ABSTRACT
BACKGROUND: The randomized, sham-controlled RADIANCE-HTN (A Study of the Recor Medical Paradise System in Clinical Hypertension) SOLO, RADIANCE-HTN TRIO, and RADIANCE II (A Study of the Recor Medical Paradise System in Stage II Hypertension) trials independently met their primary end point of a greater reduction in daytime ambulatory systolic blood pressure (SBP) 2 months after ultrasound renal denervation (uRDN) in patients with hypertension. To characterize the longer-term effectiveness and safety of uRDN versus sham at 6 months, after the blinded addition of antihypertensive treatments (AHTs), we pooled individual patient data across these 3 similarly designed trials. METHODS: Patients with mild to moderate hypertension who were not on AHT or with hypertension resistant to a standardized combination triple AHT were randomized to uRDN (n=293) versus sham (n=213); they were to remain off of added AHT throughout 2 months of follow-up unless specified blood pressure (BP) criteria were exceeded. In each trial, if monthly home BP was ≥135/85 mm Hg from 2 to 5 months, standardized AHT was sequentially added to target home BP <135/85 mm Hg under blinding to initial treatment assignment. Six-month outcomes included baseline- and AHT-adjusted change in daytime ambulatory, home, and office SBP; change in AHT; and safety. Linear mixed regression models using all BP measurements and change in AHT from baseline through 6 months were used. RESULTS: Patients (70% men) were 54.1±9.3 years of age with a baseline daytime ambulatory/home/office SBP of 150.5±9.8/151.0±12.4/155.5±14.4 mm Hg, respectively. From 2 to 6 months, BP decreased in both groups with AHT titration, but fewer uRDN patients were prescribed AHT (P=0.004), and fewer additional AHT were prescribed to uRDN patients versus sham patients (P=0.001). Whereas the unadjusted between-group difference in daytime ambulatory SBP was similar at 6 months, the baseline and medication-adjusted between-group difference at 6 months was -3.0 mm Hg (95% CI, -5.7, -0.2; P=0.033), in favor of uRDN+AHT. For home and office SBP, the adjusted between-group differences in favor of uRDN+AHT over 6 months were -5.4 mm Hg (-6.8, -4.0; P<0.001) and -5.2 mm Hg (-7.1, -3.3; P<0.001), respectively. There was no heterogeneity between trials. Safety outcomes were few and did not differ between groups. CONCLUSIONS: This individual patient-data analysis of 506 patients included in the RADIANCE trials demonstrates the maintenance of BP-lowering efficacy of uRDN versus sham at 6 months, with fewer added AHTs. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02649426 and NCT03614260.
Subject(s)
Hypertension , Renal Artery , Female , Humans , Male , Antihypertensive Agents/therapeutic use , Blood Pressure , Blood Pressure Monitoring, Ambulatory , Denervation/adverse effects , Denervation/methods , Hypertension/diagnosis , Hypertension/drug therapy , Kidney , Renal Artery/diagnostic imaging , Sympathectomy/methods , Treatment Outcome , Middle AgedABSTRACT
BACKGROUND: Renal denervation (RDN) has demonstrated clinically relevant reductions in blood pressure (BP) among individuals with uncontrolled hypertension despite lifestyle intervention and medications. The safety and effectiveness of alcohol-mediated RDN have not been formally studied in this indication. METHODS: TARGET BP I is a prospective, international, sham-controlled, randomized, patient- and assessor-blinded trial investigating the safety and efficacy of alcohol-mediated RDN. Patients with office systolic BP (SBP) ≥150 and ≤180 mm Hg, office diastolic BP ≥90 mm Hg, and mean 24-hour ambulatory SBP ≥135 and ≤170 mm Hg despite prescription of 2 to 5 antihypertensive medications were enrolled. The primary end point was the baseline-adjusted change in mean 24-hour ambulatory SBP 3 months after the procedure. Secondary end points included mean between-group differences in office and ambulatory BP at additional time points. RESULTS: Among 301 patients randomized 1:1 to RDN or sham control, RDN was associated with a significant reduction in 24-hour ambulatory SBP at 3 months (mean±SD, -10.0±14.2 mm Hg versus -6.8±12.1 mm Hg; treatment difference, -3.2 mm Hg [95% CI, -6.3 to 0.0]; P=0.0487). Subgroup analysis of the primary end point revealed no significant interaction across predefined subgroups. At 3 months, the mean change in office SBP was -12.7±18.3 and -9.7±17.3 mm Hg (difference, -3.0 [95% CI, -7.0 to 1.0]; P=0.173) for RDN and sham, respectively. No significant differences in ambulatory or office diastolic BP were observed. Adverse safety events through 6 months were uncommon, with one instance of accessory renal artery dissection in the RDN group (0.7%). No significant between-group differences in medication changes or patient adherence were identified. CONCLUSIONS: Alcohol-mediated RDN was associated with a modest but statistically significant reduction in 24-hour ambulatory SBP compared with sham control. No significant differences between groups in office BP or 6-month major adverse events were observed. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02910414.
