Clinical Applications of Remote Ischemic Preconditioning

Ischemia-reperfusion injury is a composite of damage accumulated during reduced perfusion of an organ or tissue and the additional insult sustained during reperfusion. Such injury occurs in a wide variety of clinically important syndromes, such as ischemic heart disease and stroke, which are responsible for a high degree of morbidity and mortality worldwide. Basic research has identified a number of interventions that stimulate innate resistance of tissues to ischemia-reperfusion injury. Here, we summarise the experimental and clinical trial data underpinning one of these “conditioning” strategies, the phenomenon of remote ischemic preconditioning

Clinical applications of remote ischaemic preconditioning in native and transplant acute kidney injury

Ischaemia-reperfusion (IR) injury is a composite of the injury sustained during a period of reduced or absent blood flow to a tissue or organ and the additional insult sustained upon reperfusion that limits the amount of tissue that can be salvaged. IR injury plays a central role in both native and transplant acute kidney injury (AKI). Native AKI is associated with increased morbidity and mortality in hospital inpatients, and transplant AKI contributes to graft dysfunction, ultimately limiting graft longevity. In this review, we discuss the potential therapeutic benefits of a cost-effective and low-risk intervention, remote ischaemic preconditioning (RIPC), and its applicability in the prevention and reduction of AKI

Characterisation of leukocytes in a human skin blister model of acute inflammation and resolution.

There is an increasing need to understand the leukocytes and soluble mediators that drive acute inflammation and bring about its resolution in humans. We therefore carried out an extensive characterisation of the cantharidin skin blister model in healthy male volunteers. A novel fluorescence staining protocol was designed and implemented, which facilitated the identification of cell populations by flow cytometry. We observed that at the onset phase, 24 h after blister formation, the predominant cells were CD16hi/CD66b+ PMNs followed by HLA-DR+/CD14+ monocytes/macrophages, CD11c+ and CD141+ dendritic cells as well as Siglec-8+ eosinophils. CD3+ T cells, CD19+ B cells and CD56+ NK cells were also present, but in comparatively fewer numbers. During resolution, 72 h following blister induction, numbers of PMNs declined whilst the numbers of monocyte/macrophages remain unchanged, though they upregulated expression of CD16 and CD163. In contrast, the overall numbers of dendritic cells and Siglec-8+ eosinophils increased. Post hoc analysis of these data revealed that of the inflammatory cytokines measured, TNF-α but not IL-1β or IL-8 correlated with increased PMN numbers at the onset. Volunteers with the greatest PMN infiltration at onset displayed the fastest clearance rates for these cells at resolution. Collectively, these data provide insight into the cells that occupy acute resolving blister in humans, the soluble mediators that may control their influx as well as the phenotype of mononuclear phagocytes that predominate the resolution phase. Further use of this model will improve our understanding of the evolution and resolution of inflammation in humans, how defects in these over-lapping pathways may contribute to the variability in disease longevity/chronicity, and lends itself to the screen of putative anti-inflammatory or pro-resolution therapies

Clinical practice guidelines of remote ischemic conditioning for the management of cerebrovascular diseases

Remote ischemic conditioning (RIC) using transient limb ischemia and reperfusion has been shown in small clinical studies to reduce myocardial injury and infarction in cardiac patients, although larger clinical outcome studies have been neutral. Experimental and emerging clinical studies have also reported beneficial effects of limb RIC in a number of different settings of cerebrovascular disease including stroke (ischemic and hemorrhagic), carotid artery stenosis, intracranial artery stenosis, aneurysms, small vessel disease, and vascular cognitive impairment. Although limb RIC has many advantages, in that it is non-invasive, easy to administer, relatively innocuous, cost-effective, has few or no contraindications, and may be deployed under various circumstances (e.g., home, ambulance, and hospital), several questions remain regarding its clinical application for cerebrovascular disease. Therefore, in this document, we aim to provide practicing clinicians with a coherent synthesis of the latest scientific evidence, and we propose several recommendations to help facilitate the clinical application of limb RIC for the management of cerebrovascular disease

