Targeting Blood Vessel Stiffness to Protect Kidney Function

Cardiovascular disease (CVD) commonly accompanies CKD. Although 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, studies show that CKD itself is a major independent risk factor (1). In one large Canadian study, patients ages 30 years old with CKD stage 3B (eGFR=30–44 ml/min per 1.73 m²) or 4 (15–29 ml/min per 1.73 m²) had reductions in life expectancy of around 17 or 25 years, respectively, compared with individuals with normal kidney function (2). In patients on dialysis, mortality from CVD is >10–20 times that of the general population; for a patient <45 years old, this rises to 100 times (3). Such figures led the US National Kidney Foundation Task Force on CVD in Chronic Renal Disease to recognize in 1998 that patients with chronic renal disease should be considered in the highest risk group for subsequent cardiovascular events (4).

Both epidemiologic 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 damage (6), but the medial calcification seen in CKD also leads to arterial stiffening. This stiffening not only causes an elevation in central systolic 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).

Much of the early data in studies of arterial stiffness concentrated on patients with ESRD. Increased arterial stiffness (as measured by well validated indices of stiffness: augmentation index 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 patients with ESRD by Guerin et al. (10) has shown that, after long–term BP reduction, cardiovascular survival is observed mainly in those patients showing both adequate BP and 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. Epidemiologic studies tell us that there is increased cardiovascular risk early on in CKD, and this risk increases as eGFR declines (11). In parallel with this, there is also an increase in PWV related to progression through the CKD stages (12,13). However, 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 Clinical Journal of the American Society of Nephrology, Sedaghat et al. (17) present interesting and novel data from a large population–based study in Rotterdam backed up by a meta-analysis of other studies. Sedaghat et al. (17) measured pulse pressure (PP), carotid stiffness, and carotid-femoral PWV in approximately 3700 subjects and then, assessed annual decline in eGFR over a median follow-up period of 11 years. Furthermore, on the basis of ten single-nucleotide polymorphisms associated with PP and nine single-nucleotide polymorphisms associated with PWV, Sedaghat et al. (17) 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, when Sedaghat et al. (17) combined their data with those of three 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 SD higher PP and PWV was associated with 16% and 8% increased risk of incident CKD, respectively. Whereas genetic risk scoring for PP was associated with eGFR decline, genetic scoring for PWV was not.

Clearly, these data raise the intriguing possibility that targeting PWV from a therapeutic perspective (unstiffening the large vessels) might slow the progression of 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 (8). However, there are few clinical trials to date showing that lowering of PWV with medical treatment results in different cardiovascular or renal outcomes (10,18) independent of BP. However, the importance of such studies is underscored by epidemiologic data that suggest that PWV is an independent risk factor for CVD morbidity and mortality (9,19,20). Karalliedde et al. (21) showed a BP-independent reduction in PWV with valsartan compared with amlodipine in patients with type 2 diabetes and proteinuria, and the same has been shown after brief administration of an endothelin antagonist to nondiabetic patients with CKD who are proteinuric (22). There also exists other mechanisms to reduce arterial stiffness that do not involve BP lowering; these include the use of phosphate binders, such as sevelamer (23).

One might ask about the generalizability of the results of this study (17). The population studied had a mean age of 65 years old, and 60% were women. No information on race is given, but it is likely to be predominantly white. BP was normal, and there was an approximately 8% prevalence of diabetes and clinically apparent coronary artery disease at the start of the study. Baseline eGFR was approximately 80 ml/min per 1.73 m². Over the 11-year follow-up period, there was an approximately 16% incidence of new CKD. These data are all consistent with a representative Western population, although the mean PWV of 12.2 m/s is higher than one might expect for such a population (24), and 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. (25) 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, London et al. (25) found that, such as for PWV, aortic bifurcation diameter (and aortic taper—defined as ascending aorta-to-aorta bifurcation diameters ratio) independently predicted all-cause and cardiovascular mortality. Because those with earlier stages of CKD are more likely to die from CVD than reach ESRD, they should certainly be the focus of future studies. Nevertheless, it is important to remember that patients with ESRD, especially those on hemodialysis, are at the greatest risk of CVD. Given that they attend medical facilities three times per 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 stiffness and left ventricular mass alongside aortic geometry and endothelial function.

Disclosures

None.