Inflammation and Oxidative Damage in Ischaemic Renal Disease

Ischaemic renal disease as result of atherosclerotic renovascular disease activates a complex biological response that ultimately leads to fibrosis and chronic kidney disease. Large randomised control trials have shown that renal revascularisation in patients with atherosclerotic renal artery disease does not confer any additional benefit to medical therapy alone. This is likely related to the activation of complex pathways of oxidative stress, inflammatory cytokines and fibrosis due to atherosclerotic disease and hypoxic injury due to reduced renal blood flow. New evidence from pre-clinical trials now indicates a role for specific targeted therapeutic interventions to counteract this complex pathogenesis. This evidence now suggests that the focus for those with atherosclerotic renovascular disease should be a combination of revascularisation and renoprotective therapies that target the renal tissue response to ischaemia, reduce the inflammatory infiltrate and prevent or reduce the fibrosis.

Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles Elicit Better Preservation of the Intra-Renal Microvasculature Than Renal Revascularization in Pigs with Renovascular Disease

Background: Percutaneous transluminal renal angioplasty (PTRA) confers clinical and mortality benefits in select ‘high-risk’ patients with renovascular disease (RVD). Intra-renal-delivered extracellular vesicles (EVs) released from mesenchymal stem/stromal cells (MSCs) protect the kidney in experimental RVD, but have not been compared side-by-side to clinically applied interventions, such as PTRA. We hypothesized that MSC-derived EVs can comparably protect the post-stenotic kidney via direct tissue effects. Methods: Five groups of pigs (n = 6 each) were studied after 16 weeks of RVD, RVD treated 4 weeks earlier with either PTRA or MSC-derived EVs, and normal controls. Single-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were assessed in vivo with multi-detector CT, and renal microvascular architecture (3D micro CT) and injury pathways ex vivo. Results: Despite sustained hypertension, EVs conferred greater improvement of intra-renal microvascular and peritubular capillary density compared to PTRA, associated with attenuation of renal inflammation, oxidative stress, and tubulo-interstitial fibrosis. Nevertheless, stenotic kidney RBF and GFR similarly rose in both PTRA- and EV-treated pigs compared RVD + Sham. mRNA sequencing reveled that EVs were enriched with pro-angiogenic, anti-inflammatory, and antioxidants genes. Conclusion: MSC-derived EVs elicit a better preservation of the stenotic kidney microvasculature and greater attenuation of renal injury and fibrosis compared to PTRA, possibly partly attributed to their cargo of vasculo-protective genes. Yet, both strategies similarly improve renal hemodynamics and function. These observations shed light on diverse mechanisms implicated in improvement of post-stenotic kidney function and position EVs as a promising therapeutic intervention in RVD.

Atypical Chest Pain and Hypertension in a Young Woman

Hypertension among young people is fairly common, affecting one quarter of the global population and 1 in 8 adults aged between 20 and 40 years. It is one of the main modifiable risk factors for cardiovascular disease and mortality. Since many forms of secondary hypertension led to “treatment-resistant” hypertension, it is important to determine the likely causes and this evaluation partly depends on the degree of difficulty in controlling blood pressure. It is recommended that clinicians should look for the clinical clues that suggest secondary hypertension as it is too expensive and time consuming to perform a complete evaluation for secondary hypertension in every hypertensive patient. The most common causes of secondary hypertension among young adults are hypothyroidism (1.9%), renovascular disease (1.7%), renal insufficiency (1.5%), primary hyperaldosteronism (1.2%), Cushing syndrome (0.5%), and pheochromocytoma (<0.3%).

Renovascular hypertension in children

Paediatric hypertension, defined as systolic blood pressure > 95th percentile for age, sex and height is often incidentally diagnosed. Renovascular hypertension (RVH) is responsible for 5–25% of hypertension in children. Renal artery stenosis and middle aortic syndrome can both can be associated with various conditions such as fibromuscular dysplasia, Williams syndrome & Neurofibromatosis type 1. This paper discusses the approaches to diagnosis and interventional management and outcomes of renovascular hypertension in children. Angiography is considered the gold standard in establishing the diagnosis of renovascular disease in children. Angioplasty is beneficial in the majority of patients and generally repeated angioplasty is considered more appropriate than stenting. Surgical options should first be considered before placing a stent unless there is an emergent requirement. Given the established safety and success of endovascular intervention, at most institutions it remains the preferred treatment option.

Renovascular Disease Induces Senescence in Renal Scattered Tubular-Like Cells and Impairs Their reparative Potency

Scattered tubular-like cells (STCs), dedifferentiated renal tubular epithelial cells, contribute to renal self-healing, but severe injury might blunt their effectiveness. We hypothesized that ischemic renovascular disease (RVD) induces senescence in STC and impairs their reparative potency. CD24+/CD133+ STCs were isolated from swine kidneys after 16 weeks of RVD or healthy controls. To test their reparative capabilities in injured kidneys, control or RVD-STC (5×10 5 ) were prelabeled and injected into the aorta of 2 kidneys, 1-clip (2k,1c) mice 2 weeks after surgery. Murine renal function and oxygenation were studied in vivo 2 weeks after injection using micro-magnetic resonance imaging, and fibrosis, tubulointerstitial injury, capillary density, and expression of profibrotic and inflammatory genes ex vivo. STC isolated from swine RVD kidneys showed increased gene expression of senescence and senescence-associated secretory phenotype markers and positive SA-β-gal staining. Delivery of normal pig STCs in 2k,1c mice improved murine renal perfusion, blood flow, and glomerular filtration rate, and downregulated profibrotic and inflammatory gene expression. These renoprotective effects were blunted using STC harvested from RVD kidneys, which also failed to attenuate hypoxia, fibrosis, tubular injury, and capillary loss in injured mouse 2k,1c kidneys. Hence, RVD may induce senescence in endogenous STC and impair their reparative capacity. These observations implicate cellular senescence in the pathophysiology of ischemic kidney disease and support senolytic therapy to permit self-healing of senescent kidneys.