REVIEW URRENT C OPINION
Arterial stiffness in chronic kidney disease: an update Maarten W. Taal
Purpose of review Epidemiological studies have established arterial stiffness as an important risk factor for cardiovascular events and mortality in people with chronic kidney disease (CKD) at all stages. Although much has been learned about the mechanisms that lead to arterial stiffening in CKD, many questions remain unanswered and the optimal interventions for attenuating arterial stiffness remain to be determined. Recent findings Recent data have confirmed the value of arterial stiffness as a predictor of both cardiovascular and renal risk. Advanced glycation end-product accumulation and chronic cytomegalovirus infection have been identified as novel potential contributors to arterial stiffening, but fibroblast growth factor 23 has not. Genetic studies suggest that the association between chronic kidney and cardiovascular disease is a result of clinical and environmental rather than genetic factors. Treatment with angiotensin-converting enzyme inhibitor or aldosterone inhibitor improves arterial stiffness in association with lowering blood pressure, but several potential novel interventions for reducing arterial stiffness await further investigation. Summary Arterial stiffness is increasingly recognized as an important potentially modifiable measure of subclinical vascular disease in people with CKD. The introduction of arterial stiffness into routine practice awaits research focussed on including pulse wave velocity in renal and cardiovascular risk prediction tools, as well as interventions for ameliorating arterial stiffness. Keywords arterial stiffness, chronic kidney disease, pulse wave velocity
INTRODUCTION The recognition that chronic kidney disease (CKD) is associated with a substantially increased risk of cardiovascular disease (CVD), which, in the majority of cases, exceeds the risk of progression to end-stage kidney disease (ESKD), has prompted a search for mechanisms that mediate this association and interventions that may abrogate the risk. Studies to date have revealed that although occlusive atherosclerotic arterial disease undoubtedly occurs, the CVD associated with CKD is characterized by arteriosclerosis resulting in arterial stiffness (assessed as the pressure required to achieve a unit increase in volume) that provokes structural heart disease. Aortic stiffening exposes the left ventricle to greater systolic pressures, leading to ventricular hypertrophy and fibrosis that may progress to cardiac failure. In addition, stiffening of the normally elastic aorta and large arteries results in loss of the essential buffering function that dampens the fluctuations in blood pressure (BP) associated with ventricular ejection. Thus, arterial stiffness results in greater
transmission of fluctuations in pressure and exposure of smaller arteries in the brain and kidneys to higher systolic blood pressure. This in turn may provoke microvascular damage in the brain and kidneys [1]. Arterial stiffness resulting from CKD may, therefore, also contribute to the progression of CKD, as suggested by some [2,3] but not all previous studies [4]. Early research explored multiple methods for assessing arterial stiffness and led to a consensus that aortic pulse wave velocity (PWV) should be regarded as the ‘gold standard’ [5 ]. Several studies have confirmed that increased PWV is an independent risk factor for cardiovascular events and &
Department of Renal Medicine, Royal Derby Hospital, Derby, UK Correspondence to Maarten W. Taal, Department of Renal Medicine, Royal Derby Hospital, Uttoxeter Road, Derby, Derbyshire, DE22 3NE, UK. Tel: +44 1332 789344; fax: +44 1332 789352; e-mail: maarten. [email protected] Curr Opin Nephrol Hypertens 2014, 23:169–173 DOI:10.1097/01.mnh.0000441153.40072.e0
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KEY POINTS Arterial stiffness is a predictor of both cardiovascular events and kidney disease progression. Advanced glycation end-product accumulation and chronic cytomegalovirus infection have been identified as novel potential contributors to arterial stiffening, but FGF23 has not. Genetic studies suggest that the association between chronic kidney and cardiovascular disease is a result of clinical and environmental rather than genetic factors. Before PWV measurements can be recommended for routine clinical practice, further evidence is required to confirm the ability of new more convenient methods to predict long-term outcomes as well as specific interventions to improve arterial stiffness. Future research should focus on including PWV in renal and cardiovascular risk prediction tools as well as interventions for ameliorating arterial stiffness.
mortality in populations with and without CKD [1]. Measurement of PWV was previously limited by the equipment available, which required an applanation tonometry probe to be placed simultaneously on the carotid and femoral arteries. Though well validated as a predictor of outcomes, this method is operator dependent, time consuming and causes potential discomfort to patients because of the need to expose the groin area. Newer devices use automated cuffs placed around the neck and mid-thigh [6] or derive aortic PWV from an oscillometric measurement of the brachial artery waveform [7]. These methods are much quicker to use, operator independent and more convenient for patients, making them more suitable for routine clinical use. However, large long-term studies are required to confirm that these newer methods perform equally well as predictors of adverse cardiovascular outcomes. Although much has been learned about the mechanisms that lead to arterial stiffening in CKD, many questions remain unanswered and the optimal interventions for attenuating arterial stiffness remain to be determined. Whether or not the measurement of PWV should be introduced into routine clinical practice also remains to be determined. In this article, we will review recent progress in these important areas.
