Atherosclerotic renal artery stenosis

Atherosclerotic renal artery stenosis (ARAS), or atherosclerotic renovascular disease (ARVD), is an important contributor to renal failure and secondary (renovascular) hypertension. In addition of atherosclerosis, fibromuscular dysplasias (FMD), embolic disease, and other causes can lead to renovascular obstruction and hypertension (Herrmann & Textor, 2018). ARAS activates RAAS, oxidative stress, inflammation, reduced microvasculature, and thickening of the small blood vessels. Cortical and medullary blood flow is reduced in ARAS patients. Localized cortical hypoxia may contribute to the pathogenesis, although kidneys generally are resistant to substantial reductions in blood flow, and in moderate renal artery stenosis the oxygenation level in cortex and medulla is preserved (Gloviczki et al., 2010; Evans et al., 2011; Eirin & Lerman, 2013; Kwon and Lerman, 2015), and evident only in advanced disease (Abumoawad et al., 2019). Reduced blood flow may lead to “hibernation”, and hypoxia may not be seen even in kidneys with total arterial occlusion (Textor et al., 2008).

Inflammation initially induces angiogenesis, but the new vessels are nonfunctional and leaky, promoting additional infiltration of white blood cells into the interstitial space (Eirin & Lerman, 2013). Activated RAAS stimulates production of extracellular matrix constituents, and prolonged RAAS activation may lead to renal fibrosis. In experimental renal artery stenosis the fibrinogenic factors, including TGF-β, PAI-1, and TIMP-1, are upregulated. TGF-β released from the stenotic kidneys may even be one cause of cardiac injury. The normal function of mitochondria leads to production of reactive oxygen species (ROS), and in the kidneys, the medullary thick ascending limb of Henle is the predominant site of superoxide production. Angiotensin II increases ROS generation, and induces apoptosis. Endothelial NO production is reduced, and released NO is inactivated by ROS. Inflammatory, oxidative, and fibrotic mechanisms lead to permanent damage that cannot be reversed by revived blood flow (Textor & Lerman, 2015; Chade & Hall, 2016).

Statins, ACE inhibitors (including enalapril and imidapril), and angiotensin receptor 1 blockers (ARBs) may slow down the loss of renal function. Enalapril and imidapril also inhibit matrix metalloproteinases.

Renal artery revascularization restores renal blood flow, and it can can sometimes restore kidney function, but not in most cases. Randomized clinical studies have shown that revascularization offers no benefit compared to medical treatment (Kwon and Lerman, 2015). The inflammation in ARAS kidneys continues after revascularization. Renal blood flow and fibrosis is incompletely restored by angioplasty in swine model of renal artery stenosis (Favreau et al., 2010). Currently it is not known how to identify the sub-group of patients that would benefit from revascularization therapy; larger parenchymal volume to GFR ratio may be one such indicator (Cheung et al., 2010; Chrysochou et al., 2017). One possibility is that stenotic kidney should be treated at an earlier phase (de Leeuw et al., 2018).

In a dog model, renal artery stenosis and catopril reduced markedly RBF, assessed using [82Rb]Rb+ (Tamaki et al., 1988). In a pig model of renal artery stenosis perfusion ratio was assessed using [15O]H2O PET, and it was markedly decreased in stenosis, and slightly more reduced with lisinopril. Renal uptake of [11C]KR31173, targeting angiotensin II type 1 receptors (AT1Rs) was increased, and not abolished by lisinopril (Xia et al., 2008).

In ARAS, and other atherosclerotic vascular diseases, the smaller arteries commonly have different level of stenosis. This leads to very variable perfusion and metabolic status in different renal regions (Textor et al., 2008), which must be considered in the image analysis. In BOLD MRI studies this has been accounted for by calculating fractional tissue hypoxia as the percentage of image section where R2* is above a certain threshold (Saad et al., 2013; Prijm et al., 2017; Abumoawad et al., 2019).


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References:

Alpern RJ, Caplan MJ, Moe OW (eds.): Seldin and Giebisch’s The Kidney - Physiology and Pathophysiology, 5th ed., Academic Press, 2013, ISBN: 978-0-12-381462-3.

Ashley C, Morlidge C (eds.): Introduction to Renal Therapeutics. Pharmaceutical Press, 2008, ISBN: 978-0-85369-688-9.

Chade AR. Renal vascular structure and rarefaction. Compr Physiol. 2013; 3(2): 817-831. doi: 10.1002/cphy.c120012.

Fogo AB, Cohen AH, Jennette JC, Bruijn JA, Colvin RB: Fundamentals of Renal Pathology. Springer, 2006.

Fogo AB, Kashgarian M: Diagnostic Atlas of Renal Pathology, 3rd ed., Elsevier, 2017. ISBN: 978-0-323-39053-8.

Krishnan N, Perazella MA. The role of PET scanning in the evaluation of patients with kidney disease. Adv Chronic Kidney Dis. 2017; 24(3): 154-161. doi: 10.1053/j.ackd.2017.01.002.

Koivuviita N: Vascular function in chronic kidney disease and in renovascular disease. Thesis, 2011. http://urn.fi/URN:ISBN:978-951-29-4590-0

Lerman LO, Textor SC (eds.): Renal Vascular Disease. Springer, 2014. doi: 10.1007/978-1-4471-2810-6.

Pallone TL, Edwards A, Mattson DL. Renal medullary circulation. Compr Physiol. 2012; 2(1): 97-140. doi: 10.1002/cphy.c100036.



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Updated at: 2019-03-27
Created at: 2017-02-23
Written by: Vesa Oikonen