Core Curriculum

Membranous Nephropathy: Core

Curriculum 2021
Loulwa Alsharhan and Laurence H. Beck Jr

The understanding and management of membranous nephropathy, a common cause of nephrotic Complete author and article
syndrome that is more frequently encountered in adults than in children, has rapidly evolved over the information provided at end
of article.
past decade. Identification of target antigens has allowed for more precise molecular diagnoses, and
the ability to monitor circulating autoantibodies has added a new vantage point in terms of disease Am J Kidney Dis.
monitoring and decisions about immunosuppression. Although immunosuppression with alkylating 77(3):440-453. Published
online January 21, 2021.
agents combined with corticosteroids, or with calcineurin inhibitor–based regimens, has been the
historical mainstay of treatment, observational and now randomized controlled trials with the doi: 10.1053/
B-cell–depleting agent rituximab have moved this agent to the forefront of therapy for primary mem- j.ajkd.2020.10.009
branous nephropathy. In this Core Curriculum, we discuss the typical features of primary and sec- © 2020 by the National
ondary disease; highlight the target antigens such as the phospholipase A2 receptor, thrombospondin Kidney Foundation, Inc.
type 1 domain-containing 7A, neural epidermal growth factor-like 1, and semaphorin-3B; describe the
relationship between the immunologic and clinical courses of disease; and review modern manage-
ment with supportive care or immunosuppressive treatment based on these composite parameters.

Introduction b) Duplex ultrasonography of her renal vessels

c) Titer of phospholipase A2 receptor (PLA2R) FEATURE EDITOR:
Membranous nephropathy (MN) is a common antibodies Asghar Rastegar
cause of adult nephrotic syndrome and is seen d) Antiphospholipid antibody test
less commonly in children. The field has ADVISORY BOARD:
advanced significantly and rapidly in the past For the answer to the question, see the Ursula C. Brewster
decade, with the introduction of new tools to following text. Michael Choi
Ann O'Hare
diagnose, classify, and monitor disease activ-
Manoocher Soleimani
ity. This Core Curriculum is intended to up- MN represents a spectrum of diseases The Core Curriculum
date the reader on the recent progress in the sharing a common histopathologic pattern, aims to give trainees
field and provide a general guide for the namely the presence of immunoglobulin and in nephrology a
clinical management of disease. complement-containing immune deposits in a strong knowledge
base in core topics in
subepithelial position (see Kidney Pathology). the specialty by
Classification Historically, MN has been classified as idio- providing an overview
pathic or secondary MN on the basis of clinical of the topic and citing
Case: A 46-year-old Asian woman is referred and pathologic clues. The identification of key references,
for a gradual 10-pound weight gain and new- target autoantigens in adult idiopathic MN, including the founda-
onset leg edema, as well as protein (3+) and tional literature that
starting with the description in 2009 of anti- led to current clinical
trace blood on urine analysis. She denies
bodies against the M-type PLA2R, was a approaches.
recent infections, joint pains, or new rashes.
Physical examination is significant for blood
turning point in our understanding of this
pressure 145/85 mm Hg, normal findings of disease and rapidly led to new methods for
heart and lung examinations, but pitting edema diagnosis and monitoring.
(2+). Laboratory testing shows a serum creat- The nomenclature and classification of MN
inine level of 1.03 mg/dL, serum albumin level is rapidly evolving as an increasing number of
of 3.1 g/dL, total cholesterol level of 278 mg/ target antigens are being identified and new
dL, and total urinary protein-creatinine ratio of phenotypes of disease become apparent. We
6.7 g/g. She is up to date on her age- will use the term “primary” to describe those
appropriate cancer screening, and antinuclear subtypes of disease in which there is a hu-
antibody, hepatitis serologic findings, and moral autoimmune response to a normal
complement levels are within the normal
podocyte antigen in the absence of secondary
ranges. You initiate supportive care for her
nephrotic syndrome with renin-angiotensin
features or etiologies of disease. “Secondary”
system inhibition, diuretics and sodium restric- MN refers to cases that arise in the setting of
tion, and a statin. systemic processes such as infection, malig-
nancy, or drug exposure in which treatment
Question 1: Which additional test would of the underlying disorder is expected to lead
be most helpful at this point? to the resolution of the MN. The subtype of
a) Kidney biopsy MN should be specified by underlying antigen

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Alsharhan and Beck Jr

Box 1. Common Causes of Primary, Secondary, or Alloimmune Alloimmune

MN
Primary MNa
• PLA2R-associated
• THSD7A-associated Secondary
• NELL-1–associated
• Sema3B-associated
• Uncharacterized
Secondary MN
• Autoimmune/collagen-vascular disease: SLE and mixed EXT1/EXT2
connective tissue disease (includes EXT1/EXT2-associated), PLA2R
Sjogren’s, thyroiditis, sarcoidosis, dermatitis herpetiformis
• Infection: HBV and HCV, malaria, secondary or congenital NELL-1
syphilis, leprosy
• Drugs, toxins, other adulterants: NSAIDs, gold salts, penicil- Uncharacterized
lamine, mercury, cationic bovine serum albumin (infant
formula) Sema3B
• Malignancy: more commonly solid-organ carcinomas (lung, THSD7A
breast, colon, and kidney), NHL, leukemia; rarely associated
with THSD7A expression in tumor; NELL-1–associated MN Figure 1. Spectrum of disease within the larger pathologic clas-
linked to underlying malignancy sification of MN according to the observation that secondary en-
Alloimmune MN tities represent approximately 30% of all MN. The percentages of
• Antenatal alloimmune MN caused by anti-NEP antibodies MN associated with the newer antigens NELL-1, Sema3B, and
• De novo MN in kidney allograft EXT1/EXT2 are estimates, and larger cohorts are needed to
• Graft-vs-host disease determine the true prevalence of these subtypes of MN. The
Abbreviations: EXT1/EXT2, Exostosin 1/Exostosin 2; HBV, hepatitis B virus; uncharacterized group reflects those cases of presumed primary
HCV, hepatitis C virus; MN, membranous nephropathy; NELL-1, neural epidermal MN in which the target antigen has yet to be described.
growth factor-like 1; NEP, neutral endopeptidase; NHL, non-Hodgkin lymphoma;
NSAID, nonsteroidal anti-inflammatory drug; PLA2R, phospholipase A2 receptor;
Sema3B, semaphorin-3B; SLE, systemic lupus erythematosus; THSD7A,
thrombospondin type 1 domain-containing 7A. in adult primary MN. THSD7A is a 250-kDa multidomain
a
Primary MN reflects an autoimmune process that targets an intrinsic podocyte
protein (see text). NELL-1–associated MN is included here even though the protein expressed at the basal surface of the podocyte
source of the antigen is not yet clear. Several more target antigens are under immediately beneath the slit diaphragm. Autoantibodies
investigation but are listed here as uncharacterized.
against THSD7A account for 1%-3% of MN cases in
Western countries. THSD7A is also overexpressed by
certain malignancies and may incite a humoral reaction
against tumor and glomerular THSD7A, leading to MN.
(eg, PLA2R-associated MN) when feasible, as we are Although the exact mechanism of how anti-THSD7A an-
learning that certain MN subtypes may have features that tibodies lead to the nephrotic state of MN is not known, in
blur the distinction between primary and secondary dis- a mouse model, human and rabbit anti-THSD7A anti-
ease (Box 1; Fig 1). bodies have been observed to cause disease.

