Idiopathic membranous nephropathy (IMN) is characterized by the presence of proteinuria and incrassation of the glomerular basement membrane with spike-like pathologic changes. The incidence of IMN is considerably high in adults, with gender predominance in males. While the pathogenesis of IMN is not clearly understood, immunofluorescence (IF) has revealed that granulated complement C3 and IgG gradually accumulate along the glomerular capillary wall (GCW) in the kidneys of diseased patients. Moreover, phospholipase A2 receptor (PLA2R), present in glomerular podocytes, and thrombospondin type-1 domain-containing 7A (THSD7A) act as antigens, when bound to antibodies (mainly IgG4), they lead to the activation of complements in 70-80% of cases. This may result in the in situ deposition of circulating immunocomplexes under neath glomerular epithelial cells.1,2 These events are peculiar to IMN and are rare in secondary membranous nephropathy, therefore, IMN has been considered as an autoimmune disease.

Despite treatment, patients with IMN could have either worsening renal function (WRF) or undesired release. Regardless of immunosuppressive therapy, Hogan et al.3 reported that the 5-, 10-, and 15-year survival rates in 1189 cases with IMN were 86%, 65%, and 59%, respectively. Furthermore, 40% of patients ended up with end-stage renal disease (ESRD). Meanwhile, Aaltonen et al.4 noted spontaneous remission (mostly within 12 months after diagnosis) in 13/76 cases with IMN, among whom five cases had recurrent disease later Meanwhile, others had spontaneous remission after four years. Chen Y et al.5 indicated that 32% of IMN patients who had not received any treatment could achieve spontaneous remission and have a favorable prognosis, of which only 5.7% were recurrent afterward. While most patients usually have stable renal functions, some patients may advance to renal failure with poor prognosis. Therefore, there is a possibility of either spontaneous remission or end-stage renal disease with impaired renal function due to the slow progression process of IMN.

Currently, cytotoxic drugs such as cyclophosphamide (CTX), chlorambucil (CH) and cyclosporine A (CsA) are widely used in the treatment of IMN. In the Clinical Practice Guidelines of KDIGO,6 CTX in combination with a glucocorticoid is recommended as a prioritized regimen to treat IMN. Other agents have also been used, such as tacrolimus (TAC) and calcineurin inhibitor (CNI, such as cyclosporine). To date, the choice of the therapeutic regimen has not been optimized and standardized with no clear guidelines to support treatment decisions. Therefore, we conducted this investigation to compare the efficacy and safety of the administration of TAC, CsA, and CTX in combination with steroids for successive 48 weeks for the treatment of IMN.

Patients with membranous nephropathy (MN) are diagnosed as IMN upon the exclusion of all MN-causing factors. It is noteworthy that there are several break through in understanding the pathogenesis of IMN. In 2009, Jr BL et al.7 discovered M-type phospholipase A2 receptor (PLA2R) and anti-PLA2R antibodies, representing a milestone in understanding IMN pathogenesis. WhilePLA2R is weakly expressed in normal human glomerular podocytes, its expression is significantly increased in most glomerular podocytes of PLA2R-associated IMN patients, suggesting that enhanced glomerular PLA2R antigen staining is a more direct and sensitive biomarker for the diagnosis of PLA2R-associated IMN. Anti-PLA2R antibodies are mainly IgG4, which co-localize with PLA2R antigen in glomerular capillary loops, relying on conformational epitope. Later, several studies have revealed that anti-PLA2R antibodies display dynamic changes in titer, which correlates with the prognosis of IMN patients and therefore can be used as a marker to monitor disease status, therapeutic response, and recurrence.8

The present study targeted a major subset of patients with PLA2R-positive IMN, in whom IgG4 was the main type of IgG (C1q negative). The results indicated that IMN patients responded rapidly to TAC, followed by CTX, whereas the slowest response was observed in the CsA group. The analysis also revealed that the overall remission rates of patients treated with these 3 regimens were similar after 48 weeks of intervention. Noteworthy, patients with IMN might benefit more from CTX or TAC than CsA, as more patients achieved CR after being treated with TAC and CTX. Treatment with either TAC, CTX, and CsA resulted in significant improvement in the kidney functions of IMN patients, which is reflected by a marked reduction in 24-h urinary protein levels and marked elevation of serum albumin levels at 48 weeks compared to baseline data. This improvement of 24-h urinary protein levels and serum albumin levels was pronounced more in the TAC and CTX groups at 48 weeks, respectively.

Our observations suggest that the efficacy of the3 regimens, with respect to improvement of renal function, is very similar at the end of the 48th week, while the action of CsA seemed a bit slower than TAC and CTX in elevating serum albumin. Overall, all three interventional regimens were effective against IMN, manifested by a drastic increase in remission rates along with a marked improvement of renal function in addition to being well-tolerated.

