Effectiveness of renal sympathetic denervation in renal function and blood pressure in CKD and non-CKD patients with controlled vs. uncontrolled hypertension.

Hypertension remains a major global public health burden, leading attributed cause of mortality worldwide [1]. Every 20/10-mm Hg increase in blood pressure (BP) is associated with a doubling of cardiovascular mortality [2], [3]. Epidemiological studies have shown that awareness of this disease is low, with only half of hypertensives adequately treated to target BP levels [4], [5], [6]. Nowadays, out-of-office BP is an important adjuvant method to be associated with conventional office BP measurement, but this last one currently continues to be the most important tool for hypertension screening, diagnosis, and treatment. Office BP was enshrined over time. However, this method has important limitations, which have led to the increasingly frequent suggestion that 24-hour ambulatory blood pressure measurements (ABPM) play an important role in hypertension management [7]. Hypertension is defined as mean systolic BP levels ≥ 130 mm Hg and/or diastolic BP ≥ 80 mm Hg in 24-hour ABPM [7].

Sympathetic hyperactivity is well known to increase cardiovascular risk in chronic kidney disease (CKD) patients and is a hallmark of an essential hypertensive state that occurs early in the clinical course of the disease [8], [9], [10]. In both conditions, hypertension and kidney failure, the mechanisms of hyperadrenergic state are varied and include reflex and neurohumoral pathways [8], [9], [11]. In CKD, the sympathetic hyperactivity seems to be expressed at the earliest clinical stage of the disease, showing a direct relationship with the severity of the condition of renal impairment [12], [13], [14], [15]. The interruption of sympathetic hyperactivity and feedback of the renin–angiotensin–aldosterone system cycle can at least partly be beneficial for this population. Based on these pathophysiological mechanisms, renal sympathetic denervation (RSD) in CKD and hypertensive patients may ameliorate renal function and blood pressure control. The aim of this prospective study was to compare the magnitude of the effects on renal function and blood pressure control in CKD and non-CKD patients with controlled hypertension (CHT) vs. uncontrolled hypertension (UHT).

We conducted a prospective, longitudinal study of 187 hypertensive subjects, being 60 CKD CHT, 48 CKD UHT, 37 non-CKD CHT, and 42 non-CKD UHT patients. The study was conducted in accordance with the Helsinki Declaration and approved by the local ethics committee. All patients gave written informed consent before inclusion. This study was conducted in the state of Rio de Janeiro, Brazil in the Hospital e Clínica São Gonçalo. Patients were recruited from June 2012 to January 2016 and were derived from the hospital and the public health network of the state county. Patients who had the combination of the following criteria were consecutively enrolled: (i) CHT: mean 24-hour ABPM < 130/<80 mm Hg; (ii) UHT: mean 24-hour ABPM ≥ 130/≥80 mm Hg despite treatment with non-pharmacological measures and use of at least three antihypertensive drugs (including a diuretic) on maximally tolerated doses or confirmed intolerance to medications; (iii) CKD: glomerular filtration rate estimated by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation, eGFR [16], > 60 mL/min/1.73 m2 between 15 and 89 mL/min/1.73 m2 (patients with eGFR > 60 mL/min/1.73 m2 were required to have microalbuminuria); (iv) non-CKD: glomerular filtration rate estimated by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation, eGFR [16], > 60 mL/min/1.73 m2 (without microalbuminuria); (v) age from 18 to 80 years; and (vi) able to read, understand and sign the informed consent form, and attend clinic visits and exams. Patients with any of the following criteria were excluded: (i) pregnancy; (ii) valvular heart disease with significant adverse sequelae; (iii) myocardial infarction, unstable angina, stroke or transient ischemic attack within the previous six months; (iv) renovascular abnormalities; (v) psychiatric disease; (vi) allergy to ionic contrast; (vii) inability to be followed clinically after the procedure; and (viii) serious disease, which in the opinion of the investigator, may adversely affect the safety and/or efficacy of the participant or the study.

The 24-hour ABPM [17] and the renal sympathetic denervation are previously described [18] by our group.

