Renal denervation prevents long-term sequelae of ischemic renal injury.
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ABSTRACT:
SUBMITTER: Kim J
PROVIDER: S-EPMC4312521 | biostudies-literature | 2015 Feb
REPOSITORIES: biostudies-literature
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Project description:ObjectivesRenal denervation (RDN) proved to significantly lower blood pressure (BP) at 2-6 months in patients on and off antihypertensive drugs. Given a lack of longer-term follow-up data, our aim was to assess the safety and efficacy of RDN up to five years taking into account antihypertensive drug regimen changes over time.MethodsIn the present single-center study, patients underwent RDN for (therapy resistant) hypertension. Patients underwent protocolized yearly follow-up out to five years. Data were collected on 24-h ambulatory BP and office BP monitoring, renal function, antihypertensive drug regimen, and safety events, including non-invasive renal artery imaging at 6/12 months. Efficacy analyses were performed using linear mixed-effects models.ResultsSeventy-two patients with mean age 63.3 ± 9.5 (SD) years (51% female) were included. Median follow-up time was 3.5 years and Clark's Completeness Index was 72%. Baseline ambulatory daytime BP was 146.1/83.7 ± 17.4/12.2 mmHg under a mean number of 4.9 ± 2.7 defined daily doses (DDD). At five years, ambulatory daytime systolic BP as calculated from the mixed model was 120.8 (95% CI 114.2-127.5) mmHg and diastolic BP was 73.3 (95% CI 69.4-77.3) mmHg, implying a reduction of -20.9/-8.3 mmHg as compared to baseline estimates (p < 0.0001). The number of DDDs remained stable over time (p = 0.87). No procedure-related major adverse events resulting in long-term consequences were observed.ConclusionsThe BP-lowering effect of RDN was safely maintained at least five years post-procedure as reflected by a significant decrease in ambulatory daytime BP in the absence of escalating antihypertensive drug therapy over time.
| S-EPMC9622524 | biostudies-literature
Project description:Hypertension is one of the most prevalent chronic diseases worldwide and the incidence of resistant hypertension is increasing. Catheter-based renal denervation (RDN) offers a new approach to reaching blood pressure goals by targeting the renal nerves. The technique has demonstrated significant and sustained reductions in blood pressure (BP) in the Symplicity HTN-1 and Symplicity HTN-2 clinical trials. The Global SYMPLICITY Registry aims to demonstrate safety and effectiveness in a 'real-world' patient population. Real-world RDN experience has emphasised that patient selection is crucial to successful outcomes; a multidisciplinary referral network is recommended to increase awareness of the procedure and identify patients who are likely to respond best to RDN. Further advances in catheter technology have led to the development of the multi-electrode Symplicity Spyral™ multi-electrode catheter; preliminary data from the feasibility study using the Symplicity Spyral catheter indicate clinical efficacy and procedural safety with reduced procedure times. The Symplicity Spyral catheter is not yet commercially available. The indications of RDN may also expand beyond resistant hypertension - encouraging data have been seen in patients with moderate treatment resistant hypertension. Furthermore, RDN may be beneficial in other clinical states characterised by sympathetic nervous system overactivation including heart failure and chronic kidney disease. Additional data are needed to evaluate the efficacy of RDN in these disease states.
| S-EPMC5808595 | biostudies-other
Project description:Crizotinib is highly effective against anaplastic lymphoma kinase-positive and c-ros oncogen1-positive non-small cell lung cancer. Renal dysfunction is associated with crizotinib therapy but the mechanism is unknown. Here, we report a case of anaplastic lymphoma kinase positive non-small cell lung cancer showing multiple cysts and dysfunction of the kidneys during crizotinib administration. We also present results demonstrating that long-term crizotinib treatment induces fibrosis and dysfunction of the kidneys by activating the tumor necrosis factor-α/nuclear factor-κB signaling pathway. In conclusion, this study shows the renal detrimental effects of crizotinib, suggesting the need of careful monitoring of renal function during crizotinib therapy.
| S-EPMC6213486 | biostudies-literature
Project description:The contribution of p53 to kidney dysfunction, inflammation, and tubular cell death, hallmark features of ischemic renal injury (IRI), remains undefined. Here, we studied the role of proximal tubule cell (PTC)-specific p53 activation on the short- and long-term consequences of renal ischemia/reperfusion injury in mice. After IRI, mice with PTC-specific deletion of p53 (p53 knockout [KO]) had diminished whole-kidney expression levels of p53 and its target genes, improved renal function, which was shown by decreased plasma levels of creatinine and BUN, and attenuated renal histologic damage, oxidative stress, and infiltration of neutrophils and macrophages compared with wild-type mice. Notably, necrotic cell death was attenuated in p53 KO ischemic kidneys as well as oxidant-injured p53-deficient primary PTCs and pifithrin-α-treated PTC lines. Reduced oxidative stress and diminished expression of PARP1 and Bax in p53 KO ischemic kidneys may account for the decreased necrosis. Apoptosis and expression of proapoptotic p53 targets, including Bid and Siva, were also significantly reduced, and cell cycle arrest at the G2/M phase was attenuated in p53 KO ischemic kidneys. Furthermore, IRI-induced activation of TGF-β and the long-term development of inflammation and interstitial fibrosis were significantly reduced in p53 KO mice. In conclusion, specific deletion of p53 in the PTC protects kidneys from functional and histologic deterioration after IRI by decreasing necrosis, apoptosis, and inflammation and modulates the long-term sequelae of IRI by preventing interstitial fibrogenesis.
