Adipose-derived MSC to Treat Rejection in Kidney Transplant Recipients

Safety of Intraarterial Infusion of Adipose Tissue-derived Mesenchymal Stromal Cells to Treat Antibody-mediated and Cellular Rejection in Adult Kidney Transplant Recipients (AMSCAR)

This research study is being done to learn if an experimental treatment of infusing allogeneic adipose-derived mesenchymal stromal cells (allo-A-MSC ) directly into the renal artery is safe and can help reduce inflammation in the transplanted kidney and treat rejection.

Inclusion Criteria:

• Able to understand and provide informed consent.
• Have received a renal transplant (first or repeat), and the most recent protocol biopsy within 3 months of consent is diagnostic for ABMR or cellular rejection.

Clinical Inclusion Criteria:

• Stable renal function:
• Serum creatinine at the time of surveillance biopsy cannot be > 15% greater than the serum creatine prior to the biopsy (must be within 3 months of the biopsy);
• Estimated eGFR > 30 ml/min by MDRD.

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.

Exclusion Criteria:

• Nephrotic range proteinuria (≥ 3.5g/24h), detected more than once in the year preceding screening.

• History of post-transplant intervention for obstructive uropathy

• One or more of the following laboratory values:

  o 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).

• One or more of the following parameters:

  o Temperature ≥ 38°C (100.4°F), Respiratory rate ≥ 20/min, Oxygen saturation (SpO2) ≤ 90%, Systemic systolic blood pressure >160mmHg or < 100 mmHg, Pulse < 45/min or > 140/min

• Patients with the following grades/classes of vascular diseases:

  • NYHA Class 3-4 CHF
  • Uncontrolled arrhythmia, defined as: atrial fibrillation with rapid ventricular response, supraventricular tachycardia, Wolff-Parkinson-White syndrome, ventricular fibrillation, or sick sinus syndrome. Subjects with rate-controlled chronic atrial fibrillation will be allowed to participate.
  • Cerebrovascular accident (CVA) within 90 days of screening
  • Peripheral Arterial Disease (PAD), patients who have had prior vascular interventions for PAD in the index lower extremity.

• 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. History of adequately treated in-situ cervical carcinoma and/or adequately treated skin cancer (basal or squamous cell) will be permitted

• 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. Subjects with previously treated Hepatitis C (NAT negative, HCV IgG positive), or those with HBV surface antibody positive but HBV core antibody negative subjects will not be excluded from the study.

• 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. If subjects fall into either the high or the moderate thrombotic risk, they will be deemed to be not safe to interrupt anticoagulation:

  • High thrombotic risk: Mechanical heart valve: Any mitral valve prosthesis, any caged-ball or tilting disc aortic valve prosthesis, recent (within 6 months) stroke or transient ischemic attack; Atrial Fibrillation: CHADS2 score 5-6, CHA2DS2-VASc score 7-9, recent (within 3 months) stroke or transient ischemic attack, rheumatic valvular heart disease; Venous thromboembolism: Recent (within 3 months) VTE, severe thrombophilia (e.g. deficiency of protein C, protein S, or antithrombin; antiphospholipid antibodies; multiple abnormalities)
  • Moderate thrombotic risk: Mechanical heart valve: Bileaflet aortic valve prosthesis and 1 or more of the of following risk factors: atrial fibrillation, prior stroke or transient ischemic attack, hypertension, diabetes, congestive heart failure; Atrial Fibrillation: CHADS2 score 3-4, CHA2DS2-VASc score 4-6; Venous thromboembolism: VTE within the past 3 to 12 months, non-severe thrombophilia (e.g. heterozygous factor V Leiden or prothrombin gene mutation), recurrent VTE
  • For all other subjects, anticoagulation can be safely interrupted for 3 days prior to infusion and resumed a day after the infusion.

• 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