State of the Art

Arterial Stiffness: A Novel Risk Factor for Kidney Injury Progression? Panagiotis I. Georgianos,1 Pantelis A. Sarafidis,2 and Vassilios Liakopoulos1 damage of small intra-renal arterioles. Further, prospective observational studies have shown that reduced aortic compliance is closely associated with the annual rate of renal function decline and represents independent predictor of kidney injury progression to end-stage renal disease among patients with CKD. This article provides insights into the cross-talk between macrocirculation and renal microcirculation and summarizes the currently available clinical evidence linking increased arterial stiffness with kidney disease progression.

Hypertension is the most common chronic disorder worldwide and represents a well-documented risk factor for kidney injury progression and the second more frequent cause of chronic kidney disease (CKD).1,2 In addition, prevalence of CKD follows an increasing trend during the past 2 decades and is currently estimated to affect above 10% of the adult population in both sites of the Atlantic.3 Among hypertensive patients with CKD, increased systolic BP (SBP), reduced diastolic BP (DBP) and elevation in pulse pressure (PP) are typical features of BP profile. This particular pattern of isolated systolic hypertension is indicative of arterial remodeling in CKD, which is characterized by premature vascular ageing and accelerated arterial stiffening.4–6 Arterial stiffness is a long-term process of structural alterations in the viscoelastic properties of biomaterial constituting the media of the aortic wall. These alterations occur from the early stages of renal impairment and are progressed in parallel with renal function decline, leading to arterial enlargement, wall thickening, and hardening. Increased arterial stiffness is considered the main pathogenic mechanism of left ventricular hypertrophy, subendocardial hypo-perfusion, and congestive heart failure.4,5 It is therefore unsurprising that prospective cohort studies have demonstrated that aortic pulse wave velocity (PWV), a direct marker of aortic stiffness, is powerful predictor of all-cause and cardiovascular mortality in several diseased populations,7 including those with CKD.8 Apart from the well-documented effect of arterial stiffness on left ventricular work load, downstream transmission

of increased flow and pressure pulsatility to the level of microcirculation is suggested to play also important role in promoting injury of other susceptible organs.9 This may be of particular importance for kidney injury progression, as unique features of renal microvasculature (i.e., continuous and passive renal perfusion, low input impedance of renal microvessels, reduced wave reflections at the kidney level) make kidneys particularly vulnerable to the damaging effect of excessive pulsatile energy transmission to the glomerulus.9,10 On this basis, earlier studies suggested the presence of an inverse association between aortic PWV and estimated glomerular filtration rate (eGFR) in patients with or without established CKD.11,12 During the past 4 years, prospective cohort studies evaluating “hard” renal endpoints have advanced our knowledge, providing evidence that increased arterial stiffness is closely associated with the annual rate of eGFR decline and is predictor of kidney injury progression to end-stage renal disease (ESRD) requiring dialysis.13–16 This article provides insights into the complex mechanistic background of arterial remodeling in CKD and cross-talk between macrocirculation and renal microcirculation and summarizes the accumulated evidence from observational studies associating arterial stiffness with kidney disease progression.

Correspondence: Panagiotis I. Georgianos ([email protected]).

1Section of Nephrology and Hypertension, 1st Department of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; 2Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Initially submitted December 5, 2014; date of first revision January 3, 2015; accepted for publication January 5, 2015; online publication February 15, 2015.

958  American Journal of Hypertension  28(8)  August 2015

Keywords: arterial stiffness; blood pressure; CKD progression; hypertension; kidney damage; pulsatile pressure. doi:10.1093/ajh/hpv004

PATHOGENESIS OF ARTERIAL STIFFNESS IN CKD

Arteriosclerotic process in CKD is characterized by longterm structural alterations in intrinsic stiffness of biomaterial

© American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: [email protected]

Downloaded from http://ajh.oxfordjournals.org/ at Georgetown University on August 25, 2015

Arterial stiffness is typical feature of vascular remodeling in chronic kidney disease (CKD). Increased arterial stiffness raises flow and pressure pulsatility and is considered the principle pathogenic mechanism of isolated systolic hypertension, left ventricular hypertrophy, and congestive heart failure. Apart from the impact of arterial stiffness on left ventricular afterload, downstream transmission of pressure pulsatility to the level of microcirculation is suggested to promote injury of other susceptible organs. This may be of particular importance for kidney injury progression, since passive renal perfusion along with low resistance and input impedance in renal microvessels make kidneys particularly vulnerable to the damaging effect of systemic pulsatile pressure. Recent studies have provided evidence that arterial stiffness culminates in elevated pulsatility and resistance in renal microvasculature, promoting structural

Arterial Stiffness and Kidney Injury

constituting the arterial wall. These alterations include fibroelastic intimal thickening, calcification of elastic lamellae, increased extracellular matrix deposition, elastynolysis and inflammation, elevated collagen along with reduced elastic fiber content. Although the mechanistic background of arterial stiffening in CKD is complex and not yet fully elucidated, a growing body of evidence from background and clinical studies suggests that a number of traditional and nontraditional CKD-related risk factors, such as impaired mineral metabolism and vascular calcification, overactivity of the renin-angiotensin-system (RAS), endothelial dysfunction, inflammation may play important role in adverse arterial remodeling associated with CKD (Figure 1).