| S-EPMC4243356 | biostudies-literature
Project description:Pediatric traumatic brain injury (TBI) remains one of the leading causes of morbidity and mortality in children. Experimental and clinical studies demonstrate that the developmental age, the type of injury (diffuse vs. focal) and sex may play important roles in the response of the developing brain to a traumatic injury. Advancements in acute neurosurgical interventions and neurocritical care have improved and led to a decrease in mortality rates over the past decades. However, survivors are left with life-long behavioral deficits underscoring the need to better define the cellular mechanisms underlying these functional changes. A better understanding of these mechanisms some of which begin in the acute post-traumatic period may likely lead to targeted treatment strategies. Key considerations in designing pre-clinical experiments to test therapeutic strategies in pediatric TBI include the use of age-appropriate and pathologically-relevant models, functional outcomes that are tested as animals age into adolescence and beyond, sex as a biological variable and the recognition that doses and dosing strategies that have been demonstrated to be effective in animal models of adult TBI may not be effective in the developing brain. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury".
| S-EPMC6309300 | biostudies-literature
Project description:Inflammation and adaptive immunity play a crucial role in the development of hypertension. Angiotensin II and probably other hypertensive stimuli activate the central nervous system and promote T-cell activation and end-organ damage in peripheral tissues.To determine if renal sympathetic nerves mediate renal inflammation and T-cell activation in hypertension.Bilateral renal denervation using phenol application to the renal arteries reduced renal norepinephrine levels and blunted angiotensin II-induced hypertension. Bilateral renal denervation also reduced inflammation, as reflected by decreased accumulation of total leukocytes, T cells, and both CD4+ and CD8+ T cells in the kidney. This was associated with a marked reduction in renal fibrosis, albuminuria, and nephrinuria. Unilateral renal denervation, which partly attenuated blood pressure, only reduced inflammation in the denervated kidney, suggesting that this effect is pressure independent. Angiotensin II also increased immunogenic isoketal-protein adducts in renal dendritic cells (DCs) and increased surface expression of costimulation markers and production of interleukin (IL)-1?, IL-1?, and IL-6 from splenic DCs. Norepinephrine also dose dependently stimulated isoketal formation in cultured DCs. Adoptive transfer of splenic DCs from angiotensin II-treated mice primed T-cell activation and hypertension in recipient mice. Renal denervation prevented these effects of hypertension on DCs. In contrast to these beneficial effects of ablating all renal nerves, renal afferent disruption with capsaicin had no effect on blood pressure or renal inflammation.Renal sympathetic nerves contribute to DC activation, subsequent T-cell infiltration and end-organ damage in the kidney in the development of hypertension.
| S-EPMC4629828 | biostudies-literature
Project description:The clinical benefits of renal denervation are still under discussion, since randomized controlled clinical studies have provided inconsistent results. The present retrospective study examined the clinical effects of renal denervation with focus on office blood pressure, heart rate, and changes in renal function. Patients with treatment-resistant hypertension (blood pressure ≥ 140/90 mm Hg in spite of 3 antihypertensive drugs including a diuretic) underwent renal denervation at the University Hospital of Zurich, Switzerland and were followed up until 36 months. Renal denervation was performed using 3 different renal denervation systems. The primary outcome consisted of change in office blood pressure, heart rate, and plasma creatinine at 1, 6, 12, 24, and 36 months after renal denervation. 58 patients underwent renal denervation between August 2010 and December 2017. After exclusion, 50 patients were included in the analyses. At 36 months, the mean office systolic and diastolic blood pressure change was -26.4/-8.8 mm Hg (95% CI: -34.6 to -18.2/-13.5 to -4.2 mm Hg; P < .001 for both). Office heart rate showed no significant change during follow-up (P = .361). Plasma creatinine increased from 90.6 µmol/L (95% CI: 82.1 to 99.0 µmol/L) at baseline to 102.1 µmol/L (95% CI: 95.8 to 108.3 µmol/L) at 36 months (P = .007). No major adverse events occurred. Renal denervation is a safe and effective procedure for patients with treatment-resistant hypertension with a clinically significant antihypertensive effect. Further randomized trials are needed to determine the specific context within which renal denervation should be considered a therapeutic option in antihypertensive care.
