A-MSC Therapy for Kidney Transplant Rejection

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Mayo Clinic

Disqualifiers: Nephrotic proteinuria, Uncontrolled arrhythmia, Malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 1 day

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment, Adipose-derived MSC (mesenchymal stromal cells), which might reduce inflammation and rejection in transplanted kidneys. The process involves infusing cells derived from fat tissue directly into the kidney's blood supply. Participants will receive either a high or low dose to assess safety and effectiveness. Individuals who have had a kidney transplant and show signs of rejection without obvious symptoms might be suitable for this study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that anticoagulation (blood-thinning) medications can be safely interrupted for 3 days before the infusion and resumed a day after. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that fat-derived stem cells are generally safe. In one study, administering these cells to people caused no major side effects. Another study found them safe when injected directly into the bloodstream.

These cells have demonstrated potential in reducing inflammation. Although no serious safety issues have been reported, it is important to remember that this research is still in its early stages. Participants in such trials help gather more information to confirm these findings. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about Adipose-derived MSC (A-MSC) therapy for kidney transplant rejection because it represents a novel approach compared to standard treatments like immunosuppressive drugs. A-MSC therapy uses mesenchymal stem cells derived from fat tissue, which have the ability to modulate the immune system in a more targeted way, potentially reducing the risk of side effects common with traditional drugs. This treatment offers promise for addressing both antibody-mediated and cellular rejection, providing a more comprehensive solution for transplant recipients. Additionally, by offering both high and low dose options, A-MSC therapy could be tailored to individual patient needs, potentially improving outcomes and quality of life for those experiencing subclinical rejection.

What evidence suggests that this treatment might be an effective treatment for kidney transplant rejection?

Research has shown that special cells from fat tissue, called adipose-derived mesenchymal stromal cells (A-MSCs), can help with kidney transplant rejection. In animal studies, these cells lowered rejection rates and helped the transplanted kidney last longer. Some studies also suggest that A-MSCs reduce early rejection, which often occurs soon after a kidney transplant. These cells decrease inflammation, a major factor in rejection. In this trial, participants will receive either a high dose or a low dose of allogeneic A-MSCs to evaluate their effectiveness. Overall, early evidence suggests that A-MSCs could potentially improve outcomes for kidney transplant recipients. ^{2 6 7 8 9}

Who Is on the Research Team?

Timucin Taner, MD, PhD

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

This trial is for kidney transplant recipients who can consent, have had a recent biopsy showing rejection, stable renal function with eGFR > 30 ml/min, and specific inflammation or rejection signs in the biopsy. Excluded are those with severe heart conditions, vascular diseases, acute illnesses within 30 days, allergies to contrast agents, unwilling to use contraception for 12 months post-treatment, substance abuse issues, active COVID-19 or other infections like CMV or BK virus.

Inclusion Criteria

I understand the study and agree to participate.

Histologic Criteria for Eligibility: ABMR: microvascular inflammation scores for glomerulitis (g) and peritubular capillaritis (ptc) (g:1 or 2; ptc:1 or 2). Cellular rejection: tubulitis (t) (t:1or 2); interstitial inflammation (i) (i:1 or 2); intimal arteritis (v) (v: 1 or 2). Mixed ABMR and cellular rejection

My kidney function is stable, with creatinine levels not much higher than before my biopsy.

Exclusion Criteria

I have had high levels of protein in my urine multiple times in the last year.

Hemoglobin (Hb} ≤ 8 g/dL, Potassium (K) ≥ 5.5 mEq/dL, Alanine aminotransferase (ALT) ≥ 60 U/L, Hemoglobin A1C (HbA1c) ≥ 7%, International Normalized Ratio (INR) ≥ 2.0, Platelet count < 50 x 109/L (patients who receive a platelet transfusion to increase their platelet count will not be excluded)

