**The Effect of Convective Dialytic Modalities on Arterial Stiffness in End-Stage Renal Disease Patients**

Panagiotis I. Georgianos, Evangelia Dounousi, Theodoros Eleftheriadis and Vassilios Liakopoulos

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/63369

#### **Abstract**

Among end-stage renal disease (ESRD) patients receiving hemodialysis, increased arterial stiffness is an independent cardiovascular risk predictor. Over the past few years, arterial stiffness attenuation has been increasingly recognized as a novel therapeutic target toward cardiovascular risk reduction in the dialysis population. Structural alterations related to the long-term arteriosclerotic process are difficult to modify; with the exception of blood pressure (BP)-lowering, there are no other therapeutic interventions with well-documented benefits in delaying the progression of arteriosclerosis among dialysis patients. Enhanced clearance of middle-to-high molecular weight solutes by combining convective and diffusive transport through hemodiafiltration and the associated benefits on microvascular endothelial function have generated the hypothesis that convective dialytic modalities may be advanta‐ geous in improving large-artery stiffness. This notion is supported by some clinical studies showing that switching ESRD patients from low-flux hemodialysis to highefficiency on-line hemodiafiltration was associated with significant reduction in arterial stiffness. These beneficial effects, however, were not confirmed in a recent subanaly‐ sis of the CONvective TRAnsport STudy (CONTRAST) trial. In this chapter, we summarize the currently available evidence on the effect of hemodiafiltration versus hemodialysis on arterial stiffness, discussing also the potential clinical implications of this effect.

**Keywords:** arterial stiffness, hemodiafiltration, hemodialysis, pulse wave velocity, vascular calcification

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **1. Introduction**

Patients with end-stage-renal-disease (ESRD) receiving maintenance hemodialysis have one of the highest rates of cardiovascular morbidity and mortality [1, 2]. Although classical atheromatosis of middle-sized arteries is an important contributor to this elevated cardio‐ vascular risk, atherosclerotic cardiovascular events (i.e., myocardial infarction and stroke) can only partially explain the huge burden of cardiovascular mortality in ESRD. Among these patients, serious arrhythmias and sudden cardiac deaths related to the high preva‐ lence of left ventricular (LV) hypertrophy and disturbances in electrolyte balance repre‐ sent another major cause of cardiovascular death [3]. This phenomenon is explained by the fact that the spectrum of arterial remodeling in ESRD is much broader, including also longterm structural alterations in the visco-elastic properties of the biomaterial constituting the wall of the aorta and large conduit arteries [4, 5]. The so-called "arteriosclerotic process" is accompanied by substantial hemodynamic alterations and is considered one of the most important pathogenic mechanisms of isolated systolic hypertension, LV hypertrophy, and subendocardial hypoperfusion [4, 5]. It is therefore unsurprising that among ESRD pa‐ tients, increased arterial stiffness is a strong and powerful predictor of cardiovascular morbidity and mortality [6, 7].

Given the strong prognostic association of arterial stiffness with cardiovascular outcomes, regression of the arteriosclerotic process is increasingly recognized as a novel therapeutic target toward cardiovascular risk reduction in dialysis patients. However, whether arterial stiffness in this particular population is modifiable and if so, which therapeutic interven‐ tions are effective in delaying the progression of arteriosclerosis are aspects that remain unclear [5, 8]. Observational evidence and a few randomized studies suggested that blood pressure (BP)-lowering and use of agents blocking the renin-angiotensin-aldosteronesystem (RAAS) may be of some benefit [5, 8, 9]. The modality of renal replacement therapy is suggested to be another factor possibly determining the progression of arteriosclerosis in dialysis patients. In this regard, higher clearance of middle-to-large molecular weight solutes by combining diffusive and convective transport and the associated improvement in phos‐ phate control, endothelial dysfunction, and circulating inflammatory biomarkers [10–14] is proposed to be translated into a beneficial impact of hemodiafiltration on large-artery structure and function in dialysis patients.