Patients’ and kidney care team’s perspectives of treatment burden and capacity in older people with chronic kidney disease: a qualitative study

Objective: Chronic kidney disease (CKD) is often a multimorbid condition and progression to more severe disease is commonly associated with increased management requirements, including lifestyle change, more medication, and greater clinician involvement. This study explored patients’ and kidney care team’s perspectives of the nature and extent of this workload (treatment burden) and factors that support capacity (the ability to manage health) for older individuals with CKD. Design: Qualitative semi-structured interview and focus group study Setting and Participants: Adults (aged 60+) with pre-dialysis CKD stages G3-5 (identified in two general practitioner surgeries and two renal clinics) and a multi-professional secondary kidney care team in the United Kingdom.Results: 29 individuals and 10 kidney team members were recruited. Treatment burden themes were: (a) understanding CKD, its treatment and consequences, (b) adhering to treatments and management, and (c) interacting with others (e.g.: clinicians) in the management of CKD. Capacity themes were: (a) personal attributes (e.g. optimism, pragmatism), (b) support network (family/friends, service providers), (c) financial capacity, environment (e.g.: geographical distance to unit) and life responsibilities (e.g.: caring for others). Patients reported poor provision of CKD information and lack of choice in treatment, whereas kidney care team members discussed health literacy issues. Patients reported having to withdraw from social activities and loss of employment due to CKD, which further impacted their capacity. Conclusion: Improved understanding of and measures to reduce the treatment burden (e.g. clear information, simplified medication, joined up care, free parking) associated with CKD in individuals as well as assessment of their capacity and interventions to improve capacity (social care, psychological support) will likely improve patient experience and their engagement with kidney care services

Early changes in scores of chronic damage on transplant kidney protocol biopsies reflect donor characteristics, but not future graft function.

The amount of irreversible injury on renal allograft biopsy predicts function, but little is known about the early evolution of this damage. In a single-center cohort, we examined the relationship between donor-, recipient-, and transplantation-associated factors and change in a morphometric index of chronic damage (ICD) between protocol biopsies performed at implantation and at 2-3 months. We then investigated whether early delta ICD predicted subsequent biochemical outcomes. We found little evidence to support differences between the study group, who had undergone serial biopsies, and a contemporaneous control group, who had not. In allografts with serial biopsies (n = 162), there was an increase in ICD between implantation (median: 2%, IQR:0-8) and 2-3 months post-transplant (median 8% IQR:4-15; p < 0.0001). Donation from younger or live donors was independently associated with smaller early post-transplant increases in ICD. There was no evidence for a difference in delta ICD between donation after cardiac death vs. donation after brain death, nor association with length of cold ischemia. After adjustment for GFR at the time of the second biopsy, delta ICD after three months did not predict allograft function at one yr. These findings suggest that graft damage develops shortly after transplantation and reflects donor factors, but does not predict future biochemical outcomes

Defining an ageing-related pathology, disease or syndrome: International Consensus Statement

Around the world, individuals are living longer, but an increased average lifespan does not always equate to an increased health span. With advancing age, the increased prevalence of ageing-related diseases can have a significant impact on health status, functional capacity and quality of life. It is therefore vital to develop comprehensive classification and staging systems for ageing-related pathologies, diseases and syndromes. This will allow societies to better identify, quantify, understand and meet the healthcare, workforce, well-being and socioeconomic needs of ageing populations, whilst supporting the development and utilisation of interventions to prevent or to slow, halt or reverse the progression of ageing-related pathologies. The foundation for developing such classification and staging systems is to define the scope of what constitutes an ageing-related pathology, disease or syndrome. To this end, a consensus meeting was hosted by the International Consortium to Classify Ageing-Related Pathologies (ICCARP), on February 19, 2024, in Cardiff, UK, and was attended by 150 recognised experts. Discussions and voting were centred on provisional criteria that had been distributed prior to the meeting. The participants debated and voted on these. Each criterion required a consensus agreement of ≥ 70% for approval. The accepted criteria for an ageing-related pathology, disease or syndrome were (1) develops and/or progresses with increasing chronological age; (2) should be associated with, or contribute to, functional decline or an increased susceptibility to functional decline and (3) evidenced by studies in humans. Criteria for an ageing-related pathology, disease or syndrome have been agreed by an international consortium of subject experts. These criteria will now be used by the ICCARP for the classification and ultimately staging of ageing-related pathologies, diseases and syndromes