Antigens Implicated in Primary MN Neural Epidermal Growth Factor-Like-1

PLA2R Autoantibodies to the 90-kDa secreted protein neural
PLA2R is a 180-kDa transmembrane glycoprotein epidermal growth factor-like 1 (NELL-1) are a recent
expressed by the human podocyte, where its precise addition to the MN disease spectrum and may be more
function is not clear. Autoantibodies to PLA2R may be prevalent than anti-THSD7A antibodies. NELL-1 was
responsible for primary MN in as many as 80% of patients identified through a mass spectrometric approach that
(reflecting approximately 55% of all MN cases found on identified the enrichment of peptides from candidate an-
biopsy). The discovery of this antibody has allowed a tigens within laser-capture microdissected glomeruli from
serologic assay for diagnosis, obviating kidney biopsy in patients with uncharacterized MN. The evidence for NELL-
certain situations. Data are highly suggestive of a causal 1 being a podocyte protein is not as strong as that for
relationship between anti-PLA2R antibody (henceforth PLA2R and THSD7A. NELL-1–associated MN was identified
simply anti-PLA2R) and MN pathogenesis, but further in approximately 16% of PLA2R-negative MN cases
studies are needed to ascertain this relationship. without any identifiable secondary associations, repre-
senting an approximate 2.5% prevalence across the entire
THSD7A spectrum of MN (Fig 1). Unlike PLA2R- and THSD7A-
Thrombospondin type 1 domain-containing 7A (THSD7A) associated MN, autoantibodies in NELL-1–associated MN
was the next podocyte protein identified as a target antigen are immunoglobulin (Ig) G1-predominant. The current

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 Alsharhan and Beck Jr

literature suggests a connection between NELL- autoantibodies. The enzyme-linked immunosorbent assay
1–associated MN and malignancy. reports the titer of anti-PLA2R IgG and is useful for initial
detection of anti-PLA2R as well as monitoring the change
Semaphorin-3B in titer over time. Values <14 RU/mL are considered
Further study of uncharacterized MN cases by laser-capture negative by the manufacturer, but some studies have
microdissection mass spectrometry (LCM-MS) revealed shown that levels in the 2-14 RU/mL range may represent
another MN antigen, semaphorin-3B (Sema3B), with very low titers of anti-PLA2R that can be verified in other
associated circulating autoantibodies. Anti-Sema3B auto- assays. The indirect immunofluorescence (IF) test uses cells
antibodies were found to be predominantly IgG1 and transfected with recombinant human PLA2R to assay for
detected the protein on immunoblot only under reducing the antibodies. Although more sensitive than the enzyme-
conditions, suggesting the existence of a potentially cryptic linked immunosorbent assay for low-titer anti-PLA2R, the
epitope. Of note, most cases were identified in infants or indirect IF test yields only semiquantitative titers (eg, 1:10,
children, and the deposits were present in a segmental 1:100, 1:300). These tests for circulating antibodies
pattern in the glomerular tuft and occasionally in the complement the histopathologic stains for the accumulated
tubular basement membrane as well. antigen within the immune deposits on biopsy (see Kidney
Pathology).
Exostosin 1/Exostosin 2 The answer to question 1 is (c), as it represents a
Detection of this protein complex within immune deposits noninvasive test that can establish the diagnosis of PLA2R-
is associated with systemic autoimmune diseases such as associated MN and provide a baseline titer. Kidney biopsy
lupus (class V lupus nephritis; see Secondary MN). Circulating (a) should be considered if the anti-PLA2R test result is
autoantibodies to Exostosin 1/Exostosin 2 (EXT1/EXT2) negative. There are no clinical signs to warrant immediate
have not been identified, but histopathologic staining for testing for antiphospholipid antibodies (d) or the need for
this complex may be helpful to identify certain cases of duplex ultrasonography (b) to look for a renal vein
MN in the setting of these autoimmune disorders. thrombosis.

Secondary MN Additional Readings

As many as 30% of all biopsy diagnoses of MN represent ➢ Beck LH Jr, Bonegio RG, Lambeau G, et al. M-type phospholi-
disease that is most likely secondary to autoimmune/ pase A2 receptor as target antigen in idiopathic membranous
collagen vascular disease; infections; drugs, toxins, or nephropathy. N Engl J Med. 2009;361(1):11-21. +ESSENTIAL
other adulterants; or malignancy (Box 1). The precise READING
pathologic mechanisms and target antigens responsible for ➢ Tomas NM, Beck LH Jr, Meyer-Schwesinger C, et al. Thrombo-
spondin type-1 domain-containing 7A in idiopathic membranous
disease are less well defined in secondary MN. It is
nephropathy. N Engl J Med. 2014;371(24):2277-2287.
commonly assumed that circulating antigens (endogenous ➢ Sethi S, Madden BJ, Debiec H, et al. Exostosin 1/exostosin 2-
or exogenous), immune complexes, or even monoclonal associated membranous nephropathy. J Am Soc Nephrol.
immunoglobulins may become “planted” on the sub- 2019;30(6):1123-1136.
epithelial side of the glomerular basement membrane ➢ Sethi S, Debiec H, Madden B, et al. Neural epidermal growth
(GBM) by virtue of size and/or charge and thereby initiate factor-like 1 protein (NELL-1) associated membranous ne-
immune complex formation in the subepithelial position. phropathy. Kidney Int. 2020;97(1):163-174.
➢ Sethi S, Debiec H, Madden B, et al. Semaphorin 3B-associated
membranous nephropathy is a distinct type of disease predom-
Alloimmune MN
inantly present in pediatric patients. Kidney Int.
Finally, there are alloimmune etiologies of MN (antenatal 2020;98(5):1253-1264.
and de novo posttransplantation MN) in which in-
consistencies between host and donor antigens and hu-
moral immune systems lead to the phenotype of MN. Epidemiology, Clinical Features, and Natural
History
Laboratory Testing for Circulating Epidemiology
Autoantibodies MN is one of the most common causes of nephrotic syn-
The identification of the target antigen PLA2R and the drome in White, nondiabetic adults. Despite this general-
ability to detect and monitor circulating anti-PLA2R auto- ization, it can be found in all races and ethnicities. MN has
antibodies has established a paradigm by which to an incidence of approximately 1 case per 100,000 persons
approach MN for clinical purposes and to conceptualize its per year. PLA2R-associated MN is typically more common
pathophysiology. It is expected that the same principles in male patients, although some of the more recently
will apply for the more recently discovered autoantibodies. described subtypes such as THSD7A- or NELL-1–associated
There are currently 2 tests approved by the US Food and MN may have less of a male predominance.
Drug Administration for clinical use to detect anti-PLA2R The median age of onset is in the early 50s, although
to assess the presence and amount of circulating there is a wide distribution of age at presentation ranging

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from children to the very elderly. In the pediatric popu- disease course after an incidental finding of proteinuria.
lation, primary MN is quite rare, and secondary forms such Urinary sediment usually shows evidence of lipiduria with
as those associated with hepatitis B virus (HBV) infection oval fat bodies and fatty casts (Fig 2). Microscopic he-
or lupus should be considered. In very young children, maturia is not uncommon but is usually trace or 1+ (unless
Sema3B- or cationic bovine serum albumin–associated MN renal vein thrombosis is present, in which case it can be
should also be considered. more significant). Red blood cell casts are not seen,
although fatty casts, with their pleiomorphic circular fat
Clinical Features droplets, can sometimes be mistaken for such casts.
The clinical presentations of MN from a renal standpoint Blood pressure is normal at presentation in 70% of
are similar in primary and secondary forms of disease and patients, and glomerular filtration rate (GFR) is preserved
often involve features of the nephrotic syndrome: heavy in most patients. If GFR is or becomes reduced, one should
proteinuria, hypoalbuminemia, edema or anasarca, consider a coexisting diagnosis such as renal vein throm-
hyperlipidemia, and lipiduria. These features tend to bosis, concomitant interstitial nephritis or crescentic
develop slowly and can be overlooked for months, unlike glomerulonephritis, or an iatrogenic effect of therapy
other more explosive causes of nephrotic syndrome such caused by overdiuresis or introduction of inhibitors of the
as minimal change disease. In its earliest stages, MN can renin angiotensin system or the calcineurin pathway.
have an indolent course. Conceptually, this is due to the Hyperlipidemia is common in the presence of nephrotic-
gradual but progressive growth of immune deposits and range proteinuria. Venous thromboembolic events may
resultant podocyte injury (see Pathophysiology). Proteinuria be the initial reason why a patient presents for clinical
has typically been ongoing for months to even years at a attention (see Anticoagulation).
subclinical level before diagnosis. The degree of protein- Clinical clues to help distinguish primary from sec-
uria at presentation is variable, ranging from subnephrotic ondary causes of MN can often be obtained with a careful
to more than 20 g/d. history, laboratory studies, and histologic features on bi-
Eighty percent of patients present with nephrotic syn- opsy. In some cases, the offending agent or the underlying
drome, and the remainder are diagnosed earlier in the disease can predate the diagnosis of MN by months to

A B

Figure 2. Examples of lipiduria from a patient with MN. Oval fat bodies in a cluster (A) or embedded within a cast (B). (C) Fatty cast
with a single oval fat body at the tip. Note that the lipid droplets are of unequal size, which can distinguish a fatty cast from a red blood
cell cast, in which the cells are more similar in size.