The results were expressed as the mean and standard deviation (mean ± SD) of the mean in the case of normal distribution and as the median with inter-quartile range otherwise. Statistical tests were all two-sided. Comparisons between two paired values were performed by the paired t-test in case of Gaussian distribution or, alternatively, by the Wilcoxon test. Comparisons between more than two paired values were performed by ANOVA for repeated measures or with Kruskal-Wallis ANOVA as appropriate complemented by a post hoc test. Frequencies were compared with Fisher's Exact Test. P-values < 0.05 were considered significant. Correlations between two variables were performed by Pearson in the case of Gaussian distribution or, alternatively, with the Spearman correlation test. All statistical analyses were performed using the program GraphPad Prism v 7.0 (GraphPad Software, La Jolla, CA, USA).

The general features of the 187 hypertensive patients, divided into 60 CKD CHT, 48 CKD UHT, 37 non-CKD CHT, and 42 non-CKD UHT individuals are listed in Table 1. During the six months of follow-up, the changes in mean 24-hour ABPM, serum creatinine, eGFR and ACR are displayed in Table 2. The variation (∆) between all the comparisons at the 6th month post RSD for all groups related to the parameters aforementionated and their respective P values are displayed in Table 3.

Table 1

General features of patients at baseline.

Parameters	CKD CHT	CKD UHT	Non-CKD CHT	Non-CKD UHT	Overall P-value
N	60	48	37	42	–
Age, years	54.2 ± 11.3	57.5 ± 10.2	59.4 ± 15.7	61.0 ± 16.5	0.0657
Body mass index, kg/m2	28.5 ± 6.3	26.8 ± 5.4	28.0 ± 6.4	27.3 ± 5.1	0.4672
Male sex (%)	43 (72%)	31 (65%)	22 (59%)	28 (67%)	0.6561
White ethnicity (%)	46 (77%)	30 (63%)	20 (54%)	30 (71%)	0.1033
Atrial fibrillation	22 (37%)	14 (29%)	14 (38%)	17 (40%)	0.7045
Hypertension	60 (100%)	48 (100%)	37 (100%)	42 (100%)	1.0000
Type 2 diabetes mellitus	35 (58%)	22 (46%)	17 (46%)	21 (50%)	0.5328
Hyperlipidemia	40 (67%)	30 (63%)	24 (65%)	31 (74%)	0.4958
Chronic kidney disease	60 (100%)	48 (100%)	0 (0%)	0 (0%)	< 0.0001
Stage 2	27 (45%)	20 (42%)	–	–	0.8455†
Stage 3	20 (33%)	14 (29%)	–	–	0.6814†
Stage 4	13 (22%)	14 (29%)	–	–	0.3821†
Creatinine, mg/dL	1.36 ± 0.70⁎	1.42 ± 0.97⁎	0.90 ± 0.11⁎	1.02 ± 0.14⁎	0.0002
eGFR, mL/min/1.73 m2	58.7 ± 24.8⁎⁎	55.7 ± 33.0⁎⁎	93.0 ± 10.0⁎⁎	82.1 ± 14.6⁎⁎	< 0.0001
Albumin:creatinine ratio, mg/g	88.2 ± 33.5⁎⁎	97.5 ± 30.6⁎⁎	14.5 ± 8.4⁎⁎	12.2 ± 6.5⁎⁎	< 0.0001
Antihypertensive
ACE-inhibitors/ARB	60 (100%)	48 (100%)	37 (100%)	42 (100%)	1.0000
Diuretics	60 (100%)	48 (100%)	37 (100%)	42 (100%)	1.0000
DHP Ca++ channel blockers	60 (100%)	48 (100%)	27 (73%)	31 (74%)	< 0.0001
β-Blockers	17 (28%)	31 (65%)	20 (54%)	30 (71%)	< 0.0001
α-Blockers	9 (15%)	23 (48%)	5 (14%)	22 (52%)	< 0.0001
Spironolactone	13 (22%)	39 (81%)	12 (32%)	35 (83%)	< 0.0001
Mean 24-hour ABPM, mm Hg
Systolic	123.5 ± 6.2	158.6 ± 9.6	122.0 ± 4.3	143.4 ± 8.0	< 0.0001╪
Diastolic	74.0 ± 4.7	110.6 ± 6.5	73.6 ± 5.4	102.3 ± 4.4	< 0.0001╪

