The effect of chronic kidney disease on tissue formation of in situ tissue-engineered vascular grafts

Vascular in situ tissue engineering encompasses a single-step approach with a wide adaptive potential and true off-the-shelf availability for vascular grafts. However, a synchronized balance between breakdown of the scaffold material and neo-tissue formation is essential. Chronic kidney disease (CKD) may influence this balance, lowering the usability of these grafts for vascular access in end-stage CKD patients on dialysis. We aimed to investigate the effects of CKD on in vivo scaffold breakdown and tissue formation in grafts made of electrospun, modular, supramolecular polycarbonate with ureido-pyrimidinone moieties (PC-UPy). We implanted PC-UPy aortic interposition grafts (n = 40) in a rat 5/6th nephrectomy model that mimics systemic conditions in human CKD patients. We studied patency, mechanical stability, extracellular matrix (ECM) components, total cellularity, vascular tissue formation, and vascular calcification in CKD and healthy rats at 2, 4, 8, and 12 weeks post-implantation. Our study shows successful in vivo application of a slow-degrading small-diameter vascular graft that supports adequate in situ vascular tissue formation. Despite systemic inflammation associated with CKD, no influence of CKD on patency (Sham: 95% vs CKD: 100%), mechanical stability, ECM formation (Sirius red +, Sham 16.5% vs CKD 25.0%-p:0.83), tissue composition, and immune cell infiltration was found. We did find a limited increase in vascular calcification at 12 weeks (Sham 0.08% vs CKD 0.80%-p:0.02) in grafts implanted in CKD animals. However, this was not associated with increased stiffness in the explants. Our findings suggest that disease-specific graft design may not be necessary for use in CKD patients on dialysis. </p

Chapter VI: Follow-up after Revascularisation

AbstractStructured follow-up after revascularisation for chronic critical limb ischaemia (CLI) aims at sustained treatment success and continued best patient care. Thereby, efforts need to address three fundamental domains: (A) best medical therapy, both to protect the arterial reconstruction locally and to reduce atherosclerotic burden systemically; (B) surveillance of the arterial reconstruction; and (C) timely initiation of repeat interventions. As most CLI patients are elderly and frail, sustained resolution of CLI and preserved ambulatory capacity may decide over independent living and overall prognosis. Despite this importance, previous guidelines have largely ignored follow-up after CLI; arguably because of a striking lack of evidence and because of a widespread assumption that, in the context of CLI, efficacy of initial revascularisation will determine prognosis during the short remaining life expectancy. This chapter of the current CLI guidelines aims to challenge this disposition and to recommend evidentially best clinical practice by critically appraising available evidence in all of the above domains, including antiplatelet and antithrombotic therapy, clinical surveillance, use of duplex ultrasound, and indications for and preferred type of repeat interventions for failing and failed reconstructions. However, as corresponding studies are rarely performed among CLI patients specifically, evidence has to be consulted that derives from expanded patient populations. Therefore, most recommendations are based on extrapolations or subgroup analyses, which leads to an almost systematic degradation of their strength. Endovascular reconstruction and surgical bypass are considered separately, as are specific contexts such as diabetes or renal failure; and critical issues are highlighted throughout to inform future studies

Cohort profile: the Utrecht Cardiovascular Cohort-Second Manifestations of Arterial Disease (UCC-SMART) Study-an ongoing prospective cohort study of patients at high cardiovascular risk in the Netherlands

PURPOSE: The Utrecht Cardiovascular Cohort-Second Manifestations of Arterial Disease (UCC-SMART) Study is an ongoing prospective single-centre cohort study with the aim to assess important determinants and the prognosis of cardiovascular disease progression. This article provides an update of the rationale, design, included patients, measurements and findings from the start in 1996 to date. PARTICIPANTS: The UCC-SMART Study includes patients aged 18-90 years referred to the University Medical Center Utrecht, the Netherlands, for management of cardiovascular disease (CVD) or severe cardiovascular risk factors. Since September 1996, a total of 14 830 patients have been included. Upon inclusion, patients undergo a standardised screening programme, including questionnaires, vital signs, laboratory measurements, an ECG, vascular ultrasound of carotid arteries and aorta, ankle-brachial index and ultrasound measurements of adipose tissue, kidney size and intima-media thickness. Outcomes of interest are collected through annual questionnaires and adjudicated by an endpoint committee. FINDINGS TO DATE: By May 2022, the included patients contributed to a total follow-up time of over 134 000 person-years. During follow-up, 2259 patients suffered a vascular endpoint (including non-fatal myocardial infarction, non-fatal stroke and vascular death) and 2794 all-cause deaths, 943 incident cases of diabetes and 2139 incident cases of cancer were observed up until January 2020. The UCC-SMART cohort contributed to over 350 articles published in peer-reviewed journals, including prediction models recommended by the 2021 European Society of Cardiology CVD prevention guidelines. FUTURE PLANS: The UCC-SMART Study guarantees an infrastructure for research in patients at high cardiovascular risk. The cohort will continue to include about 600 patients yearly and follow-up will be ongoing to ensure an up-to-date cohort in accordance with current healthcare and scientific knowledge. In the near future, UCC-SMART will be enriched by echocardiography, and a food frequency questionnaire at baseline enabling the assessment of associations between nutrition and CVD and diabetes

