Should we take renal denervation with a grain of salt?

In the current issue of the Journal of Clinical Hypertension, De Beus and colleagues investigated the effect of salt intake on blood pressure (BP) response after percutaneous renal denervation in patients with resistant hypertension. The authors found no relationship between baseline sodium excretion and change in BP.1

Hypertension is one of the leading attributable risk factors for kidney disease and cardiovascular morbidity and mortality.2 A subgroup of patients with hypertension do not achieve target BP levels despite concurrent use of three or more antihypertensive agents (one being diuretic). These patients are considered to have “resistant hypertension.” The incidence of resistant hypertension ranges from 10% to 12%.3 These patients have more target organ damage compared with patients with hypertension who achieve target BPs with treatment. There is no accepted therapeutic norm for these patients, which has created a longstanding therapeutic dilemma.4, 5 However, a new emerging technique was recently introduced: renal sympathetic denervation. In initial studies, renal sympathetic denervation was demonstrated to be effective in reducing BP in patients with resistant hypertension.6, 7 These initial findings created much interest and enthusiasm among researchers, scientists, and clinicians, which led to many studies being performed, most of which were poorly designed and observational.8 However, this initial enthusiasm has declined with the findings of more informative studies, namely the SYMPLICITY HTN‐3 trial. This trial has shown that there was no significant reduction of systolic BP in patients with resistant hypertension 6 months after renal sympathetic denervation as compared with a sham control.9

Although the reasons for these conflicting findings are not completely known, the different degree of sympathetic hyperactivity in different patients and incomplete sympathetic denervation may be one of the explanations.10 Along this line of reasoning, it is wise to ask the question: What are the factors determining sympathetic hyperactivity in patients with hypertension?

One of the most important factors for sympathetic activity is volume status. Since volume status is largely determined by the kidney, there must be close interaction between the kidney and the sympathetic system. Indeed, it is well known that bidirectional signaling via sympathetic nervous system fibers to and from the kidney plays an integral role in health and diseased states. Efferent fibers originating in the brain travel within the spinal cord and reach the kidney terminating in the cortex at the juxtaglomerular apparatus. Efferent nerve stimulation results in vasoconstriction, renin release, sodium and water retention, and reduced renal blood flow.11 Afferent fibers from mechanoreceptors and chemoreceptors in the renal pelvis travel through the spinal cord to the midbrain and promote sympathetic nervous system activity in response to injury.12 Moreover, it was shown that interruption of afferent renal nerves reduces sympathetic activation, as assessed by norepinephrine turnover in the brain and prevents the development of hypertension.13

Dietary sodium intake is also known to be related to sympathetic activity, and lower intake is associated with higher sympathetic drive.14 Conversely, efferent sympathetic activity directly increases tubular sodium absorption.15 Thus, hypothetically, it can be concluded that renal sympathetic denervation can cause decreased vasoconstriction, renin release, and decreased sodium and water retention. In this context it can be hypothesized that sodium intake may be an important factor for the success of renal sympathetic denervation.

These data, taken into account alongside the study in which de Beus and colleagues investigated the role of basal sodium intake on BP response after percutaneous renal denervation in patients with resistant hypertension, yielded no statistically significant relationship between baseline sodium excretion and change in BP. Percutaneous renal denervation decreased BP with similar salt intake, suggesting a decrease in salt sensitivity. However, the same decline in BP was also observed in the control group; thus, percutaneous renal denervation did not seem to impact this decrease in BP.1 Although the study is informative, the results must be interpreted with caution.

First, the generalizability of the study should be considered. The trial excluded patients with severe renal ınsufficiency (estimated glomerular filtration rate <20 mL/min per 1.73 m²). The relationship between sympathetic activity, sodium intake, and BP may be different in different stages of kidney function. This suggestion is currently only a hypothesis, and we believe that more studies are needed to clarify this issue.

Second, although measurements were performed, there were no direct measurements of sympathetic hyperactivity before and after intervention. This issue may be important since it was suggested that there may be different levels of decrease in sympathetic hyperactivity during surgical or catheter ablation techniques. It is not clear whether and has never been documented that partial renal denervation works and whether there is a threshold of sympathetic fiber interruption required to see effects on BP. Total sympathetic fiber interruption and norepinephrine reduction >90% should be the goal of catheter‐based renal denervation techniques. Most experimental studies using catheter‐based renal denervation and radiofrequency as the source of thermal energy can achieve lesions up to 3 to 5 mm in depth. Sympathetic fibers, however, are found as much as 12 mm from the renal artery lumen, and radiofrequency energy from current platforms is not capable of reaching those. It is not known whether there is a threshold percentage of nerve interruption required or a dose‐response relationship for BP lowering. Thus, although this limitation is inherent for all of these studies, one must be careful before claiming that renal sympathetic denervation is not related to sodium intake and one must be sure that effective sympathetic denervation has been performed.7 To support this view, there were greater reductions in BP with a higher number of renal artery ablations.16

Third, the authors acknowledge that salt sensitivity was not measured by standard method. Instead, the relationship of sodium excretion with systolic BP measured in the same 24 hours was compared at baseline and at 6 months after renal denervation. Thus, the same degree of change in salt sensitivity in patients with and without intervention should be judged with caution.

Increased salt intake not only functionally impacts BP (by altering the sympathetic system or renin‐angiotensin system function) but may also impact vessel wall structure. Indeed, increased salt intake has been shown to change arterial wall structure and function.17, 18, 19 Therefore, increased sodium intake may result in adverse remodeling of the central and peripheral arterial vasculature and may relate to arterial stiffness.20

Thus, the lack of correlation of baseline sodium intake with BP after renal denervation may be caused by a relatively more important contribution by structural changes compared with functional changes after sympathetic denervation. The vessel structure may not be the same in patients undergoing renal denervation, which may impact the results.

One of the explanations for these null relationships between salt intake, salt sensitivity, and renal denervation may be the result of a reciprocal relationship between salt intake and sympathetic activity. During salt restriction, sympathetic activity increases as a feedback mechanism.21 In the current study, the sodium intake of the patient population was already low, meaning that the sympathetic system was already activated. After intervention, BPs decreased with no correlation between salt intake and salt sensitivity. Thus, the findings of the study could be positive in patients who ingest more sodium. Additional studies or subgroup analyses (patients who consume higher salt) would be informative in this context.

The current study, which investigates an understudied subject, is valuable with respect to its findings. However, the results must be evaluated with caution. More studies are recommended to increase the external generalizability of these results.

AUTHOR CONTRIBUTIONS

All authors approved the final version of this article.

CONFLICT OF INTEREST

The authors have no conflicts of interest to disclose.

Afsar B, Sag AA, Kanbay M. Should we take renal denervation with a grain of salt? J Clin Hypertens. 2017;19:1134–1136. 10.1111/jch.13069