Various basic and clinical studies on blood pressure have advanced knowledge on the physiology and pathophysiology of blood pressure regulation and the treatment of hypertension represented by antihypertensive medicines. However, some patients still have poorly controlled blood pressure. Therefore, further advances in hypertension treatment are required. The current clinical study by Guenes-Altan et al. links two keywords “skin sodium,” which is a recent topic in the research field of blood pressure, and “renal denervation”, which is attracting attention as a novel treatment for hypertension [1]. The development of sodium-magnetic resonance imaging (Na-MRI) has enabled measurement of tissue Na levels in humans. This technique has led to research on the association between local tissue Na levels and various diseases, such as hypertension, infection, and inflammatory disease [2,3,4,5]. In particular, Na, which is an important factor that affects blood pressure, is elevated in the skin in hypertensive patients [2, 3]. Therefore, the concept of skin Na storage has received attention in the research field of hypertension. Renal denervation is a promising new treatment for hypertension [6, 7]. However, several critical clinical issues remain to be clarified. These issues include whether renal denervation should be indicated for treatment-resistant patients who cannot improve hypertension by multiple antihypertensive medications. Additionally, whether general hypertensive patients should be treated with renal denervation or which hypertensive patients should not be treated with renal denervation is unknown. The possibility that the measurement of tissue Na levels could be useful to address these clinical issues has been mentioned in this issue of Hypertension Research [1].

Guenes-Altan et al. studied the measurement of tissue Na levels by Na-MRI before and 6 months after renal denervation [1]. A previous study reported that there were no significant differences in skin or muscle Na levels 6 months after renal denervation in treatment-resistant hypertensive patients [8]. Guenes-Altan et al. also showed that renal denervation did not alter skin or muscle Na levels 6 months after this procedure [1]. The authors focused on whether tissue Na levels are related to the efficacy of renal denervation. They found that skin Na levels, sex, low-density lipoprotein cholesterol levels, baseline heart rate, and the presence or absence of aldosterone antagonist use were predictors of responders and nonresponders to the blood pressure-lowering effect of renal denervation [1]. Notably, blood pressure responders to renal denervation were characterized by low skin Na levels, female sex, high low-density lipoprotein cholesterol levels, a high baseline heart rate, and intake of aldosterone antagonists in treatment-resistant hypertensive patients [1]. These findings suggest that the measurement of skin Na levels, in addition to clinical parameters, is a useful tool in determining the indication for renal denervation. The measurement of skin Na levels may contribute to the development of personal medicine regarding hypertension and renal denervation (Fig. 1).

Fig. 1
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Skin sodium levels may become a predictor of the blood pressure-lowering effect of renal denervation

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Although Guenes-Altan et al.’s study was a clinical study [1], basic research that can approach the decision of whether we should perform renal denervation for hypertensive patients should also be considered. In the study by Guenes-Altan et al., nonresponders (no reduction in blood pressure after renal denervation) showed high skin Na levels, but responders showed low skin Na levels in treatment-resistant hypertensive patients [1]. However, why this finding occurred is still unclear. Studies have shown that higher skin Na accumulation is associated with enhanced vascular remodeling and left ventricular hypertrophy [9, 10]. Therefore, patients with high Na skin levels may be in a more advanced stage of hypertension, and renal denervation may not be able to decrease blood pressure in these patients. Although future basic and clinical research is essential, renal denervation may exhibit a better effect on blood pressure early in hypertension. Additionally, not all hypertensive patients have high skin Na accumulation, and the pathophysiological mechanism and clinical significance of differences in skin Na levels in hypertensive patients and basic animal models remain to be clarified. The effects of renal denervation on differences in skin Na levels in hypertension should also be further examined in clinical and basic studies. If these issues are clarified in future studies, we may be able to use skin Na levels with other clinical parameters more appropriately to determine indications of renal denervation. While the primary focus of Guenes-Altan et al.’s study was on skin Na levels, other predictors for the blood pressure-lowering effect of renal denervation are also mentioned in their article [1]. Regarding the high baseline heart rate in responders, renal denervation may be more effective in hypertensive patients with high sympathetic nerve activity. However, the reasons why women, low-density lipoprotein cholesterol levels, and aldosterone antagonist use are predictors for the blood pressure-lowering effect of renal denervation are unclear. Associations between skin Na levels and some factors have been reported in previous studies [2, 3]. Men have higher skin Na levels than women, and patients with Conn syndrome, who have hyperaldosteronism, exhibit high skin Na levels that are decreased by surgical treatment or by an aldosterone antagonist [2, 3]. Although the interactions and causal relationships among these factors remain unclear, future integrated studies of these predictors, including skin Na levels, may lead to better predictors of the blood pressure-lowering effect of renal denervation. The mechanism of why skin Na levels are a predictor of the blood pressure-lowering effect of renal denervation remains to be determined, and further basic and clinical research is expected.

One issue that should be addressed, even if skin Na levels measured by Na-MRI are a useful clinical tool to determine renal denervation efficiency, is that Na-MRI is still a special technology and has not been widely implemented in healthcare institutions. Previous Na-MRI-related studies have shown the importance and clinical significance of tissue Na measurement [2,3,4,5]. Based on the evidence regarding Na-MRI, future advances in scientific technology that can measure tissue Na levels anytime, anywhere, and at low cost, are expected. When these advances occur, the measurement of tissue Na levels may become one of the decision-making tools for renal denervation therapy.

From a different perspective, there is the issue regarding whether blood pressure alone is sufficient to evaluate the efficacy of renal denervation. Notably, several previous basic studies have reported that renal denervation leads to blood pressure-independent beneficial effects, such as organ-protective effects and suppression of sympathetic nerve activity coupled with a reduction in heart rate [11,12,13,14]. Additionally, renal denervation decreases heart rate in humans [15]. Taking into consideration that high sympathetic nerve activity and/or a heart rate are risk factors for cardiovascular events, the efficacy of renal denervation may be beyond antihypertensive treatment. However, which patients should receive renal denervation for organ protection and suppression of cardiovascular events is still unclear and an important issue. Future basic and clinical studies regarding renal denervation and organ protection including predictors are expected.