The Renal Dangers of an Increased Cardio-Ankle Vascular Index

The palpation of the pulse is a fundamental part of physical examination since the early ages of the Greek and Chinese medicine. The Chinese masters used their fingertips and their powers of observation to associate “hardening of the pulse” with adverse outcomes in people who ingested too much salt.1 However, only in last decades, systematic scientific evaluation of viscoelastic properties of large arteries (i.e., the aortic system and its central branches) has matured as a clinical and research discipline.1 The modern history of arterial stiffness measurement begins in 1985, when Levy, Targett, and their coworkers described the first device and computer program to automatically record and calculate pulse wave velocity (PWV).2 The measurement of PWV is generally accepted today as the most simple, noninvasive, and reproducible method with which to determine arterial stiffness.1,3 The basic principle of PWV assessment is that the pulse wave runs along the arterial tree at a speed which depends on the elasticity of the wall itself: the stiffer (i.e., less elastic) the wall, the higher the velocity of propagation.1 Although PWV can be measured in any arterial segment, PWV of the aorta (aPWV) is considered the “gold-standard” measurement of arterial stiffness. The aorta is a major vessel of interest when determining regional arterial stiffness, since the aorta and its first branches are what the left ventricle “sees” and are the vessels responsible for most of the pathophysiological effects of arterial stiffness, as the majority of arterial “buffering” occurs in the aorta.1,3 In addition, unlike PWV of other arterial segments,4,5 aPWV is independently associated with adverse cardiovascular outcomes in large-scale prospective studies.1,3–5 Moreover, improving risk classification, aPWV may enable better identification of high-risk populations.4 In the vast majority of studies measuring aPWV to date, devices endowed with probes placed on the carotid and femoral arteries were used. However, these require access to the femoral artery at the groin, which takes time and may cause discomfort for the patient. This has promoted the use of newer devices, which derives values of aPWV from oscillometric measurements of the brachial artery waveform.6,7 Some of these devices have versions developed for 24-hour blood pressure (BP) and arterial stiffness monitoring, opening a new field of research interest.6,7 Although these new devices are promising, they do not yet have the robust outcome data of the older ones.3 All techniques based on PWV used to assess arterial stiffness are intrinsically dependent on the BP values at the time of measurement, because the arterial wall becomes stiffer when distending pressure increases. This is due to the transfer of stress from the stretchable elastin to the stiff collagen fibers in the arterial wall, as BP increases. This places some limitations on the clinical utility of PWV as a measure of arterial stiffness, with higher values being caused by either intrinsic changes in arterial structure or higher distending pressure. One of the methods proposed to correct, at least in part, PWV for its BP dependency is the cardio-ankle vascular index (CAVI). Its measurement is performed using a portable machine that requires placement of electrocardiogram electrodes on both wrists, a microphone for phonocardiography on the sternum, and 4 BP cuffs wrapped around the 4 limbs. The upper arm and ankle pulse waves, as well as BP, can all be measured.8 This method is based on the estimate of the arterial stiffness index, β, of the aorta and the iliac, femoral, and tibial arteries. It is a surrogate measure of the increase in arterial stiffness occurring from end-diastole to end-systole (diastolic-to-systolic “stiffening”), and incorporates information on arterial properties during the entirety of systole. The stiffness parameter β is obtained by linearization of logarithmic expression of the ratio between internal pressure in blood vessels and change in vascular diameter.8 There is some evidence suggesting that an increased CAVI is associated positively with an enhanced risk of cardiovascular events.8 There is a very large and consistent body of evidence suggesting that chronic kidney diseases (CKD) and even mild renal abnormalities, are cross-sectionally associated with an increased aortic PWV1,8–10 and an increased CAVI.11 Controversy exists as to whether arterial stiffness causes renal function decline, or kidney dysfunction leads to stiffening or whether the association is mutual, this latter being the most probable hypothesis.11–15 Larger artery stiffness is characterized by reduction in buffering capabilities of the vascular wall. The resulting increased central pulse pressure contributes to a highly pulsatile flow in the aorta and its branching arteries, including the renal vessels.1,9 Although the precise mechanisms are not fully clear, there is evidence from animal models that sustained exposure to increased BP pulsatility induces microvascular remodeling such as fibrosis that in turn blunts renal autoregulation.1,9 In this way, the torrential pulsatile flow is transmitted to the vulnerable renal microvasculature, and the resulting barotrauma may cause loss of kidney function. The low resistance in the kidney allows the pressure wave of each heartbeat to penetrate deeply into the microvasculature.1–9,12 Deep penetration would be favored by the disappearance of reflections