ARTERIAL STIFFNESS AS A RISK FACTOR IN CHRONIC KIDNEY DISEASE Several epidemiological studies have established PWV as an important risk factor for cardiovascular 170
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events and mortality in people with CKD at all stages. A recent analysis of data from the NephroTest study confirmed that PWV was an independent predictor of all-cause mortality and fatal or nonfatal cardiovascular events in 439 people with CKD stages 3–5. Moreover, in a model employing hypothetical patients, the addition of PWV to traditional risk factors (age, systolic and diastolic blood pressure, history of cardiovascular events, diabetes, dyslipidaemia and smoking) significantly improved the stratification of risk for all-cause mortality [8]. One recent study has confirmed that higher PWV also predicts cardiovascular risk in kidney transplant recipients. In a cohort of 253 incident kidney transplant recipients, both aortic calcification and PWV (subgroup of n ¼ 115) were independent risk factors for subsequent cardiovascular events after a mean follow-up of 36 months [9]. Early reports regarding the role of arterial stiffness as a risk factor for the progression of CKD were derived from small or short-duration studies, but these observations have recently been confirmed in two large, prospective cohorts. In one analysis of data from 4853 adults without CKD or CVD at baseline recruited into the Multi-Ethnic Study of Atherosclerosis (MESA), higher pulse pressure (a measure of arterial stiffness) and lower arterial elasticity were each independently associated with a greater decline in estimated glomerular filtration rate (eGFR) over 5 years of followup (but flow-mediated dilation, a measure of endothelial function, was not) [10 ]. Similarly, in 2129 older people (age 70–79 years) included in the Health, Aging and Body Composition study, higher pulse pressure was independently associated with a more rapid decline in eGFR (derived from serum cystatin C) and an increased risk of incident CKD, whereas higher PWV was independently associated with an increased risk of incident CKD only [11 ]. There is now, therefore, a substantial body of evidence confirming that arterial stiffness is a risk factor both for CVD and progressive GFR decline in people with CKD. Further research is required to develop comprehensive renal and cardiovascular risk prediction tools for people with CKD that include PWV. &&
&&
PATHOGENESIS OF ARTERIAL STIFFNESS IN CHRONIC KIDNEY DISEASE Previous research has identified multiple factors that contribute to the pathogenesis of arterial stiffness, including reduced elastin and increased collagen in the medial layer, calcification and hypertrophy of vascular smooth muscle cells (VSMCs; Fig. 1) [1]. Recent efforts have focussed on identifying any additional factors that may account for the link between CKD and arterial stiffness. Volume 23 Number 2 March 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Arterial stiffness in chronic kidney disease: an update Taal
Alterations of extracellular matrix Ageing
Diet AGEs RAAS
Chronic kidney disease
Inflammation
CKD-MBD, PO4
Uraemic toxins
Arterial stiffness
Vascular calcification
Endothelial dysfunction
FIGURE 1. The multiple mechanisms whereby chronic kidney disease may provoke or accelerate the development of arterial stiffness. AGEs, advanced glycation end-products; CKD-MBD, chronic kidney disease-mineral bone disorder; PO4, phosphate; RAAS, renin–angiotensin–aldosterone system. Reproduced from [1].
