Roland E. Schmieder

Background: Endovascular ultrasound renal denervation (uRDN) offers the opportunity to modulate sympathetic nervous system activity, thereby lowering blood pressure (BP) and potentially improving or stabilizing renal outcomes. Objective: We hypothesized that in patients with chronic kidney disease (CKD) stage 3 and uncontrolled hypertension, endovascular ultrasound-based RDN will lower BP after 6 months. Methods: This multicenter, prospective, randomized, sham-controlled, blinded, clinical trial, investigated the effects of uRDN or sham in patients with CKD stage 3 and uncontrolled hypertension. The primary and secondary endpoints were changes in ambulatory BP (ABP) and office BP at 6 months. The study was prematurely stopped due to slow enrollment. Results: Twenty subjects (uRDN: N = 10, sham: N = 10) completed the 6-month visit. At 6 months, the sham-corrected change from baseline in 24 h systolic ABP was −5.60 mmHg (95% CI −10.7, −0.54 mmHg; P = 0.170). The sham corrected change from baseline in 24-h diastolic ABP was −5.90 mmHg (95% CI −9.25, −2.55; P = 0.035) and from baseline daytime ABP −6.85 mmHg (95% CI −10.6, −3.08; P = 0.030). Sensitivity analysis restricting the analysis to those patients who were fully adherent to medication ( N = 7 in each group) found a sham-corrected change from baseline 24-h diastolic ABP of −5.71 mmHg (95% CI −9.40, −2.03; P = 0.053) at 6 months. Based on the composite endpoint of 24 h ABP and office BP for systolic/diastolic BP, a win ratio of 1.71 (95% 1.26–2.34; P = 0.014) was found for systolic BP and a win ratio of 4.59 (95% CI 2.94–7.16, P < 0.001) was found for diastolic BP, indicating significant changes in BP following RDN. Estimated glomerular filtration rate remained stable over 6 months, with no difference between the groups. There were no safety signals associated with uRDN. Conclusions: This prospective randomized, sham controlled, blinded trial in patients with uncontrolled hypertension and CKD was prematurely stopped, resulted in small number of patients and we did not find a statistically significant effect on systolic BP, whereas a consistent reduction in diastolic BP following uRDN was observed. These data should guide the design of a larger confirmatory trial in patients with CKD.

Obesity is a chronic, recurrent, and heterogeneous disease whose effective treatment requires an approach that goes beyond assessment of body mass index and short-term weight loss. Contemporary management should integrate assessment of adipose tissue distribution and function, obesity phenotype, complications, and cardiometabolic risk with individualized nutritional, behavioral, pharmacological, and—if appropriate—surgical interventions. This paper presents the ADIPO–CARE Plan, a practical, structured model for the comprehensive assessment and long-term treatment of people living with obesity. The model comprises two interconnected stages. The ADIPO defines a comprehensive clinical assessment process: A—Assess adiposity, which includes assessing the degree and distribution of excess adipose tissue; D—Define obesity phenotype, which aims to identify the clinical phenotype of obesity; I—Identify complications, which includes detecting obesity-related diseases and complications; P—Profile cardiometabolic risk, which serves to determine global cardiometabolic risk and disease severity; and O—Overall treatment goals, defining individual, realistic therapeutic goals that go beyond weight loss. The second phase, CARE, organizes the treatment and long-term follow-up strategy: C—Comprehensive lifestyle intervention, with particular emphasis on nutritional therapy, physical activity, behavioral interventions, and lifestyle modifications; A—Anti-obesity pharmacotherapy, encompassing the rational use of pharmacotherapy as a complement to lifestyle interventions; R—Response-guided treatment optimization, involving systematic assessment of response and intensification or modification of therapy; and E—Evaluate long-term effectiveness, focusing on maintenance of effects, safety, adherence, relapse prevention, and long-term disease control. The ADIPO–CARE Plan proposes a shift from an approach focused primarily on body weight to a model focused on phenotype, risks, complications, and long-term health benefits. This framework can facilitate the systematization of clinical decisions and the integration of nutritional therapy with other elements of modern, personalized obesity therapy.

Dyslipidaemia remains a major contributor to cardiovascular morbidity and mortality, despite the availability of effective lipid-lowering therapies and well-established European Society of Cardiology/European Atherosclerosis Society guidelines. In clinical practice, the implementation of these recommendations is often suboptimal, with persistent therapeutic inertia and fragmented decision-making processes. The CARDIOLIPID Plan is a proposed cardiovascular risk-centred implementation framework designed to support the practical application of guideline-based care. The model integrates two key components of clinical decision-making: comprehensive cardiovascular risk assessment (CARDIO) and personalised lipid-lowering intervention (LIPID), structured into a sequential and clinically applicable pathway. While the individual elements of the CARDIOLIPID Plan are derived from current evidence and guideline recommendations, their organisation within this framework reflects an interpretation by experts aimed at improving clarity, usability and clinical implementation. The model emphasises early and appropriate treatment intensification, reduction of therapeutic inertia and a holistic, patient-centred approach to cardiovascular risk management. The CARDIOLIPID Plan may serve as a practical tool to enhance the translation of evidence into clinical practice. However, as a conceptual and implementation-oriented framework, it requires validation in real-world settings to assess its impact on treatment outcomes and cardiovascular risk reduction.

