Novel Treatments Paradigms: Membranous Nephropathy: Table 1
Novel Treatments Paradigms: Membranous Nephropathy: Table 1
Novel Treatments Paradigms: Membranous Nephropathy: Table 1
Primary membranous nephropathy (MN) is a kidney-specific autoimmune glomerular disease and the
leading cause of nephrotic syndrome (NS) in White adults, usually caused by antiphospholipase A2 re-
ceptor (PLA2R) antibodies, although several new target antigens have been recently identified. It is
characterized by the diffuse thickening of the glomerular basement membrane secondary to immune
complex deposition. In patients with persistent NS without response to maximizing conservative therapy
including the use of renin-angiotensin system (RAS) blockers, the use of immunosuppressive agents is
warranted. However, the optimal immunosuppressive treatment has not yet been established. Classical
immunosuppressants, such as cyclophosphamide plus steroids, are effective but may cause clinically
relevant adverse effects, limiting their use. Rituximab offers efficacy with a better safety profile whereas
calcineurin inhibitors (CNIs) are marred by high relapse rates and nephrotoxicity. Nevertheless, up to 30%
of patients fail to respond to standard therapy. Novel and specific therapies targeting B cells and plasma
cells have shown encouraging preliminary results, in terms of clinical efficacy and safety profile, especially
in patients with poor tolerance or refractory to conventional treatments. In this brief review, we discuss the
benefits and limitations of the current therapeutic approach to MN and describe emerging novel therapies
that target its pathogenesis.
Kidney Int Rep (2023) 8, 419–431; https://doi.org/10.1016/j.ekir.2022.12.011
KEYWORDS: anti-PLA2R; biological treatment; cyclophosphamide; membranous nephropathy; rituximab; tacrolimus
ª 2022 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
N is the main cause of NS in White adults, the In patients with persistent proteinuria >4 g/24 h
M second cause in African American and Hispanic
individuals, and almost twice more frequent in men.1
despite RAS blockers, several studies have consis-
tently demonstrated that rituximab, cyclophospha-
Primary MN is a kidney-specific autoimmune glomer- mide, and CNIs glucocorticoids, can induce
ular disease caused by circulating podocyte-targeted proteinuria remission. However, up to 30% of pa-
autoantibodies, mainly anti-PLA2R (70%75%).1 tients have a poor response, which is associated
Recently, novel autoantibodies and podocyte antigens with a high risk of progression to kidney failure.3
have been described using laser-capture microdissec- Some patients develop drug intolerance or serious
tion/mass spectrometry (Table 1).2 The formation and adverse effects (e.g., major infections, myelosup-
deposits of immune complexes containing immuno- pression, neoplasms, nephrotoxicity, metabolic dis-
globulins and complement induce podocyte damage orders). In addition, relapses are common. This has
and alter the glomerular basement membrane, resulting led to the search for more specific and better
in the development of proteinuria, that frequently tolerated immunomodulatory drugs, aiming at
progress to full blown NS, and if persistent, progres- improving long-term clinical outcomes. In this brief
sion to kidney failure1,2 (Figure 1). review, we discuss the current therapeutic approach
and novel immunomodulatory agents and their po-
tential role in the treatment of MN. We also high-
light the unmet needs that should be addressed in
Correspondence: Jorge E. Rojas-Rivera, Department of future research.
Nephrology and Hypertension, Hospital Universitario Fundación
Jiménez Díaz, Av. De los Reyes Católicos 2, Madrid 28040, Spain.
E-mail: jerori2003@yahoo.com; or Fernando C. Fervenza, Current Therapies Available for MN
Department of Nephrology and Hypertension, Mayo Clinic, 200 Patients with MN should be treated with supportive
First St. SW, Rochester, Minnesota 55905, USA. E-mail: fervenza.
fernando@mayo.edu nephroprotective and cardiovascular disease preven-
Received 13 October 2022; revised 6 December 2022; accepted 12 tive strategies, and immune suppression should be
December 2022; published online 2 January 2023 considered for patients at risk for progressive kidney
Kidney International Reports (2023) 8, 419–431 419
REVIEW JE Rojas-Rivera et al.: Treatment of Membranous Nephropathy
CNTN1, contactin 1; EXT1/EXT2, exostosin 1/2; FAT1, Protocadherin FAT1; GBMg glomerular basement membrane; HS, heparan sulfate; HSCT, hematopoietic stem cell transplant; HTRA1, High Temperature Requirement A serine peptidase 1; Ig,
immunoglobulin; MN, membranous nephropathy; NA, not available; NCAM1, neural cell adhesion molecule 1; NELL1, NEL-like protein 1; NS, nervous system; NTNG1, netrin G1; PCDH7, protcadherin-7; PLA2R, phospholipase 2 receptor; SEMA3B,
Diagnosis, prognosis, monitoring
Diagnosis, prognosis, monitoring
gression if they have normal or stable estimated
Diagnosis, prognosis?
Diagnosis, prognosis
Clinical utility glomerular filtration rate (eGFR) over the preceding 6
months with proteinuria <4 g/24h with either negative
Diagnosis
Diagnosis
Diagnosis
Diagnosis
Diagnosis
Diagnosis
Diagnosis
Diagnosis
PLA2R or low PLA2R antibody levels (<50 RU/ml) that
are decreasing by $25%. These patients do not require
immunosuppressive therapy and should be treated
with supportive therapy (see next section). Renal
function, serum albumin, and 24-hour proteinuria
Uncommon
70%–85%
Frequency
30% SLE
2%–5%
3%–4%
1%–3%
<1%
1%
semaphorin 3B; SLE, systemic lupus erythematosus; TBM, tubular basement membrane; TGFBR3, TGFb receptor type 3; THSD7A, thrombospondin type-1 domain-containing protein 7A.
