International Journal of Cardiology 199 (2015) 10–12

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Letter to the Editor

Improvement of the renal function after renal sympathetic denervation in refractory hypertensive patients with chronic kidney disease: Possible predictors Márcio Galindo Kiuchi a,b, Miguel Luis Graciano a, Shaojie Chen c,d, Maria Angela Magalhães de Queiroz Carreira a, Tetsuaki Kiuchi b, Bruno Rustum Andrea e, Jocemir Ronaldo Lugon a,⁎ a

Renal Division, Department of Medicine, Universidade Federal Fluminense, Niterói, RJ, Brazil Hospital Regional Darcy Vargas, Rio Bonito, RJ, Brazil Department of Cardiology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China d Fellowship of European Heart Rhythm Association/European Society of Cardiology, Department of Cardiology, Elisabethinen University Teaching Hospital Linz, Linz, Austria e Abteilung Elektrophysiologie, Herzzentrum, Universität Leipzig, Leipzig, Sachsen, Germany b c

a r t i c l e

i n f o

Article history: Received 3 May 2015 Received in revised form 21 June 2015 Accepted 27 June 2015 Available online 7 July 2015 Keywords: Hypertension Chronic kidney disease Renal denervation Blood pressure reduction Improvement of renal function

Hypertension is recognized as one of the most important risk factors for the development and progression of chronic kidney disease (CKD) [1]. The majority of the patients with CKD are hypertensive. High levels of blood pressure (BP) are associated with a faster progression of CKD and cardiovascular risk. The major consequences of CKD include progressive loss of kidney function leading to end-stage renal disease (ESRD), accelerated cardiovascular disease (CVD) and death. Recently, Ott et al. reported an observational pilot study in patients with CKD stages 3 and 4 which indicates that treatment of hypertension with renal sympathetic denervation (RSD) decreases BP and slows or even halts the decline of renal function [2], in agreement with our previous results that showed BP control and an increase in estimated glomerular filtration rate (eGFR), especially in the mild stages of CKD ⁎ Corresponding author at: Centro de Diálise, Hospital Universitário Antônio Pedro, Rua Marquês do Paraná 303, 2°andar, Niterói, RJ 24033-900, Brazil. Tel.: +55 212 6299 169; fax: +55 212 6299 260. E-mail address: [email protected] (J.R. Lugon).

http://dx.doi.org/10.1016/j.ijcard.2015.06.140 0167-5273/© 2015 Published by Elsevier Ireland Ltd.

[3–5], after RSD. Subjects that were considered responders to RSD regarding renal function presented changes in eGFR with order of magnitude higher than 6.2% [4]. However, it is not clear which variables are related to eGFR response after RSD. All patients in this study provided written informed consent and were selected according to previously published protocol [5]. The Committee of Ethics in Research of the Medical School of Universidade Federal Fluminense approved the study. In the period from June 2011 to December 2012, thirty consecutive patients underwent RSD. All of them had resistant hypertension and CKD (stages 2, 3 and 4), as shown in Table 1. They underwent laboratory tests and assessment of renal function at baseline and 24 h post-procedure, before discharge. The procedures were performed in the catheterization laboratory with direct visualization using fluoroscopy and radiopaque contrast. In some cases, we also used the three-dimensional mapping system EnSite Velocity (St. Jude Medical, St. Paul, Minnesota, USA) for construction of renal arteries and aorta anatomy, as well as for radiofrequency application in the selected sites. All patients remained under unconscious sedation. All the patients received i.v. sodium bicarbonate (3 ml/kg) and 0.9% saline for 1 h, as prophylaxis for attenuation of iodinated contrast media-associated nephrotoxicity [6,7]. The ablation procedure of the renal arteries using a standard irrigation cardiac ablation catheter was performed as previously described [5]. At the end of procedure, patients were submitted to another infusion of sodium bicarbonate (1 ml/kg/h) for 6 h [6,7]. Patients were discharged after 24 hour hospitalization, clinically stable, walking without difficulty. Bruising or aneurismal formation was not seen at the puncture site. According to the protocol [5], in the follow-up period, Doppler ultrasound of the renal arteries was performed one and 6 months after the procedure in all patients and did not show any complication or change in blood flow. The increase in glomerular filtration was early and progressive. At the end of the 1st month, an increase in eGFR of 23% (+14.27 ml/min/ 1.73 m2, P b 0.0001) from baseline was already noticed, while at the