Values are expressed as Mean ± SD; ABPM, ambulatory blood pressure measurements; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; CHT, controlled hypertension; DHP, dihydropyridine; eGFR, estimated glomerular filtration rate; RSD, renal sympathetic denervation; UHT, uncontrolled hypertension. Creatinine: *P < 0.05 for CKD CHT vs. non-CKD CHT, CKD CHT vs. non-CKD UHT, CKD UHT vs. non-CKD CHT, and CKD UHT vs. non-CKD UHT; eGFR and albumin:creatinine ratio: **P < 0.0001 for CKD CHT vs. non-CKD CHT, CKD CHT vs. non-CKD UHT, CKD UHT vs. non-CKD CHT, and CKD UHT vs. non-CKD UHT. CKD stages: †comparison between only CKD CHT and CKD UHT; Mean 24-hour ABPM: ╪P < 0.0001 for all comparisons, except for CKD CHT vs. non-CKD CHT;

Table 2

Parameters at 6th month after renal sympathetic denervation.

Variable	CKD CHT 6th month (n = 60)	P-value CKD CHT baseline vs. 6th month	CKD UHT 6th month (n = 48)	P-value CKD UHT baseline vs. 6th month	Non-CKD CHT 6th month (n = 37)	P-value non-CKD CHT baseline vs. 6th month	Non-CKD UHT 6th month (n = 42)	P-value non-CKD UHT baseline vs. 6th month
Mean 24-hour ABPM, mm Hg
Systolic	121.8 ± 8.0	0.1958	134.3 ± 12.5	< 0.0001	121.6 ± 6.1	0.7454	122.4 ± 5.2	< 0.0001
Diastolic	75.5 ± 4.0	0.0622	86.3 ± 11.2	< 0.0001	74.0 ± 5.9	0.7618	85.4 ± 8.8	< 0.0001
Creatinine, mg/dL	1.04 ± 0.32	0.0017	0.86 ± 0.24	0.0002	0.92 ± 0.19	0.5812	0.96 ± 0.17	0.0812
eGFR, mL/min/1.73 m2 (CKD-EPI)	81.3 ± 15.8	< 0.0001	94.3 ± 16.1	< 0.0001	92.1 ± 10.0	0.6926	85.4 ± 11.8	0.2579
ACR, mg/g	47.8 ± 24.6	< 0.0001	33.8 ± 21.0	< 0.0001	13.7 ± 10.4	0.7665	11.2 ± 9.6	0.5777

Values are presented as mean ± SD; ABPM, ambulatory blood pressure measurements; ACR, albumin:creatinine ratio; CKD, chronic kidney disease; CHT, controlled hypertension; eGFR, estimated glomerular filtration rate; UHT, uncontrolled hypertension.

Table 3

Variation (∆) between groups at 6th month after renal sympathetic denervation.

Comparisons	CKD CHT vs. CKD UHT		CKD CHT vs. non-CKD CHT		CKD CHT vs. non-CKD UHT		Non-CKD UHT vs. non-CKD CHT		CKD UHT vs. non-CKD UHT		Non-CKD CHT vs. non-CKD UHT
Variables	∆	P-value	∆	P-value	∆	P-value	∆	P-value	∆	P-value	∆	P-value
Mean 24-hour ABPM, mmHg
Systolic	− 12.5	< 0.0001	0.2	0.9995	− 0.6	0.9857	12.7	< 0.0001	11.9	< 0.0001	− 0.8	0.9763
Diastolic	− 10.8	< 0.0001	1.5	0.7971	− 9.9	< 0.0001	12.3	< 0.0001	0.9	0.9484	− 11.4	< 0.0001
Creatinine, mg/dL	0.18	0.0016	0.12	0.0979	0.08	0.3784	− 0.06	0.6857	− 0.10	0.2273	− 0.04	0.8906
eGFR, mL/min/1.73 m2 (CKD-EPI)	− 13	< 0.0001	− 10.8	0.0018	− 4.1	0.4709	2.2	0.8911	8.9	0.0164	6.7	0.1531
ACR, mg/g	14	0.0022	34.1	< 0.0001	36.6	< 0.0001	20.1	< 0.0001	22.6	< 0.0001	2.5	0.9385

Values are presented as variation (∆) between means; ABPM, ambulatory blood pressure measurements; ACR, albumin:creatinine ratio; CKD, chronic kidney disease; CHT, controlled hypertension; eGFR, estimated glomerular filtration rate; UHT, uncontrolled hypertension.

Funding

This study was funded by Pacemed (US$ 300,000).

Conflict of interest

None declared.