NYHA Class 3-4 CHF, Uncontrolled arrhythmia, Cerebrovascular accident (CVA) within 90 days of screening, Peripheral Arterial Disease (PAD), Acute illness within 30 days of screening, History of allergy or intolerance to iodinated contrast agents, Women of childbearing potential or male subjects with female partners of childbearing potential unwilling to use an effective method of contraception during and for 12 months post-treatment, History of or current evidence of alcohol abuse, illicit drug use or dependence, Active COVID 19 or positive test for the SARS-CoV-2 virus, History of malignancy within 5 years of enrollment, Serologic evidence of human immunodeficiency virus 1 or 2 infection, Epstein Barr Virus (EBV) sero-negativity (EBV naïve), Cytomegalovirus (CMV) sero-negativity, Active post-transplant opportunistic infections at the time of screening (CMV, BK virus, polyoma virus, EBV), Active Hepatitis B or Hepatitis C infection (e.g. NAT positive), and/or HBV core antibody positivity, Have received a kidney transplant from a Hepatitis C positive donor and plan to receive anti-viral treatment after transplant, Any chronic condition for which anti-coagulation cannot be safely interrupted for kidney biopsy based on the CHA2DS2-VASc score of ≥ 6 risk stratum, Positive pregnancy test, Participation in any other studies that involved investigational drugs or regimens in the preceding year, Any other condition, in the investigator's judgment, that increases the risk of A-MSC infusion or prevents safe trial participation, Unwilling or unable to adhere to study requirements and procedures, Per Banff criteria category 6: the presence of other changes not considered to be caused by acute or chronic rejection, BK-Virus Nephropathy, Posttransplant Lymphoproliferative Disorder, Calcineurin Inhibitor Toxicity, Acute Tubular Injury, Recurrent Disease, De Novo Glomerulopathy (Other Than TG), Pyelonephritis or Drug-Induced Interstitial Nephritis

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive an infusion of allogeneic adipose-derived mesenchymal stromal cells (allo-A-MSC) directly into the renal artery

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including monitoring for adverse events and kidney allograft rejection

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Adipose-derived MSC

Trial Overview The study tests if infusing different doses of adipose-derived mesenchymal stromal cells (A-MSC) into the renal artery can safely reduce inflammation and treat kidney transplant rejection. Participants will receive either a low dose or high dose of A-MSC directly into their transplanted kidney's blood supply.

How Is the Trial Designed?

Group I: Low Dose Group Experimental Treatment 1 Intervention

Adult kidney transplant recipients with subclinical rejection (biopsy-proven antibody-mediated and/or cellular rejection, including borderline rejection) will be administered one low dose of allogeneic A-MSC.

Group II: High Dose Group Experimental Treatment 1 Intervention

Adult kidney transplant recipients with subclinical rejection (biopsy-proven antibody-mediated and/or cellular rejection, including borderline rejection) will be administered one high dose of allogeneic A-MSC.

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

Published Research Related to This Trial

A 29-year-old male with end-stage renal disease successfully received a kidney transplant with the co-infusion of donor-derived mesenchymal stem cells and hematopoietic stem cells, leading to stable kidney function for over 3 years.

Remarkably, the patient has maintained normal kidney function without any immunosuppression for 2.5 years, showing no signs of rejection or donor-specific antibodies, suggesting that the stem cell therapy may have contributed to achieving transplantation tolerance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pre-transplant co-infusion of donor-adipose tissue derived mesenchymal stem cells and hematopoietic stem cells may help in achieving tolerance in living donor renal transplantation. Vanikar, AV., Trivedi, HL., Gopal, SC., et al.[2014]

In a study involving 285 patients, co-infusion of donor adipose-derived mesenchymal stem cells (AD-MSC) and hematopoietic stem cells (HSC) during kidney transplantation was found to be safe and effective in minimizing immunosuppression, with the best outcomes observed in the group receiving both cell types.

At 1 and 5 years post-transplant, the group receiving AD-MSC + HSC showed the highest patient and graft survival rates, along with fewer rejection episodes and lower immunosuppression requirements compared to the control group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Co-infusion of donor adipose tissue-derived mesenchymal and hematopoietic stem cells helps safe minimization of immunosuppression in renal transplantation - single center experience. Vanikar, AV., Trivedi, HL., Kumar, A., et al.[2022]

Mesenchymal stromal cells (MSC) have shown promise in kidney transplantation, demonstrating safety and feasibility in initial clinical studies, with potential to reduce the need for immunosuppressive drugs.