Chronic kidney disease-mineral bone disorder (CKD-MBD) has for several years been recognized as an important cause of vascular calcification associated with CKD. Fibroblast growth factor (FGF) 23, recently identified as an important phosphaturic hormone that becomes elevated early in the course of CKD to maintain phosphate balance, has been reported as an independent predictor of all-cause mortality in people with CKD, but one study found no association between FGF23 levels and coronary or aortic calcification in 1501 people with CKD [12 ], and other studies have reported no association with arterial stiffness [13,14]. We have recently also found no association between PWV and FGF23 concentration in a cohort of 1664 people with CKD in the Renal Risk in Derby (RRID) study (unpublished observation). Further studies suggest that the association between FGF23 and mortality in CKD may be because of an effect of FGF23 on promoting left ventricular hypertrophy rather than arterial stiffness [15]. Nevertheless, other mediators in the pathogenesis of CKD-MBD have been associated with arterial stiffness. Serum phosphate correlated with PWV in a mouse model of CKD [16], and high serum phosphate was independently associated with high ankle brachial index, a marker of peripheral arterial stiffness in 1370 people recruited into MESA with and without CKD [17]. Decreased levels of soluble Klotho, the co-receptor for FGF23, were associated with higher PWV in 114 people with CKD [18]. Decreased levels of fetuin A, an endogenous inhibitor of calcification, and increased osteoprotegerin, an antiosteoclastic factor, were independently &
associated with higher PWV in 81 people requiring haemodialysis [19]. Advanced glycation end-products (AGEs) accumulate in people with CKD and have been proposed as a marker of cumulative metabolic stress. Skin AGE accumulation, assessed clinically by measuring skin autofluorescence, is independently associated with all-cause and cardiovascular mortality in people receiving haemodialysis [20,21 ]. AGE accumulation is associated with cross-linking of extracellular proteins, which may play a role in the pathogenesis of arterial stiffness. In support of this hypothesis, skin autofluorescence was found to correlate with PWV, independent of age, in 120 people receiving haemodialysis in Japan [22]. In the RRID study, we found a correlation between skin autofluorescence and PWV in univariate but not multivariable analysis among people with CKD stage 3 [23], and an independent association was observed in multivariable analysis in a subgroup of those with CKD and diabetes [24]. Other investigators have found an independent association between the magnitude of increase in PWV over 12 months and the baseline levels of serum pentosidine (an AGE molecule) in 109 people on haemodialysis [25], and an association between serum autofluorescence (a measure of serum AGEs) and PWV in univariate but not multivariable analysis [26]. More detailed studies in larger study populations are required to further explore the relationship between AGE accumulation in CKD and arterial stiffness. An association between chronic infections and cardiovascular risk has been proposed, but data have been inconsistent. One candidate is cytomegalovirus (CMV), a common herpes virus that causes chronic subclinical infection and is widely prevalent in humans. Seropositivity for CMV has been associated with increased cardiovascular risk in some but not all studies. Associations have also been reported between CMV seropositivity and carotid artery distensibility. One recent study, examined the relationship between CMV status and PWV in 215 people with CKD stages 2–4 and found that CMV seropositivity was an independent determinant of higher PWV as well as lower proximal descending and distal aortic distensibility [27 ]. The authors hypothesize that chronic CMV infection may increase the arterial stiffness by modifying VSMC function and causing inflammation and fibrosis in the media of arteries. The close association between CKD and CVD has prompted a search for genetic factors that may predispose people to both diseases. In an analysis that combined data from several large studies, investigators sought to identify single-nucleotide polymorphisms (SNPs) associated with clinical
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&
&
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Clinical nephrology
markers of both CVD (including PWV) and CKD. Overall, there was little overlap between SNPs for CKD and CVD (though one locus associated with both was identified), suggesting that environmental and clinical factors are primarily responsible for the association, either by a direct causal link or through a common causal pathway [28 ]. &&
