Editorial for ‘Clinical Journal of the American Society of Nephrology’
Re. Arterial stiffness and the risk of chronic kidney disease
Sedaghatet al., 2015
Targeting blood vesselstiffness to protect kidney function
Neeraj Dhaun MD *†
David J Webb MD FRCP *
* University/British Heart Foundation Centre of Research Excellence, University of Edinburgh
The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh. EH16 4TJ
† Department of Renal Medicine, Royal Infirmary of Edinburgh
Correspondence to: Dr Neeraj Dhaun
The Queen’s Medical Research Institute
3rd Floor Centre, Room C3.27
47 Little France Crescent
Edinburgh
EH16 4TJ
Telephone: (+44)-131-242-6786
E-mail:
No of words: 1,104
Pages: 8
Cardiovascular disease (CVD) commonly accompanies chronic kidney disease (CKD). While many patients with CKD have other risk factors for CVD (for example, diabetes or smoking), and part of the increased risk is attributable to these other risk factors, studies demonstrate CKD itself is a major independent risk factor.1In one large Canadian study patients aged 30 years with CKD stage 3B (estimated glomerular filtration rate (eGFR)30–44 mL/min/1.73m2) or 4(15–29 mL/min/1.73 m2) had reductions in lifeexpectancy of around 17 or 25 years, respectively, comparedwith individuals with normal kidney function.2In dialysis patients mortality from CVD is 10-20 times greater than the general population; for a patient under 45, this rises to 100 times.3 Such figures led the US National Kidney Foundation Task Force on CVD in Chronic Renal Disease to recognise in 1998 that patients with chronic renal disease should be considered in the ‘highest risk group’ for subsequent cardiovascular events.4
Both epidemiological and clinical data show that damage to large arteries contributes to the increased cardiovascular risk observed in CKD.5 Atherosclerosis is the most frequent cause of arterial damage6 but the medial calcification seen in CKD also leads to arterial stiffening. This stiffening not only causes an elevation in central systolic blood pressure (BP), increasing left ventricular workload with the gradual development of left ventricular hypertrophy, but also causes a fall in diastolic BP, impairing coronary blood flow. Arterial calcification and stiffness are important independent predictors of all-cause and cardiovascular mortality in patients with CKD.7
Many of the early data in studies of arterial stiffness concentrated on patients with end-stage renal disease (ESRD). Increased arterial stiffness (as measured by well-validated indices of stiffness: augmentation index (AIx) and pulse wave velocity (PWV)8), is a strong independent predictor of mortality in patients with ESRD.9 This reflects the elevated central pressure, increased cardiac workload, impaired coronary perfusion, and development of left ventricular hypertrophy associated with increased stiffness. Moreover, a therapeutic trial in ESRD patients by Guerin et al10 has shown that after long-term BP reduction, cardiovascular survival is observed mainly in those patients showing both adequate BPand PWV reduction.10 Patients with appropriate BP reduction but who maintained elevated PWV did not survive, an observation that underlines the critical deleterious influence of increased arterial stiffness on mortality in ESRD. Epidemiological studies tell us that there is increased cardiovascular risk early on in CKDand this risk increases as eGFR declines.11 In parallel with this there is also an increase in PWV related to progression through the CKDstages.12,13However, studies examining whether measures of arterial stiffness might predict future development or decline of CKD have been conflicting.14-16
In this issue of the Journal, Sedaghat and colleagues present interesting and novel data from a large population-based study in Rotterdam, backed up by a meta-analysis of other studies. The authors measured pulse pressure (PP), carotid stiffness and carotid-femoral PWVin ~3,700 subjects and then assessed annual decline in eGFR over a median follow-up period of 11 years. Furthermore, based on 10 single nucleotide polymorphisms (SNPs) associated with PP and 9 SNPs associated with PWV, the authors calculated a genetic risk score for these measures for all participants. After correcting for confounding factors (including BP), both PP and carotid stiffness predicted incident CKD and annual eGFR decline whereas, perhaps surprisingly, PWV did not. Interestingly, whenthe authors combined their data with those of 3 other population-based studies using similar methodologies (a total of >10,000 subjects with follow-up periods of 5-10 years)they found that each standard deviation higher PP and PWV were associated with 16% and 8% increased risk of incident CKD, respectively. Whereas genetic risk scoring for PP was associated with eGFR decline, this was not the case for PWV.
Clearly these data raise the intriguing possibility that targeting PWV from a therapeutic perspective (‘unstiffening’ the large vessels) might slow the progressionof existing CKD and, more importantly perhaps from an economic and public health perspective, prevent incident CKD.We already know that lowering BP will reduce PWV.8However, there are few clinical trials to date demonstrating that lowering of PWV with medical treatment, results in different cardiovascular or renal outcomes10,17independent of blood pressure. However, the importance of such studies is underscored by epidemiological data that suggest that PWV is an independent risk factor for CVD morbidity and mortality.9,18,19 Karalliedde et al showed a BP-independent reduction in PWV with valsartan compared to amlodipine in patients with type 2 diabetes and proteinuria 20 and the same has been demonstrated following brief administration of an endothelin antagonist to non-diabetic proteinuric CKD patients.21 There also exist other mechanisms to reduce arterial stiffness that do not involve BP lowering; these include the use of phosphate binders such as sevelamer.22
One might ask how generalisable the results of the current study are. The population studied had a mean age of 65 years and 60% were women. No information on race is given, but it is likely to be predominantly Caucasian. BP was normal and there was ~8% prevalence of diabetes and clinically apparent coronary artery disease at the start of the study. Baseline eGFR was ~80 mL/min/1.73m2. Over the 11-year follow-upperiod there was ~16% incidence of new CKD. These data are all consistent with a representative Westernpopulation, though the mean PWV of 12.2 m/s is higher than one might expect for such a population23and the reasons for this are not immediately clear. Furthermore, no data are available on proteinuria, central BP components or incident CVD, all of which are linked to arterial stiffness and would be of interest.
A recent paper by London et al has added to the field by suggesting that in addition to assessing aortic stiffness in patients with renal disease, aortic geometry may also provide valuable prognostic information. In patients with ESRD established on hemodialysis the authors found that, as for PWV, aortic bifurcation diameter (and ‘aortic taper’ – defined as ascending aorta/aorta bifurcation diameters ratio) independently predicted all-cause and cardiovascular mortality.24As those with earlier stages of CKD aremore likely to die from CVD than they are of reaching ESRD they should certainly be the focus of future studies. Nevertheless, it is important to remember that ESRD patients, especially those on hemodialysis, are at the greatest risk of CVD. Given they attend medical facilities 3-times a week they represent a captive audience for future clinical trials in a group where few therapeutic interventions have been shown to improve outcome. This group has marked arterial stiffness, and there is now an urgent need for trials addressing reversal of arterial stiffnessand left ventricular mass, alongside aortic geometry andendothelial function.
Disclosures: None
Sources of funding: ND is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/13/30/29994).
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