Vascular calcifications, a common complication in CKD, are strongly associated with aortic PWV in kidney disease patients and represent strong and independent predictors of all-cause and cardiovascular mortality.17,18 The calcification process is characterized by osteo/chondrocytic transformation of vascular smooth muscle cells (VSMCs) in the intima or media of arterial wall.19 CKD-related disturbances in mineral metabolism play a pivotal role in all steps of this process, as hyperphosphatemia enhances the apoptosis and osteoblastic differentiation of VSMCs and delays the monocyte/ macrophage transformation into osteoclastic-like cells.18,20 Fibroblast growth factor-23 (FGF-23), a phosphaturic hormone that is elevated from the early stages of CKD to maintain phosphate balance,21 is also suggested to play a direct role in the calcification process.22 This is supported by experimental studies showing that FGF-23 is localized in the cytoplasm of VSMCs, suggesting the possibility of local synthesis at the level of vasculature. In other studies, FGF-23 was isolated from calcified segments of human carotid artery specimens.23 In addition, in experimental models of mice with moderate CKD fed on a high-phosphorus containing diet, levels of FGF-23 (and not levels of serum phosphorus) TRADITIONAL CV RISK FACTORS Age, Hypertension, Dyslipidemia, Obesity, Diabetes, Smoking

Impaired mineral metabolism, Vascular calcifications, RAS, Endothelial dysfunction, ET-1, Inflammation, Oxidative stress

CV RISK FACTORS ASSOCIATED WITH CKD Figure 1.  Factors associated with arterial remodeling and stiffness in CKD.

Overactivity of the RAS

The proliferative, inflammatory, and fibrotic actions of angiotensin II on vasculature is suggested to be another factor involved in pathogenesis of arterial stiffness in CKD. Of note, excessive activation of the RAS is a common feature and major mechanistic pathway of kidney injury progression in patients with CKD.28 Experimental studies have shown that angiotensin II reduces elastin synthesis, enhances collagen formation and deposition and promotes the hypertrophy of VSMCs.29,30 Angiotensin II maybe also involved in the arterial calcification process, as animal studies have shown that angiotensin II can promote the phenotypic transformation of VSMCs to ostoblast-like cells, through up-regulation of the bone morphogenetic protein 2 and osteocalcin.31 In addition, recent animal studies have suggested that blockade of the RAS ameliorates the degradation of elastin and reduces the collagen content of the aortic wall, leading to improvement of arterial stiffness in a BP-independent manner.32 Of major importance, these beneficial actions on arterial wall structure in experimental models were confirmed in several randomized clinical studies showing that pharmacological inhibition of the RAS culminates in regression of arteriosclerotic process in hypertensive patients with or without CKD.33,34 Endothelial dysfunction

Endothelial dysfunction is characterized by increased circulating levels of endothelial microparticles and endothelial cells detached from the vessel wall along with impaired survival and function of endothelial progenitor cells, reflecting an imbalance between endothelial injury and repair.35 Endothelial dysfunction is an early event in the natural course of CKD and is proposed to be another contributing factor to the arteriosclerotic process in these individuals. At the molecular level, endothelin-1, a potent endothelialderived vasoconstrictor that is over-expressed in experimental and human CKD, promotes vascular inflammation through actions on proliferation, migration, and contraction of inflammatory cells and enhances adverse arterial remodeling via stimulation of extracellular matrix components and growth factors.36,37 Apart from the effects on arterial wall structure, other studies have shown that NO-induced changes on tone of VSMCs are functional regulators of local artery stiffness in vivo. In this context, clinical studies have American Journal of Hypertension  28(8)  August 2015  959

Downloaded from http://ajh.oxfordjournals.org/ at Georgetown University on August 25, 2015

Elevated calcium-phosphate product and vascular calcification

were directly associated with development and progression of vascular calcifications.24 Vascular calcification is an active and auto-regulated process, with several factors inducing and other factors opposing it. Important regulators are plasma constituents, such as fetuin-A, osteoprotegerin, osteopontin, and matrix Gla protein; these proteins act as circulating calcification inhibitors, whose role is to maintain minerals in a soluble form and to inhibit their deposition in the vascular tissue.18,20 Recent clinical studies have revealed independent inverse associations between aortic PWV and circulating levels of fetuin-A in kidney disease populations.25–27

Georgianos et al.

revealed the presence of an inverse association between endothelium-dependent flow-mediated vasodilatation at the level of brachial artery and aortic PWV in patients with CKD.38,39 Vascular inflammation

ARTERIAL STIFFNESS: CROSSTALK BETWEEN MACRO- AND MICROCIRCULATION

The main functional role of the aorta and large central arteries is to dampen the high BP oscillations caused by the intermittent left ventricular ejection and to transform the pulsatile blood flow in arteries into the continuous flow pattern required for perfusion of organs and tissues (so-called, arterial cushioning function).5,46 This is achieved through the elastic properties of large arteries, which can accommodate 50% of stroke volume by distending their walls during systole. Ejection of stroke volume from left ventricle to the ascending aorta generates a pulse wave (incident or forwardtraveling) that is propagated across the arterial tree.5,47 The speed of propagation of this wave (i.e., PWV) is directly related to arterial stiffness. This forward-traveling wave is reflected at any point of structural and functional discontinuity of the arterial tree, generating a reflected wave that travels from the periphery back to the aorta. Forward- and 960  American Journal of Hypertension  28(8)  August 2015

