INTRODUCTION
Primary membranous nephropathy (pMN) accounts for approximately 75% of membranous nephropathy and is the most common pathological type of nephrotic syndrome in adults.[ 1 ] The basic pathogenesis is the formation of immune complex deposition under the glomerular podocyte, including antigen, immunoglobulin G, and complement, and the activation of the complement system, in which the immune response mediated by antibodies against some podocyte intrinsic antigens may play a critical role. In 2009, the M-type phospholipase A2 receptor (PLA2R), a main intrinsic protein located in the podocyte, was identified as an essential target antigen and could result in proteinuria in 75% of patients with pMN.[ 2 ] Recently, Tomas found that approximately 2.5%–5% of patients with pMN have autoantibodies against thrombospondin type-1 domain-containing 7A in podocytes, corresponding to 8%–14% of the patients who are seronegative for anti-PLA2R1 antibodies.[ 3 ] Numerous clinical studies have shown that approximately 30% of patients who received optimized supportive treatment, including angiotensin-converting enzyme inhibitor (ACEI) / angiotensin receptor blocker (ARB) drugs, can spontaneously achieve remission, and 30%–40% of patients progress to end-stage kidney disease (ESKD) over 5–15 years.[ 1,4–7 ] Multifarious immunosuppressants including cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil, rituximab, and synthetic adrenocorticotropic hormone, have been applied in the clinical treatment of pMN.[ 8–16 ] The 2021 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practices Guideline for the Management of Glomerular Diseases (2021 KDIGO Guideline) recommends rituximab, calcineurin inhibitors, or cyclophosphamide using different combinations, for patients with pMN and at risk of kidney disease progression.[ 17 ] However, the serious adverse effects, high relapse rate, and high cost impinge on the therapeutic effects and patients' quality of life.[ 18–20 ] Therefore, looking for a therapeutic regimen with superior efficacy and fewer adverse events is still essential for the clinical practice of nephrologists.
For decades, a multitarget therapy regimen has been adopted for antirejection treatment following solid organ transplantation.[ 21,22 ] The multitarget regimen has recently been successfully used for treating lupus nephritis in the induction and maintenance phases.[ 23–25 ] In addition, several studies have confirmed that a low-dose multitarget regimen (LDMT) is effective, well-tolerated, and safer, and renal function remains stable in treating lupus nephritis and in kidney transplantation.[ 21,23–25 ]
In 2016, Xu et al . suggested the morbidity of pMN was significantly increased after long-term exposure to PM2.5 air pollution.[ 26 ] Although insights into the underlying pathogenesis mechanism and randomized controlled clinical trials on pMN have made outstanding progress, the treatment choice for pMN is still a challenge for nephrologists. A multitarget regimen might be effective and safe for patients with pMN as it targets the different pathogenic pathways and uses low drug dosages and has fewer adverse effects. Consequently, we retrospectively analyzed the efficacy and safety of LDMT for treating patients with pMN and compared it with corticosteroids plus intravenous cyclophosphamide (PC group).
PATIENTS AND METHODS
Patients
From January 2013 to March 2017, 244 patients aged 18 to 75 years, with biopsy-proven pMN, were screened at the Department of Nephrology at Xi'an Jiaotong University's second Affiliated Hospital. According to the inclusion and exclusion criteria, 84 patients who received LDMT or PC were enrolled. The enrollment criteria were persistent urinary protein (UTP) level ≥ 4.0 g/d and a serum albumin (ALB) level < 30 g/L, and serum creatinine (Scr) level ≤ 3.0 mg/dL (265.2 μmol/L), with or without edema and hyperlipidemia. The main exclusion criteria were as follows: (1) use of other immunosuppressants such as corticosteroids combined with cyclosporine A or with mycophenolate mofetil or leflunomide; (2) contraindications to glucocorticoid, tacrolimus, mycophenolate mofetil, or cyclophosphamide; (3) lack of compliance with the clinicians' orders; (4) treatment duration < 6 months; (5) lack of data on the majority of laboratory tests; (6) severe heart and lung dysfunction; and (7) pregnancy or lactation.[ 27 ]
Patients with secondary MN were screened and excluded. All patients included in this study completed a 1-year treatment period, and were subsequently followed up for another year. The human research committee at Xi'an Jiaotong University's Second Affiliated Hospital approved the study protocol after all patients gave informed consent (2018009). The drugs used were not donated specifically for this study.
