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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=-2.28±0.85 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, -1.35 to -0.29). 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, -2.22 to -0.40; 95% confidence interval of indirect effect including renal vascular resistance, -2.51 to -0.76). 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.

SUBMITTER: Woodard T

PROVIDER: S-EPMC4413769 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Mediation analysis of aortic stiffness and renal microvascular function.

Woodard Todd T Sigurdsson Sigurdur S Gotal John D JD Torjesen Alyssa A AA Inker Lesley A LA Aspelund Thor T Eiriksdottir Gudny G Gudnason Vilmundur V Harris Tamara B TB Launer Lenore J LJ Levey Andrew S AS Mitchell Gary F GF

Journal of the American Society of Nephrology : JASN 20141007 5

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 pulsatil ...[more]

PMID: 25294231

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Project description:BackgroundOrgan stiffening can be caused by inflammation and fibrosis, processes that are common causes of transplant kidney dysfunction. Magnetic resonance elastography (MRE) is a contrast-free, noninvasive imaging modality that measures kidney stiffness. The objective of this study was to assess the ability of MRE to serve as a prognostic factor for renal outcomes.MethodsPatients were recruited from the St Michael's Hospital Kidney Transplant Clinic. Relevant baseline demographic, clinical, and Banff histologic information, along with follow-up estimated glomerular filtration rate (eGFR) data, were recorded. Two-dimensional gradient-echo MRE imaging was performed to obtain kidney "stiffness" maps. Binary logistic regression analyses were performed to examine for relationships between stiffness and microvascular inflammation score. Linear mixed-effects modeling was used to assess the relationship between stiffness and eGFR change over time controlling for other baseline variables. A G2-likelihood ratio Chi-squared test was performed to compare between the baseline models with and without "stiffness."ResultsSixty-eight transplant kidneys were scanned in 66 patients (mean age 56 ± 12 y, 24 females), with 38 allografts undergoing a contemporaneous biopsy. Mean transplant vintage was 7.0 ± 6.8 y. In biopsied allografts, MRE-derived allograft stiffness was associated only with microvascular inflammation (Banff g + ptc score, Spearman ρ = 0.43, P = 0.01), but no other histologic parameters. Stiffness was negatively associated with eGFR change over time (Stiffness × Time interaction β = -0.80, P < 0.0001), a finding that remained significant even when adjusted for biopsy status and baseline variables (Stiffness × Time interaction β = -0.46, P = 0.04). Conversely, the clinical models including "stiffness" showed significantly better fit (P = 0.04) compared with the baseline clinical models without "stiffness."ConclusionsMRE-derived renal stiffness provides important prognostic information regarding renal function loss for patients with allograft dysfunction, over and above what is provided by current clinical variables.

Project description:Background:Increased carotid-femoral pulse wave velocity (cf-PWV), a surrogate of increased aortic stiffness, is a risk factor for cardiovascular events and all-cause mortality in end-stage renal disease (ESRD). To minimize the deleterious effects of an increased aortic stiffness in ESRD patients, several interventions have been developed and cf-PWV has been used to monitor responses. Objective:The aim of this study was to determine the effects of pharmacologic interventions that target aortic stiffness on cf-PWV and systolic blood pressure (SBP) in adults with ESRD. Study design:This study implements a systematic review and meta-analysis. Data sources:MEDLINE, EMBASE, Cochrane Central, Health Technology Assessment, and EBM databases were searched. Study eligibility participants and interventions:Randomized and non-randomized studies involving adults (>18 years) with ESRD of any duration, receiving or not renal replacement therapy (hemodialysis, peritoneal dialysis) and exposed to a pharmacologic intervention whose effects were assessed by cf-PWV. Methods:Study screening, selection, data extraction, and quality assessments were performed by 2 independent reviewers. Narrative synthesis and quantitative data analysis summarized the review. Results:We included 1027 ESRD participants from 13 randomized and 5 non-randomized studies. Most pharmacologic interventions targeted bone mineral metabolism disorder or hypertension. Treatment with vitamin D analogues or cinacalcet did not decrease cf-PWV or SBP over placebo or matched controls (P > .05). Calcium-channel blockers (CCB) decreased cf-PWV and SBP compared with placebo or standard care (P < .05). Renin-angiotensin system inhibitors did not show any advantage over placebo in decreasing cf-PWV (P > .05). Limitations:Quality of evidence ranged from very low to moderate. Overall evidence was limited by the low number of studies, small sample sizes, and methodological inconsistencies. Conclusions:Pharmacologic interventions targeting aortic stiffness in ESRD have mixed effects on reducing cf-PWV, with some strategies suggesting potential benefit. The quality of evidence, however, is insufficient to draw definitive conclusions on their use to slow progression of aortic stiffness in ESRD. Further well-designed studies are needed to confirm these associations and their impact on cardiovascular outcomes in ESRD.Registered in PROSPERO (CRD42016033463).

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Mediation analysis of aortic stiffness and renal microvascular function.

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Mediation analysis of aortic stiffness and renal microvascular function.

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