boembolic event), with moderately elevated PLA2R
“primary” and lupus MN levels (50150 RU/ml) that are stable over a span of 6
“primary” MN, cancer
children, females
“primary” MN
“primary” MN
“primary” MN
“primary” MN
Lupus MN
IgG1, IgG3
IgG4, IgG2
IgG1, IgG2
IgG1, IgG3
IgG1, IgG4
IgG4
Subendothelial
Subepithelial
Subepithelial
Subepithelial
Subepithelial
Subepithelial
Subepithelial
Subepithelial
Subepithelial
Subepithelial
Subepithelial
Subepithelial
Subepithelial
Mesangial
Mesangial
Cardiovascular Protection
Serum antibodies
Anti-SEMA3B
Anti-THSD7A
Anti-NCAM1
Anti-PCDH7
Anti-NTNG1
Anti-CNTN1
Anti-HTRA1
Anti-PLA2R
Anti-NELL1
NA
No
GBM, TBM
Podocyte
Podocyte
Podocyte
Podocyte
GBM
GBM
NS development
TGFb coreceptor
HS biosynthesis
Serine protease
TGFBR3
Antigen
NCAM1
NELL1
FAT1
an -CD20
(Rituximab, Obinutuzumab, Ofatumumab) Proteasome
Dendri c cell inhibitor
(Bortezomib)
an -BLyS (Belimumab)
↑ Th2 response
an -CD38
↑ Th17 ac vity (daratumumab,
B
BAFF BAFF
(↑ IL-4, IL1B, IL-6, IL-17A)
(BLyS) (BLyS)
felzartamab)
Treg cell
CD20 BAFF-R CD20 BAFF-R CD38
C 8 Proteasomee
Pr
CD20
An -THSD7A
An -PLA2R
PLA2R
R An -THSD7A
THSD7A An -PLA2R
Pro-B cell
P Pre-B cell Immature B cell Mature and
Cyclophosphamide
BCX9930 Podocyte
P d Podoc te loss Progres
Progression to
injury
Glomerular sclerosis kidney failure
Figure 1. Classical immunosuppressors and targeted novel therapies for the treatment of membranous nephropathy. MN is characterized by the
presence of subepithelial immune deposits in the glomerular capillary wall. Although these deposits may contain exogeneous planted antigens
(e.g., cationic bovine serum albumin), more often, they are composed of autoantibodies directed against podocyte antigens (Table 1) and
complement. Complement targeting prevents preclinical podocyte injury and MN and there is systemic evidence for complement activation in
human MN. T cells cooperate in the immune response with CD20þ B cells. Affinity-maturated, class-switched B cells may circulate as CD20þ
memory B cells or terminally differentiate into CD20-/CD38þ plasma cells, the main source of antibodies and autoantibodies. Cyclophosphamide
principally affects the activation and proliferation of T cells and early B cells. CNIs inhibit T-cell differentiation and proliferation, but they can
also reduce the glomerular expression of PLA2R (tacrolimus) and decrease proteinuria through hemodynamic effects and stabilization of
podocyte cytoarchitecture. Rituximab and other anti-CD20 drugs induce death of CD20þ B cells at early and intermediate stages, reducing the
progression to late B cells and plasma cells and reducing the production of autoantibodies. Belimumab targets BAFF, leading to B-cell
apoptosis, blockade of progression to plasmacytes, and reduced autoantibody production. Anti-CD38 drugs and proteasome inhibitors target
plasma cells and reduce the production of autoantibodies, especially in relapsing and refractory cases. Eculizumab and avacopan inhibit the
final stage of the complement system, but there is no experience with these drugs in primary MN, except for cases with concurrent thrombotic
microangiopathy for eculizumab. Iptacopan (LNP023) inhibits the effect of factor B on the C3 convertase, limiting the continuous complement
activation. An ongoing RCT phase 2 is comparing iptacopan and rituximab for MN. BCX9930 inhibits Factor D and an ongoing RCT is enrolling
MN patients, as for narsoplimab (OMS721) which inhibits MASP-2, i.e., the lectin pathway for complement activation. PLA2R
for cardiovascular disease prevention purposes in normotensive and unable to tolerate maximum RAS
nondiabetic patients with CKD and recommend their blockade let alone the combined use of a mineralocor-
use if the CKD patient is diabetic.5 Experience with ticoid receptor antagonist. Nevertheless, a holistic
steroidal mineralocorticoid receptor antagonist in MN approach to cardiorenal protection combining RAS
has been generally negative from the point of view of blockade and SGLT2 inhibitor (adding a nonsteroidal
tolerance and effectiveness on proteinuria.6 However, mineralocorticoid receptor antagonist will depend on
finerenone, a nonsteroidal mineralocorticoid receptor blood pressure levels) could be explored as supportive
antagonist, improved kidney and cardiovascular out- therapy in patients who reach immunologic remission
comes in patients with diabetes and CKD, the best re- but remain with subnephrotic proteinuria following
sults being observed in patients on both SGLT2 immunosuppression therapy in MN.
inhibitor and finerenone.7 However, no data are
available for patients with MN. In addition, these Classical Immunosuppression
agents have relatively weak antiproteinuric effect and Current recommendations for immunosuppressive
unlikely to significantly improve proteinuria in pa- treatment of MN are based on the stratification of the
tients with severe NS (e.g., >10 g/24 h). In addition, risk of progression.3 Immunosuppressive treatment
the majority (80%) of patients with MN are should be started for persistent NS or proteinuria
Kidney International Reports (2023) 8, 419–431 421
REVIEW JE Rojas-Rivera et al.: Treatment of Membranous Nephropathy
a Current approach to
Current
Membranous Nephropathy Therapy
Progressio ssessment
JERR-2022
Cardionephroprotection
Cardionephroprotection
Immunosuppression: Possibly
Immunosuppression: No • First wait and see during 3-6 monthss 1º cycle of IS Non-Response
Wait and see (3-6 months)
• ↑ Proteinuria, ↓ eGFR, ↑ aPLA2R
1º cycle of IS
RTX ± CNI or (Resistant MN)
Response CYC + GC Response
aer 3-6 months: start RTX ± CNI CYC + GC
Response
2º cycle of IS*
Non-Response
(↓aPLA2R ± ↓uPCR) (↑aPLA2R ± ↑uPCR) Response Non-Response
(↓aPLA2R ± ↓uPCR) (Persists ↑aPLA2R ± ↑uPCR)
Non-Response** Wait up to 3 months
(Refractory MN) to evaluate response
Connue New risk Connue New risk
Nephroprotecon assessment Nephroprotecon assessment
Enrollment
Relapse Kidney biopsyy Combined New biologicals
Relapse in RCTs
(↑aPLA2R ± ↑uPCR) Repeat RTX ± CNI (chronic changes) therapies (B & plasma cells)
(↑aPLA2R ± ↑uPCR) (Expert Center)
Proteinuria (g/24h)
ST se
m g
IS therapy- induced
aapy
py
Anti-PLA2R
immunological response
Medium risk (connue with ST and
periodic monitoring)
No IS therapy
50 4.0
4
S
m g (connue with ST and
Low risk No IS therapy periodic monitoring)
<2 <0.5
Undetectable an-PLA2R Undetectable an-PLA2R Undetectable an-PLA2R
Figure 2. Current approach to membranous nephropathy therapy and role of anti-PLA2R in monitoring disease (2a). Therapeutic algorithm
designed, adapted, and modified from figures 30 and 31 of reference 3. Control of anti-PLA2R serum levels should be performed at intervals of 3 to 6
months from baseline determination. However, shorter, or longer intervals could be considered depending on the patient’s clinical evolution.
