Kidney Transplantation, Antibody-mediated Rejection
Conditions
Keywords
Daratumumab, Banff 2022 classification, Azathioprine, Natural killer cell, Donor specific antibody, eGFR slope, Chronic active AMR, CD38 antibody, Sequential immunosuppression
Brief summary
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.
Detailed description
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).
Interventions
BIOLOGICALCD38
Single 1800 mg subcutaneous injection at baseline to induce rapid depletion of plasma cells (source of DSA) and NK cells (key effectors of microvascular injury in caABMR). Marketed anti-CD38 mAb (off-label use in this indication).
Oral azathioprine maintenance (replaces mycophenolate), individualized starting dose 2.0-3.0 mg/kg/day (normal TPMT/NUDT15 metabolizer) or 30-80% reduced (intermediate metabolizer), titrated per serial NK cell counts and hematologic tolerance. Long-term NK suppression to maintain immune balance and protect graft.
OTHERStandard Triple Immunosuppression Maintenance
Continued per local practice with protocol targets
Sponsors
wujianyong
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Voluntary written informed consent. 2. Age ≥18 years. 3. Kidney transplant (living or deceased donor) ≥180 days prior. 4. eGFR ≥30 mL/min/1.73 m² (CKD-EPI 2021). 5. Currently on stable triple immunosuppression (CNI + MMF + steroid) for ≥4 weeks, no severe related adverse effects. 6. Positive HLA Class I and/or Class II donor-specific antibodies (DSA). 7. Transplant kidney biopsy meeting Banff 2022 criteria for chronic active antibody-mediated rejection (caABMR). 8. TPMT/NUDT15 genotyping: non-homozygous mutant (normal or intermediate metabolizer).
Exclusion criteria
1. Participating in another clinical trial. 2. Age \<18 years. 3. Pregnant, breastfeeding, or inadequate contraception in females. 4. ABO-incompatible transplant. 5. TPMT/NUDT15 homozygous mutant genotype. 6. Biopsy shows any of: T-cell mediated rejection (TCMR), new/recurrent severe thrombotic microangiopathy, or polyomavirus nephropathy. 7. Received anti-rejection therapy in prior 3 months. 8. Received other immunomodulatory monoclonal/polyclonal antibodies (anti-CD20, bortezomib, anti-C5, anti-IL-6/IL-6R) in prior 3 months. 9. Total bilirubin \>2×ULN or ALT/AST \>2.5×ULN. 10. Hemoglobin \<8 g/dL. 11. Platelets \<100×10\^9/L. 12. WBC \<3×10\^9/L or neutrophils \<1.5×10\^9/L. 13. Hypogammaglobulinemia: IgG \<400 mg/dL. 14. Active bacterial, viral, or fungal infection. 15. Active malignancy requiring intensified immunosuppression. 16. Latent or active tuberculosis. 17. Live vaccine within 6 weeks of screening. 18. History of alcohol or illicit drug abuse. 19. Severe medical or psychiatric illness likely to impair study participation. 20. Active hepatitis B. 21. Known hypersensitivity to CD38 mAb, azathioprine, or study drug components, or severe drug allergy history.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Slope of estimated glomerular filtration rate (eGFR) decline | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Quantitative detection of lymphocyte subpopulations (NK, T, B cells) in peripheral blood via flow cytometry; evaluate the absolute count and relative percentage changes at each follow-up time point. |
| 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 | Estimated glomerular filtration rate (eGFR) is calculated by the CKD-EPI 2021 formula. Both absolute value and relative percentage change of eGFR will be evaluated at all scheduled follow-up visits. |
| Percentage change in urine protein-to-creatinine ratio (UPCR) | Baseline and Week 28 | Urine protein-to-creatinine ratio (UPCR) measured in mg/g or mg/mmol. Urine protein is tested via pyrogallol red molybdate method, and creatinine is detected using sarcosine oxidase assay. The relative percentage change of UPCR is used to evaluate renal therapeutic efficacy. |
| Relative percentage change in donor-specific antibody (DSA) mean fluorescence intensity (MFI) | Baseline, Week 8, Week 28 | Donor-specific antibody MFI is detected via Luminex single-antigen bead assay. Relative percentage change from baseline will be calculated to evaluate the reduction of alloantibody levels. |
| Change in Transplant Kidney Biopsy Pathology Scores (Banff 2022) | Baseline, Week 28 | Banff 2022 renal allograft pathology scoring system is applied for the interpretation of protocol kidney biopsy specimens. The scores include microcirculation inflammation, tubulitis, interstitial inflammation, chronic glomerulopathy, transplant glomerulitis and chronic arteriopathy. The pathological scores are recorded at screening baseline and week-28 follow-up biopsy. The variation of each individual Banff lesion score between two time-points will be analyzed. Higher Banff lesion scores represent more severe renal allograft injury. |
| Incidence of Acute Rejection (TCMR, AMR, or Mixed) | Through Week 28 | Cumulative incidence (%) of biopsy-proven acute rejection, including T cell-mediated rejection (TCMR), antibody-mediated rejection (AMR), and mixed rejection, diagnosed according to Banff 2022 classification criteria. |
| Patient overall survival rate | Week 28 | The proportion of subjects who remain alive without all-cause mortality at the designated follow-up time point |
| Graft survival rate | Week 28 | Percentage of participants with functioning renal allograft, defined as no return to maintenance dialysis and no secondary kidney retransplantation |
| Incidence of BK Virus (BKV) Infection | Through Week 28 | Cases of BK virus infection are categorized as BKV viruria (\>10³ copies/mL), BKV viremia (≥10⁴ copies/mL), or biopsy-confirmed BKV nephropathy identified by renal histology combined with SV40 IHC or ISH staining. Cumulative incidence percentage will be calculated for each category. |
| Incidence of Cytomegalovirus (CMV) Infection | Through Week 28 | Cytomegalovirus infection is defined as detectable CMV DNA ≥10³ copies/mL quantified via quantitative PCR (qPCR). Cumulative incidence percentage of affected subjects will be summarized. |
| Incidence of Neutropenia | Through Week 28 | Neutropenia is stratified by absolute neutrophil count (ANC): mild ANC \<1.5×10⁹/L, moderate ANC \<1.0×10⁹/L, severe ANC \<0.5×10⁹/L. Cumulative incidence percentage will be stratified by severity grades defined per NCI CTCAE or study protocol criteria. |
Contacts
CONTACTChunchun Wei, MD
PRINCIPAL_INVESTIGATORJianyong Wu, MD
Zhejiang University
Outcome results
None listed