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years, whereas, in other cases (malignancy or lupus), the ➢ van den Brand JA, van Dijk PR, et al. Long-term outcomes in
nephrotic state induced by MN may be the presenting idiopathic membranous nephropathy using a restrictive treatment
clinical feature of the underlying disease. strategy. J Am Soc Nephrol. 2014;25(1):150-158.

Natural History Kidney Pathology

One of the most vexing issues with MN is its highly var-
The characteristic histopathologic features of MN seen by
iable clinical course and the few baseline parameters that
light microscopy, IF, and electron microscopy are shown
can predict its ultimate course. Even patients in a highly
in Fig 3. These changes are due to the immune complexes
nephrotic state have the potential to undergo spontaneous
of antigen, immunoglobulin, and complement compo-
remission, but are often treated with immunosuppression
nents that form beneath the podocyte (ie, are sub-
to avoid the adverse consequences of the prolonged
epithelial) or to the reaction of the podocyte to injury,
nephrotic state. On average, one third of patients will
which includes simplification, loss of slit diaphragms and
exhibit spontaneous remission (slightly more when base-
foot processes, and production of new matrix material
line proteinuria level is <8 g/d), but it may take 15-20
between and around the deposits. These features may be
months to achieve a partial remission and 25-40 months to
more or less pronounced depending on when during the
reach a complete remission. Any type of remission,
course of the disease the biopsy was performed. Keep in
whether spontaneous or induced by immunosuppressive
mind that “membranous nephropathy” is merely a
therapy, is beneficial in terms of kidney survival. In
descriptor for a particular lesion as detected by histopa-
contrast, cases that remain nephrotic typically progress to
thology and does not by itself refer to a single disease or
advanced kidney disease or kidney failure. Ten-year
common pathophysiology.
follow-up data from 2 independent trials demonstrate a
35%-40% rate of reaching kidney failure in patients treated Light Microscopy
conservatively, compared with an 8%-11% rate in patients
Early in the course of the disease, the only change noted
treated with an alkylating agent/corticosteroid regimen.
may be rigid-appearing capillary walls without evidence of
Because of the slow time frame in which MN resolves,
deposits. The Jones silver stain highlights extracellular
patients often experience a partial remission (>50%
matrix elements of the GBM but does not stain the immune
decrease in proteinuria from baseline to <3.5 g/d) well
deposits. With very close observation, areas of trans-
before they experience a complete remission (<0.3 g/d).
lucency (“craters”) representing the deposits might be
Therefore, long-term follow-up (≥5 years) is needed in
observed early in the course of the disease. As the deposits
any given trial to determine the full rate of complete re-
persist and grow in size, increased matrix is deposited by
missions. Relapses of MN occur in approximately 25%-
the injured podocyte between the deposits and results in
30% of cases, often years after a complete remission. Rates
spike-like projections seen by silver stain. As the reaction
of relapse are higher after partial clinical remission and
progresses, the matrix encircles the deposits, resulting in a
may reflect incompletely-suppressed immunologic activity
lace-like splitting or laddering appearance of the GBM.
at the time immunosuppression is withdrawn.
In longstanding disease, signs of chronic damage
In secondary MN, treatment of the underlying disease
including glomerular sclerosis, interstitial fibrosis, and
or cessation of the offending agent should result in even-
tubular atrophy can be found. These features are associated
tual remission, with the understanding that it will take
with an inferior kidney prognosis. Coexisting conditions
months for the proteinuria to dissipate. In class V
such as glomerular crescent formation or tubulointerstitial
(“membranous”) lupus nephritis, prognosis depends on
nephritis may be noted and may require additional sero-
whether it is found alone or in combination with another
logic testing.
class of lupus nephritis. In general, isolated class V lupus
nephritis has an excellent prognosis, with reported 10-year IF and Immunohistochemistry
kidney survival rates of 72%-98%.
IF is generally more sensitive than light or electron mi-
Additional Readings croscopy in detecting early deposits. For routine cases, the
➢ Donadio JV Jr, Torres VE, Velosa JA, et al. Idiopathic membranous
renal pathologist will stain frozen kidney biopsy tissue
nephropathy: the natural history of untreated patients. Kidney Int. sections for IgG, IgA, IgM, C3, and C1q. In primary MN,
1988;33(3):708-715. IgG and C3 are nearly always positive, appearing in a fine
➢ Schieppati A, Mosconi L, Perna A, et al. Prognosis of untreated granular, peripheral capillary loop pattern. The ability to
patients with idiopathic membranous nephropathy. N Engl J stain for PLA2R and THSD7A by IF or, on fixed tissues,
Med. 1993;329(2):85-89. with immunohistochemistry has become an important
➢ Hladunewich MA, Troyanov S, Calafati J, et al. The natural history
adjunctive test to aid in the classification of MN. Less
of the non-nephrotic membranous nephropathy patient. Clin J
Am Soc Nephrol. 2009;4(9):1417-1322.
frequent and emerging antigens such as NELL-1 or Sema3B
➢ Polanco N, Gutierrez E, Covarsí A, et al. Spontaneous remission can be assayed in a similar manner. The target antigens,
of nephrotic syndrome in idiopathic membranous nephropathy. J which accumulate over time with immunoglobulin within
Am Soc Nephrol. 2010;21(4):697-704. +ESSENTIAL READING the immune deposits, exhibit a staining pattern identical to

444 AJKD Vol 77 | Iss 3 | March 2021

Alsharhan and Beck Jr

A B C

D E F

Figure 3. Kidney pathology of MN. Jones silver stain (A and B) reveals thickening of the GBM in A. A higher-resolution image (B)
reveals “spikes” of positively staining basement membrane reaction (red arrows) and craters (yellow arrows) representing the nega-
tively staining immune complexes. (C) Immunofluorescence staining for IgG with granular subepithelial and intramembranous immune
deposits. Representative electron microscopy images are shown in D–F. (D) Mixed stage 1 (thin arrow) and 2 (thick arrow) deposits
abutting an effaced podocyte. (E) Mixed intramembranous stage 3 (thin arrow) and electron-lucent stage 4 (thick arrows). (F) Tubu-
loreticular inclusion (arrow) in an endothelial cell, characteristic of interferon-mediated processes such as systemic lupus
erythematosus.

those of IgG and C3. Although most MN lesions are global predominant diseases, although a significant proportion
and affect all portions of the glomerular tuft, some sub- of NELL-1–associated cases are associated with malignancy.
types (such as NELL-1-associated MN) may exhibit
segmental lesions. Electron Microscopy
Features suggestive of a secondary etiology of MN The Ehrenreich-Churg stage of the electron-dense immune
include a moderate to strong presence of IF reactants deposits is assessed by electron microscopy. It is not un-
beyond C3 and IgG, such as the “full-house” pattern (IgG/ common to find mixed stages of deposits: stage 1 (small
IgA/IgM and C3/C1q) often seen in class V lupus and discrete deposits immediately beneath the podocyte),
nephritis. The presence of EXT1/EXT2 staining in a fine stage 2 (deposits separated from each other by newly
granular capillary-loop pattern can be seen in class V lupus formed matrix material), stage 3 (deposits completely
or similar systemic autoimmune conditions. Another encircled by matrix), and stage 4 (electron-lucent; reflect
recently described entity is membranous-like glomerul- resorption of the immune complexes).
opathy with masked IgGκ light-chain deposits for which Podocyte foot processes will show effacement and loss
pronase digestion is required to expose the IgG deposits. of slit diaphragms, and the apical surface will typically
Many of these cases were associated with systemic auto- show significant microvillous change. The presence of
immune diseases. subendothelial or significant mesangial deposits, as well as
Staining for IgG subclasses can assist in the determina- the presence of tubuloreticular structures in the endothe-
tion of etiology. Although there is usually a mixture of IgG lium, is suggestive of secondary disease.
subclasses in any type of MN, IgG4 tends to be predomi-
nant or codominant in primary forms of MN. In contrast, Additional Readings
in secondary causes such as lupus or malignancy, IgG1, ➢ Larsen CP, Messias NC, Silva FG, Messias E, Walker PD.
Determination of primary versus secondary membranous glo-
IgG2, or IgG3 may predominate. It is not yet clear why
merulopathy utilizing phospholipase A2 receptor staining in renal
MN associated with NELL-1 or Sema3B are IgG1- biopsies. Mod Pathol. 2013;26(5):709-715.

