Mediation Analysis of Aortic Stiffness and Renal Microvascular Function

Abstract

Aortic stiffening, assessed by carotid-femoral pulse wave velocity, is associated with CKD. Transmission of excessive flow pulsatility into the low-impedance renal microvasculature may mediate this association. However, direct analyses of macrovascular-microvascular relations in the kidney are limited. Using arterial tonometry, iohexol clearance, and magnetic resonance imaging, we related arterial stiffness, GFR, urinary albumin excretion, and potential mediators, including renal artery pulsatility index, renal vascular resistance, and arterial volume in the cortex, in 367 older adults (ages 72-92 years) participating in the Age, Gene/ Environment Susceptibility-Reykjavik Study. In a model adjusted for age, sex, heart rate, and body size, aortic stiffness was related to GFR (Slope of regression B=22.2860.85 ml/min per SD, P=0.008) but not urine albumin (P=0.09). After accounting for pulsatility index, the relation between aortic stiffness and GFR was no longer significant (P=0.10). Mediation analysis showed that 34% of the relation between aortic stiffness and GFR was mediated by pulsatility index (95% confidence interval of indirect effect, 21.35 to 20.29). An additional 20% or 36% of the relation was mediated by lower arterial volume in the cortex or higher renal vascular resistance, respectively, when offered as mediators downstream from higher pulsatility index (95% confidence interval of indirect effect including arterial volume in the cortex, 22.22 to 20.40; 95% confidence interval of indirect effect including renal vascular resistance, 22.51 to 20.76). These analyses provide the first evidence that aortic stiffness may contribute to lower GFR by transferring excessive flow pulsatility into the susceptible renal microvasculature, leading to dynamic constriction or vessel loss.

Arterial stiffness and renal function—a complex relationship

“…1 An overall view of the interaction between arteriosclerosis and renal function may open new horizons in the approach to treatment of patients with hypertension. The new data from Woodard et al 3 suggest that a reduction in pulsatility index might protect the kidney microcirculation against damage generated by high pressure pulsatility. In the setting of hypertension characterized by high pulse pressure, drugs that reduce pulsatility index and renal vascular resistance (such as RAS blockers) should, therefore, be preferred.…”

“…Higher vascular resistance and lower arterial volume in the renal cortex mediated 36% and 20% of this relationship, respec tively, when considered as downstream mediators of a high pulsatility index. In their analysis of renal haemodynamic measures, Woodard et al 3 were not able to distinguish between permanent structural vascular loss and functional vasoconstriction. Despite this limitation, their data suggest a patho genetic link between aortic stiffness and renal damage through transfer of a highly pulsatile flow into the renal microvascu lature.…”

“…In a recent report published in the Journal of the American Society of Nephrology, Woodard et al 3 analyse the complex rela tionship between large arterial function and microvascular kidney disease. They performed a comprehensive assessment of renal haemodynamics in 367 elderly individuals (aged 72-92 years).…”

“…4 The use of anti hyper tensive drugs could also be an important confounder; 75% of the participants in the study by Woodard et al 3 were treated for hypertension. Renin-angiotensin system …”

Reversal of Aging‐Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein‐Protein Interfaces

“…Recent clinical studies document that increased aortic stiffness, as measured by pulse wave velocity, is an early and independent biomarker for negative cardiovascular outcomes such as myocardial infarction, cognitive decline, and renal disease 2, 5, 6, 7, 8, 9. Greater aortic stiffness increases transmission of pressure and flow pulsatility associated with cardiac contraction into delicate microvessels, particularly in high‐flow organs such as the brain and kidney 2, 3, 5, 7, 9, 10. Aortic stiffening (arteriosclerosis) is distinct from atherosclerosis11 and is thought to cause secondary morphological changes in microvessels that contribute to the pathogenesis of hypertension and cardiovascular disease 10, 12, 13…”