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Clinical Profile and Long-Term Outcomes of Patients with Primary Membranous Nephropathy: A Comparison of Different Immunosuppressive Therapies
, Puru Tyagi1, Pooja Prakash Prabhu1,, Gurudev K.C1, Girish M.S1,, Rajashekar1, Mohammed Yusuf1, Hamsa V2,
Corresponding author: Pooja Prakash Prabhu, Department of Nephrology, M S Ramaiah Medical College, Bengaluru, Karnataka, India. E-mail: pooja_sadvidya@yahoo.com
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Received: ,
Accepted: ,
Abstract
Background
Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. Few studies from India have evaluated the efficacy of different forms of therapy in achieving long-term remission.
Materials and Methods
This is a retrospective observational study of patients done over 15 years. Patients were stratified into low, moderate, or high risk category. Those in the moderate to high risk category received immunosuppressive therapy, including rituximab (RTX), cyclical cyclophosphamide (CTX) and corticosteroids, or tacrolimus (TAC). These patients were followed up for achievement of remission/nonresponse/relapse or progression to CKD.
Results
A total of 116 patients classified as moderate or high risk were started on immunosuppressive medications. A total of 105 patients were followed up for a mean of 7.5 years; 42% were in complete remission, 17% in partial remission at the last follow-up, and 19 patients had relapsed during the follow-up period. At the end of 1 year, the overall remission rate was 77.1%. (55.3% -complete remission, 22.7%-partial remission). The remission rates (complete plus partial remission) in the three groups were similar (75% in RTX, 75% in cyclophosphamide, 80% in TAC , p = 0.8). TAC was associated with a 2.8-fold higher risk of relapse than RTX (p = 0.018). There was no statistically significant difference in complications between those who received either therapy.
Conclusion
There was no difference in remission rates among the three groups at 1 year. RTX was comparable to cyclophosphamide and TAC in achieving remission and good renal outcomes.
Keywords
Complication
Cyclophosphamide
Membranous nephropathy
Remission rate
Rituximab
Tacrolimus
Introduction
Membranous nephropathy (MN) is a predominant cause of nephrotic syndrome in adults.1 There are various therapies available for MN; however, cyclical cyclophosphamide (CTX) and corticosteroids therapy has stood the test of time. KDIGO 2021 guidelines recommend that patients at risk for disease progression could be treated with “rituximab (RTX) or alternate month glucocorticoids and cyclophosphamide for 6 months, or tacrolimus (TAC)-based therapy for ≥6 months, depending on the estimate of risk”.2 Also, the guidelines advocate cyclophosphamide for patients at very high risk, including life-threatening nephrotic syndrome or rapidly deteriorating kidney function. Few studies from India have evaluated the efficacy and safety of all three forms of therapy in primary MN. This study aims to analyze the clinic-pathological profile, efficacy of various immunosuppressive regimens, safety, and long-term renal outcomes in patients diagnosed with primary MN.
Materials and Methods
This is a single-center retrospective observational study conducted at Ramaiah Medical College Hospital, Bengaluru. Data of all patients with biopsy-proven MN over 15 years (2008-2023) were collected after obtaining scientific and ethical committee permissions. A total of 235 adult patients were diagnosed with MN during this period. Secondary MN were ruled out by performing appropriate tests, including chest X-ray, Ultrasound of the abdomen and pelvis, Serological tests for HIV, HBsAg, anti-HCV antibody levels, ANA (by IF), and serum PSA levels. Endoscopy and colonoscopy were performed if required. Ultimately, 153 patients were classified as primary MN based on clinical and immunohistochemical criteria and included in the study. Anti-PLA2R antibody levels were tested in only 20 patients, as this test has been available at our center only in the last few years. The clinical profile, proteinuria level, and renal function were recorded. All patients were stratified into three risk categories based on proteinuria levels, renal function, and histopathological findings as follows: low risk - normal eGFR and proteinuria <3.5 g/day or 50% reduction in proteinuria within 6 months of conservative therapy; moderate risk - normal eGFR, proteinuria >3.5 grams per day and no reduction in proteinuria by ≥50% within 6 months of conservative therapy; high risk: eGFR <60 mL/min/1.73 m2, or proteinuria >8 grams/day for 6 months, normal eGFR and proteinuria >3.5 grams/day, with ≥50% reduction after 6 months of conservative therapy and either serum albumin <2.5 mg/dL and anti-PLA2R antibodies >50 RU/ml.
