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Previous work of ours suggests that the sensitivity of renal afferent neurons is decreased under pathological conditions. Here we tested the hypothesis that pathologically decreased sensitivity of renal afferent neurons due to high salt diet is normalized after renal denervation. 6 male Sprague Dawley (SD) rats were put on high salt diet (HS; 8% NaCl) for 10 days. In another group of 18 rats on high salt diet (HS) left kidneys were denervated (DNX) 7 days prior to examination. 17 rats on standard diet with and without DNX were used as controls. Dorsal root ganglion neurons with renal afferents were investigated in primary neuronal cell culture using current clamp mode to assess action potential generation during current injection. Neurons were characterized as tonic highly active (> 5 action potentials, AP) and phasic less active neurons (≤ 5 AP upon stimulation)In renal neurons from rats on HS the relation of tonic to phasic neurons shifted towards less active phasic units (62% tonic neurons in control vs. 42% on HS, p

Afferent renal nerve pathways likely play a role in salt sensitive hypertension. We recently reported that high salt diet (HS) impairs these afferent renal pathways in rats. Now we tested the hypothesis that during HS a decrease in sensitivity of renal afferent neurons is prevented by the SGLT2 inhibitor empagiflozin.Respective groups of rats were put on HS containing 8% NaCl or a normal diet. Two groups (HS, controls) received empagiflozin 20 mg/kg BW/day orally. Renal neurons were retrogradely labeled with DiI. In culture, labeled dorsal root ganglion neurons (DRG Th11-L2) with renal afferents were investigated electrophysiologically using current clamp mode to assess action potential generation during current injection. Neurons were characterized as tonic highly active (> 5 action potentials, AP) and phasic less active neurons (≤ 5 AP upon stimulation. )In neurons from rats on HS, the relation of tonic highly active neurons to less active phasic neurons shifted consistently towards phasic units (63,8% tonic neurons in controls vs. 42%* on HS, *p

Previous data suggest that renal afferent nerve activity is increased in hypertension exerting sympathoexcitatory effects. Hence, we wanted to test the hypothesis that in renovascular hypertension, the activity of dorsal root ganglion (DRG) neurons with afferent projections from the kidneys is augmented depending on the degree of intrarenal inflammation. For comparison, a nonhypertensive model of mesangioproliferative nephritis was investigated. Renovascular hypertension (2-kidney, 1-clip [2K1C]) was induced by unilateral clipping of the left renal artery and mesangioproliferative glomerulonephritis (anti-Thy1.1) by IV injection of a 1.75-mg/kg BW OX-7 antibody. Neuronal labeling (dicarbocyanine dye [DiI]) in all rats allowed identification of renal afferent dorsal root ganglion (DRG) neurons. A current clamp was used to characterize neurons as tonic (sustained action potential [AP] firing) or phasic (1–4 AP) upon stimulation by current injection. All kidneys were investigated using standard morphological techniques. DRG neurons exhibited less often tonic response if in vivo axonal input from clipped kidneys was received (30.4% vs. 61.2% control, p p

Background: Angiotensin II (Ang II) and the renal sympathetic nervous system exert a strong influence on renal sodium and water excretion. We tested the hypothesis that already low doses of an Ang II inhibitor (candesartan) will result in similar effects on tubular sodium and water reabsorption in congestive heart failure (CHF) as seen after renal denervation (DNX). Methods: Measurement of arterial blood pressure, heart rate (HR), renal sympathetic nerve activity (RSNA), glomerular filtration rate (GFR), renal plasma flow (RPF), urine volume, and urinary sodium. To assess neural control of volume homeostasis, 21 days after the induction of CHF via myocardial infarction rats underwent volume expansion (0.9% NaCL; 10% body weight) to decrease RSNA. CHF rat and controls with or without DNX or pretreated with the Ang II type-1 receptor antagonist candesartan (0.5 ug i.v.) were studied. Results: CHF rats excreted only 68 + 10.2% of the volume load (10% body weight) in 90 min. CHF rats pretreated with candesartan or after DNX excreted from 92 to 103% like controls. Decreases of RSNA induced by volume expansion were impaired in CHF rats but unaffected by candesartan pointing to an intrarenal drug effect. GFR and RPF were not significantly different in controls or CHF. Conclusion: The prominent function of increased RSNA – retaining salt and water – could no longer be observed after renal Ang II receptor blockade in CHF rats.