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➢ Huang CC, Lehman A, Albawardi A, et al. IgG subclass staining

Pathophysiology of Primary MN
in renal biopsies with membranous glomerulonephritis indicates
subclass switch during disease progression. Mod Pathol. Overview
2013;26(6):799-805. Decades ago, studies in the Heymann nephritis rat model
➢ Fogo AB, Lusco MA, Najafian B, Alpers CE. AJKD atlas of renal
pathology: membranous nephropathy. Am J Kidney Dis.
of MN established a paradigm for the underlying patho-
2015;66(3):E15-E17. physiology of MN. Rats express megalin (LRP2) both in
the proximal tubular brush border and (unlike humans) in
podocytes. When anti-megalin antibodies were introduced
Genetics
actively or passively, there was aggregation of immune
Like many autoimmune diseases, there is a heritable complexes at the basal surface of the podocyte. Comple-
component of MN and a very strong link to the human ment activation led to assembly and insertion of the ter-
leukocyte antigen (HLA) locus on chromosome 6, with minal complement components C5b-9 into the podocyte
associations with certain HLA class II phenotypes common cell membrane, resulting in sublethal injury, proteinuria,
in the White population such as DR3. A European genome- and eventually elaboration of new basement membrane
wide association study of 556 cases of idiopathic MN material.
indeed demonstrated a significant association of disease Observations that megalin is not expressed by the hu-
with a single-nucleotide variation in the class II HLA- man podocyte led to a decades-long search culminating in
DQA1 locus. A second peak of association mapped to an the identification of neutral endopeptidase in a rare form
intronic region of PLA2R1. Homozygosity for both risk of alloimmune antenatal MN in 2002 (see below) and
alleles conferred an odds ratio for disease of nearly 80, PLA2R as the major antigen in adult MN in 2009. In
showing strong interaction between the alleles. keeping with what we have learned from the Heymann
Larger cohorts from international populations, espe- nephritis model, antibodies targeting these and other
cially China, have shown associations at other HLA class II subsequently identified podocyte antigens bind these
loci such as DRB1 and DRB3. The allelic risk variants have proteins in situ, leading to the formation and accumulation
been mapped to positions within the peptide-binding of subepithelial immune deposits.
groove of the class II HLA molecule. It is suggested that The main target antigens identified to date in primary
genetic risk at the HLA class II locus can enhance or MN are PLA2R, THSD7A, NELL-1, and Sema3B, with even
discourage presentation of antigenic peptides derived from more in the pipeline. Although PLA2R, THSD7A, and
PLA2R to the immune system. Sema3B are clearly proteins expressed by the human
A recent very large international genome-wide associ- podocyte, NELL-1 is less convincingly so in the native state
ation study has confirmed previous findings about a ge- but could potentially be induced as a “neoantigen.”
netic interaction with the PLA2R1 locus and class II HLA Circulating antibodies to other intracellular antigens such
genes, with risk alleles in both East Asian and European as aldose reductase, superoxide dismutase, and α-enolase
populations mapping to the peptide-binding region of have been detected in primary MN and may also represent
HLA DRB1. The intronic single-nucleotide variation within neoantigens that secondarily become targeted after cellular
PLA2R1 is closely linked to an enhancer region that seems injury. What remains a mystery is how tolerance to these
to direct increased expression of the gene in kidney tissue. normal proteins is broken. Possible triggers that have been
Important for further insights into the immunologic proposed include molecular mimicry due to exposure to
pathogenesis of MN, 2 new highly significant peaks of microbial antigens or environmental exposures such as air
association were identified within NFKB1 and IRF4, genes pollution with high concentrations of particles smaller
with important roles in the regulation of immune than 2.5 μm.
responses. We know from Heymann nephritis that epitope
spreading from amino-terminal portions of the antigen to
Additional Readings more distal regions is necessary for development of dis-
➢ Stanescu HC, Arcos-Burgos M, Medlar A, et al. Risk HLA-DQA1
ease. Similar evidence exists for PLA2R and THSD7A. The
and PLA(2)R1 alleles in idiopathic membranous nephropathy.
N Engl J Med. 2011;364(7):616-626.
immunodominant epitope (recognized in every PLA2R-
➢ Cui Z, Xie LJ, Chen FJ, et al. MHC Class II risk alleles and amino associated case of MN with circulating antibodies) lies
acid residues in idiopathic membranous nephropathy. J Am Soc within the amino-terminal cysteine-rich domain. Howev-
Nephrol. 2017;28(5):1651-1664. er, patients often have additional autoantibody reactivity
➢ Le WB, Shi JS, Zhang T, et al. HLA-DRB1*15:01 and HLA- with epitopes in the C-type lectin-like domains 1, 7, and 8.
DRB3*02:02 in PLA2R-related membranous nephropathy. J Am Both epitope spreading and high titers of anti-PLA2R have
Soc Nephrol. 2017;28(5):1642-1650.
been associated with fewer remissions and more adverse
➢ Xie J, Liu L, Mladkova N, Li Y, et al. The genetic architecture of
membranous nephropathy and its potential to improve non-
kidney outcomes; however, there is controversy whether
invasive diagnosis. Nature Comm. 2020;11:1600. these 2 risk factors are independent of each other.

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Role of Complement Secondary MN