Subject(s)
Antihypertensive Agents , Blood Pressure , Hypertension , Kidney , Humans , Female , Male , Middle Aged , Antihypertensive Agents/therapeutic use , Hypertension/physiopathology , Hypertension/drug therapy , Hypertension/surgery , Blood Pressure/drug effects , Aged , Kidney/innervation , Prospective Studies , Ethanol/adverse effects , Ethanol/administration & dosage , Ethanol/pharmacology , Treatment Outcome , Blood Pressure Monitoring, Ambulatory , Sympathectomy/adverse effects , Sympathectomy/methods , Renal Artery/innervationABSTRACT
BACKGROUND: Use of sodium-glucose-cotransporter-2 (SGLT2) inhibitors often causes an initial decline in glomerular filtration rate (GFR). This study addresses the question whether the initial decline of renal function with SGLT2 inhibitor treatment is related to vascular changes in the systemic circulation. METHODS: We measured GFR (mGFR) and estimated GFR (eGFR) in 65 patients with type 2 diabetes (T2D) at baseline and after 12 weeks of treatment randomized either to a combination of empagliflozin and linagliptin (SGLT2 inhibitor based treatment group) (n = 34) or metformin and insulin (non-SGLT2 inhibitor based treatment group) (n = 31). mGFR was measured using the gold standard clearance technique by constant infusion of inulin. In addition to blood pressure (BP), we measured pulse wave velocity (PWV) under standardized conditions reflecting vascular compliance of large arteries, as PWV is considered to be one of the most reliable vascular parameter of cardiovascular (CV) prognosis. RESULTS: Both mGFR and eGFR decreased significantly after initiating treatment, but no correlation was found between change in mGFR and change in eGFR in either treatment group (SGLT2 inhibitor based treatment group: r=-0.148, p = 0.404; non-SGLT2 inhibitor based treatment group: r = 0.138, p = 0.460). Noticeably, change in mGFR correlated with change in PWV (r = 0.476, p = 0.005) in the SGLT2 inhibitor based treatment group only and remained significant after adjustment for the change in systolic BP and the change in heart rate (r = 0.422, p = 0.018). No such correlation was observed between the change in eGFR and the change in PWV in either treatment group. CONCLUSIONS: Our main finding is that after initiating a SGLT2 inhibitor based therapy an exaggerated decline in mGFR was related with improved vascular compliance of large arteries reflecting the pharmacologic effects of SGLT2 inhibitor in the renal and systemic vascular bed. Second, in a single patient with T2D, eGFR may not be an appropriate parameter to assess the true change of renal function after receiving SGLT2 inhibitor based therapy. TRIAL REGISTRATION: clinicaltrials.gov (NCT02752113).
Subject(s)
Benzhydryl Compounds , Diabetes Mellitus, Type 2 , Glomerular Filtration Rate , Glucosides , Kidney , Linagliptin , Pulse Wave Analysis , Sodium-Glucose Transporter 2 Inhibitors , Humans , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Glomerular Filtration Rate/drug effects , Male , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/physiopathology , Diabetes Mellitus, Type 2/diagnosis , Middle Aged , Female , Benzhydryl Compounds/therapeutic use , Benzhydryl Compounds/adverse effects , Aged , Treatment Outcome , Kidney/drug effects , Kidney/physiopathology , Glucosides/therapeutic use , Glucosides/adverse effects , Time Factors , Linagliptin/therapeutic use , Linagliptin/adverse effects , Metformin/therapeutic use , Insulin , Diabetic Nephropathies/physiopathology , Diabetic Nephropathies/diagnosis , Diabetic Nephropathies/drug therapy , Vascular Stiffness/drug effects , Drug Therapy, Combination , Hypoglycemic Agents/therapeutic use , Hypoglycemic Agents/adverse effects , Biomarkers/blood , Clinical Relevance , Sodium-Glucose Transporter 2ABSTRACT
BACKGROUND AND AIMS: Obesity has been shown to be an independent risk factor for the development of CKD. Little is known about pathways of interaction of visceral fat mass estimated by waist circumference (WC) and metabolic factors with the renal and intraglomerular hemodynamic profile in healthy, non-obese individuals. METHODS AND RESULTS: The study population of this post-hoc analysis in 80 healthy individuals, who participated in a randomized, controlled clinical trial (www. CLINICALTRIALS: gov: NCT02783456) was divided into two groups based on median of WC (high WC and low WC group). Renal hemodynamic profiles were analyzed using steady state input clearance (infusion of para-amino-hippuric acid and inulin). Intraglomerular pressure (IGP) and resistances of the afferent (RA) and efferent (RE) arterioles were calculated (Gomez equation). The analysis included healthy, non-smoking individuals, aged 27 ± 9 years with median WC of 84.75 ± 9 cm. Glomerular filtration rate (GFR) (110 ± 15 vs. 127 ± 16 ml/min/m2, p < 0.001), renal plasma flow (RPF) (620 ± 109 vs. 700 ± 104 ml/min, p = 0.001) and IGP (36.7 ± 2.3 vs. 38.5 ± 3.1 mmHg, p = 0.003) were lower in the high WC compared to the low WC group. Patients in the high WC group showed higher renal vascular resistance (RVR) (85 ± 19 vs. 70 ± 12 mmHg/(ml/min), p < 0.001), higher RA (4034 ± 1177 vs. 3069 ± 786 dyn∗s/cm5, p < 0.001) and higher RE (2283 ± 339 vs. 2118 ± 280 dyn∗s/cm5, p = 0.021) compared to the low WC group. Individuals in the high WC group showed higher leptin levels (p = 0.003) and higher HOMA-IR (p = 0.024) compared to the low WC group. CONCLUSION: Increased WC in healthy young individuals was associated with reduced GFR and RPF likely mediated by increased RVR.