Some patients treated with MSC therapy exhibited biomarkers indicating immunomodulation, leading to successful and safe complete discontinuation of immunosuppression in one case, highlighting the potential for personalized treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mesenchymal stromal cells in kidney transplantation. Casiraghi, F., Remuzzi, G.[2021]

Adipose tissue-derived stem cells (ADSCs) significantly reduced kidney transplant rejection in rats, leading to prolonged graft survival and decreased infiltration of T cells, indicating their potential as an effective immunomodulatory treatment in organ transplantation.

The mechanism of action involves ADSCs increasing the production of TSG-6, a protein that suppresses T cell activation and infiltration, thereby enhancing the anti-inflammatory response during kidney transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adipose tissue-derived stem cells suppress acute cellular rejection by TSG-6 and CD44 interaction in rat kidney transplantation. Kato, T., Okumi, M., Tanemura, M., et al.[2022]

In a dose escalation study involving 21 subjects, adipose-derived human mesenchymal stem cell (MSC) therapy showed no significant cellular or renal toxicity, indicating a favorable safety profile.

The therapy led to improvements in renal oxygenation and glomerular filtration rate, along with a reduction in inflammatory markers, suggesting potential efficacy in treating renovascular disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving human kidney function in renovascular disease with mesenchymal stem cell therapy. Sivanathan, KN., Coates, PT.[2020]

The combination of donor adipose tissue-derived mesenchymal stem cells (h-AD-MSC) with hematopoietic stem cell transplantation (HSCT) was found to be safe and more effective in promoting donor hypo-responsiveness compared to HSCT alone, as evidenced by lower acute rejection episodes and better graft function over 18 months in a study of 200 renal allograft recipients.

Patients receiving h-AD-MSC showed a higher peripheral blood chimerism (4% vs. 1.8%) and a mean serum creatinine level of 1.59 mg%, indicating better kidney function and stability compared to the HSCT-only group, which had a mean serum creatinine of 1.49 mg% and higher rates of graft loss.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of co-transplantation of mesenchymal stem cells and hematopoietic stem cells as compared to hematopoietic stem cell transplantation alone in renal transplantation to achieve donor hypo-responsiveness. Vanikar, AV., Trivedi, HL., Feroze, A., et al.[2021]

Adipose-derived stem cells (ADSCs) isolated from renal adipose capsules proliferate faster and in greater numbers compared to those from groin adipose tissues, suggesting they are a more effective source for potential kidney disease treatments.

The study found that renal ADSCs have a lower expression of CD44 compared to groin ADSCs, indicating distinct biological characteristics that may influence their therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Study on the biological characteristics of adipose stem cells derived from renal adipose capsule cultured in vitro]. Wu, W., Zheng, HG., Zhang, DW., et al.[2010]

Triple injections of adipose-derived stem cells (ADSCs) significantly improved skin graft survival in a human-to-rat xenograft model by delaying cell-mediated rejection compared to single injections and control groups.

The enhanced survival was linked to increased vascularization and collagen production, along with reduced levels of proinflammatory cytokine IFN-γ and increased immunosuppressive prostaglandin E synthase (PGES) in the grafts, indicating a strong immunomodulatory effect of ADSCs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple Injections of Adipose-Derived Stem Cells Improve Graft Survival in Human-to-Rat Skin Xenotransplantation through Immune Modulation. Jeon, S., Kim, I., Na, YR., et al.[2023]

The study evaluated the safety and efficacy of autologous adipose-derived stem cell (ASC) therapies in 17 patients with severe conditions, finding no serious adverse events over a follow-up period of up to 54 months.