Cardiovasc Diabetol

Lower-extremity arterial disease (LEAD) is a major endemic disease with an alarming increased prevalence worldwide. It is a common and severe condition with excess risk of major cardiovascular events and death. It also leads to a high rate of lower-limb adverse events and non-traumatic amputation. The American Diabetes Association recommends a widespread medical history and clinical examination to screen for LEAD. The ankle brachial index (ABI) is the first non-invasive tool recommended to diagnose LEAD although its variable performance in patients with diabetes. The performance of ABI is particularly affected by the presence of peripheral neuropathy, medial arterial calcification, and incompressible arteries. There is no strong evidence today to support an alternative test for LEAD diagnosis in these conditions. The management of LEAD requires a strict control of cardiovascular risk factors including diabetes, hypertension, and dyslipidaemia. The benefit of intensive versus standard glucose control on the risk of LEAD has not been clearly established. Antihypertensive, lipid-lowering, and antiplatelet agents are obviously worthfull to reduce major cardiovascular adverse events, but few randomised controlled trials (RCTs) have evaluated the benefits of these treatments in terms of LEAD and its related adverse events. Smoking cessation, physical activity, supervised walking rehabilitation and healthy diet are also crucial in LEAD management. Several advances have been achieved in endovascular and surgical revascularization procedures, with obvious improvement in LEAD management. The revascularization strategy should take into account several factors including anatomical localizations of lesions, medical history of each patients and operator experience. Further studies, especially RCTs, are needed to evaluate the interest of different therapeutic strategies on the occurrence and progression of LEAD and its related adverse events in patients with diabetes

Treatment of Critical Limb Ischemia: A shifting paradigm

Critical limb ischemia (CLI), the most advanced stage of peripheral artery disease (PAD), is characterized by severely impaired perfusion of the lower limbs, which results in rest pain and/or tissue loss. It is associated with high risk for major amputation and cardiovascular events resulting in 6-month mortality rates up to 20%. These figures exceed numbers for every other form of occlusive cardiovascular disease and reflect the high systemic atherosclerotic burden. With an estimated annual incidence of 500-1,000 new cases per million individuals, CLI poses a substantial burden on patients, health care providers and resources. Over the past decades novel revascularizing strategies have been introduced and prognosis of CLI has gradually improved. However, current guidelines for the treatment of CLI are generally based on expert opinion and extrapolation of results from studies in milder PAD populations. Joining forces in transatlantic or continental initiatives may be necessary to be able to complete large randomized controlled trials (RCTs) in this specific population, ultimately leading to improved evidence-based treatment in CLI. Despite improvements in treatment of CLI, prognosis with respect to life and limb are still poor. CLI patients experience substantial functional impairment and pain, which leads to poor quality of life. This, together with the large number of CLI patients that is not eligible for conventional revascularization (25-40%) urges the need for novel therapeutic options aimed at improved limb perfusion. The discovery of a putative bone marrow (BM)-derived endothelial progenitor cell, resulted in a concept that BM-derived cells contribute to postnatal neovascularization. This led to the notion that BM cells might be used as a therapeutic agent in ischemic disease, such as CLI. Our recently performed meta-analysis on twelve RCTs that studied BM-derived cell therapy in CLI underlines the promising potential of this therapy, but also shows divergent results between placebo-controlled and non-placebo-controlled RCTs, stressing the need for a large, well-designed, placebo-controlled RCT with clinically relevant endpoints. Our randomized, double-blinded, placebo-controlled Juventas-trial, was designed to investigate whether repetitive intra-arterial infusion of BM-derived mononuclear cells (BM-MNC) reduces amputation rates in a large cohort of no-option CLI patients. With inclusion of 160 patients the Juventas-trial is currently the largest RCT in the field. The trial results show no benefit of BM-MNC compared to placebo infusion on all outcomes, e.g. amputation rates, ankle-brachial index, and quality of life. Moreover, the study shows general improvement in both the BM-MNC as well as the placebo group for objective and subjective outcomes. Our results contradict the reports of mainly small, non-placebo-controlled and non-randomized studies but seem in line with the results of our meta-analysis. The lack of effect of BM-MNC in the Juventas-trial could be related to our observations of reduced progenitor cell number and function in atherosclerotic CLI and related cardiovascular risk factors, which may hamper effect of autologous cell therapy in these patients. Future studies are warranted to investigate whether modified cell-based approaches, such as administration of specific cell subpobulations or interventions to restore progenitor cell function via pre-treatment strategies are effective in CLI