Arterial stiffness and renal microcirculation

Renal microcirculation has unique characteristics and differs substantially from other vascular beds. The kidneys are continuously and passively perfused at high flow-volume throughout systole and diastole and their microvascular resistance is very low. Notably, impendence and blood flow patterns at the level of renal microvessels are comparable to those normally seen in other vascular beds during vasodilatation. Further, wave reflections from the kidneys are very low, favoring higher pulsatile energy transmission into the glomerulus.10,50 Although excessive pulsatile energy transmission into the susceptible renal microvasculature has been for long suggested as an important mechanism of progression of kidney damage,11,12 it is only few years that clinical studies using modern hemodynamic and imaging techniques provided evidence on the causal association of arterial stiffness with impaired renal function. In this regard, recent studies conducted in patients with diabetes and/or hypertension have associated aortic PWV with increased renal resistive index (RI), a measure of vascular resistance in small renal vessels.51–53 Other studies showed that the amplitude of the pulse wave reflected at peripheral sites is associated with filtration fraction and urinary albuminto-creatinine-ratio independently from mean arterial

Downloaded from http://ajh.oxfordjournals.org/ at Georgetown University on August 25, 2015

Vascular inflammation is proposed to be another pathogenic mechanism of arteriosclerotic process in CKD. This pathway maybe of particular importance, as in advanced stage CKD, pro-inflammatory and anti-inflammatory cytokines are typically several-fold higher than in other chronic diseases due to both decreased renal clearance and elevated production, resulting in a state of “persistent inflammation.” Vascular inflammation stimulates the cell release of matrix metalloproteinases (MMPs; including MMP-2 and MMP-9), which were shown to modify proteoglycan composition and enhance infiltration of arterial wall by inflammatory cells around the vasa vasorum, causing microvascular ischemia.40,41 Other experiments have shown that macrophage-derived inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-a, and transforming growth factor (TGF)-β enhance the osteoblastic differentiation of VSMCs, promoting in this way the arterial calcification process.42,43 In a recent experimental study, Chang et al. investigated the role of angiopoietin-2, a legend of the Tie-2 receptor, which in addition to angiogenesis plays important regulatory role in several pathophysiological processes, including vascular inflammation.44 In an experimental model of 5/6 nephrectomized mice producing increased levels of angiopoietin-2, this molecule was shown to stimulate endothelial expression of chemokines and adhesion molecules for monocytes, increased the expression of the profibrotic cytokine TGF-β1 in aortic endothelial cells and enhanced the formation and deposition of collagen in the aortic wall.45 In a clinical part of this study involving 416 patients with stage 3–5 CKD, plasma levels of angiopoietin-2 were independently associated with severity of arterial stiffness, as assessed by measuring aortic PWV.45

backward-traveling pulse waves overlap and the final amplitude and shape of the measured wave at any point of the arterial tree is determined by the phase relationship between the separate component waves.5,47 In young subjects with elastic arteries, the arrival of the reflected waves back to the aorta occurs during next diastole; with ageing and in clinical conditions characterized by increased arterial stiffness (such as CKD), the higher PWV results in premature arrival of reflected waves during systole rather than diastole of the next cardiac cycle. This phenomenon leads to aortic pressure augmentation during systole and reduction in aortic pressure during diastole, raising pulsatile component of BP.5,48 The structure of the arterial system is characterized by progressive increase in stiffness from the ascending aorta to the peripheral arterial segments (so-called, stiffness gradient).4,9 This structural characteristic plays a major regulatory role in opposing pulsatile energy transmission from macroto microcirculation. With ageing, aortic stiffness increases preferentially more than rigidity of peripheral musculartype arteries49; in such a case, the arterial stiffness gradient is attenuated and wave reflection sites are now closer to the microcirculation, favoring delivery of pulsatile pressure to the small branches of the arterial tree and promoting endorgan damage.4,9 The arteriolar network is the major site of resistance and reflection of pulse wave and represents the main protective mechanism against transmission of pressure pulsatility to microvasculature. This is attributed to the unique properties of peripheral vascular beds to autoregulate blood perfusion of each organ according to its metabolic requirements. This auto-regulatory mechanism is achieved through vasoconstriction and elevated vascular resistance at the level of the pre-capillary arterioles.4,9

Arterial Stiffness and Kidney Injury ARTERIAL STIFFNESS AND KIDNEY DISEASE PROGRESSION Studies evaluating the association between arterial stiffness and incident CKD/albuminuria in patients with preserved renal function

