First Results With Autologous Tissue-Engineered Vascular Grafts for Hemodialysis Access Encouraging

April 23, 2009 — Five of 10 autologous tissue-engineered vascular grafts, implanted as arteriovenous shunts for hemodialysis access in patients with end-stage renal disease, continued to function effectively for hemodialysis up to 20 months after implantation, according to the results of a study published in the April 25 issue of The Lancet.

"Application of a tissue-engineered vascular graft for small-diameter vascular reconstruction has been a long awaited and much anticipated advance for vascular surgery," write Todd N. McAllister, PhD, from Cytograft Tissue Engineering, Novato, California, and colleagues.

In 1998, the investigators reported a new process called sheet-based tissue engineering, which enabled them to produce blood vessels using human cells that had what they describe as "supraphysiological burst strength without the need for chemical modification, fixation, synthetic scaffolds, or exogenous biomaterials."

There is a need for such blood vessels because at this time about half of all dialysis patients have their blood filtered via a plastic tube arteriovenous shunt. These shunts are prone to significantly higher failure rates than those created from the patient's own vein, but only half of patients have vein segments that are suitable for making a shunt.

In the present study, Dr. McAllister and colleagues looked at 10 patients implanted with grafts made from their own cells. The patients were enrolled from centers in Argentina and Poland between September 2004 and April 2007. All were older than 21 years and had experienced a previous hemodialysis access failure. They all had a functioning access that was judged by the attending physicians to have a high probability of failure within the next 12 months. None of the patients had a suitable native vein for a fistula and were therefore candidates for an expanded polytetrafluoroethylene graft.

The authors explain that they chose the arteriovenous shunt model rather than a less mechanically challenging model such as a leg vascular bypass for the first clinical test of a tissue-engineered vascular graft because of safety concerns. The frequent hemodialysis visits allowed close surveillance and the chance to intervene early if the grafts showed signs of failure. Also, this population of hemodialysis patients would tolerate graft failures relatively well if they did occur.

The study was divided into several phases. First, a biopsy sample was taken from the patient, from which endothelial cells and fibroblasts were extracted to provide the material for the tissue-engineered vascular graft. Then, the graft was implanted and mechanical stability was assessed during a 3-month safety phase in the first 6 patients. The patients were followed up with physical exams during dialysis, as well as Doppler ultrasound, intravascular ultrasound, angiography, and computer tomography angiography. During this safety phase, successful vascular grafts were not punctured.

Finally, hemodialysis was started in the full cohort of 10 patients to establish the effectiveness of the graft.

Three of the grafts failed during the safety phase of the study, which is consistent with failure rates expected for this high-risk patient population. One patient was withdrawn from the study because of severe gastrointestinal bleeding shortly before implantation, and another patient died of unrelated causes during the safety phase of the study.

The remaining 5 patients had grafts functioning for hemodialysis 6 to 20 months after implantation, for a total of 68 patient-months of patency. The authors report that 1 of these patients required surgical correction to maintain secondary patency.

Overall, the primary patency rate was 78% at 1 month after implantation and 60% at 6 months after implantation. "Our proportion of primary patency in this high-risk cohort approaches Dialysis Outcomes Quality Initiative objectives (76% of patients 3 months after implantation)," the authors explain.

The investigators also write that it is too early to determine whether the "excellent results" will be replicated across a broader range of patients. "Clearly with only 68 patient-months of graft patency, statistically meaningful comparisons with the standard of care would be premature."

Still, they conclude that their results are encouraging. "Even in view of the challenges associated with this patient population and our conservative protocol, this patency rate seems reasonable for this early clinical study."

They add that they will also start to investigate the utility of allogeneic tissue-engineered vascular grafts. Such allogeneic approaches, they write, "would address the key limitations (eg. Scale-up, production costs, and availability) associated with autologous cell-based therapies."

In an accompanying editorial, Vladimir Mironov, MD, PhD, from the Medical University of South Carolina, Charleston, and Vladimir Kasyanov, DSc, PhD, from Riga Stradins University, Latvia, call the report of the high level of patency of tissue-engineered blood vessels used as access for hemodialysis "a remarkable accomplishment."

They note that the length of time needed to create the tissue-engineered grafts — 6 to 9 months — as well as the potential high cost of the technology are of concern.

"Thus, the further optimization and simplification of the original cell-sheet technology and the use of rapid biofabrication processes could eventually lead to a clinically and commercially successful product. The successful clinical testing of the first commercial tissue-engineered vascular graft is a revolutionary milestone, manifesting the emergence of clinical vascular tissue engineering," they conclude.

The study was funded by Cytograft Tissue Engineering, Novado, California. Dr. McAllister disclosed that he is a cofounder and significant stockholder in Cytograft Tissue Engineering. Coauthor Nathalie Dusserre disclosed that she is an employee of Cytograft Tissue Engineering. Senior author Nicolas L'Heureux disclosed that he is chief scientific officer of Cytograft Tissue Engineering and invented sheet-based tissue engineering. All other authors have disclosed no relevant financial relationships. Dr. Mironov and Dr. Kasyanov have disclosed no relevant financial relationships.

Lancet. 2009;373:1402–1404, 1440–1446.