Bioengineered human acellular vessels for dialysis access in patients with end-stage renal disease: two phase 2 single-arm trials

Abstract

Background: For patients with end-stage renal disease who are not candidates for fistula, dialysis access grafts are the best option for chronic haemodialysis. However, polytetrafluoroethylene arteriovenous grafts are prone to thrombosis, infection, and intimal hyperplasia at the venous anastomosis. We developed and tested a bioengineered human acellular vessel as a potential solution to these limitations in dialysis access.

Methods: We did two single-arm phase 2 trials at six centres in the USA and Poland. We enrolled adults with end-stage renal disease. A novel bioengineered human acellular vessel was implanted into the arms of patients for haemodialysis access. Primary endpoints were safety (freedom from immune response or infection, aneurysm, or mechanical failure, and incidence of adverse events), and efficacy as assessed by primary, primary assisted, and secondary patencies at 6 months. All patients were followed up for at least 1 year, or had a censoring event. These trials are registered with ClinicalTrials.gov, NCT01744418 and NCT01840956.

Findings: Human acellular vessels were implanted into 60 patients. Mean follow-up was 16 months (SD 7·6). One vessel became infected during 82 patient-years of follow-up. The vessels had no dilatation and rarely had post-cannulation bleeding. At 6 months, 63% (95% CI 47-72) of patients had primary patency, 73% (57-81) had primary assisted patency, and 97% (85-98) had secondary patency, with most loss of primary patency because of thrombosis. At 12 months, 28% (17-40) had primary patency, 38% (26-51) had primary assisted patency, and 89% (74-93) had secondary patency.

Interpretation: Bioengineered human acellular vessels seem to provide safe and functional haemodialysis access, and warrant further study in randomised controlled trials.

Funding: Humacyte and US National Institutes of Health.

Conflict of interest statement

Declaration of interests

LEN, AJP, HLP, and JHL own stock or stock options in Humacyte. AJP and MHG work as consultants for Humacyte. The other authors declare no competing interests.

Copyright © 2016 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Production of arteriovenous grafts

Smooth muscle cells are seeded onto a biocompatible scaffold within a single-use bioreactor. During culture, a cellular bioengineered vessel is grown, which is then decellularised to produce the human acellular vessel. Gross appearance is an off-white uniform tubular structure, and haematoxylin and eosin stain and Masson’s trichrome stain show dense extracellular matrix without cellular or nuclear remnants. SMC=smooth muscle cell.

Figure 2. Kaplan-Meier curves for human acellular vessel patencies

Data from the USA and Poland were combined for this analysis.

Figure 3. Human acellular vessel remodelling

Immunoperoxidase histology staining of explant at 16 weeks shows abluminal repopulation by (A) CD68 positive cells; (B) smooth muscle actin positive cells; and (C) CD31 positive cells on the graft lumen. Haematoxylin counterstain shows nuclei. Immunoperoxidase histological staining of explant at 55 weeks shows (D) few CD68 positive brown cells; (E) extensive smooth muscle actin positive cell repopulation extending almost throughout the graft wall; and (F) CD31 positive staining on the graft lumen. Histological assessment of midgraft segments resected at 44 weeks because of infected perigraft haematoma shows two previous cannulation sites. Haematoxylin and eosin staining shows (G) a very recent cannulation site with fresh clot in the cannulation tract; (H) a healing cannulation site with cell repopulation occurring from the luminal surface. (I) CD31 immunoperoxidase stain shows luminal positive cells in this mid-vessel segment. For all panels, the vessel lumen is at the bottom of the panel. SMA=smooth muscle actin. H&E=haematoxylin and eosin.