THERAPY TO ATTENUATE ARTERIAL STIFFNESS Arterial hypertension is closely associated with arterial stiffness and it is, therefore, difficult to separate the antihypertensive effects of drugs from their effect on arterial stiffness. However, in one observational study, failure to achieve a reduction in PWV with BP lowering was an independent determinant of all-cause and cardiovascular mortality in people receiving haemodialysis, suggesting a BP-independent component [29]. The renin–angiotensin system has been implicated in the pathogenesis of arterial stiffness and treatment with an angiotensinconverting enzyme inhibitor (ACEI) attenuates this [30]. Aldosterone also promotes arterial stiffness and aldosterone levels may remain elevated despite treatment with an ACEI or angiotensin receptor blocker (ARB). One randomized trial of the aldosterone antagonist spironolactone added to ACEI or ARB treatment in people with CKD stages 2–3 reported a reduction in PWV and left ventricular hypertrophy, but this was also associated with a reduction in systolic blood pressure [31]. A small trial of a newer selective aldosterone antagonist, eplerenone, failed to show a benefit in reducing the arterial stiffness, but was underpowered [32]. Further trials are, therefore, required to determine whether aldosterone antagonism improves arterial stiffness independent of the BP. The focus on CKD-MBD as a contributor to the pathogenesis of arterial stiffness has prompted several studies to examine the effect of phosphate binders. Despite a reduction in PWV observed with sevelamer treatment in a mouse model [33], relatively small randomized trials have not observed a reduction in PWV associated with phosphate binder treatment, either with sevelamer [34] or lanthanum carbonate [35]. On the basis of our current understanding of the pathogenesis of arterial stiffness, several further treatment options remain to be explored, including matrix metalloproteinase inhibitors to reduce elastin breakdown, dietary AGE restriction or AGE cross-link breakers to reduce AGE accumulation, endothelin antagonists, anti-inflammatory agents and interventions to improve endothelial function. 172
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CONCLUSION Recent data have confirmed the value of arterial stiffness as a predictor of both cardiovascular and renal risk. AGE accumulation and chronic CMV infection have been identified as novel contributors to arterial stiffening, but FGF23 has not. Treatment with ACEI or aldosterone inhibitors improves arterial stiffness in association with BP lowering, but several potential novel interventions await further investigation. The question of whether to introduce PWV measurement into routine clinical practice remains unanswered. Equipment is now available to allow quick, convenient measurements to be made, but long-term studies are required to confirm that PWV measured by these methods is also reliable as a predictor of adverse outcomes. Furthermore, we currently lack evidence for specific treatments to reduce arterial stiffness independent of BP. Therefore future research should focus on including PWV in renal and cardiovascular risk prediction tools as well as interventions for ameliorating arterial stiffness. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Chue CD, Townend JN, Steeds RP, Ferro CJ. Arterial stiffness in chronic kidney disease: causes and consequences. Heart 2010; 96:817– 823. 2. Taal MW, Sigrist MK, Fakis A, et al. Markers of arterial stiffness are risk factors for progression to end-stage renal disease among patients with chronic kidney disease stages 4 and 5. Nephron Clin Pract 2007; 107:c177–c181. 3. Ford ML, Tomlinson LA, Chapman TP, et al. Aortic stiffness is independently associated with rate of renal function decline in chronic kidney disease stages 3 and 4. Hypertension 2010; 55:1110–1115. 4. Chue CD, Edwards NC, Davis L J, et al. Serum phosphate but not pulse wave velocity predicts decline in renal function in patients with early chronic kidney disease. Nephrol Dial Transplant 2011; 26:2576– 2582. 5. Tomlinson L A. Methods for assessing arterial stiffness: technical considera& tions. Curr Opin Nephrol Hypertens 2012; 21:655–660. A comprehensive review discussing important technical aspects of arterial stiffness assessment. 6. Hickson SS, Butlin M, Broad J, et al. Validity and repeatability of the Vicorder apparatus: a comparison with the SphygmoCor device. Hypertens Res 2009; 32:1079–1085. 7. Baulmann J, Schillings U, Rickert S, et al. A new oscillometric method for assessment of arterial stiffness: comparison with tonometric and piezoelectronic methods. J Hypertens 2008; 26:523–528. 8. Karras A, Haymann JP, Bozec E, et al. Large artery stiffening and remodeling are independently associated with all-cause mortality and cardiovascular events in chronic kidney disease. Hypertension 2012; 60:1451– 1457. 9. Claes KJ, Heye S, Bammens B, et al. Aortic calcifications and arterial stiffness as predictors of cardiovascular events in incident renal transplant recipients. Transpl Int 2013; 26:973–981.
