Predictive Factors Affecting the Success of Nephrectomy for the Treatment of Nephrogenic Hypertension: Multicenter Study.

INTRODUCTION: The aim of our study is to evaluate the predictive factors affecting the success of treatment with nephrectomy in patients with poorly functioning kidney and nephrogenic hypertension. METHODS: Data for patients who underwent nephrectomy with a diagnosis of nephrogenic hypertension in 3 centers between May 2010 and January 2020 were analyzed. In the postoperative period, if the blood pressure (BP) was below 140/90 mm Hg without medical treatment, it was accepted as complete response; if the arterial BP was below 140/90 mm Hg with medical treatment or less medication, it was accepted as partial response; and if BP did not decrease to normal values, it was accepted as unresponsive. Demographic characteristics, duration of hypertension, preoperative and postoperative BP values, and presence of metabolic syndrome were statistically evaluated. RESULTS: Our study consisted of 91 patients with a mean preoperative hypertension duration of 23.3 ± 12.1 months. Among patients, 42 (46.2%) had complete response, 18 (19.8%) had partial response, and 31 (34.0%) had no response. Preoperative systolic and diastolic BP values were not effective on treatment success (p = 0.071, p = 0.973, respectively), but the increase in age and hypertension duration (p = 0.030 and p < 0.001, respectively) and the presence of metabolic syndrome (p = 0.002) significantly decreased the complete response rates. CONCLUSIONS: Preoperative hypertension duration, advanced age, and presence of metabolic syndrome are predictive factors affecting the response to treatment in patients who undergo nephrectomy due to nephrogenic hypertension.

Activated double-negative T cells (CD3+CD4-CD8-HLA-DR+) define response to renal denervation for resistant hypertension.

PURPOSE: To explore the cellular immune response of patients with resistant hypertension treated with renal denervation (RDN). METHODS AND RESULTS: Twenty-three patients were included and blood samples were obtained in six timings, pre and post procedure. Response was evaluated at six-months and one year and was observed in 69.6% and 82.6% of patients, respectively. Absolute values of HLA-DR+ double negative (DN) T cells were significantly lower in the group of 'responders' at one year, and interaction between the timings were found in three T cell subsets (T CD4, T CD8 and naïve T CD8 cells), with the 'responders' tending to present with lower absolute values and little inter-timing variation. CONCLUSIONS: 'Responders' significantly present with lower absolute values of activated DN T cells and have lower and more stable values of total T CD8+, CD4+, and naïve T CD8+ cells. These cell types may be able to predict response to RDN.

Renal sensory nerves increase sympathetic nerve activity and blood pressure in 2-kidney 1-clip hypertensive mice.

Renal denervation lowers arterial blood pressure (ABP) in multiple clinical trials and some experimental models of hypertension. These antihypertensive effects have been attributed to the removal of renal afferent nerves. The purpose of the present study was to define the function, anatomy, and contribution of mouse renal sensory neurons to a renal nerve-dependent model of hypertension. First, electrical stimulation of mouse renal afferent nerves produced frequency-dependent increases in ABP that were eliminated by ganglionic blockade. Stimulus-triggered averaging revealed renal afferent stimulation significantly increased splanchnic, renal, and lumbar sympathetic nerve activity (SNA). Second, kidney injection of wheat germ agglutinin into male C57Bl6 mice (12-14 wk; Jackson Laboratories) produced ipsilateral labeling in the T11-L2 dorsal root ganglia. Next, 2-kidney 1-clip (2K1C) hypertension was produced in male C57Bl6 mice (12-14 wk; Jackson Laboratories) by placement of a 0.5-mm length of polytetrafluoroethylene tubing around the left renal artery. 2K1C mice displayed an elevated ABP measured via telemetry and a greater fall in mean ABP to ganglionic blockade at day 14 or 21 vs. day 0. Renal afferent discharge was significantly higher in 2K1C-clipped vs. 2K1C-unclipped or sham kidneys. In addition, 2K1C-clipped vs. 2K1C-unclipped or sham kidneys had lower renal mass and higher mRNA levels of several proinflammatory cytokines. Finally, both ipsilateral renal denervation (10% phenol) or selective denervation of renal afferent nerves (periaxonal application of 33 mM capsaicin) at time of clipping resulted in lower ABP of 2K1C mice at day 14 or 21. These findings suggest mouse renal sensory neurons are activated to increase SNA and ABP in 2K1C hypertension. NEW & NOTEWORTHY This study documents the function, anatomy, and contribution of mouse renal sensory nerves to neurogenic hypertension produced by renal stenosis. Activation of renal afferents increased sympathetic nerve activity and blood pressure. Renal afferent activity was elevated in hypertensive mice, and renal afferent denervation lowered blood pressure. Clinically, patients with renal stenosis have been excluded from clinical trials for renal denervation, but this study highlights the potential therapeutic efficacy to target renal nerves in these patients.