†
Selectivity index is calculated as clearance of IgG/clearance of albumin. ††Cardionephroprotection involves strict control of blood pressure and
proteinuria using the maximum tolerable dose of RAS inhibitors. Weight control, dietary salt restriction and, in general, healthy lifestyle habits are
also mandatory.
Response to any type of treatment necessarily implies a decrease in anti-PLA2R antibodies, initially accompanied or not by a proteinuria
reduction, which is usually posterior to antibodies drop.
*The second cycle of immunosuppression depends on the first used treatment. For patients with rituximab as initial treatment, a one-second
cycle of rituximab can be used with the addition of (if kidney function is stable) or without the addition of CNIs. In addition, (continued)
422 Kidney International Reports (2023) 8, 419–431
JE Rojas-Rivera et al.: Treatment of Membranous Nephropathy REVIEW
despite RAS blockers, impaired renal function and/or therapy for CRþPR (35% vs. 21%) in 75 nephrotic MN
high anti-PLA2R autoantibody titers (Figure 2). The patients, although serum albumin increased and anti-
evidence on classical immunosuppressants is summa- PLA2R antibodies decreased. Interestingly, after 17
rized in Table 2, and their advantages, and limitations months, rituximab was significantly superior to RAS
are summarized in Table 3. blockade (CR: 19% vs. 3%, CRþPR: 65% vs. 35%,
respectively). SAEs were uncommon, but contrary to
Rituximab: the First Option for Most Patients previous results, kidney function was lower with
According to 2021 KDIGO guidelines, for moderate- rituximab.
high risk MN, the first option is rituximab (CNIs).3 MENTOR, a multicenter and noninferiority RCT in
Rituximab is an anti-CD20 chimeric IgG1 monoclonal 130 patients with persistent nephrotic MN, showed
antibody that depletes CD20þ pre-B/mature B cells that rituximab (1 g, 2 doses, repeated at 6 months in
(Figure 1) for at least 6 to 12 months through patients who showed >25% reduction in proteinuria at
complement-dependent cytotoxicity, antibody- 6 months) was superior to cyclosporine A (CsA, 35
dependent cellular cytotoxicity, and apoptotic cell mg/kg/d for 612 months) for achieving CRþPR from
death. Rituximab may also protect podocytes by sta- month 18 (62% vs. 23%) up to month 24 (60% vs.
bilizing sphingomyelin-phosphodiesterase-acid-like-3b 20%).9 Treatment failure was defined as reduction of
expression and preventing downregulation of acid- proteinuria <25% at 6 months. Rituximab induced a
sphingomyelinase activity, thereby decreasing actin faster (52% vs. 28% at 6 months) and persistent
cytoskeleton disruption and apoptosis.13 immunologic response, and a better follow-up kidney
In observational studies, rituximab was effective in function, compared to patients treated with CNI who
reducing anti-PLA2R antibody titers and nephrotic exhibited persistent nephrotoxicity at 24 months
proteinuria, improving kidney function, with an despite CNI discontinuation. Adverse events (AEs)
acceptable safety profile.14 In an Italian cohort of 100 were similar in both groups, but more SAEs were seen
nephrotic MN patients, rituximab induced complete with CsA (31% vs. 17%).
remission or partial remission (CRþPR) in 65% after 29 There is also evidence on rituximab efficacy in re-
months, without differences according to prior immu- fractory or advanced MN. In a prospective study of 36
nosuppressors, with good tolerance, and without Chinese MN patients without response to prior immu-
serious adverse events (SAEs).15 Several observational nosuppression, rituximab produced CRþPR in 42% of
studies showed that serum anti-PLA2R antibody patients.19 Similar efficacy has been shown in Italian
reduction preceded the proteinuria remission, patients who failed to respond to previous immuno-
becoming a potential early marker of response to suppressive treatment.20 Even more, when anti-PLA2R
treatment.16-18 titers remain persistently high, a second course of rit-
GEMRITUX was the first randomized controlled trial uximab may be effective.21 In a retrospective analysis
(RCT) with rituximab,8 After 6 months, rituximab of 13 nephrotic MN patients with anti-PLA2R and
showed no difference when compared to supportive eGFR <30 ml/min per 1.73 m2, rituximab improved
=
Figure 2. (continued) a valid approach is directly changing to CYCþGC if there is a decrease in kidney function (especially in patients with
eGFR <45 ml/min). For patients with CYCþGC as initial treatment, rituximab is a valid option in the second cycle of treatment, or if the
patient had a good initial tolerance to alkylating agents, give a second course of CYCþGC, trying to use the lowest effective dose possible.
