Diurnal Variation in Blood Pressure and Arterial Stiffness in Chronic Kidney Disease

Abstract

day) becomes more apparent. Importantly, loss of nocturnal dipping is associated with CKD progression.11 However, these studies did not explore interventions to restore BP dipping.Arterial stiffness also contributes significantly to the CVD risk in CKD. 12 Although some studies have examined daytime variations in arterial stiffness, none has included patients with CKD. 13,14 Furthermore, no study has as yet addressed ambulatory arterial stiffness and its 24-hour variation. Thus, there is a need for newer treatments in CKD that will not only lower BP beyond the levels achieved with standard therapies but also favorably affect the 24-hour profile of BP and arterial stiffness, leading to additional cardiovascular and renal protection.Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor produced within the vasculature. 15 ET-1 also promotes cardiovascular proliferation, inflammation, and fibrosis, all of which may contribute to poor outcomes. ET-1 is produced Abstract-Hypertension and arterial stiffness are important independent cardiovascular risk factors in chronic kidney disease (CKD) to which endothelin-1 (ET-1) contributes. Loss of nocturnal blood pressure (BP) dipping is associated with CKD progression, but there are no data on 24-hour arterial stiffness variation. We examined the 24-hour variation of BP, arterial stiffness, and the ET system in healthy volunteers and patients with CKD and the effects on these of ET receptor type A receptor antagonism (sitaxentan). There were nocturnal dips in systolic BP and diastolic BP and pulse wave velocity, our measure of arterial stiffness, in 15 controls (systolic BP, −3.2±4.8%, P<0.05; diastolic BP, −6.4±6.2%, P=0.001; pulse wave velocity, −5.8±5.2%, P<0.01) but not in 15 patients with CKD. In CKD, plasma ET-1 increased by 1.2±1.4 pg/mL from midday to midnight compared with healthy volunteers (P<0.05). Urinary ET-1 did not change. In a randomized, double-blind, 3-way crossover study in 27 patients with CKD, 6-week treatment with placebo and nifedipine did not affect nocturnal dips in systolic BP or diastolic BP between baseline and week 6, whereas dipping was increased after 6-week sitaxentan treatment (baseline versus week 6, systolic BP: −7.0±6.2 versus −11.0±7.8 mm Hg, P<0.05; diastolic BP: −6.0±3.6 versus −8.3±5.1 mm Hg, P<0.05). There was no nocturnal dip in pulse pressure at baseline in the 3 phases of the study, whereas sitaxentan was linked to the development of a nocturnal dip in pulse pressure. In CKD, activation of the ET system seems to contribute not only to raised BP but also the loss of BP dipping. The clinical significance of these findings should be explored in future clinical trials. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01770847 and NCT00810732. within the kidney and is implicated in both the development and progression of CKD. 16 The effects of ET-1 are mediated via 2 receptors, the ET A and ET B receptors, with the major pathological effects in CKD being ET A receptor mediated. 17Recen...

Correlation Between Endothelial Dysfunction and Left Ventricular Remodeling in Patients with Chronic Kidney Disease

“…Left ventricular hypertrophy is an important complication of chronic kidney disease, and there was a significant positive correlation between elevated plasma endothelin-1 and LVMI. As seen in Table 4, after adjusting the regression equation by systolic blood pressure, it can prove that ET-1 induced ventricular hypertrophy non-dependent of blood pressure [18]. …”

Circadian regulation of renal function

“…Diabetes and hypertension are the leading causes of CKD, but interestingly, the loss of normal BP rhythms in individuals with CKD has been well documented and may be a contributing factor for CKD progression [124,161,162]. The association and prevalence of non-dipping BP with a decline in renal function has also been previously reported [163–165], suggesting an impairment of the circadian clock mechanism in patients with the disease.…”

“…In healthy individuals, there is a diurnal difference in the levels of plasma ET-1, with lower levels observed at night [124], but this is less evident in rats [76] (Fig. 5).…”

Endothelin in Nondiabetic Chronic Kidney Disease: Preclinical and Clinical Studies

“…These additional effects may, in theory, confer improved cardiovascular and renal protection. 90,116 With regard to the safety data from this study, in contrast to the effects of other ERAs in diabetic nephropathy, it is worth noting that there was no evidence of fluid retention within this cohort. Sitaxentan has been shown to have no functional effect on ET B in vivo in human beings 117 and these observations would be consistent with a role for ET B in fluid accumulation.…”

“…In patients with CKD, however, ET A activity appears increased, with a preferential effect on the efferent arteriole, raising the possibility that ET-1 promotes hyperfiltration in CKD. The vasoconstrictor effect of BQ788 in both health and disease suggests that ET B plays an important role in maintaining basal systemic 90,115,116 Sitaxentan therapy also improved markers of arterial stiffness, improved nocturnal BP dip, and reduced plasma asymmetric dimethylarginine (ADMA) and uric acid and renal vascular tone, and indicates that its blockade in CKD may have negative consequences on both systemic BP and renal blood flow. 111 A further acute study, using BQ123, in 22 patients with nondiabetic proteinuric CKD found that BQ123 caused significant reductions in BP and arterial stiffness and increased renal blood flow while causing a decrease in proteinuria of approximately 30%.…”