Original Article
Renal denervation preserves renal function in patients with chronic kidney disease and resistant hypertension Christian Ott a, Felix Mahfoud b, Axel Schmid c, Stefan W. Toennes d, Sebastian Ewen b Tilmann Ditting a, Roland Veelken a, Christian Ukena b, Michael Uder c, Michael Bo¨hm b Roland E. Schmieder a
Objectives: Arterial hypertension and increased sympathetic activity are underlying pathogenetic mechanisms of the progressive loss of renal function in patients with chronic kidney disease (CKD). Meta-analyses have shown that impaired renal function is an independent cardiovascular risk factor. We hypothesized that renal denervation (RDN) decreases the decline of renal function in patients with CKD stages 3 and 4 and treatmentresistant hypertension. Methods: We performed an observational study of 27 patients with CKD stages 3 and 4, office blood pressure (BP) 140/90 mmHg, while on at least three antihypertensive drug classes including diuretic, and diagnosis confirmed by 24-h ambulatory BP measurement 130/80 mmHg. All patients underwent catheter-based RDN using the Symplicity Flex RDN System (Medtronic Inc., Santa Rosa, California, USA). Renal function was evaluated for up to 3 years prior and 1 year after RDN. The change in estimated glomerular filtration rate (eGFR) was calculated by regression slope individually for each patient before and after RDN. The study was registered at www.clinicaltrials.gov (ID: NCT01442883). Results: Mean baseline BP was 156 12/82 13 mmHg, despite treatment with 6.2 1.1 antihypertensive drugs. One year after RDN, office BP was reduced by 20 20 (P < 0.001)/8 14 mmHg (P ¼ 0.005) and average 24-h ambulatory BP by 9 14 (P ¼ 0.009)/4 7 mmHg (P ¼ 0.019). Before RDN, eGFR declined by –4.8 3.8 ml/ min per 1.73 m2 per year, and after RDN eGFR improved by R1.5 10 ml/min per 1.73 m2 at 12 months (P ¼ 0.009). Conclusions: Our observational pilot study in patients with CKD stages 3 and 4 indicates that treatment of hypertension with RDN decreases BP and slows or even halts the decline of renal function. Keywords: blood pressure, chronic kidney disease, renal denervation, renal function, treatment-resistant hypertension Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease; RAS, renin–angiotensin system; RDN, renal denervation; TRH, treatment-resistant hypertension
INTRODUCTION
T
here is a strong association between arterial hypertension, chronic kidney disease (CKD), and cardiovascular disease. In a population-based cohort study in patients with CKD, reduced estimated glomerular filtration rate (eGFR) was frequently associated with treatmentresistant hypertension (TRH) [1]. Moreover, meta-analyses have shown that impaired renal function is an independent cardiovascular risk factor [2]. In a meta-analysis of randomized prospective, long-term studies in nondiabetic and diabetic patients with renal disease, achieving better blood pressure (BP) control was associated with better preservation of renal function [3]. However, the latest tested treatment strategies for slowing the progression of renal function loss [e.g., dual renin–angiotensin system (RAS) blockade, bardoxolone] failed or were associated with higher side-effects in patients with CKD [4–6]. New treatment modalities that slow or even halt the progressive loss of kidney function are therefore urgently needed. Experimental models [7] and human studies [8,9] have identified elevated sympathetic nervous system activity (in addition to hypertension) as a major contributor to the progression of renal function decline. Increased muscle sympathetic nerve activity assessed by microneurography was closely related to decreased eGFR in hypertensive patients [9]. In patients with impaired renal function, renal function decline was attenuated in patients treated with moxonidine compared with those treated with nitrendipine. As BP was only slightly affected, this finding points to a BP-independent effect of moxonidine, a drug known to decrease sympathetic activity [10].
Journal of Hypertension 2015, 33:1261–1266 a Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, bKlinik fu¨r Innere Medizin III, Universita¨tsklinikum des Saarlandes, Homburg/ Saar, cDepartment of Radiology, University of Erlangen-Nuremberg, Erlangen and d Department of Forensic Toxicology, Institute of Legal Medicine, Goethe University, Frankfurt/Main, Germany
Correspondence to Prof. Dr Roland E. Schmieder, Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Ulmenweg 18, Erlangen 91054, Germany. Tel: +49 9131 853 6245; fax: +49 9131 853 6215; e-mail: [email protected] Received 17 October 2014 Revised 28 January 2015 Accepted 28 January 2015 J Hypertens 33:1261–1266 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI:10.1097/HJH.0000000000000556
Journal of Hypertension
www.jhypertension.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
1261
Ott et al.
