Tilmann Ditting

Renal Denervation in Moderate Treatment-Resistant Hypertension

OBJECTIVES This study sought to investigate the effect of renal denervation (RDN) in patients with treatment-resistant hypertension according to the established definition (Joint National Committee VII and European Society of Hypertension/European Society of Cardiology guidelines), that is, office blood pressure (BP) ≥140/90 mm Hg (with at least three antihypertensive drugs, including a diuretic, in adequate doses) and confirmed by 24-h ambulatory BP monitoring (ABPM). BACKGROUND RDN emerged as an innovative interventional antihypertensive therapy. However, so far, only patients with severe hypertension (systolic BP ≥160 mm Hg or ≥150 mm Hg for patients with type 2 diabetes) have been investigated. METHODS In this study, there were 54 patients with moderate treatment-resistant hypertension (office BP ≥140/90 mm Hg and <160/100 mm Hg and diagnosis confirmed by 24-h ABPM of ≥130/80 mm Hg) who underwent catheter-based RDN using the Symplicity catheter (Medtronic Inc., Mountain View, California). RESULTS Patients were treated with 5.1 ± 1.4 antihypertensive drugs on average. Office BP was significantly reduced by 13/7 mm Hg 6 months after RDN (systolic: 151 ± 6 mm Hg vs. 138 ± 21 mm Hg, p < 0.001; diastolic: 83 ± 11 mm Hg vs. 75 ± 11 mm Hg, p < 0.001). In patients (n = 36) who underwent ABPM 6 months after treatment, there was a reduction in average 24-h ABPM by 14/7 mm Hg (systolic: 150 ± 16 mm Hg vs. 136 ± 16 mm Hg, p < 0.001; diastolic: 83 ± 10 mm Hg vs. 76 ± 10 mm Hg, p < 0.001). In 51% of patients, office BP was controlled below 140/90 mm Hg after RDN. In addition, heart rate decreased from 67 ± 11 to 63 ± 10 beats/min (p = 0.006). CONCLUSIONS Our data indicate that RDN may reduce office and 24-h ambulatory BP substantially in patients with moderate treatment-resistant hypertension. (Renal Denervation in Treatment Resistant Hypertension; NCT01687725).

Renal denervation preserves renal function in patients with chronic kidney disease and resistant hypertension.

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 treatment-resistant 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 = 0.005) and average 24-h ambulatory BP by 9 ± 14 (P = 0.009)/4 ± 7 mmHg (P = 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 +1.5 ± 10 ml/min per 1.73 m2 at 12 months (P = 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.

Improvement of albuminuria after renal denervation

OBJECTIVES The primary objective of this study was the effect of renal denervation (RDN) on elevated urinary albumin-to-creatinine ratio (UACR) in treatment-resistant hypertensive patients. In addition, patients were stratified according their UACR at baseline into micro- (30-300 mg/g, n=37) and macroalbuminuria (≥ 300 mg/g, <2,200 mg/g, n=22). BACKGROUND Increased albuminuria indicates cardiovascular and renal damage in hypertension. RDN emerged as an innovative interventional approach to reduce blood pressure (BP) and may thus reduce albumin urinary excretion. METHODS Fifty-nine treatment-resistant hypertensive patients with elevated UACR at baseline underwent catheter-based RDN using the Symplicity Flex™ catheter (Medtronic Inc., Santa Rosa, CA). RESULTS In the whole and pre-specified subgroups both office and 24-h ambulatory BP were significantly reduced 6 months after RDN. In parallel, a significant reduction in UACR occurred in all patients (160 (65-496) versus 89 (29-319) mg/g creatinine, p<0.001) and in both subgroups (microalbuminuria: 83 (49-153) versus 58 (17-113) mg/g creatinine, p=0.001; macroalbuminuria: (536 (434-1483) versus 478 (109-1080) mg/g creatinine, p<0.001). In accordance, the prevalence of micro- and macroalbuminuria decreased significantly. Regression analysis revealed a modest positive relationship between the decrease of UACR and the fall of systolic BP (β=0.340, p=0.039) independent of renal function. Renal function remained unchanged after RDN. CONCLUSIONS In summary, following RDN, the magnitude of albuminuria as well as the prevalence of micro- and macroalbuminuria decreased in treatment-resistant hypertensive patients. Since albuminuria is an independent renal and cardiovascular risk factor, our findings suggest a reduction of renal and cardiovascular risk in these patients.