Treatments
The LDMT group received oral prednisone 10 mg once daily, oral tacrolimus 1.0 mg twice daily, and mycophenolate mofetil 0.5 g two times daily. The tacrolimus dose was adjusted mainly according to its plasma concentration, maintained at 5–10 ng/mL. All drugs were tapered after 9 months of treatment during the total treatment duration of 1 year.
For patients in the PC group, oral prednisone was initiated at a dose of 1.0 mg/kg for 2 months (maximum dose ≤ 70 mg daily), subsequently tapered by 5 mg every 2 weeks to 20 mg/d, and tapered slowly to the maintenance dose of 10 mg daily. Cyclophosphamide was given at the dosage of 0.75 g/m2
Most patients in both groups received optimized supportive treatment receiving ACEI or ARB therapy with the maximum labeled or tolerated dose for more than 90 days.
Outcomes and definitions
Remission rate
Complete remission (CR) was defined as a 24-h UTP level < 0.3 g/d, and ALB level ≥ 35 g/L, with normal Scr levels. Partial remission (PR) was defined as a UTP level < 3.5 g/d and a decrease ≥ 50% compared with baseline levels, ALB level ≥ 30 g/L, with stable Scr levels (an increase ≤ 50% of the baseline levels).
Extent of changes in laboratory parameters
The extent to which laboratory parameters such as levels of UTP, ALB, Scr, fasting plasma glucose (FBG), serum total cholesterol (TC), and total triglyceride (TG) changed before and after treatment was evaluated.
Relapse
Relapse was defined as a recurrence of nephrotic syndrome after CR or PR, mainly determined through clinical manifestations and laboratory tests.
Adverse events
The occurrence of adverse events (AEs) related to drug use, including myelotoxicity, infections, liver dysfunction, gastrointestinal dysfunction, hyperglycemia, doubling of serum creatinine levels, menstrual disorders, alopecia, digestive tract hemorrhage, new-onset hypertension, pulmonary thromboembolism, was monitored and evaluated. These AEs were mainly recorded through outpatient follow-up, electronic medical records, and telephone follow-up.
Statistical analysis
All statistical analysis was performed with SPSS 26.0 software (IBM, NY, USA). Data were expressed as mean ± standard deviation (SD), medians (interquartile ranges [IQRs]), frequencies and proportions for normally distributed, skewed, and categorical variables, respectively. Categorical data were summarized as counts and percentages. Differences between the two groups were evaluated using t , Wilcoxon rank-sum, and Chi-squared or Fisher's exact tests as appropriate. The Kaplan-Meier curve was used to evaluate the cumulative probability of remission and the median time to achieve remission. Differences between the two curves were calculated using the log-rank test. A generalized estimating equation (GEE) analysis was used to examine laboratory test results during the follow-up period. The relapse rate and incidence of adverse events were analyzed with Fisher's exact test. A P value < 0.05 was considered statistically significant.
RESULTS
Patient inclusion and baseline characteristics at treatment initiation
A total of 244 patients with biopsy-proven pMN between January 2013 and March 2017 at our hospital were screened. According to the inclusion and exclusion criteria, 84 patients were enrolled in the study, with 30 in the LDMT group and 54 in the PC group. The detailed flow diagram of the patient selection process is shown in Figure 1 .
Figure 1:: Study design and flow diagram showing patient selection process. pMN, primary membranous nephropathy; LDMT, low dose multitarget regimen; IVCY, intravenous cyclophosphamide.