Both ASC-derived products—a scaffold-free osteogenic graft for bone non-union and a biological dressing for chronic wounds—were successfully manufactured and implanted without contamination or genomic issues, demonstrating their feasibility for clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human Adipose-Derived Mesenchymal Stem Cells in Cell Therapy: Safety and Feasibility in Different "Hospital Exemption" Clinical Applications. Vériter, S., André, W., Aouassar, N., et al.[2022]

Adipose-derived mesenchymal stem cells (AD-MSC) significantly protect against kidney injury caused by 45 minutes of renal ischemia followed by 48 hours of reperfusion in rats, as evidenced by improved serum creatinine and blood urea nitrogen levels.

Histological analysis revealed that AD-MSC treatment reduced tubular necrosis and other signs of kidney damage, indicating their potential as a therapeutic intervention for acute kidney injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of adipose-derived mesenchymal stem cells on renal function and histopathology in a rat model of ischemia-reperfusion induced acute kidney injury. Changizi-Ashtiyani, S., Hafazeh, L., Ghasemi, F., et al.[2022]

Adipose tissue-derived mesenchymal stem cells (MSCs) maintain their anti-inflammatory and immune-modulating properties even in the presence of human kidney disease or uremic serum, suggesting they could be effective in treating kidney conditions.

The potential for using autologous (patient-derived) adipose tissue-derived MSCs in clinical settings highlights the need for further research to establish their long-term safety and efficacy in kidney disease treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adipose tissue-derived mesenchymal stem cells: a fat chance of curing kidney disease? Lin, F.[2023]

Citations

1. trialfinder.panfoundation.org trialfinder.panfoundation.org/en-US/trial/listing/350375

Adipose-derived MSC to Treat Rejection in Kidney ... Primary outcome measures · Worsening kidney allograft rejection (28 days after A-MSC infusion) · Adverse Events (1 year) ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8538841/

Adipose-Derived Stem/Stromal Cells in Kidney ... Current data demonstrate excellent results in term of early acute rejection rates and successful CNI sparing, but the overall impact on DGF ...

3. withpower.com withpower.com/trial/phase-1-kidney-transplantation-7-2022-d1a30

A-MSC Therapy for Kidney Transplant Rejection Adipose tissue-derived stem cells (ADSCs) significantly reduced kidney transplant rejection in rats, leading to prolonged graft survival and decreased ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0955470X22000374

Review article Therapeutic efficacy of extracellular vesicles ... EVs are promising candidates to suppress allograft rejection and improve kidney transplant outcome. Immune cell-EVs showed their superiority over MSC-EVs.

5. heraldopenaccess.us heraldopenaccess.us/openaccess/mesenchymal-stem-cells-derived-from-adipose-tissue-ameliorate-chronic-allograft-rejection-in-the-long-term-in-a-rat-experimental-model-of-kidney-transplantation

Mesenchymal Stem Cells Derived from Adipose Tissue ... The aim of this study was to analyze the possible beneficial effects of Adipose-Derived Stem Cells (ASC) on chronic renal allograft nephropathy ...

6. mayo.edu mayo.edu/research/clinical-trials/cls-20532372

Adipose-derived MSC to Treat Rejection in Kidney ... The overall goal of this study is to determine the safety and feasibility of infusing adipose-derived mesenchymal stem cells directly into ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05308836

Evaluate Safety of Adipose Derived Mesenchymal Stem ... The purpose of this study is to evaluate the safety of intravenously (IV) administered adipose-derived mesenchymal stem cell (AD-MSC) in treatment 10 patients ...

8. journals.lww.com journals.lww.com/kidney360/fulltext/2024/11000/safety_and_tolerability_of_adipose_derived.13.aspx

Safety and Tolerability of Adipose-Derived Mesenchymal ... This prospective clinical trial assessed the safety and tolerability of adipose-derived mesenchymal stem cell (ASC) therapy and evaluated its therapeutic ...

9. frontierspartnerships.org frontierspartnerships.org/journals/transplant-international/articles/10.3389/ti.2022.10772/full

Autologous Mesenchymal Stem Cells for Treatment of Chronic ... The aim of this study was to evaluate the safety and efficacy of autologous MSCs in combination with standard therapy in KTRs with biopsy-proven chronic active ...