Comparations of efficacy and safety of rituximab, calcineurin inhibitors and cyclophosphamide in primary membranous nephropathy: a single-center retrospective analysis

doi:10.21203/rs.3.rs-3963185/v1

Background Rituximab (RTX), calcineurin inhibitor (CNI) and cyclophosphamide (CTX) plus glucocorticoids are first-line therapeutic options for primary membranous nephropathy (PMN).

Methods Totally 478 biopsy-proven PMN patients in single center were retrospectively included. After 1:1 propensity score matching (PSM), 258 patients were included in RTX, CNI or CTX group (86 patients in each group).

Results After PSM, there were no differences on serum creatinine, eGFR, serum albumin, urine protein, anti-PLA2R antibody among groups. The follow-up duration was 12 (10.5, 18) months in CNI group, 12 (12, 18) months in CTX group and 12 (12, 18) months in RTX group. Throughout entire follow-up period, 39 patients (45.3%) in CNI group, 47 patients (54.7%) in CTX group, and 59 patients (68.6%) in RTX group achieved composite response (complete remission and partial remission). The survival curve showed a higher composite response in RTX group than CNI group (p=0.018). A relapse occurred in 15 of 39 (38.5%) patients in CNI group, significantly higher than CTX group (4.3%, p<0.001) and RTX group (3.4%, p<0.001). In CNI group, 36% patients had a ≥25% decline in eGFR, and 15.1% of patients had a ≥50% decline in eGFR.

Conclusions RTX may be more effective than CNI in inducing remission in PMN and showed similar efficacy to CTX. CNI may have a high risk of proteinuria relapse and eGFR decline.

Primary membranous nephropathy

Calcineurin inhibitor

Cyclophosphamide

Rituximab.

Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults and accounts for approximately 20–35% of adult nephrotic syndrome cases(1). It is pathologically characterized by diffuse thickening of glomerular basement membrane and deposition of subepithelial immune complexes. The discovery of kidney-specific podocyte antigens and its autoimmune antibodies, over the past decade, bring us new insights into the disease recognition, diagnosis, and treatment. M-type phospholipase A2 receptor (PLA2R) is the major target antigen, with the anti-PLA2R antibody detectable in approximately 75–80% of patients with primary MN (PMN)(2,3). The level of serum anti-PLA2R antibody and other antibodies has enabled the prediction of treatment response, recurrence, and the risk of progression to end-stage renal disease (ESRD)(4,5).

Still, PMN is one of the leading causes of progression to ESRD in patients with primary glomerular disease. The 10-year renal survival rate is around 65–75%(6,7). Timing appropriate therapeutic intervention is necessary for the management of patients with PMN. The 2021 Kidney Disease: Improving Global Outcomes (KDIGO) Guidelines for Glomerulonephritis recommended calcineurin inhibitor (CNI) alone or in combination with glucocorticoids, cyclophosphamide (CTX) plus glucocorticoids, and rituximab (RTX) as the first-line therapeutic options for the treatment of PMN(8). While comparisons of the efficacy of these three immunosuppressive regimens are still a matter of debate. No previous studies have compared the efficacy of these three treatment options simultaneously.

In this retrospectively study, we describe our experience in the treatments efficacy and safety of PMN patients, including RTX alone, CNI and CTX plus glucocorticoids.

This retrospective study was performed at a single center, the Kidney Disease Center of the First Affiliated Hospital, Zhejiang University School of Medicine. Adult patients with PMN who were biopsy-diagnosed between January 2017 to May 2022 were eligible for enrollment. We have obtained informed consent from all patients and received approval from the hospital's ethics committee (Ref no. 2020571). The inclusion and exclusion criteria were (1) with biopsy-proven PMN; (2) older than 18 years at the onset; (3) with initial serum creatinine < 176 µmol/L and urinary protein-to-creatinine ratio (UPCR) ≥ 3.0 g/g, (4) under any of the following three treatment regimens (CNI monotherapy or CNI plus glucocorticoids, CTX plus glucocorticoids, RTX monotherapy) for at least 6 months; (5) absence of concomitant autoimmune disease or any other systemic disease known to be associated with secondary MN, such as systemic lupus erythematosus, malignancy, and hepatitis B and C virus infection, etc.