A number of observational studies aimed to explore the longitudinal association between arterial stiffness and kidney injury progression in patients with preserved renal function at study enrollment (Table  1). Bouchi et  al.13 evaluated prospectively 461 Japanese patients with type 2 diabetes and eGFR 84.2 ml/ min/1.73 m2 for a median follow-up of 5.9  years. The study revealed a significant association of aortic PWV with the annual rate of eGFR decline. Importantly, elevated aortic PWV was associated with 26% higher risk of progression from normo- to microalbuminuria (hazard ratio (HR): 1.26; 95% confidence interval (CI): 1.13–1.41, P 3 ml/min/1.73 m2 per year) and on incident CKD (defined as decrease in eGFR 25% decline in eGFR during follow-up (HR: 1.001; 95% CI: 1.000–1.002 per 1 cm/sec rise in baPWV).66 Further, Su et  al.67 explored the prognostic significance of elevated arterial stiffness on kidney injury progression in 363 Taiwan patients with stage 3–4 CKD. Patients lying within the highest tertile of baseline baPWV had significantly higher annual rate of eGFR reduction than those in the lowest baPWV tertile (-2.68 ± 0.35 vs. +0.86 ± 0.25 ml/ min/1.73 m2/year, P 25% decline in eGFR or initiation of dialysis over 3.1 years of follow-up (HR: 5.93; 95% CI: 2.94–11.99 for the highest vs. lowest baPWV tertile).67 A more detailed overview of arterial remodeling in CKD and its impact on the progression of kidney injury was provided by the Nephrotest cohort study, in which aortic PWV data and carotid stiffness parameters were assessed in 180 patients with stage 3–4 CKD.14 After a mean follow-up period of 3.1 years, stiffness of carotid artery was elevated by 0.28 ± 0.05 m/sec, in contrast to aortic PWV that remained stable over time. Internal diameter of carotid artery was increased, whereas intima-media thickness was significantly reduced during follow-up. Absence of arterial wall thickening in response to the enlarged lumen diameter resulted in a significant elevation of 2.08 ± 0.43 kPa/year in the circumferential wall stress over time. Of note, circumferential tensile stress was shown to be associated with 40% higher risk of incident ESRD during follow-up (HR: 1.40; 95% CI: 1.08–1.83); in contrast, aortic PWV did not provide any prognostic associations with the risk of CKD progression.14 Future studies including measurements of arterial stiffness in the aorta and in more peripheral segments of the arterial tree will be required to confirm this observation.

Downloaded from http://ajh.oxfordjournals.org/ at Georgetown University on August 25, 2015

risk of developing CKD (incidence rate ratio (IRR): 1.39; 95% CI: 1.09–1.77). Brachial PP was associated with both rapid renal function decline (OR: 1.10; 95% CI: 1.04–1.16) and incident CKD (IRR: 1.06; 95% CI: 1.01–1.11).16 In another study including 2,053 middle-aged Japanese employees with normal renal function and absence of albuminuria at study enrollment, Tomiyama et al.60 showed that brachial-ankle PWV (baPWV) was related to higher annual rate of decline in eGFR, whereas each 1 m/sec rise in baPWV was associated with 36% elevated risk of developing CKD during 5.6 years of follow-up (OR: 1.36; 95% CI: 1.09–1.70). In contrast to the above, a prospective analysis of arterial stiffness data obtained from 1,675 third generation offspring participants in the Framingham Heart Study (mean age: 40 years) showed that aortic PWV could not predict the risk of developing CKD over a 7- to 10-year-long observational period (OR: 1.06; 95% CI: 0.89–1.26).61 Aortic PWV exhibited only a modest association with the risk of progression from normo- to microalbuminuria during follow-up in the age- and gender-adjusted models (OR: 1.19; 95% CI: 1.01–1.40), an association that did not persist after adjustment for additional confounding factors (OR: 1.14; 95% CI: 0.94–1.42).61 A  plausible explanation provided by the study investigators for this nonsignificant trend toward higher risk of incident microalbuminuria with increasing arterial stiffness was the low statistical power of this longitudinal analysis. Indeed, the study was reported to have only 30% power to detect an 8% incidence rate for CKD and 34% power to detect a 10% incidence rate for microalbuminuria. Perhaps, the lower age of study subjects resulted in lower than expected occurrence of the outcomes under investigation. The association between arterial stiffness and renal function decline was also investigated in 2 recently published observational studies. In the first, 577 type 2 diabetic patients with mean eGFR 91 ml/min/1.73 m2 were prospectively followed for 12 months; baPWV was inversely associated with the annual change in eGFR and was independent predictor of rapid renal function decline (OR: 1.072; 95% CI: 1.011– 1.136).62 In the second study that included 913 subjects with mean eGFR of 84 ml/min/1.73 m2, both aortic PWV and baPWV were not associated with elevated risk of rapid eGFR decline during a median follow-up of 3.2 years (OR: 1.39; 95% CI: 0.41–4.65 for aortic PWV and OR: 2.51; 95% CI: 0.66– 9.46 for baPWV, respectively).63 In contrast, each 10 mm Hg increment in brachial PP was related to higher incidence of rapid renal function decline throughout the observational period (OR: 1.22; 95% CI: 1.01–1.48).63 It has to be noted, however, that this study followed a retrospective design; thus, the possibility of recording bias cannot be excluded.

