Eva E. Vink

Eligibility for percutaneous renal denervation: the importance of a systematic screening.

Objective: Percutaneous renal denervation (pRDN) is a new and promising therapy for resistant hypertension. Among patients suspected of having resistant hypertension, the actual presence of this condition needs to be well established; pseudoresistant hypertension and significant white-coat effect (WCE) should be excluded. This analysis presents the results of a standardized screening programme for patients referred for pRDN. Methods: All patients referred to our centre for pRDN underwent a standardized stepwise screening and were subsequently discussed in a multidisciplinary team. The screening included a 24-h ambulatory blood pressure measurement (ABPM), collection of plasma, urine and saliva, and finally imaging of the renal arteries. Results: From August 2010 till October 2012, 181 patients were referred for pRDN. Mean blood pressure (BP) was 182/100 mmHg, and median use was three antihypertensives. Ultimately, 121 patients (67%) were excluded from pRDN. Main reasons for exclusion were BP-related. Twenty-three patients (19%) had an office SBP less than 160 mmHg and 26 patients (22%) showed a WCE. Fourteen patients (12%) had a so far undetected underlying cause of hypertension, the majority being primary aldosteronism (n = 11). Nine patients had an ineligible renal anatomy. Conclusion: A high percentage of patients were excluded from treatment with pRDN due to secondary causes of hypertension, WCE or a BP below the currently advised thresholds. Treatment of these excluded patients would lead to inappropriate use of pRDN, leading most likely to little benefit for the patients and a burden to healthcare. Therefore, it is recommended to use a standardized screening before treatment with pRDN.

Eligibility for Renal Denervation: Experience at 11 European Expert Centers

Based on the SYMPLICITY studies and CE (Conformité Européenne) certification, renal denervation is currently applied as a novel treatment of resistant hypertension in Europe. However, information on the proportion of patients with resistant hypertension qualifying for renal denervation after a thorough work-up and treatment adjustment remains scarce. The aim of this study was to investigate the proportion of patients eligible for renal denervation and the reasons for noneligibility at 11 expert centers participating in the European Network COordinating Research on renal Denervation in treatment-resistant hypertension (ENCOReD). The analysis included 731 patients. Age averaged 61.6 years, office blood pressure at screening was 177/96 mm Hg, and the number of blood pressure–lowering drugs taken was 4.1. Specialists referred 75.6% of patients. The proportion of patients eligible for renal denervation according to the SYMPLICITY HTN-2 criteria and each center’s criteria was 42.5% (95% confidence interval, 38.0%–47.0%) and 39.7% (36.2%–43.2%), respectively. The main reasons of noneligibility were normalization of blood pressure after treatment adjustment (46.9%), unsuitable renal arterial anatomy (17.0%), and previously undetected secondary causes of hypertension (11.1%). In conclusion, after careful screening and treatment adjustment at hypertension expert centers, only ≈40% of patients referred for renal denervation, mostly by specialists, were eligible for the procedure. The most frequent cause of ineligibility (approximately half of cases) was blood pressure normalization after treatment adjustment by a hypertension specialist. Our findings highlight that hypertension centers with a record in clinical experience and research should remain the gatekeepers before renal denervation is considered.Based on the SYMPLICITY studies and CE (Conformite Europeenne) certification, renal denervation is currently applied as a novel treatment of resistant hypertension in Europe. However, information on the proportion of patients with resistant hypertension qualifying for renal denervation after a thorough work-up and treatment adjustment remains scarce. The aim of this study was to investigate the proportion of patients eligible for renal denervation and the reasons for noneligibility at 11 expert centers participating in the European Network COordinating Research on renal Denervation in treatment-resistant hypertension (ENCOReD). The analysis included 731 patients. Age averaged 61.6 years, office blood pressure at screening was 177/96 mm Hg, and the number of blood pressure–lowering drugs taken was 4.1. Specialists referred 75.6% of patients. The proportion of patients eligible for renal denervation according to the SYMPLICITY HTN-2 criteria and each center’s criteria was 42.5% (95% confidence interval, 38.0%–47.0%) and 39.7% (36.2%–43.2%), respectively. The main reasons of noneligibility were normalization of blood pressure after treatment adjustment (46.9%), unsuitable renal arterial anatomy (17.0%), and previously undetected secondary causes of hypertension (11.1%). In conclusion, after careful screening and treatment adjustment at hypertension expert centers, only ≈40% of patients referred for renal denervation, mostly by specialists, were eligible for the procedure. The most frequent cause of ineligibility (approximately half of cases) was blood pressure normalization after treatment adjustment by a hypertension specialist. Our findings highlight that hypertension centers with a record in clinical experience and research should remain the gatekeepers before renal denervation is considered. # Novelty and Significance {#article-title-32}

Limited destruction of renal nerves after catheter-based renal denervation: results of a human case study

Renal denervation (RDN) is a promising novel treatment for resistant hypertension. Effectiveness of treatment is, however, highly variable and unpredictable. Incomplete denervation of the renal nerves is a plausible explanation for the variable blood pressure lowering effect of RDN. Here, we present for the first time a histopathological evaluation of the effects of RDN on perivascular nerves of the renal arteries in a human patient. Our findings potentially have important implications for future directions with RDN.