The enrolled PMN patients were divided into CNI group, CTX group and RTX group. Patients in CNI group were administered either tacrolimus (TAC) or cyclosporine (CsA) alone, or in combination with glucocorticoids. Oral TAC is initiated at a dose of 0.05 mg/kg/d and monitored to maintain a trough concentration level between 4–8 ng/ml. Oral CsA is started at a dose of 3–5 mg/kg/d and adjusted to achieve a target trough concentration level at 125–175 ng/ml. Gradually tapered after 6–9 months’ administration, and maintain the minimum effective dose for at least 12 months. Some patients in CNI group were treated with a combination of CNI with oral prednisone 0.3-0.5mg/kg/d for 4–8 weeks, and gradually tapered. Patients with poor treatment response are suggested to withdraw or change treatment regimen after 6 months follow-up. Cyclophosphamide was administered in a single dose of 500–750 mg/m² by intravenous infusion monthly for the initial 6 months, and once every 2–3 months for the later period. All patients in CTX group received a combination of oral prednisone 0.6–0.8 mg/kg/d for 4–8 weeks, and gradually tapered. Patients in RTX group received a dose of 375mg/m² intravenous rituximab once every two weeks until their peripheral blood B-cell count was 0/µl. Re-administration of rituximab was determined by degree of B-cell recovery, anti-PLA2R antibodies level and clinical remission status.

Complete remission (CR) was defined as UPCR < 0.3 g/g, normal serum albumin concentration and stable renal function. Partial remission (PR) was defined as a UPCR of 0.3–3.0 g/g with at least a 50% reduction from baseline, serum albumin concentration ≥ 30 g/l and stable renal function. Proteinuria failed to meet the criteria of CR or PR was considered as no response (NR). Relapse was defined as UPCR ≥ 3.0 g/g in two consecutive measurements after achieving CR or PR. The renal outcome was defined as the composite of end-point of renal function progression. eGFR was calculated according to chronic kidney disease epidemiology collaboration (CKD-EPI) formula. ESRD was defined as a permanent drop in eGFR to < 15 mL/min/1.73 m² requiring dialysis or kidney transplantation. Renal function decline was defined as a ≥ 25%, and ≥ 50% decline in eGFR compared with baseline value. The primary outcome was clinical remission rate at 6 and 12 months. Secondary outcomes included the incidence of relapse, progression to ESRD and renal function decline.

Statistical analysis was performed with SPSS (version 26.0) and Graph Pad Prism (version 9.3). Quantitative variables with normal distribution were described as mean ± standard deviation (SD), compared with T-test or one-way ANOVA. Quantitative variables with skewed distribution were described as medians (interquartile ranges), compared with the Kruskal-Wallis test or Mann-Whitney test. Categoric variables were described as frequencies (percentages), and were analyzed using the Chi-squared test or Fisher’s exact test. Cumulative incidences were calculated by the Kaplan-Meier method and compared by Log-rank test. A p value < 0.05 was considered statistically significant. Propensity score matching (PSM) was used to obtain balance among three groups, we used 1:1 nearest-neighbor matching without replacement within a match tolerance width of 0.02.

A total of 1126 patients with renal biopsy-proven MN were screened. Patients lost follow-up (n = 165), secondary MN (n = 105), optimized supportive care only (n = 179), severe renal dysfunction at the onset (n = 21), non-nephrotic proteinuria (n = 80), insufficient data (n = 21), and less than 6 months of follow-up (n = 81) were excluded. 478 patients with PMN met the criteria and their median follow-up time was 12 (12, 24) months. The study enrollment flow chart is shown in Fig. 1, with 219 patients in CNI group, 106 patients in CTX group, and 153 patients in RTX group.

To minimize the treatment options selection bias, a PSM was performed to balance confounders among the three groups. PSM was conducted using a 1:1 nearest-neighbor matching method without replacement and a caliper of 0.02 with CNI group as the reference group.

