A Multicenter Exploratory Clinical Study of Targeted NK Cell Inhibition for Transplant Kidney Chronic Active Antibody-Mediated Rejection (caABMR): Single Induction With CD38 Monoclonal Antibody Followed by Sequential Maintenance With Azathioprine
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 发起方
- 入组人数
- 20
- 主要终点
- Slope of estimated glomerular filtration rate (eGFR) decline
研究概览
简要总结
This multicenter, prospective, single-arm exploratory study evaluates the efficacy and safety of a novel sequential regimen for chronic active antibody-mediated rejection (caABMR) in kidney transplant recipients: single-dose CD38 monoclonal antibody (1800 mg subcutaneous) induction to deplete plasma cells and NK cells, followed by long-term maintenance with azathioprine (replacing mycophenolate mofetil) plus standard triple immunosuppression (steroid + calcineurin inhibitor). The regimen aims to control DSA-driven injury, stabilize or improve graft function (primary: eGFR decline slope), reduce DSA, improve pathology (Banff 2022), and minimize infection/nephrotoxicity risks associated with intensified or prolonged biologic therapy. Twenty patients across 6 Chinese transplant centers will be enrolled. CD38 mAb, azathioprine, key monitoring tests (HLA antibody, pharmacogenomics, immune profiling) are provided free by the study team (~40,000 RMB per patient). Ethics approved; informed consent obtained.
详细描述
Background: caABMR is the leading cause of late kidney allograft loss. Current therapies (plasmapheresis, IVIG, rituximab, bortezomib, long-term CD38 mAb) have limited efficacy, high recurrence, significant side effects, and high cost with no approved standard.
Rationale: CD38 mAb depletes antibody-producing plasma cells and pathogenic NK cells, rapidly lowering DSA and micro vascular inflammation. However, long-term monotherapy is costly and may increase infection risk. This study uses single induction dose + switch to azathioprine (safe, inexpensive, long-used in transplantation, suppresses NK activity) for durable, affordable maintenance. TPMT/NUDT15 genotyping guides personalized AZA dosing; serial NK cell monitoring targets <20/μL.
Design: Multicenter (6 centers), prospective, open-label, single-arm, exploratory (N=20).
Intervention: Baseline: CD38 mAb 1800 mg SC x1 + immediate switch MMF→AZA (dose per genotype: normal metabolizer 2-3 mg/kg/d; intermediate 0.6-2.4 mg/kg/d). Maintain triple IS (steroid + AZA + Tac target 5-7 ng/mL or CsA 150-250 ng/mL).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Voluntary written informed consent.
- •Age ≥18 years.
- •Kidney transplant (living or deceased donor) ≥180 days prior.
- •eGFR ≥30 mL/min/1.73 m² (CKD-EPI 2021).
- •Currently on stable triple immunosuppression (CNI + MMF + steroid) for ≥4 weeks, no severe related adverse effects.
- •Positive HLA Class I and/or Class II donor-specific antibodies (DSA).
- •Transplant kidney biopsy meeting Banff 2022 criteria for chronic active antibody-mediated rejection (caABMR).
- •TPMT/NUDT15 genotyping: non-homozygous mutant (normal or intermediate metabolizer).
排除标准
- •Participating in another clinical trial.
- •Age <18 years.
- •Pregnant, breastfeeding, or inadequate contraception in females.
- •ABO-incompatible transplant.
- •TPMT/NUDT15 homozygous mutant genotype.
- •Biopsy shows any of: T-cell mediated rejection (TCMR), new/recurrent severe thrombotic microangiopathy, or polyomavirus nephropathy.
- •Received anti-rejection therapy in prior 3 months.
- •Received other immunomodulatory monoclonal/polyclonal antibodies (anti-CD20, bortezomib, anti-C5, anti-IL-6/IL-6R) in prior 3 months.
- •Total bilirubin >2×ULN or ALT/AST >2.5×ULN.
- •Hemoglobin <8 g/dL.
- •Platelets <100×10^9/L.
- •WBC <3×10^9/L or neutrophils <1.5×10^9/L.
- •Hypogammaglobulinemia: IgG <400 mg/dL.
- •Active bacterial, viral, or fungal infection.
- •Active malignancy requiring intensified immunosuppression.
- •Latent or active tuberculosis.
- •Live vaccine within 6 weeks of screening.
- •History of alcohol or illicit drug abuse.
- •Severe medical or psychiatric illness likely to impair study participation.
- •Active hepatitis B.
- •Known hypersensitivity to CD38 mAb, azathioprine, or study drug components, or severe drug allergy history.
结局指标
主要结局
Slope of estimated glomerular filtration rate (eGFR) decline
时间窗: Baseline through Week 28, planned assessments at weeks 0, 4, 8, 12, 16, 20, 24, 28
The primary efficacy endpoint is the slope of eGFR decline over 28 weeks, calculated from serial serum creatinine measurements (every 4 weeks) using the 2021 CKD-EPI equation. Serum creatinine is measured by enzymatic method or isotope dilution mass spectrometry. Slope is estimated via linear mixed-effects model or ordinary least-squares regression per patient, then summarized. Negative slope indicates ongoing graft loss; less negative or positive slope indicates stabilization or improvement of renal function after treatment.
次要结局
- Change in peripheral blood NK cell, T cell and B cell subset counts and percentages measured by flow cytometry(Baseline, Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28)
- Absolute and relative percentage change in estimated glomerular filtration rate calculated by CKD-EPI 2021 formula(Baseline, Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28)
- Percentage change in urine protein-to-creatinine ratio (UPCR)(Baseline and Week 28)
- Relative percentage change in donor-specific antibody (DSA) mean fluorescence intensity (MFI)(Baseline, Week 8, Week 28)
- Change in Transplant Kidney Biopsy Pathology Scores (Banff 2022)(Baseline, Week 28)
- Incidence of Acute Rejection (TCMR, AMR, or Mixed)(Through Week 28)
- Patient overall survival rate(Week 28)
- Graft survival rate(Week 28)
- Incidence of BK Virus (BKV) Infection(Through Week 28)
- Incidence of Cytomegalovirus (CMV) Infection(Through Week 28)
- Incidence of Neutropenia(Through Week 28)
研究者
wujianyong
Director, Nephrology Center / Chief Physician
First Affiliated Hospital of Zhejiang University