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Arterial stiffness in chronic kidney disease: an update Taal 10. Peralta CA, Jacobs DR Jr, Katz R, et al. Association of pulse pressure, arterial elasticity, and endothelial function with kidney function decline among adults with estimated GFR >60 mL/min/1.73 m(2): the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Kidney Dis 2012; 59:41–49. A large cohort study showing that measures of arterial stiffness are independently associated with a greater decline in eGFR over 5 years. 11. Madero M, Peralta C, Katz R, et al. 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. A large cohort study in older people showing that markers of arterial stiffness were independently asociated with rapid GFR decline and increased risk of incident CKD. 12. Scialla JJ, Lau WL, Reilly MP, et al. Fibroblast growth factor 23 is not & associated with and does not induce arterial calcification. Kidney Int 2013; 83:1159–1168. An important negative study reporting that FGF23 is not associated with arterial calcification in vitro or in clinical observations. 13. Desjardins L, Liabeuf S, Renard C, et al. FGF23 is independently associated with vascular calcification but not bone mineral density in patients at various CKD stages. Osteoporos Int 2012; 23:2017–2025. 14. Houston J, Smith K, Isakova T, et al. Associations of dietary phosphorus intake, urinary phosphate excretion, and fibroblast growth factor 23 with vascular stiffness in chronic kidney disease. J Ren Nutr 2013; 23:12–20. 15. Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest 2011; 121:4393–4408. 16. Six I, Maizel J, Barreto FC, et al. Effects of phosphate on vascular function under normal conditions and influence of the uraemic state. Cardiovasc Res 2012; 96:130–139. 17. Ix JH, De Boer IH, Peralta CA, et al. Serum phosphorus concentrations and arterial stiffness among individuals with normal kidney function to moderate kidney disease in MESA. Clin J Am Soc Nephrol 2009; 4:609–615. 18. Kitagawa M, Sugiyama H, Morinaga H, et al. A decreased level of serum soluble Klotho is an independent biomarker associated with arterial stiffness in patients with chronic kidney disease. PLoS One 2013; 8:e56695. 19. Pateinakis P, Papagianni A, Douma S, et al. Associations of fetuin-A and osteoprotegerin with arterial stiffness and early atherosclerosis in chronic hemodialysis patients. BMC Nephrol 2013; 14:122. 20. Meerwaldt R, Hartog JW, Graaff R, et al. Skin autofluorescence, a measure of cumulative metabolic stress and advanced glycation end products, predicts mortality in hemodialysis patients. J Am Soc Nephrol 2005; 16:3687– 3693. 21. Arsov S, Trajceska L, van Oeveren W, et al. Increase in skin autofluorescence & and release of heart-type fatty acid binding protein in plasma predicts mortality of hemodialysis patients. Artif Organs 2013; 37:E114–E122. Recent observations confirming that skin autofluorescence predicts mortality in people on haemodialysis. &&
22. Ueno H, Koyama H, Tanaka S, et al. Skin autofluorescence, a marker for advanced glycation end product accumulation, is associated with arterial stiffness in patients with end-stage renal disease. Metabolism 2008; 57:1452–1457. 23. McIntyre NJ, Fluck RJ, McIntyre CW, et al. Determinants of arterial stiffness in chronic kidney disease stage 3. PLoS One 2013; 8:e55444. 24. McIntyre NJ, Fluck RJ, McIntyre CW, Taal MW. Skin autofluorescence and the association with renal and cardiovascular risk factors in chronic kidney disease stage 3. Clin J Am Soc Nephrol 2011; 6:2356–2363. 25. Utescu MS, Couture V, Mac-Way F, et al. Determinants of progression of aortic stiffness in hemodialysis patients: a prospective longitudinal study. Hypertension 2013; 62:154–160. 26. Strozecki P, Kurowski R, Flisinski M, et al. Advanced glycation end products and arterial stiffness in diabetic and nondiabetic patients with chronic kidney disease. Pol Arch Med Wewn 2013; 123:609–616. 27. Wall NA, Chue CD, Edwards NC, et al. Cytomegalovirus seropositivity is & associated with increased arterial stiffness in patients with chronic kidney disease. PLoS One 2013; 8:e55686. An interesting study presenting evidence that chronic CMV infection may contribute to the development of arterial stiffness in people with CKD. 28. Olden M, Teumer A, Bochud M, et al. Overlap between common genetic && polymorphisms underpinning kidney traits and cardiovascular disease phenotypes: the CKDGen consortium. Am J Kidney Dis 2013; 61:889–898. Important observations from the combined data of several large genetic studies showing that the association between chronic kidney and cardiovascular disease is a result of clinical and environmental rather than genetic factors. 29. Guerin AP, Blacher J, Pannier B, et al. Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure. Circulation 2001; 103:987– 992. 30. Mitchell GF, Dunlap ME, Warnica W, et al. 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. 31. Edwards NC, Steeds RP, Stewart PM, et al. Effect of spironolactone on left ventricular mass and aortic stiffness in early-stage chronic kidney disease: a randomized controlled trial. J Am Coll Cardiol 2009; 54:505–512. 32. Boesby L, Elung-Jensen T, Strandgaard S, Kamper AL. Eplerenone attenuates pulse wave reflection in chronic kidney disease stage 3–4 – a randomized controlled study. PLoS One 2013; 8:e64549. 33. Maizel J, Six I, Dupont S, et al. Effects of sevelamer treatment on cardiovascular abnormalities in mice with chronic renal failure. Kidney Int 2013; 84:491–500. 34. Chue CD, Townend JN, Moody WE, et al. Cardiovascular effects of sevelamer in stage 3 CKD. J Am Soc Nephrol 2013; 24:842–852. 35. Seifert ME, de las Fuentes L, Rothstein M, et al. Effects of phosphate binder therapy on vascular stiffness in early-stage chronic kidney disease. Am J Nephrol 2013; 38:158–167.