BACKGROUND: Renal denervation (RDN) is an invasive intervention to treat drug-resistant arterial hypertension. Its therapeutic value is contentious. Here we examined the effects of RDN on inflammatory and infectious kidney disease models in mice. METHODS: Mice were unilaterally or bilaterally denervated, or sham operated, then three disease models were induced: nephrotoxic nephritis (NTN, a model for crescentic GN), pyelonephritis, and acute endotoxemic kidney injury (as a model for septic kidney injury). Analytical methods included measurement of renal glomerular filtration, proteinuria, flow cytometry of renal immune cells, immunofluorescence microscopy, and three-dimensional imaging of optically cleared kidney tissue by light-sheet fluorescence microscopy followed by algorithmic analysis. RESULTS: Unilateral RDN increased glomerular filtration in denervated kidneys, but decreased it in the contralateral kidneys. In the NTN model, more nephritogenic antibodies were deposited in glomeruli of denervated kidneys, resulting in stronger inflammation and injury in denervated compared with contralateral nondenervated kidneys. Also, intravenously injected LPS increased neutrophil influx and inflammation in the denervated kidneys, both after unilateral and bilateral RDN. When we induced pyelonephritis in bilaterally denervated mice, both kidneys contained less bacteria and neutrophils. In unilaterally denervated mice, pyelonephritis was attenuated and intrarenal neutrophil numbers were lower in the denervated kidneys. The nondenervated contralateral kidneys harbored more bacteria, even compared with sham-operated mice, and showed the strongest influx of neutrophils. CONCLUSIONS: Our data suggest that the increased perfusion and filtration in denervated kidneys can profoundly influence concomitant inflammatory diseases. Renal deposition of circulating nephritic material is higher, and hence antibody- and endotoxin-induced kidney injury was aggravated in mice. Pyelonephritis was attenuated in denervated murine kidneys, because the higher glomerular filtration facilitated better flushing of bacteria with the urine, at the expense of contralateral, nondenervated kidneys after unilateral denervation.

Afferent renal nerves exhibit a dual function controlling central sympathetic outflow via afferent electrical activity and influencing intrarenal immunological processes by releasing peptides such as calcitonin gene-related peptide (CGRP). We tested the hypothesis that increased afferent and efferent renal nerve activity occur with augmented release of CGRP in anti-Thy1.1 nephritis, in which enhanced CGRP release exacerbates inflammation. Nephritis was induced in Sprague-Dawley rats by intravenous injection of OX-7 antibody (1.75 mg/kg), and animals were investigated neurophysiologically, electrophysiologically, and pathomorphologically 6 days later. Nephritic rats exhibited proteinuria (169.3 ± 10.2 mg/24 h) with increased efferent renal nerve activity (14.7 ± 0.9 bursts/s vs. control 11.5 ± 0.9 bursts/s, n = 11, P < 0.05). However, afferent renal nerve activity (in spikes/s) decreased in nephritis (8.0 ± 1.8 Hz vs. control 27.4 ± 4.1 Hz, n = 11, P < 0.05). In patch-clamp recordings, neurons with renal afferents from nephritic rats showed a lower frequency of high activity following electrical stimulation (43.4% vs. 66.4% in controls, P < 0.05). In vitro assays showed that renal tissue from nephritic rats exhibited increased CGRP release via spontaneous (14 ± 3 pg/mL vs. 6.8 ± 2.8 pg/ml in controls, n = 7, P < 0.05) and stimulated mechanisms. In nephritic animals, marked infiltration of macrophages in the interstitium (26 ± 4 cells/mm2) and glomeruli (3.7 ± 0.6 cells/glomerular cross-section) occurred. Pretreatment with the CGRP receptor antagonist CGRP8–37reduced proteinuria, infiltration, and proliferation. In nephritic rats, it can be speculated that afferent renal nerves lose their ability to properly control efferent sympathetic nerve activity while influencing renal inflammation through increased CGRP release.

