A first-in-human, phase I clinical trial using stem cells to prevent venous stenosis formation in arteriovenous (AV) fistulas yields promising results. Sanjay Misra (Mayo Clinic, Rochester, USA) presented these results at the 31st annual International Symposium on Endovascular Therapy (ISET; 27-30 January 2019, Hollywood, USA), and won the award for best poster for the same research.
This was the first time this research had been presented at a meeting, and generated much buzz about the potential of autologous adipose-derived mesenchymal stem cells (AMSCs) for increasing maturation and preventing venous stenosis formation in AV fistulas used for haemodialysis.
To contextualise the importance of this research, Misra says: “At one year, nearly 60% of AV fistulas will develop a malfunction, often due to venous stenosis formation, and nearly 40% fail to mature. Pathologically, AV fistulas fail due to venous neointimal hyperplasia caused by an increase in pro-inflammatory gene expression, including monocyte chemoattractant protein-1 and tissue necrosis factor-1 alpha.”
Recognising that with the primary patency of surgical creation of AV fistulas being between 60–70% means there is a high failure rate of approximately 30%, Misra became interested in using stem cells derived from patients as their own therapy or drug.
Following preliminary research conducted in mice, the research group was granted an IND [Investigational New Drug application] from the US Food and Drug Administration (FDA) to pursue the study, which was a phase I safety trial. “Our primary concern was around safety. Would these cells be creating more infections? Will they be less irritating with respect to fevers? So we did a randomised trial comparing patients who received stem cells or no cells and followed them for one year,” Misra explains.
In the phase I, single centre, prospective, blinded, randomised trial, the study investigators reported no adverse events related to stem cell delivery, and a success in terms of maturation rate with the stem cell cohort compared to the control arm. Crucially, the team at Rochester also reported no safety issues with respect to the cellular delivery.
One month after periadventitial delivery of the autologous AMSCs to the outflow vein of the AV fistula, the maturation rate for radial-cephalic fistulas was 100% in the stem cell arm, versus 66% in the control group. For brachial-cephalic fistulas, the maturation rate was 100% in both the stem cell and the control cohorts (there were four patients in each group).
Nine patients were followed up to 12 months’ post-procedure. At this last follow-up, patients in the control group were receiving more interventions than those in the treatment arm: three patients in the control cohort (one brachial-cephalic and two radial-cephalic) underwent five fistulograms with four percutaneous transluminal angioplasties of the cannulation zone, compared with one patient in the stem cell group. “So we are seeing an effect related to the cells, less frequency of interventions,” says Misra.
The Rochester-based team are continuing to enrol patients in this prospective, phase I trial, and a future study is being planned to help determine the efficacy of this therapy. To date, 16 patients have been enrolled (11 men and five women). Patients have an average age of approximately 65 years and an average BMI of 37.99. All of the 16 patients in the study were hypotensive, 10 had a history of diabetes mellitus, five were on haemodialysis, six had a history of coronary artery disease, and 11 had dyslipidemia.
Misra indicated that a possible future direction of this work could be its use in conjunction with angioplasty for stenotic AVF. He told delegates at ISET that there was interest from the cardiothoracic surgeons at Rochester in using this therapy in coronary artery bypass grafting (CABG), and concluded by remarking that “Obviously, we can start to think about using this in the lower extremity as well.”
He and his colleagues are in the process of filling an IDE for using this stem cell therapy with angioplasty and periadventitial catheters.