Sympathetic Hyperactivity in Chronic Kidney Disease: Pathophysiology and (New) Treatment Options

Abundant evidence shows that chronic kidney disease (CKD) is a disease state characterized by increased sympathetic activation. Kidney injury (ischemia) plays a central role in this pathogenesis. Sympathetic excitation is associated with an increased risk of cardiovascular morbidity and mortality. Several pharmacologic strategies are developed to decrease sympathetic activity. However, these medications have limitations. Percutaneous catheter-based renal denervation has the potential to become a new treatment option for CKD. This current report focuses on the effects of sympathetic hyperactivity in CKD, and gives an overview in experimental as well as clinical evidence for a central role of the kidneys in the pathophysiology of sympathetic hyperactivity. Moreover, the effect of pharmacologic treatment and the potential beneficial effect of renal denervation will be discussed.

Evidence and consequences of the central role of the kidneys in the pathophysiology of sympathetic hyperactivity.

Chronic elevation of the sympathetic nervous system has been identified as a major contributor to the complex pathophysiology of hypertension, states of volume overload – such as heart failure – and progressive kidney disease. It is also a strong determinant for clinical outcome. This review focuses on the central role of the kidneys in the pathogenesis of sympathetic hyperactivity. As a consequence, renal denervation may be an attractive option to treat sympathetic hyperactivity. The review will also focus on first results and the still remaining questions of this new treatment option.

Denervation of the Renal Arteries in Metabolic Syndrome The DREAMS-Study

Chronic elevation of sympathetic nervous system is a key factor in metabolic syndrome. Because renal denervation (RDN) is thought to modulate sympathetic activity, we performed the Denervation of the Renal Arteries in Metabolic Syndrome (DREAMS)–study to investigate the effects of RDN on insulin sensitivity and blood pressure (BP) in patients with metabolic syndrome. Twenty-nine patients fulfilling the criteria for metabolic syndrome and who used a maximum of 1 antihypertensive or 1 antidiabetic drug or 1 of both gave informed consent and were treated by RDN. Glucose tolerance tests and 24-hour ambulatory BP measurements were performed at baseline, at 6 and 12 months of follow-up. Moreover, we performed self-monitored BP measurements at home every month. To assess sympathetic activity, we performed muscle sympathetic nerve activity and heart rate variability measurements at baseline and follow-up. The majority of the included patients was men (57%), mean body mass index was 31±5 kg/m2. Median insulin sensitivity as assessed by the Simple Index assessing Insulin Sensitivity oral glucose tolerance test did not change at 6- and 12-month follow-up (P=0.60 and P=0.77, respectively). Mean 24-hour BP decreased by 6±12/5±7 mm Hg 12 months after RDN (P=0.04/0.01). However, self-monitored BP measurements data showed no reduction over time. Measurements of sympathetic activity showed no reduction in systemic sympathetic activity. In conclusion, RDN did not lead to a significant improvement of insulin sensitivity ⩽12 months after treatment. Although a significant reduction in ambulatory BP was observed in this nearly drug-naïve population, the self-monitored BP measurements data suggest that this may be explained by regression to the mean. Moreover, no effect in systemic sympathetic activity was observed.

