Chronic kidney disease: Arterial stiffness and renal function [mdash] a ...

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Dec 9, 2014 - chronic kidney disease (CKD) is supported by a number of studies.1 However, the way in which the viscoelastic properties of the aorta might ...
NEWS & VIEWS CHRONIC KIDNEY DISEASE

Arterial stiffness and renal function—a complex relationship Paolo Salvi and Gianfranco Parati

New data suggest that aortic stiffness results in the transmission of excessive flow pulsatility to the renal microcirculation. Further understanding of the mechanisms that regulate the relationship between large arteries and the renal microcirculation could lead to new strategies to protect the kidneys from increased blood pressure load owing to systemic hypertension. Salvi, P. & Parati, G. Nat. Rev. Nephrol. 11, 11–13 (2015); published online 9 December 2014; doi:10.1038/nrneph.2014.226

A close link between aortic stiffness and chronic kidney disease (CKD) is supported by a number of studies.1 However, the way in which the viscoelastic properties of the aorta might affect renal function has not yet been clearly established. Although small vessels in the systemic circulation are gener­ ally protected from increased blood pressure load by upstream arterial vasoconstriction activity, the renal vascular bed is character­ ized by low resistance and low impedance. The kidneys are, therefore, continually and passively perfused through systole and dia­ stole by a high-volume pulsatile flow.2 These flow characteristics make renal parenchyma particularly vulnerable to an increase in the amplitude of pulse pressure and to the wide variation in systolic and diastolic flow caused by large artery stiffness. In a recent report published in the Journal of the American Society of Nephrology, Woodard et al.3 analyse the complex rela­ tionship between large-arterial function and microvascular kidney disease. They performed a comprehensive assessment of renal haemodynamics in 367 elderly individuals (aged 72–92 years). A sophis­ ticated phase-contrast MRI of aortic and renal blood flow was used to compute renal blood flow, renal vascular resistance (RVR), renal artery pulsatility index (defined as the maximum flow minus the minimum flow divided by the mean flow) and arterial volume in the renal cortex. Central blood pressure and carotid–femoral pulse wave velocity (PWV, a marker of aortic stiff­ ness) were non-invasively measured using

applanation tonometry. The study showed a significant inverse association between PWV and glomerular filtration rate (GFR) measured using iohexol clearance (slope of regression –2.28 ± 0.858 m/min per SD, P = 0.008). This relationship was attenu­ ated and no longer significant when pul­ satility index and/or RVR were included in the multivariable model, giving rise to the hypothesis that these factors might mediate the relationship between PWV and GFR. To investigate the putative causal relation­ ship between arterial stiffening and loss of kidney function the researchers performed a mediation analysis. This type of statisti­ cal analysis can quantify the influence of a potential mediator on the association between a candidate mechanism and the hypothesized outcome. Although not provid­ ing direct proof of causality because the ana­ lysis uses cross-sectional data, this method can nevertheless provide evidence to support the occurrence of causal mechanisms in bio­ logical processes. The mediation analysis showed that 34% of the observed relation­ ship between aortic stiffness and GFR was mediated by pulsatility index, suggesting that a stiff aorta increases the delivery of pulsatile energy into the kidney circulation. The researchers postulate that the haemo­ dynamic impact of this pulsatile flow is transferred to the vulnerable renal microvas­ culature because of its low impedance, and can lead to constriction of resistance vessels and subsequently to structural damage. In support of this mechanistic view, mediation analyses also identified an increase in renal

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vascular resistance and the redistribution of kidney circulation as significant mediators of the relationship between stiffness and GFR. Higher vascular resistance and lower arterial volume in the renal cortex mediated 36% and 20% of this relationship, respec­ tively, when considered as downstream mediators of a high pulsatility index. In their analysis of renal haemodynamic measures, Woodard et al.3 were not able to distinguish between permanent structural vascular loss and functional vasoconstriction. Despite this limitation, their data suggest a patho­ genetic link between aortic stiffness and renal damage through transfer of a highly pulsatile flow into the renal microvascu­ lature. Consistent with this finding, a high pulse pressure secondary to aortic stiffening without an accompanying increase in flow pulsatility did not increase transmission of pulsatile power into the vascular bed nor result in microvascular damage. It is important to stress that, although mainly determined by arterial pulse pres­ sure, pulsatility index in the kidney cir­ culation can be affected by other factors, such as RVR, renal reflected waves, local arterial viscoelastic properties, renal artery stenosis, heart rate and blood pressure variability (Figure 1).4 The use of anti­hyper­ tensive drugs could also be an important confounder; 75% of the participants in the study by Woodard et al.3 were treated for hypertension. Renin–angiotensin system Arterial stiffness

Baroreflex sensitivity Aortic pulse pressure

Arterial media calcifications

Blood pressure variability

Renal artery stenosis and distensibility Renal artery flow pulsatility Reflected waves Renal vascular resistance Chronic kidney disease

Kidney microvascular damage

Figure 1 | The complex relationship between Reviews | Nephrology arterial stiffness Nature and chronic kidney disease.

VOLUME 11  |  JANUARY 2015 © 2015 Macmillan Publishers Limited. All rights reserved

NEWS & VIEWS (RAS) blockade has been shown to reduce pulsatility index and RVR in normotensive and hypertensive patients.5 Unfortunately, Woodard et al. do not provide data obtained in the subgroup of participants who were not receiving antihypertensive treatment. An assessment of the effects of such treat­ ment on the relationship between arterial stiffness and pulsatility index, RVR and urinary albumin-to-creatinine ratio would have been interesting. The study makes a substantial contribution to clarifying the relationship between arterial stiffness and kidney microcirculatory damage, but further work is needed to investigate the patho­ physiological mechanisms that underlie the relationships between macrocirculation and ­microcirculation in the kidney.