**A refractory MN implies nonresponse to 2 cycles of different treatments, including at least, a course of CYC-GC.
Before insisting on further immunosuppression, it would be important, if the patient’s clinical condition allows, to perform a kidney biopsy to rule
out the presence of chronic irreversible changes in the renal tissue that would justify discontinuing immunosuppression. If immunosuppression
is still feasible, treatments targeting B cells (obinutuzumab or belimumab) or plasma cells (bortezomib or daratumumab) could be given. Other
alternatives include the combination of different drugs (rituximab-belimumab, rituximab-cyclophosphamide, etc.), patient derivation to expert
centers in the treatment of glomerular diseases, or inclusion in RCTs focused on new therapeutic targets. (2b). The therapeutic approach to the
patients depends to a great extent on the baseline values (risk of progression) and the monitoring of the anti-PLA2R antibodies. In case of
values <50 RU/ml, the probability of spontaneous remission is very high and only periodic monitoring is required. On the contrary, very high
baseline values (>150 RU/ml) justify the start of immunosuppressive therapy. For intermediate values, more frequent monitoring can be per-
formed, and immunosuppression can be started if an increase in anti-PLA2R or proteinuria is evident. The response to treatment is also
assessed by the decrease in anti-PLA2R antibodies that usually precedes the reduction in proteinuria by weeks or months. The black curves
imply a poor outcome in response to immunosuppressive treatment, and the blue curves show an adequate response of anti-PLA2R antibodies
after immunosuppressive treatment or supportive treatment.
ACEi, angiotensin converting-enzyme inhibitors; aPLA2R, anti-PLA2R autoantibodies; ARB, angiotensin II receptor blocker; BP, blood pressure;
CNI, calcineurin inhibitors; CYC, cyclophosphamide; GC, glucocorticoids; GFR, glomerular filtration rate; IS, Immunosuppression or immuno-
suppressive; MN, membranous nephropathy; MRA, mineralocorticoid receptor antagonist; PLA2R, type M phospholipase A2 receptor; RCTs,
randomized clinical trials, RTX, Rituximab; ST, supportive therapy; uPCR, urinary protein-creatinine ratio (or its equivalent in g/24 h).
CR, complete remission; CsA, cyclosporine A; CYC, cyclophosphamide; eGFR, estimated glomerular filtration rate (expressed in ml/min per 1.73 m2); ESRD, end-stage renal disease; GC, glucocorticoids, IR, immunologic remission (defined as negative
anti-PLA2R); ITT, intention to treat analysis; N, sample size; NIAT, nonimmunosuppressive antiproteinuric therapy; PP, per protocol analysis; PR, partial remission; RASi, renin-angiotensin system inhibitors; RCT, randomized clinical trial; Ref, reference
Not specified
0% vs. 0%
0% vs. 2%
2% vs. 0%
5% vs. 0%
ESRD
in 69% (9/13) of patients, and immunologic remission
Note that none of the ESRD cases was reported in patients randomized to rituximab. All patients were adults with biopsy-proven primary nephropathy, with nephrotic proteinuria, eGFR $ 30 ml/min per 1.73 m2, and on top of RASi therapy.
was associated with clinical response.22 A recent Indian
2-year prospective observational study with 64 inci-
12 moc
24 mo
24 mo
72 mo
6 moa
point
Concerns
N
Alternating cyclophosphamide-glucocorticoids is
number; RTX, Rituximab; SAESs, serious adverse events; TAC, tacrolimus.
Results were 62% vs. 28% for relapsed-free remission (P-value < 0.05).
T cells
Target
RI-CYCLO11
GEMRITUX8
MENTOR9
STARMEN
Table 3. Advantages and limitations of immunosuppressive drugs currently used in membranous nephropathy
Therapeutic intervention
Characteristic CYCþGC CNIs Rituximab
Evidence-supporting studies RCT, cohort studies RCT, cohort studies RCT, cohort studies
More recommended profile patient Very-high risk Moderate risk Moderate and high risk
Short-term efficacya (3–6 mo) 74%–79% 44%–74% 35%–60%
Medium-term efficacya (18–24 mo) 84%–86% 20%–75% 60%–80%
Long-term efficacya (>24 mo) 80%–88% 53% 60%–65%
Nonresponse (24 mo) 15%–20% 25%–80% 25%–30%
Relapses (24 mo) 3%–33% 53%–64% 5%–13%
Main adverse effects Cytopenia Nephrotoxicity Infusion reaction
Severe infection HT, Hyperkalemia Leukopenia (rare)
Cushing syndrome, Infertility, cancerb Metabolic disorders Mild infection (rare)
Distal tremor Ig depletionc
NNT-Bd (95% CI) for CRþPR 4 (2–14) 4 (2–13) 3 (2–4)
Patient tolerance Low-moderate Moderate High
Patient adherence Variable Variable High
Costse Low Low-medium Medium-high
95% CI, 95% confidence interval; CR, complete remission; CNIs, calcineurin inhibitors (includes cyclosporine and tacrolimus); CYC, cyclophosphamide; GC, glucocorticoids; HT, hy-
pertension; Ig, immunoglobulins; NNT-B, number needed to treat (Benefit); PR, partial remission; RCT, randomized controlled trial; SAEs, serious adverse event.
a
Efficacy was defined as complete and partial remission (CR þ PR). Data were obtained from major RCTs, and cohort studies included in this review.
b
Especially with the use of high doses and by long duration.
c
Uncommon effect. This is more frequent in antineutrophil cytoplasmic antibodies vasculitis, principally because of repeat dose of rituximab.
d
The NNT-B indicates the number of patients who need to be treated with the drug to obtain a clinical benefit (in our case, to achieve CRþPR) and is calculated as the inverse of the risk
difference of outcome between the experimental drug and the control drug. The optimal value is 1, which means that for each patient treated, the desired outcome is obtained. In this
review, NNT-B was calculated for CRþPR at 24 months, as following: from the STARMEN study for CYCþGC, from Ramachandran et al.12 study for CNIs, and from the MENTOR study for
rituximab.
e
They may vary depending on the final dose administered of rituximab, the type of CNI, the geographic region and the type of health care system.