Baseline characteristics before and after PSM for PMN patients are presented in Table 1. Before PSM, there were no significant differences of sex, age, blood pressure, serum cholesterol, UPCR, anti-PLA2R antibody positive rate, and use of angiotensin-converting enzyme (ACEI)/angiotensin 2 receptor blocker (ARB) among three groups (p > 0.05). Patients in CNI group showed lower serum creatinine (p < 0.001) and higher eGFR levels (p < 0.001) compared with those in CTX group and RTX group. Furthermore, statistical differences were observed in the levels of serum albumin (p = 0.041) and anti-PLA2R antibody titers (p = 0.035) among the three treatments. Therefore, the factors that might influence the choice of treatment options were considered as covariates for conducting a 1:1 PSM.

Table 1

Baseline characteristics before and after propensity score matching
Characteristic	Before PSM				After PSM
Characteristic	CNI, n = 219	CTX, n = 106	RTX, n = 153	p	CNI, n = 86	CTX, n = 86	RTX, n = 86	p
Age, yr	57 (45, 64)	56 (50, 65)	56 (47, 65)	0.749	58 (45, 65)	56 (49.8, 64.3)	55 (46.5, 60)	0.074
Male, n (%)	140 (63.9)	75 (70.8)	108 (70.6)	0.293	61 (70.9)	58 (67.4)	57 (66.3)	0.793
Systolic BP, mmHg	130 (115, 141)	131 (118, 143)	130 (120, 140)	0.839	128 (114, 138)	133 (117, 143)	129 (118, 140)	0.344
Diastolic BP, mmHg	79.93 ± 14.13	81.27 ± 12.72	80.18 ± 13.44	0.699	79.31 ± 15.00	80.87 ± 13.36	79.53 ± 14.15	0.738
Serum cholesterol, mmol/L	6.89 (5.83, 8.80)	6.95 (5.50, 8.92)	6.76 (5.51, 7.92)	0.082	7.30 (5.98, 8.90)	6.85 (5.50, 8.71)	6.62 (5.40, 7.71)	0.063
Serum creatinine, µmol/L	76 (63, 88)	87 (72, 105)**	86 (71, 108)**	< 0.001	80 (68, 94)	82 (69, 92)	81 (67, 97)	0.966
Serum albumin, g/L	24.8 (21.1, 28.4)	23.4 (20.2, 26.3)	23.4 (20.0, 27.8)	0.041	24.6 ± 5.5	23.9 ± 4.8	24.9 ± 5.4	0.486
eGFR, mL/min/1.73m²	93.9 (78.6, 105.5)	83.7 (66.3, 96.5)**	83 (62.7, 99.9)**	< 0.001	88.9 (71.1, 100.7)	90.2 (72.4, 97.7)	91.2 (71.9, 104.1)	0.604
UPCR, g/g	4.47 (3.53, 5.23)	4.23 (3.55, 6.00)	4.48 (3.60, 6.62)	0.108	4.21 (3.60, 5.26)	4.21 (3.48, 5.94)	4.26 (3.49, 5.54)	0.983
PLA2R-Ab-positive, n (%)^a	86/108 (79.6)	66/83 (79.5)	127/146 (87)	0.203	37/48 (77.1)	60/74 (81.1)	70/81 (86.4)	0.384
PLA2R-Ab titer, RU/ml	36.6 (5.7, 113.1)	41.1 (7.3, 109.3)	68.2 (16.6, 168.7)	0.035	35.9 (3.5, 100.3)	42.8 (7.0, 112.5)	62.8 (16.8, 164.0)	0.154
ACE inhibitor/ARB use, n (%)	116 (53)	59 (55.7)	90 (58.8)	0.535	42 (48.8)	48 (55.8)	50 (58.1)	0.444
Prior immunosuppressive therapy, n (%)	14 (6.4)	41 (38.7)**	74 (48.4)**	< 0.001	5 (5.8)	30 (34.9)**	50 (58.1)**^^	< 0.001
Follow-up, month	18 (12, 24)	12 (12, 18)**	12 (12, 15)**	< 0.001	12 (10.5, 18)	12 (12, 18)	12 (12, 18)	0.939
Data are shown as n (%), median (IQR), or mean ± SD. ^aA part of patients lack baseline PLA2R-Ab tests, are shown as n/N. Significance values were adjusted by the Bonferroni correction for multiple comparisons. p < 0.05, *p < 0.01, CNI group as control; ^^p < 0.01, CTX group as control.ACE, angiotensin-converting enzyme; ARB, angiotensin 2 receptor blocker; BP, blood pressure; CNI, calcineurin inhibitor; CTX, cyclophosphamide; eGFR, estimated glomerular filtration rate; PLA2R-Ab, M-type phospholipase A2 receptor antibody; PSM, propensity score matching; RTX, Rituximab; UPCR, urine protein-to-creatinine ratio.

