Overview

This study is a single-center, prospective, exploratory Phase I clinical trial initiated by the team led by Associate Professor He Lijie from the Department of Nephrology, Xijing Hospital.

Prior to receiving CAR-T cell therapy, patients will undergo lymphodepletion chemotherapy with cyclophosphamide (fludarabine will be added if necessary). After prophylactic administration of antihistamines and acetaminophen, patients will be infused with CD19 CAR-T cells at a dose of 1×10⁶ cells/kg.

In the subsequent 2 weeks, patients will be hospitalized for monitoring of vital signs and adverse reactions. The planned follow-up duration of this study is 1 years.

Eligibility

Inclusion Criteria:

• Confirmed as primary membranous nephropathy (PMN) by renal biopsy.
• Classified as moderate-risk or high-risk refractory membranous nephropathy (rMN).
• Moderate-risk rMN is defined as: eGFR ≥ 90 ml/min/1.73m² AND 24-hour urinary protein \> 3.5g/d, with a reduction of no more than 50% within 6 months of receiving renin-angiotensin system inhibitor (RASi) therapy.
• High-risk rMN is defined as meeting one of the following:
  1. eGFR \< 60 ml/min/1.73m² and/or persistent proteinuria \> 8g/d for more than 6 months.
  2. Normal eGFR with proteinuria \> 3.5g/d and ≤50% reduction after 6 months of RASi therapy, PLUS at least one of the following: Serum albumin \< 25g/L; PLA2R antibody \> 50 RU/mL; Urinary α1-microglobulin \> 40 μg/min; Urinary IgG \> 1 μg/min; Urinary β2-microglobulin \> 250 mg/d; IgG/albumin clearance ratio \> 0.20.
• Diagnosis of rMN requires failure of adequate first-line immunosuppressive therapy (≥6 months of steroids+cyclophosphamide, CNI, or rituximab), defined by any of the following: persistent high-titer anti-PLA2R antibody; for antibody-negative patients, persistent nephrotic syndrome (protein \>3.5g/d, albumin \<30g/L); \<50% reduction in proteinuria.
• Age ≥ 18 years.
• Adequate organ function, defined as:
  1. Renal: eGFR ≥ 30 ml/min/1.73m².
  2. Hepatic: ALT and AST ≤ 2.5 x ULN; Total bilirubin ≤ 1.5 x ULN.
  3. Cardiac: LVEF ≥ 50%; NYHA Class I or II; No significant arrhythmias requiring intervention; No major cardiovascular events within the past 6 months.
  4. Respiratory: SpO2 \> 92% on room air.
• Ability to understand and willingness to sign an Informed Consent Form.

Exclusion Criteria:

• Secondary membranous nephropathy (e.g., due to SLE, malignancy, drugs, infection).
• Active infection requiring IV antibiotics, active tuberculosis, or positive viral serology indicating active infection, including:
  1. HBV: HBsAg (+) and/or HBcAb (+) with detectable HBV DNA.
  2. HCV: HCV Ab (+) with detectable HCV RNA.
  3. HIV Ab (+).
  4. Active EBV or CMV infection (IgM+ or DNA above normal).
  5. Positive syphilis (Treponema pallidum) antibody (requires evaluation for active infection).
• Severe uncontrolled comorbidities, including:
  1. Uncontrolled hypertension (persistent SBP \> 160 mmHg or DBP \> 100 mmHg).
  2. Uncontrolled diabetes (HbA1c \> 8% or random glucose ≥11.1 mmol/L) or diabetic nephropathy.
  3. Symptomatic deep vein thrombosis or pulmonary embolism within the past 6 months.
  4. Active peptic ulcer or gastrointestinal bleeding within the past 6 months.
  5. Severe congenital or acquired immunodeficiency.
  6. Severe CNS diseases (e.g., catastrophic APS, uncontrolled epilepsy).
  7. End-stage organ failure not attributable to PMN.
• History of malignancy within the past 5 years, except for adequately treated non-melanoma skin cancer, cervical carcinoma in situ, or thyroid cancer.
• Specific treatment history or plans, including:
  1. Prior receipt of any cell therapy (e.g., MSCs, HSCT).
  2. Major surgery within 24 weeks before or planned within 24 weeks after enrollment.
  3. Planned kidney transplantation within 3 years.
  4. History of substance abuse.
• Participation in another interventional clinical trial within 3 months prior to enrollment.
• Pregnant or lactating women.
• Inability to understand the study or provide informed consent (e.g., severe dementia, mental illness).
• Any other condition deemed by the investigator to increase risk, interfere with assessment, or affect compliance.