The early outcomes of candidates with portopulmonary hypertension after liver transplantation.

BACKGROUND: Portopulmonary hypertension (PPH) was once regarded as a contraindicaton to liver transplantation (LT). However, growing evidence has indicated that PPH patients undergoing LT may show similar outcomes compared to those without PPH, and researchers have recommended it not be an absolute contraindication. Given this controversy, we aimed to identify and review the current evidence on this topic and to provide a comparison of the outcomes after LT between candidates with PPH and those without. METHODS: We systematically searched the MEDLINE, EMBASE and Cochrane Library databases for all studies that compared the outcomes of PPH patients and those without PPH after LT. All studies reporting outcomes of PPH patients versus those without PPH (Control) were further considered for inclusion in this meta-analysis. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to compare the pooled data between PPH and Control groups. RESULTS: Eleven retrospective trials and one prospective, randomized, controlled trial, involving 37,686 transplant recipients were included. The PPH patients had increased 1-year mortality with an OR of 1.59 (95% CI = 1.26-2.01, P = 0.0001) compared to the control group. There was no significant difference in graft loss and 30-day mortality after LT between the two groups. CONCLUSIONS: Patients with PPH who underwent LT had increased 1-year mortality compared to those without PPH, while graft loss and 30-day mortality were similar. Nevertheless, LT may be a reasonable therapeutic option for some patients with PPH, but further studies are needed to identify those select patients with PPH who would benefit most from LT.

Reduced blood pressure-lowering effect of catheter-based renal denervation in patients with isolated systolic hypertension: data from SYMPLICITY HTN-3 and the Global SYMPLICITY Registry.

Aims: Catheter-based renal artery denervation (RDN) has been shown to lower blood pressure (BP) in certain patients with uncontrolled hypertension. Isolated systolic hypertension (ISH) (systolic BP [SBP] ≥140 mmHg and diastolic BP <90 mmHg), characterized by increased vascular stiffness, is the predominant hypertensive phenotype in elderly patients. This study compared baseline characteristics and SBP change at 6 months between patients with ISH and combined systolic­diastolic hypertension (CH). Methods and Results: This study pooled data from 1103 patients from SYMPLICITY HTN-3 and the Global SYMPLICITY Registry. A total of 429 patients had ISH, and 674 had CH. Patients with ISH were significantly older than those with CH (66 vs. 55 years), had more type 2 diabetes mellitus (52.9 vs. 34.6%), and a lower estimated glomerular filtration rate (71.8 vs. 78.6 mL/min/1.73 m2); all P < 0.001. At 6 months, the SBP drop for CH patients was −18.7 ± 23.7 mmHg compared with a reduction of −10.9 ± 21.7 mmHg for ISH patients −7.8 mmHg, 95% confidence interval, CI, −10.5, −5.1, P < 0.001). The change in 24-h SBP at 6 months was −8.8 ± 16.2 mmHg in patients with CH vs. −5.8 ± 15.4 mmHg in ISH (−3.0 mmHg, 95% CI −5.4, −0.6, P = 0.015). Presence of ISH at baseline but not age was associated with less pronounced BP changes following the procedure. The strongest predictor of office SBP reduction at 6 months was CH, followed by aldosterone antagonist use and non-use of vasodilators. Conclusion: The reduction in BP among patients with ISH following RDN was less pronounced than the reduction in patients with CH. Clinical.trials.gov Identifiers: NCT01534299 and NCT01418261.