Sympathetic nerve activity is a hallmark of hypertension in end-stage renal disease (ESRD). An initial proof-of-concept study implies that renal denervation (RDN) is feasible and safe in RDN, but overall data are limited. In this single-centre prospective pilot study six patients with ESRD and treatment resistant hypertension were consecutively included. Ambulatory blood pressure (ABP) was measured before and 6 months after RDN (Symplictiy Flex™, Medtronic Inc., Santa Rosa, CA). Moreover, haemodialysis parameters which may affect BP reduction were monitored closely. In all patients bilateral RDN was successful done, without documentation of peri- or postprocedural complications. There was a significant reduction in 24-h ABP by 20 ± 17/15 ± 12 mmHg 6 months after RDN (systolic: 163 ± 16 versus 143 ± 9 mmHg, p = 0.043; diastolic: 96 ± 9 versus 81 ± 15 mmHg, p = 0.043), with similar results for day-, and nighttime values, respectively. Antihypertensive medication was kept stable as well as there was no change in haemodialysis parameters during follow-up. In addition, ultrafiltration/week (1.4 ± 1.4 versus 2.2 ± 1.4 l, p = 0.08) as well as hematocrit (measured at baseline and 6 months after RDN) (33.7 ± 4.3 versus 33.1 ± 3.9%, p = 0.715) revealed no change in volume status. Our single-centre pilot study not only supports current data on renal safety of RDN even in small arteries of patients with ESRD, but also enhances the knowledge towards an effective ABP reduction in this type of hypertensive patients.

We demonstrated earlier that renal afferent pathways combine very likely “classical” neural signal transduction to the central nervous system and a substance P (SP)–dependent mechanism to control sympathetic activity. SP content of afferent sensory neurons is known to mediate neurogenic inflammation upon release. We tested the hypothesis that alterations in SP-dependent mechanisms of renal innervation contribute to experimental nephritis. Nephritis was induced by OX-7 antibodies in rats, 6 days later instrumented for recording of blood pressure (BP), heart rate (HR), drug administration, and intrarenal administration (IRA) of the TRPV1 agonist capsaicin to stimulate afferent renal nerve pathways containing SP and electrodes for renal sympathetic nerve activity (RSNA). The presence of the SP receptor NK-1 on renal immune cells was assessed by FACS. IRA capsaicin decreased RSNA from 62.4 ± 5.1 to 21.6 ± 1.5 mV s (*p + dendritic cells (DCs). An enhanced frequency of CD11c+NK1R+ cell, NK-1 receptor+ macrophages, and DCs was assessed in nephritis. Administration of the NK-1R antagonist aprepitant during nephritis reduced CD11c+NK1R+ cells, macrophage infiltration, renal expression of chemokines, and markers of sclerosis. Hence, SP promoted renal inflammation by weakening sympathoinhibitory mechanisms, while at the same time, substance SP released intrarenally from afferent nerve fibers aggravated immunological processes i.e. by the recruitment of DCs.

Renal denervation (RDN) has been introduced for reducing blood pressure (BP) in treatment-resistant hypertension (TRH). The precise mechanism how RDN exerts its BP-lowering effects are not yet fully understood. It is widely accepted that sodium (Na+) plays a crucial role in the pathogenesis of hypertensive disease. However, there is increasing evidence of osmotically inactive Na+ storage. We investigated the impact of RDN on Na+ homeostasis using estimation of salt intake, and measurement of tissue Na+ content. In a study 41 patients with TRH (office BP ≥140/90 mmHg and diagnosis confirmed by 24-h ambulatory BP monitoring) underwent RDN. Tissue Na+ content was assessed non-invasively with 3.0 T magnetic resonance imaging before and 6 months after RDN. In addition, 24-h urinary Na+ excretion as an estimate of salt intake and spot urine Na+/K+ excretion were assessed. The study was registered at http://www.clinicaltrials.gov (ID: NCT01687725). There was a significant fall in BP (office: −17 ± 20/−10 ± 12 mmHg; 24-h: −11 ± 13/−6 ± 9 mmHg, all p

