1. Main purpose:

   To evaluate the efficacy and safety of rituximab combined with tacrolimus in the treatment of intermediate and high-risk primary membranous nephropathy

2. Secondary research purposes:

   To describe the survival of patients with intermediate and high-risk primary membranous nephropathy treated with rituximab combined with tacrolimus; To describe renal survival in patients with intermediate and high-risk primary membranous nephropathy treated with rituximab combined with tacrolimus;

3. Exploratory research purposes:

Feasibility of glucocorticoids-free therapy (rituximab combined with tacrolimus) in the treatment of intermediate and high-risk primary membranous nephropathy

Membranous nephropathy (MN) is the leading cause of primary nephrotic syndrome in adults, with a peak incidence in middle-aged and elderly patients. The typical pathological features are: thickening of the basement membrane, deposition of immunofluorescent IgG with or without C3 along the basement membrane, and deposition of epithelial electron-dense deposits. It is divided into primary MN (Primary membranous nephropathy, PMN) and secondary MN (which can be secondary to connective tissue diseases, infections, malignant tumors, drugs/toxicants, etc.). Clinically, it usually presents with massive proteinuria and edema, and some patients gradually progress to end stage renal disease (ESRD).

In recent years, the prevalence of PMN in China has increased year by year. It has been reported that the proportion of MN in primary glomerular diseases in renal biopsy increased from 10.4% in 2003-2006 to 24.1% in 2011-2014 [1], and some trend of youth.

For a long time, the treatment of PMN has mainly used glucocorticoids combined with alkylating agents or calcineurin inhibitors (CNIs). With the continuous exploration and in-depth understanding of the pathogenesis of MN, it has been developed to the molecular level. The KDIGO 2021 Glomerular Disease Management Guidelines are being published [2] Compared with the 2012 KDIGO Glomerular Disease Management Guidelines, the diagnosis and treatment of MN has undergone major changes (Figure 1). Due to the toxicity of alkylating agents and the long-term nephrotoxicity of CNIs, as well as their high risk of relapse when used as monotherapy (with or without prednisone), anti-CD20 biotherapeutics (especially Rituximab, RTX)) is gaining popularity as first-line therapy.

Both international and domestic guidelines recommend that moderate and severe MN require immunosuppressive therapy. RTX is an anti-CD20 monoclonal antibody, which can block the generation of B cells, differentiate into plasma cells, reduce the production of antibodies (such as PLA2R), and avoid processes such as glomerular basement membrane damage. TAC is a calcineurin inhibitor that has been used in PMN for many years. It mainly acts through various mechanisms such as immune regulation and stabilization of the pod cytoskeleton. Two-drug sequential therapy can work from multiple mechanisms, potentially achieving better and faster therapeutic effects.

Inclusion Criteria:

• gender is not limited；
• Age 18-75；
• Kidney biopsy pathology suggests primary membranous nephropathy;
• Serological or histological PLA2R positive;
• 24-hour urine protein quantification ≥3.5g/d and serum albumin <30g/L;
• Glomerular filtration rate [eGRF (CKD-EPI formula)] ≥ 45ml/min/1.73m2;

Exclusion Criteria:

• Secondary membranous nephropathy (tumor-related, lupus-related, hepatitis B-related, infection-related, drug-related, etc.);
• Renal biopsy pathology showed severe tubulointerstitial lesions;
• Severe infection, severe cardiac insufficiency, severe hepatic insufficiency, gastrointestinal bleeding, ketoacidosis and other life-threatening complications within one month;
• Glucocorticoids and/or immunosuppressive therapy (cyclophosphamide, MMF, tacrolimus) within 3 months;
• Have a history of kidney transplantation;
• Breastfeeding or pregnant women;
• Patients with mental disorders or unable to cooperate ;