An apparent paradox for subtypes of primary MN like Nonrenal (exogenous) antigens have been associated
PLA2R-associated MN is that the predominant IgG4 sub- with specific forms of secondary MN. These include
class does not activate the classical complement pathway. antigens derived from infectious causes (hepatitis B vi-
Although C3 is typically strong on IF staining of the bi- rus, treponemes in syphilis), inflamed or malignant
opsy, C1q is usually weak or absent, suggesting a minor tissues (thyroglobulin in thyroiditis, tumor antigens),
role for the classical pathway. There is experimental evi- and even ingested substances such as cationic bovine
dence that IgG4 may activate the lectin pathway of com- serum albumin that may become derivatized in the
plement activation. MN subtypes with more predominant manufacture of infant formula. It seems likely that free
IgG1 (such as EXT1/EXT2-, NELL-1–, and Sema3B- antigen becomes localized beneath the podocyte, where
associated MN) may have more activation of the classical it can serve as a nidus for immune complex formation,
pathway. No matter which pathway initiates the comple- although there may also be circulating immune com-
ment cascade, the alternative pathway is most likely the plexes. The pathogenesis of HBV-associated MN has
main maintenance pathway that amplifies complement been attributed to subepithelial deposition of immune
activation and results in formation of the podocytopathic complexes of hepatitis B e antigen and anti–hepatitis B e
membrane attack complex C5b-9. antibodies. The EXT1/EXT2 complex was recently
Animal models in which relevant antigens such as identified as a biomarker and potential antigen in a form
PLA2R (which is not normally expressed by the mouse of PLA2R-negative MN associated with systemic auto-
podocyte) and THSD7A were used have not yet convinc- immunity such as lupus. The contribution of these
ingly supported a major role for complement in these proteins to pathogenesis has not been established.
systems. However, understanding the precise role of The link between MN and malignancy has long been
complement in the initiation and maintenance of the dis- controversial. In some cases, there could merely be coin-
ease will be important as more therapeutic agents become cidence of 2 disease processes in an older demographic
available to target these pathways. Although controlling group. In other circumstances, a humoral immune
the process of autoantibody production will be paramount response to tumor antigens or another etiologic relation-
in any treatment scheme, being able to halt glomerular ship may exist. Tumoral overexpression of THSD7A has
damage through inhibition of the complement system may been demonstrated as a possible link between certain
help stop disease progression while other therapies have cancers and THSD7A-associated MN. In an instructive case,
time to work. Hoxha et al demonstrated localized polysomy in a gall-
bladder cancer leading to THSD7A overexpression and a
Additional Readings local lymph-node reaction to THSD7A. They speculate that
➢ Ronco P, Debiec H. Pathophysiological advances in membra- this sequence of events led to the development of a hu-
nous nephropathy: time for a shift in patient's care. Lancet. moral response to THSD7A that consequently led to the in
2015;385(9981):1983-1992. situ glomerular immune deposits causing MN. A signifi-
➢ Seitz-Polski B, Dolla G, Payr
e C, et al. Epitope spreading of
autoantibody response to PLA2R associates with poor prognosis
cant proportion of NELL-1 MN cases are also associated
in membranous nephropathy. J Am Soc Nephrol. with malignancy.
2016;27(5):1517-1533. +ESSENTIAL READING
➢ Tomas NM, Hoxha E, Reinicke AT, et al. Autoantibodies against Alloimmune MN
thrombospondin type 1 domain-containing 7A induce membra- Alloimmunity develops when there is a discrepancy
nous nephropathy. J Clin Invest. 2016;126(7):2519-2532. between host and recipient antigens and is characterized
+ESSENTIAL READING
by an immune response to a previously unfamiliar an-
➢ Meyer-Schwesinger C, Tomas NM, Dehde S, et al. A novel
mouse model of phospholipase A2 receptor 1-associated
tigen. This is common in the setting of organ trans-
membranous nephropathy mimics podocyte injury in patients. plantation and likely reflects the late development of de
Kidney Int. 2020;97(5):913-919. novo MN in kidney transplants (see below). The first
➢ Ma H, Sandor DG, Beck LH Jr. The role of complement in evidence of circulating antibodies to a distinct human
membranous nephropathy. Semin Nephrol. 2013;33(6):531- podocyte protein is also an example of alloimmunity.
542. Antenatal alloimmune MN has been described in
mothers genetically deficient in neutral endopeptidase
who are immunized against this protein from a previous
Pathophysiology of Secondary and Alloimmune pregnancy and miscarriage. The circulating anti–neutral
MN endopeptidase alloantibodies cross the placenta and
The pathophysiology of secondary and alloimmune forms target neutral endopeptidase on the fetal podocytes such
of MN shares basic features with primary MN, such as the that the neonate is born with MN. The infant typically
presence of complement-activating subepithelial deposits, recovers quickly when the maternal antibodies have
but, as a whole, we know less about precise mechanisms. cleared.

AJKD Vol 77 | Iss 3 | March 2021 447

 Alsharhan and Beck Jr

Additional Readings Figure 4 describes the 2 courses of disease (immunologic/

➢ Vivarelli M, Emma F, Pell
e T, et al. Genetic homogeneity but IgG serologic and clinical) and highlights the temporal lag
subclass-dependent clinical variability of alloimmune membra- between changes in autoantibody and clinical manifesta-
nous nephropathy with anti-neutral endopeptidase antibodies. tions. Although this conceptual model is based on anti-
Kidney Int. 2015;87(3):602-609. PLA2R, it will likely hold true for the more recently
➢ Debiec H, Lefeu F, Kemper MJ, et al. Early-childhood membra-
identified autoantibodies in MN.
nous nephropathy due to cationic bovine serum albumin. N Engl
J Med. 2011;364(22):2101-2110. Irrespective of the exact mechanism by which tolerance
➢ Hoxha E, Wiech T, Stahl PR, et al. A mechanism for cancer- is broken, low levels of anti-PLA2R are produced, begin to
associated membranous nephropathy. N Engl J Med. circulate, and soon find abundant antigen in the glomer-
2016;374(20):1995-1996. +ESSENTIAL READING ulus, where they start to form tiny subepithelial deposits.
The affinity of anti-PLA2R for the amino-terminal epitope
of PLA2R is quite strong, and much of the low-level
Relationship Between Immunologic and Clinical antibody is likely cleared from the circulation, making it
Course of Disease nearly impossible to detect circulating autoantibody at this
Case, continued: The anti-PLA2R titer for your patient is
time point (the “kidney-as-a-sink” hypothesis). A kidney
185 RU/mL. After discussing with her the likely diagnosis, biopsy would show these very early deposits of IgG and
she still would like to confirm the diagnosis by kidney biopsy PLA2R but is virtually never performed because patients are
in case you and she decide on immunosuppressive treat- asymptomatic at this point.
ment in the future. The biopsy is uncomplicated and shows As the humoral response to PLA2R grows and more
stage 2 MN with strong staining of the deposits for antibody-antigen complexes are formed, 2 things occur:
PLA2R. At her return visit in 3 months, repeat testing reveals anti-PLA2R becomes detectable in increasing amounts in
a serum creatinine level of 1.1 mg/dL, serum albumin level of the circulation and sufficient damage to the podocyte has
2.9 g/dL, and urinary protein-creatinine ratio of 7.6 g/g occurred that proteinuria appears. The speculation that
despite 100 mg losartan. Her blood pressure is better autoantibodies and nascent deposits predate clinically sig-
controlled at 132/78 mm Hg, and her leg edema has
nificant proteinuria is based on observations with recurrent
resolved with diuretic treatment. A repeat anti-PLA2R mea-
surement is 312 RU/mL.
MN in the kidney allograft (see below). As immune de-
posits grow and glomerular damage worsens, patients ul-
Question 2: What do you now recommend? timately come to clinical attention as a result of the
a. Watchful waiting with 6-month follow-up to see if her uri- nephrotic syndrome. Significant immunologic disease ac-
nary protein-creatinine ratio has decreased to <4 g/g tivity (as measured by anti-PLA2R) can be found in the
b. Initiation of immunosuppression because spontaneous majority of patients at the time of clinical presentation.
remission is unlikely with increasing anti-PLA2R titers Podocyte foot processes are typically fully effaced, and the
c. Repeat kidney biopsy to assess for progression to MN immune deposits and resulting membrane reaction
with stage 3 deposits markedly distort the GBM. These structural changes to the
For the answer to the question, see the following text. GBM are likely the features that cause such a slow clinical
resolution of the disease, even after the production of anti-
PLA2R has ceased and the antibodies decrease and disap-
The ability to measure specific autoantibodies in MN in pear from the circulation.
clinical practice has opened a new window onto the In the process of spontaneous or treatment-induced
immunologic course of disease. Understanding this rela- remission, anti-PLA2R levels will decrease in a manner
tionship is crucial for the clinical management of MN. that precedes and predicts the clinical response. In those

Patients are usually missed in

this period due to insidious
onset of MN Disease Resolution Period
↓
Proteinuria
Anti-PLA2R

partial remission
detectable serum
anti-PLA2R complete remission

Anti-PLA2R - + + + + - -
Tissue PLA2R +/- + + + + + +

Kidney as a sink
hypothesis

Figure 4. Schematic representation of the immunologic and clinical courses of disease in PLA2R-associated MN.