After PSM, a total of 258 patients (86 patients in each group) were selected for further statistical analysis, and no significant difference was found among three groups in terms of serum creatinine, eGFR, serum albumin, anti-PLA2R antibody levels, and follow-up time (p > 0 .05). However, the RTX group still had a significantly higher rate of previous immunosuppressant application than the other two groups (p < 0.001).

Table 1. Baseline characteristics before and after propensity score matching (at the bottom of this document)

Comparison of response to treatment

All patients were successfully monitored and treated for a minimum of six months. The median follow-up duration for CNI group was 12 (10.5, 18) months, while the CTX group was monitored for 12 (12, 18) months and the RTX group for 12 (12, 18) months. Primary and secondary outcomes were listed in Table 2.

Table 2

Primary and secondary endpoints.
Complete remission
Primary and secondary endpoints	CNI, n = 86	CTX, n = 86	RTX, n = 86
6 months, n (%)	5/86 (5.8)	3/86 (3.5)	2/86 (2.3)
12 months, n (%)	5/65 (7.7)	11/66 (16.7)	9/74 (12.2)
End of follow-up, n (%)	11/86 (12.8)	18/86 (20.9)	18/86 (20.9)
Complete or partial remission
6 months, n (%)	27/86 (31.4)	33/86 (38.4)	31/86 (36)
12 months, n (%)	25/65 (38.5)	36/66 (54.5)	51/74 (68.9)**
End of follow-up, n (%)	39/86 (45.3)	47/86 (54.7)	59/86 (68.6)**
Relapse
Relapse, n (%)	15/39 (38.5)	2/47 (4.3)**	2/59 (3.4)**
Time from remission to relapse, months	11.6 ± 8.1	3, 21^a	12, 21^a
Renal function progression
≥ 25% decline in eGFR, n (%)	31/86 (36)	14/86 (16.3)**	8/86 (9.3)**
≥ 50% decline in eGFR, n (%)	13/86 (15.1)	4/86 (4.7)	0**
ESRD/dialysis, n (%)	4/86 (4.7)	3/86 (3.5)	0

Data are shown as n/N (%) or mean ± SD. ^aTime from remission to relapse for the two patients are separately listed in the table.**p < 0.01, CNI group as control. CNI, calcineurin inhibitor; CTX, cyclophosphamide; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; RTX, Rituximab.

A total of 25 patients (38.5%) in CNI group, 36 patients (54.5%) in CTX group, and 51 patients (68.9%) in RTX group achieved a composite response (either complete or partial remission) at 12 months. Furthermore, throughout the entire follow-up period, 39 patients (45.3%) in the CNI group, 47 patients (54.7%) in the CTX group, and 59 patients (68.6%) in the RTX group had the composite outcome of remission. Compared to the CNI group, the RTX group demonstrated a significantly higher composite response rate both at 12 months (68.9% vs 38.5%, p < 0.001) and at the end of the follow-up (68.6% vs 45.3%, p = 0.002). However, no difference was found at 6 months in the composite response rate among three groups (p > 0.05). The complete remission rates were similar among three groups at 6 months, 12 months, and the last follow-up (p > 0.05).