Background: The SPYRAL HTN‐ON MED (Global Clinical Study of Renal Denervation With the Symplicity Spyral Multielectrode Renal Denervation System in Patients With Uncontrolled Hypertension on Standard Medical Therapy) trial showed that radiofrequency renal denervation (RDN) using the Symplicity Spyral catheter yielded significant blood pressure (BP) reductions at 6 and 24 months compared with sham control in patients with hypertension on antihypertensive medications. In this prespecified analysis through the final follow‐up, we evaluate the durability of BP reductions, antihypertensive medication use, and safety through 3 years. Methods: SPYRAL HTN‐ON MED is a global, randomized, sham‐controlled trial enrolling patients with uncontrolled hypertension. Patients were prescribed 1 to 3 antihypertensive medications and randomized to RDN or a sham procedure. After 6 months, patients were unblinded, and sham patients could cross over to RDN. Crossover patients' values for BP and antihypertensive medications were imputed to 36 months using their last observation before crossover to RDN carried forward. Statistical analyses, including imputation, were exploratory and conducted on the intention‐to‐treat population. Results: After 6 months, 74% of sham patients crossed over to undergo RDN. Patients undergoing RDN had statistically significant 24‐hour ambulatory systolic BP reductions (treatment difference, –4.7 mm Hg; P =0.0028) and office systolic BP reductions (difference, –7.5 mm Hg; P =0.0002) compared with the sham control group through 36 months. At 36 months, the antihypertensive medication burden was balanced between groups (RDN, 5.2±5.0 versus 5.5±9.9; P =0.63). Crossover patients had significantly better office BP control after RDN. Clinical adverse events were rare. Conclusions: Compared with sham patients through 3 years, patients undergoing RDN had significantly greater 24‐hour ambulatory and office BP reductions, with a similar medication burden. RDN maintained a durable safety profile through 3 years. REGISTRATION: URL: https://clinicaltrials.gov/study ; Unique identifier: NCT02439775.

Key Points: Treatment with semaglutide compared with placebo for 24 weeks reduced lean body mass and fat mass in adults with CKD and overweight or obesity. Changes in lean body mass or fat mass during semaglutide treatment did not correlate with changes in creatinine or cystatin C‑eGFR or measured GFR. Semaglutide significantly reduced extracellular water and BP, and changes in BP correlated with extracellular water. Background: The glucagon-like peptide-1 receptor agonist semaglutide reduces hemoglobin A1c, body weight, BP, and GFR decline. Semaglutide may influence serum creatinine and cystatin C levels by nonkidney-related mechanisms and thereby affect eGFR. We studied the relationship between changes in body composition, eGFR and measured GFR (mGFR), and BP during semaglutide treatment. Methods: We performed a prespecified analysis of a randomized placebo-controlled double-blind clinical trial in 101 adults with CKD with overweight status or obesity and without type 2 diabetes. Participants were randomized to 24 weeks of semaglutide 2.4 mg/wk subcutaneously or matched placebo treatment. We measured GFR with iohexol clearance, estimated GFR with creatinine and cystatin C, and used bioimpedance spectroscopy to determine lean body mass, fat mass, and extracellular water. Results: After 24 weeks of treatment, semaglutide compared with placebo changed total body weight, lean body mass, and fat mass by −9.1 (95% confidence interval [CI], −11.0 to −7.2), −2.5 (95% CI, −6.6 to 1.6), and −3.9 (95% CI, −7.8 to 0.0) kg, respectively. No correlations were present between changes in total body weight, lean body mass, and fat mass with changes in eGFR (creatinine or cystatin C) or mGFR during semaglutide treatment (all Spearman correlation coefficients P = 0.005). Conclusions: Semaglutide reduced lean body mass and fat mass in patients with CKD with overweight status or obesity. These changes did not correlate with changes in creatinine or cystatin C eGFR or mGFR, suggesting that body weight reductions of 10% with semaglutide do not influence GFR estimates. Clinical Trial registry name and registration number: ClinicalTrials.gov, NCT04889183.

BACKGROUND: Uncontrolled hypertension is common in patients with chronic kidney disease (CKD), putting these patients at high risk for adverse cardiovascular events. Radiofrequency renal denervation (RDN) lowers blood pressure (BP) in patients with hypertension. The Global SYMPLICITY Registry DEFINE enrolled over 3500 patients with uncontrolled hypertension worldwide, including patients with moderate-to-severe CKD. METHODS: Patients were categorized by their baseline estimated glomerular filtration rate (estimated glomerular filtration rate [eGFR], mL/min per 1.73 m ² ): eGFR ≥60 (no-CKD, n=2539), eGFR ≥45 to P P =0.007). CONCLUSIONS: In patients with uncontrolled hypertension and moderate-to-severe CKD, radiofrequency RDN results in clinically meaningful and durable BP reduction without renal or vascular safety concerns. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01534299.