Sodium can be accumulated without commensurate water retention in the skin (non-osmotic sodium storage). Macrophages play a pivotal role in this context and their depletion can induce salt-sensitive hypertension (ssHTN). On the other hand renal afferent peptidergic nerves are involved in ssHTN. Since the skin is also densely innervated by afferent peptidergic nerves we hypothesized that high salt diet might enhance the release of neuropeptides from these nerve fibers. In a cross-over design, two groups of rats (n=6, each) were fed either low salt diet (LS; 0.2%) with free access to tab water for 14 days or high salt diet (HS; 8%) with free access to 0.9% saline as drinking water. After 14 days a skin sample (3x3mm) of the groin area was excised, and the diet was switched for another 14 days. Then a contralateral skin sample was taken. Tissue analyzed in an organ-bath and calcitonin gene related peptide (CGRP) content in the supernatant was measured with ELISA. After two baseline measurements within 5 min, the tissue was superfused with hypertonic saline (4.5%) for 5 min, and three further samples of the supernatant were taken every 5 min. Baseline CGRP release was similar with both diets (LS 11.9±1.5 vs HS 13.6±1.5ng/g skin). Maximum release was higher with HS diet (LS 17.5±1.8 vs HS 29.8±1.3ng/g skin; P

Electrical accidents are not reported very frequently, and may occur undetected as the signs are often manifold and not very specific. We report the case of a 43-year-old woman admitted to hospital due to a fall of unclear cause, with loss of consciousness, partial amnesia, paresis of both legs and crush syndrome. Only by thorough and repeated history-taking, and a careful physical examination that revealed burns typical of electrical current injuries, was the case resolved. With this case presentation, we would like to make the reader aware of electrocution as a possible cause of bruises and unconsciousness of unclear origin. LEARNING POINTS Bruises and loss of consciousness of unclear origin should make one think of electric shock as a possible cause. Rhabdomyolysis and crush syndrome are rarely seen conditions in low-voltage current accidents. Thorough physical examination and careful history-taking are very important and can provide precious hints for our clinical work.

BACKGROUND Copeptin, the C-terminal peptide of provasopressin, is released from the neurohypophysis and reflects the activity of the hormone arginine vasopressin in patients with hypertension. Elevated copeptin levels are associated with increased cardiovascular and all-cause mortality. The aim of this study is to compare copeptin levels in patients with treatment-resistant hypertension (TRH) before and 6 months after renal denervation (RDN). METHODS Copeptin was measured in 34 patients with TRH and 30 patients with primary hypertension stage 1 or 2 (HT). In addition, copeptin levels were measured in patients with TRH at 6-month follow-up visit after RDN. RDN was performed by an experienced interventionalist applying at least 4 ablations longitudinally and rotationally within the lengths of each renal artery to cover a full 4-quadrant ablation. RESULTS In patients with TRH 24-hour ambulatory blood pressure (BP) decreased from 154 ± 15/87 ± 12 mm Hg to 146 ± 13/83 ± 7.9 mm Hg after RDN (systolic: P = 0.001, diastolic: P = 0.034). There was no significant change in copeptin levels in these 34 patients with TRH before vs. 6 months after RDN (median 8.4 [interquartile range 3.6–14] vs. 8.5 [4.5–13] pmol/l, P = 0.334). Patients with TRH had higher copeptin levels (P = 0.024) than patients with HT (24-hour ambulatory BP: 142 ± 11/91 ± 8.3 mm Hg, copeptin: 4.2 [2.8–6.3] pmol/l). CONCLUSION Patients with TRH showed 2-fold higher copeptin levels than patients with HT. RDN did not lead to any change of copeptin levels in patients with TRH 6 months after procedure despite significant fall in BP. CLINICAL TRIAL REGISTRATION NCT01318395, NCT01687725

