Université Paris Descartes, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, INSERM U970, Paris, France
Correspondence to Professor Stéphane Laurent, Pharmacology Department and INSERM U 970, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015, Paris, France. Tel: +33 1 56 09 39 91; fax: +331 56 09 39 92; e-mail: firstname.lastname@example.org
Normal arterial aging is characterized by arterial enlargement, wall-thickening and stiffening, which predominate at large arteries . Arterial enlargement and stiffening occur in parallel with glomerular filtration rate (GFR) decline in patients with chronic kidney disease (CKD) . In CKD patients, arterial enlargement is associated with a lack of arterial wall-thickening, resulting in an increased circumferential wall stress [3,4]. The relationships between central hemodynamics [either arterial stiffness or central blood pressure (BP)] and GFR decline are complex, and depend mainly on both the stage of the disease – early CKD, advanced CKD or end-stage renal disease – and the level of BP – optimal BP, high normal and grade I-II hypertension [2–4].
O’Rourke and Safar  suggested that the torrential flow and low resistance to flow in the kidney expose small arterial vessels of the glomerulus to the high-pressure fluctuations that exist in the renal arteries. Such fluctuations, measurable as central pulse pressure, increase three-fold to four-fold with age. Exposure of small vessels to highly pulsatile pressure and flow may explain microvascular damage to the glomerulus through altered myogenic tone and result in renal insufficiency . In addition, aortic stiffness and central BP are associated with higher risk of incident hypertension . Thus, it is tempting to speculate that a vicious pathophysiological circle, involving large/small artery cross-talk , can start from any rise in BP, leading to higher aortic stiffness, which itself increases central BP pulsatility, damaging in turn the renal function, which may ultimately exaggerate the rise in BP, thus increasing the incidence of sustained hypertension. An important issue is the degree of involvement of renal dysfunction in this pathophysiological pathway, that is whether renal dysfunction is required for the development of hypertension in response to higher arterial stiffness.
The article by Tomiyama et al. published in the present issue of Journal of Hypertension provides an important contribution with regard to this issue. The authors determined arterial stiffness from the measurement of brachial-ankle pulse wave velocity (baPWV) and central SBP from the second peak of the radial pressure waveform (SP2), and estimated GFR from the serum cystatin C (eGFRcys) in 1229 middle-aged normotensive Japanese men with preserved renal function, at baseline and at the end of a 3-year-study period. They showed, in a logistic regression analysis with adjustment, that both baPWV and eGFRcys independently predicted incident hypertension (127 cases) at the end of the 3-year-study period. Therefore, the question is whether baPWV could have favored the development of hypertension through the decline in kidney function. The answer, given by the authors, is negative for at least two reasons. First, they observed no interaction between baPWV and eGFRcys. Second, no significant relationship was observed between baPWV measured at initial examination and the renal function parameters measured at the end of the 3-year-study period. Similar results were obtained with central SBP, measured as radial SP2: SP2 had a significant odds ratio (2.16) for predicting the short-term development of hypertension, independently of eGFRcys, with no interaction. Thus, two independent mechanisms may contribute to the development of hypertension. The first one relates to the causal role of the renal function, which is well accepted. The second one relates to the concept of ‘early vascular aging’ (EVA) [9,10], which states that aortic stiffness, measured in the general population, reflects the cumulative damage of cardiovascular risk factors, either easily measurable (age, sex, BP, lipids, etc…) or measurable in a more complex way (oxidative stress, chronic low grade inflammation, fetal programming, etc…), on the arterial wall of large arteries, and thus give information on the whole past exposition of the arterial system to damaging factors leading to hypertension. That, in the present study, radial SP2, a measure of central SBP, was a better predictor of the short-term development of hypertension than the baPWV, is consistent with the EVA concept. Indeed, one of the mechanisms relating aortic stiffness to the development of hypertension is the increase in SBP in response to increased amplitude and shorter timing of reflected pressure waves, overlapping incident pressure waves.
The findings by Tomiyama et al. are stimulating from an additional point of view. Indeed, the authors confirmed, in a population of middle-aged normotensive individuals with preserved renal function, previous findings observed in CKD patients with direct estimation of GFR by isotopic method 51Cr EDTA, that is the arterial stiffness and central BP had no predictive value for the decline in GFR . One may argue that the present study , as well as the previous study , had a too short follow-up (3 and 3.5 years, respectively) to unmask a significant relationship, when dealing with a slowly occurring renal damage, and that a longer follow-up is required. However, with such a short follow-up, it has been possible to demonstrate the predictive value of carotid wall stress for the decline in directly measured GFR . Another possibility is that CKD progression and aortic stiffening have different mechanisms, and particularly that nonhemodynamic factors are associated with GFR decline. A third possibility is that CKD progression and aortic stiffening have common mechanisms but either the aorta is protected during CKD progression or the kidney is protected during aortic stiffening. For instance, an adequate autoregulatory capability of the glomerulus could be maintained for years before the high local pressure pulsatility generated by aortic stiffening starts damaging the glomerulus.
The study by Tomiyama et al. has, however, some limitations, which have been underlined by the authors: short-term follow-up; no measurement of microalbuminuria; BP measurements on the same day; and focus on men only. Additional limitations are the indirect determination of central SBP through radial pressure waveform analysis, as SP2, and the lack of direct measurement of central pulse pressure (PP). Finally, arterial stiffness has been measured as baPWV in the present study, which raises the issue of the arterial pathway, that is whether baPWV reflects mainly aortic stiffness or additionally takes into account the stiffness of muscular arteries. Indeed, the measurement of baPWV includes a much longer trajectory of the pressure wave along the muscular arteries of the upper and lower limbs than along the aortic pathway. By contrast, carotid-femoral PWV, which is considered as gold standard for determining aortic stiffness , is calculated as the ratio of the transit time between the feet of the carotid and femoral pressure waveforms, and the carotid-femoral distance. However, whatever the arterial pathway, a major demonstration of the utility of a stiffness parameter is the finding of the predictive value for CV events in several populations. This has been done in several studies with baPWV  and synthesized in a meta-analysis .
In conclusion, the study by Tomiyama et al. provides a valuable contribution to the ongoing research on the development of hypertension. Results are stimulating also for a better understanding of the pathophysiology of hypertension-induced decline in renal function. Further studies are needed to determine whether longer follow-up confirms these findings, and which part of the large artery pathway contributes the most to the development of hypertension through arterial stiffening.
Conflicts of interest
There are no conflicts of interest related to the present paper.
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