Letter to the Editor Table 1 General features of patients at baseline. N Age (years) Female sex (%) Ethnicity (non-white) (%) Body mass index, kg/m2 Coronary artery disease (%) Atrial fibrillation (%) Stroke (%) Type 2 diabetes (%) LDL-cholesterol N 130 mg/dl (%) Smoking (%) Number of antihypertensives (%) eGFR, ml/min/1.73 m2 (CKD-EPI) Stages of CKD 2 3 4 Blood pressure, mm Hg a

Table 4 Univariate analysis to test associations with improved glomerular filtration rate at the end of the 12th month after percutaneous renal denervation.

30 55 ± 10a 17 (57%) 21 (70%) 30.8 ± 4.9 5 (17%) 2 (7%) 6 (20%) 11 (37%) 19 (63%) 3 (10%) 4.6 ± 1.4 61.9 ± 23.9

Variables tested

19 (63%) 6 (20%) 5 (17%) 185 ± 18/107 ± 13

Mean + SD; eGFR, estimated glomerular filtration rate.

Table 2 Univariate analysis to test associations with improved glomerular filtration rate at the end of the 6th month after percutaneous renal denervation. Variables tested Age (years) Gender Type 2 diabetes mellitus Smoking SBP at the entrance (mm Hg) DBP at the entrance (mm Hg) SBP reduction at the end of the 1st month (mm Hg) DBP reduction at the end of the 1st month (mm Hg) eGFR ≥ 45 ml/min/1.73 m2 at the entrance SBP controlled a the 6th month according to JNC 8 Withdrawal of ACE-inhibitors/ARB Withdrawal of diuretics

OR

95% CI

P value

0.855 0.714 0.500 0.714 0.978 1.042 1.030

0.723–1.011 0.119–4.297 0.082–3.060 0.061–8.397 0.932–1.026 0.964–1.126 0.981–1.082

0.067 0.713 0.453 0.789 0.366 0.297 0.239

1.001

0.933–1.074

0.985

14.000 1.667

1.741–112.551 0.275–10.094

0.013 0.578

1.000 0.824

0.091–11.028 0.122–5.573

1.000 0.842

ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; SBP: systolic blood pressure.

end of the 6th and 12th months the increase was approximately 30% (+ 18.40 ml/min/1.73 m2, P b 0.0001) and 39% (+ 24.23 ml/min/ 1.73 m2, P b 0.0001), respectively. We also observed that the cumulative percentage of cases with an increase in eGFR was 73.3% at the 1st month, 80.0% at the 6th month and 86.6% at the 12th month post-procedure. To better analyze the factors associated with elevated GFR at 6 and 12 months, logistic regression models were employed, Tables 2–5. For increases in GFR in the 6th month, only the variables age and GFR N 45 ml/min/1.73 m2 at the entrance showed high probability of association (P b 0.10) in the univariate analysis and were therefore included in the multivariate model. At the end, only the GFR N 45 ml/min/ 1.73 m2 was significantly associated with the recovery of GFR at 6 months (OR 28.103; 95% CI 1.704–463.426; P = 0.020). When the

Table 3 Multivariate analysis to test associations with improved glomerular filtration rate at the end of the 6th month after percutaneous renal denervation. Variables tested

OR

95% CI

P value

Age (years) eGFR ≥ 45 ml/min/1.73 m2 at the entrance

0.815 28.103

0.656–1.013 1.704–463.426

0.065 0.020

eGFR: estimated glomerular filtration rate.