Vascular and Renal Hemodynamic Changes after Renal Denervation

BACKGROUND AND OBJECTIVES Renal denervation (RDN) has been shown to be effective in reducing BP in treatment-resistant hypertension. Measurement of the renal and sympathetic activity revealed a decrease in sympathetic drive to the kidney and small resistance vessels after RDN. However, the consequences on renal perfusion and renal vascular resistance (RVR), as well as central hemodynamics, are unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Nineteen patients with treatment-resistant hypertension (office BP≥140/90 mmHg, despite at least three antihypertensive drugs [including a diuretic], and diagnosis confirmed by 24-hour ambulatory BP monitoring) underwent RDN between January and October 2011. Renal perfusion and RVR were noninvasively assessed by magnetic resonance imaging with arterial spin labeling, and renal function was assessed by estimating GFR before (day -1), after (day +1), and again after 3 months of RDN. Central hemodynamics was assessed using pulse wave analysis at day -1 and after 6 months of RDN. RESULTS Peripheral office BP (systolic, 158±26 versus 142±23 mmHg, P=0.002; diastolic, 83±13 versus 76±9 mmHg, P=0.02) and mean systolic 24-hour ambulatory BP (159±17 versus 152±17 mmHg, P=0.02) were significantly reduced 6 months after RDN. Renal perfusion was not statistically different between day -1 and day +1 (256.8 [interquartile range (IQR), 241-278] versus 263.4 [IQR, 252-277] ml/min per 100 g; P=0.17) as well as after 3 months (256.8 [IQR, 241-278] versus 261.2 [IQR, 240-285] ml/min per 100 g; P=0.27) after RDN. RVR dropped (432.1 [IQR, 359-525] versus 390.6 [IQR, 338-461] AU; P=0.02), whereas renal function was not statistically different at any time point. Central systolic BP (145±31 versus 131±28 mmHg; P=0.009), diastolic BP (85±18 versus 80±14 mmHg; P=0.03), and central pulse pressure (61±18 versus 52±18 mmHg; P=0.02) were significantly reduced 6 months after RDN. Central augmentation index (24±8 versus 20±8%; P=0.02) was decreased 6 months after RDN. CONCLUSION The data indicate that RDN significantly reduced peripheral and central BP. Despite reduced systemic BP, renal perfusion and function did not change after RDN.

Renal Denervation in a Hypertensive Patient With End‐Stage Renal Disease and Small Arteries: A Direction for Future Research

J Clin Hypertens (Greenwich). 2012;14:799–801. ©2012 Wiley Periodicals, Inc.