than cyclophosphamide for serious (including cancer In the RI-CYCLO pilot trial of 75 nephrotic MN pa-
and death) and nonserious AEs (24% vs. 61%), but tients with relatively preserved kidney function (eGFR
achieving similar efficacy for complete remission (40% 84 24 ml/min per 1.73 m2) and milder proteinuria (6
vs. 42%).29 Recently, better quality evidence emerged g/24h), CR and CRþPR at 12 months for
from trials that compared cyclophosphamide- cyclophosphamide-glucocorticoids and rituximab (1g,
glucocorticoids with regimens that included ritux- days 115) were 32% versus 16%, and 73% versus
imab, with a more appropriate supportive therapy. 62%, respectively.11 At 24 months, in which 77% of
STARMEN was an open-label RCT of 86 nephrotic the initial population was assessed, CR and relapses
MN patients.10 At 24 months, cyclophosphamide- were 35% versus 42%, and 22% versus 13% for
glucocorticoids were superior to sequential treatment cyclophosphamide-glucocorticoids and rituximab, the
with tacrolimus (9 months) plus rituximab (1 g at 6 difference no longer significant, respectively. The
months) for achieving CRþPR and CR (84 vs. 58%, and immunologic responses and the percentage of patients
60 vs. 26%, respectively). This superiority was with AEs and SAEs were similar at 12 months. In their
observed starting at month 3, but there were no dif- subgroup analysis, both trials showed greater efficacy
ferences at 24 months in the proportion of patients of cyclophosphamide-glucocorticoids in males and in
with preserved kidney function (eGFR $45 ml/min per patients with more severe disease.
1.73 m2) (93% vs. 86%). The immunologic response Other cyclophosphamide-based regimens have been
occurred earlier with cyclophosphamide- tried, including the use of lower doses, and intrave-
glucocorticoids but was similar after 24 months (88% nous routes with encouraging results.30 In a retro-
vs. 83%). Cyclophosphamide-glucocorticoids induced spective cohort study of 60 nephrotic MN patients, the
more AEs per patient, without relevant differences in combination of rituximab, low-dose cyclophospha-
SAEs (19% vs. 14%). Within the sequential treatment mide, and a rapid tapering glucocorticoids regimen was
regimen, most of AEs were related to tacrolimus. The effective and safe, achieving 100% of immunologic
addition of rituximab after 6 months reduced the response at 6 months, 83% of CR at 24 months, and a
relapse rate post-tacrolimus withdrawal (w12%) as low relapse rate (10%).31
compared with historic studies but resulted in a lag In patients with advanced CKD, the evidence is
time in anti-PLA2R antibodies reduction of 6 months scarce. In a British multicenter RCT of 108 nephrotic
from the first cyclophosphamide-glucocorticoids dose, MN patients with creatinine clearance #50 ml/min and
which together with the low rituximab dose used could progressive loss of kidney function, cyclic
have limited its efficacy. chlorambucil-based regimen diminished the
Kidney International Reports (2023) 8, 419–431 425
REVIEW JE Rojas-Rivera et al.: Treatment of Membranous Nephropathy
probability of kidney function reduction by $20% B-cell depletion or targeting plasma cells, which could
with respect to CsA or supportive therapy, after 3 years potentially produce pathogenic autoantibodies
of follow-up, but was associated with more AEs and (Figure 1).
SAEs, especially cytopenias.32 There is no standardized definition of resistant or
We conclude that alternating cyclophosphamide- refractory MN. Before the clinical use of anti-PLA2R
glucocorticoids is an effective option to treat MN. antibodies, resistant or refractory NM was based on
Tolerance and safety concerns could be reduced by persistent proteinuria after immunosuppressive ther-
using lower doses, especially less intravenous methyl- apy. Currently, for patients with PLA2R-associated
prednisolone, shorter treatment courses, or combining MN, we define resistant as persistence of anti-PLA2R
with rituximab, although these therapeutic schemes antibodies despite adequate immunosuppression. For
require validation through appropriate RCTs. patients treated with rituximab that means unchanged
or increasing anti-PLA2R levels despite persistent anti-
Monitoring of MN: Role of Anti-PLA2R CD20þ B cells depletion (e.g., 0 cells/ml) at 6 months.
Antibodies The same is true for patients treated with cyclical
The presence or absence of anti-PLA2R antibodies adds cyclophosphamide-based regimen. Patients treated
important information to clinical and immunopatho- with a CNI at adequate target levels that show no
logic data in patients with MN. Levels of anti-PLA2R changes or increasing anti-PLA2R levels at 6 months
antibodies tightly correlate with disease activity. Low should also be considered resistant to therapy
baseline (<50 RU/ml) and decreasing anti-PLA2R (Figure 2a and 2b).
antibody levels strongly predict spontaneous remis- Failure to respond to one therapy does not implies
sion, thus favoring conservative therapy. Conversely, resistant to alternative therapies. Therefore, if there is
high baseline (>150 RU/ml) or increasing anti-PLA2R lack of response to initial treatment with rituximab,
antibody levels associate with NS and progressive patients can be considered for treatment with a CNI if
loss of kidney function, thereby guiding initiation of kidney function is preserved, or switching to a cyclical
immunosuppressive therapy (Figure 2b). Serum anti- CYC-GC regimen. Regardless of treatment use, we
PLA2R antibody profiles reliably predict response to recommend monitoring anti-PLA2R and proteinuria
therapy, and levels at completion of therapy can fore- levels every 2 to 3 months, initially (Figure 2b). Pa-
cast long-term outcome. Re-emergence of or increase in tients who are resistant to 2 or more lines of treatment
antibody titers precedes a clinical relapse. Therefore, with currently available immunosuppressants are can-
an individualized serology-based approach to the didates for new therapeutic approaches,1,3 which we
diagnosis and treatment of MN was proposed.33 discuss in the next section.