Subject(s)
Hemodynamics , Kidney , Humans , Waist Circumference , Obesity/epidemiology , Vascular ResistanceABSTRACT
Since the publication of the 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) Guidelines for the Management of Arterial Hypertension, several high-quality studies, including randomised, sham-controlled trials on catheter-based renal denervation (RDN) were published, confirming both the blood pressure (BP)-lowering efficacy and safety of radiofrequency and ultrasound RDN in a broad range of patients with hypertension, including resistant hypertension. A clinical consensus document by the ESC Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) on RDN in the management of hypertension was considered necessary to inform clinical practice. This expert group proposes that RDN is an adjunct treatment option in uncontrolled resistant hypertension, confirmed by ambulatory BP measurements, despite best efforts at lifestyle and pharmacological interventions. RDN may also be used in patients who are unable to tolerate antihypertensive medications in the long term. A shared decision-making process is a key feature and preferably includes a patient who is well informed on the benefits and limitations of the procedure. The decision-making process should take (i) the patient's global cardiovascular (CV) risk and/or (ii) the presence of hypertension-mediated organ damage or CV complications into account. Multidisciplinary hypertension teams involving hypertension experts and interventionalists evaluate the indication and facilitate the RDN procedure. Interventionalists require expertise in renal interventions and specific training in RDN procedures. Centres performing these procedures require the skills and resources to deal with potential complications. Future research is needed to address open questions and investigate the impact of BP-lowering with RDN on clinical outcomes and potential clinical indications beyond hypertension.
Subject(s)
Hypertension , Renal Artery , Humans , Adult , Hypertension/surgery , Hypertension/drug therapy , Kidney/blood supply , Blood Pressure , Antihypertensive Agents/therapeutic use , Antihypertensive Agents/pharmacology , Denervation/methods , Treatment Outcome , Sympathectomy/methodsABSTRACT
The clinical implications of hypertension in addition to a high prevalence of both uncontrolled blood pressure and medication nonadherence promote interest in developing device-based approaches to hypertension treatment. The expansion of device-based therapies and ongoing clinical trials underscores the need for consistency in trial design, conduct, and definitions of clinical study elements to permit trial comparability and data poolability. Standardizing methods of blood pressure assessment, effectiveness measures beyond blood pressure alone, and safety outcomes are paramount. The Hypertension Academic Research Consortium (HARC) document represents an integration of evolving evidence and consensus opinion among leading experts in cardiovascular medicine and hypertension research with regulatory perspectives on clinical trial design and methodology. The HARC document integrates the collective information among device-based therapies for hypertension to better address existing challenges and identify unmet needs for technologies proposed to treat the world's leading cause of death and disability. Consistent with the Academic Research Consortium charter, this document proposes pragmatic consensus clinical design principles and outcomes definitions for studies aimed at evaluating device-based hypertension therapies.
Subject(s)
Hypertension , Clinical Trials as Topic , Consensus , Humans , Hypertension/diagnosis , Hypertension/therapyABSTRACT
Peripheral neurons with renal afferents exhibit a predominantly tonic firing pattern of higher frequency that is reduced to low frequencies (phasic firing pattern) in renal inflammation. We wanted to test the hypothesis that the reduction in firing activity during inflammation is due to high-activity tonic neurons switching from higher to low frequencies depending on altered sodium currents. We identified and cultivated afferent sensory neurons with renal projections from the dorsal root ganglia (Th11-L2). Cultivated neurons were incubated with the chemokine CXCL1 (1,5 nmol/ml) for 12 h. We characterized neurons as "tonic," i.e., sustained action potential (AP) firing, or "phasic," i.e., < 5 APs upon stimulation in the current clamp. Their membrane currents were investigated in a voltage clamp. Data analyzed: renal vs. non-renal and tonic vs. phasic neurons. Renal afferent neurons exposed to CXCL1 showed a decrease in tonic firing pattern (CXCL1: 35,6% vs. control: 57%, P < 0.05). Na+ and K+ currents were not different between control renal and non-renal DRG neurons. Phasic neurons exhibited higher Na+ and K+ currents than tonic resulting in shorter APs (3.7 ± 0.3 vs. 6.1 ± 0.6 ms, P < 0.01). In neurons incubated with CXCL1, Na+ and K+ peak current density increased in phasic (Na+: - 969 ± 47 vs. - 758 ± 47 nA/pF, P < 0.01; K+: 707 ± 22 vs. 558 ± 31 nA/pF, P < 0.01), but were unchanged in tonic neurons. Phasic neurons exposed to CXCL1 showed a broader range of Na+ currents ([- 365- - 1429 nA] vs. [- 412- - 4273 nA]; P < 0.05) similar to tonic neurons. After CXCL1 exposure, significant changes in phasic neurons were observed in sodium activation/inactivation as well as a wider distribution of Na+ currents characteristic of tonic neurons. These findings indicate a subgroup of tonic neurons besides mere tonic or phasic neurons exists able to exhibit a phasic activity pattern under pathological conditions.