The baseline demographics, clinical characteristics, and kidney pathological features of patients are shown in Table 1 . The UTP level was 7.01 ± 2.55 g/24h in the LDMT group, similar to that in the PC group (6.37 ± 2.14 g/24 h, P = 0.219). Baseline ALB and Scr levels between the two groups were also similar (ALB: 25.72 ± 2.06 vs. 25.43 ± 3.54 g/L, P = 0.634; Scr: 66.82 [58.81–77.85] vs. 62.09 [53.88–78.15] μmol/L, P = 0.444). Other parameters at baseline, including age, sex, blood pressure, pathologic classification, FBG, TC, and TG, showed no significant differences between the two groups (P > 0.05). In addition, 93.33% of patients in the LDMT group and 87.04% in the PC group used ACEI/ARB drugs. Only a small percentage of patients did not receive ACEI/ARB drugs because of low blood pressure or contraindications to the drugs There was no significant difference in the use of ACEI/ARB drugs between the two groups (P > 0.05). All patients receiving ACEI/ARB drugs were given the maximum labeled or tolerated dose to maintain blood pressure at 125/75 mmHg (UTP level > 1 g) or 130/80 mmHg (UTP level < 1 g).
Table 1 -
Baseline characteristics of patients in the LDMT and PC groups
Characteristics
LDMT group (n = 30)
PC group(n = 54)
P -Value
Age, year
52.07 (12.27)
46.96 (12.58)
0.076
Male/Female
18/12
32/22
0.947
Systolic BP, mmHg
128 (112–141)
120 (110–130)
0.208
Diastolic BP, mmHg
80 (76–90)
80 (70–85)
0.178
Pathologic classification, n (%)
0.776
Stage I
20 (66.66)
32 (59.26)
Stage II
8 (26.67)
17 (31.48)
Stage III
2 (6.67)
5 (9.26)
Stage IV;+V
0
0
ALB, g/L
25.72 (2.06)
25.43 (3.54)
0.634
UTP, g/24 h
7.01 (2.55)
6.37 (2.14)
0.219
Scr, μmol/L
66.82 (58.81–77.85)
62.09 (53.88–78.15)
0.444
FBG, mmol/L
5.07 (0.81)
4.83 (0.54)
0.158
TC, mmol/L
8.01 (2.30)
8.06 (2.16)
0.928
TG, mmol/L
3.35 (1.58)
2.86 (1.03)
0.131
Treatment with ACEI/ARB drugs, n (%)
28 (93.33)
47 (87.04)
0.599
Data are expressed as means (SDs) or medians (interquartile ranges) or proportions (%). LDMT: low dose multitarget regimen, PC: prednisone plus intravenous cyclophosphamide, BP: blood pressure, ACEI: angiotensin converting enzyme inhibitor, ARB: angiotensin receptor blockers, UTP: urine total protein, ALB: serum albumin, Scr: serum creatinine, TC: total cholesterol, TG: triglyceride, FBG: fasting blood glucose.
Remission rate at follow-up
In the 6th month of follow-up, the PR rate in the LDMT group was 76.67%, slightly lower than that in the PC group (87.04%), but was not significantly different. At the 12th and 24th month of follow-up, the PR rates were similar between the two groups (93.33% vs. 92.59%, 93.33% vs. 94.44%) [Figure 2A ]. Additionally, Kaplan-Meier survival analysis revealed similar cumulative PR rates at the 3rd , 6th , 9th , 12th , and 15th month in the LDMT and PC groups (50.00% vs. 42.59%, 76.67% vs. 88.89%, 96.11% vs. 92.59%, 96.11% vs. 92.59% and 96.11% vs. 92.59%, respectively; log-rank test, P = 0.87) [Figure 2B ]. These results indicated that most patients with pMN in the LDMT or PC groups achieved a PR at approximately 9 months.
Figure 2:: Changes in clinical remission in the LDMT and PC groups during follow-up. (A) The rate of partial remission at the 6th , 12th and 24th month after treatment. (B) The Kaplan-Meier curve for partial remission. (C) The rate of complete remission at the 6th , 12th and 24th month after treatment. (D) The Kaplan-Meier curve for complete remission. LDMT, low dose multitarget regimen; PC, prednisone plus intravenous cyclophosphamide.