Recent trials GEMRITUX, MENTOR, STARMEN,
and RI-CYCLO have confirmed that approach showing Alternative or Additional Anti-B-cell Therapies:
that an early decline of serum anti-PLA2R titers pre- Obinutuzumab and Belimumab
dicts response to treatment.34 Undetectable anti-PLA2R Obinutuzumab is a humanized anti-CD20 type-II
allows discontinuation of immunosuppression, or pro- monoclonal antibody that produces greater cytotox-
gressive dose reduction for CNI. Persistent anti-PLA2R icity and B-cell apoptosis than rituximab, by targeting
antibody levels (after initial fall), in the presence of a different epitope on CD20 and has a higher affinity for
recovering CD20þ B cells (>5 cells/ml) may require a Fcɣ-RIII, thus enhancing antibody-dependent cellular
second dose of rituximab. Increasing anti-PLA2R levels cytotoxicity and phagocytosis by NK cells and macro-
despite immunosuppressive therapy requires modifi- phages (Figure 1). It is effective in B-cell neoplasms,
cation of therapy.1,3. Anti-PLA2R titers at 6 months are and recently, as add-on therapy in patients with lupus
key to decide the continuation of treatment. Absent or nephritis, including membranous lupus glomerulone-
low titers allow immunosuppressant withdrawal and/or phritis. In 2 case series, 1 of them including nephrotic
tapering for CNI. Patients with persistent or increasing patients with primary and post-transplant MN, re-
levels anti-PLA2R levels without proteinuria remission fractory to several immunosuppressors, obinutuzumab
despite adequate immunosuppression should be depleted anti-PLA2R antibodies and induced protein-
considered as resistant to therapy (Figure 2b). uria remission in >60% of patients.35,36 A pilot, open-
label, and noncontrolled Italian phase-2 trial will enroll
Novel Approaches: Targeted Therapies 20 nephrotic MN patients with eGFR $30 ml/min per
AEs associated with classic immunosuppressants and 1.73 m2 who are resistant, dependent, or intolerant to
the lack of response in 20% to 30% of patients has led rituximab, to evaluate CRþPR at 12 months and the
to the search of alternative therapies.1,3 These include safety profile (NCT05050214). Another randomized
new therapeutic options aiming at more effectively open-label US phase-3 trial will enroll 140 nephrotic
426 Kidney International Reports (2023) 8, 419–431
Table 4. Ongoing trials with novel immunomodulators agents
Kidney International Reports (2023) 8, 419–431
C3G, C3 glomerulopathy; CR, complete remission; eGFR, estimated glomerular filtration rate; IgAN, IgA nephropathy; LN, lupus nephritis; MN, membranous nephropathy; MoA, mechanism of action; PK, pharmacokinetics, PR, partial remission; RCT,
randomized clinical trial; UACR, urinary albumin/creatinine ratio; UPCR, urinary protein/creatinine ratio; D, change.
REVIEW
427
REVIEW JE Rojas-Rivera et al.: Treatment of Membranous Nephropathy
CKD, chronic kidney disease; CNIs, calcineurin inhibitors; CYC, cyclophosphamide; eGFR, estimated glomerular filtration rate; MRAs, mineralocorticoids receptor antagonists; MN,
membranous nephropathy; PLA2R, phospholipase A2 receptor; RCTs, randomized clinical trials; RTX, Rituximab; SGLT2i, sodium-glucose cotransporter type 2 inhibitor; THSD7A,
thombospondin type-1 domain-containing protein 7A.
MN patients with eGFR $40 ml/min per 1.73 m2 to immunosuppressants. Bortezomib is a selective and
compare CR at 2 years between obinutuzumab and reversible proteasome inhibitor in high-turnover
tacrolimus (NCT04629248). Results are expected in plasma cells, producing caspase-mediated apoptosis
early 2025. and plasma cell depletion (Figure 1). It is successfully
Belimumab is a human IgG1l monoclonal antibody used to treat multiple myeloma and non-Hodgkin
that binds to soluble B-lymphocyte-stimulating protein lymphoma. It can induce response in refractory lupus
(BlyS/BAFF/TNFSF13B), blocking binding to receptors nephritis, and similarly, in refractory nephrotic MN
on B cells. Thus, belimumab decreases B-cell survival patients, producing anti-PLA2R depletion and pro-
and differentiation to immunoglobulin-producing teinuria remission, including CR at 12 months.38-40
plasma cells (Figure 1). Belimumab has been autho- Daratumumab and felzartamab (MOR202) are human
rized to treat active lupus nephritis following the IgG1k monoclonal antibodies targeting CD38 protein,
BLISS-LN 2-year phase-3 trial, which included patients which is highly expressed on plasmablasts and short or
with membranous class. In a recent open-label pro- long lived plasma cells, that depletes plasma cells
spective British study with 14 persistent nephrotic MN through complement-dependent cytotoxicity,
patients (3 with prior immunosuppression), belimumab antibody-mediated cytotoxicity, and antibody-
(10 mg/kg/month for 104 weeks) induced CRþPR in 9 dependent cellular phagocytosis. Daratumumab is
patients (64%). Anti-PLA2R reduction was observed approved for the treatment of multiple myeloma and
from week 12 onwards and proteinuria reduction from light-chain amyloidosis but has not yet been formally
week 36.37 There were few AEs and no patient deaths. studied in MN. One recent case report showed that
Exploring potential add-on effect on CD20þ cell daratumumab induced a rapid anti-PLA2R and pro-
depletion and efficacy, an ongoing multicenter phase-2, teinuria reduction in a woman with MN refractory to
double-blind RCT will compare the impact of cyclophosphamide and rituximab, but the effect was
belimumab-rituximab versus rituximab on CR after 2 short lasting, probably because of induced B-cell hy-
years in 124 nephrotic adult MN patients with perreactivity.41 The M-PLACE proof-of-concept study
eGFR $30 ml/min per 1.73 m2 (NCT03949855). Results (NCT04733040) has so far shown that felzartamab
are expected in 2027. rapidly and substantially reduces anti-PLA2R anti-
bodies titers in patients with anti-PLA2Rþ MN
Targeting Plasma Cells: Proteasome Inhibitors (interim results from the M-PLACE Study. ASN Kidney
and Anti-CD38 Agents Week. Published 2021. Accessed May 30, 2022. https://
Antiplasma cell therapy is a logical approach for pa- www.asn-online.org/education/ kidney week/2021/
tients with relapsing MN or resistance to conventional program-abstract.aspx? control). A small open-label
428 Kidney International Reports (2023) 8, 419–431
JE Rojas-Rivera et al.: Treatment of Membranous Nephropathy REVIEW
phase-2 trial will assess the efficacy, safety, and phar- the Catedra Mundipharma-UAM of diabetic kidney disease
macokinetics or pharmacodynamics of felzartamab in and the Catedra Astrazeneca-UAM of chronic kidney dis-
nephrotic anti-PLA2Rþ MN patients (NCT04145440), ease and electrolytes. FCF reports having consultancy
and another trial is evaluating felzartamab as rescue agreements with Alexion Pharmaceuticals, Alnylam, and
therapy in MN patients with prior failure of anti-CD20 ByoCrystal; receiving research funding from Chemo-
therapies (NCT04893096). These studies would be centryx, Genentech Inc., Janssen Pharmaceutical, and
completed in 2024 (Table 4). Questcor/Mallinckrodt; being a scientific advisor for, or
member of, Kidney International, Nephrology, Nephrology
Targeting Complement System: Beyond Dialysis Transplantation, and UpToDate; and receiving
Thrombotic Microangiopathy honoraria from UpToDate.