The relapses were analyzed in 145 patients who achieved partial or complete remission throughout the entire follow-up period. Notably, 15 patients (38.5%) experienced proteinuria relapse in CNI group, which is significantly higher than those in CTX group (2 patients, 4.3%, p < 0.001) and in RTX group (2 patients, 3.4%, p < 0.001). No statistical difference in disease-free duration was found among groups (p > 0.05).

For renal outcomes, a decline in eGFR was more frequently observed in CNI group. However, the risk of progressing to ESRD was comparable among three groups (p > 0.05). A more than 25% decline in eGFR was noted in 31 patients (36%) in CNI group, which was higher than those in CTX group (14 patients, 16.3%, p = 0.003) and in RTX group (8 patients, 9.3%, p < 0.001). In addition, there were 13 patients (15.1%) in CNI group, 4 patients (4.7%) in CTX group, and no patients in RTX group observed a more than 50% decline in eGFR. Compared to CNI group, RTX group may have a lower risk for severe renal function decline (p < 0.001).

Probabilities of remission and relapse rates are shown in Fig. 2. The RTX group showed potential for superiority in terms of the cumulative composite response rate (Log-rank HR 1.54, 95%CI 1.04–2.29, p = 0.018) compared to CNI group. However, there was no discernible difference between CTX group and RTX group (p > 0.05). The cumulative complete remission rates were comparable among three groups (p > 0.05).

The cumulative incidence of relapse was significantly higher in CNI group compared to CTX group (Log-rank HR 8.91, 95% CI 3.43–23.13, p < 0.001) and RTX group (Log-rank HR 8.45, 95% CI 3.26–21.91, p < 0.001).

Factors influence the treatment response

The clinical characteristics of remission and no response are summarized in Table 3. A total of 145 patients experienced complete or partial remission, whereas 113 patients did not respond to treatments (NR). Factors such as age (p = 0.003), treatment selection (p = 0.008), and duration of follow-up (p < 0.001) may impact the response to treatments. Thus, a multivariate Cox regression model was fitted to mitigate the risk of confounding. Factors may influence the treatment response were listed in the Supplementary materials.

Table 3

Baseline characteristics in patients with different response to treatment
Characteristic	Remission, n = 145	No response, n = 113	p
Age, yr	55 (45, 62)	57 (51, 67)	0.003
Male, n (%)	100 (69)	76 (67.3)	0.770
Systolic BP, mmHg	130 (113, 140)	131 (118.5, 142)	0.203
Diastolic BP, mmHg	79.65 ± 13.10	80.24 ± 15.44	0.089
Serum cholesterol, mmol/L	6.80 (5.48, 8.28)	6.89 (5.80, 8.64)	0.432
Serum creatinine, µmol/L	83 (68.5, 96.5)	80 (67, 92.5)	0.643
Serum albumin, g/L	24.9 ± 5.5	23.8 ± 4.9	0.227
eGFR, mL/min/1.73m²	90.6 (71.3, 101.8)	90.5 (72.7, 99.3)	0.609
UPCR, g/g	4.22 (3.53, 5.68)	4.24 (3.52, 5.28)	0.796
PLA2R-Ab-positive, n (%)^a	100/124 (80.6)	67/79 (84.8)	0.449
PLA2R-Ab titer, RU/ml	41.10 (4.56, 110.63)	70.86 (22.26, 156.34)	0.015
ACE inhibitor/ARB use, n (%)	77 (53.1)	63 (55.8)	0.672
Treatment			0.008
CNI, n (%)	39 (26.9)	47 (41.6)	0.013
CTX, n (%)	47 (32.4)	39 (34.5)	0.723
RTX, n (%)	49 (40.7)	27 (23.9)	0.005
Prior immunosuppressive therapy, n (%)	51 (35.2)	34 (30.1)	0.389
Follow-up, month	15 (12, 24)	12 (6, 15)	< 0.001

Data are shown as n (%), median (IQR) or mean ± SD. ^aA part of patients lack baseline PLA2R-Ab tests, are shown as n/N. ACE, angiotensin-converting enzyme; ARB, angiotensin 2 receptor blocker; BP, blood pressure; CNI, calcineurin inhibitor; CTX, cyclophosphamide; eGFR, estimated glomerular filtration rate; PLA2R-Ab, M-type phospholipase A2 receptor antibody; RTX, Rituximab; UPCR, urine protein-to-creatinine ratio.