At the 6th , 12th , and 24th month of follow-up, 6.67%, 40.00%, and 56.67% of patients in the LDMT group and 16.67%, 53.70%, and 62.96% of patients in the PC group achieved CR. At each time point, the CR rate in the LDMT group was slightly lower than that in the PC group; however, there was no significant difference between the two groups (P > 0.05) [Figure 2C ]. Additionally, Kaplan–Meier survival analysis showed that the cumulative CR rates between the LDMT and PC groups at the 6th , 12th , 18th , and 24th month were similar (6.67% vs. 16.67%, 47.56% vs. 60.84%, 66.29% vs. 71.53%, and 83.14% vs. 81.02%, respectively; log-rank test, P = 0.62) [Figure 2D ]. These results showed that patients in both groups could achieve a favorable CR rate after standard treatment.
The median (IQR) time to PR in the LDMT group was 3.00 (2.00–5.75) months after treatment, which was relatively shorter than the PC group (4.00 [2.00–5.25] months), indicating that patients receiving the LDMT treatment were more likely to achieve PR within a short term. In addition, the median (IQR) time to CR in the LDMT group was 10.00 (7.50–13.00) months, which was slightly longer than that in the PC group (8.50 [6.00–11.00] months). However, the difference between the two groups was not significant (P = 0.689, P = 0.844).
Changes in UTP and ALB levels during follow-up
A significant decrease in UTP levels was observed during the follow-up period in both the LDMT and PC groups [Table 2 ]. At the 3rd , 6th , 12th , and 24th month of follow-up, the UTP level in the LDMT group was 2.54 (1.72–3.94), 1.80 (0.73–3.07), 0.40 (0.19–0.79) and 0.12 (0.08–0.20) g/24 h, whereas that in the PC group was 3.05 (1.42–4.23), 1.19 (0.50–2.75), 0.32 (0.17–0.82) and 0.24 (0.14–0.44) g/24 h, respectively. Furthermore, it was observed that the rate of UTP level decline in the LDMT group was significantly faster than that in the PC group in the first 3 months. However, in the follow-up period of 6–9 months, the decrease in UTP levels in the PC group was more remarkable. Further observation showed that during the follow-up period from 9 to 24 months, the extent of changes in UTP levels were similar between the two groups [Figure 3A ]. Next, we used GEE analysis to analyze the changes in UTP levels in the two groups during the observation period. GEE analysis showed that with the prolongation of treatment time, the levels of UTP in both groups were significantly reduced (P = 0.000) (Supplementary Table 1 , https://links.lww.com/IMNA/A2
Figure 3:: Changes in clinical parameters during the follow-up period. (A) Urine protein excretion levels. (B) Serum albumin levels. (C) Serum creatinine levels. LDMT, low dose multitarget regimen; PC, prednisone plus intravenous cyclophosphamide.
Table 2 -
Changes in clinical parameters before and after treatment in the two groups
Groups
UTP (g/24 h)
ALB (g/L)
Scr (μmol/L)
TC (mmol/L)
TG (mmol/L)
FBG (mmol/L)
LDMT group (n = 30)
Baseline
6.95 (4.73–8.22)
25.72 (2.06)
66.82 (58.81–77.85)
8.01 (2.30)
3.35 (1.58)
5.07 (0.81)
3rd month
2.54 (1.72–3.94)*
38.06 (4.92)*
66.58 (58.25–78.58)
6.76 (1.91)*
2.73 (1.18)*
5.26 (0.66)*
6th month
1.80 (0.73–3.07)*
40.25 (6.10)*
68.83 (57.66–76.78)
5.92 (1.39)*
2.16 (0.71)*
5.80 (1.71)*‡
12th month
0.40 (0.19–0.79)*
42.89 (5.57)*
66.02 (59.43–79.47)
5.07 (1.09)*
1.67 (0.61)*
5.75 (1.52)*
24th month
0.12 (0.08–0.20)*
46.70 (3.43)*
65.08 (54.27–80.80)
4.45 (0.71)*
1.56 (0.57)*
5.61 (1.52)*