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Arterial stiffness in chronic kidney disease: an update Maarten W. Taal
Purpose of review Epidemiological studies have established arterial stiffness as an important risk factor for cardiovascular events and mortality in people with chronic kidney disease (CKD) at all stages. Although much has been learned about the mechanisms that lead to arterial stiffening in CKD, many questions remain unanswered and the optimal interventions for attenuating arterial stiffness remain to be determined. Recent findings Recent data have confirmed the value of arterial stiffness as a predictor of both cardiovascular and renal risk. Advanced glycation end-product accumulation and chronic cytomegalovirus infection have been identified as novel potential contributors to arterial stiffening, but fibroblast growth factor 23 has not. Genetic studies suggest that the association between chronic kidney and cardiovascular disease is a result of clinical and environmental rather than genetic factors. Treatment with angiotensin-converting enzyme inhibitor or aldosterone inhibitor improves arterial stiffness in association with lowering blood pressure, but several potential novel interventions for reducing arterial stiffness await further investigation. Summary Arterial stiffness is increasingly recognized as an important potentially modifiable measure of subclinical vascular disease in people with CKD. The introduction of arterial stiffness into routine practice awaits research focussed on including pulse wave velocity in renal and cardiovascular risk prediction tools, as well as interventions for ameliorating arterial stiffness. Keywords arterial stiffness, chronic kidney disease, pulse wave velocity
INTRODUCTION The recognition that chronic kidney disease (CKD) is associated with a substantially increased risk of cardiovascular disease (CVD), which, in the majority of cases, exceeds the risk of progression to end-stage kidney disease (ESKD), has prompted a search for mechanisms that mediate this association and interventions that may abrogate the risk. Studies to date have revealed that although occlusive atherosclerotic arterial disease undoubtedly occurs, the CVD associated with CKD is characterized by arteriosclerosis resulting in arterial stiffness (assessed as the pressure required to achieve a unit increase in volume) that provokes structural heart disease. Aortic stiffening exposes the left ventricle to greater systolic pressures, leading to ventricular hypertrophy and fibrosis that may progress to cardiac failure. In addition, stiffening of the normally elastic aorta and large arteries results in loss of the essential buffering function that dampens the fluctuations in blood pressure (BP) associated with ventricular ejection. Thus, arterial stiffness results in greater
transmission of fluctuations in pressure and exposure of smaller arteries in the brain and kidneys to higher systolic blood pressure. This in turn may provoke microvascular damage in the brain and kidneys [1]. Arterial stiffness resulting from CKD may, therefore, also contribute to the progression of CKD, as suggested by some [2,3] but not all previous studies [4]. Early research explored multiple methods for assessing arterial stiffness and led to a consensus that aortic pulse wave velocity (PWV) should be regarded as the ‘gold standard’ [5 ]. Several studies have confirmed that increased PWV is an independent risk factor for cardiovascular events and &
Department of Renal Medicine, Royal Derby Hospital, Derby, UK Correspondence to Maarten W. Taal, Department of Renal Medicine, Royal Derby Hospital, Uttoxeter Road, Derby, Derbyshire, DE22 3NE, UK. Tel: +44 1332 789344; fax: +44 1332 789352; e-mail: maarten. [email protected] Curr Opin Nephrol Hypertens 2014, 23:169–173 DOI:10.1097/01.mnh.0000441153.40072.e0
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Clinical nephrology
KEY POINTS Arterial stiffness is a predictor of both cardiovascular events and kidney disease progression. Advanced glycation end-product accumulation and chronic cytomegalovirus infection have been identified as novel potential contributors to arterial stiffening, but FGF23 has not. Genetic studies suggest that the association between chronic kidney and cardiovascular disease is a result of clinical and environmental rather than genetic factors. Before PWV measurements can be recommended for routine clinical practice, further evidence is required to confirm the ability of new more convenient methods to predict long-term outcomes as well as specific interventions to improve arterial stiffness. Future research should focus on including PWV in renal and cardiovascular risk prediction tools as well as interventions for ameliorating arterial stiffness.
mortality in populations with and without CKD [1]. Measurement of PWV was previously limited by the equipment available, which required an applanation tonometry probe to be placed simultaneously on the carotid and femoral arteries. Though well validated as a predictor of outcomes, this method is operator dependent, time consuming and causes potential discomfort to patients because of the need to expose the groin area. Newer devices use automated cuffs placed around the neck and mid-thigh [6] or derive aortic PWV from an oscillometric measurement of the brachial artery waveform [7]. These methods are much quicker to use, operator independent and more convenient for patients, making them more suitable for routine clinical use. However, large long-term studies are required to confirm that these newer methods perform equally well as predictors of adverse cardiovascular outcomes. Although much has been learned about the mechanisms that lead to arterial stiffening in CKD, many questions remain unanswered and the optimal interventions for attenuating arterial stiffness remain to be determined. Whether or not the measurement of PWV should be introduced into routine clinical practice also remains to be determined. In this article, we will review recent progress in these important areas.
