1. Introduction
Idiopathic membranous nephropathy (IMN) is an immune-mediated disease
with subepithelial immune complex deposition and glomerular basement
membrane changes [1]. Patients are mainly manifested by proteinuria,
hypoproteinemia, hypertension, and edema [2]. The auto-antigens like
M-type phospholipase A2 receptor (PLA2R) [3] and thrombospondin type
1 domain containing 7A
(THSD7A)
[4] can be detected in most MN patients. As surrogates of
immunologic activity, PLA2R and THSD7A provide a new direction for the
diagnosis and treatment of IMN [5].
The treatment of IMN is always controversial. Most patients with MN and
non-nephrotic proteinuria are sensitive to supportive therapy which
includes angiotensin-converting-enzyme (ACE) inhibitors and
angiotensin-receptor blockers (ARBs) [6]. However, in patients with
the highest risk of disease progression and the decrease of proteinuria
is seldom > 30% from pretreatment value, It mainly used
alkylating agents and calcineurin inhibitors in treatment [7, 8].
Alkylating agent (mainly cyclophosphamide) is usually used for high-risk
patients who failed to respond to 6-month supportive therapy [9] and
can effectively prevent IMN from ESRD and death. Calcineurin inhibitors
(mainly tacrolimus) can improve therapeutic effects and reduce toxicity
to achieve the purpose of reducing the rate of proteinuria and renal
function loss [9-12]. However, the efficacy of cyclophosphamide and
tacrolimus in IMN treatment has controversy.
RTX is an anti-CD20 monoclonal antibody [13] that targets to trigger
B cell to death through apoptosis [14, 15], complement-mediated
cytotoxicity [16], and antibody-dependent cellular cytotoxicity
[17, 18]. The efficacy of RTX as initial treatment is similar to
traditional immunosuppressants treatment (alkylating agents plus steroid
combination therapy and calcineurin inhibition therapy) [19-21]. The
standard protocol of RTX for MN is intravenous injection of 375
mg/m2 every week for 4 weeks, or two doses of 1000 mg
infusions 2 weeks apart or 1×375 mg/m2 intravenously
at a 14-day interval [22, 23]. Since the ideal RTX dosage and the
long-term side effects of a larger cumulative dose are unknown, and some
studies have demonstrated the effectiveness of low-dose regimens versus
conventional dosage (standard protocol or two doses of RTX (500 mg each)
) [22], nephrologists argued for the use of low doses of RTX (B
cell-driven treatment or the dose of RTX is 1×375
mg/m2 or 2×375 mg/m2 or 100 mg of
RTX or two doses of RTX (500mg each) infusion 7 days apart).
Compared to KDIGO (Kidney Disease: Improving Global Outcomes) 2012
guidelines, KDIGO 2020 guidelines emphasize the role of RTX in patients
with a moderate (pre-study proteinuria greater than 3.5 g/d and less
than 8 g/d) and high (pre-study proteinuria more than 8 g/d) risk of
IMN, but evidence regarding the efficacy and safety of RTX in MN
treatment remains elusive [9, 24]. There is still not meta-analysis
that can provide evidence of the RTX therapeutic advantages by
stratifying inclusion studies based on the risk of progression of renal
function loss in patients. At the same time, the efficacy of different
doses of RTX is controversial and uncertain. To guide the clinical use
of RTX, this article used statistical methods to summarize several
studies on MN treatment with RTX or conventional therapy and explore the
therapeutic effect of different RTX dosages (low dose versus standard
dose).
2. Methods
2.1. Data sources and searches
We systematically searched the randomized controlled trials (RCTs),
clinical studies, and cohort studies on the efficacy and safety of RTX
in the treatment of adult MN from Pubmed, Web of Science, Cochrane
Library, Embase, ScienceDirect, and SinoMed from inception until 1
December 2020. Additional articles come from the references of reviews,
meta-analyses, systematic reviews, reports, and guidelines. All these
articles are English. The appropriate keywords and medical subject
headings in logical combinations we used included “Rituximab”,
“Rituximab CD20 Antibody”, “Mabthera”, “IDEC-C2B8 Antibody”,
“Rituxan”, “GP2013”, “Membranous Nephropathy” “Membranous
Glomerulonephritides”, “Primary Membranous Nephropathy”, “Idiopathic
Membranous Glomerulonephritis” and “Heymann Nephritis”.
2.2. Inclusion and exclusion criteria
The
inclusion criteria contains: a)RCTs, cohort studies, clinical trials,
case-control study, and single-center experience; b)All patients in the
selected studies were confirmed to have IMN by renal biopsy. Each
patient was older than 18 years old, and c) Outcome events and remission
(CR or/and PR) need to be reported. The CR was defined as proteinuria
< 0.3 g/day accompanied by a normal serum albumin
concentration and normal serum creatinine (Scr). The PR was defined as
proteinuria < 3.5 g/day and a 50% or greater reduction from
peak values, accompanied by an improvement or normalization of the serum
albumin concentration and stable Scr. The study needs to evaluate the
efficacy of RTX in patients for at least 6 months.
The exclusion criteria contains: a) Any review articles, books, and
documents, meta-analysis, meeting records, case reports, ongoing
research, and other non-randomized studies were excluded; b) The results
of the study were related to the use of RTX in patients with secondary
MN or other patients with non-MN, and c) The study looked at RTX in
combination with other unsupportive agents for MN.
2.3. Data extraction and quality
assessment
Two
independent
reviewers
reviewed the original study reports and sifted and extracted the data.
Data includes the type of study, time of publication, author, region or
country, study duration, intervention, and control. Additionally,
reviewers also extracted demographic, clinical, immunological, and
pathological variables of patients. Outcome data is also extracted from
the study articles by the observers, mainly including CR, PR, TR.