Histopathological examination
A single nephropathologist evaluated the kidney biopsies. Diagnosis of MN involved identifying thickening of the glomerular basement membrane (GBM) and a spike in the GBM on light microscopy, along with granular IgG and C3 staining along the GBM on immunofluorescence. Interstitial fibrosis (IF) and tubular atrophy (TA) were graded on a scale from 0 to 3:- 0- No IFTA; 1 (mild) <10% IFTA; 2 (moderate)- 10-50% IFTA; 3 (severe)- >50% IFTA.
Study groups and treatment modalities
Those patients who had subnephrotic range proteinuria and eGFR >60 mL/min were considered to be low risk, hence managed with conservative therapy. Also, patients with IFTA >50% on biopsy and eGFR <30 mL/min at presentation were managed conservatively and not offered immunosuppression. They had been started on Renin-Angiotensin-Aldosterone System (RAAS) blockade, salt and protein restriction, lipid management, and lifestyle modifications.
Those patients in the moderate-to-high risk group were given immunosuppressive medications at the clinician’s discretion if persistent proteinuria persisted despite conservative management. Patients were stratified into three treatment groups based on the primary immunosuppressive regimen: RTX Group- patients received four doses of rituximab- 375mg/m2/dose intravenous infusion one week apart; CTX and corticosteroids Group- patients underwent a 6-month course of alternating corticosteroids - Injection Methylprednisolone 500 mg/day for 3 consecutive days at the beginning of the month followed by oral prednisolone 0.5 mg/kg/day for the remaining 27 days at months 1, 3 and 5; and oral cyclophosphamide 2 mg/kg/day for 30 days at months 2, 4, 6 and TAC Group- Patients received TAC at a starting dose of 0.05 mg/kg/day, adjusted to maintain trough levels of 4 - 6 ng/mL, along with tapering doses of steroids.
All patients had undergone regular monitoring of proteinuria and renal function, and follow-up data were assessed to determine achievement of remission, relapse, or progression to kidney failure. The definitions are: complete remission: 24 h proteinuria <0.3g and serum albumin >3.5g/dL; partial remission: 50% decline in proteinuria, 24 h proteinuria >0.3 g and <3 g, a rise of serum albumin to >3 g/dL, and stable renal function; no Response: Reduction in 24 h proteinuria by <25% or increase in proteinuria from the baseline or worsening renal function; relapse: Defined as the recurrence of nephrotic-range proteinuria (>3.5 g per 24 h) following achievement of either complete or partial remission during the follow-up period and progression to end-stage renal disease (ESRD): Defined as a sustained decline in estimated glomerular filtration rate (eGFR) to <15 mL/min/1.73 m2 or the initiation of renal replacement therapy (hemodialysis, peritoneal dialysis, or kidney transplantation).
Statistical methods
All patients during the study period were included in the study. Continuous variables were expressed as mean ± SD or median with interquartile range (IQR), depending on the distribution. Categorical variables were presented as frequencies and percentages. For comparisons between groups: a. Categorical variables were compared using the Chi-square test (χ2) or Fisher’s exact test when expected cell frequencies were <5.b. Continuous variables were compared using one-way ANOVA for normally distributed data or the Kruskal-Wallis test for non-normally distributed data. Time-to-event outcomes, including time to remission, were analyzed using Kaplan-Meier survival curves. The log-rank test was used to compare renal survival curves between different treatment groups. Cox proportional hazards regression was used to calculate hazard ratios for relapse risk between treatment regimens.A p <0.05 was considered statistically significant for all analyses.