Data on the blood pressure (BP)-lowering effect of renal denervation (RDN) in moderate treatment-resistant hypertension (TRH) are limited. Moreover, change of adherence to medication, as one potential confounder of BP response, has never been analyzed rigorously in this group of patients. We analyzed the effect of RDN on BP in patients with moderate TRH who were retrospectively found to be completely adherent to their antihypertensive medication.Our study cohort comprised 40 patients with moderate TRH [office BP ≥ 140/90 but160/100 mmHg and 24-h ambulatory BP monitoring (ABPM) ≥130/80 mmHg] who underwent catheter-based RDN. Further major inclusion criterion was complete adherence to their medication (≥80% intake of their prescribed antihypertensive drugs) at baseline (assessed by retrospective toxicological analysis).Six months after RDN, office BP was reduced by -10/-6 mmHg (SBP: 149 ± 6 vs. 139 ± 15 mmHg; DBP: 81 ± 12 vs. 75 ± 10 mmHg; both P 0.001) and 24-h ABPM by -7/-4 mmHg (SBP: 150 ± 14 vs. 143 ± 16 mmHg, P = 0.005; DBP: 82 ± 10 vs. 78 ± 9 mmHg, P = 0.009). Number of prescribed antihypertensive medication [6.0 (5.0-6.0) vs. 5.5 (5.0-6.0), P = 0.013] and adherence rate (95.2 ± 7.6 vs. 91.7 ± 13.9%, P = 0.065) was slightly reduced 6 months after RDN, both likely to underestimate the true BP reduction.Thus, our data indicate that even after given full respect to drug adherence as potential confounder of BP response after RDN, both office and 24-h ABPM were substantially reduced in patients with moderate TRH.

Renal denervation (DNX) is a treatment for resistant arterial hypertension. Efferent sympathetic nerves regrow, but reinnervation by renal afferent nerves has only recently been shown in the renal pelvis of rats after unilateral DNX. We examined intrarenal perivascular afferent and sympathetic efferent nerves after unilateral surgical DNX. Tyrosine hydroxylase (TH), CGRP, and smooth muscle actin were identified in kidney sections from 12 Sprague-Dawley rats, to distinguish afferents, efferents, and vasculature. DNX kidneys and nondenervated kidneys were examined 1, 4, and 12 wk after DNX. Tissue levels of CGRP and norepinephrine (NE) were measured with ELISA and mass spectrometry, respectively. DNX decreased TH and CGRP labeling by 90% and 95%, respectively ( P < 0.05) within 1 wk. After 12 wk TH and CGRP labeling returned to baseline with a shift toward afferent innervation ( P < 0.05). Nondenervated kidneys showed a doubling of both labels within 12 wk ( P < 0.05). CGRP content decreased by 72% [3.2 ± 0.3 vs. 0.9 ± 0.2 ng/gkidney; P < 0.05] and NA by 78% [1.1 ± 0.1 vs. 0.2 ± 0.1 pmol/mgkidney; P < 0.05] 1 wk after DNX. After 12 wk, CGRP, but not NE, content in DNX kidneys was fully recovered, with no changes in the nondenervated kidneys. The use of phenol in the DNX procedure did not influence this result. We found morphological reinnervation and transmitter recovery of afferents within 12 wk after DNX. Despite morphological evidence of sympathetic regrowth, NE content did not fully recover. These results suggest a long-term net surplus of afferent influence on the DNX kidney may be contributing to the blood pressure lowering effect of DNX.

Recently, we showed that renal afferent neurons exhibit a unique firing pattern, i.e., predominantly sustained firing, upon stimulation. Pathological conditions such as renal inflammation likely alter excitability of renal afferent neurons. Here, we tested whether the proinflammatory chemokine CXCL1 alters the firing pattern of renal afferent neurons. Rat dorsal root ganglion neurons (Th11-L2), retrogradely labeled with dicarbocyanine dye, were incubated with CXCL1 (20 h) or vehicle before patch-clamp recording. The firing pattern of neurons was characterized as tonic, i.e., sustained action potential (AP) firing, or phasic, i.e.

