Renal denervation for the treatment of resistant hypertension: review and clinical perspective

Abstract

When introduced clinically 6 years ago, renal denervation was thought to be the solution for all patients whose blood pressure could not be controlled by medication. The initial two studies, SYMPLICITY HTN-1 and HTN-2, demonstrated great magnitudes of blood pressure reduction within 6 mo of the procedure and were based on a number of assumptions that may not have been true, including strict adherence to medication and absence of white-coat hypertension. The SYMPLICITY HTN-3 trial controlled for all possible factors believed to influence the outcome, including the addition of a sham arm, and ultimately proved the demise of the initial overly optimistic expectations. This trial yielded a much lower blood pressure reduction compared with the previous SYMPLICITY trials. Since its publication in 2014, there have been many analyses to try and understand what accounted for the differences. Of all the variables examined that could influence blood pressure outcomes, the extent of the denervation procedure was determined to be inadequate. Beyond this, the physiological mechanisms that account for the heterogeneous fall in arterial pressure following renal denervation remain unclear, and experimental studies indicate dependence on more than simply reduced renal sympathetic activity. These and other related issues are discussed in this paper. Our perspective is that renal denervation works if done properly and used in the appropriate patient population. New studies with new approaches and catheters and appropriate controls will be starting later this year to reassess the efficacy and safety of renal denervation in humans.

Keywords: denervation; hypertension; pathophysiology; renal nerves; resistance.

Fig. 1.

Increased renal sympathetic nerve activity (RSNA) leads to chronic increases in blood pressure by decreasing sodium excretion (orange boxes and lines). The 3 major pathways by which changes in RSNA affect sodium excretion are through alterations in activation of the renin-angiotensin system (red boxes and lines), sodium reabsorption (blue box and line), and glomerular hemodynamics (purple boxes and lines). Light blue and light purple lines represent mechanisms indirectly affected by RSNA. Continuous lines represent stimulatory effects; dotted lines reflect inhibitory effects. E.A., efferent arteriole; A.A., afferent arteriole; GFR, glomerular filtration rate.

Fig. 2.

Development of hypertension with weight gain and the effects of global and renal-specific sympathoinhibition by baroreflex activation and bilateral surgical renal denervation, respectively, in the established phase of obesity. Abolition of hypertension by renal denervation emphasizes the importance of increased renal sympathetic nerve activity in the pathogenesis of obesity-induced hypertension and the role of renal-specific suppression of sympathetic activity in mediating the antihypertensive effects of baroreflex activation. Values are means ± SE from 24-h recordings of arterial pressure. During days 4–31, obesity hypertension was induced by feeding dogs a high-fat diet. During this time, body weight increased ∼50%. After day 31, dietary fat was minimal, and there were no further changes in body weight throughout the remainder of the study.

Fig. 3.

Chronic neurohormonal responses to prolonged baroreflex activation and bilateral renal denervation in dogs with obesity-induced hypertension. Suppression of plasma renin activity (PRA) during baroreflex activation and renal denervation suggests that inhibition of the renin-angiotensin system contributes to the sustained lowering of arterial pressure during both global and renal-specific sympathoinhibition in obesity hypertension (Fig. 2). Values are means ± SE. Lean control values (open bars) are also presented for reference. *P < 0.05 vs. day 34 of obesity hypertension. †P < 0.05 vs. day 48 of obesity hypertension.

Fig. 4.

Effects of prolonged baroreflex activation on mean arterial pressure before and after induction of aldosterone hypertension (HT), and the response of aldosterone hypertension to bilateral renal denervation. Blood pressure lowering in response to global and especially renal-specific sympathoinhibition was diminished in aldosterone hypertension. Values are means ± SE from 24-h recordings of arterial pressure. *P < 0.05 vs. values before either global or renal-specific sympathoinhibition.

Fig. 5.

While both baroreflex activation and renal denervation abolish hypertension (Fig. 2), global and renal-specific sympathoinhibition have differential effects on hyperfiltration and tubular function in obesity. Values are means ± SE. Lean control values (open bars) are also presented for reference. *P < 0.05 vs. day 34 of obesity hypertension. †P < 0.05 vs. day 48 of obesity hypertension.