Tonic Postganglionic Sympathetic Inhibition Induced by Afferent Renal Nerves

Other than efferent sympathetic innervation, the kidney has peptidergic afferent fibers expressing TRPV1 receptors and releasing substance P. We tested the hypothesis that stimulation of afferent renal nerve activity with the TRPV1 agonist capsaicin inhibits efferent renal sympathetic nerve activity tonically by a neurokinin 1 receptor–dependant mechanism. Anesthetized Sprague-Dawley rats were instrumented as follows: (1) arterial and venous catheters for recording of blood pressure and heart rate and drug administration; (2) left-sided renal arterial catheter for selective intrarenal administration of the TRPV1 agonist capsaicin (3.3, 6.6, 10, 33*10−7 M; 10 &mgr;L; after 15, 30, 45, and 60 minutes, respectively) to stimulate afferent renal nerve activity; (3) right-sided bipolar electrode for continuous renal sympathetic nerve recording; and (4) specialized renal pelvic and renal artery catheters to separate pelvic from intrarenal afferent activity. Before and after intrarenal capsaicin application, increasing intravenous doses of the neurokinin 1 receptor blocker RP67580 were given. Intrarenal capsaicin decreased integrated renal sympathetic activity from 65.4±13.0 mV*s (baseline) to 12.8±3.2 mV*s (minimum; P<0.01). This sustained renal sympathetic inhibition reached its minimum within 70 minutes and was not directly linked to the transient electric afferent response to be expected with intrarenal capsaicin. Suppressed renal sympathetic activity transiently but completely recovered after intravenous administration of the neurokinin 1 blocker (maximum: 120.3±19.4 mV*s; P<0.01). Intrarenal afferent activity could be unequivocally separated from pelvic afferent activity. For the first time we provide direct evidence that afferent intrarenal nerves provide a tonically acting sympathoinhibitory system, which seems to be rather mediated by neurokinin release acting via neurokinin 1 receptor pathways rather than by electric afferent effects on central sympathetic outflow.

Impaired cardiovascular reflexes precede deoxycorticosterone acetate-salt hypertension.

We hypothesized that impaired cardiopulmonary reflexes but not altered baroreceptor reflexes precede deoxycorticosterone acetate (DOCA)-salt hypertension. Uninephrectomized rats were given either DOCA and 0.9% NaCl as drinking water, 0.9% NaCl alone, or tap water. We measured mean blood pressure, heart rate, and renal sympathetic nerve activity. After 8 days, mean blood pressure was not different in DOCA-salt and control rats. Volume-sensitive cardiopulmonary reflexes were tested by intravenous volume loading with saline (10% body weight in 15 minutes), which decreased renal sympathetic nerve activity without changing mean blood pressure or heart rate. This response was blunted in DOCA-salt rats. Chemosensitive cardiopulmonary reflexes were tested by 15-minute infusions of the serotonin 5-HT3 agonist phenylbiguanide, which decreased renal sympathetic nerve activity without changing mean blood pressure or heart rate. Sustained decreases in renal sympathetic nerve activity occurred during phenylbiguanide infusion in controls but were blunted over time in DOCA-salt rats. The arterial baroreflex responses to graded infusions of methoxamine and nitroprusside were analyzed by sigmoidal curve fitting. There were no differences in gain of renal sympathetic nerve activity or heart rate between the groups. Thus, DOCA-salt rats exhibit impaired cardiopulmonary reflexes before the onset of hypertension; the volume-sensitive reflexes are more severely affected than chemosensitive reflexes. The arterial baroreceptor reflex is unaltered. The decreased sensitivity of cardiopulmonary reflexes may contribute to DOCA-salt hypertension.

Do distinct populations of dorsal root ganglion neurons account for the sensory peptidergic innervation of the kidney

Peptidergic afferent renal nerves (PARN) have been linked to kidney damage in hypertension and nephritis. Neither the receptors nor the signals controlling local release of neurokinines [calcitonin gene-related peptide (CGRP) and substance P (SP)] and signal transmission to the brain are well-understood. We tested the hypothesis that PARN, compared with nonrenal afferents (Non-RN), are more sensitive to acidic stimulation via transient receptor potential vanilloid type 1 (TRPV1) channels and exhibit a distinctive firing pattern. PARN were distinguished from Non-RN by fluorescent labeling (DiI) and studied by in vitro patch-clamp techniques in dorsal root ganglion neurons (DRG; T11-L2). Acid-induced currents or firing due to current injection or acidic superfusion were studied in 252 neurons, harvested from 12 Sprague-Dawley rats. PARN showed higher acid-induced currents than Non-RN (transient: 15.9 +/- 5.1 vs. 0.4 +/- 0.2* pA/pF at pH 6; sustained: 20.0 +/- 4.5 vs. 6.2 +/- 1.2* pA/pF at pH 5; *P < 0.05). The TRPV1 antagonist capsazepine inhibited sustained, amiloride-transient currents. Forty-eight percent of PARN were classified as tonic neurons (TN = sustained firing during current injection), and 52% were phasic (PN = transient firing). Non-RN were rarely tonic (15%), but more frequently phasic (85%), than PARN (P < 0.001). TN were more frequently acid-sensitive than PN (50-70 vs. 2-20%, P < 0.01). Furthermore, renal PN were more frequently acid-sensitive than nonrenal PN (20 vs. 2%, P < 0.01). Confocal microscopy revealed innervation of renal vessels, tubules, and glomeruli by CGRP- and partly SP-positive fibers coexpressing TRPV1. Our data show that PARN are represented by a very distinct population of small-to-medium sized DRG neurons exhibiting more frequently tonic firing and TRPV1-mediated acid sensitivity. These very distinct DRG neurons might play a pivotal role in renal physiology and disease.