PC group (n = 54)
Baseline
5.96 (4.74–7.90)
25.43 (3.54)
62.09 (53.88–78.15)
8.06 (2.16)
2.86 (1.03)
4.83 (0.54)
3rd month
3.05 (1.42–4.23)†
36.04 (5.85)†
66.76 (57.53–77.21)
6.43 (1.57)†
2.41 (1.64)†
4.98 (0.95)†
6th month
1.19 (0.50–2.75)†
39.40 (5.45)†
66.25 (56.86–75.79)
6.04 (1.48)†
2.17 (0.93)†
5.07 (0.74)†
12th month
0.32 (0.17–0.82)†
43.02 (5.46) †
66.50 (55.59–77.98)
5.27 (1.21)†
2.03 (1.22)†
5.30 (0.68)†
24th month
0.24 (0.14–0.44)†
45.50 (4.64)†
71.46 (52.21–84.22)
4.99 (0.92)†
2.27 (1.70)†
5.40 (0.70)†
Data are expressed as means (SDs) or medians (interquartile ranges). Compared with the levels of different time points in the LDMT group during the treatment period, *P < 0.0001. Compared with the levels of different time points in the PC group during the treatment period, † P < 0.0001. In the LDMT group, compared with the levels in the PC group, ‡ P < 0.05. LDMT: low dose multitarget regimen, PC: prednisone plus intravenous cyclophosphamide, UTP: urine total protein, ALB: serum albumin, Scr: serum creatinine, TC: total cholesterol, TG: triglyceride, FBG: fasting blood glucose.
Similarly, ALB levels in both groups were significantly improved after treatment [Table 2 ]. At the 3rd , 6th , 12th , and 24th month of follow-up, ALB levels in the LDMT group was 38.06 ± 4.92, 40.25 ± 6.10, 42.89 ± 5.57, and 46.70 ± 3.43 g/L, and that in the PC group was 36.04 ± 5.85, 39.40 ± 5.45, 43.02 ± 5.46, and 45.50 ± 4.64 g/L, respectively. Additionally, we found that the LDMT group had a more pronounced increase in ALB levels than the PC group during the first 3 months of treatment, whereas the changes in ALB levels were similar between the two groups from the 6th to 24th month [Figure 3B ]. Meanwhile, GEE analysis showed that ALB levels in both groups increased significantly after treatment (P = 0.000); however, there was no significant difference in ALB levels between the two groups at the different observation time points (P = 0.332) (Supplementary Table 2 , https://links.lww.com/IMNA/A2
These results show that UTP and ALB levels improved significantly in the LDMT group than in the PC group during the first 3 months, which is consistent with the fact that patients in the LDMT group achieved more PR within a shorter time. However, the changes in UTP and ALB levels were not significantly different between the two groups.
Changes in Scr levels during follow-up
Scr is one of the most important and commonly used parameters for assessing patients' kidney function. At the 3rd , 6th , 12th , and 24th month of follow-up, Scr level in the LDMT group was 66.58 (58.25–78.58) μmol/L, 68.83 (57.66–76.78) μmol/L, 66.02 (59.43–79.47) μmol/L and 65.08 (54.27–80.80) μmol/L, and that in the PC group was 66.76 (57.53–77.21) μmol/L, 66.25 (56.86–75.79) μmol/L, 66.50 (55.59–77.98) μmol/L and 71.46 (52.21–84.22) μmol/L, respectively [Table 2 ]. Further analysis revealed that Scr level in the PC group remained stable throughout the observation period, indicating that PC regimen had little effect on renal function. In the LDMT group, Scr levels increased slightly at the 9th and 12th month of follow-up; however, they were not significantly different compared to the baseline [Table 2 , Figure 3C ]. GEE analysis showed that Scr levels of the two groups remained stable throughout the observation period (all P > 0.05), and were not significantly different at the different time points (P = 0.261) (Supplementary Table 3 , https://links.lww.com/IMNA/A2