448 AJKD Vol 77 | Iss 3 | March 2021

Alsharhan and Beck Jr

patients in whom anti-PLA2R ultimately disappears, the Question 3: Which therapy is most likely to achieve a
proteinuria continues to decrease to a point of a partial complete remission at 24 months in this patient?
remission, followed later by a complete remission in the a) Prednisone
absence any permanent structural changes to the glomer- b) Cyclosporine
ulus or tubulointerstitium from chronic damage. Those c) Mycophenolate
patients in whom circulating autoantibody has not been d) Rituximab
eliminated by the end of treatment are at risk for a rapid For the answer to the question, see the following text.
resurgence of immunologic and clinical disease activity.
This is the rationale for monitoring anti-PLA2R every few
months during and after the intended course of therapy is Overview
complete. It may take years before the GBM architecture All patients with MN should receive supportive manage-
has normalized to a sufficient level to allow a complete ment with antiproteinuric measures including
remission of proteinuria. angiotensin-converting enzyme inhibitors or angiotensin-
Understanding that autoantibody levels must decrease receptor blockers, optimal blood pressure control, dietary
and disappear before any significant clinical remission can sodium restriction, and diuretic therapy as needed (oral vs
occur is the reason why high anti-PLA2R titers are associ- intravenous depending on the severity of the nephrotic
ated with increased severity of disease, adverse kidney syndrome). Cholesterol-lowering therapies are often
outcomes, and decreased likelihood of remission. The necessary as a result of hyperlipidemia. Prophylactic anti-
longer proteinuria continues, the higher the chance of coagulation to prevent venous and arterial thromboem-
developing decreased GFR. In contrast, low or undetect- bolisms will be discussed below.
able anti-PLA2R (in a patient known to have PLA2R-asso- Decisions regarding the initiation of immunosuppres-
ciated disease by virtue of biopsy staining) is a good sive therapy should be made in consideration of the risks
prognostic sign, reflective of a higher chance of remission of treatment versus those of disease progression, taking
and improved kidney outcomes. These patients are nearly into consideration baseline GFR, degree of proteinuria,
always at the end of their disease course (Fig 4, right), as and autoantibody titer. An updated algorithm based on
early-stage disease is usually clinically silent. the upcoming revision of the KDIGO (Kidney Disease:
The answer to the question is (b), as the patient’s anti- Improving Global Outcomes) guideline for glomerulo-
PLA2R titer, serum albumin, and urine protein levels are all nephritis is shown in Fig 5. Patients are first classified as
worsening. Spontaneous remission with significant being at low, moderate, high, or very high risk for dis-
reduction of proteinuria to less than 4 g/g (a) is unlikely ease progression. Based on that classification, a clinical
in the near future. A repeat biopsy (c) is unnecessary decision can be made about watchful waiting versus
because increasing anti-PLA2R already indicates ongoing immediate treatment with immunosuppression. The tra-
immunologic activity. jectory of anti-PLA2R, followed every 1-3 months ac-
cording to clinical context, is important as well: patients
Additional Readings in a nephrotic state with increasing autoantibody titers
➢ Beck LH Jr, Fervenza FC, Beck DM et al. Rituximab-induced would be expected to worsen clinically and might war-
depletion of anti-PLA2R autoantibodies predicts response in
membranous nephropathy. J Am Soc Nephrol.
rant more rapid initiation of immunosuppressive treat-
2011;22(8):1543-1550. ment, whereas decreasing titers or disappearance of anti-
➢ Hoxha E, Thiele I, Zahner G, et al. Phospholipase A2 receptor PLA2R could justify further watchful waiting for a
autoantibodies and clinical outcome in patients with primary spontaneous remission. In patients who start immuno-
membranous nephropathy. J Am Soc Nephrol. suppression, decreasing titers indicate response to treat-
2014;25(6):1357-1366. ment, and unchanged or increasing titers are indicative of
➢ Ruggenenti P, Debiec H, Ruggiero B, et al. Anti-phospholipase treatment failure and warrant modification of therapy.
A2 receptor antibody titer predicts post-rituximab outcome of
membranous nephropathy. J Am Soc Nephrol.
Several studies have shown that stopping immunosup-
2015;26(10):2545-2558. pression before the anti-PLA2R has completely dis-
➢ De Vriese AS, Glassock RJ, Nath KA, Sethi S, Fervenza FC. A appeared can lead to an early relapse of disease as
proposal for a serology-based approach to membranous ne- autoantibody titers rebound. Evidence is lacking for
phropathy. J Am Soc Nephrol. 2017;28(2):421-430. THSD7A, but similar principles likely apply.
+ESSENTIAL READING Before discussing the main treatment options for adult
primary MN, we should emphasize that corticosteroid
monotherapy has been shown to be ineffective as immu-
Treatment and Response nosuppression and should be avoided. The possible
Case, continued: You and your patient agree to starting exception is in the pediatric patient, who tends to have a
immunosuppressive treatment, but, as a result of fears about more benign disease course, exhibits a higher rate of
the adverse effects, she would like to avoid spontaneous remission, and is often empirically treated
cyclophosphamide. with steroids from the outset. If steroids do not achieve

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 Alsharhan and Beck Jr

Risk factors for disease progression

Low Risk: Moderate Risk: High Risk: Very High Risk:

• Normal eGFR • Normal eGFR • eGFR < 60 • Life-threatening

• Proteinuria < 3.5 g/d • Proteinuria > 4 g/d and ml/min/1.73m² nephrotic syndrome
and/or serum albumin > no reduction >50% after • Proteinuria > 8 g/d for • Rapid decline of kidney
3.0 g/dL 6 mo of conservative >6 mo function not otherwise
therapy with RAASi • PLA2R Ab > 150 RU/ml explained
• PLA2R Ab < 50 RU/ml

Watchful waiting RTX or

or CP or
Watchful waiting RTX or CNI CNI + RTX CP

Figure 5. This algorithm classifies patients into 4 different risk groups with the subsequent recommended therapy plan. The thresh-
olds for anti-PLA2R titer are somewhat arbitrary. Consideration should also be given to anti-PLA2R trajectory, as a decreasing titer
over time might warrant continued monitoring with antiproteinuric therapy alone, whereas increasing titer might increase the level of
risk. Abbreviations: CP, cyclophosphamide-based protocol; eGFR, estimated glomerular filtration rate; Ab, antibody; RAASi, renin-
angiotensin-aldosterone system inhibition; RTX, rituximab.

remission for pediatric MN, the B-cell–depleting agent or Rituximab

calcineurin inhibitors (CNIs) should be tried. Pioneering pilot studies from Bergamo, Italy, and the
Mayo Clinic/University of Toronto demonstrated the
Cyclophosphamide and Corticosteroids utility of the anti–B-cell agent rituximab for the treatment
The best long-term follow-up data for the treatment of of primary MN. The Bergamo group assembled a large
primary MN come from 2 studies comparing a regimen of observational cohort of patients with MN effectively
alternating corticosteroids and alkylating agents with treated with rituximab as first- or second-line therapy, and
supportive therapy. This high-level evidence supports the much of our knowledge about long-term remission rates,
recommendation to strongly consider their use for patients relapses, and effects on anti-PLA2R come from this
at very high risk of disease progression. important cohort.
The original Ponticelli protocol used alternating months There are 3 randomized controlled trials comparing
of corticosteroids and chlorambucil for a period of 6 rituximab with supportive care or other immunosuppres-
months, which proved to be very effective in terms of sive treatment. An initial study (GEMRITUX) did not show
inducing remission of proteinuria while preserving GFR. better efficacy of rituximab versus conservative anti-
This regimen was later compared with a similar regimen proteinuric therapy at the 6-month end point, but long-
that substituted the alternative alkylating agent cyclo- term follow-up for a median of 17 months showed
phosphamide alternating with corticosteroids for a 6- higher remission rates in the rituximab arm. The MENTOR
month period (the modified Ponticelli protocol) and trial, designed as a noninferiority trial that compared the
resulted in comparable efficacy with less toxicity. A use of rituximab and cyclosporine in primary MN,
regimen known as the Dutch protocol used daily cyclo- demonstrated not only equal efficacy at 12 months, but
phosphamide for as long as 1 year with 6 months of daily superiority of rituximab at achieving and maintaining
or alternate-day prednisone followed by a tapering steroid remission at 24 months. This trial lends strong support for
dose. This protocol also achieved a good clinical response, the use of rituximab as first-line treatment for primary
but with significant adverse events that were associated MN. The recently-published STARMEN trial (Clinical-
with a higher cumulative dose of cyclophosphamide. Trials.gov identifier NCT01955187) compares 24-month
In terms of treatment-specific adverse events, cyclo- remission rate after sequential therapy with tacrolimus
phosphamide is associated with cytopenias, in particular and rituximab versus the modified Ponticelli regimen in
leukopenia, which predisposes patients to infections. It is primary MN. The rationale for dual therapy is to admin-
also known to increase the risk of bladder cancer in ister rituximab prior to tapering the tacrolimus in an
smokers. A more concerning toxicity for young patients is attempt to reduce the rate of relapse that is otherwise
oligospermia in male patients and premature ovarian fail- common in this setting.
ure in female patients. These risks tend to be associated Because of the more limited adverse effects of ritux-
with higher cumulative doses used in cancer chemo- imab, it may be considered in patients with advanced
therapy, but nonetheless need to enter into the risk/benefit chronic kidney disease and immunologically active MN, as
analysis for each individual patient. successful treatment of the MN may help to preserve