Safety profiles

Adverse events recorded in this study are shown in Table 4. At least one adverse event was observed in 14 (16.3%), 19 (22.1%), and 22 (25.6%) patients in CNI group, CTX group and RTX group respectively. Seven patients in the RTX group experienced leukopenia, which was notably higher compared to CNI and CTX groups (p = 0.001), where only one patient reported leukopenia. It is surprising that we observed more leukopenia events in RTX group, rather than CTX group. This may be attributed to the combination use of glucocorticoid with cyclophosphamide, while RTX was in monotherapy. While the incidence of other adverse events was not statistically different among three treatments (p > 0.05).

Table 4

Adverse events
Adverse events	CNI, n = 86	CTX, n = 86	RTX, n = 86
Nausea/diarrhea	1	3	0
Allergies/rashes	1	0	2
hypertrichosis	2	0	0
Impaired glucose tolerance	1	2	1
Diabetes	3	3	1
Osteoporosis	0	0	2
Leukopenia	1	1	7*
Elevated liver enzymes	3	1	6
Pneumonia	1	3	3
Other infection	2	6	1
Cancer	3	2	0
Cardio-cerebrovascular events	3	1	0
Death	2	3	0

Data are shown as n. *p < 0.05.

In this study, we compared the efficacy and safety of CNI, CTX, and RTX in the treatment of PMN. We found that these three regimens were of similar efficacy at the outset of first 6 months. However, RTX might be more efficient in inducing proteinuria remission than CNI after 12 months. In terms of cumulative remission rates, RTX was potentially superior to CNI but comparable to CTX. Patients with CNI therapy have the highest risk of proteinuria relapse and renal function decline.

Rituximab, a monoclonal antibody targeting the CD20 antigen, effectively targets exhausted B cells. In recent years, an increasing number of prospective randomized controlled trials have elevated rituximab to the forefront of treatment for PMN. In this study, 68.9% of patients in RTX group achieved a complete or partial remission at the end of 12 months, which is comparable to the results of 60% in the MENTOR trial(9) and 62% in the RI-CYCLO trial(10). Our center adopted a low-dose rituximab therapy (375mg/m² every 2 weeks until peripheral blood B cell count was 0/µl), and 13 patients (15.1%) achieved clinical remission after twice injections of rituximab, with a median remission time of 9 (IQR 3, 12) months. Although high-dose rituximab is more effective in inducing depletion of B cells and remission of proteinuria(11), the value of low-dose rituximab in the treatment of PMN still deserves recognition.

Cyclophosphamide in combination with glucocorticoids is the preferred treatment of choice for patients at high risk for progression of renal function. Previous non-randomized studies have reported a 12-month remission rate of approximately 50–60% with CTX therapy(12,13). While, more promising results have arisen from recent trials. The remission rates at the end of 12 months, as reported in the STARMEN trial and the RI-CYCLO trial were around 70%(10,14). We reported a 12-month complete remission of 16.7% and a composite remission rate of 54.5%, which is lower than our expectation. A relatively frequent replacement of the regimen during the CTX therapy course may account for it. Although most of the patients in this study exhibited good tolerance to the regimen during their treatment, the potential toxic side effects of CTX have been a source of concern.

CNI used to be an alternative first-line treatment option for high-risk patients who declined CTX therapy or for those in whom CTX was contraindicated. Both cyclosporine and tacrolimus are effective in reducing proteinuria. Results of previous non-randomized studies have reported 12-month remission rates of approximately 70–75% for cyclosporine and 80–90% for tacrolimus(15–17). A network meta-analysis of 72 RCTs suggests that tacrolimus and cyclosporine may be more effective than CTX in the treatment of PMN(18). However, in this study, the 12-month remission rate of CNI was only 38.5%, which is the least effective compared to the other two regimens. The part of patients with CNI monotherapy may be the reason. So, we compared the efficacy of CNI alone with CNI plus glucocorticoids therapy and found a difference in the complete remission rate, while the other outcomes showed comparable efficacy. (Supplementary materials).