ABSTRACT
BACKGROUND: Renal denervation has been shown to lower blood pressure in the presence of antihypertensive medications; however, long-term safety and efficacy data from randomised trials of renal denervation are lacking. In this pre-specified analysis of the SPYRAL HTN-ON MED study, we compared changes in blood pressure, antihypertensive drug use, and safety up to 36 months in renal denervation versus a sham control group. METHODS: This randomised, single-blind, sham-controlled trial enrolled patients from 25 clinical centres in the USA, Germany, Japan, the UK, Australia, Austria, and Greece, with uncontrolled hypertension and office systolic blood pressure between 150 mm Hg and 180 mm Hg and diastolic blood pressure of 90 mm Hg or higher. Eligible patients had to have 24-h ambulatory systolic blood pressure between 140 mm Hg and less than 170 mm Hg, while taking one to three antihypertensive drugs with stable doses for at least 6 weeks. Patients underwent renal angiography and were randomly assigned (1:1) to radiofrequency renal denervation or a sham control procedure. Patients and physicians were unmasked after 12-month follow-up and sham control patients could cross over after 12-month follow-up completion. The primary endpoint was the treatment difference in mean 24-h systolic blood pressure at 6 months between the renal denervation group and the sham control group. Statistical analyses were done on the intention-to-treat population. Long-term efficacy was assessed using ambulatory and office blood pressure measurements up to 36 months. Drug surveillance was used to assess medication use. Safety events were assessed up to 36 months. This trial is registered with ClinicalTrials.gov, NCT02439775; prospectively, an additional 260 patients are currently being randomly assigned as part of the SPYRAL HTN-ON MED Expansion trial. FINDINGS: Between July 22, 2015, and June 14, 2017, among 467 enrolled patients, 80 patients fulfilled the qualifying criteria and were randomly assigned to undergo renal denervation (n=38) or a sham control procedure (n=42). Mean ambulatory systolic and diastolic blood pressure were significantly reduced from baseline in the renal denervation group, and were significantly lower than the sham control group at 24 and 36 months, despite a similar treatment intensity of antihypertensive drugs. The medication burden at 36 months was 2·13 medications (SD 1·15) in the renal denervation group and 2·55 medications (2·19) in the sham control group (p=0·26). 24 (77%) of 31 patients in the renal denervation group and 25 (93%) of 27 patients in the sham control group adhered to medication at 36 months. At 36 months, the ambulatory systolic blood pressure reduction was -18·7 mm Hg (SD 12·4) for the renal denervation group (n=30) and -8·6 mm Hg (14·6) for the sham control group (n=32; adjusted treatment difference -10·0 mm Hg, 95% CI -16·6 to -3·3; p=0·0039). Treatment differences between the renal denervation group and sham control group at 36 months were -5·9 mm Hg (95% CI -10·1 to -1·8; p=0·0055) for mean ambulatory diastolic blood pressure, -11·0 mm Hg (-19·8 to -2·1; p=0·016) for morning systolic blood pressure, and -11·8 mm Hg (-19·0 to -4·7; p=0·0017) for night-time systolic blood pressure. There were no short-term or long-term safety issues associated with renal denervation. INTERPRETATION: Radiofrequency renal denervation compared with sham control produced a clinically meaningful and lasting blood pressure reduction up to 36 months of follow-up, independent of concomitant antihypertensive medications and without major safety events. Renal denervation could provide an adjunctive treatment modality in the management of patients with hypertension. FUNDING: Medtronic.
Subject(s)
Antihypertensive Agents , Hypertension , Antihypertensive Agents/therapeutic use , Blood Pressure , Blood Pressure Monitoring, Ambulatory , Denervation/methods , Humans , Hypertension/surgery , Kidney , Single-Blind Method , Sympathectomy/methods , Treatment OutcomeABSTRACT
BACKGROUND: Subclinical damage to both the small and large vessels may contribute to the development and progression of cardiovascular disease. Scanning laser Doppler flowmetry (SLDF), an established method used to measure retinal microcirculation, has been successfully applied in hypertensive and post-stroke patients. METHODS: Retinal microcirculation was assessed in 158 patients with type 1 diabetes and 38 age-matched healthy controls. The diabetics were divided into 3 groups: group A with diabetes duration <12 months, group B with diabetes with 1-10 years, and group C >10 years of diabetes. Retinal capillary structure and perfusion were evaluated using a Heidelberg retina flowmeter and automatically analyzed with full-field perfusion imaging. RESULTS: Age and BMI were comparable in all the diabetic patients and the controls (mean age 24.8 ± 4.7 years, mean BMI 22.9 ± 4.1). In the univariate analyses, RCF (retinal capillary flow) was significantly higher in group A (297 ± 121 arbitrary units [AU]) vs group B (236 ± 52 AU; p = 0.007) and group C (236 ± 70 AU; p = 0.008) and comparable to that of the controls (p = 0.46). Additionally, the WLR (Wall-to-Lumen Ratio) was highest in group C compared to the other diabetic subgroups and controls (p = 0.001). Multivariate regression analyses including age, BMI, sex, HbA1c, smoking, systolic blood pressure, and diabetes duration as covariates, showed, that only diabetes duration was significantly associated with WLR variations, whereas HbA1c was significantly linked to retinal capillary flow levels. CONCLUSIONS: New-onset diabetes is associated with an increase in RCF, which then gradually decreased with the duration of the disease. Structural changes of the retinal arterioles estimated via WLR are evident later in the course of diabetes, especially when the disease duration exceeded 10 years.