The aim of this chapter was to review the currently available evidence on the effect of hemo‐ diafiltration versus hemodialysis on the long-term progression of the arteriosclerotic process and discuss the potential implications that this effect may have in the choice of the most appropriate dialytic modality for ESRD patients.

### **2. Arterial stiffness in dialysis patients**

Acceleration of the arteriosclerotic process is the typical feature of arterial remodeling in ESRD. Aortic and carotid-artery stiffness is significantly higher in ESRD patients than in age-, sex-, and BP-matched controls with normal renal function [15]. Among dialysis pa‐ tients, arteriosclerotic process is a pathophysiological continuum of structural alterations that begin from the early stages of renal impairment, with several studies showing a step‐ wise increase in arterial stiffness with advancing stage of chronic kidney disease (CKD) [16, 17]. Structural alterations related to arterial stiffening in ESRD include fibro-elastic intimal thickening, calcification of elastic lamellae, increased extracellular matrix deposi‐ tion, elastynolysis and inflammation, increased collagen, and decreased elastic fiber con‐ tent [4, 18, 19]. The mechanistic background of these arterial wall alterations is complex and not yet fully elucidated. Apart from the contribution of accumulated traditional cardi‐ ovascular risk factors, it is suggested that specific mechanistic pathways related to the ESRD status and renal replacement therapy may play a particular role in the progression of arteriosclerosis in this population. Some of the most important ESRD-specific mecha‐ nisms involved in the pathogenesis of arteriosclerosis include impaired mineral metabo‐ lism and elevated calcium-phosphate product, vascular calcification, excessive activation of the RAAS, endothelial dysfunction, inflammation, oxidative stress, and chronic volume overload [4, 18, 19]. Compared with traditional cardiovascular risk factors, these ESRDspecific pathways were shown to be stronger determinants of the progression of arterio‐ sclerosis over time [20].

**1. Introduction**

46 Advances in Hemodiafiltration

morbidity and mortality [6, 7].

structure and function in dialysis patients.

appropriate dialytic modality for ESRD patients.

**2. Arterial stiffness in dialysis patients**

Patients with end-stage-renal-disease (ESRD) receiving maintenance hemodialysis have one of the highest rates of cardiovascular morbidity and mortality [1, 2]. Although classical atheromatosis of middle-sized arteries is an important contributor to this elevated cardio‐ vascular risk, atherosclerotic cardiovascular events (i.e., myocardial infarction and stroke) can only partially explain the huge burden of cardiovascular mortality in ESRD. Among these patients, serious arrhythmias and sudden cardiac deaths related to the high preva‐ lence of left ventricular (LV) hypertrophy and disturbances in electrolyte balance repre‐ sent another major cause of cardiovascular death [3]. This phenomenon is explained by the fact that the spectrum of arterial remodeling in ESRD is much broader, including also longterm structural alterations in the visco-elastic properties of the biomaterial constituting the wall of the aorta and large conduit arteries [4, 5]. The so-called "arteriosclerotic process" is accompanied by substantial hemodynamic alterations and is considered one of the most important pathogenic mechanisms of isolated systolic hypertension, LV hypertrophy, and subendocardial hypoperfusion [4, 5]. It is therefore unsurprising that among ESRD pa‐ tients, increased arterial stiffness is a strong and powerful predictor of cardiovascular

Given the strong prognostic association of arterial stiffness with cardiovascular outcomes, regression of the arteriosclerotic process is increasingly recognized as a novel therapeutic target toward cardiovascular risk reduction in dialysis patients. However, whether arterial stiffness in this particular population is modifiable and if so, which therapeutic interven‐ tions are effective in delaying the progression of arteriosclerosis are aspects that remain unclear [5, 8]. Observational evidence and a few randomized studies suggested that blood pressure (BP)-lowering and use of agents blocking the renin-angiotensin-aldosteronesystem (RAAS) may be of some benefit [5, 8, 9]. The modality of renal replacement therapy is suggested to be another factor possibly determining the progression of arteriosclerosis in dialysis patients. In this regard, higher clearance of middle-to-large molecular weight solutes by combining diffusive and convective transport and the associated improvement in phos‐ phate control, endothelial dysfunction, and circulating inflammatory biomarkers [10–14] is proposed to be translated into a beneficial impact of hemodiafiltration on large-artery