450 AJKD Vol 77 | Iss 3 | March 2021

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remaining GFR. It is also important to mention that months for the patient. As shown by the MENTOR study,
second-generation anti-CD20 agents such as ofatumumab incomplete remissions and relapses make cyclosporine (b)
have been used successfully in cases in which MN becomes an incorrect choice. Prednisone monotherapy (a) is not
refractory to rituximab. indicated for MN, and mycophenolate (c) has had inferior
In terms of adverse events, infusion-related reactions are and inconsistent results in primary MN.
very common and can range from a mild skin rash to
anaphylaxis. Pretreatment with dexamethasone and Treatment of Secondary MN
diphenhydramine is standard and can decrease the risk of In treatment of secondary MN, the general rule is to treat
these reactions. Because rituximab results in prolonged B- the underlying disease or stop the offending agent. In cases
cell depletion, there is an increased risk of reactivation of of malignancy-associated MN, treatment of the malignancy
HBV and tuberculosis, and prophylactic treatment of both should be paramount, and MN can initially be treated
conditions during the B-cell depletion period should be supportively. If the patient subsequently does not show
considered in previously exposed patients. Other serious evidence of a remission of proteinuria, a trial of immu-
infections have also been reported. Very rarely, rituximab nosuppression following the algorithm for primary MN is
can cause progressive multifocal leukoencephalopathy. recommended.
The treatment of class V lupus nephritis will vary
CNIs depending on whether it exists as a solitary lesion or in
CNIs have immunosuppressive and antiproteinuric effects combination with a proliferative form (class III/IV lupus
and can be effective in achieving remission in primary MN. nephritis). In the latter case, treatment should be focused
Trials with cyclosporine and low-dose prednisone or with on the proliferative classes. However, if membranous
tacrolimus monotherapy have shown increased remission lupus nephritis is the primary lesion, treatment with
rates compared with supportive therapy alone. The major immunosuppression can be started if there is nephrotic-
issue with the use of CNIs is the very high rate and rapidity range proteinuria with or without nephrotic syndrome
of relapses when the agents have been tapered and dis- and/or progressive decrease in GFR. All patients should be
continued. If these agents are to be used for therapy for taking antimalarial agents in the absence of contraindica-
primary MN, serum autoantibodies should be followed tions, as there is evidence that they reduce risk of flares,
every 3-6 months and therapy continued until there is a delay progression to kidney failure, and improve 12-
decrease and disappearance of autoantibodies before the month renal response rates. The optimal treatment for
CNIs are tapered and stopped. membranous lupus nephritis is not known, as published
In terms of adverse events, the doses used for the trials are not well powered, but it is well established that
treatment of MN are typically much lower than those used patients require immunosuppression. Agents commonly
in prevention of solid-organ transplant rejection, and used are cyclophosphamide, mycophenolate, and CNIs
therefore acute CNI toxicities are rare. Clinicians should combined with corticosteroids. Mycophenolate mofetil has
monitor patients for the development of a decrease in been found to be comparable to cyclophosphamide in 2
estimated GFR and development of hypertension or prospective studies and is therefore now used as first-line
neurologic changes with prolonged therapy. therapy.
Treatment of MN due to chronic HBV infection requires
Other Therapies agents directed against the infection, such as pegylated
Limited data suggest a utility of adrenocorticotropic hor- interferon, entecavir, or tenofovir.
mone for the treatment of MN, as adrenocorticotropic
hormone–related melanocortin peptides have immuno- Additional Readings
modulatory effects as well as direct podocyte effects that ➢ Ponticelli C, Zucchelli P, Passerini P et al. A 10-year follow-up of
can limit proteinuria. Mycophenolate monotherapy is not a randomized study with methylprednisolone and chlorambucil in
effective for the treatment of MN, although mycopheno- membranous nephropathy. Kidney Int. 1995;48(5):1600-1604.
➢ Jha V, Ganguli A, Saha TK, et al. A randomized, controlled trial of
late may have a role as an alternative therapy when com-
steroids and cyclophosphamide in adults with nephrotic syn-
bined with corticosteroids or a CNI. drome caused by idiopathic membranous nephropathy. J Am
Soc Nephrol. 2007;18(6):1899-1904.
Future Therapies: Antigen-Specific Therapies ➢ Ruggenenti P, Cravedi P, Chianca A, et al. Rituximab in idiopathic
As we are learning more about the antigens and epitopes membranous nephropathy. J Am Soc Nephrol.
targeted in primary MN, there has been discussion about 2012;23(8):1416-1425.
tolerance induction or specific depletion of B cells pro- ➢ Fervenza FC, Appel GB, Barbour SJ et al. Rituximab or cyclo-
sporine in the treatment of membranous nephropathy. N Engl J
ducing the pathogenic autoantibodies. No antigen-specific
Med. 2019;381(1):36-46. +ESSENTIAL READING
therapy is currently available, although the field is hopeful ➢ Dahan K, Debiec H, Plaisier E, et al. Rituximab for severe mem-
that such agents can be developed to limit adverse effects branous nephropathy: a 6-month trial with extended follow-up. J
of more generalized immunosuppression. Am Soc Nephrol. 2017;28(1):348-358.
The answer to question 3 is (d): rituximab is the best ➢ Bomback AS, Fervenza FC. Membranous nephropathy: ap-
choice of therapy to achieve complete remission at 24 proaches to treatment. Am J Nephrol. 2018;47(suppl 1):30–42.

AJKD Vol 77 | Iss 3 | March 2021 451

 Alsharhan and Beck Jr

Table 1. Clinical and Pathologic Features That Distinguish Recurrent from De Novo MN
Category Recurrent MN De Novo MN
Epidemiology • 10%-45% recurrence rate (higher rates in • 1%-2% posttransplant with increasing inci-
centers with protocol biopsies) dence with time; reported as ~5.3% at 8 y
• Clinically apparent by 13-15 mo, but protein- • Higher incidence in pediatric population,
uria can begin within months of reaching ~9%
transplantation
Pathogenesis • Anti-PLA2R at time of transplantation is a risk • Not fully known
factor • Has been associated with chronic and/or
• Can appear years later with reemergence of antibody-mediated rejection
autoantibodies when transplant immunosup-
pression decreased
Clinical presentation • Similar to primary MN • Can be asymptomatic or with various degrees
• May be detected earlier with lower amounts of of proteinuria many years after transplantation
proteinuria due to heightened surveillance
(especially with protocol biopsy)
Diagnosis • MN present on biopsy of native kidney • Diagnosis other than MN in biopsy of native
• Presence of anti-PLA2R can support recurrent kidney
MN if native diagnosis not known • Typically not associated with anti-PLA2R anti-
• Positive PLA2R staining within deposits in body or PLA2R staining of deposits
70%-80% • Evidence of chronic and/or antibody-
• IgG4 is the dominant or codominant IgG mediated rejection
subclass • IgG1 is predominant IgG subclass
Treatment • Can closely follow if low titer anti-PLA2R, • Unknown natural history but 50% graft loss
subnephrotic proteinuria, stable kidney has been reported
function • Treat underlying rejection and implement
• Transplant immunosuppression may cause antiproteinuric therapy
decrease and disappearance of • Increase maintenance immunosuppression,
autoantibodies consider plasmapheresis if chronic rejection is
• Heightened concern warranted as process present
already resulted in loss of native kidneys • Consider rituximab or cyclophosphamide if
• Rituximab for worsening disease in setting of kidney function is rapidly declining
transplant immunosuppression
IgG, immunoglobulin G; MN, membranous nephropathy; PLA2R, phospholipase A2 receptor.