Predictive factors for successful renal denervation: should we use them in clinical trials?

Renal denervation (RDN) is facing various challenges to its initial claimed value in hypertension treatment. Major concerns are the choice of the patients and the technical efficacy of the RDN. Different factors have been described as predicting the capacity of RDN to decrease blood pressure. These factors are related to the patients, the procedure and the tools to confirm successful neural ablation. Their use in future trials should help to improve RDN trials understanding and outcomes. This review summarizes the different predictive factors available and their potential benefits in patient selection and in procedure guidance.

Cardiac innervation and sudden cardiac death.

Afferent and efferent cardiac neurotransmission via the cardiac nerves intricately modulates nearly all physiological functions of the heart (chronotropy, dromotropy, lusitropy, and inotropy). Afferent information from the heart is transmitted to higher levels of the nervous system for processing (intrinsic cardiac nervous system, extracardiac-intrathoracic ganglia, spinal cord, brain stem, and higher centers), which ultimately results in efferent cardiomotor neural impulses (via the sympathetic and parasympathetic nerves). This system forms interacting feedback loops that provide physiological stability for maintaining normal rhythm and life-sustaining circulation. This system also ensures that there is fine-tuned regulation of sympathetic-parasympathetic balance in the heart under normal and stressed states in the short (beat to beat), intermediate (minutes to hours), and long term (days to years). This important neurovisceral/autonomic nervous system also plays a major role in the pathophysiology and progression of heart disease, including heart failure and arrhythmias leading to sudden cardiac death. Transdifferentiation of neurons in heart failure, functional denervation, cardiac and extracardiac neural remodeling has also been identified and characterized during the progression of disease. Recent advances in understanding the cellular and molecular processes governing innervation and the functional control of the myocardium in health and disease provide a rational mechanistic basis for the development of neuraxial therapies for preventing sudden cardiac death and other arrhythmias. Advances in cellular, molecular, and bioengineering realms have underscored the emergence of this area as an important avenue of scientific inquiry and therapeutic intervention.

The sympathetic nervous system alterations in human hypertension.

Several articles have dealt with the importance and mechanisms of the sympathetic nervous system alterations in experimental animal models of hypertension. This review addresses the role of the sympathetic nervous system in the pathophysiology and therapy of human hypertension. We first discuss the strengths and limitations of various techniques for assessing the sympathetic nervous system in humans, with a focus on heart rate, plasma norepinephrine, microneurographic recording of sympathetic nerve traffic, and measurements of radiolabeled norepinephrine spillover. We then examine the evidence supporting the importance of neuroadrenergic factors as promoters and amplifiers of human hypertension. We expand on the role of the sympathetic nervous system in 2 increasingly common forms of secondary hypertension, namely hypertension associated with obesity and with renal disease. With this background, we examine interventions of sympathetic deactivation as a mode of antihypertensive treatment. Particular emphasis is given to the background and results of recent therapeutic approaches based on carotid baroreceptor stimulation and radiofrequency ablation of the renal nerves.

Renal sympathetic denervation for the treatment of refractory hypertension.

Resistant hypertension poses significant health concerns. There are strong demands for new and safe therapies to control resistant hypertension while addressing its common causes, specifically poor compliance to lifelong polypharmacy, lifestyle modifications, and physician inertia. The sympathetic nervous system plays a significant pathophysiological role in hypertension. Surgical sympathectomy for blood pressure reduction is an old but extremely efficacious therapeutic concept, now abandoned with the dawn of a safer contemporary pharmacology era. Recently, clinical studies have revealed promising results for safe and sustained blood pressure reduction with percutaneous renal sympathetic denervation. This is a novel, minimally invasive, device-based therapy, specifically targeting and ablating the renal artery nerves with radiofrequency waves without permanent implantation. There are also reported additional benefits in related comorbidities, such as impaired glucose metabolism, renal impairment, left ventricular hypertrophy, heart failure, and others. This review focuses on how selective renal sympathetic denervation works, its present and potential therapeutic indications, and its future directions.