Results
Among 235 cases, 153 with biopsy-confirmed primary MN over the past 15 years (2008-2023) were included in the study. Anti-PLA2R antibody testing was done in 20 and was positive in 16 at presentation. The mean age distribution was 42 ± 12 years, and the majority of patients were males (60.1%). The most common clinical presentations were facial puffiness and pedal oedema (88.2%), followed by microhematuria and pedal oedema (11%). Hypertension was present in 51 patients (33.1%) and diabetes mellitus in 9 patients (5.8%).
Among the cohort, 25 low-risk patients who had sub-nephrotic range proteinuria with a mean proteinuria (2452 mg/day) and a mean albumin (3.1 mg/dL) were managed conservatively. Twelve patients who had low GFR (< 30ml/min) at presentation with severe IFTA (>50%) on biopsy were also managed conservatively and not offered immunosuppressive therapy.
The remaining 116 patients, classified as moderate or high risk, were started on one of the three immunosuppressive medications. The overall remission rate was 77.1% at the end of 1 year. 64 (55.3%) and 26 (22.7%) patients achieved complete remission and partial remission after 1 year following immunosuppressive therapy. At the end of 1 year, there was no statistically significant difference in remission rates between the three groups [Table 1]; 36 (23.5%) patients remained refractory to their initial immunosuppressive regimen and were offered alternate therapy, of which 22 achieved remission (complete remission (CR) + partial remission (PR)) and 14 were offered 3rd line of therapy; despite this 11 (9.4%) patients did not respond to any form of therapy and were labelled as non-responders [Tables 1 and 2].
| Treatment | Mean age (years) | Mean 24-hour proteinuria (mg) | Mean creatinine (mg/dL) | Serum albumin (g/dL) | Anti -PLA2R positivity | Total no. remission at 1 year (%) | p value |
|---|---|---|---|---|---|---|---|
| Rituximab (n= 40) | 41.3 | 10,920 | 1.16 | 2.35 | 10 | 30 (75) | 0.812 |
| Modified ponticelli and cyclical cyclophosphamide (n=16) | 44.5 | 9278 | 1.03 | 2.06 | 2 | 12 (75) | |
| Tacrolimus (n=60) | 46.2 | 9454 | 0.91 | 2.54 | 12 | 48 (80) |
CR: Complete remission, PR: Partial remission
| Treatment Total no. 116 | Moderate risk | High risk | CR @ 1year | PR @ 1 year | No remission | 2nd line therapy | CR | PR | No remission | 3rd line therapy | CR | PR | Non responders |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Rituximab (n=40) | 28 | 12 | 19 | 11 | 10 | TAC-5 CTX-5 | 2 | 3 | 5 | TAC-2 CTX-3 | - | - | 5 |
| Modified Ponticelli (n=16) | 6 | 10 | 10 | 2 | 4 | RTX -4 | 0 | 0 | 4 | TAC-4 | - | - | 4 |
| Tacrolimus (n=60) | 48 | 12 | 25 | 13 | 22 | RTX -12 CTX -10 | 8 | 9 | 5 | CTX-4 RTX-3 | - | 1 | 7 |
CR: Complete remission, PR: Partial remission
RTX group: Forty patients received rituximab as the first-line therapy. Of these, 19 (47%) achieved complete remission, 11 (27%) achieved partial remission, and 10 received second-line therapies. In this subgroup, CTX and corticosteroids induced complete remission in two patients, and TAC achieved partial remission in three patients. Five patients did not respond to any form of therapy and were labelled as non-responders.
TAC group: Sixty patients received TAC plus steroids as first-line therapy. The majority belonged to the moderate risk category; 35 (58%) achieved complete remission, 13 (21%) achieved partial remission, and 22(36%) were transitioned to alternative regimens. 10 received the CTX and corticosteroids, and 12 received RTX. Despite these interventions, 5 patients did not achieve remission and were treated with third-line therapies. Of these, 4 patients remained non-responders despite multiple treatment attempts.
CTX and corticosteroid group: Sixteen patients received this regimen as first-line therapy. Of these, 12 achieved complete or partial remission, while 4 patients did not respond. The non-responders were treated with rituximab and TAC, but still failed to achieve remission.