➢ Radhakrishnan J, Moutzouris DA, Ginzler EM, et al. Mycophe- agents such as apixaban for prophylaxis needs further
nolate mofetil and intravenous cyclophosphamide are similar as study.
induction therapy for class V lupus nephritis. Kidney Int.
2010;77(2):152-160.
Additional Readings
• Lionaki S, Derebail VK, Hogan SL, et al. Venous thromboembolism
Anticoagulation in patients with membranous nephropathy. Clin J Am Soc Nephrol.
The nephrotic syndrome represents a hypercoagulable state 2012;7(1):43-51.
with increased risk of venous thromboembolism (VTE) • Kerlin BA, Ayoob R, Smoyer WE. Epidemiology and pathophysi-
ology of nephrotic syndrome-associated thromboembolic disease.
such as deep vein or renal vein thrombosis and pulmonary Clin J Am Soc Nephrol. 2012;7(3):513-520.
embolism. There is a lower, but still increased, risk for • Lee T, Biddle AK, Lionaki S, et al. Personalized prophylactic anti-
arterial thromboembolic events. The risk of VTE is coagulation decision analysis in patients with membranous ne-
particularly high in MN for unclear reasons. The best ev- phropathy. Kidney Int. 2014;85(6):1412-1420. +ESSENTIAL
idence supporting the use of prophylactic anticoagulation READING
in MN comes from a cohort study of 2 large glomerulo- • Lee T, Derebail VK, Kshirsagar AV, et al. Patients with primary
membranous nephropathy are at high risk of cardiovascular
nephritis registries that demonstrated that the VTE risk
events. Kidney Int. 2016;89(5):1111-1118.
starts to increase at a serum albumin level lower than 2.8
g/dL and increases further with lower values. However,
the risk of bleeding due to anticoagulation needs to be
weighed against the benefit of preventing a major Kidney Transplantation
thromboembolic event. A risk/benefit analysis equation Case, continued: Your patient, despite exhibiting initial
has been developed to guide decisions about anti- remission of her MN with rituximab, has several relapses over
coagulation based on serum albumin and bleeding risk. the next decade and is ultimately diagnosed with stage 5
Warfarin and low-molecular-weight heparin can be used chronic kidney disease with no evidence of the nephrotic
for VTE prophylaxis, and the dosing and target Interna- syndrome. She is deemed an acceptable candidate for pre-
tional Normalized Ratio are identical for the general emptive kidney transplantation, and her healthy daughter
treatment of VTE; the use of direct oral anticoagulant would like to donate a kidney. As part of the

452 AJKD Vol 77 | Iss 3 | March 2021

Alsharhan and Beck Jr

peritransplantation process, your patient is found to have an Additional Readings

anti-PLA2R titer of 43 RU/mL. ➢ Rodriguez EF, Cosio FG, Nasr SH, et al. The pathology and
clinical features of early recurrent membranous glomerulone-
phritis. Am J Transplant. 2012;12(4):1029-1038.
Question 4: How should you proceed in terms of
➢ Debiec H, Hanoy M, Francois A, et al. Recurrent membranous
transplantation?
nephropathy in an allograft caused by IgG3κ targeting the PLA2
a) Treat with rituximab and await disappearance of anti-
receptor. J Am Soc Nephrol. 2012;23(12):1949-1954.
PLA2R before proceeding with transplantation ➢ Grupper A, Cornell LD, Fervenza FC, et al. Recurrent membra-
b) Insist on another donor, as a living-related donor is highly nous nephropathy after kidney transplantation: treatment and
likely to lead to recurrence of MN in the allograft long-term implications. Transplantation. 2016;100(12):2710-
c) Proceed with transplantation and monitor anti-PLA2R and 2716.
proteinuria closely ➢ Leon J, P erez-S
aez MJ, Batal I, et al. Membranous nephropathy
d) Perform plasmapheresis in the peritransplantation period posttransplantation: an update of the pathophysiology and
management. Transplantation. 2019;103(10):1990-2002.
For the answer to the question, see the following text.
+ESSENTIAL READING
➢ Batal I, Vasilescu ER, Dadhania DM, et al. Association of HLA
MN, when it occurs in the kidney allograft, can repre- typing and alloimmunity with posttransplantation membranous
sent a recurrence of the same disease that occurred in the nephropathy: a multicenter case series. Am J Kidney Dis.
2020;76(3):374-383.
native kidneys (ie, recurrent MN) or as de novo disease in
a recipient who experienced kidney failure due to other
causes. The features of these two forms are quite different
Conclusion
(Table 1).
The progress made in the field of MN has been sub-
Recurrent MN stantial as a result of the identification of multiple target
The development of recurrent MN likely recapitulates the antigens, the ability to monitor disease course with
earliest stages of MN in the native kidney, when circu- circulating autoantibodies, advances in the genetics of
lating autoantibodies have started to target intrinsic this disease, and therapeutic trials identifying effective
podocyte proteins (eg, PLA2R) in the donor kidney and treatments with fewer adverse effects, such as rituximab.
form immune deposits of increasing size. Although the We expect that this progress will continue in the next
humoral response is typically quite mature by the time decade and urge the readers of this Core Curriculum
someone has progressed to kidney failure and requires to stay abreast of the new studies in this fascinating
transplantation, transplant immunosuppression itself can disease.
mitigate the humoral response and is sometimes able to
cause decrease and disappearance of circulating anti-
Article Information
bodies. Knowledge of autoantibody status in the peri-
transplantation period is critical. In those with low Authors’ Full Names and Academic Degrees: Loulwa Alsharhan,
antibody titers, transplantation can often proceed, with MD, and Laurence H. Beck Jr, MD, PhD.
careful monitoring of autoantibody titer after trans- Authors’ Affiliations: Section of Nephrology, Department of
Medicine, Boston Medical Center, Boston, MA (LA, LHB) and
plantation; the answer to question 4 is therefore (c). In Section of Nephrology, Department of Medicine, Boston University
those with high titers, it is less likely that transplant School of Medicine, Boston, MA (LHB).
immunosuppression alone will fully treat the autoim- Address for Correspondence: Laurence H. Beck Jr, MD, PhD,
mune process before clinically significant recurrent dis- Section of Nephrology, Department of Medicine, Boston University
ease can occur and potentially threaten the allograft. In School of Medicine and Boston Medical Center, 650 Albany St,
this case, consideration should be given to treatment X-536, Boston, MA 02118. E-mail: [email protected]
before transplantation. Support: The preparation of this work was supported by institutional
funding from Boston Medical Center and the Department of
De Novo MN Medicine’s Glomerular Disease Center.

It has been proposed that de novo MN occurs as a result of Financial Disclosure: Dr Beck reports being a coinventor on the US
patent “Diagnostics for Membranous Nephropathy” with royalties
multiple triggers that all lead to formation of antigen- from Boston University; Dr Beck has served on advisory boards
antibody complexes in the subepithelial space of the for Visterra, Ionis, and Genentech; has received research support
GBM, resulting in podocyte injury and MN. These antigens in the area of MN from Sanofi Genzyme and Pfizer; and receives
are exposed as a result of a prior episode of rejection or royalties from UpToDate for topics related to MN. Dr Alsharhan
planted in the subepithelium as a result of an infection in declares that he has no relevant financial interests.
an immunocompromised host. It has also been proposed Peer Review: Received May 29, 2020, in response to an invitation
from the journal. Evaluated by 2 external peer reviewers and a
that episodes of rejection can lead to disturbance in the member of the Feature Advisory Board, with direct editorial input
GBM architecture, rendering it susceptible to formation of from the Feature Editor and a Deputy Editor. Accepted in revised
subepithelial deposits. form October 1, 2020.

AJKD Vol 77 | Iss 3 | March 2021 453