Subject(s)
Diabetes Mellitus, Type 1 , Humans , Young Adult , Adult , Arterioles , Glycated Hemoglobin , Hemodynamics , Retinal Vessels , Laser-Doppler Flowmetry/methods , Blood Flow VelocityABSTRACT
Supported by several high-quality randomized controlled trials and registry analyses, catheter-based renal denervation is becoming an important adjunctive treatment modality for the safe and efficacious treatment of hypertension besides lifestyle modifications and antihypertensive medication. Renal denervation is of particular interest to nephrologists as the intervention may provide additional benefits to hypertensive people with chronic kidney disease (CKD), a condition typically characterized by sympathetic hyperactivity. A growing body of clinical evidence supports the safety and efficacy of renal denervation in this difficult-to-control population. In addition, preclinical and clinical research works indicate potential nephroprotective effects in CKD patients. The current review examines recent research on renal denervation with a focus on renal disease and assesses the latest findings and their implications from a nephrologist's perspective.
Subject(s)
Hypertension , Renal Insufficiency, Chronic , Humans , Kidney , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/surgery , Antihypertensive Agents/therapeutic use , Treatment Outcome , Denervation , Sympathectomy , Blood PressureABSTRACT
Diabetic kidney disease (DKD) develops in â¼40% of patients with diabetes and is the most common cause of chronic kidney disease (CKD) worldwide. Patients with CKD, especially those with diabetes mellitus, are at high risk of both developing kidney failure and cardiovascular (CV) death. The use of renin-angiotensin system (RAS) blockers to reduce the incidence of kidney failure in patients with DKD dates back to studies that are now ≥20 years old. During the last few years, sodium-glucose co-transporter-2 inhibitors (SGLT2is) have shown beneficial renal effects in randomized trials. However, even in response to combined treatment with RAS blockers and SGLT2is, the renal residual risk remains high with kidney failure only deferred, but not avoided. The risk of CV death also remains high even with optimal current treatment. Steroidal mineralocorticoid receptor antagonists (MRAs) reduce albuminuria and surrogate markers of CV disease in patients already on optimal therapy. However, their use has been curtailed by the significant risk of hyperkalaemia. In the FInerenone in reducing kiDnEy faiLure and dIsease prOgression in DKD (FIDELIO-DKD) study comparing the actions of the non-steroidal MRA finerenone with placebo, finerenone reduced the progression of DKD and the incidence of CV events, with a relatively safe adverse event profile. This document presents in detail the available evidence on the cardioprotective and nephroprotective effects of MRAs, analyses the potential mechanisms involved and discusses their potential future place in the treatment of patients with diabetic CKD.
Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Nephropathies , Renal Insufficiency, Chronic , Renal Insufficiency , Humans , Young Adult , Adult , Mineralocorticoid Receptor Antagonists/therapeutic use , Diabetes Mellitus, Type 2/complications , Renal Insufficiency, Chronic/complications , Diabetic Nephropathies/etiology , Renal Insufficiency/complicationsABSTRACT
Importance: Two initial sham-controlled trials demonstrated that ultrasound renal denervation decreases blood pressure (BP) in patients with mild to moderate hypertension and hypertension that is resistant to treatment. Objective: To study the efficacy and safety of ultrasound renal denervation without the confounding influence of antihypertensive medications in patients with hypertension. Design, Setting, and Participants: Sham-controlled, randomized clinical trial with patients and outcome assessors blinded to treatment assignment that was conducted between January 14, 2019, and March 25, 2022, at 37 centers in the US and 24 centers in Europe, with randomization stratified by center. Patients aged 18 years to 75 years with hypertension (seated office systolic BP [SBP] ≥140 mm Hg and diastolic BP [DBP] ≥90 mm Hg despite taking up to 2 antihypertensive medications) were eligible if they had an ambulatory SBP/DBP of 135/85 mm Hg or greater and an SBP/DBP less than 170/105 mm Hg after a 4-week washout of their medications. Patients with an estimated glomerular filtration rate of 40 mL/min/1.73 m2 or greater and with suitable renal artery anatomy were randomized 2:1 to undergo ultrasound renal denervation or a sham procedure. Patients were to abstain from antihypertensive medications until the 2-month follow-up unless prespecified BP criteria were exceeded and were associated with clinical symptoms. Interventions: Ultrasound renal denervation vs a sham procedure. Main Outcomes and Measures: The primary efficacy outcome was the mean change in daytime ambulatory SBP at 2 months. The primary safety composite outcome of major adverse events included death, kidney failure, and major embolic, vascular, cardiovascular, cerebrovascular, and hypertensive events at 30 days and renal artery stenosis greater than 70% detected at 6 months. The secondary outcomes included mean change in 24-hour ambulatory SBP, home SBP, office SBP, and all DBP parameters at 2 months. Results: Among 1038 eligible patients, 150 were randomized to ultrasound renal denervation and 74 to a sham procedure (mean age, 55 years [SD, 9.3 years]; 28.6% female; and 16.1% self-identified as Black or African American). The reduction in daytime ambulatory SBP was greater with ultrasound renal denervation (mean, -7.9 mm Hg [SD, 11.6 mm Hg]) vs the sham procedure (mean, -1.8 mm Hg [SD, 9.5 mm Hg]) (baseline-adjusted between-group difference, -6.3 mm Hg [95% CI, -9.3 to -3.2 mm Hg], P < .001), with a consistent effect of ultrasound renal denervation throughout the 24-hour circadian cycle. Among 7 secondary BP outcomes, 6 were significantly improved with ultrasound renal denervation vs the sham procedure. No major adverse events were reported in either group. Conclusions and Relevance: In patients with hypertension, ultrasound renal denervation reduced daytime ambulatory SBP at 2 months in the absence of antihypertensive medications vs a sham procedure without postprocedural major adverse events. Trial Registration: ClinicalTrials.gov Identifier: NCT03614260.