Renal denervation (RDN) has emerged as an innovative interventional approach to decrease renal and central sympathetic activity and reduce BP in patients with TRH [11–15]. These studies mainly focused on patients with preserved renal function (eGFR >45 ml/min per 1.73 m2) and eGFR was introduced in these trials only as a safety parameter. The extended long-term follow-up of the Symplicity HTN-1 trial, as well as the Symplicity HTN-2 trial, demonstrated stable eGFR after 1 year [16,17]. In contrast, only limited data (N ¼ 5 with 12 months follow-up) are available in patients with TRH and eGFR < 45 ml/min per 1.73 m2, and no comparison to a control group or retrospective evaluations of renal function decline prior to RDN have been performed [18]. In the present study, we aimed to assess the decline of renal function in the treatment of hypertensive patients with CKD stages 3 and 4 over time and analyze whether reducing BP by RDN may preserve renal function.
METHODS Study cohort This pilot study included 27 patients with CKD stages 3 and 4 (eGFR < 60 ml/min/1.73 m2, but > 15 ml/min per 1.73 m2) and TRH (JNC 7 [19] and ESH/ESC guidelines [20]) who underwent RDN. Patients had to be on a stable drug regime (i.e. without change in dose or medication) for at least 4 weeks. In line with the recent position articles of the ESH [21,22] and the ESC [23], main exclusion criteria were renal artery anatomy that was ineligible for treatment (main renal arteries 45 ml/min per 1.73 m2) and eGFR was only included as a safety parameter in the study protocol. Our study included patients with CKD stages 3 and 4 and required as an additional inclusion criteria true TRH (office BP 140/90 mmHg, despite being treated with at least three antihypertensive drugs including a diuretic and confirmation by 24-h ABPM). Estimated GFR is generally accepted as the best clinical parameter of kidney function and small fluctuations in eGFR are common and do not necessarily indicate progressive decline of renal function. Therefore, we evaluated the decline of renal function retrospectively up to 3 years prior to RDN and monitored eGFR prospectively 1 year after RDN, thereby providing data for an intraindividual comparison in each patient. We calculated eGFR using the MDRD formula, since it has been shown that MDRD has greater accuracy and less bias at lower levels (
Renal denervation preserves renal function in patients with chronic kidney disease and resistant hypertension Christian Ott a, Felix Mahfoud b, Axel Schmid c, Stefan W. Toennes d, Sebastian Ewen b Tilmann Ditting a, Roland Veelken a, Christian Ukena b, Michael Uder c, Michael Bo¨hm b Roland E. Schmieder a
Objectives: Arterial hypertension and increased sympathetic activity are underlying pathogenetic mechanisms of the progressive loss of renal function in patients with chronic kidney disease (CKD). Meta-analyses have shown that impaired renal function is an independent cardiovascular risk factor. We hypothesized that renal denervation (RDN) decreases the decline of renal function in patients with CKD stages 3 and 4 and treatmentresistant hypertension. Methods: We performed an observational study of 27 patients with CKD stages 3 and 4, office blood pressure (BP) 140/90 mmHg, while on at least three antihypertensive drug classes including diuretic, and diagnosis confirmed by 24-h ambulatory BP measurement 130/80 mmHg. All patients underwent catheter-based RDN using the Symplicity Flex RDN System (Medtronic Inc., Santa Rosa, California, USA). Renal function was evaluated for up to 3 years prior and 1 year after RDN. The change in estimated glomerular filtration rate (eGFR) was calculated by regression slope individually for each patient before and after RDN. The study was registered at www.clinicaltrials.gov (ID: NCT01442883). Results: Mean baseline BP was 156 12/82 13 mmHg, despite treatment with 6.2 1.1 antihypertensive drugs. One year after RDN, office BP was reduced by 20 20 (P < 0.001)/8 14 mmHg (P ¼ 0.005) and average 24-h ambulatory BP by 9 14 (P ¼ 0.009)/4 7 mmHg (P ¼ 0.019). Before RDN, eGFR declined by –4.8 3.8 ml/ min per 1.73 m2 per year, and after RDN eGFR improved by R1.5 10 ml/min per 1.73 m2 at 12 months (P ¼ 0.009). Conclusions: Our observational pilot study in patients with CKD stages 3 and 4 indicates that treatment of hypertension with RDN decreases BP and slows or even halts the decline of renal function. Keywords: blood pressure, chronic kidney disease, renal denervation, renal function, treatment-resistant hypertension Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease; RAS, renin–angiotensin system; RDN, renal denervation; TRH, treatment-resistant hypertension
INTRODUCTION
T