Despite evidence of a key role of the complement sys-
tem in the pathogenesis of MN,2 currently there is no ACKNOWLEDGMENTS
published experience with complement inhibitors, Alberto Ortíz research is supported by FIS/Fondos FED-
beyond some case reports of patients with primary or ER(PI18/01366, PI19/00588, PI19/00815, PI21/00251, ERA-
post-transplant MN patients who had concurrent PerMed-JTC2018 KIDNEY ATTACK AC18/00064, ISCIII-
thrombotic microangiopathy and were treated with RETIC REDinREN RD016/0009), Sociedad Española de
eculizumab.42 Ongoing clinical studies are exploring Nefrología, Sociedad Madrileña de Nefrología (SOMANE),
the inhibition of several complement pathways FRIAT, Instituto de Salud Carlos III (ISCIII) RICORS program
(NCT05162066/ NCT04154787/NCT02682407) (Figure 1, to RICORS2040 (RD21/0005/0001) funded by European
Table 4). Union – Next Generation EU, Mecanismo para la Recu-
peración y la Resiliencia and SPACKDc PMP21/00109,
CONCLUSIONS FEDER funds.
prevention in clinical practice. Eur J Prev Cardiol. 2021;42: Chinese cohort. Nephrol Dial Transplant. 2018;33:1158–1163.
3227–3337. https://doi.org/10.1093/ndt/gfx295
6. Cravedi P, Brusegan V, Ruggenenti P, et al. Spironolactone 20. Cravedi P, Sghirlanzoni MC, Marasà M, et al. Efficacy and
plus full-dose ACE inhibition in patients with idiopathic safety of rituximab second-line therapy for membranous
membranous nephropathy and nephrotic syndrome: does it nephropathy: a prospective, matched-cohort study. Am J
really work? Pharmaceuticals (Basel). 2010;3:1–9. https://doi. Nephrol. 2011;33:461–468. https://doi.org/10.1159/000327611
org/10.3390/ph3010001 21. Dahan K, Johannet C, Esteve E, et al. Retreatment with rit-
7. Rossing P, Anker SD, Filippatos G, et al. Finerenone in pa- uximab for membranous nephropathy with persistent
tients with chronic kidney disease and type 2 diabetes by elevated titers of anti-phospholipase A2 receptor antibody.
sodium-glucose cotransporter 2 inhibitor treatment: the FI- Kidney Int. 2019;95:233–234. https://doi.org/10.1016/j.kint.
DELITY analysis. Diabetes Care. 2022:dc220294. https://doi. 2018.08.045
org/10.2337/dc22-0294 22. Hanset N, Esteve E, Plaisier E, et al. Rituximab in patients with
8. Dahan K, Debiec H, Plaisier E, et al. Rituximab for severe phospholipase A2 receptor associated membranous ne-
membranous nephropathy: a 6-month trial with extended phropathy and severe CKD. Kidney Int Rep. 2020;5:331–338.
follow-up. J Am Soc Nephrol. 2017;28:348–358. https://doi. https://doi.org/10.1016/j.ekir.2019.12.006
org/10.1681/ASN.2016040449 23. Ramachandran R, Prabakaran R, Priya G, et al. Immunosup-
9. Fervenza FC, Appel GB, Barbour SJ, et al. Rituximab or pressive therapy in primary membranous nephropathy with
cyclosporine in the treatment of membranous nephropathy. compromised renal function. Nephron. 2022;146:138–145.
N Engl J Med. 2019;381:36–46. https://doi.org/10.1056/ https://doi.org/10.1159/000518609
NEJMoa1814427 24. Faul C, Donnelly M, Merscher-Gomez S, et al. The actin
10. Fernandez-Juarez G, Rojas-Rivera J, van de Logt A-E, et al. cytoskeleton of kidney podocytes is a direct target of the
The STARMEN trial indicates that alternating treatment with antiproteinuric effect of cyclosporine A. Nat Med. 2008;14:
corticosteroids and cyclophosphamide is superior to 931–938. https://doi.org/10.1038/nm.1857
sequential treatment with tacrolimus and rituximab in pri- 25. Praga M, Barrio V, Juárez GF, et al. Tacrolimus monotherapy
mary membranous nephropathy. Kidney Int. 2021;99:986– in membranous nephropathy: a randomized controlled trial.
998. https://doi.org/10.1016/j.kint.2020.10.014 Kidney Int. 2007;71:924–930. https://doi.org/10.1038/sj.ki.
11. Scolari F, Delbarba E, Santoro D, et al. Rituximab or cyclo- 5002215
phosphamide in the treatment of membranous nephropathy:
26. Gong L, Xu M, Xu W, et al. Efficacy and safety of tacrolimus
the RI-CYCLO randomized trial. J Am Soc Nephrol. 2021;32:
monotherapy versus cyclophosphamide-corticosteroid com-
972–982. https://doi.org/10.1681/ASN.2020071091
bination therapy for idiopathic membranous nephropathy: a
12. Ramachandran R, Kumar V, Bharati J, et al. Long-term follow- meta-analysis. Medicine. 2021;100:e26628. https://doi.org/10.
up of cyclical cyclophosphamide and steroids versus tacro- 1097/MD.0000000000026628
limus and steroids in primary membranous nephropathy.