‘‘

…a stiff aorta increases the delivery of pulsatile energy into the kidney circulation

’’

Importantly, arterial stiffness can sub­ stantially influence not only the pulsatile behaviour of systemic blood pressure, but also the beat-to-beat and short-term vari­ ability of pressure and flow.6 Through both a reduction in baroreflex sensitivity and the passive effect of loss of arterial wall elastic properties, arterial stiffness increases blood pressure variability, which, in turn, might contribute to the development and progression of renal damage. 7 The link between arterial stiffness and renal func­ tion is undoubtedly complex and is not a one-way relationship. Several biological processes are involved in the progression of atherosclerosis and arteriosclerosis in CKD. The disease is associated with acceler­ ated vascular ageing; activation of the RAS, aortic inflammation and vascular metallo­ proteinase activity lead to changes in the extra­cellular matrix and to endothelial dys­ function, paving the way to arterial stiffen­ ing. Indeed, increased arterial stiffness is

JANUARY 2015  |  VOLUME 11

observed even in the early stages of CKD, suggesting that arterial remodelling occurs early in the course of the disease.8 Intima and media calcifications also occur in CKD and are associated with increased morbidity and mortality. Calcifications in the arterial medial layer are early phenom­ ena in the course of the disease. Formation of these calcifications is often triggered by active processes involving inflammatory cytokines and metalloproteinases in the absence of athero­sclerosis.9 Hyperparathyroidism and dis­ordered calcium and phosphate metabo­ lism, which are common features of advanced CKD, might also contribute to vascular calci­ fication.8 Moreover, art­erial stiffness increases pulse pressure and left ventricular afterload, causing left ventricular hyper­trophy.10 When considered as a marker of vascular damage, both arterial stiffness and indices of aortic calcification show their greatest predictive value for cardio­vascular events in patients with e­ nd-stage renal disease.1 An overall view of the interaction between arteriosclerosis and renal function may open new horizons in the approach to treatment of patients with hypertension. The new data from Woodard et al.3 suggest that a reduction in pulsatility index might protect the kidney microcirculation against damage generated by high-pressure pulsatility. In the setting of hypertension characterized by high pulse pressure, drugs that reduce pulsatility index and renal vascular resistance (such as RAS blockers) should, therefore, be preferred. The importance of vascular calcifications as determinants of arterial stiffness suggests that treatment strategies aimed at suppress­ ing or inhibiting their formation, such as supplementation with Vitamin K, mag­ nesium salts and possibly pyrophosphate, may be highly effective in maintaining art­ erial function, reducing cardiovascular risk and interrupting the vicious cycle between arterial stiffness and kidney microvascu­ lar damage. Development of drugs that are able to reduce arterial stiffness and to buffer



increased blood pressure variability would likely further improve the current approach to treatment of arterial hypertension. Istituto Auxologico Italiano, Laboratory of Cardiovascular Research (P.S.), Istituto Auxologico Italiano and Department of Health Sciences, University of Milano-Bicocca (G.P.), Piazza Brescia 20, 20149 Milan, Italy. Correspondence to: P.S. [email protected] Competing interests P.S. is a consultant for DiaTecne s.r.l., manufacturer of a pulse wave analysis system. G.P. declares no competing interests. 1.

Blacher, J., Guerin, A. P., Pannier, B., Marchais, S. J. & London, G. M. Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 38, 938–942 (2001). 2. O’Rourke, M. F. & Safar, M. E. Relationship between aortic stiffening and microvascular disease in brain and kidney: cause and logic of therapy. Hypertension 46, 200–204 (2005). 3. Woodard, T. et al. Mediation analysis of aortic stiffness and renal microvascular function. J. Am. Soc. Nephrol. http://dx.doi.org/10.1681/ ASN.2014050450. 4. Petersen, L. J. et al. The pulsatility index and the resistive index in renal arteries. Association with long-term progression in chronic renal failure. Nephrol. Dial. Transplant. 12, 1376–1380 (1997). 5. Bardelli, M., Jensen, G., Volkmann, R., Caidhal, K. & Aurell, M. Experimental variation in renal vascular resistance in normal man as detected by means of ultrasound. Eur. J. Clin. Invest. 22, 619–624 (1992). 6. Schillaci, G. et al. Relationship between shortterm blood pressure variability and large-artery stiffness in human hypertension: findings from 2 large databases. Hypertension 60, 369–377 (2012). 7. Parati, G., Ochoa, J. E. & Bilo, G. Blood pressure variability, cardiovascular risk, and risk for renal disease progression. Curr. Hypertens. Rep. 14, 421–431 (2012). 8. Amann, K. Media calcification and intima calcification are distinct entities in chronic kidney disease. Clin. J. Am. Soc. Nephrol. 3, 1599–1605 (2008). 9. Chue, C. D., Townend, J. N., Steeds, R. P. & Ferro, C. J. Arterial stiffness in chronic kidney disease: causes and consequences. Heart 96, 817–823 (2010). 10. Salvi, P. Pulse waves. How Vascular Hemodynamics Affects Blood Pressure 17–44 (Springer, 2013).

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