here is a strong association between arterial hypertension, chronic kidney disease (CKD), and cardiovascular disease. In a population-based cohort study in patients with CKD, reduced estimated glomerular filtration rate (eGFR) was frequently associated with treatmentresistant hypertension (TRH) [1]. Moreover, meta-analyses have shown that impaired renal function is an independent cardiovascular risk factor [2]. In a meta-analysis of randomized prospective, long-term studies in nondiabetic and diabetic patients with renal disease, achieving better blood pressure (BP) control was associated with better preservation of renal function [3]. However, the latest tested treatment strategies for slowing the progression of renal function loss [e.g., dual renin–angiotensin system (RAS) blockade, bardoxolone] failed or were associated with higher side-effects in patients with CKD [4–6]. New treatment modalities that slow or even halt the progressive loss of kidney function are therefore urgently needed. Experimental models [7] and human studies [8,9] have identified elevated sympathetic nervous system activity (in addition to hypertension) as a major contributor to the progression of renal function decline. Increased muscle sympathetic nerve activity assessed by microneurography was closely related to decreased eGFR in hypertensive patients [9]. In patients with impaired renal function, renal function decline was attenuated in patients treated with moxonidine compared with those treated with nitrendipine. As BP was only slightly affected, this finding points to a BP-independent effect of moxonidine, a drug known to decrease sympathetic activity [10].
Journal of Hypertension 2015, 33:1261–1266 a Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, bKlinik fu¨r Innere Medizin III, Universita¨tsklinikum des Saarlandes, Homburg/ Saar, cDepartment of Radiology, University of Erlangen-Nuremberg, Erlangen and d Department of Forensic Toxicology, Institute of Legal Medicine, Goethe University, Frankfurt/Main, Germany
Correspondence to Prof. Dr Roland E. Schmieder, Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Ulmenweg 18, Erlangen 91054, Germany. Tel: +49 9131 853 6245; fax: +49 9131 853 6215; e-mail: [email protected] Received 17 October 2014 Revised 28 January 2015 Accepted 28 January 2015 J Hypertens 33:1261–1266 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI:10.1097/HJH.0000000000000556
Journal of Hypertension
www.jhypertension.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
1261
Ott et al.
Renal denervation (RDN) has emerged as an innovative interventional approach to decrease renal and central sympathetic activity and reduce BP in patients with TRH [11–15]. These studies mainly focused on patients with preserved renal function (eGFR >45 ml/min per 1.73 m2) and eGFR was introduced in these trials only as a safety parameter. The extended long-term follow-up of the Symplicity HTN-1 trial, as well as the Symplicity HTN-2 trial, demonstrated stable eGFR after 1 year [16,17]. In contrast, only limited data (N ¼ 5 with 12 months follow-up) are available in patients with TRH and eGFR < 45 ml/min per 1.73 m2, and no comparison to a control group or retrospective evaluations of renal function decline prior to RDN have been performed [18]. In the present study, we aimed to assess the decline of renal function in the treatment of hypertensive patients with CKD stages 3 and 4 over time and analyze whether reducing BP by RDN may preserve renal function.
METHODS Study cohort This pilot study included 27 patients with CKD stages 3 and 4 (eGFR < 60 ml/min/1.73 m2, but > 15 ml/min per 1.73 m2) and TRH (JNC 7 [19] and ESH/ESC guidelines [20]) who underwent RDN. Patients had to be on a stable drug regime (i.e. without change in dose or medication) for at least 4 weeks. In line with the recent position articles of the ESH [21,22] and the ESC [23], main exclusion criteria were renal artery anatomy that was ineligible for treatment (main renal arteries 45 ml/min per 1.73 m2) and eGFR was only included as a safety parameter in the study protocol. Our study included patients with CKD stages 3 and 4 and required as an additional inclusion criteria true TRH (office BP 140/90 mmHg, despite being treated with at least three antihypertensive drugs including a diuretic and confirmation by 24-h ABPM). Estimated GFR is generally accepted as the best clinical parameter of kidney function and small fluctuations in eGFR are common and do not necessarily indicate progressive decline of renal function. Therefore, we evaluated the decline of renal function retrospectively up to 3 years prior to RDN and monitored eGFR prospectively 1 year after RDN, thereby providing data for an intraindividual comparison in each patient. We calculated eGFR using the MDRD formula, since it has been shown that MDRD has greater accuracy and less bias at lower levels (
