in our understanding of
recurrent primary glomerulonephritis after kidney trans-
plantation. Kidney Int 91: 304–314, 2017
Clin J Am Soc Nephrol 12: 983–997, June, 2017
85. Gupta G, Fattah H, Ayalon R, Kidd J, Gehr T, Quintana LF, Kimball P,
Sadruddin S, Massey HD, Kumar D, King AL, Beck LH Jr: Pre-transplant
phospholipase A2 receptor autoantibody concentration is associated
with clinically significant recurrence of membranous nephropathy
post-kidney transplantation. Clin Transplant 30: 461–469, 2016
86. Hofstra JM, Wetzels JF: Phospholipase A2 receptor antibodies in
membranous nephropathy: Unresolved issues. J Am Soc Nephrol
25: 1137–1139, 2014
87. Willcocks L, Barrett C, Brenchley P, Schmidt T, Gisbert S, Cai G,
Savage C, Jones R Effect of Belimumab on proteinuria and anti-
PLA2R autoantibody in idiopathic membranous nephropathy - 6
months data. Nephrol Dial Transplant 30[Suppl 3]: iii32–iii33, 2015
88. Cattran DC, Brenchley PE: Membranous nephropathy: integrating
basic science into improved clinical management. Kidney Int 91:
566–574, 2017
89. French LE, Tschopp J, Schifferli JA: Clusterin in renal tissue:
Preferential localization with the terminal complement complex
and immunoglobulin deposits in glomeruli. Clin Exp Immunol 88:
389–393, 1992
Membranous Nephropathy, Couser 997
90. Couser WG, Johnson RJ: The etiology of glomerulonephritis:
Roles of infection and autoimmunity. Kidney Int 86: 905–914,
2014
91. Larsen CP, Ambuzs JM, Bonsib SM, Boils CL, Cossey LN, Messias
NC, Silva FG, Wang YH, Gokden N, Walker PD: Membranous-
like glomerulopathy with masked IgG kappa deposits. Kidney Int
86: 154–161, 2014
92. Hogan JJ, Markowitz GS, Radhakrishnan J. Drug-induced glo-
merular disease: Immune-mediated injury. Clin J Am Soc Nephrol
10: 1300–1310, 2015
93. Medrano AS, Escalante EJ, Cáceres CC, Pamplona IA, Allende MT,
Terrades NR, Carmeno NV, Roldán EO, Agudelo KV, Vasquez JJ:
Prognostic value of the dynamics of M-type phospholipase A2
receptor antibody titers in patients with idiopathic membranous
nephropathy treated with two different immunosuppression
regimens. Biomarkers 20: 77–83, 2015
Published online ahead of print. Publication date available at www.
cjasn.org.