27. Waldman M, Beck LH Jr, Braun M, et al. Membranous ne-
Kidney Int Rep. 2021;6:2653–2660. https://doi.org/10.1016/j.
phropathy: pilot study of a novel regimen combining cyclo-
ekir.2021.07.028
sporine and rituximab. Kidney Int Rep. 2016;1:73–84. https://
13. Takahashi Y, Ikezumi Y, Saitoh A. Rituximab protects podo- doi.org/10.1016/j.ekir.2016.05.002
cyte and exerts anti-proteinuric effects in rat adriamycin-
28. Jha V, Ganguli A, Saha TK, et al. A randomized, controlled
induced nephropathy independent of B lymphocytes. Neph-
trial of steroids and cyclophosphamide in adults with
rol (Carlton). 2017;22:49–57. https://doi.org/10.1111/nep.12737
nephrotic syndrome caused by idiopathic membranous ne-
14. Fervenza FC, Abraham RS, Erickson SB, et al. Rituximab phropathy. J Am Soc Nephrol. 2007;18:1899–1904. https://doi.
therapy in idiopathic membranous nephropathy: a 2-year org/10.1681/ASN.2007020166
study. Clin J Soc Nephrol. 2010;5:2188–2198. https://doi.org/
29. van den Brand JAJG, Ruggenenti P, Chianca A, et al. Safety
10.2215/CJN.05080610
of rituximab compared with steroids and cyclophospha-
15. Ruggenenti P, Cravedi P, Chianca A, et al. Rituximab in idio- mide for idiopathic membranous nephropathy. J Am Soc
pathic membranous nephropathy. J Am Soc Nephrol. Nephrol. 2017;28:2729–2737. https://doi.org/10.1681/ASN.
2012;23:1416–1425. https://doi.org/10.1681/ASN.2012020181 2016091022
16. Beck LH Jr, Fervenza FC, Beck DM, et al. Rituximab-induced 30. Mathrani V, Alejmi A, Griffin S, Roberts G. Intravenous
depletion of anti-PLA2R autoantibodies predicts response in cyclophosphamide and oral prednisolone is a safe and
membranous nephropathy. J Am Soc Nephrol. 2011;22:1543– effective treatment option for idiopathic membranous ne-
1550. https://doi.org/10.1681/ASN.2010111125 phropathy. Clin Kidney J. 2017;10:450–454. https://doi.org/10.
17. Hoxha E, Thiele I, Zahner G, et al. Phospholipase A2 receptor 1093/ckj/sfw152
autoantibodies and clinical outcome in patients with primary 31. Zonozi R, Laliberte K, Huizenga NR, et al. Combination of
membranous nephropathy. J Am Soc Nephrol. 2014;25:1357– rituximab, low-dose cyclophosphamide, and prednisone for
1366. https://doi.org/10.1681/ASN.2013040430 primary membranous nephropathy: a case series with
18. Ruggenenti P, Debiec H, Ruggiero B, et al. Anti-phospholi- extended follow-up. Am J Kidney Dis. 2021;78:793–803.
pase A2 receptor antibody titer predicts post-rituximab out- https://doi.org/10.1053/j.ajkd.2021.04.014
comes of membranous nephropathy. J Am Soc Nephrol. 32. Howman A, Chapman TL, Langdon MM, et al. Immunosup-
2015;26:2545–2558. https://doi.org/10.1681/ASN.2014070640 pression for progressive membranous nephropathy: a UK
19. Wang X, Cui Z, Zhang Y-M, et al. Rituximab for non- randomized controlled trial. Lancet. 2013;381:744–751. https://
responsive idiopathic membranous nephropathy in a doi.org/10.1016/S0140-6736(12)61566-9
33. De Vriese AS, Glassock RJ, Nath KA, et al. A proposal for a 38. Hartono C, Chung M, Kuo SF, et al. Bortezomib therapy for
serology-based approach to membranous nephropathy. nephrotic syndrome due to idiopathic membranous ne-
J Am Soc Nephrol. 2017;28:421–430. https://doi.org/10.1681/ phropathy. J Nephrol. 2014;27:103–106. https://doi.org/10.
ASN.2016070776 1007/s40620-013-0028-x
34. Rojas-Rivera J, Fervenza FC, Ortiz A. Recent clinical trials in- 39. Geara AS, Bhoj V, Hogan JJ. Bortezomib treatment for re-
sights into the treatment of primary membranous nephrop- fractory PLA2R-positive membranous nephropathy. Glom
athy. Drugs. 2022;82:109–132. https://doi.org/10.1007/s40265- Dis. 2021;1:40–43. https://doi.org/10.1159/000515087
021-01656-1 40. Salhi S, Ribes D, Colombat M, et al. Bortezomib plus dexa-
35. Klomjit N, Fervenza FC, Zand L. Successful treatment of pa- methasone for rituximab-resistant PLA2Rþ membranous
tient with refractory PLA2R-associated membranous ne- nephropathy. Kidney Int. 2021;100:708–709. https://doi.org/10.
phropathy with obinutuzumab: a report of 3 cases. Am J 1016/j.kint.2021.04.011
Kidney Dis. 2020;76:883–888. https://doi.org/10.1053/j.ajkd. 41. Vink CH, van Cranenbroek B, van der Heijden JW, et al.
2020.02.444 Daratumumab for multidrug-resistant phospholipase-A2
36. Sethi S, Kumar S, Lim K, Jordan SC. Obinutuzumab is receptor-related membranous nephropathy. Kidney Int.
effective for the treatment of refractory membranous ne- 2022;101:646–647. https://doi.org/10.1016/j.kint.2021.12.
phropathy. Kidney Int Rep. 2020;5:1515–1518. https://doi.org/ 019
10.1016/j.ekir.2020.06.030 42. Saleem M, Shaikh S, Hu Z, et al. Post-transplant thrombotic
37. Barret C, Willcoks LC, Jones RB, et al. Effect of Belimumab on microangiopathy due to a pathogenic mutation in comple-
proteinuria and anti-phospholipase A2 receptor autoantibody ment factor I in a patient with membranous nephropathy:
in membranous nephropathy. Nephrol Dial Transplant. case report and review of literature. Front Immunol. 2022;13:
2020;35:599–606. https://doi.org/10.1093/ndt/gfz086 909503. https://doi.org/10.3389/fimmu.2022.909503