Time-to-event outcomes: Among 116 patients, the median time to any remission (CR+PR) was 5.0 months (95% CI: 4.5-6.0) - RTX: 4.1 months (IQR: 2.8-6.3); CTX and corticosteroids: 5.4 months (IQR: 3.9-7.2) and TAC: 3.7 months (IQR: 2.5-5.6). There was no significant difference in remission rates across regimens (p = 0.8).
Long-term follow-up data
Out of 153 patients, 115 cases were diagnosed with MN between 2008-2019. Out of them, 10 cases were lost to follow-up after 1 year. Remaining 105 patients were followed up for a mean of 7.5 years (range 5-11 years), 22 patients who were in the low risk group continued to be in sustained remission and did not receive any form of immunosuppressive treatment during follow-up; 45 (42%) were in complete remission and 18 (17%) were in partial remission till the last follow-up [Supplementary Figures 1 and 2]. 19 patients in the TAC group were in complete remission (14 of them belonged to the moderate risk category).
Sixteen patients progressed CKD stage II-IV (15% in RTX, 14% in CTX, and 20% in the TAC group). There was no statistically significant difference between the progression rates (Ӽ2= 0.62, p = 0.71). Four patients progressed to CKD stage V and were initiated on dialysis. Mean time to ESRD post diagnosis was 5.5 years, 2 patients underwent renal transplant, and 2 patients died in the follow-up period.
Relapses and dual/triple therapy
Nineteen patients had relapse during the follow-up period. The relapse rates and median time to relapse have been listed in Table 3. TAC was associated with a 2.8-fold higher risk of relapse than RTX (p = 0.018). 30 patients received RTX plus TAC (as a combination therapy) either due to no response to the first therapy or as a therapy for relapse. 16 patients who received second-line therapy were in either complete or partial remission to date. Seven patients received TAC and CTX as dual therapy, 5 progressed to CKD. Three patients who received all three forms of immunosuppression sequentially had no remission and progressed to CKD.
| Treatment group | Relapses (%) | Median time to relapse (months) |
|---|---|---|
| Rituximab | 5 (12) | 28.4 |
| Modified ponticelli | 2 (12.5) | 31.2 |
| Tacrolimus | 12 (20) | 18.6 |
p = 0.66, Ӽ2 = 0.8
2-year follow-up
Out of the total, 38 patients were diagnosed with MN between 2020-2023, 8 were lost to follow-up, and the rest were followed up for a mean period of 2.6 years; 12 patients were in complete remission, 8 were in partial remission till last follow-up, 7 patients were labelled CKD stage II-IV, two patients were initiated on dialysis, and one underwent transplantation.
Histopathological correlation
Upon histopathological correlation, those who had <10% interstitial fibrosis and tubular atrophy (IFTA) (n=125) had significantly better therapeutic outcomes (p <0.01). Renal insufficiency (GFR< 60 mL/min) at presentation emerged as a critical predictor of non- response or relapse (p <0.001). TAC group had higher relapses or non-responders (n = 22), and CTX group had the least relapses (4 patients).
Comparison of moderate risk group versus high risk group
There were 71 patients in the moderate-risk category and 45 in the high-risk category. Most patients (n = 48) received TAC in the moderate-risk group. Almost an equal number of patients received all 3 forms of therapy in the high-risk category. Data from 83 patients were available at follow-up (mean 7.5 years). More than half of the patients in the moderate- and high-risk groups (52% and 57%) were in remission (CR + PR) till the last follow-up [Table 4].
