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Arterial Stiffness in the Heart Disease of CKD - Kidney/Cardio Connection
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JASN June 2019
CKD frequently leads to chronic cardiac dysfunction. This complex relationship has been termed as cardiorenal syndrome type 4 or cardio-renal link. Despite numerous studies and reviews focused on the pathophysiology and therapy of this syndrome, the role of arterial stiffness has been frequently overlooked. In this regard, several pathogenic factors, including uremic toxins (i.e., uric acid, phosphates, endothelin-1, advanced glycation end-products, and asymmetric dimethylarginine), can be involved. Their effect on the arterial wall, direct or mediated by chronic inflammation and oxidative stress, results in arterial stiffening and decreased vascular compliance. The increase in aortic stiffness results in increased cardiac workload and reduced coronary artery perfusion pressure that, in turn, may lead to microvascular cardiac ischemia. Conversely, reduced arterial stiffness has been associated with increased survival. Several approaches can be considered to reduce vascular stiffness and improve vascular function in patients with CKD. This review primarily discusses current understanding of the mechanisms concerning uremic toxins, arterial stiffening, and impaired cardiac function, and the therapeutic options to reduce arterial stiffness in patients with CKD.
The link between CKD and cardiovascular (CV) events is well recognized.1-3 CV risk increases in a graded fashion with progressive decrease in kidney function and reaches a zenith in ESRD, but can be reduced by renal transplantation. It is widely accepted that only part of this excessive CV risk is explained by traditional risk factors. The relationship between CKD and chronic cardiac dysfunction is complex and has been named cardiorenal syndrome type 4 or cardio-renal link.1,2
Arterial stiffness is a vascular biomarker4 that is increased in patients with CKD,5-8 even in those with a mildly impaired renal function,5 and is associated with an independent increase in CV risk.7,8 Conversely, at least in patients with advanced CKD, the reduction in aortic stiffness is associated with an improved survival independent of BP changes.7 The increase of arterial stiffness in CKD is mostly caused by reduced renal excretion of vascular toxins, maladaptive metabolic and hormonal processes, and as a result, premature vascular aging. Also, in ESRD, RRT (dialysis) plays a role in the stiffening process and its consequences. Several therapeutic options have been proposed to reduce arterial stiffness, but most of them have been tested primarily in other settings (i.e., hypertension and diabetes).
Herein, we review the role of arterial stiffening as an independent mediator of myocardial dysfunction in CKD and the strategies to reduce arterial stiffness and, possibly, CV risk.
From CKD to Vascular Risk
The Role of Chronic Inflammation

Several mechanisms are involved in determining arterial stiffening in patients with CKD (Figure 1). Most of them are shared with other physiologic (i.e., age-related changes) and pathologic conditions (i.e., chronic inflammatory disorders, hypertension, and diabetes). Patients with CKD have elevated levels of proinflammatory cytokines, such as TNF9 and IL-6.10 In patients with ESRD, chronic inflammation can be detected. In this context, dialysis can stimulate the immune system and lead to chronic inflammation. Moreover, short fragments of bacterial DNA, endotoxins, and small muramyl dipeptides can potentially be found in the dialysate and, after crossing through high-flux membranes, can induce the production of IL-6. Furthermore, the catheters used for either hemodialysis or peritoneal dialysis, as well as synthetic grafts, are potential sources of inflammation. In peritoneal dialysis, the high glucose content and glucose degradation products in conventional dialysis solutions can lead to the formation of advanced glycation end-products, oxidative stress, and chronic inflammation.11
Chronic inflammation can lead to arterial stiffening through several mechanisms. Increased levels of TNF can interfere with the activity of endothelial nitric oxide synthase (eNOS) and induce the production of reactive oxidative species.12 Moreover, nitric oxide (NO) deficiency may itself cause oxidative stress.13 Oxidative stress can lead to endothelial dysfunction through the reduction of the endothelial production of NO, and to structural arterial stiffening through the phenotypic switching of vascular smooth muscle cells (VSMCs), the production of matrix metalloproteinases, and the inhibition of the tissue inhibitors of matrix metalloproteinases.14 In addition, TNF activates LDL receptor gene transcription, increases alkaline phosphatase protein expression, and reduces α-smooth muscle actin protein expression.15 All of these processes, together with the infiltration of white blood cells into blood vessels and the direct toxic action of several uremic toxins (such as inorganic phosphate, advanced glycation end-products, and indoxyl sulfate [IS]), lead to the proliferation and changes in phenotype of VSMCs and the consequent release of matrix metalloproteinases, elastin fragmentation, collagen degradation, vascular calcification, and structural arterial stiffening.15-17 The effect of TNF on the arterial wall is partially mediated by the release of IL-6 from VSMCs and endothelial cells. In other models of chronic severe inflammation (i.e., inflammatory bowel disease and rheumatoid arthritis), chronic inflammation is associated with increased arterial stiffness and early return of reflected waves.18-20 In these individuals, the inflammation-dependent aortic stiffening is at least in part reversible by anti-TNF therapy.21,22 Despite these promising results in other models of chronic inflammation, baseline low-grade inflammation did not predict changes in arterial stiffness over time in CKD,23 suggesting that, in parallel with chronic inflammation, other pathways can be involved in arterial stiffening in CKD. In this regard, the progressive accumulation of uremic toxins during CKD can also lead to arterial stiffening via a direct toxicity on the arterial wall (see above).

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