Quality assessment is carried out through the Cochrane Collaboration’s
tool. If there is a disagreement between two independent reviewers about
the data, then the independent reviewers should discuss and reach a
consensus.
2.4. Data analysis
To analyze whether RTX has an advantage over other conventional
therapies in the treatment of MN, this meta-analysis using the Stata
software (Stata Corporation, Texas, USA). In subgroup analysis, patients
are grouped according to their pre-study proteinuria. RTX dose is used
as a variable for the analysis of the therapeutic effect of MN.
Inconsistency index (I2 ) statistics are used to
analyze the heterogeneity of the included studies. To analyze the
endpoints of TR, we choose the Mantel-Haenszel method of the random
effects model and applied effect index odds ratio (OR), this is because
significant heterogeneity (P < 0.1 orI2 > 50%) exists in included
studies. To analyze the effects of different doses of RTX on Scr,
proteinuria and ALB after treatment, we used the invariance fixed-effect
method and invariance random effect method and selected the mean
difference (MD) as the continuous outcome. Score statistics and precise
binomial method were used to calculate 95% CI for effect sizes.
STATA/MP-14 software was used for all data analysis. And all 2-sidedP < 0.05 was considered to indicate statistical
significance.
3. Results
3.1. Description of included trials
A total of 1675 relevant pieces of literature were identified in this
paper through a database search (Figure. 1), including 281 pieces from
Pubmed, 565 pieces from Web of Science, 73 pieces from Cochrane Library,
550 pieces from Embase, 82 pieces from Science Direct, 124 pieces from
SinoMed. The Endnote software was used to remove 1102 repeated articles
between different databases. Two inspectors removed reviews, Case
reports, Meta-analysis, and Off-topic types. Finally, six articles
[25-30] were included in the study comparing the therapeutic
advantages of RTX with conventional therapy. Twelve studies [30-42]
were included in the efficacy studies of different doses of RTX. The
studies provided information on 643 patients. Baseline data
characteristics of the included studies are summarized in Table 1 and
Table 2, respectively.
3.2. Quality assessment
We assessed the quality of the included studies by Cochrane Handbook and
assessed the quality of the included studies by giving “author
judgments” of ”low risk” or ”unclear risk” or ”high risk” for different
types of offset evaluation entries. The results showed that most of the
included studies were low-risk or unclear risk related to the offset
items, indicating that the quality of the included studies in this paper
was good.
3.3. Efficacy of RTX compared with other therapeutic agents in MN
(Totally remission)
Forest plots (Figure. 2) show the overall and subgroup efficacy and
safety of RTX in the treatment of MN compared to conventional agents.
Six articles reported TR and all RTX regimens are uniform dosages (4×375
mg/m2). The included studies showed that there is no
significant difference in TR (OR = 1.659, 95% CI 0.668 to 4.119,I2 of 61.9% indicating heterogeneity, P= 0.275) for MN with RTX compared to conventional therapy. In the
subgroup analysis, for patients with pre-study
proteinuria < 8 g/d, RTX had a higher TR
(OR = 2.663, 95% CI 1,361 to 5.210, I2 of
0.0% indicating heterogeneity, P = 0.004) than conventional
therapy, however, for patients with pre-study
proteinuria > 8 g/d, there was no
significant difference in TR (OR = 0.691, 95% CI 0.064 to 7.423,I2 of 83.3% indicating heterogeneity, P= 0.761).
3.4. Effect of RTX dose on the therapeutic of IMN
3.4.1. Proteinuria (g/24 hour)
The post-treatment proteinuria index was evaluated in twelve studies
(Figure. 3A). Results of meta-analysis showed RTX significantly reduced
proteinuria (MD = -4.885, 95% CI -6.340 to -3.370,I2 of 69.2% indicating heterogeneity, P< 0.0001) in patients with MN. In the subgroup analysis,
low-dose RTX was not effective than conventional dosage of RTX in
reducing proteinuria (Low dose MD = -3.999, 95% CI -6.177 to -1.820,I2 of 33.3% indicating heterogeneity, P< 0.0001; standard dose MD = -5.220, 95% CI -7.160 to -3.279
, I2 of 78.4% indicating heterogeneity,P < 0.0001).
3.4.2. Serum albumin
(g/L)
There are eleven articles reported the lever of ALB (Figure. 3B), which
shows that RTX treatment was associated with a statistically significant
increase in ALB (MD = 0.884, 95% CI 0.740 to 1.185,I2 of 72.0% indicating heterogeneity, P< 0.0001). In the subgroup analysis, low dose RTX improved ALB
(MD = 0.601, 95% CI 0.052 to 1.150, I2 of
83.2% indicating heterogeneity, P = 0.032). However, RTX can be
more significantly in increasing ALB (MD = 0.963, 95% CI 0.740 to
1.185, I2 of 53.7% indicating heterogeneity,P < 0.0001) in the standard dose subgroup.
3.4.3. Serum creatinine (mg/dL)
Scr at the end of treatment was reported in nine articles (Figure. 4).
Treatment with RTX led to no significant reduction Scr (MD = -0.027,
95% CI -0.196 to 0.142, I2 of 48.8%
indicating heterogeneity, P = 0.758). In subgroup analyses, both
low dose RTX and standard dose RTX did not significantly reduce Scr (Low
dose MD = 0.110, 95% CI -0.050 to 0.271, I2 of
0.0% indicating heterogeneity, P = 0.177. Standard dose MD =
-0.176, 95% CI -0.456 to 0.103, I2 of 56.5%
indicating heterogeneity, P = 0.216).