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 Fishers 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.

Acknowledgments

The authors thank all the participants in this study, especially, to Pacemed by stimulating the development of research and for the technical support.

References

  1. [1] K. Wolf-Maier, R.S. Cooper, H. Kramer, J.R. Banegas, S. Giampaoli, M.R. Joffres, N. Poulter, P. Primatesta, B. Stegmayr, M. Thamm; Hypertension treatment and control in five European countries, Canada, and the United States; Hypertension, 43 (2004), pp. 10–17
  2. [2] S. Lewington, R. Clarke, N. Qizilbash, R. Peto, R. Collins; Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies; Lancet, 360 (2002), pp. 1903–1913
  3. [3] A.V. Chobanian, G.L. Bakris, H.R. Black, W.C. Cushman, L.A. Green, J.L. Izzo Jr., D.W. Jones, B.J. Materson, S. Oparil, J.T. Wright Jr., E.J. Roccella; Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; Hypertension, 42 (2003), pp. 1206–1252
  4. [4] D. Lloyd-Jones, R.J. Adams, T.M. Brown, M. Carnethon, S. Dai, G. De Simone, T.B. Ferguson, E. Ford, K. Furie, C. Gillespie, A. Go, K. Greenlund, N. Haase, S. Hailpern, P.M. Ho, V. Howard, B. Kissela, S. Kittner, D. Lackland, L. Lisabeth, A. Marelli, M.M. McDermott, J. Meigs, D. Mozaffarian, M. Mussolino, G. Nichol, V.L. Roger, W. Rosamond, R. Sacco, P. Sorlie, R. Stafford, T. Thom, S. Wasserthiel-Smoller, N.D. Wong, J. Wylie-Rosett; Heart disease and stroke statistics: 2010 update–a report from the American Heart Association; Circulation, 121 (2010), pp. e46–e215
  5. [5] World Health Organization (WHO); Global Health Risks: Mortality and Burden of Disease Attributable to Selected Major Risks; World Health Organization, Geneva, Switzerland (2009)
  6. [6] P.M. Kearney, M. Whelton, K. Reynolds, P. Muntner, P.K. Whelton, J. He; Global burden of hypertension: analysis of worldwide data; Lancet, 365 (2005), pp. 217–223
  7. [7] G. Mancia, R. Fagard, K. Narkiewicz, J. Redon, A. Zanchetti, M. Böhm, T. Christiaens, R. Cifkova, G. De Backer, A. Dominiczak, M. Galderisi, D.E. Grobbee, T. Jaarsma, P. Kirchhof, S.E. Kjeldsen, S. Laurent, A.J. Manolis, P.M. Nilsson, L.M. Ruilope, R.E. Schmieder, P.A. Sirnes, P. Sleight, M. Viigimaa, B. Waeber, F. Zannad; Task force for the management of arterial hypertension of the European Society of Hypertension and the European Society of Cardiology. 2013 ESH/ESC practice guidelines for the management of arterial hypertension; Eur. Heart J., 34 (2013), pp. 2159–2219
  8. [8] G. Grassi; Sympathetic neural activity in hypertension and related diseases; Am. J. Hypertens., 23 (2010), pp. 1052–1060
  9. [9] G. Grassi; Assessment of sympathetic cardiovascular drive in human hypertension: achievements and perspectives; Hypertension, 54 (2009), pp. 690–697
  10. [10] J.F. Paton, M.K. Raizada; Neurogenic hypertension; Exp. Physiol., 95 (2010), pp. 569–571
  11. [11] B.P. McGrath, J.G. Ledingham, C.R. Benedict; Catecholamines in peripheral venous plasma in patients on chronic haemodialysis; Clin. Sci. Mol. Med., 55 (1978), pp. 89–96
  12. [12] T. Tinucci, S.B. Abrahao, J.L. Santello, D. Mion Jr.; Mild chronic renal insufficiency induces sympathetic overactivity; J. Hum. Hypertens., 15 (2001), pp. 401–406
  13. [13] M.P. Schlaich, F. Socratous, S. Hennebry, N. Eikelis, E.A. Lambert, N. Straznicky, et al.; Sympathetic activation in chronic renal failure; J. Am. Soc. Nephrol., 20 (2009), pp. 933–939
  14. [14] J. Neumann, G. Ligtenberg, I.I. Klein, H.A. Koomans, P.J. Blankestijn; Sympathetic hyperactivity in chronic kidney disease: pathogenesis, clinical relevance, and treatment; Kidney Int., 65 (2004), pp. 1568–1576
  15. [15] G. Grassi, S. Bertolli, G. Seravalle; Sympathetic nervous system: role in hypertension and in chronic kidney disease; Curr. Opin. Nephrol. Hypertens., 21 (2012), pp. 46–51
  16. [16] A.S. Levey, L.A. Stevens, C.H. Schmid, Y.L. Zhang, A.F. Castro III, H.I. Feldman, J.W. Kusek, P. Eggers, F. Van Lente, T. Greene, J. Coresh, CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration); A new equation to estimate glomerular filtration rate; Ann. Intern. Med., 150 (2009), pp. 604–612
  17. [17] M.G. Kiuchi, G.R. E Silva, L.M. Paz, S. Chen, G.L. Souto; Proof of concept study: renal sympathetic denervation for treatment of polymorphic premature ventricular complexes; J. Interv. Card. Electrophysiol., 30 (May 2016) (Epub ahead of print)
  18. [18] M.G. Kiuchi, D. Mion Jr., M.L. Graciano, M.A. de Queiroz Carreira, T. Kiuchi, S. Chen, J.R. Lugon; Proof of concept study: improvement of echocardiographic parameters after renal sympathetic denervation in CKD refractory hypertensive patients; Int. J. Cardiol., 207 (2016), pp. 6–12
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