Immunological Reset to Enable Access to Hla-compatible Kidney Transplantation in Highly Sensitized Patients (RESET) (HIPER-RESET)

Immune Reset to Allow Access to Hla-compatible Kidney Transplantation in Hyperimmunized Patients

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.

Study Overview

• Status: Recruiting
• Conditions: Kidney Failure, Chronic; Kidney Transplantation; HLA Sensitization; Alloimmunization; Highly Sensitized Patients Awaiting Kidney Transplant; End Stage Cronic Kidney Disease
• Intervention / Treatment: Biological: Autologous Hematopoietic Stem Cell Transplantation

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.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Oriol Bestard, Nephrologist; Phone Number: 4661 34932607400; Email: oriol.bestard@vallhebron.cat

Study Locations

• Spain
  • Catalonia
    • Barcelona, Catalonia, Spain, 08035
      • Recruiting
      • Hospital Universitari Vall d'Hebrón
      • Contact: Oriol Bestard, Nephrologist; Phone Number: 4661 34932607400; Email: oriol.bestard@vallhebron.cat
      • Principal Investigator: Oriol Bestard, Nephrologist

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Autologous Hematopoietic Stem Cell Transplantation (AHSCT); Participants undergo a non-myeloablative conditioning regimen for intense lymphodepletion consisting of intravenous Rituximab, Cyclophosphamide (adjusted for end-stage renal disease), and Thymoglobulin (rATG). This is followed by peripheral blood stem cell collection via leukapheresis, CD34+ immunomagnetic selection, and the reinfusion of purified autologous CD34+ progenitors (target dose >= 3 x 10⁶ cells/kg). At 6 months post-AHSCT, patients are reactivated on the deceased-donor kidney transplant waiting list.

Biological: Autologous 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.; Other Names: AHSCT; Autologous CD34+ stem cell infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Calculated Panel Reactive Antibody (cPRA) Levels	Assessment of the efficacy of the AHSCT protocol in reducing or eliminating circulating anti-HLA antibodies. Efficacy is defined as a significant percentage reduction in cPRA levels compared to baseline, which expands the patient's likelihood of finding a compatible organ donor.	Baseline compared to 6 months post-AHSCT (at the time of re-listing).
Incidence of Treatment-Emergent Adverse Events (Safety Profile)	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).	From baseline up to 12 months post-AHSCT.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Successful Kidney Transplantation	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.	Up to 12 months post-AHSCT

Collaborators and Investigators

• Sponsor: Hospital Universitari Vall d'Hebron Research Institute
• Collaborators: Hospital Clinic of Barcelona
• Investigators: Principal Investigator: Oriol Bestard, Hospital Vall d'Hebron

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2024
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: May 19, 2026
• First Submitted That Met QC Criteria: May 19, 2026
• First Posted (Actual): May 26, 2026

Study Record Updates

• Last Update Posted (Actual): May 26, 2026
• Last Update Submitted That Met QC Criteria: May 19, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Autologous Hematopoietic Stem Cell Transplantation; Kidney Transplantation; Desensitization; End-Stage Kidney Disease; AHSCT; Highly sensitized; CD34+ Cells; Anti-HLA Antibodies; Immune Reset; Hyperimmunized; Transplant Immunology
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Chronic Disease; Disease Attributes; Renal Insufficiency; Renal Insufficiency, Chronic; Pathological Conditions, Signs and Symptoms; Kidney Failure, Chronic
• Other Study ID Numbers: 2023-506478-11-01 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be shared to protect patient privacy and maintain confidentiality, in accordance with institutional data protection policies and the small sample size of this pilot study.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No