Renal denervation for the treatment of cardiovascular high risk-hypertension or beyond?

Hypertension imposes a major burden of morbidity and mortality and is associated with sympathetic nervous system overactivity. Renal sympathetic denervation has been shown to reduce office blood pressure, ambulatory blood pressure, and sympathetic activity in patients with resistant hypertension. Therefore, the procedure has attracted a lot of attention. Beyond blood pressure, renal denervation has been shown to improve glucose tolerance, microalbuminuria, and arrhythmias in several experimental models and, in admittedly, often uncontrolled clinical studies. It has been demonstrated to reduce myocardial hypertrophy in a blood pressure-independent and blood pressure-dependent way. The first studies on heart failure with preserved and reduced ejection fraction are ongoing. Renal sympathetic denervation holds promise for future indications in hypertension and related comorbidities and consequences, such as metabolic disease, renal failure, and heart failure. Published data in a placebo-control blinded study, however, are needed. The aim of this review is to provide a critical and comprehensive overview of heretofore generated data on renal denervation in experimental models, in human hypertension, and on early developments in new indications, which should indicate the way to powered and performed, controlled clinical studies appropriately.

First report of monomicrobial Candida parapsilosis necrotizing fasciitis.

Candida parapsilosis is an emerging pathogen worldwide. It commonly causes soft tissue infection; however, to our knowledge there has been no previous report of monomicrobial necrotizing soft tissue infection (NSTI) secondary to C. parapsilosis. We report the first case of NSTI caused by C. parapsilosis in an immunocompromised renal transplant patient, with the diagnosis proven both histologically and microbiologically. Our patient required aggressive surgical intervention and antifungal therapy, with postoperative survival at 90 days.

Renal Sympathetic Denervation: Hibernation or Resurrection?

The most current versions of renal sympathetic denervation have been invented as minimally invasive approaches for the management of drug-resistant hypertension. The anatomy, physiology and pathophysiology of renal sympathetic innervation provide a strong background supporting an important role of the renal nerves in the regulation of blood pressure (BP) and volume. In addition, historical data with surgical sympathectomy and experimental data with surgical renal denervation indicate a beneficial effect on BP levels. Early clinical studies with transcatheter radiofrequency ablation demonstrated impressive BP reduction, accompanied by beneficial effects in target organ damage and other disease conditions characterized by sympathetic overactivity. However, the failure of the SYMPLICITY 3 trial to meet its primary efficacy end point raised a lot of concerns and put the field of renal denervation into hibernation. This review aims to translate basic research into clinical practice by presenting the anatomical and physiological basis for renal sympathetic denervation, critically discussing the past and present knowledge in this field, where we stand now, and also speculating about the future of the intervention and potential directions for research.

Renal denervation for the treatment of resistant hypertension: review and clinical perspective.

When introduced clinically 6 years ago, renal denervation was thought to be the solution for all patients whose blood pressure could not be controlled by medication. The initial two studies, SYMPLICITY HTN-1 and HTN-2, demonstrated great magnitudes of blood pressure reduction within 6 mo of the procedure and were based on a number of assumptions that may not have been true, including strict adherence to medication and absence of white-coat hypertension. The SYMPLICITY HTN-3 trial controlled for all possible factors believed to influence the outcome, including the addition of a sham arm, and ultimately proved the demise of the initial overly optimistic expectations. This trial yielded a much lower blood pressure reduction compared with the previous SYMPLICITY trials. Since its publication in 2014, there have been many analyses to try and understand what accounted for the differences. Of all the variables examined that could influence blood pressure outcomes, the extent of the denervation procedure was determined to be inadequate. Beyond this, the physiological mechanisms that account for the heterogeneous fall in arterial pressure following renal denervation remain unclear, and experimental studies indicate dependence on more than simply reduced renal sympathetic activity. These and other related issues are discussed in this paper. Our perspective is that renal denervation works if done properly and used in the appropriate patient population. New studies with new approaches and catheters and appropriate controls will be starting later this year to reassess the efficacy and safety of renal denervation in humans.