Arterial Stiffness and Kidney Injury Table 2.  Studies evaluating the effect of arterial stiffness on kidney injury progression in patients with predialysis CKD Study ID

Population

Arterial stiffness assessment

Follow-up

Outcome

Ford et al.15 Hypertension 2010

133 patients with stage 3–4 CKD

Aortic PWV

Weber et al.64 Am J Hypertens 2011

111 patients with stage 3–4 CKD

AIx, AP

3.6 years Each 10% increase in AIx and each 10 mm Hg rise in AP were associated with 47% and 56% elevated risks of the composite endpoint of doubling of serum creatinine, dialysis or transplantation (HR: 1.474; 95% CI: 1.020–2.030 for AIx and HR: 1.559; 95% CI: 1.015–2.394 for AP)

Chen et al.65 CJASN 2011 145 patients with stage 3–4 CKD

baPWV

1.3 years baPWV was independent predictor of the combined endpoint of >25% decline in eGFR or death (HR: 1.001; 95% CI: 1.000–1.001 for each 1 cm/sec rise in baPWV)

Chen et al.66 Hypertens Res 2011

baPWV

2.6 years baPWV was related to increased risk of >25% decline in eGFR (HR: 1.001; 95% CI: 1.000–1.002 per 1 cm/sec rise in baPWV)

baPWV

3.1 years Patients in the highest baPWV tertile had 5.93 times higher risk of the composite renal outcome of >25% decline in eGFR or dialysis than those in the lowest tertile (HR: 5.93; 95% CI: 2.94–11.99)

Su et al.67 Am J Hypertens 363 patients with stage 3–4 2011 CKD

Briet et al.14 JASN 2011

180 stage 3–4 CKD patients participating in the Nephrotest cohort study

Circumferential wall stress in the common carotid artery

3.1 years Circumferential wall stress was associated with 40% elevated risk of reaching ESRD (HR: 1.40; 95% CI: 1.08–1.83)

Abbreviations: AIx, augmentation index; AP, augmentation pressure; baPWV, brachial-ankle PWV; CI, confidence intervals; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HR, harard ratio; PWV, pulse wave velocity.

CONCLUSION

Although several aspects in the complex pathophysiology of arterial remodeling in CKD still remain unclear, a number of factors related to deterioration of renal function, such as elevated calcium-phosphate product and vascular calcifications, excess activation of the RAS, endothelial dysfunction, persistent vascular inflammation and aggravated oxidative stress, are proposed by background and clinical studies to be important mediators of arteriosclerosis. Arterial stiffness raises flow and pressure pulsatility and impairs cushioning function of the aorta and large central arteries. Downstream transmission of enhanced pressure pulsatility to the level of microcirculation is long considered one major mediator of progression of end-organ damage in hypertension. Recent clinical studies using modern imaging techniques that can approximate intra-renal hemodynamic parameters have shown that increased arterial stiffness may be a major pathway through which excessive pulsatile energy is transmitted to the low-impendence renal microvasculature, causing dynamic constriction of renal resistance vessels and promoting intraglomerular hyper-perfusion. Additional support to the link between arterial stiffness and progression of kidney damage is provided by prospective observational studies consistently showing that aortic PWV is associated with the annual rate of eGFR decline and represents predictor of kidney injury

progression to ESRD requiring dialysis. Together these data suggest that arterial stiffness is not only a powerful cardiovascular risk predictor, but also a novel marker of kidney injury progression. Future studies are urgently warranted to elucidate whether arterial stiffness attenuation represents another therapeutic tool in order to slow the progression of CKD.

ACKNOWLEDGMENTS

The authors report no specific funding in relation to this work. DISCLOSURE

The authors declared no conflict of interest.

REFERENCES 1. Mancia G, Fagard R, Narkiewicz K, Redón J, Zanchetti A, Böhm M, Christiaens T, Cifkova R, De Backer G, Dominiczak A, Galderisi M, Grobbee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ, Nilsson PM, Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B, Zannad F; Task Force Members. 2013 ESH/ESC

American Journal of Hypertension  28(8)  August 2015  963

Downloaded from http://ajh.oxfordjournals.org/ at Georgetown University on August 25, 2015

167 patients with stage 3 CKD

1.5 years Aortic PWV was independently associated with the combined renal outcome of >25% decline in eGFR or dialysis (r = 0.48, P = 0.002)

Georgianos et al.