Subject(s)
Denervation , Hypertension , Ultrasonography, Interventional , Female , Humans , Male , Middle Aged , Antihypertensive Agents/therapeutic use , Denervation/methods , Endovascular Procedures , Hypertension/surgery , Kidney/diagnostic imaging , Kidney/innervation , Ultrasonography, Interventional/methods , Vascular Surgical Procedures , Single-Blind MethodABSTRACT
In the last 4 years, several evidence-based, national, and international guidelines on the management of arterial hypertension have been published, mostly with concordant recommendations, but in some aspects with discordant opinions. This in-depth review takes these guidelines into account but also addresses several new data of interest. Although being somewhat obvious and simple, accurate blood pressure (BP) measurement with validated devices is the cornerstone of the diagnosis of hypertension, but out-of-office BP measurements are of crucial importance as well. Simplified antihypertensive drug treatment such as single-pill combinations enhances the adherence to medication and speeds up the process of getting into the BP target range, a goal not so far adequately respected. Recommended (single-pill) combination therapy includes diuretics as part of the first step of antihypertensive therapy, and updated analysis does not provide evidence to exclude diuretics from this first step because of the recently discussed potential risk of increasing cancer incidence. Target BP goals need to be individualized, according to comorbidities, hypertension-mediated organ damage, coexistence of cardiovascular risk factors (including age), frailty in older patients, and individual tolerability. There are also concordant recommendations in the guidelines that an office BP between 120 and 140 mm Hg systolic and between 70 and 80 mm Hg diastolic should be achieved. The BP target of Kidney Disease: Improving Global Outcomes for hypertensive patients with chronic kidney disease are not applicable for clinical practice because they heavily rely on 1 study that used a study-specific, nontransferable BP measurement technique and excluded the most common cause of chronic kidney disease, namely, diabetic nephropathy. Actual data even from a prospective trial on chronotherapy have to be disregarded, and antihypertensive medication should not be routinely dosed at bedtime. Rigorously conducted trials justify the revival of renal denervation for treatment of (at least, but not only) uncontrolled and treatment-resistant hypertension.
Subject(s)
Hypertension , Aged , Antihypertensive Agents/therapeutic use , Blood Pressure , Blood Pressure Monitoring, Ambulatory/methods , Humans , Hypertension/diagnosis , Hypertension/drug therapy , Hypertension/epidemiology , Prospective StudiesABSTRACT
BACKGROUND: Endovascular renal denervation reduces blood pressure in patients with mild-to-moderate hypertension, but its efficacy in patients with true resistant hypertension has not been shown. We aimed to assess the efficacy and safety of endovascular ultrasound renal denervation in patients with hypertension resistant to three or more antihypertensive medications. METHODS: In a randomised, international, multicentre, single-blind, sham-controlled trial done at 28 tertiary centres in the USA and 25 in Europe, we included patients aged 18-75 years with office blood pressure of at least 140/90 mm Hg despite three or more antihypertensive medications including a diuretic. Eligible patients were switched to a once daily, fixed-dose, single-pill combination of a calcium channel blocker, an angiotensin receptor blocker, and a thiazide diuretic. After 4 weeks of standardised therapy, patients with daytime ambulatory blood pressure of at least 135/85 mm Hg were randomly assigned (1:1) by computer (stratified by centres) to ultrasound renal denervation or a sham procedure. Patients and outcome assessors were masked to randomisation. Addition of antihypertensive medications was allowed if specified blood pressure thresholds were exceeded. The primary endpoint was the change in daytime ambulatory systolic blood pressure at 2 months in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02649426. FINDINGS: Between March 11, 2016, and March 13, 2020, 989 participants were enrolled and 136 were randomly assigned to renal denervation (n=69) or a sham procedure (n=67). Full adherence to the combination medications at 2 months among patients with urine samples was similar in both groups (42 [82%] of 51 in the renal denervation group vs 47 [82%] of 57 in the sham procedure group; p=0·99). Renal denervation reduced daytime ambulatory systolic blood pressure more than the sham procedure (-8·0 mm Hg [IQR -16·4 to 0·0] vs -3·0 mm Hg [-10·3 to 1·8]; median between-group difference -4·5 mm Hg [95% CI -8·5 to -0·3]; adjusted p=0·022); the median between-group difference was -5·8 mm Hg (95% CI -9·7 to -1·6; adjusted p=0·0051) among patients with complete ambulatory blood pressure data. There were no differences in safety outcomes between the two groups. INTERPRETATION: Compared with a sham procedure, ultrasound renal denervation reduced blood pressure at 2 months in patients with hypertension resistant to a standardised triple combination pill. If the blood pressure lowering effect and safety of renal denervation are maintained in the long term, renal denervation might be an alternative to the addition of further antihypertensive medications in patients with resistant hypertension. FUNDING: ReCor Medical.
