Singh, Prabh G

The creation of an arteriovenous fistula in a uremic pig induces cardiac remodeling, which resembles contemporary clinical findings in patients with end-stage kidney disease (ESKD) and includes increased end-diastolic volumes and cardiomyocyte hypertrophy, potentially driven by fibrosis and senescence. This novel large animal model may now enable mechanistic and therapeutic studies aiming to ease the unacceptably high burden of cardiovascular disease on patients with ESKD.

Key Points This study reveals the temporal development and progression of senescence in an arteriovenous fistula of uremic mice. Senescent genes including p21 increased 7 days after arteriovenous fistula placement, and p16 and phosphorylated p53 cells accumulate between days 14 and 28. Transcriptomic analyses confirm established genes in arteriovenous fistula failure and suggest a collection of novel genes of interest. Background Hemodialysis therapy for ESKD requires suitable vascular access, most commonly the arteriovenous fistula (AVF). Forty percent of AVFs fail within 1 year, leading to morbidity and care costs. Failure mechanisms remain unclear, and current therapies are inadequate. Cellular senescence may be critical in AVF failure, and ESKD itself may accelerate senescence and subsequent vascular dysfunction. Senescence follows AVF placement in rodents with normal kidney function, but the temporal and spatial features in uremic conditions are unknown. This study aimed to characterize AVF changes in uremic mice over time and versus control vessels. Methods Six- to eight-week-old male C57BL6/J mice underwent five/six nephrectomy. Twenty-eight days later, an AVF was created by cuff anastomosis (right carotid artery to the right jugular vein). Transcriptomic analysis was performed 7 days post-AVF, and further samples were collected at 14 and 28 days post-AVF creation for histologic assessment. Results AVF outflow vein morphometry showed reduced neointimal cell density. Whole transcriptomic analysis of outflow versus control veins at 7 days post-AVF placement revealed 1187 upregulated and 3256 downregulated genes. Differentially expressed genes were significantly enriched in two established senescence-related gene sets, SenMayo (a curated panel of approximately 125 genes validated across species to capture senescence and associated proteins) and SenSig (a broader panel assessed to represent fibrotic and stress-induced cell response). Histologically, senescence markers p16, p21, and phospho53 increased between days 14 and 28. Genes common to our dataset, SenMayo, and SenSig were validated with quantitative reverse transcription PCR. Conclusions These data support established markers of AVF failure, such as matrix-metalloproteinases and monocyte chemokines, and identify potential novel modulators of AVF survival that may inform senolytic strategies to improve patency. In summary, this study reveals for the first time the chronologic progression of vascular senescence in the AVF of uremic mice.

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.

ABSTRACT Atraumatic and precise drug delivery to arteries and veins remains an unmet need in interventional medicine, with significant implications for managing vascular diseases and long-term patient outcomes. Conventional endovascular methods, such as drug-coated balloons and drug-eluting stents, often damage vessel endothelium and compromise wall integrity, leading to reduced therapeutic efficacy and severe complications including restenosis and thrombosis. To address these limitations, we introduce EndoBot, an untethered soft millirobot designed for atraumatic vessel navigation and localized drug delivery under physiological blood flow. EndoBot achieves this through magnetically actuated corkscrew propulsion and mechanically adaptive surface crawling, exerting low radial pressure (< 1 kPa) to preserve endothelial integrity. We validated its performance in phantom vessels, ex vivo human umbilical veins under normothermic perfusion, and in vivo rat inferior vena cava under fluoroscopic guidance using a human-scale magnetic manipulation platform. Despite dynamic vessel contractions and compressions along non-uniform cross-sections, mechanically adaptive locomotion strategy ensures safe navigation and protects the inner endothelial lining. EndoBot is deployable and retrievable via clinical vascular sheaths and remains stable even under supra-physiological blood flow conditions (> 155 cm/s). Extensive blood compatibility tests demonstrated minimal hemolysis (<0.01%), low platelet activation on the robot surface, and no increased coagulation tendency. For drug delivery, a hydrophobic transfer coating enables EndoBot to gently deposit a stable, flow-resistant drug layer onto the vessel wall without fragmentation. This novel platform enables safer and more effective targeted endovascular drug delivery, paving the way for transformative approaches to address early-stage vascular pathologies and deliver more effective preventive interventions.