Table 3 -
AEs during the treatment period (
n [%])
AEs
LDMT group(n = 30)
PC group(n = 54)
P -Value
All events
14 (46.67)
39 (72.22)
0.020
Myelotoxicity
2 (6.67)
15 (27.78)
0.024
Leukopenia
2 (6.67)
6 (11.11)
0.705
Anemia
3 (10.00)
7 (12.96)
0.744
Thrombocytopenia
1 (3.33)
6 (11.11)
0.413
Infections
6 (20.00)
26 (48.15)
0.011
Upper respiratory tract infection
4 (13.33)
10 (18.52)
0.761
Pneumonia
3 (10.00)
5 (9.26)
0.912
Urinary tract infection
5 (16.67)
22 (40.74)
0.024
Varicella zoster virus
1 (3.33)
0
0.357
Liver dysfunction
2 (6.67)
22 (40.74)
0.001
Gastrointestinal dysfunction
4 (13.33)
17 (31.48)
0.066
Upper gastrointestinal symptoms
3 (10.00)
15 (27.78)
0.094
Diarrhea
2 (6.67)
6 (11.11)
0.705
Digestive tract hemorrhage
1 (3.33)
0
0.357
Hyperglycemia
8 (26.67)
6 (11.11)
0.067
Doubling of serum creatinine level
2 (6.67)
1 (1.85)
0.289
Menstrual disorders
0
2 (3.70)
0.535
Alopecia
1 (3.33)
6 (11.11)
0.413
New onset hypertension
2 (6.67)
1 (1.85)
0.289
Pulmonary thromboembolism
1 (3.33)
0
0.357
Death
0
1 (1.85)
0.999
Others*
0
2 (3.70)
0.535
*Two patients suffered visual impairment. LDMT: low dose multitarget regimen, PC: prednisone plus intravenous cyclophosphamide, AEs: adverse events.
Changes in serum lipid levels during follow-up
Hyperlipidemia is common in patients with pMN. It makes the blood hypercoagulable, thereby causing patients to be prone to thrombosis and serious outcomes. At the 3rd , 6th , 12th , and 24th month of follow-up, TC level in the LDMT group was 6.76 ± 1.91, 5.92 ± 1.39, 5.07 ± 1.09, and 4.45 ± 0.71 mmol/L, and the TG level was 2.73 ± 1.18, 2.16 ± 0.71, 1.67 ± 0.61, and 1.56 ± 0.57 mmol/L, respectively. TC level in the PC group was 6.43 ± 1.57, 6.04 ± 1.48, 5.27 ± 1.21, and 4.99 ± 0.92 mmol/L, and TG level in the PC group was 2.41 ± 1.64, 2.17 ± 0.93, 2.03 ± 1.22, and 2.27 ± 1.70 mmol/L, at the 3rd , 6th , 12th , and 24th month of follow-up, respectively (Table 2 ). It was obvious that TC and TG levels in both groups improved significantly after treatment. GEE analysis also suggested that TC and TG levels in the two groups decreased significantly after treatment. However, blood lipid levels in the two groups were similar at the different time points (Supplementary Table 4 and 5, https://links.lww.com/IMNA/A2
Relapse rate
At the end of the follow-up, 50 patients in the PC group and 28 in the LDMT group had a CR or PR. Notably, 11 patients, including 4 with CR and 7 with PR in the PC group, and 6 with PR in the LDMT group, experienced relapses. The relapse rates were parallel between the two groups (21.43% vs. 22.00%, P = 0.953). In the LDMT group, 6 patients relapsed at a mean time of 4.29 ± 3.73 months after PR. In the PC group, 4 patients with CR and 7 with PR relapsed at a mean time of 8.00 ± 3.46 months and 5.71 ± 5.85 months after remission, respectively. During the entire follow-up period, no relapse occurred in patients with CR in the LDMT group, suggesting that the LDMT regimen could effectively maintain the remission of patients with pMN.
Adverse events
The incidence of all adverse events in the LDMT group was 46.67%, which was significantly lower than that in the PC group (72.22% [P = 0.020]). In addition, fewer patients in the LDMT group experienced infection, liver dysfunction, and myelotoxicity compared to those in the PC group (20.00% vs. 48.15%, 6.67% vs. 40.74%, 6.67% vs. 27.78%; P = 0.011, 0.001, 0.024, respectively).