The aim of this chapter was to review the currently available evidence on the effect of hemo‐ diafiltration versus hemodialysis on the long-term progression of the arteriosclerotic process and discuss the potential implications that this effect may have in the choice of the most

Acceleration of the arteriosclerotic process is the typical feature of arterial remodeling in ESRD. Aortic and carotid-artery stiffness is significantly higher in ESRD patients than in

The main physiological role of the aorta and large conduit arteries is (i) to dampen the high-pressure oscillations generated from the intermittent LV ejection and (ii) to transform the cyclic blood flow in the aorta into a continuous capillary flow pattern required for perfusion of organs and tissues [4, 19, 21]. During systole, the stroke volume ejected by the left ventricle interacts with the elastic properties of the aorta to generate a pulse wave (incident or forward-traveling) that is propagated at a pulse wave velocity (PWV) that progressively increases across the arterial tree. Structure of the arterial system is normally characterized by progressive increase in arterial wall stiffness from the ascending aorta to the peripheral muscular-type arteries (so-called stiffness gradient) [4, 19, 21]. Impendence mismatches at the transition between these segments generate pulse wave reflections. These reflected waves travel from the periphery back to the ascending aorta (backwardtraveling reflected wave), opposing pulsatile energy transmission downstream to microcir‐ culation. In young subjects with elastic central arteries, this process is coupled with slower pulse wave propagation and the overlap of the incident and reflected waves in the ascending aorta occurs in late systole or early diastole. This phenomenon results in rise of diastolic aortic pressure, favoring coronary perfusion during diastole. Arteriosclerotic process, however, affects preferentially the wall of the aorta and large central arteries, re‐ versing the normal stiffness gradient between central and peripheral arterial segments [22]. In conditions of accelerated arterial stiffness, such as ESRD, there is premature arriv‐ al of reflected waves back to the ascending aorta, during systole rather than diastole [4, 19, 21]. This results in augmentation of central aortic systolic pressure, thereby increasing cardiac after load and promoting adverse myocardial remodeling toward fibrosis and hy‐ pertrophy. In addition, greater pulsatile energy transmission from macro- to microcircula‐ tion promotes microvascular damage in peripheral organs and tissues (**Figure 1**) [4, 19, 21].

**Figure 1.** Pathophysiological role of increased arterial stiffness in ESRD.

The close pathophysiological association of arterial stiffness with promotion of end-organ damage is in line with a strong epidemiological association of increased arterial stiffness with worse cardiovascular outcomes. Among dialysis patients, prospective observational studies have for long-connected higher aortic PWV with increased risk of all-cause and cardiovascular mortality independently from other cardiovascular risk factors [7]. In the first study conducted in the late 1990s in a cohort of 241 hemodialysis patients prospectively followed for a mean period of 6 years, Blacher et al. [6] showed that the fully adjusted odds ratio (OR) for aortic PWV > 12.0 versus PWV < 9.4 m/s was 5.4 [95% confidence intervals (CIs): 2.4–11.9] for allcause mortality and 5.9 (95% CI: 2.3–15.5) for cardiovascular mortality [6]. The strong prog‐ nostic association between aortic PWV and cardiovascular outcomes was confirmed in several subsequent cohorts of hemodialysis patients [15, 23]. Similarly to patients receiving hemo‐ dialysis, more recent observational studies have demonstrated the strong and independent prognostic significance of arterial stiffness in the whole spectrum of CKD, showing that aortic PWV is an independent predictor of mortality in patients receiving peritoneal dialysis [24] in renal transplant recipients [25] and in patients with CKD not yet on dialysis [26]. Most importantly, regression of arterial stiffness in response to BP-lowering was shown to be associated with improvement in survival [9], providing evidence that arterial stiffness is not simply a risk predictor, but a true cardiovascular risk factor in the dialysis population.