| Characteristics | Moderate risk (n = 71) | High risk (n = 45) |
|---|---|---|
| Mean age (years) | 41 ± 12 | 50.3 ± 10 |
| Mean 24-hr urine protein (mg) | 5690 ± 1230 | 13,329 ± 4032 |
| Mean creatinine (mg/dL) | 0.9 ± 0.34 | 1.68 ± 0.45 |
| Mean albumin (g/dL) | 2.55 ± 0.45 | 2.27 ± 0.3 |
| Hypertension | 32.4% | 36.4% |
| Diabetes mellitus | 5.6% | 8% |
| First-line therapy: | ||
| Rituximab | 28 | 12 |
| Cyclical cyclophosphamide and corticosteroids | 6 | 10 |
| Tacrolimus | 48 | 12 |
| Outcome mean follow-up 7.5 years | Total patients followed up = 83 | |
| Moderate risk | High risk | |
| Complete remission | 29 | 13 |
| Partial remission (PR) | 8 | 13 |
| Chronic kidney disease (CKD) | 6 | 10 |
| CKD on maintenance hemodialysis | 1 | 3 |
Complications
There was no significant increase in complications in those who received either RTX/CTX/TAC/Dual therapy/Triple therapy. Dual therapy refers to the use of second line of treatment in case of relapse or not achieving any form of remission to primary therapy. Triple therapy is when patient received all three forms of treatment in view of either relapse or no remission. Six patients had thromboembolic complications during presentation and were managed conservatively. Serious infectious complications were seen more in the CTX group. One patient developed severe left ventricular systolic dysfunction following RTX infusion. One patient on TAC therapy developed accelerated hypertension and PRES.
Discussion
In this long-term cohort of MN, all three commonly used immunosuppressive regimens, RTX, cyclophosphamide, and TAC, achieved similar remission rates in the first year of therapy. However, with extended follow-up, important distinctions became evident. Cyclophosphamide produced the most durable remissions, with a substantial proportion of patients remaining in stable remission without further treatment. TAC, despite strong early responses, was associated with frequent relapses and a considerable need for second-line therapy, reflecting its limited ability to maintain long-term disease control. RTX demonstrated an intermediate pattern, combining good durability of remission with a markedly better safety profile, particularly with respect to infectious and non-infectious adverse events.
An randomised controlled trial (RCT) by Ramachandran et al.3 found that remission induction with both TAC- and CTX-based regimens at 1 year was comparable (71% with TAC vs 77% with CTX, p = 0.78). There are at least 3 randomized control trials from China that have compared the efficacy of TAC with CTX, and have found that they are comparable in terms of short-term outcomes.4-6
In our study, we found no statistically significant difference in remission rates between RTX and CTX at 1 year. Due to the fear of increased risk of infections and malignancies associated with CTX, a larger number of our patients belonging to the high-risk group had received RTX. Our study results are consistent with the RI-CYCLO study, which compared RTX with CTX and found no difference in the rates of complete or partial remission between the 2 groups at 12, 24, and 36 months.7 A recent study from PGIMER, India8 also compared the efficacy of RTX and CTX based regimen in compromised renal function (GFR <60 mL/min). Out of 64 adults, 43.8% and 46.9% patients were in remission at 12 and 24 months, respectively. They concluded that both CTX and RTX had equal efficacy in inducing remission of nephrotic state in this group of patients. The comparison of complete and partial responses of patients with MN in various studies (e.g.: STARMEN trial, MENTOR trial, GEMRITUX trial) versus our cohort has been tabulated in Table 5.7,9-13
| RCT comparison | Year | eGFR (mL/min/1.73m2) mean (SD) | Proteinuria (g/24 h) | CR/PR at 12 months (%) | Serious adverse events (%) |
|---|---|---|---|---|---|
|
Our study RTX(2g) vs. CTX Vs CNI |
2025 | 87 (23) | 9.7 |
RTX- 75 CTX-75 CNI- 80 |
RTX- 7 CTX- 30 CNI- 6 |
|
RI-CYCLO7 RTX(2g) vs. CTX |
2021 | 84 (24) | 6.0 |
RTX-62 CTX- 73 |
RTX-19 CTX-14 |
|
STARMEN9 CNI+RTX(1g) vs. CTX |
2021 | 80 (24) | 7.4 |
CNI+RTX-51 CTX- 79 |
CNI+RTX-14 CTX-19 |
|
MENTOR10 RTX(4g) vs. CNI |
2019 | 85 (30) | 8.9 |
RTX- 60 CNI- 52 |
RTX-11 CNI- 31 |
|
GEMRITUX11 RTX (1.5G) vs. supportive |
2017 | 67 (55-83) | 7.6 | NA |
RTX-16 Suppo-42 |
|
Jha et al.12 CTX vs. Supportive |
2007 | 84 (22) | 5.9 |
CTX- 35 Supportive- 8 |
CTX- 15 Supp- 24 |
|
Ponticelli et al.13 Chlorambucil vs. Supportive |
1989 | Creatinine 1.06 mg/dL | 6.2 |
CLR- 61 Supp- 12.8 |
NA |
RTX: Rituximab, CTX: Glucocorticoid plus cyclophosphamide, CNI: Calcinuerin inhibitors, CLR: Chlorambucil
There are very few studies that have compared all three different modalities of treatment in MN. A recent retrospective observational study from South India by Khan et al.14 compared a small group (n = 41) and found that all patients treated with a CTX-based regimen had achieved remission at 1 year. However, <50% patients treated with RTX or TAC had achieved remission at 1 year, which was less compared to our cohort.