Adherence to Antihypertensive Medication in Treatment‐Resistant Hypertension Undergoing Renal Denervation

Background Adherence to medication has been repeatedly proposed to represent a major cause of treatment‐resistant hypertension (TRH); however, treatment decisions such as treating TRH with renal denervation depend on accurate judgment of adherence. We carefully analyzed adherence rates to medication before and after renal denervation and its effect on blood pressure (BP) control. Methods and Results Eighty patients with TRH were included in 2 prospective observational studies that assessed the difference of potential antihypertensive and nephroprotective effects of renal denervation. To compare prescribed with actual medication intake (representing a measure of adherence), we analyzed urine samples collected at baseline and at 6 months after renal denervation for antihypertensive compounds or metabolites (by liquid chromatography–mass spectrometry). In addition to office BP, 24‐hour ambulatory BP and central hemodynamics (central systolic pressure, central pulse pressure) were assessed. Informed consent for analyses of urine metabolites was obtained from 79 of 80 patients. Actual intake of all antihypertensive drugs was detected at baseline and at 6 months after renal denervation in 44 (56%) and 52 (66%) patients, respectively; 1 drug was missing in 22 (28%) and 17 (22%) patients, respectively, and ≥2 drugs were missing in 13 (16%) and 10 (13%) patients, respectively. At baseline, 24‐hour ambulatory BP (P=0.049) and central systolic BP (P=0.012) were higher in nonadherent patients. Adherence did not significantly change overall (McNemar‐Bowker test, P=0.362). An increase in adherence was observed in 21 patients, and a decrease was observed in 11 patients. The decrease in 24‐hour ambulatory BP was not different in those with stable adherence 6 months after renal denervation (n=41, −7±13 mm Hg) compared with those with increased adherence (n=21, −10±13 mm Hg) and decreased adherence (n=11, −7±14 mm Hg) (P>0.20). Our study is limited by the relatively small sample size and potentially by the specific health environment of our university center (Northern Bavaria, Germany). Conclusions Nonadherence to medication among patients with TRH was relatively low: ≈1 of 6 patients with TRH did not take ≥2 of the prescribed drugs. Adherence pattern did not change significantly after renal denervation and had no impact on the overall observed BP changes, supporting the concept that renal denervation is an effective treatment in patients with TRH. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifiers: NCT00888433, NCT01442883 and NCT01687725.

Autonomous innervation in renal inflammatory disease—innocent bystander or active modulator?

Increasing evidence suggests a significant interrelation between the autonomic nervous system and the immune system. The kidney is innervated by efferent sympathetic nerves as well as by peptidergic sensory afferent nerve fibers. Inflammation in the kidney may be affected by both types of fibers. Peptidergic “sensory” neurons might play a particularly important role: These fibers can induce local neurogenic inflammation via paracrine effects of their transmitters and evoke increased efferent sympathetic nerve outflow via their projections to the central nervous system. Several reports support the notion that renal innervation does indeed contribute to inflammation and sclerosis in kidney diseases. Hence, receptor antagonists interfering with the interaction of innervation and the immune system may prove useful to mitigate inflammatory processes in the kidney.