Revisiting renovascular imaging for renal sympathetic denervation: current techniques and applications.

UNLABELLED: Renal sympathetic denervation (RDN) is an emerging technique in the treatment of resistant hypertension, most commonly performed using an endovascular approach. Clinical and anatomical criteria for RDN are well established and imaging plays an integral role in selecting patients with suitable anatomy, procedural planning and device selection. Nevertheless, the current body of literature surrounding imaging related to RDN remains limited. The purpose of this article is to illustrate the expectations and limitations of various imaging techniques, including Doppler ultrasound, CT angiography, MR angiography and newer techniques such as non-contrast MR angiography, in the context of RDN. KEY POINTS: • To understand the role of imaging in renal denervation • To understand strengths and weaknesses of current imaging techniques • To understand the relevant imaging findings in the context of renal denervation.

Renal denervation for hypertension: observations and predictions of a founder.

The 6-year anniversary of the first catheter-based renal denervation procedure for resistant hypertension has passed, and the 3-year follow-up results of the Symplicity HTN-1 are now published. At the 'end of the beginning', it is timely to reflect on the observations to-date for this revolutionary therapy, and to predict the next phase in its development and clinical application in hypertension treatment. In essence, on observations to hand, the procedure is efficacious and seems safe and durable. But will the blood pressure lowering truly be permanent (or might it be cancelled out by renal sympathetic nerve regrowth)? How can patient selection for the renal denervation procedure be optimized, given that some patients do not respond with a blood pressure fall? Will blood pressure lowering with renal denervation reduce the rate of clinical cardiovascular endpoints? Will long-term safety be acceptable? Can milder hypertension be cured? And there are unresolved procedural and technical questions: how much renal denervation is optimal; is unilateral denervation, now commonly used, beneficial; will renal denervation show a 'class effect', with the different energy forms now used for renal nerve ablation producing equivalent blood pressure lowering? At the 12-year anniversary, I expect these questions will be answered, and catheter-based renal denervation will have an established clinical role in the care of patients with severe grades of hypertension. Less certain is the common prediction of its application in early, mild hypertension, in parallel with, or even before anti-hypertensive drug prescribing.

[Diagnosis and treatment of patients with secondary arterial hypertension of adrenal and renal genesis].

A multidisciplinary approach to the diagnosis and treatment of patients with symptomatic arterial hypertension enabled us to identify 154 patients with adrenal tumors. These patients underwent adrenalectomy for following reasons: pheochromocytoma--73 patients, aldosteronoma-- 43 patients, corticosteroma--22 patients, incidentalomas--16 patients. After surgery, stable normalization of blood pressure (BP) occurred in 84.4% of cases. Requirement of antihypertensive therapy was preserved in 15.6% cases, but blood pressure did not reach the preoperative levels in any of the treated patients. Among 81 patients with renal hypertension, 67 patients underwent balloon angioplasty with stent implantation. Cause of narrowing of renal artery was atherosclerotic lesion in 48 (71.6%) patients, fibromuscular dysplasia--in 18 (26.8 %) patients, and Takayasu's disease--in 12 year-old girl. In the immediate postoperative period, normalization of blood pressure was occurred in all patients who underwent surgery for renovascular hypertension.

Influence of renal sympathetic denervation on quality of life.