A mean of 7.5 years of follow-up data of 115 patients was available. The highest rate of complete remissions was observed in the TAC group. Probably this could be due to a larger number of moderate-risk category patients being started on TAC therapy. But the number of relapses was also higher in the same group, and they had to receive second-line therapy. Fifty percent of patients who achieved remission with CTX continued to be in remission till the last follow-up and did not require any further immunosuppressive therapy. A similar long-term follow-up study by Ramachandran et al.15, which has provided follow-up data for a median of 84 months, also found that 88% in CTX group vs. 53% in TAC group were in remission at the end of 6years. They also reiterated the fact that complete remission rates were higher in the CTX group compared to TAC group (RR-1.61, 95% CI-0.9 to 3.2). Less than half (40%) of our patients who received RTX as primary therapy were in remission (CR+PR) until the last follow-up.
A meta-analysis of follow-up studies of RTX has shown a very good number of patients in remission on follow-up.16 Another study by Van den Brand et al.17 compared the effectiveness of RTX vs. CTX, with a median follow-up of 40 months. The remission rates were similar. The combined endpoints of doubling of serum creatinine, ESRD, and deaths were not different between the RTX and CTX groups.
In our study, there were more patients in the TAC group who progressed to CKD, but it was not statistically significant. It has been observed from the transplant data registry that 3/4 of the subjects on CNI develop biopsy-proven nephrotoxicity in 1 year,18 which could be a reason for progression to CKD.
There were a few infectious complications seen in our patients, which were comparable to other studies. None of our patients died due to therapy complications or infections. A study by Van den Brand et al.,9 evaluated the long-term safety (40 months) of RTX and CTX in patients with primary MN and found that the RTX group had significantly fewer adverse events than the CTX group (63 vs. 173; p <0.001). Exposure to CTX is a risk for the development of malignancies like non-melanoma skin cancer, bladder cancer, etc. The development of these cancers in the long run is cumulative dose dependent (>36 g). There were no malignancies reported in our patients with long-term follow-up. However, a study10 has suggested that there is a 3-fold increased risk of malignancies in those who received CTX for primary MN. But they have also stated that the risk should be weighed against the benefit of preserving renal function.
This was a retrospective observational study with inherent limitations, including a lack of randomization and potential selection bias in treatment allocation based on clinician discretion. A significant limitation was the lack of anti-PLA2R antibody assessment in all patients, as this biomarker is increasingly recognized as important for risk stratification and treatment monitoring in MN.
In conclusion, this study reports comprehensive outcomes of patients with membranous nephropathy treated with three different immunosuppressive regimes.
Author contributions
Concepts, design: ME; Clinical studies, data acquisition, data analysis: JG; Definition of intellectual content, clinical studies: PT; Data acquisition, data analysis, manuscript writing, editing: PPP; Design, manuscript editing and review: GKC; Concepts, design: GM; Data acquisition: RR; Concepts, literature research: MY; Clinical studies: HV. All authors provided final approval to the work.
Conflicts of interest
There are no conflicts of interest.
The authors declare that no generative AI or AI-assisted tools were used in drafting, editing, or preparing this manuscript.
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