Alloimmunization, End Stage Cronic Kidney Disease, Highly Sensitized Patients Awaiting Kidney Transplant, HLA Sensitization, Kidney Failure, Chronic, Kidney Transplantation
Conditions
Keywords
Autologous Hematopoietic Stem Cell Transplantation, AHSCT, Kidney Transplantation, Highly sensitized, Hyperimmunized, Desensitization, Anti-HLA Antibodies, CD34+ Cells, Transplant Immunology, End-Stage Kidney Disease, Immune Reset
Brief summary
The purpose of this clinical trial is to evaluate whether a temporary reprogramming of the immune system can help highly sensitized (hyperimmunized) patients with end-stage kidney disease safely receive a compatible kidney transplant. Patients who are highly sensitized have developed an extremely high level of antibodies against human leukocyte antigens (HLA), often due to previous transplants, pregnancies, or blood transfusions. This condition makes it nearly impossible for them to find a compatible organ donor, leaving them stuck on dialysis indefinitely. This study tests an innovative strategy using Autologous Hematopoietic Stem Cell Transplantation (AHSCT). The procedure involves an intensive conditioning regimen using a combination of medications (cyclophosphamide, thymoglobulin, and rituximab) to deeply clear out the patient's existing mature immune cells. This is followed by the reinfusion of the patient's own previously collected and purified blood stem cells (CD34+ cells) to rebuild the immune system from scratch. The investigators hypothesize that this procedure will eliminate the "immunological memory" cells responsible for producing the problematic anti-HLA antibodies, resetting the immune system to a "naive" or inactive state. This immune reset is expected to eliminate or significantly lower circulating HLA antibodies, creating a critical window of opportunity for these patients to successfully receive a compatible kidney transplant from the deceased-donor waiting list.
Detailed description
This single-center, open-label, non-randomized phase Ib/II pilot study will evaluate the safety, feasibility, and immunological effects of autologous hematopoietic stem cell transplantation (AHSCT) in highly sensitized patients awaiting kidney transplantation. A total of 10 hyperimmunized patients on the kidney transplant waiting list will be enrolled in two sequential phases. In Phase 1, four participants will undergo AHSCT with close safety monitoring during a 12-month follow-up period. In the absence of severe adverse events, participants will be reactivated on the deceased-donor kidney transplant waiting list at 6 months post-AHSCT. Following safety evaluation of the initial cohort, an additional six participants will be enrolled in Phase 2 to further assess the efficacy and safety of the strategy. The intervention includes a non-myeloablative lymphodepletion and stem cell mobilization regimen followed by collection, CD34+ selection, and reinfusion of autologous hematopoietic progenitor cells. After AHSCT, eligible participants may undergo deceased-donor kidney transplantation following confirmation of HLA compatibility by standard crossmatch techniques. Kidney transplant recipients will receive standard-of-care induction and maintenance immunosuppressive therapy according to institutional clinical practice. The study also includes longitudinal immunological monitoring to characterize adaptive immune reconstitution and anti-HLA responses after AHSCT and kidney transplantation. Peripheral blood and bone marrow samples will be collected at predefined time points to evaluate T- and B-cell memory compartments, donor-specific antibodies, and pathogen-specific immune responses. Primary objectives include assessment of safety and feasibility, as well as evaluation of changes in sensitization status and access to HLA-compatible kidney transplantation following AHSCT.
Interventions
BIOLOGICALAutologous Hematopoietic Stem Cell Transplantation
A comprehensive cell therapy protocol involving intense non-myeloablative lymphodepletion followed by stem cell rescue. The intervention includes sequential intravenous administration of Rituximab, Cyclophosphamide (specifically dose-adjusted for end-stage renal disease), and rabbit Thymoglobulin (rATG). Following conditioning, participants receive an intravenous reinfusion of purified autologous CD34+ hematopoietic progenitor cells collected via peripheral blood leukapheresis at a target dose of \>= 3 x 10⁶ cells/kg, with a cryopreserved backup aliquot maintained for safety.
Sponsors
Hospital Universitari Vall d'Hebron Research Institute
Hospital Clinic of Barcelona
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a single-arm, open-label pilot study with a two-stage sequential design focused on safety monitoring. The trial initially enrolls a cohort of 4 patients in Phase 1 to evaluate safety over 12 months. Upon confirming an optimal safety profile, the trial proceeds to Phase 2 to enroll the remaining 6 patients. All 10 participants undergo the identical conditioning regimen and autologous hematopoietic stem cell transplantation protocol.
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Patients aged between 18 and 60 years. * Diagnosis of end-stage kidney disease (ESRD) currently maintained on chronic dialysis. * Highly sensitized/hyperimmunized status, defined by a high calculated Panel Reactive Antibody (cPRA) level (e.g., \>= 95%). * Active status on the deceased-donor kidney transplant waiting list. * Adequate bone marrow, hepatic, cardiac, and pulmonary function to safely undergo the conditioning regimen and AHSCT. * Capable of understanding the study requirements and providing written informed consent.
Exclusion criteria
* Contraindications to the conditioning regimen medications (rituximab, cyclophosphamide, or rATG). * Active, uncontrolled systemic infection, or chronic active infection (including HIV, active Hepatitis B or C, or active tuberculosis). * Significant cardiac dysfunction (e.g., Left Ventricular Ejection Fraction \< 50%) or severe underlying pulmonary disease. * History of malignant neoplasm within the past 5 years, excluding successfully treated non-melanoma skin cancer or carcinoma in situ. * Previous autologous or allogeneic hematopoietic stem cell transplantation. * Pregnancy or breastfeeding. * Any psychiatric, medical, or geographical condition that, in the investigator's opinion, prevents compliance with the protocol and long-term follow-up.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Calculated Panel Reactive Antibody (cPRA) Levels | Baseline compared to 6 months post-AHSCT (at the time of re-listing). | Assessment of changes in circulating anti-HLA antibodies following the AHSCT protocol, measured by calculated Panel Reactive Antibody (cPRA) levels compared to baseline. Changes in cPRA levels may influence the patient's likelihood of identifying a compatible organ donor. |
| Incidence of Treatment-Emergent Adverse Events (Safety Profile) | From baseline up to 12 months post-AHSCT. | Evaluation of the safety and tolerability of the intense conditioning regimen and autologous hematopoietic stem cell transplantation (AHSCT). This includes monitoring the number, severity, and type of serious and non-serious adverse events, evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Successful Kidney Transplantation | Up to 12 months post-AHSCT | The proportion of highly sensitized patients who successfully receive an HLA-compatible deceased-donor kidney transplant after being reactivated on the waiting list following the immune reset. |
Countries
Spain
Contacts
CONTACTOriol Bestard, Nephrologist
PRINCIPAL_INVESTIGATOROriol Bestard
Hospital Vall d'Hebron
Outcome results
None listed