Effects of renal denervation on end organ damage in hypertensive patients

Background Renal denervation (RDN) is believed to reduce sympathetic nerve activity and is a potential treatment for resistant hypertension. The present study investigated the effects of RDN on end organ damage (EOD). Design The present study was a prospective cohort study (registered as NCT01427049). Methods Uncontrolled hypertensive patients underwent a work-up prior to and one year after RDN. Cardiac magnetic resonance (CMR) imaging was used to determine left ventricular (LV)-mass; pulse wave analysis and pulse wave velocity (PWV) were used for evaluation of central blood pressure (BP) and arterial stiffness and 24-hour urine was collected for assessment of urinary albumin excretion. The 24-hour ambulatory BP measurement (ABPM) was used to evaluate the effect of RDN on BP. Results Fifty-four patients gave informed consent for study participation. Mean age was 58 ± 10 years, 50% were male. One year after RDN, mean ABPM decreased by 7 ± 18/5 ± 11 mm Hg (p = 0.01/p < 0.01). In the patients followed-up in a standardised fashion ABPM decreased by 5 ± 18/4 ± 12 mm Hg (n = 34; p = 0.11/p = 0.09). Mean body surface area indexed LV-mass decreased by 3.3 ± 11.5 g/m2 (corresponding to a 3 ± 11% reduction; p = 0.09). PWV increased by 2.9 (−2.2 to +6.1) m/s (p = 0.04). Augmentation index corrected for 75 beats per min did not change (median increase 3.0 (−7 to +17) mm Hg; p = 0.89). Urinary albumin excretion did not change during follow-up (mean decrease 10 ± 117 mg/24 hour; p = 0.61). Conclusion In the current study, we observed a modest effect from renal denervation. Moreover, RDN did not result in a statistical significant effect on end organ damage 12 months after treatment.

The blood pressure-lowering effect of renal denervation is inversely related to kidney function.

Objectives: In renal denervation (RDN), a wide range in the blood pressure (BP)-lowering effect has been reported. On the basis of the current knowledge of pathophysiology, we hypothesized that the BP-lowering effect of RDN would be inversely related to kidney function. Second, we investigated whether direct and indirect variables of the renin–angiotensin–aldosterone system (RAAS) and the sympathetic nervous system (SNS) would be related as well. Methods: Sixty-seven patients from a prospective cohort of patients treated with RDN with completed 6 months follow-up were included. Data collected during routine standardized work-up before RDN were used: 24-h urine excretion of creatinine, albumin, sodium and catecholamines, plasma creatinine, renin activity and aldosterone, ambulatory BP-monitoring and a captopril challenge test. When considered well tolerated, antihypertensive drugs were stopped before these investigations. Results: The BP-lowering was inversely related to estimated glomerular filtration rate (eGFR) in patients who stopped antihypertensive drugs prior to testing (ß: 0.46, P = 0.013). There was a positive relation between SBP at baseline and the BP-lowering effect of RDN (ß:–0.55 mmHg per mmHg, P < 0.001). Parameters related to the rennin–angiotensin system (aldosterone, captopril test) and the sympathetic nervous system (dipping pattern and catecholamines in urine) positively related to the BP-lowering effect of RDN. Conclusion: The present explorative study shows an inverse relation between the BP-lowering effect of RDN and eGFR. Second, we found relations between variables of the RAAS and SNS with the BP-lowering effect of RDN. The data complement current concepts on pathophysiology of sympathetic hyperactivity and hypertension and may give some insight in the wide range of the effect of RDN.

Renal denervation in multiple renal arteries

In most previous studies investigating efficacy of renal denervation (RDN), patients with multiple renal arteries are generally excluded from treatment. This study was designed to determine the prevalence of multiple renal arteries in patients referred for RDN, to propose a classification for anatomical eligibility and to investigate the relation between the presence of multiple arteries and blood pressure (BP)‐lowering effect.

Renal BOLD-MRI relates to kidney function and activity of the renin-angiotensin-aldosterone system in hypertensive patients

Background: The renin–angiotensin–aldosterone system (RAAS) and the sympathetic nervous system are key factors in the pathophysiology of hypertension. Renal hypoxia is the putative mechanism stimulating both systems. Blood oxygen level-dependent MRI (BOLD-MRI) provides a noninvasive tool to determine renal oxygenation in humans. The aim of the current study was to investigate the relation between blood pressure (BP) and kidney function with renal BOLD-MRI. Moreover, the relation between direct and indirect variables of the RAAS and sympathetic nervous system and renal BOLD-MRI was studied. Method: Seventy-five hypertensive patients (38 men) were included. Antihypertensive medication was temporarily stopped. Patients collected urine during 24 h (sodium, catecholamines), blood samples were taken (creatinine, renin, aldosterone), a captopril challenge test was performed, and ambulatory BP was measured. Results: Mean age was 58 (±11) years, day-time BP was 167 (±19)/102 (±16) mmHg, and estimated glomerular filtration rate was 75 (±18) ml/min per 1.73 m2). In multivariable regression analysis, renal medullary R2*-values inversely related to estimated glomerular filtration rate (P = 0.02). Moreover, the BP-lowering effect of captopril positively related to cortical (P = 0.02) and medullary (P = 0.008) R2*-values, as well as to P90 (P = 0.02). Conclusion: In patients with hypertension, kidney function relates to medullary R2*-values. Activation of the RAAS is also positively related to the renal R2*-values.