Both glucocorticoids and tacrolimus can affect blood glucose level in patients with pMN. At the 3rd , 6th , 12th , and 24th month of follow-up, FBG level in the LDMT group was 5.26 ± 0.66, 5.80 ± 1.71, 5.75 ± 1.52, and 5.61 ± 1.52 g/L, and that in the PC group was 4.98 ± 0.95, 5.07 ± 0.74, 5.30 ± 0.68, and 5.40 ± 0.70 mmol /L, respectively [Table 2 ]. The FBG levels of the two groups were a little higher than the baseline; however, there was no significant difference between the two groups [Table 3 ]. No patients in the LDMT group had Cushing's syndrome.
DISCUSSION
One of the most common pathological types of nephrotic syndrome in adults is pMN. The appropriate treatment options for patients with pMN, especially those with a high risk of progressing to ESKD, relapse, or refractory, are still the focus of clinical attention.[ 28 ] Although the Ponticelli regimen is the classical therapy for patients with pMN, the cumulative dosages of prednisone and cyclophosphamide are higher than 10 g, causing various adverse events, which seriously affect the quality of life and prognosis of patients.[ 8,19,29,30 ] Therefore, tacrolimus is suggested as the first-line drug for moderate and high-risk patients with pMN as per the 2021 KDIGO guideline. In our study, we used a multitarget regimen consisting of low-dose prednisone, tacrolimus, and mycophenolate mofetil to investigate the efficacy and safety in patients with pMN. Our results revealed that the efficacy of LDMT regimen with a reduced dosage of immunosuppressants is not inferior to the PC regimen.
Furthermore, the incidence of adverse events is less, especially Cushing's syndrome. These findings indicate that the LDMT regimen may be a potential treatment option for patients with pMN. To our knowledge, the application of the LDMT regimen for treating patients with pMN has rarely been reported. Therefore, we provide evidence here suggesting that the LDMT regimen provides a new scheme for the clinical treatment of patients with pMN.
Achieving remission, even if partial, is particularly important for the long-term prognosis of patients with pMN. A randomized controlled trial with a 10-year follow-up has demonstrated that the probability of survival without death and dialysis was 79% and 44% with steroids plus cyclophosphamide treatment and supportive treatment alone, respectively.[ 8 ] Recently, several studies have shown that CR was not only significantly associated with a low relapse rate in patients with pMN but also favored an excellent long-term renal survival rate.[ 31–33 ] In this study, the cumulative CR rate in the LDMT group at the 6th , 12th , and 24th month was similar to those in the PC group (6.67 vs. 16.67%; 47.56% vs. 60.84%; 83.14% vs. 81.02%, respectively). Furthermore, patients in the LDMT group achieved PR in a shorter time than the PC group (3.00 [2.00–5.75] months vs. 4.00 [2.00–5.25] months); however, the differences were not significant. A multicenter study indicated that 80% of the patients treated with prednisone plus tacrolimus achieved remission after 18 months of treatment; however, the CR rate was only 42% of the overall response rate.[ 10 ] Branten A J confirmed that the cumulative incidence of remission at the 12th month in patients with pMN using corticosteroid and mycophenolate mofetil was 66%, which was significantly lower than that observed in the LDMT group in our study.[ 11 ] pMN is an organ-specific autoimmune disease, and tacrolimus and mycophenolate mofetil are potent immunosuppressants. As a calmodulin phosphatase inhibitor, tacrolimus can bind to FK506-binding protein, thereby inhibiting the activation and proliferation of T cells, blocking the transcription of various cytokines, and reducing the proliferation of Th2-dependent B lymphocytes. In addition, studies have found that tacrolimus can bind to TRPC6, inhibit its activity, reduce podocyte damage, and directly act on podocytes to reduce the damage caused by calcium influx, stabilize the cytoskeleton structure, and reduce the formation of proteinuria.[ 34,35 ] Mycophenolate mofetil is rapidly converted to mycophenolic acid (MPA) immediately after administration. MPA is a strong inhibitor of inosine monophosphate dehydrogenase, which can inhibit de novo synthesis of purines. Therefore, mycophenolate mofetil can effectively inhibit DNA synthesis and lymphocyte proliferation. Further, mycophenolate mofetil exerts anti-inflammatory and antiproteinuric effects. Its anti-inflammatory action is related to the downregulation of the expression of adhesion molecules, inhibition of the migration of lymphocytes and monocytes/macrophages, and reduction of cytokine production from these cells.[ 36,37 ] Based on these findings, the LDMT regimen might significantly improve the remission rate than tacrolimus or mycophenolate mofetil alone.