Ischaemia-reperfusion injury in chronic kidney disease

When an organ or tissue is rendered ischaemic, there is inevitable cell death and tissue injury, the extent of which can be limited by timely reperfusion. However, paradoxically, an additional injury occurs upon reperfusion that limits the amount of tissue that can be salvaged. This composite injury is termed ‘ischaemia-reperfusion (IR) injury’. Ischaemic preconditioning (IPC) is an innate protective phenomenon whereby brief non-lethal periods of ischaemia and reperfusion may protect against subsequent more sustained IR injury. IR injury was modelled in healthy volunteers and patients with chronic kidney disease (CKD) using an arterial model of endothelial function, flow-mediated dilatation (FMD). Healthy volunteers sustained a significant reduction in FMD following experimental IR injury. IPC and its systemic phenotype, remote ischaemic preconditioning (RIPC) failed to protect against IR injury. Patients with CKD sustained minimal IR injury in this model. The venodilatory response to bradykinin was demonstrated to be significantly reduced following IR injury. RIPC protected against IR injury in this model, as did preinfusion with sodium nitrite. The effect of nitrite was abolished by prior treatment with oral allopurinol, suggesting a role of xanthine oxoreductase in the reduction of nitrate to nitric oxide during ischaemia. Vitamin D deficiency has been associated with IR injury and endothelial dysfunction however a detrimental effect of deficiency on FMD or arterial IR injury could not be demonstrated in either CKD patients or controls. Additionally, vitamin D deficient CKD patients undergoing transplantation did not have increased graft fibrosis or worse kidney function at 1 year. Lastly a European multicentre randomised controlled trial, REnal Protection Against Ischaemia-Reperfusion in transplantation (REPAIR) demonstrated a trend towards increased 1-year iohexol glomerular filtration rate (GFR), and a statistically significant improvement in 1 year estimated GFR in patients who received RIPC immediately prior to live donor kidney transplantation

Novel cyclopentadienyl transition metal complexes

The preparation of chiral cyclopentadienyl transition metal complexes and their application to enantioselective synthesis was reviewed.The synthesis of known chiral zirconocene (-)-(n-5-cyclopentadienyl)(n5-{1-[(1S, 2S, 5R)-2-isopropyl-5-methylcyclohexyl]-4,5,6,7-tetrahydroindenyl}) zirconium dichloride was repeated and the yields optimised. Application of this complex to a recently reported co-cyclisation / elimination reaction gave an e.e. of 11%.A series of complexes were designed and synthesised, based on the structure of (-)-(n-5-cylcopentadienyl)(n5-{1-[(1S, 2S, 5R)-2-isopropyl-5-methylcyclohexyl]-4,5,6,7-'tetrahydroindenyl}) zirconium dichloride. Three novel metallocenes were prepared and X-ray crystal structures obtained. However, these new complexes displayed no significant improvement over the enantioinductive properties of the parent system. A new class of cyclopentadienyl ligand was designed comprising a tethered heteroatom held over one face by a rigid [2,2,2] bicyclic backbone. A synthesis was developed to allow the preparation of a number of ligands with differing heteroatoms and substitution around the cyclopentadienyl ring.A new ligand with an OCH3 group held over one face of the cyclopentadienyl ring was prepared. Complexation to CpTiCl3 gave a mixture from which only one compound could be isolated in 40% yield. NMR and nOe experiments showed that the titanium was bound to the opposite face to the heteroatom linker. Two further complexes bearing ligands of this type were synthesised, however both were difficult to isolate. Nevertheless, comparison of NMR data suggested that in both cases the metal selectivity binds to the least sterically hindered face.Novel complexes were tested for suitability as propene polymerisation catalysts.</p