Evidence of Reduced Efferent Renal Sympathetic Innervation After Chemical Renal Denervation in Humans

Abstract

Background: Renal denervation (RDN) is effective at lowering blood pressure. However, it is unknown if ablative procedures elicit sympathetic denervation of the kidneys in humans. The aim of this investigation was to assess sympathetic innervation of the renal cortex following perivascular chemical RDN, which may be particularly effective at ablating perivascular efferent and afferent nerves.

Methods: Seven hypertensive patients (4F:3M; 50-65 years) completed PET-CT sympathetic neuroimaging of the renal cortex using 11C-methylreboxetine (11C-MRB, norepinephrine transporter ligand) and 6-[18F]-fluorodopamine (18F-FDA; substrate for the cell membrane norepinephrine transporter) before and 8 weeks after chemical RDN (Peregrine System Infusion Catheter, Ablative Solutions; n = 4; 2F:2M) or control renal angiography (n = 3; 2F:1M). Patients completed physiological phenotyping including 24-hour ambulatory blood pressure, hemodynamics, muscle sympathetic nerve activity, and 24-hour urine collection.

Results: RDN decreased 11C-MRB-derived radioactivity by ~30% (Δ 11C-MRB/chamber: -0.95 a.u. confidence interval (CI): -1.36 to -0.54, P = 0.0002), indicative of efferent RDN. In contrast, 18F-FDA-derived radioactivity increased (Δ 18F-FDA/chamber: 2.72 a.u. CI: 0.73-4.71, P = 0.009), consistent with reduced vesicular turnover. Controls showed no change in either marker. Ambulatory systolic pressure decreased in 3 of 4 patients (-9 mm Hg CI: -27 to 9, P = 0.058), and central systolic pressure decreased in all patients (-23 mm Hg CI: -51 to 5, P = 0.095).

Conclusions: These results are the first to show efferent sympathetic denervation of the renal cortex following RDN in humans. Further studies of mechanisms underlying variable blood pressure lowering in the setting of documented RDN may provide insights into inconsistencies in clinical trial outcomes.

Clinical trials registration: Trial Number NCT03465917.

Keywords: blood pressure; hypertension; renal denervation; sympathetic nervous system.

© American Journal of Hypertension, Ltd 2021. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Figures

Figure 1.

Effect of chemical renal denervation (RDN) on renal sympathetic innervation in humans. (a) Representative positron emission tomographic scans depicting renal 11C-methylreboxetine (11C-MRB, norepinephrine transporter ligand)-derived radioactivity before, and 8 weeks after chemical RDN in humans. (b) Mean 11C-MRB- and (c) 6-[18F]-fluorodopamine (18F-FDA; substrate for norepinephrine transporter uptake)-derived radioactivity in the renal cortex normalized to radioactivity of arterial blood in the left ventricular chamber (cortex/chamber). Four patients received bilateral renal denervation, 1 patient received unilateral denervation (dashed line), and 2 patients did not undergo denervation (controls). Control kidneys, n = 5; RDN kidneys, n = 9. ANOVA interaction 11C-MRB (P = 0.009) and 18F-FDA (P = 0.031). *P < 0.05 vs. Pre.

Figure 2.

Effect of chemical renal denervation (RDN) on 24-hour ambulatory blood pressure and central blood pressure. 24-Hour ambulatory monitoring of (a) systolic blood pressure (SBP) and (b) diastolic blood pressure (DBP), and assessment of (c) central systolic blood pressure (cSBP) and (d) central diastolic blood pressure (cDBP) by applanation tonometry before (Pre), and 8 weeks after (Post) chemical RDN in humans. Control patients, n = 3; RDN patients, n = 4. Dashed lines indicate a patient that received unilateral RDN. All P > 0.05.

Figure 3.

Effect of chemical renal denervation (RDN) on muscle sympathetic nervous system activity (MSNA), and 24-hour urine, and plasma markers of neurohormonal activation. Direct measurement of MSNA (a) burst frequency, (b) burst incidence, and (c) total activity, as well as markers of neurohormonal activation including plasma-derived (d) norepinephrine (NE), (e) aldosterone, (f) renin, and 24-hour urine-derived (g) NE, (h) normetanephrine (NMN), (i) vanillylmandelic acid (VMA) before (Pre), and 8 weeks after (Post) chemical RDN in humans. Control patients, n = 3; RDN patients, n = 4. Dashed lines indicate a patient that received unilateral RDN. All P > 0.05.

Figure 4.

Effect of chemical renal denervation (RDN) on supine hemodynamics and autonomic regulation of blood pressure during head-up tilt (HUT). Supine (a) mean arterial pressure (MAP; electrosphygmomanometry), (b) cardiac output (Qc; acetylene rebreathe), and (c) calculated total peripheral resistance (TPR), and the change in (d) MAP, (e) Qc, and (f) TPR in response to 30° HUT during minutes 2–5, 60° HUT during minutes 2–5, and 60° HUT during minutes 8–10 before (Pre), and 8 weeks after (Post) chemical RDN in humans. Control patients, n = 3; RDN patients, n = 4. Dashed lines indicate a patient that received unilateral RDN. All P > 0.05.