Effects of catheter‐based renal denervation on renin‐aldosterone system, catecholamines, and electrolytes: A systematic review and meta‐analysis

Abstract In recent years, catheter‐based renal denervation (RDN) has emerged as a promising instrumental therapy for hypertension. The interruption of sympathetic nervous system was regarded as a possible mechanism for RDN regulating blood pressure. While the results reflected by renin‐angiotensin‐aldosterone system (RAAS), catecholamines and electrolytes remained inconsistent and was never systematically assessed. Pubmed, Embase, and Web of Science were comprehensively searched from inception to September 5, 2021. Studies that evaluated the effects of RDN on RAAS, catecholamines, and electrolytes were identified. Primary outcomes were changes in RAAS hormones after RDN, and secondary outcomes involved changes in plasma norepinephrine, serum, and urinary sodium and potassium. Out of 6391 retrieved studies, 20 studies (two randomized controlled studies and 18 observational studies) involving 771 persons were eventually included. Plasma renin activity had a statistically significant reduction after RDN (0.24 ng/mL/h, 95% CI 0.04 to 0.44, P = .02). While no significant change was found regarding plasma aldosterone (1.53 ng/dL, 95% CI ‐0.61 to 3.67, P = .16), norepinephrine (0.42 nmol/L, 95% ‐0.51 to 1.35, P = 0.38), serum sodium and potassium (0.16 mmol/L, 95% CI ‐0.17 to 0.49, P = .34; ‐0.02 mmol/L, 95% CI ‐0.09 to 0.04, P = .48, respectively), and urinary sodium and potassium (3.95 mmol/24 h, 95% CI ‐29.36 to 37.26, P = .82; 10.22 mmol/24 h, 95% CI ‐12.11 to 32.54, P = .37, respectively). In conclusion, plasma renin activity significantly decreased after RDN, while no significant change was observed in plasma aldosterone, plasma norepinephrine, and serum and urinary electrolytes.


INTRODUCTION
Hypertension (HTN) remains one of the heaviest burdens of public health worldwide, as the number of adults affected by HTN maintains an upward trend, which is predicted to reach a total of 1.56 billion in 2025. 1 Though with the popularization of antihypertensive drugs, the treatment and control rates of HTN in some countries were still low. 2 According to existed reports, blood pressure (BP) was still not controlled in 13.72-16.24% hypertensives under treatment of at least triple combinations of drugs, 3 which was defined as resistant hypertension (RH). To meet the growing needs and achieve better BP control, catheter-based renal denervation (RDN) emerged as a promising interventional approach to complement pharmaceutical therapies in HTN patients, especially in those with RH. [4][5][6] The important role of the sympathetic nervous system in the pathogenesis of HTN has been proved by previous research. 7 The blockage of renal efferent sympathetic nerves was also regarded as part of the mechanisms of RDN reducing BP, through altering renal blood flow, increasing urinary salt excretion, and decreasing renin release from the kidney. 8 While the results regarding the direct effect of RDN on the sympathetic nervous system, reflected by changes in plasma renin, aldosterone, catecholamines, and subsequent serum and urinary electrolytes, are inconsistent and have never been systematically assessed.
The objective of this study was to undertake a systematic review and meta-analysis of research to determine whether such changes existed after the procedure of catheter-based RDN in HTN patients.

METHODS
We conducted the systematic review and meta-analysis according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines. 9

Search strategy
The goal of the search was to find studies that documented the changes in plasma renin, plasma aldosterone, plasma and urinary cate-

Study selection
The search results were screened independently by two reviewers.
Inclusion criteria were studies reporting data on plasma renin, plasma aldosterone, plasma and urinary catecholamines, serum and urinary sodium or potassium before and after RDN procedure in HTN patients.
Studies with at least one outcome of interest above were included.
Only full-text published articles were qualified for inclusion. Exclusion criteria were as follows: 1. Conference abstracts, case reports, reviews, editorials and letters; 2. Animal studies; 3. Articles with incomplete data; 4. Studies not targeted at hypertension patients. As for publications from the same population, reporting on different follow-up period data, only the one with the longest follow-up time was used for the overall analysis. Discrepancies in the screening results between the two reviewers were solved by further discussion and consensus.

Outcomes
The primary outcomes were changes in RAAS hormones after RDN, including plasma renin and plasma aldosterone. The secondary outcomes involved changes in plasma catecholamines, serum and urinary sodium and potassium, and blood pressure.

Study selection and characteristics
The search strategy identified a total of 7546 records from the three databases. After removing the duplicates and excluding results not meeting the inclusion and exclusion criteria, 20 articles were eventually retrieved for data extraction. Detailed process is presented in Figure 1.

Quality assessment
Quality assessment was performed using the MINORS score system. The scores of all the included studies ranged from 13 to 16 points, which were acceptable for the present meta-analysis (Table 2).

Effect of RDN on plasma renin and blood pressure
Comparisons of plasma renin activity levels before and after RDN were extracted in ten studies (n = 330). As presented in Figure 2, pooled PRA showed a significantly decrease after RDN (0.24 ng/mL/h, 95% CI 0.04 to 0.44, P = .02). No apparent heterogeneity or publication bias was observed (I 2 = 0, Egger test = 0.4210, Begg test = 0.7205).
Blood pressure data were subsequently extracted from those ten studies, out of which 5 (n = 134) reported on changes in ambulatory blood pressure, and 8 (n = 340) reported on office blood pressure. As shown in Figure2 Meta-regression analyses were performed between baseline PRA and changes in BP values after the surgery. Baseline PRA was positively associated with 24-hour SBP reduction (coefficient = 0.017, 95% CI 0.002-0.032, P = .025, Table S1).