In our study, the relapse rates of patients with pMN in the LDMT and PC groups were similar (21.43% vs. 22.00%). However, the findings also indicated that patients with PR were more likely to have a higher risk of relapse than those with CR. Studies have confirmed that patients treated with tacrolimus suffer a relapse as high as 40%–44% after drug withdrawal.[ 10,18 ] A clinical trial of the efficacy and safety of mycophenolate mofetil in the treatment of pMN suggested that the relapse rate was 38%.[ 11 ] Notably the relapse rate reported in previous studies is higher than that of the LDMT group in this study.
During medication treatment, adverse events are often unavoidable. For example, du Buf-Vereijken et al . reported that approximately 10% of patients treated with corticosteroids plus cyclophosphamide stopped drug usage due to serious side effects.[ 30 ] Meanwhile, the incidence of malignancy significantly increased after an extensive dose of cyclophosphamide.[ 8,38,39 ] As such, clinicians must pay attention to adverse events during the long-term use of immunosuppressants. In this study, the incidence of all adverse events was 46.67% in the LDMT group and 72.22% in the PC group. In particular, patients in the PC group more easily experienced urinary tract infection, liver dysfunction, and myelotoxicity than those in the LDMT group. Although the incidence rate of hyperglycemia in the LDMT group was higher than that in the PC group, FBG gradually returned to normal level with the reduction or withdrawal of drugs. In Liu and Zhang's research on lupus nephritis, they reported that the incidence of adverse events in multitarget therapy was significantly fewer than that in the PC group, which is consistent with our results.[ 23,24 ]
In clinical treatment, the nephrotoxicity of tacrolimus is crucial to the survival of the kidney. The main nephrotoxicity of tacrolimus includes endothelial injury, renal tubular epithelial cell vacuolar degeneration, atrophy, microcalcification, and irreversible interstitial fibrosis.[ 40 ] In the Symphony study, low-dose calcineurin inhibitors had no significant effect on kidney function in patients 3 years after transplantation.[ 41 ] In our study, Scr levels of the two groups remained stable before and after treatment. Only one patient in the LDMT group had a sharp increase in Scr level because of gastrointestinal bleeding. Zhang et al . reported that during the follow-up period of 18 months, no obvious renal function deterioration was observed in patients with lupus nephritis treated with multitarget therapy. Moreover, the markers of renal tubular injury, including urinary N-acetyl-β-Dglucosaminidase level and retinol-binding protein excretion, did not increase after treatment.[ 24 ] Hence, we believe that patients with pMN may have a good tolerance for long-term use of LDMT regimen.
This study has some limitations. In our study, most patients adopted a regimen of glucocorticoids combined with tacrolimus and mycophenolate mofetil because of the relatively low total glucocorticoid use. However, few patients adopted LDMT regimen after failing to respond to tacrolimus monotherapy. Therefore, this could have led to a selection bias and affected the study results. In addition, this was a retrospective, single-center study on the Chinese population. Moreover, the number of patients in this study was small. To confirm the efficacy and safety of the LDMT regimen for treating pMN, a multicenter, randomized controlled prospective trial with long-time follow-up is needed.
CONCLUSION
In conclusion, the LDMT regimen displays similar remission and relapse rates but fewer total adverse events than the PC regimen, and results in stable renal function, suggesting that it may be an effective and safe alternative therapeutic option for patients with pMN.
Financial support and sponsorship
This work was supported by the National Natural Science Foundation of China (82170697) and the Natural Science Foundation of Shaanxi Province (2022JM-472).
Ethics approval and consent to participate
The human research committee at Xi'an Jiaotong University's Second Affiliated Hospital approved the study protocol after all patients gave informed consent (2018009).
Conflicts of interest
Xuefei Tian is an Editorial Board Member of the journal. The article was subject to the journal's standard procedures, with peer review handled independently of this member and his research group.
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