964  American Journal of Hypertension  28(8)  August 2015

to variation in phosphate intake in healthy volunteers. Kidney Int 2003; 64:2272–2279. 22. Silswal N, Touchberry CD, Daniel DR, McCarthy DL, Zhang S, Andresen J, Stubbs JR, Wacker MJ. FGF23 directly impairs endothelium-dependent vasorelaxation by increasing superoxide levels and reducing nitric oxide bioavailability. Am J Physiol Endocrinol Metab 2014; 307:E426–E436. 23. Voigt M, Fischer DC, Rimpau M, Schareck W, Haffner D. Fibroblast growth factor (FGF)-23 and fetuin-A in calcified carotid atheroma. Histopathology 2010; 56:775–788. 24. El-Abbadi MM, Pai AS, Leaf EM, Yang HY, Bartley BA, Quan KK, Ingalls CM, Liao HW, Giachelli CM. Phosphate feeding induces arterial medial calcification in uremic mice: role of serum phosphorus, fibroblast growth factor-23, and osteopontin. Kidney Int 2009; 75:1297–1307. 25. Hermans MM, Brandenburg V, Ketteler M, Kooman JP, van der Sande FM, Gladziwa U, Rensma PL, Bartelet K, Konings CJ, Hoeks AP, Floege J, Leunissen KM. Study on the relationship of serum fetuin-A concentration with aortic stiffness in patients on dialysis. Nephrol Dial Transplant 2006; 21:1293–1299. 26. Pateinakis P, Papagianni A, Douma S, Efstratiadis G, Memmos D. Associations of fetuin-A and osteoprotegerin with arterial stiffness and early atherosclerosis in chronic hemodialysis patients. BMC Nephrol 2013; 14:122. 27. Raggi P, Bellasi A, Ferramosca E, Islam T, Muntner P, Block GA. Association of pulse wave velocity with vascular and valvular calcification in hemodialysis patients. Kidney Int 2007; 71:802–807. 28. Sarafidis PA, Ruilope LM. Aggressive blood pressure reduction and renin-angiotensin system blockade in chronic kidney disease: time for re-evaluation? Kidney Int 2014; 85:536–546. 29. Benetos A, Levy BI, Lacolley P, Taillard F, Duriez M, Safar ME. Role of angiotensin II and bradykinin on aortic collagen following converting enzyme inhibition in spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol 1997; 17:3196–3201. 30. Touyz RM. Molecular and cellular mechanisms in vascular injury in hypertension: role of angiotensin II. Curr Opin Nephrol Hypertens 2005; 14:125–131. 31. Ng K, Hildreth CM, Avolio AP, Phillips JK. Angiotensin-converting enzyme inhibitor limits pulse-wave velocity and aortic calcification in a rat model of cystic renal disease. Am J Physiol Renal Physiol 2011; 301:F959–F966. 32. Vavrinec P, van Dokkum RP, Goris M, Buikema H, Henning RH. Losartan protects mesenteric arteries from ROS-associated decrease in myogenic constriction following 5/6 nephrectomy. J Renin Angiotensin Aldosterone Syst 2011; 12:184–194. 33. Guerin AP, Blacher J, Pannier B, Marchais SJ, Safar ME, London GM. Impact of aortic stiffness attenuation on survival of patients in endstage renal failure. Circulation 2001; 103:987–992. 34. Mitchell GF, Dunlap ME, Warnica W, Ducharme A, Arnold JM, Tardif JC, Solomon SD, Domanski MJ, Jablonski KA, Rice MM, Pfeffer MA; Prevention of Events With Angiotensin-Converting Enzyme Inhibition Investigators. Long-term trandolapril treatment is associated with reduced aortic stiffness: the prevention of events with angiotensin-converting enzyme inhibition hemodynamic substudy. Hypertension 2007; 49:1271–1277. 35. Brunet P, Gondouin B, Duval-Sabatier A, Dou L, Cerini C, DignatGeorge F, Jourde-Chiche N, Argiles A, Burtey S. Does uremia cause vascular dysfunction? Kidney Blood Press Res 2011; 34:284–290. 36. Bouallegue A, Daou GB, Srivastava AK. Endothelin-1-induced signaling pathways in vascular smooth muscle cells. Curr Vasc Pharmacol 2007; 5:45–52. 37. Ivey ME, Osman N, Little PJ. Endothelin-1 signalling in vascular smooth muscle: pathways controlling cellular functions associated with atherosclerosis. Atherosclerosis 2008; 199:237–247. 38. Verbeke FH, Agharazii M, Boutouyrie P, Pannier B, Guérin AP, London GM. Local shear stress and brachial artery functions in end-stage renal disease. J Am Soc Nephrol 2007; 18:621–628. 39. Verbeke FH, Pannier B, Guérin AP, Boutouyrie P, Laurent S, London GM. Flow-mediated vasodilation in end-stage renal disease. Clin J Am Soc Nephrol 2011; 6:2009–2015. 40. Roman MJ, Devereux RB, Schwartz JE, Lockshin MD, Paget SA, Davis A, Crow MK, Sammaritano L, Levine DM, Shankar BA, Moeller E, Salmon JE. Arterial stiffness in chronic inflammatory diseases. Hypertension 2005; 46:194–199.

Downloaded from http://ajh.oxfordjournals.org/ at Georgetown University on August 25, 2015

Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2013; 31:1281–1357. 2. Wheeler DC, Becker GJ. Summary of KDIGO guideline. What do we really know about management of blood pressure in patients with chronic kidney disease? Kidney Int 2013; 83:377–383. 3. Kidney Disease Outcomes Quality Initiative (K/DOQI). K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis 2004; 43:S1–S290. 4. Briet M, Pierre B, Laurent S, London GM. Arterial stiffness and pulse pressure in CKD and ESRD. Kidney Int 2012; 82:388–400. 5. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, Pannier B, Vlachopoulos C, Wilkinson I, Struijker-Boudier H. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 2006; 27:2588–2605. 6. Wallace SM, Yasmin, McEniery CM, Mäki-Petäjä KM, Booth AD, Cockcroft JR, Wilkinson IB. Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Hypertension 2007; 50:228–233. 7. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol 2010; 55:1318–1327. 8. Georgianos PI, Sarafidis PA, Lasaridis AN. Arterial stiffness: a novel cardiovascular risk factor in kidney disease patients. Curr Vasc Pharmacol, published online 3 September 2013 (doi:10.2174/157016111131199901 47). 9. Safar ME, Nilsson PM, Blacher J, Mimran A. Pulse pressure, arterial stiffness, and end-organ damage. Curr Hypertens Rep 2012; 14:339–344. 10. O’Rourke MF, Safar ME. Relationship between aortic stiffening and microvascular disease in brain and kidney: cause and logic of therapy. Hypertension 2005; 46:200–204. 11. Mourad JJ, Pannier B, Blacher J, Rudnichi A, Benetos A, London GM, Safar ME. Creatinine clearance, pulse wave velocity, carotid compliance and essential hypertension. Kidney Int 2001; 59:1834–1841. 12. Townsend RR, Wimmer NJ, Chirinos JA, Parsa A, Weir M, Perumal K, Lash JP, Chen J, Steigerwalt SP, Flack J, Go AS, Rafey M, Rahman M, Sheridan A, Gadegbeku CA, Robinson NA, Joffe M. Aortic PWV in chronic kidney disease: a CRIC ancillary study. Am J Hypertens 2010; 23:282–289. 13. Bouchi R, Babazono T, Mugishima M, Yoshida N, Nyumura I, Toya K, Hanai K, Tanaka N, Ishii A, Uchigata Y, Iwamoto Y. Arterial stiffness is associated with incident albuminuria and decreased glomerular filtration rate in type 2 diabetic patients. Diabetes Care 2011; 34:2570–2575. 14. Briet M, Collin C, Karras A, Laurent S, Bozec E, Jacquot C, Stengel B, Houillier P, Froissart M, Boutouyrie P. Arterial remodeling associates with CKD progression. J Am Soc Nephrol 2011; 22:967–974. 15. Ford ML, Tomlinson LA, Chapman TP, Rajkumar C, Holt SG. Aortic stiffness is independently associated with rate of renal function decline in chronic kidney disease stages 3 and 4. Hypertension 2010; 55:1110–1115. 16. Madero M, Peralta C, Katz R, Canada R, Fried L, Najjar S, Shlipak M, Simonsick E, Lakatta E, Patel K, Rifkin D, Hawkins M, Newman A, Sarnak M. Association of arterial rigidity with incident kidney disease and kidney function decline: the Health ABC study. Clin J Am Soc Nephrol 2013; 8:424–433. 17. Haydar AA, Covic A, Colhoun H, Rubens M, Goldsmith DJ. Coronary artery calcification and aortic pulse wave velocity in chronic kidney disease patients. Kidney Int 2004; 65:1790–1794. 18. London GM, Guérin AP, Marchais SJ, Métivier F, Pannier B, Adda H. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 2003; 18:1731–1740. 19. Ng K, Hildreth CM, Phillips JK, Avolio AP. Aortic stiffness is associated with vascular calcification and remodeling in a chronic kidney disease rat model. Am J Physiol Renal Physiol 2011; 300:F1431–F1436. 20. Briet M, Burns KD. Chronic kidney disease and vascular remodelling: molecular mechanisms and clinical implications. Clin Sci (Lond) 2012; 123:399–416. 21. Larsson T, Nisbeth U, Ljunggren O, Jüppner H, Jonsson KB. Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response

Arterial Stiffness and Kidney Injury 55. Woodard T, Sigurdsson S, Gotal JD, Torjesen AA, Inker LA, Aspelund T, Eiriksdottir G, Gudnason V, Harris TB, Launer LJ, Levey AS, Mitchell GF: Mediation analysis of aortic stiffness and renal microvascular function. J Am Soc Nephrol, published online 7 October 2014 (doi:ASN.2014050450). 56. Bidani AK, Griffin KA, Williamson G, Wang X, Loutzenhiser R. Protective importance of the myogenic response in the renal circulation. Hypertension 2009; 54:393–398. 57. Christensen PK, Hansen HP, Parving HH. Impaired autoregulation of GFR in hypertensive non-insulin dependent diabetic patients. Kidney Int 1997; 52:1369–1374. 58. Hill GS, Heudes D, Bariéty J. Morphometric study of arterioles and glomeruli in the aging kidney suggests focal loss of autoregulation. Kidney Int 2003; 63:1027–1036. 59. Palmer BF. Disturbances in renal autoregulation and the susceptibility to hypertension-induced chronic kidney disease. Am J Med Sci 2004; 328:330–343. 60. Upadhyay A, Hwang SJ, Mitchell GF, Vasan RS, Vita JA, Stantchev PI, Meigs JB, Larson MG, Levy D, Benjamin EJ, Fox CS. Arterial stiffness in mild-to-moderate CKD. J Am Soc Nephrol 2009; 20:2044–2053. 61. Tomiyama H, Tanaka H, Hashimoto H, Matsumoto C, Odaira M, Yamada J, Yoshida M, Shiina K, Nagata M, Yamashina A. Arterial stiffness and declines in individuals with normal renal function/early chronic kidney disease. Atherosclerosis 2010; 212:345–350. 62. Sheen YJ, Lin JL, Li TC, Bau CT, Sheu WH. Peripheral arterial stiffness is independently associated with a rapid decline in estimated glomerular filtration rate in patients with type 2 diabetes. Biomed Res Int 2013; 2013:309294. 63. Kim CS, Kim HY, Kang YU, Choi JS, Bae EH, Ma SK, Kim SW. Association of pulse wave velocity and pulse pressure with decline in kidney function. J Clin Hypertens (Greenwich) 2014; 16:372–377. 64. Weber T, Ammer M, Gündüz D, Bruckenberger P, Eber B, Wallner M. Association of increased arterial wave reflections with decline in renal function in chronic kidney disease stages 3 and 4. Am J Hypertens 2011; 24:762–769. 65. Chen SC, Chang JM, Liu WC, Tsai YC, Tsai JC, Hsu PC, Lin TH, Lin MY, Su HM, Hwang SJ, Chen HC. Brachial-ankle pulse wave velocity and rate of renal function decline and mortality in chronic kidney disease. Clin J Am Soc Nephrol 2011; 6:724–732. 66. Chen SC, Lin TH, Hsu PC, Chang JM, Lee CS, Tsai WC, Su HM, Voon WC, Chen HC. Impaired left ventricular systolic function and increased brachial-ankle pulse-wave velocity are independently associated with rapid renal function progression. Hypertens Res 2011; 34:1052–1058. 67. Su HM, Lin TH, Hsu PC, Chu CY, Lee WH, Tsai WC, Chen SC, Voon WC, Lai WT, Sheu SH. Brachial-ankle pulse wave velocity and systolic time intervals in risk stratification for progression of renal function decline. Am J Hypertens 2012; 25:1002–1010.