Subject(s)
Denervation/methods , Endovascular Procedures/methods , Hypertension/therapy , Renal Artery/innervation , Renal Artery/surgery , Ultrasonic Surgical Procedures/methods , Angiotensin Receptor Antagonists/therapeutic use , Blood Pressure Monitoring, Ambulatory , Calcium Channel Blockers/therapeutic use , Drug Resistance , Female , Humans , Kidney/blood supply , Male , Middle Aged , Single-Blind Method , Sodium Chloride Symporter Inhibitors/therapeutic useABSTRACT
BACKGROUND: Diabetic kidney disease (DKD), the most common cause of kidney failure and end-stage kidney disease worldwide, will develop in almost half of all people with type 2 diabetes. With the incidence of type 2 diabetes continuing to increase, early detection and management of DKD is of great clinical importance. MAIN BODY: This review provides a comprehensive clinical update for DKD in people with type 2 diabetes, with a special focus on new treatment modalities. The traditional strategies for prevention and treatment of DKD, i.e., glycemic control and blood pressure management, have only modest effects on minimizing glomerular filtration rate decline or progression to end-stage kidney disease. While cardiovascular outcome trials of SGLT-2i show a positive effect of SGLT-2i on several kidney disease-related endpoints, the effect of GLP-1 RA on kidney-disease endpoints other than reduced albuminuria remain to be established. Non-steroidal mineralocorticoid receptor antagonists also evoke cardiovascular and kidney protective effects. CONCLUSION: With these new agents and the promise of additional agents under clinical development, clinicians will be more able to personalize treatment of DKD in patients with type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Nephropathies , Kidney Failure, Chronic , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Diabetic Nephropathies/drug therapy , Glucagon-Like Peptide 1/therapeutic use , Humans , Mineralocorticoid Receptor Antagonists/therapeutic useABSTRACT
BACKGROUND: In patients with type 2 diabetes (T2D) sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve glycaemic control as well as cardiovascular and renal outcomes. Their effects on L-arginine (Arg) related risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA) and the protective biomarker L-homoarginine (hArg) linking T2D to cardiovascular and renal disease have not yet been reported. METHODS: Plasma and 24-h urine samples taken before and after 6 weeks of treatment were available from two prospective, randomized, double-blind, placebo-controlled, cross-over trials with empagliflozin (71 patients analyzed, NCT02471963) and dapagliflozin (59 patients analyzed, NCT02383238). In these samples, concentrations of hArg, Arg, ADMA, SDMA, and creatinine were determined by liquid-chromatography coupled to tandem mass-spectrometry. Additionally, intraindividual changes of the biomarkers in plasma were correlated with intraindividual changes of clinical parameters. RESULTS: Treatment with empagliflozin and dapagliflozin was associated with a reduction of plasma hArg by 17.5% and 13.7% (both p < 0.001), respectively, and increase in plasma SDMA concentration of 6.7% and 3.6%, respectively (p < 0.001 and p < 0.05), while plasma Arg and ADMA concentrations were not significantly altered. 24-h urinary excretion of ADMA was reduced by 15.2% after treatment with empagliflozin (p < 0.001) but not after dapagliflozin treatment, while excretion of the other markers was not significantly altered. Renal clearance of SDMA was reduced by 9.1% and 3.9% for both drugs (both p < 0.05). A reduction in ADMA clearance was observable after empagliflozin treatment only (- 15.5%, p < 0.001), but not after dapagliflozin. Renal clearance of hArg and Arg was not significantly altered. Treatment effects on L-arginine related biomarkers were not constantly correlated with effects on glycated hemoglobin, fasting plasma glucose, body mass index, and systolic blood pressure. CONCLUSIONS: Treatment with SGLT-2 inhibitors has divergent effects on Arg-related biomarkers and could affect risk estimates associated with these markers. The observed effects are unlikely to explain the known cardiovascular and renal benefits of treatment with empagliflozin or dapagliflozin but still may indicate new therapeutic approaches in patients treated with SGLT-2 inhibitors. Trial registration http://www.clinicaltrials.gov : NCT02471963 (registered 15th June 2015, retrospectively registered) and NCT02383238.
Subject(s)
Arginine/analogs & derivatives , Benzhydryl Compounds/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Glucosides/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Arginine/blood , Benzhydryl Compounds/adverse effects , Biomarkers/blood , Blood Glucose/drug effects , Blood Glucose/metabolism , Cross-Over Studies , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/diagnosis , Double-Blind Method , Female , Glucosides/adverse effects , Glycated Hemoglobin/metabolism , Humans , Male , Middle Aged , Predictive Value of Tests , Prospective Studies , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: Guidelines recommend physical activity to reduce cardiovascular (CV) events. The association between physical activity and progression of chronic kidney disease (CKD) with and without diabetes is unknown. We assessed the association of self-reported physical activity with renal and CV outcomes in high-risk patients aged ≥ 55 years over a median follow-up of 56 months in post-hoc analysis of a previously randomized trial program. METHODS: Analyses were done with Cox regression analysis, mixed models for repeated measures, ANOVA and χ2-test. 31,312 patients, among them 19,664 with and 11,648 without diabetes were analyzed. RESULTS: Physical activity was inversely associated with renal outcomes (doubling of creatinine, end-stage kidney disease (ESRD)) and CV outcomes (CV death, myocardial infarction, stroke, heart failure hospitalization). Moderate activity (at least 2 times/week to every day) was associated with lower risk of renal outcomes and lower incidence of new albuminuria (p < 0.0001 for both) compared to lower exercise levels. Similar results were observed for those with and without diabetes without interaction for renal outcomes (p = 0.097-0.27). Physical activity was associated with reduced eGFR decline with a moderate association between activity and diabetes status (p = 0.05). CONCLUSIONS: Moderate physical activity was associated with improved kidney outcomes with a threshold at two sessions per week. The association of physical activity with renal outcomes did not meaningfully differ with or without diabetes but absolute benefit of activity was even greater in people with diabetes. Thus, risks were similar between those with diabetes undertaking high physical activity and those without diabetes but low physical activity. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov.uniqueidentifier :NCT00153101.