BACKGROUND: Therapy-resistant arterial hypertension causing psychosocial stress and is associated with cardiovascular morbidity and mortality. The aim of the study was to evaluate the effect on quality of life (QoL) in patients with resistant hypertension undergoing renal sympathetic denervation (RSD). METHODS AND RESULTS: We analyzed responses to the SF-36 Quality of Life Questionnaire provided by patients with resistant arterial hypertension after RSD. Thirty consecutive patients from 2 centers were included in this study, from October 2011 until February 2012. The phone interview was performed after the 3-month follow-up. A significant reduction (26 ± 13.5 mmHg) in systolic blood pressure (BP) was detected at the 3-month follow-up (142.0 ± 15.1 mmHg vs 168.0 ± 13.7 mmHg; P < 0.001). Seventy-five percent of the patients indicated that their health situation was a lot better (better, 21%; equal to, 4%) 3 months after RSD compared to the time before the therapeutic procedure. Furthermore, the majority of patients felt full of pep (always, 29%; mostly, 58%; quite often, 8%; sometimes, 4%), and full of energy (always, 25%; mostly, 54%; quite often, 16.7%; sometimes, 4.2%) after the procedure. Recipients of RSD indicated that they felt more light and healthy, and nearly all recipients (93%) described a loss of anxiety and indisposition. CONCLUSIONS: This investigation revealed that sufficient BP reduction by RSD and time following therapeutic success lead to significant improvements in patient QoL.

Catheter-based radiofrequency renal sympathetic denervation for resistant hypertension.

PURPOSE: To evaluate the feasibility, efficacy, and safety of catheter-based radiofrequency renal sympathetic denervation for treatment of resistant hypertension. MATERIALS AND METHODS: Twenty-four patients with essential hypertension unresponsive to at least three antihypertensive agents underwent renal denervation (RDN). Three patients had variant renal anatomy. Comorbidities included diabetes (n = 11), renal failure (n = 4), and obstructive sleep apnea (n = 2). The effect on 24-hour ambulatory blood pressure (BP) was assessed at 6 months. Patients with a decrease in systolic BP of at least 10mm Hg were considered responders. RESULTS: RDN was bilateral in 19 patients and single-sided in five. The 19 patients with bilateral RDN showed mean reductions in 24-hour ambulatory BP of 20.7/8.7mm Hg±18.1/9.9 (systolic/diastolic; P = .0001/P = .0012). Sixteen bilaterally treated patients (84.2%) showed a systolic BP reduction of at least 10mm Hg and were considered responders, whereas only one of the five patients with single-sided RDN showed a response. Two responders with sleep apnea showed improvement in polysomnography indices, and one with left concentric ventricular hypertrophy showed complete cardiac remodeling 11 months after the RDN procedure. Renal function remained unchanged in all patients, including those with renal failure. Optical coherence tomography of the renal arteries in one patient showed sporadic endothelial scarring. Renal angiograms at 9 months (one patient) and 12 months (two patients) had normal findings. CONCLUSIONS: Catheter-based RDN was carried out safely, even in patients with comorbidities, abnormal renal arteries, or anatomic variants. The response rate for bilateral RDN (84.2%) was comparable to previous reports.

Renal denervation in moderate to severe CKD.

Sympathetic activation contributes to the progression of CKD and is associated with adverse cardiovascular outcomes. Ablation of renal sympathetic nerves reduces sympathetic nerve activity and BP in patients with resistant hypertension and preserved renal function, but whether this approach is safe and effective in patients with an estimated GFR (eGFR) < 45 ml/min per 1.73 m(2) is unknown. We performed bilateral renal denervation in 15 patients with resistant hypertension and stage 3-4 CKD (mean eGFR, 31 ml/min per 1.73 m(2)). We used CO(2) angiography in six patients to minimize exposure to contrast agents. Estimated GFR remained unchanged after the procedure, irrespective of the use of CO(2) angiography. Mean baseline BP ± SD was 174 ± 22/91 ± 16 mmHg despite the use of 5.6 ± 1.3 antihypertensive drugs. Mean changes in office systolic and diastolic BP at 1, 3, 6, and 12 months were -34/-14, -25/-11, -32/-15, and -33/-19 mmHg, respectively. Night-time ambulatory BP significantly decreased (P<0.05), restoring a more physiologic dipping pattern. In conclusion, this study suggests a favorable short-term safety profile and beneficial BP effects of catheter-based renal nerve ablation in patients with stage 3-4 CKD and resistant hypertension.