American Journal of Hypertension  28(8)  August 2015  965

Downloaded from http://ajh.oxfordjournals.org/ at Georgetown University on August 25, 2015

41. Vlachopoulos C, Dima I, Aznaouridis K, Vasiliadou C, Ioakeimidis N, Aggeli C, Toutouza M, Stefanadis C. Acute systemic inflammation increases arterial stiffness and decreases wave reflections in healthy individuals. Circulation 2005; 112:2193–2200. 42. Shao JS, Cheng SL, Sadhu J, Towler DA. Inflammation and the osteogenic regulation of vascular calcification: a review and perspective. Hypertension 2010; 55:579–592. 43. Tintut Y, Patel J, Parhami F, Demer LL. Tumor necrosis factor-alpha promotes in vitro calcification of vascular cells via the cAMP pathway. Circulation 2000; 102:2636–2642. 44. Fiedler U, Reiss Y, Scharpfenecker M, Grunow V, Koidl S, Thurston G, Gale NW, Witzenrath M, Rosseau S, Suttorp N, Sobke A, Herrmann M, Preissner KT, Vajkoczy P, Augustin HG. Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med 2006; 12:235–239. 45. Chang FC, Chiang WC, Tsai MH, Chou YH, Pan SY, Chang YT, Yeh PY, Chen YT, Chiang CK, Chen YM, Chu TS, Wu KD, Lin SL. Angiopoietin-2-induced arterial stiffness in CKD. J Am Soc Nephrol 2014; 25:1198–1209. 46. London GM, Pannier B. Arterial functions: how to interpret the complex physiology. Nephrol Dial Transplant 2010; 25:3815–3823. 47. O’Rourke MF. Wave travel and reflection in the arterial system. J Hypertens Suppl 1999; 17:S45–S47. 48. Nichols WW, Denardo SJ, Wilkinson IB, McEniery CM, Cockcroft J, O’Rourke MF. Effects of arterial stiffness, pulse wave velocity, and wave reflections on the central aortic pressure waveform. J Clin Hypertens (Greenwich) 2008; 10:295–303. 49. Kimoto E, Shoji T, Shinohara K, Inaba M, Okuno Y, Miki T, Koyama H, Emoto M, Nishizawa Y. Preferential stiffening of central over peripheral arteries in type 2 diabetes. Diabetes 2003; 52:448–452. 50. Safar ME, London GM, Plante GE. Arterial stiffness and kidney function. Hypertension 2004; 43:163–168. 51. Calabia J, Torguet P, Garcia I, Martin N, Mate G, Marin A, Molina C, Valles M. The relationship between renal resistive index, arterial stiffness, and atherosclerotic burden: the link between macrocirculation and microcirculation. J Clin Hypertens (Greenwich) 2014; 16:186–191. 52. Liu CS, Pi-Sunyer FX, Li CI, Davidson LE, Li TC, Chen W, Lin CC, Huang CY, Lin WY. Albuminuria is strongly associated with arterial stiffness, especially in diabetic or hypertensive subjects—a population-based study (Taichung Community Health Study, TCHS). Atherosclerosis 2010; 211:315–321. 53. Weir MR, Townsend RR, Fink JC, Teal V, Anderson C, Appel L, Chen J, He J, Litbarg N, Ojo A, Rahman M, Rosen L, Sozio SM, Steigerwalt S, Strauss L, Joffe MM. Hemodynamic correlates of proteinuria in chronic kidney disease. Clin J Am Soc Nephrol 2011; 6:2403–2410. 54. Fesler P, du Cailar G, Ribstein J, Mimran A. Glomerular hemodynamics and arterial function in normal individuals. J Hypertens 2010; 28:2462–2467.

Arterial Stiffness: A Novel Risk Factor for Kidney Injury Progression?

Arterial stiffness is typical feature of vascular remodeling in chronic kidney disease (CKD). Increased arterial stiffness raises flow and pressure pu...
526KB Sizes 2 Downloads 6 Views