Decline in renal function is the most common adverse event of CNI therapy. Both drug nephrotoxicity and persistent proteinuria may lead to a permanent eGFR decline, which is hard to distinguish in this retrospective study. The toxicity side effect of CNI is associated with constriction of afferent arterioles, vacuolization of tubular epithelial cells, and histological damage of the glomeruli, arterioles, and tubulointerstitium(19,20). Meanwhile, prolonged administration of CNI may increase the risk of nephrotoxicity(21,22). In this study, nearly one-third patients suffered an eGFR decline after 3-year maintenance of CNI. Timing appropriate treatment withdraw or regimen replacement may better benefit in preserving renal function.

In addition, we noticed more patients had a treatment withdrawals and regimen change in the CTX and CNI group when the efficacy was not satisfactory. During their treatment course, 10 patients (11.6%) in CTX group, 23 patients (15.1%) in CNI group, and 5 patients (4.7%) in RTX group underwent regimen changes after 6 months. Reasons for regimen change including persistent proteinuria, progress in renal function, intolerance to treatment, sever infection, and discovery of malignant tumor. This kind of situation usually occurred during 6–9 months of the follow-up. However, it is noteworthy that the remission rates after 6 months of treatment were similar among three groups. Patients who received rituximab were more inclined to continue their therapy rather than opt for a regimen replacement, despite the lack of clinical remission. This could potentially attribute for the higher cumulative remission rate observed in RTX group at our center.

We acknowledge the limitations of this study. Firstly, this was a single medical center based retrospective study, with small cohort size and unequal follow-up duration. Although all patients have undergone biopsy confirmation, the baseline anti-PLA2R antibody levels were not measured in some of the patients. Secondly, the inclusion criteria placed no restrictions on the utilization of previous immunosuppressive therapy. Consequently, some patients with refractory characteristics were included, and the effectiveness of the current intervention may be influenced by the delayed impact of previous courses of therapy. However, this study had mitigated the impact of confounding variables by utilizing the PSM method that allowed us to draw conclusions about the treatment of PMN in clinical practice. Large, prospective, multi-center clinical researches are still need to further confirm these results.

In conclusion, RTX appears to be more effective than CNI in inducing remission of PMN, and show similar efficacy to CTX group. CNI therapy may have a higher risk of proteinuria relapse and renal function decline.

Acknowledgements

None.

Funding

The study was supported by the Primary Research and Development Plan of Zhejiang Province (2020C03034) to Fei Han.

Authors’ contributions

Luying Lu and Fei Han were involved in the study design, conduct of the study, data collection and interpretation. Luying Lu wrote the first draft of the manuscript, and Fei Han revised it. Huayan Zhu and Shasha Cai were involved in conduct of the study, data collection and data analysis. Guangjun Liu, Yaomin Wang, Pingping Ren, Lan Lan, Xiaoqi Shen, Liangliang Chen, Ying Xu, Jun Cheng, Xiayu Li, Jianghua Chen and Fei Han were involved in follow up the patients and data collection. All authors reviewed the manuscript drafts, provided approval of the final version for submission, and take the responsibility for the accuracy and integrity of the data.

Ethics declarations

Ethics approval and consent to participate

The study passed an ethical review by the Institutional Review Board of the First Affiliated Hospital, Zhejiang University School of Medicine (Ref no. 2020571). All subject were explained the significance and purpose of the study, and signed informed consent.

Competing interests

The authors declare no competing interests.

Consent for publication

Not Applicable.

Data availability

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

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No competing interests reported.

Supplementarymaterials.docx

Comparations of efficacy and safety of rituximab, calcineurin inhibitors and cyclophosphamide in primary membranous nephropathy: a single-center retrospective analysis

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Abstract

Figures

Introduction

Methods

Results

Comparison of response to treatment

Factors influence the treatment response

Safety profiles

Discussion

Declarations

References

Additional Declarations

Supplementary Files

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