The decision of treatment is usually made based on the level of urinary protein in MN patient, while patients with a relatively slight increase in urinary protein often do not need special treatment and can be treated only with angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blocker (ARB), or anti-platelet adhesives agents to promote the recovery of renal function.9 Immunosuppressive agents and steroids are generally not necessary for the treatment of these patients.10 However, after a standard conservative treatment with ACEI or ARB for 6 months, if 24h urinary protein continues to increase (>4g), while patients are prone to hypoproteinemia and hyperlipidemia, along with the deterioration of renal function, they should receive immunosuppressive therapy in order to reduce urinary protein, lower lipid, and prevent coagulation.11

Indeed, the findings of the present study highlight the outcomes of renal improvement following the administration of TAC, CTX, or CsA inpatients who failed to respond to conservative therapy for 6 months (worse renal functions), and how they could notably alleviate the patients’ condition. Even though the patients were well tolerant of these regimens, they should be closely monitored for some potential AEs such as infection (e.g., LRTI) and liver dysfunction.

Immunosuppressive therapy may increase the remission rate of patients with IMN.12 Despite that early treatment with immunosuppressive agents could slow down or delay the progression of nephritis, the long-term use of immunosuppressive agents might cause AEs, which in turn may worsen the prognosis of these cases. In a 20-year retrospective analysis, Sato M et al.13 demonstrated that the efficacy of steroids alone to treat IMN was no better than the standard supportive treatment. In fact, they might lead to more side effects and quicker deterioration of renal function. These findings suggest that other immunosuppressive agents combined with steroids might be needed to treat IMN.

Cytotoxic drugs, such as CTX and CsA, are widely researched for the treatment of IMN. Ponticelli et al.14 compared the efficacy of Methylprednisone (MP)+Chlorambucil (CH) and MP+CTX regimens by monitoring proteinuria. After three years of follow-up, no significant difference in the remission rate (PR and CR) was found between both groups (82% vs 93%). However, it is noteworthy that the drop-off rate of patients who failed to complete the treatment plan reached 14% in the MP+CH group. Meanwhile, Wu et al.15 adopted the modified Ponticelli regimen combining CTX with steroids to treat IMN in a Chinese cohort. They found that this therapy could relieve proteinuria in IMN patients; however, its long-term benefit remains to be defined. On the other hand, Zhou et al.16 reported that monotherapy of calcineurin inhibitor CsA exhibited a short-term effect but failed to improve the CR rate.

Furthermore, Usui et al.17 has retrospectively analyzed 32 IMN patients who were treated with CsA in a combination of low-dose steroids. It was found that while the patients achieved a satisfactory response, 50% of patients had recurrence after a follow-up period from 37.5 to 89.2 months. Ramachandran et al.18 investigated a combination of another calcineurin inhibitor TAC and steroids in comparison with the modified Ponticelli regimen. They found that the short-term remission rate in the TAC group was higher than that in the CTX group. Meanwhile, caution should be taken in the long-term use of TAC due to its potential side effects, such as amenorrhea as well as hepatic and renal toxicity. Even though several combined regimens have been reported in the literature, it remains to be determined which combined therapy is better. In the present study, the efficacies of the three regimens were comparable in terms of both renal function improvement and overall remission rate (PR+CR). The data also suggests that patients treated with CTX or TAC might gain more benefits, as they seem to have an earlier response (after 12-week treatment) with a higher probability to achieve CR than those treated with CsA.

That being said, careful consideration of the adverse effects of such regimens should be taken. In our study, one patient in the CTX group suffered from pulmonary embolism. Morbidity of MN-related pulmonary embolism and renal venous thrombosis could reach 11% and 35%, respectively.19 Thus, it is re-emphasized that close attention should be paid to monitor the coagulation activity during the treatment of IMN. In a single patient receiving TAC regimen, the intervention was temporarily discontinued due to a sharp increase in serum creatinine, however, serum creatinine level went back to the normal afterward.

Besides the insights of our findings into the treatment approach in cases with IMN, our study had several limitations. First, the small sample size of our study limited the power to identify small differences among investigated regimens. Second, we did not include patients with PLA2R-negative but THSD7A-positive IMN as THSD7A staining was not yet routinely used for the diagnosis of IMN in our clinic, and thus, this may restrict the generalization of our findings. Finally, the retrospective design of our study limits the generalizability of our findings secondary to the potential biases incorporated in our design. Therefore, further investigations for optimizing the selection of immunosuppressive agents or regimen type and determining the appropriate time to initiate therapy as well as the maintenance duration of treatment are warranted in order to make an individualized treatment plan for patients with IMN.

All three immunosuppressive regimens (TAC, CTX, and CsA) in combination with steroids are effective and well-tolerable in the treatment of patients with PLA2R-positive IMN.TAC shows better short-term efficacy (12 weeks) than CTX (24 weeks) and CsA (48 weeks). More patients achieve CR after a48-week treatment with CTX (25%) and TAC (22%) than CsA (13%).

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

None.