Arterial pulsatility

The relationship between chronic kidney disease (CKD) and hypertension has been widely investigated, however it is not well established whether hypertension precedes microvascular kidney impairment or vice versa. One insight on this issue comes from a study by Woodard et al.[1], in which the authors found that increased arterial stiffness would increase the transmission of the pulsatile energy into the kidney microcirculation, contributing to the loss of the kidney function. One important element to remember is that the arterial system is conceived to dampen the pressure and flow pulsatilities produced by the heart. Aortic and peripheral impedances contribute to preserve continuous and low pulsatile flow into target organs: the aorta through its compliance receives and stores part of the systolic volume during the systole, releasing it during the diastole; the peripheral increase of impedance contributes together with the reflection of pressure and flow waves to maintain and even amplify blood pressure (BP) assuring organ perfusion (the phenomenon of central to peripheral pressure amplification), and eventually the peripheral resistances preserve the target organ microcirculation from pulsatility. However, in physiologic conditions, the kidney microcirculation is not protected against the pulsatility of large arteries because of the relatively low resistance of the efferent arterioles [2]. It follows that the presence of increased aortic pressure/flow pulsatility, associated or not with increased arterial stiffness, leads to high renal artery flow pulsatility and renal vascular resistance; apart from, it affects the renal blood flow autoregulation, increasing the myogenic tone of the afferent arterioles. Together with the contribution of other factors like increased BP variability consequent to arterial stiffening, this eventually leads to glomerular hypertrophy, hyperfiltration, and ischemia, with loss of the renal function [3,4]. Therefore, even if the study by Woodard et al.[1] is not conclusive because of its cross-sectional nature, the hypothesis of causality is supported by pathophysiological mechanisms that might drive the kidney damage. Furthermore, a prospective evaluation of the renal function in adults revealed that higher baseline pulse pressure (PP) was related to accelerated loss of estimated glomerular filtration rate (eGFR) after 6 years [5]. Interestingly, in this issue of the Journal, Lin et al. [6] report data from a well powered cross-sectional analysis on nearly one thousand Chinese adults, which shows a significant trend for the positive association between two surrogate markers of arterial stiffness (PP and the brachial-ankle pulse wave velocity) and excess of renal filtration rate (hyperfiltration). In this field as in general, caution should be taken in the interpretation of cross-sectional studies. Anyway, the direction of the causality relationship being unknown, Lin et al.'s data [6] supports strongly a pathophysiological link between the kidney and the arteries. Another insight into the effect of BP on microcirculation comes from the research in retinal microcirculation. Indeed, cross-sectional and longitudinal studies have shown that higher SBP and mean BP, even within the normal range, in childhood (from 6 to 8 years) are associated with retinal arteriolar narrowing [7], and that higher SBP and increased SBP from childhood to adulthood are prospectively associated with both narrowing of retinal arteriolar diameter and distortion of retinal microvascular architecture in mid-adulthood [8]. These results suggest that early modifications of BP even in the normal range in youth could be responsible for structural microvascular alteration in adulthood, at least in retinal vascular bed. In this issue of the Journal, the study by Das et al.[9] investigates the association of PP evolution during early life and adulthood renal function. More than 1000 young adults (30 years old) were enrolled and several data from follow-up visits were available from 5 to 30 years. CKD was assessed by eGFR at 30 years. The authors used a group-based trajectory modelling to fit different PP trajectories. At the end of the follow-up, 7% of the population had stage 2 CKD. They found three PP trajectories: a lower one, without substantial PP modification during the follow-up; a higher one, with an almost constant increase in PP; a middle one, with initial increase and later decrease of PP. At baseline and at each follow-up visit, mean PPs in the group with normal eGFR were similar to those in the stage 2 CKD group. Baseline PP was higher in the high trajectory group than in the low and middle trajectory groups. The main result is that the higher and the middle trajectory groups had significant higher adjusted odds of developing stage 2 CKD than the lower group. Anyway, the sensitivity analysis in men and women revealed that a significant odds ratio was found only in the female group for the middle versus lower trajectory group, for the unadjusted and the adjusted models. Interestingly, no association was found between baseline PP tertiles (at 5 and 14 years) and the development of CKD, with the exception of the women group at 14 years (supplementary table 4 of the cited article). From an epidemiological point of view, it is well known that SBP, DBP, mean, and PPs behave differently with aging, sex and race. Although SBP increases throughout almost the entire lifespan, DBP tends to increase from youth to adult age and then to decrease in elderly people, so that PP would decrease in the early life course and increase subsequently. However, the real behaviour of PP in early life course has not been well established yet. Kulaga et al.[10] compared four different BP references in children and found that both SBP and DBP increase almost constantly from 7 to 17 years of age. Indeed, in the Das et al.'s study [9], the behaviour of PP in the lower and higher trajectory groups seems to reflect the respective evolution of BP in boys and girls, as shown by Dasgupta et al.[11]. In their prospective trial, they found that boys are more likely to develop higher SBP values from early to late adolescence than girls of the same age. This similarity is potentially explained by the generous prevalence of men in the higher trajectory group (87%), and of women in the lower trajectory group (91%). Differences in kidney physiology between men and women have been considered in literature. In fact, sex differences exist in terms of anatomy (with women having higher renovascular resistance [12]) and renin–angiotensin system [13], but also at molecular level [14], probably owing to sex-specific hormonal pattern [15]. Similarly, sex differences also exist in the regulation of BP, body water, and autonomic system; moreover, in women, it has been shown that the impact of estradiol and progesterone in BP and water regulation changes even during the menstrual cycle [16]. The point is of main interest, as eventually the group-based trajectory modelling proposed by Das et al. resulted mainly in splitting up the population into men and women. The main analysis can therefore be regarded as a sex comparison in the evolution of renal function. Besides, baseline information on PP tertile categories seems to be useful predictors of future CKD risk only for women. Another issue to be raised is that the definition of the CKD stage was based on the sole eGFR, whereas actual guidelines support using both eGFR and albuminuria [17], which could lead to an underestimation of the prevalence of mild CKD in the Das et al.'s study [9]. Das et al.'s study [9] indicates that early life increase in PP leads to higher odds of developing early mild CKD and supports the hypothesis of a primary causative role of high BP on renal dysfunction, but is prone to intrinsic interpretation concerns. Apart from, even if an observational relationship is present between BP and CKD, its pathophysiology, especially in youth, when BP is within the normal range and arterial compliance is thought to be preserved, is largely unknown. A new pixel has been lightened in the screen, but the case is not closed. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.