Afferent renal nerve fibers from the kidney likely counterregulate salt sensitive blood pressure increases by decreasing renal sympathetic nerve activity. We recently reported on a long-lasting tonic sympatho-inhibition due to intrarenal afferent renal nerve stimulation eliciting a TRPV1 dependent neuro-humoral pathway. We wanted to test the hypothesis that sodium influences this afferent sympatho-depressory mechanism. Groups of anesthetized SD rats (n=8) were equipped with femoral catheters (blood pressure (BP) & heart rate (HR) recording, drug application), a renal arterial catheter for intrarenal administration (IRA) of high salt (10 % NaCl, 10 μl) or Capsaicin (CAP 3.3, 6.6, 10, 33*10-7 M, 10 μl) and a bipolar electrode for RSNA recordings; eventually an intravenous (iv) bolus of the NK1-receptor blocker RP67580 (10*10-3M, 15 μl) was given. Cultured dorsal root ganglion neurons (Th11-L2) of rats with renal afferents were investigated in current clamp mode to assess action potential generation or in voltage clamp mode to investigate inward currents during 10 sec superperfusion to 4.5 % NaCl or equiosmotic mannitol. solution Results are given in mean±SEM. IRA high salt and IRA CAP decreased RSNA from baseline 4.1±0.6 μV*sec to 2.2±0.8 μV*sec (10% NaCl, p

A bidirectional relationship is known between increased sympathetic activity inducing insulin resistance and hyperinsulinemia producing sympathetic overactivity, resulting in a vicious circle [(1)][1]. Thus, it seems likely that renal denervation (RDN), introduced as an interventional approach for

High pulsatile pressure and flow in the arteries causes microvascular damage, and hence increased cardio-, and cerebrovascular complications. With advanced stages of hypertensive disease, an exaggerated pulsatile retinal capillary flow (RCF) has been shown, but data about interventional effect are missing. Fifty-one patients with true treatment-resistant hypertension (TRH) underwent renal denervation (RDN) using the Symplicity Flex™ catheter and were followed for 12 months. RCF was assessed non-invasively using Scanning laser Doppler flowmetry (SLDF) before, 6 (6 M), and 12 (12 M) months after RDN. RCF was measured in systole and diastole and pulsed RCF (difference of RCF in systole minus diastole) was calculated. In addition, flicker light-induced vasodilation (representing vasodilatory capacity) was assessed. Systolic and diastolic office blood pressure (BP) as well as 24-h ABPM decreased significantly 6 M and 12 M after RDN, compared to baseline values (all p

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: NCT 00888433, NCT 01442883 and NCT 01687725.

Background: Cardiomyopathy in experimental renal insufficiency is putatively influenced by neurogenic pathways of renal origin. We wondered if cardiac neurogenic effects in congestive heart failure could likewise harm the kidney. We hypothesized that increased renal sympathetic nerve activity (RSNA) in rats with congestive heart failure after myocardial infarction (CHF) induces renal structural damage. Methods: 21 day after induction of CHF renal morphology was evaluated by immunohistology (interstitial and glomerular mononuclear cell infiltration (ED1), cell proliferation (PCNA), collagen I,III,IV,V,VI, laminin und fibronectin). RSNA was assessed by volume challenge (VE) to decrease RSNA. CHF and control rats were investigated with and without renal denervation (DNX). Blood pressure (BP), heart rate (HR) and RSNA were recorded. Nodose ganglion neurons (NGN) with vagal cardiac afferents were cultured for 1 day. Whole cell recordings were obtained and current-voltage relationships established. Cells were characterized by osmomechanical stress with a mannitol solution. Results: In CHF rats with intact renal nerves (nonDNX) formation of collagen I occurred, that was reduced after DNX (12.2+0.7 %area vs. 9.1+1.1 %area*, n=6, * p Conclusion: CHF induced subtle renal structural damage due to increased renal sympathetic tone which was likely due to altered NGN mechanosensitivity. Afferent nerve units from cardiovascular organs obviously form a complex sympathomodulatory network.