Effect of RDN on plasma aldosterone
Changes in plasma aldosterone levels were available in nine studies (n = 341). As displayed in Figure 3A, plasma aldosterone levels tended to decrease after RDN, while the change was not statistically signifi-

Effect of RDN on plasma catecholamines
Two studies referred to plasma norepinephrine changes after RDN (n = 38). As shown in Figure 3B,

Effect of RDN on serum and urinary electrolytes
Seven studies reported changes in serum sodium after RDN (n = 373) and nine studies reported on serum potassium (n = 396), with one study containing three subgroups. Neither serum sodium nor serum potassium was significantly altered (0.16 mmol/L, 95% CI -0.17 to 0.49, P = .34; -0.02 mmol/L, 95% CI -0.09 to 0.04, P = .48, respectively) after RDN with low heterogeneity (I 2 = 0; I 2 = 19%, respectively). The details were presented in Figure 4A and Figure 4B. No significant publication bias was found (Egger test = 0.9702 and Begg test = 1.7485 for sodium; Egger test = 0.3387 and Begg test = 0.7555 for potassium). Study  I  II  III  IV  V  VI  VII  VIII  Total   M Voskuil, 2011  2  2  2  2  2  2  2  0  1  Numbers I-VIII in heading represented: I, a clearly stated aim; II, inclusion of consecutive patients; III, prospective collection of data; IV, endpoints appropriate to the aim of the study; V, unbiased assessment of the study endpoint; VI, follow-up period appropriate to the aim of the study; VII, loss of follow up less than 5%; VIII, prospective calculation of the study size.

DISCUSSION
To the best of our knowledge, this study is the first meta-analysis discussing the effects of catheter-based RDN on renin, aldosterone, catecholamines, sodium and potassium. Our study indicated that plasma renin significantly decreased after catheter-based RDN, while no significant change was found regarding plasma aldosterone, catecholamines, serum and urinary sodium and potassium.
Afferent and efferent nerves in the kidney are an important part of the whole nervous system, which are closely associated with the pathophysiology of hypertension. 34 Afferent sensory nerves are mostly located in the renal pelvic area, 35 functioning by projecting signals to the central nervous system, thus regulating systemic sympathetic activity, increasing total vascular resistance and raising BP. In contrast, efferent sympathetic nerves distribute widely in all parts of renal vasculature and nephrons, innervating three general targets in the kidney, including juxtaglomerular apparatus, vascular smooth muscle, and the entire tubular system. 36 Therefore, the activation of efferent nerves can theoretically affect BP levels in multiple ways: 1.
Increasing the secretion of circulating renin from the juxtaglomerular apparatus and activating the renin-angiotensin-aldosterone system (RAAS); 2. Constricting vessels, increasing regional vascular resistance, and decreasing blood flow in the kidney; 3. Promoting the absorption of sodium and water, and regulating blood volume. Interruption of the above processes has been considered to partially account for the antihypertensive effect of catheter-based RDN, which may be potentially reflected in the changes in circulating renin, aldosterone, catecholamines, and serum and urinary electrolytes after the surgery.
Various studies have reported relative data, while perspectives of whether such changes existed varied from each other.

RDN and RAAS
The effect of RDN on RAAS has been proved in animal models as presented by previous literature. 37,38 Nevertheless, conclusions drawn According to our study, plasma aldosterone did not change significantly after RDN. While the results presented great heterogeneity, with an I 2 up to 86%. As we all know, there were many factors affecting the measurement of RAAS hormones. Antihypertensive drugs were one of the most common influencing factors encountered in clinical settings, which could reduce the accuracy of results. 40 As reported in SYPRAL HTN-OFF MED trial, 23

RDN and catecholamines
As a marker of the total sympathetic tone, pooled plasma norepinephrine presented no significant change after catheter-based RDN in our study. Nor did other catecholamines hormones as reported by previous publications. 20

RDN and electrolytes
Neither change in serum nor urinary electrolytes after RDN was found from our pooled data. Several experimental studies indicated that sodium excretion increased in the short-term after RDN. 43 In humans, Ott C and associates 24 also reported a significant decrease in potassium excretion 1 day after RDN, while no change was observed at the 6-month follow-up. It was not surprising to find such alterations were eliminated in the long term, since human bodies possess complicated mechanisms for maintaining electrolytes homeostasis. 44

Limitations
This study had several limitations. First, heterogeneity associated with pooled plasma aldosterone, plasma norepinephrine, and urinary electrolytes might have reduced evidence quality. In addition, studies lacking available data, or presenting data in inappropriate forms were not included in this study. Too few studies reported on urinary catecholamines data to allow for meta-analysis. More studies with high quality standards and uniform outcome measures were urgently needed to validate the effect of RDN on BP control.

CONCLUSION
Catheter-based RDN appeared to have effects on RAAS to some extent. Plasma renin activity significantly decreased after catheterbased RDN, while no significant change was observed regarding plasma aldosterone, plasma norepinephrine, and serum and urinary electrolytes. Higher baseline PRA seemed to be related to greater BP reduction after RDN, which indicated that patients with high PRA might be more well-responsive to the treatment. This study might help to confirm the mechanism of RDN regulating BP, and to target the potential patients.

AUTHOR CONTRIBUTIONS
Study concept and design-Xiangyu Yang, Zhipeng Zhang, Xiaoping