11

OR

95% CI

Age (years) 0.950 0.839–1.075 Gender 2.571 0.235–28.089 Type 2 diabetes mellitus 0.148 0.013–1.652 Smoking 0.391 0.030–5.078 SBP at the entrance (mm Hg) 0.939 0.878–1.004 DBP at the entrance (mm Hg) 1.042 0.952–1.141 SBP reduction at the end of 1st month (mm Hg) 1.036 0.977–1.098 DBP reduction at the end of the 1st month 0.956 0.868–1.053 (mm Hg) eGFR ≥ 45 ml/min/1.73 m2 at the entrance 4.200 0.470–37.499 SBP controlled at the 12th month according 23.000 1.773–298.446 to JNC 8 Withdrawal of ACE-inhibitors/ARB 2.302 0.107–49.540 Withdrawal of diuretics 4.886 0.237–100.900

P value 0.413 0.439 0.121 0.473 0.064 0.370 0.238 0.357 0.199 0.016 1.000 0.287

ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; SBP: systolic blood pressure.

analysis was done to assess the increase in GFR at 12 months, the variables with high probability of association (P b 0.10) in the univariate model were the SBP at the entrance, and SBP controlled at the 12th month according to the JNC8 [8]. In the end, only the latter variable remained to have a significant association in the multivariate model (OR 18.561; 95% CI 1.186–290.524; P = 0.037). The reasons for increased eGFR in short and long terms cannot be the same. Early change in eGFR may have resulted from hemodynamic changes. An initial concern was that the increase in eGFR could be due to the increased glomerular capillary pressure which, in the medium term could be harmful to the kidney. However, patients who had an increase in GFR also showed reduction in albumin excretion [3–5], indicating that a harmful increase in glomerular pressure should not have happened. In our view, a reasonable explanation for the initial increase in eGFR would be a reduction in sympathetic tone leading to a decrease in renal vascular resistance and increased renal blood flow, which is known to be a major determinant of glomerular filtration rate [9]. Recently, a study involving 21 patients showed a significant increase in diameters of the renal arteries, six months after they have been submitted to a percutaneous RSD [10], corroborating our hypothesis. Although hemodynamic changes may explain the early increase in eGFR, its gradual increase over time suggests that other factors may have contributed to this finding. It should be remarked that the cumulative percentage of patients who increased eGFR augmented over time. It is quite plausible that the explanation in the long term involves structural changes (tissue remodeling). For this reason, we try to assess the factors associated with improvement in eGFR at 6 and 12 months in logistic regression models. Not surprisingly, the only variable associated with increased glomerular filtration at 6 months was eGFR N 45 ml/min/1.73 m2 at the entrance. In contrast, at 12 months, the only associated factor was the effective control of blood pressure according to JNC8. In this regard, due to better BP control, withdrawal of antihypertensive medications, especially those that harm the renin–angiotensin system and diuretics, should be considered as a possible explanation of the changes in eGFR. This particular point was carefully addressed and the

Table 5 Multivariate analysis to test associations with improved glomerular filtration rate at the end of the 12th month after percutaneous renal denervation. Variables tested

OR

95% CI

P value

SBP at the entrance (mm Hg) SBP controlled at the 12th month according to JNC 8

0.948 18.561

0.878–1.023 1.186–290.524

0.171 0.037

SBP: systolic blood pressure.

12

Letter to the Editor

results of logistic regression testing for both diuretics and for renin–angiotensin–aldosterone system inhibitors do not support this hypothesis. In addition, more precise methods of the assessment of GFR, such as cystatin C or iothalamate, should be used in future studies to confirm our finding regarding the effects of RSD upon the glomerular filtration rate. These diagnostic tools would be more appropriate and helpful to identify subgroups of responders to RSD than the serum creatinine employed in the present study.

References [1] G.F. DiBona, Neural control of the kidney: past, present, and future, Hypertension 41 (2003) 621–624. [2] C. Ott, F. Mahfoud, A. Schmid, S.W. Toennes, S. Ewen, T. Ditting, R. Veelken, C. Ukena, M. Uder, M. Böhm, R.E. Schmieder, Renal denervation preserves renal function in patients with chronic kidney disease and resistant hypertension, J. Hypertens. 33 (Jun 2015) 1261–1266. [3] M.G. Kiuchi, G.L. Maia, M.A. de Queiroz Carreira, T. Kiuchi, S. Chen, B.R. Andrea, M.L. Graciano, J.R. Lugon, Effects of renal denervation with a standard irrigated cardiac ablation catheter on blood pressure and renal function in patients with chronic kidney disease and resistant hypertension, Eur. Heart J. 34 (Jul 2013) 2114–2121.

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