Subject(s)
Cardiovascular Diseases/prevention & control , Diabetes Mellitus/therapy , Diabetic Nephropathies/therapy , Exercise , Healthy Lifestyle , Kidney Failure, Chronic/prevention & control , Renal Insufficiency, Chronic/therapy , Risk Reduction Behavior , Aged , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/mortality , Cardiovascular Diseases/physiopathology , Databases, Factual , Diabetes Mellitus/diagnosis , Diabetes Mellitus/mortality , Diabetes Mellitus/physiopathology , Diabetic Nephropathies/diagnosis , Diabetic Nephropathies/mortality , Diabetic Nephropathies/physiopathology , Female , Glomerular Filtration Rate , Heart Disease Risk Factors , Humans , Kidney/physiopathology , Kidney Failure, Chronic/diagnosis , Kidney Failure, Chronic/mortality , Kidney Failure, Chronic/physiopathology , Male , Middle Aged , Protective Factors , Randomized Controlled Trials as Topic , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/mortality , Renal Insufficiency, Chronic/physiopathology , Risk Assessment , Time Factors , Treatment OutcomeABSTRACT
Catheter-based renal denervation to reduce high blood pressure (BP) has received well-deserved attention after a recent series of sham-controlled trials reported significant antihypertensive efficacy and very favourable tolerability and safety of the intervention. This emerging treatment option is of high relevance to nephrologists. Patients with chronic kidney disease (CKD) are at elevated risk of cardiovascular adverse events and often present with hypertension, which is very difficult to control with medication. Renal denervation promises a new tool to reduce BP and to prevent loss of renal function in this population. The current review considers the role of the kidney and neurohormonal activation in the development of hypertension and the rationale for renal denervation. The current state of the evidence for the effectiveness and tolerability of the procedure is considered from the nephrologists' perspective, with a focus on the potential future role of renal denervation in the management of CKD patients with hypertension.
Subject(s)
Hypertension , Renal Insufficiency, Chronic , Antihypertensive Agents/therapeutic use , Blood Pressure , Denervation/methods , Female , Humans , Kidney , Male , Nephrologists , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/surgery , Sympathectomy/methods , Treatment OutcomeABSTRACT
BACKGROUND: Activity of the sympathetic nervous system is increased in patients with hypertension and chronic kidney disease (CKD). Here we compare short- and long-term blood pressure (BP)-lowering effects of renal denervation (RDN) between hypertensive patients with or without CKD in the Global SYMPLICITY Registry. METHODS: Office and 24-h ambulatory BP (ABP) were assessed at prespecified time points after RDN. The presence of CKD was defined according to the estimated glomerular filtration rate (eGFR) and enrolled patients were stratified based on the presence (n = 475, eGFR <60 mL/min/1.73 m2) or absence (n = 1505, eGFR ≥60mL/min/1.73 m2) of CKD. RESULTS: Patients with CKD were older (P < 0.001) and were prescribed more antihypertensive medications (P < 0.001). eGFR decline per year was not significantly different between groups after the first year. Office and 24-h ABP were significantly reduced from baseline at all time points after RDN in both groups (all P < 0.001). After adjusting for baseline data, patients without CKD had a greater reduction in office systolic BP (-17.3 ± 28.3 versus -11.7 ± 29.9 mmHg; P = 0.009) but not diastolic BP at 36 months compared with those with CKD. Similar BP and eGFR results were found when the analysis was limited to patients with both baseline and 36-month BP data available. There was no difference in the safety profile of the RDN procedure between groups. CONCLUSIONS: After adjusting for baseline data, 24-h systolic and diastolic ABP reduction were similar in patients with and without CKD after RDN, whereas office systolic but not diastolic BP was reduced less in patients with CKD. We conclude that RDN is an effective antihypertensive treatment option in CKD patients.
Subject(s)
Hypertension , Renal Insufficiency, Chronic , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , Blood Pressure/physiology , Denervation , Follow-Up Studies , Humans , Kidney , Registries , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/surgery , Sympathectomy/methods , Treatment OutcomeABSTRACT
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 < 0.05). However, if the nerves to the left clipped kidneys were cut 7 days prior to investigation, the number of tonic renal neurons completely recovered to well above control levels. Interestingly, electrophysiological properties of neurons that had in vivo axons from the right non-clipped kidneys were not distinguishable from controls. Renal DRG neurons from nephritic rats also showed less often tonic activity upon current injection (43.4% vs. 64.8% control, p < 0.05). Putative sympathoexcitatory and impaired sympathoinhibitory renal afferent nerve fibers probably contribute to increased sympathetic activity in 2K1C hypertension.