AIMS Enhanced vascular ageing is associated with elevated central pulse pressure (cPP), an independent predictor of cardiovascular (CV) events. Although antihypertensive treatment strategies are effective, high residual CV risk remains indicative of advanced and largely irreversible vascular damage. Renal denervation (RDN) has been shown to reduce blood pressure (BP) to various extents in patients with treatment-resistant hypertension (TRH). We hypothesised that cPP predicts BP reduction after RDN. METHODS AND RESULTS Sixty-three patients with true TRH underwent catheter-based RDN using the Symplicity Flex™ catheter and were followed for six months. At baseline, cPP was assessed by pulse wave analysis (SphygmoCor™). Patients were stratified according to their median cPP (55 mmHg), and called "low cPP" (below the median) or "high cPP" (above the median). Office BP reduction six months after RDN was greater (-22±19/-13±11 vs. -12±20/-5±13 mmHg, p=0.038/0.014) and 24-hr ambulatory blood pressure (ABP) reduction tended to be greater (-11±13/-8±10 vs. -3±18/-4±10 mmHg, p=0.070/0.112) in patients with low cPP compared to those with high cPP. Only cPP (β=0.687, p=0.001) and baseline systolic BP (β=-0.564, p

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.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 http://www.clinicaltrials.gov (ID: NCT01442883).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 m per year, and after RDN eGFR improved by +1.5 ± 10 ml/min per 1.73 m at 12 months (P = 0.009).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.

Stimulation of renal sympathetic nerves causes reduced renal blood flow. To elucidate whether renal denervation (RDN) affects renal perfusion, we analysed renal blood flow of parenchymal areas perfused by arteries that were non-treated versus treated with RDN. In a pilot study 8 patients with treatment-resistant hypertension that had multiple renal arteries in either kidney were included. All patients underwent catheter-based RDN using the Symplicity FlexTM RDN System of the main renal arteries, but not of accessory renal arteries. Renal perfusion was measured noninvasively by magnetic resonance imaging on a 1.5-T scanner with arterial spin labelling before (day-1), after (day + 1) and again after 3 months (3 M) of RDN. Renal parenchyma was divided into areas that were perfused by renal arteries which were treated with RDN versus those areas perfused by accessory renal arteries not treated with RDN. Hence, every patient could serve at its own control with respect to changes of renal blood flow in the same kidney. In addition renal function was assessed by eGFR according CKD-Epi formula. There was an acute increase of renal perfusion in areas supplied by arteries not undergoing RDN (day-1: 242.3 [229.2-263.2] vs. day + 1: 260.0 [243.5-296.6] ml/min/100 g, p = 0.008), which returned to baseline values after 3 M (257.0 [240.5-277.8] ml/min/100 g, p = 0.260). In contrast, renal perfusion did not change in areas supplied by arteries undergoing RDN in acute (day-1: 263.5 [245.9-273.6] vs. day + 1: 256.5 [242.9-273.5] ml/min/100 g, p = 0.953) and 3 M (245.4 [235.5-269.7] ml/min/100 g, p = 0.594). Accordingly, the acute change in renal perfusion between day-1 and day + 1 was significantly greater in parenchymal areas supplied by arteries without compared to areas with RDN (p = 0.014), but not after 3 M. Renal function assessed by eGFR did not change between day-1 and day + 1 (80.3 ± 20 versus 79.8 ± 20 ml/min/1.73m, p = 0.885) as well as after 3 M of RDN (80.8 ± 18 ml/min/1.73m, p = 0.889). Despite an average of 7.0 ± 1.5 antihypertensive drugs, baseline office BP was 157/85mmHg, and was reduced by -11/-7mmHg after 3 M of RDN. Our data indicate an acute increase of renal perfusion in renal parenchymal areas perfused by arteries with intact renal nerves, whereas no change occurred in parenchymal areas perfused by arteries after RDN.