DeMartino, Randall R

Worldwide, more than 4 million patients with end-stage kidney disease require hemodialysis through an arteriovenous fistula (AVF). AVFs fail because of venous neointimal hyperplasia (VNH) resulting in venous stenosis formation. A phase 1 randomized trial in patients undergoing upper extremity AVF placement was performed to evaluate the safety and efficacy of autologous adipose–derived mesenchymal stem cells (MSCs) in improving AVF function. The mechanism of action by which MSCs exert their beneficial effects was investigated using AVFs created in mice and pigs treated with allogenic MSCs and xenotransplant using patient MSCs in CD1- Foxn1nu mice. At a median follow-up of 42 months, patients with MSC-treated AVFs had reduced time to maturation with an increase in the vein diameter compared with controls. AVFs treated with allogenic MSCs in mice and pigs had an increase in M2- and M1-like macrophages with a decrease in VNH. Transcriptomic analysis of AVFs treated with allogenic MSCs in mouse and MSC xenotransplants of patients with successful AVFs showed decreased peroxisome proliferator–activated receptor gamma ( Ppar γ) and leptin receptor ( Lepr ) and increased latent transforming growth factor–beta–binding protein 2 ( Ltbp2 ). PPARγ was reduced in CD68 (+) cells from successful AVFs and allogenic MSC-treated mouse AVFs. Venous stenosis and VNH formation were mitigated in AVFs of mice with Ppar γ ablation in immune cells. Conditioned medium from MSCs of responders versus nonresponders had decreased proinflammatory genes, senescence-associated proteins, and monocyte-to-macrophage differentiation induced by phorbol 12-myristate-13-acetate. Periadventitial delivery of MSCs to AVFs promoted positive vascular remodeling through decreased inflammatory responses.

Background: We aimed to assess the effect of surgeons’ shunting practice and shunt use on the early outcomes of carotid endarterectomy (CEA) in recently symptomatic patients. Methods: We conducted a retrospective observational study based on a multicenter national prospective database. The Vascular Quality Initiative database (2010–2019) was queried for CEAs performed within 14 days after an ipsilateral stroke or transient ischemic attack. Surgeons were gauged as routine shunters if they shunted in >95% of CEAs, otherwise were classified as selective shunters. In-hospital stroke and death rates were compared between routine and selective shunters, stratifying by type of index event (transient ischemic attack versus stroke) and timing of CEA (≤2 versus >2 days). Results: Thirteen thousand four hundred sixty-nine CEAs were performed after a transient ischemic attack (43%) or stroke (57%), 3186 (24%) by routine shunters, and 10 283 (76%) by selective shunters. Comparing routine and selective shunters, in-hospital stroke (1.9% versus 2.4%; P =0.09) and death (0.4% versus 0.5%; P =0.73) rates were similar. A lower stroke rate (1.5% versus 4.2%; P =0.02) was achieved by routine shunters for CEA performed <2 days after an ischemic stroke. Among selective shunters, a higher stroke rate occurred in case of shunt use (2.9% versus 2.3%; P <0.01), mainly due to cases presenting with stroke (3.5% versus 2.4%; P <0.01) but not transient ischemic attack (1.8% versus 1.5%; P =0.57). Awake anesthesia was adopted in 7.8% of cases by selective shunters and in 0.8% by routine shunters, without impact on the perioperative stroke rate (1.8% versus 2.3%; P =0.349). Conclusions: In this large national cohort, the overall outcomes of CEA were similar between routine and selective shunters. A lower postoperative stroke rate was achieved by routine shunters in CEA performed <2 days after an ischemic stroke. Among selective shunters, intraoperatively indicated shunting determined an increased stroke rate, likely due to intraoperative hypoperfusion. These data may guide the decision regarding timing of CEA and shunting intention in symptomatic patients.

Key Points At 1 year after placement, 60% of hemodialysis arteriovenous fistulas (AVF) will develop venous neointimal hyperplasia (VNH) and subsequent venous stenosis (VS). Autologous adipose-derived mesenchymal stem cells may help reduce VS formation associated with hemodialysis AVF. There are no therapies available to prevent VS formation associated with hemodialysis AVF. Background Hemodialysis arteriovenous fistulas (AVFs) are the preferred vascular access for patients on hemodialysis. In the Hemodialysis Fistula Maturation Study, 44% of the patients achieved unassisted maturation of their fistula without needing an intervention. Venous neointimal hyperplasia (VNH) and subsequent venous stenosis are responsible for lack of maturation. There are no therapies that can prevent VNH/VS formation. The goal of this paper is to present the background, rationale, and trial design of an innovative phase 1/2 clinical study that is investigating the safety of autologous adipose-derived mesenchymal stem cells delivered locally to the adventitia of newly created upper extremity radiocephalic (RCF) or brachiocephalic fistula (BCF). Methods The rationale and preclinical studies used to obtain a physician-sponsored investigational new drug trial are discussed. The trial design and end points are discussed. Results This is an ongoing trial that will complete this year. Conclusion This is a phase 1/2 single-center, randomized trial that will investigate the safety and efficacy of autologous AMSCs in promoting maturation in new upper-extremity AVFs. Clinical Trial registration number : NCT02808208