ARTERIAL STIFFNESS AS A RISK FACTOR IN CHRONIC KIDNEY DISEASE Several epidemiological studies have established PWV as an important risk factor for cardiovascular 170
www.co-nephrolhypertens.com
events and mortality in people with CKD at all stages. A recent analysis of data from the NephroTest study confirmed that PWV was an independent predictor of all-cause mortality and fatal or nonfatal cardiovascular events in 439 people with CKD stages 3–5. Moreover, in a model employing hypothetical patients, the addition of PWV to traditional risk factors (age, systolic and diastolic blood pressure, history of cardiovascular events, diabetes, dyslipidaemia and smoking) significantly improved the stratification of risk for all-cause mortality [8]. One recent study has confirmed that higher PWV also predicts cardiovascular risk in kidney transplant recipients. In a cohort of 253 incident kidney transplant recipients, both aortic calcification and PWV (subgroup of n ¼ 115) were independent risk factors for subsequent cardiovascular events after a mean follow-up of 36 months [9]. Early reports regarding the role of arterial stiffness as a risk factor for the progression of CKD were derived from small or short-duration studies, but these observations have recently been confirmed in two large, prospective cohorts. In one analysis of data from 4853 adults without CKD or CVD at baseline recruited into the Multi-Ethnic Study of Atherosclerosis (MESA), higher pulse pressure (a measure of arterial stiffness) and lower arterial elasticity were each independently associated with a greater decline in estimated glomerular filtration rate (eGFR) over 5 years of followup (but flow-mediated dilation, a measure of endothelial function, was not) [10 ]. Similarly, in 2129 older people (age 70–79 years) included in the Health, Aging and Body Composition study, higher pulse pressure was independently associated with a more rapid decline in eGFR (derived from serum cystatin C) and an increased risk of incident CKD, whereas higher PWV was independently associated with an increased risk of incident CKD only [11 ]. There is now, therefore, a substantial body of evidence confirming that arterial stiffness is a risk factor both for CVD and progressive GFR decline in people with CKD. Further research is required to develop comprehensive renal and cardiovascular risk prediction tools for people with CKD that include PWV. &&
&&
PATHOGENESIS OF ARTERIAL STIFFNESS IN CHRONIC KIDNEY DISEASE Previous research has identified multiple factors that contribute to the pathogenesis of arterial stiffness, including reduced elastin and increased collagen in the medial layer, calcification and hypertrophy of vascular smooth muscle cells (VSMCs; Fig. 1) [1]. Recent efforts have focussed on identifying any additional factors that may account for the link between CKD and arterial stiffness. Volume 23 Number 2 March 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Arterial stiffness in chronic kidney disease: an update Taal
Alterations of extracellular matrix Ageing
Diet AGEs RAAS
Chronic kidney disease
Inflammation
CKD-MBD, PO4
Uraemic toxins
Arterial stiffness
Vascular calcification
Endothelial dysfunction
FIGURE 1. The multiple mechanisms whereby chronic kidney disease may provoke or accelerate the development of arterial stiffness. AGEs, advanced glycation end-products; CKD-MBD, chronic kidney disease-mineral bone disorder; PO4, phosphate; RAAS, renin–angiotensin–aldosterone system. Reproduced from [1].
Chronic kidney disease-mineral bone disorder (CKD-MBD) has for several years been recognized as an important cause of vascular calcification associated with CKD. Fibroblast growth factor (FGF) 23, recently identified as an important phosphaturic hormone that becomes elevated early in the course of CKD to maintain phosphate balance, has been reported as an independent predictor of all-cause mortality in people with CKD, but one study found no association between FGF23 levels and coronary or aortic calcification in 1501 people with CKD [12 ], and other studies have reported no association with arterial stiffness [13,14]. We have recently also found no association between PWV and FGF23 concentration in a cohort of 1664 people with CKD in the Renal Risk in Derby (RRID) study (unpublished observation). Further studies suggest that the association between FGF23 and mortality in CKD may be because of an effect of FGF23 on promoting left ventricular hypertrophy rather than arterial stiffness [15]. Nevertheless, other mediators in the pathogenesis of CKD-MBD have been associated with arterial stiffness. Serum phosphate correlated with PWV in a mouse model of CKD [16], and high serum phosphate was independently associated with high ankle brachial index, a marker of peripheral arterial stiffness in 1370 people recruited into MESA with and without CKD [17]. Decreased levels of soluble Klotho, the co-receptor for FGF23, were associated with higher PWV in 114 people with CKD [18]. Decreased levels of fetuin A, an endogenous inhibitor of calcification, and increased osteoprotegerin, an antiosteoclastic factor, were independently &