| S-EPMC8029726 | biostudies-literature
Project description:Frostbite is tissue damage caused by freezing temperatures and constitutes an important cause of morbidity in cold climate zones and high altitude. The direct effects of sub-zero temperatures lead to tissue freezing, electrolyte shifts and pH alterations, microvascular damage, and eventually to cell death. Upon rewarming, inflammatory reperfusion injury and thrombosis may lead to further tissue damage. Several studies and various case reports show that many patients suffer from long-term sequelae such as vasomotor disturbances (associated with susceptibility to refreezing), and neuropathic and nociceptive pain, as well as damage to skeletal structures. There are still many uncertainties regarding the pathophysiology of these sequelae. It has been shown that the transient receptor potential channel (TRP) family plays a role in cold allodynia. Botulinum Toxin type A (BTX-A) injections have been reported to be beneficial in vasomotor and neuropathic disturbances secondary to frostbite. Epidural sympathetic block has been used for short-term treatment of frostbite induced chronic pain. Furthermore, amitriptyline, gabapentinoids, and duloxetine may have some benefits. Frostbite arthritis clinically resembles regular osteoarthritis. In children there is a risk of epiphyseal cartilage damage leading to bone deformities. Despite some promising therapeutic concepts, the scarcity of data on frostbite long-term sequelae in the literature indicates the need of more in-depth studies of this pathology in all its aspects.
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Project description:Acute kidney injury (AKI) is associated with an abrupt loss of kidney function that results in significant morbidity and mortality. Considerable effort has focused around the identification of diagnostic biomarkers and the analysis of molecular events. Most studies have adopted organ-wide approaches that do not fully capture the interplay among different cell types in the pathophysiology of AKI. To extend our understanding of molecular and cellular events in AKI, we developed a mouse line that enables the identification of translational profiles in specific cell types by CRE recombinase-dependent activation of an eGFP-tagged L10a ribosomal protein subunit, and consequently, translating ribosome affinity purification (TRAP) of mRNA populations. By utilizing cell-type specific CRE-driver lines, in this study we identify distinct cellular responses in an ischemia reperfusion injury (IRI) model of AKI. Cell-specific translational expression profiles were uncovered 24 hours after IRI from four populations enriched for distinct anatomical and cellular subgroups: nephron, interstitial cell populations, vascular endothelium, and macrophages/monocytes by Affymetrix microarray. A construct containing the CAGGS promoter driving eGFP-L10a, with a loxP-site flanked triple SV40 polyA cassette between promoter and eGFP-L10a cassette was targeted into the ubiquitously active Rosa26 locus. The upstream polyA cassette is designed to block activity of the downstream eGFP-L10a cassette. CRE-dependent removal of this transcriptional block activates eGFP::L10a production within the CRE-producing cell, and all of its descendants. Mice carrying the conditional eGFP-L10a allele, referred to as L10a, were maintained in a homozygous state. L10a mice were crossed to four CRE strains to activate eGFP::L10a expression in four predominantly non-overlapping cellular compartments in the kidney. A Six2-Tet-GFP::CRE allele is active exclusively within nephron progenitors; consequently, historical labeling results in eGFP::L10a expression throughout the main body of the nephron. A Foxd1-GFP::CRE allele is active in the progenitors of many of the interstitial cell lineages including those generating mesangial and non-glomerular pericytes. In addition, Foxd1 is normally expressed in podocytes. Cdh5-CRE is reported to be active throughout the vascular endothelium, and finally, Lyz2-CRE specifically labels cells of the myeloid lineage, notably macrophages, monocytes and dendritic cells. Mice carrying any CRE allele and the L10a allele are designated generically CRE-L10a. six2-L10a, foxd1-L10a, cdh5-L10a and lyz2-L10a denote specifically mice that are compound heterozygotes for the indicated CRE driver and L10a. CRE-L10a, L10a heterozygous littermates without CRE allele, C57BL/6 wild type mice were subjected to renal bilateral warm ischemia 28 minutes followed by 24-hour reperfusion when the kidney TRAP RNA and total RNA were isolated and subjected to Affymetrix microarray. Biological triplicates for each CRE-L10a line underwent no Surgery; sham Surgery and IRI treatment.
2014-03-06 | E-GEOD-52004 | biostudies-arrayexpress
Project description:Ischemic stroke remains an important cause of disability and mortality. Hypertension is a critical risk factor for the development of ischemic stroke. Control of risk factors, including hypertension, is therefore important for the prevention of ischemic stroke. Linalyl acetate (LA) has been reported to have therapeutic effects in ischemic stroke by modulating intracellular Ca2+ concentration and having anti-oxidative properties. The preventive efficacy of LA has not yet been determined. This study therefore investigated the preventive efficacy of LA in rat aortas exposed to hypertension related-ischemic injury, and the mechanism of action of LA.Hypertension was induced in vivo following ischemic injury to the aorta induced by oxygen-glucose deprivation and reoxygenation in vitro. Effects of LA were assayed by western blotting, by determining concentrations of lactate dehydrogenase (LDH) and reactive oxygen species (ROS) and by vascular contractility assays. LA significantly reduced systolic blood pressure in vivo. In vitro, LA suppressed ischemic injury-induced expression of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47phox, as well as ROS production, LDH release, and ROS-induced endothelial nitric oxide synthase suppression. These findings indicate that LA has anti-hypertensive properties that can prevent hypertension-related ischemic injury and can prevent NADPH oxidase-induced production of ROS.
| S-EPMC5969747 | biostudies-literature