at the interface between elastic and muscular conduit arteries. It is relevant to recall the consistent evidence that (at least in vitro) pulsatile stretch affects the oxidant/antioxidant balance of vascular cells in a much more deleterious way than does steady stretch.1,9,12 The complex relationship between large-arterial function and microvascular kidney disease was analyzed in the Age, Gene/Environment Susceptibility-Reykjavik Study, in which 367 older subjects underwent a phase-contrast magnetic resonance imaging of aortic and renal blood flow to compute renal blood flow, renal vascular resistance, and renal artery pulsatility index (defined as the maximum flow minus the minimum flow divided by the mean flow). Central BP and carotid–femoral PWV were measured using applanation tonometry. The study showed a significant inverse association between PWV and glomerular filtration rate (GFR) measured using iohexol clearance.15 The mediation analysis showed that 34% of the observed relationship between aortic stiffness and GFR was mediated by pulsatility index, suggesting that aortic stiffness induces kidney damage mostly increasing the delivery of pulsatile energy into the renal circulation. It is conceivable that the impact of this pulsatile flow is transferred to the vulnerable renal microvasculature because of its low impedance, and can lead to constriction of resistance vessels and subsequently to structural damage (Figure 1).15 Putative bidirectional mechanisms linking increased aortic stiffness and chronic kidney diseases (CKD). Putative bidirectional mechanisms linking increased aortic stiffness and chronic kidney diseases (CKD). It is important to note that, pulsatility index in the kidney circulation can be affected also by other factors, such as renal vascular resistance, renal reflected waves, and BP variability. This may be increased because arterial stiffness impairs baroreflex sensitivity (Figure 1). On the other hand, a number of mechanisms have been identified in humans with CKD by which renal damage may impact on arterial elasticity, including fluid overload, alterations in the angiotensin and endothelin systems, oxidative stress, inflammation, deranged calcium/phosphate balance, insulin resistance, alteration of factors controlling arterial calcification, such as fetuin-A and osteoprotegerin, and homocysteine (Figure 1).1,9,10,12 Moreover, a direct effect of uremia on arterial stiffness is supported by evidence suggesting that vascular compliance improves after successful renal transplantation.1,12 Although a number of longitudinal investigations assessed the ability of aortic PWV to predict the development of kidney disfunction or progression of renal disease,12–14 little is known about the association of CAVI with the risk of renal function deterioration.16–18 In the current issue of the American Journal of Hypertension is published a paper of Itano et al., that adds a new piece of evidence in this scenario. The authors analyzed data from the national health checkup system in Japan, including 24,297 participants with normal baseline kidney function.16 They found that those with CAVI measurements ≥8.1 had a higher risk for CKD events compared with their counterparts with CAVI measurements <8.1, independently of cardiovascular risk factors. Participants with CAVI measurements ≥8.1 had a greater decline in annual estimated glomerular filtration rate compared with their counterparts with CAVI measurements <8.1. The association was stronger in participants with hypertension compared with those without hypertension.16 When CAVI measurements were used as a continuous variable, the hazard ratios (95% confidence interval) associated with each standard deviation higher level of CAVI measurements (+0.99 unit) were 1.15 (1.06, 1.25) for CKD events.16 These findings are in agreement with a previous smaller study performed also in Japan in which 369 outpatients without CKD at baseline were analyzed. After a follow-up of 22 ± 9 months the subjects with a CAVI ≥10 had a more than doubled chance to develop CKD.17 Similar results were also obtained by Satirapoj in 351 Thay subjects with high cardiovascular risk in which, independently of the value of baseline GFR, those with high CAVI (≥9) experienced a rapid decline in GFR.18 Some limitations in all these studies may be identified. For example, the definition of CKD is based on only one measurement of proteinuria or GFR, at variance with the KDIGO guidelines criteria requiring not less than 2 measurements at least 3 months a part. Not all the potential confounding factors, such as physical activity or measures of glucose metabolism, were taken into account assessing the risk of developing CKD. Furthermore, subjects belonging to the groups with higher values of CAVI tended to have at baseline lower kidney function, which may favor the development of CKD.16 Even with these limitations, these studies and in particular that of Itano et al. provide an important contribution to expand our knowledge about the renal effects of arterial stiffness. Further studies involving participants from countries outside Asia are warranted to understand whether the results obtained in Japanese and Thay subjects may be valid also in other racial and ethnic groups. Moreover, future research should determine whether interventions targeting CAVI will prevent CKD development and progression. The authors report no specific funding in relation to the preparation of this paper. The authors declared no conflict of interest.