associated with higher PWV in 81 people requiring haemodialysis [19]. Advanced glycation end-products (AGEs) accumulate in people with CKD and have been proposed as a marker of cumulative metabolic stress. Skin AGE accumulation, assessed clinically by measuring skin autofluorescence, is independently associated with all-cause and cardiovascular mortality in people receiving haemodialysis [20,21 ]. AGE accumulation is associated with cross-linking of extracellular proteins, which may play a role in the pathogenesis of arterial stiffness. In support of this hypothesis, skin autofluorescence was found to correlate with PWV, independent of age, in 120 people receiving haemodialysis in Japan [22]. In the RRID study, we found a correlation between skin autofluorescence and PWV in univariate but not multivariable analysis among people with CKD stage 3 [23], and an independent association was observed in multivariable analysis in a subgroup of those with CKD and diabetes [24]. Other investigators have found an independent association between the magnitude of increase in PWV over 12 months and the baseline levels of serum pentosidine (an AGE molecule) in 109 people on haemodialysis [25], and an association between serum autofluorescence (a measure of serum AGEs) and PWV in univariate but not multivariable analysis [26]. More detailed studies in larger study populations are required to further explore the relationship between AGE accumulation in CKD and arterial stiffness. An association between chronic infections and cardiovascular risk has been proposed, but data have been inconsistent. One candidate is cytomegalovirus (CMV), a common herpes virus that causes chronic subclinical infection and is widely prevalent in humans. Seropositivity for CMV has been associated with increased cardiovascular risk in some but not all studies. Associations have also been reported between CMV seropositivity and carotid artery distensibility. One recent study, examined the relationship between CMV status and PWV in 215 people with CKD stages 2–4 and found that CMV seropositivity was an independent determinant of higher PWV as well as lower proximal descending and distal aortic distensibility [27 ]. The authors hypothesize that chronic CMV infection may increase the arterial stiffness by modifying VSMC function and causing inflammation and fibrosis in the media of arteries. The close association between CKD and CVD has prompted a search for genetic factors that may predispose people to both diseases. In an analysis that combined data from several large studies, investigators sought to identify single-nucleotide polymorphisms (SNPs) associated with clinical
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Clinical nephrology
markers of both CVD (including PWV) and CKD. Overall, there was little overlap between SNPs for CKD and CVD (though one locus associated with both was identified), suggesting that environmental and clinical factors are primarily responsible for the association, either by a direct causal link or through a common causal pathway [28 ]. &&
THERAPY TO ATTENUATE ARTERIAL STIFFNESS Arterial hypertension is closely associated with arterial stiffness and it is, therefore, difficult to separate the antihypertensive effects of drugs from their effect on arterial stiffness. However, in one observational study, failure to achieve a reduction in PWV with BP lowering was an independent determinant of all-cause and cardiovascular mortality in people receiving haemodialysis, suggesting a BP-independent component [29]. The renin–angiotensin system has been implicated in the pathogenesis of arterial stiffness and treatment with an angiotensinconverting enzyme inhibitor (ACEI) attenuates this [30]. Aldosterone also promotes arterial stiffness and aldosterone levels may remain elevated despite treatment with an ACEI or angiotensin receptor blocker (ARB). One randomized trial of the aldosterone antagonist spironolactone added to ACEI or ARB treatment in people with CKD stages 2–3 reported a reduction in PWV and left ventricular hypertrophy, but this was also associated with a reduction in systolic blood pressure [31]. A small trial of a newer selective aldosterone antagonist, eplerenone, failed to show a benefit in reducing the arterial stiffness, but was underpowered [32]. Further trials are, therefore, required to determine whether aldosterone antagonism improves arterial stiffness independent of the BP. The focus on CKD-MBD as a contributor to the pathogenesis of arterial stiffness has prompted several studies to examine the effect of phosphate binders. Despite a reduction in PWV observed with sevelamer treatment in a mouse model [33], relatively small randomized trials have not observed a reduction in PWV associated with phosphate binder treatment, either with sevelamer [34] or lanthanum carbonate [35]. On the basis of our current understanding of the pathogenesis of arterial stiffness, several further treatment options remain to be explored, including matrix metalloproteinase inhibitors to reduce elastin breakdown, dietary AGE restriction or AGE cross-link breakers to reduce AGE accumulation, endothelin antagonists, anti-inflammatory agents and interventions to improve endothelial function. 172
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CONCLUSION Recent data have confirmed the value of arterial stiffness as a predictor of both cardiovascular and renal risk. AGE accumulation and chronic CMV infection have been identified as novel contributors to arterial stiffening, but FGF23 has not. Treatment with ACEI or aldosterone inhibitors improves arterial stiffness in association with BP lowering, but several potential novel interventions await further investigation. The question of whether to introduce PWV measurement into routine clinical practice remains unanswered. Equipment is now available to allow quick, convenient measurements to be made, but long-term studies are required to confirm that PWV measured by these methods is also reliable as a predictor of adverse outcomes. Furthermore, we currently lack evidence for specific treatments to reduce arterial stiffness independent of BP. Therefore future research should focus on including PWV in renal and cardiovascular risk prediction tools as well as interventions for ameliorating arterial stiffness. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
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