Exploring the association of arterial stiffness with estimated glomerular filtration rate: another chicken-egg paradigm?

W e read with interest the study of Lin et al. [1], which aimed to explore the complex association of arterial stiffness with estimated glomerular filtration rate (eGFR) in a cross-sectional analysis of 9136 Chinese adults with an age of 40 years or higher. Study participants had no evidence of chronic kidney disease (CKD), as those with an eGFR less than 60ml/min per 1.73m or urinary-albumin-to-creatinine ratio more than 30mg/g were excluded from this analysis. The study population was divided into four groups according to the agespecific quartile of eGFR; arterial stiffness was assessed by measuring brachial-ankle pulse wave velocity (baPWV) via applanation tonometry and pulse pressure (PP) at the brachial artery [1]. The main finding of this analysis was a significant positive association between increasing quartile of age-specific eGFR and arterial stiffness indexes. After multivariate adjustment, each 10ml/min per 1.73m higher eGFR was associated with 17 and 28% higher odds of having increased baPWV [odds ratio (OR): 1.17; 95% confidence interval (CI): 1.07–1.29] andPP (OR: 1.28; 95%CI: 1.16–1.41) [1]. The robustness of this association was confirmed in a propensity-score-matched analysis comparing baPWV and PP values in participants with high versus low age-specific eGFR. The interpretation provided by the authors for the above findings was that renal hyperfiltration (as reflected by the highest quartile of age-specific eGFR) is an independent determinant of high baPWV and PP. It could be argued, however, that the cross-talk between arterial stiffness and renal function is not a one-way relationship. One alternative explanation that was not adequately captured in the discussion of the article could be that arterial stiffness may promote the delivery of systemic pulsatile energy into the renal microcirculation, causing in this way ‘renal hyperfiltration’ and progressively injury to the kidney. From a pathophysiological standpoint, in sharp contrast to the autoregulatory mechanisms protecting the microvasculature in systemic circulation from downstream pulsatile energy transmission, the renal microvessels are characterized by low resistance and low impedance [2]. These flow characteristics make renal microcirculation particularly susceptible to the highly variable oscillations in systolic and diastolic blood flow resulting from the reduced aortic compliance [3]. This notion is supported by recent clinical studies assessing renal blood flow parameters with the use of modern imaging techniques, in which the association between PWV and eGFR was shown to be explained by an increase in renal artery pulsatile index and renal resistive index [4,5]. From a clinical standpoint, the notion that increased arterial stiffness is a potential risk factor for injury to the kidney is supported by recent prospective cohort studies showing that among patients with preserved renal function,highbaselinePWVorhighbaseline PP are independent predictors of the rate of eGFR decline over time and incident CKD [6–9]. In a recent meta-analysis of four observational cohort studies, it was shown that each 1 SD higher brachial PP at baseline was associated with 16% higher risk of incident CKD [pooled relative risk (RR): 1.16; 95% CI: 1.12–1.21]; each 1-SD higher baseline aortic PWV (a more direct measure of arterial stiffness) was associated with 10% increased risk of incident CKD (RR: 1.10; 95% CI: 0.98– 1.22) [10]. The cross-sectional design of the study conducted by Lin et al. [1] cannot provide cause-and-effect associations. Accordingly, it remains unclear whether renal hyperfiltration is determinant of increased arterial stiffness, or whether increased arterial stiffness mediates excessive pulsatile energy transmission to the vulnerable renal microcirculation. Undoubtedly, the results presented in this article are of particular interest and call for properly designed prospective studies using novel imaging techniques to approximate renal hemodynamics to elucidate this ‘chicken– egg’ association.