Abstract Background and study aims Management of malignant gastrointestinal obstruction (MGIO) is more challenging in the presence of peritoneal carcinomatosis (PC). Outcomes data to guide the management of MGIO with PC are lacking. We aimed to compare the clinical outcomes and adverse events between endoscopic and surgical palliation and identify predictors of stent success in patients with MGIO with PC. Patients and methods Consecutive inpatients with MGIO with PC between 2000 and 2018 who underwent palliative surgery or enteral stenting were included. Clinical success was defined as relief of obstructive symptoms. Results Fifty-seven patients with enteral stenting and 40 with palliative surgery were compared. The two groups did not differ in rates of technical success, 30-day mortality, or recurrence. Clinical success from a single intervention (63.2 % versus 95 %), luminal patency duration (27 days vs. 145 days), and survival length (148 days vs. 336 days) favored palliative surgery (all P < 0.05) but the patients in the surgery group had a trend toward better Eastern Cooperative Oncology Group (ECOG) status. The rate of adverse events (AEs) (10.5 % vs. 50 %), the severity of AEs, and length of hospital stay (4.5 days vs. 9 days) favored enteral stenting (P < 0.05). The need for more than one stent was associated with a higher likelihood of stent failure. Conclusions Our study suggests that enteral stenting is safer and associated with a shorter hospital stay than palliative surgery, although unlike other MGIOs, clinical success is lower in MGIO with PC. Identification of the right candidates and potential predictors of clinical success in ECOG-matched large-scale studies is needed to validate these results.

Abstract Background Post-surgical complications such as leaks are the source of considerable morbidity and mortality. Success of conservative interventions is highly variable. Recurrence after surgical repair is also not uncommon. Our aim was to develop novel endoscopic strategies to maximize negative intracavitary pressure to manage leaks in cases where conventional management either failed or were not feasible. Methods We have used transluminal locking loop drains with low intermittent suction in the management of non-healing leaks in various areas. An example presented here illustrates this concept where a 68-year-old male patient underwent paraesophageal hernia repair with Nissen fundoplication. Patient presented 3 weeks later with fistula leading to a 13 cm meditational abscess. Patient developed right hemiparesis requiring tissue plasminogen activator (tPA). Post-tPA patient developed hemoptysis and hematemesis requiring emergency intubation. The defect in the esophagus was 6–8 mm. Endoscopic repair with stitching or clipping would have left a large undrained cavity with a potential to expand. Endoscopic repair with transcutaneous drain placement was challenging due to recent tPA and a difficult location. Moreover there was potential to develop esophago- pleural- broncho- cutaneous fistula. Endoscopic vacuum therapy was felt to be a suboptimal choice. Patient was high-risk surgical candidate as it would have required radical surgery in the setting of tPA.Upper endoscopy was performed and the cavity was debrided. No direct communication with bronchopulmonary tree noted. A transnasal guidewire assisted 16 Fr, 60 cm locking loop drain was placed and connected to low intermittent suction that was switched to bulb based suction. Results The output from naso-cavity drain decreased nearly 100 cc per day in the first 5 days and the size reduced by 30, 50 and 80% by day 5, 9 and 12 respectively. Near complete elimination of the cavity was observed on day 15. Esophagogram showed complete resolution of the leak and computerized tomography revealed no residual cavity Conclusion Developing transluminal endoscopic strategies to maximize negative intracavitary pressure helps expedite the healing of resistant postsurgical leaks. This technique avoids the need for frequent drain changes that remains a challenge for vacuum therapy. Disclosure All authors have declared no conflicts of interest.