Aims: Sodium–glucose co-transporter 2 inhibitors have become a cornerstone in managing chronic heart failure (CHF). While their acute impact on urinary glucose and sodium excretion is well-established, their mid- and long-term persistence of these effects remains uncertain. This study investigated fluid and sodium balance over 3 months in a randomized, placebo-controlled trial (NCT03128528). Methods and results: Overall, 74 patients with New York Heart Association class II–III CHF and an ejection fraction (EF) ≤49% were randomized (2:1) to empagliflozin 10 mg (n = 48) or placebo (n = 26). Sodium, potassium, glucose, urea, and urine were determined from standardized 24-h urine collections. Free water clearance (FWC) and plasma/urine osmolality were calculated. Body weight was measured, and dedicated sodium magnetic resonance imaging (23Na-magnetic resonance imaging) was performed to quantify skin and muscle sodium levels at baseline, at 1 month, and at 3 months. Patients (mean age 66.4 years; 84% male; EF 40%; baseline N-terminal pro-B-type natriuretic peptide 707.9 pg/ml) were followed up at 1 and 3 months. Empagliflozin significantly increased natriuresis at 1 month (p = 0.040), while natriuresis returned to baseline by 3 months. Skin sodium content decreased at 1 month (p = 0.039) and remained reduced at 3 months (p = 0.013), while muscle sodium was unchanged. Persistent glucosuria (p < 0.001) increased urine osmolality at 3 months (p = 0.003). Urine volume increased transiently at 1 month (p = 0.046) but normalized by 3 months. Empagliflozin-treated patients showed a reduction in FWC at 1 and 3 months (p < 0.001), with a compensatory rise in copeptin levels, indicating increased vasopressin activity (1 month: p = 0.020; 3 months: p = 0.001). Conclusions: Mid-range effects of empagliflozin in heart failure with reduced EF include transient natriuresis and sustained glucosuria, with compensatory reductions in FWC. Reductions in skin sodium content were maintained, and volume homeostasis in CHF patients stabilized after 3 months.

Background and aims: Sympathetic overactivation plays a critical role in the pathophysiology of various conditions, such as arterial hypertension, chronic kidney disease, coronary artery disease (CAD), diabetes, metabolic syndrome, and dyslipidemia. Initially developed for hypertension management, renal denervation (RDN) has also been associated with metabolic improvements. Preclinical studies in rodent models suggest that RDN may improve lipid profiles by reducing sympathetic activity. This study analyses the effect of RDN on lipid profiles in hypertensive patients with or without CAD. Methods: This analysis includes 122 hypertensive patients with ( n = 30) or without CAD ( n = 92). All patients underwent radiofrequency, ultrasound, or alcohol-injection-based RDN. Fasting lipid profile, including total cholesterol, triglyceride, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and non-HDL levels was measured at baseline and 6 months after RDN in parallel to office and 24-h ambulatory blood pressure (BP). Results: Six months after RDN, the total cohort showed significant lipid profile improvements. The total cholesterol levels decreased by 10.3 ± 26.3 mg/dL ( p < 0.001), LDL by 7.0 ± 20.4 mg/dL ( p < 0.001), and triglycerides by 30.7 ± 69.4 mg/dL ( p < 0.001), while non-HDL cholesterol levels declined by 7.6 ± 26.3 mg/dL ( p = 0.002). These changes were independent of BP reduction. In patients with CAD, total cholesterol levels declined by 21.7 ± 29.1 mg/dL ( p < 0.001), triglycerides by 40.7 ± 80.0 mg/dL ( p = 0.009), LDL by 15.2 ± 22.0 mg/dL ( p < 0.001), HDL by 2.8 ± 4.7 mg/dL ( p = 0.003), and non-HDL by 15.0 ± 34 .8 mg/dL ( p = 0.021). Reductions in total cholesterol and LDL were greater in CAD than in non-CAD ( p = 0.011 and p = 0.006). Conclusion: We observed a significant improvement in lipid profiles in hypertensive patients with CAD after RDN. This improvement may represent an additive benefit of RDN in hypertensive patients with CAD. Graphical

Resistant hypertension is highly prevalent among individuals with chronic kidney disease (CKD) and is closely associated with accelerated decline of renal function and increased cardiovascular morbidity and mortality. Recent clinical guidelines have established clearer blood pressure (BP) targets for this population, generally recommending office BP values below 140/90 mmHg, with a more stringent target of <130/80 mmHg for patients with albuminuria, diabetes, high cardiovascular risk, or transplant. Conversely, systolic pressure <120 mmHg is not advised due to concerns regarding renal hypoperfusion and associated adverse cardiovascular outcomes. Initial treatment involves an optimized triple therapy regimen with a renin–angiotensin system blocker, a calcium channel blocker, and a diuretic, with the addition of beta-blockers in patients with cardiac comorbidities. Patients with poorly controlled BP require a fourth agent. Spironolactone remains a preferred option when the estimated glomerular filtration rate is ≥30 ml/min/1.73 m², but long-term adherence is poor. Chlorthalidone is suitable in more advanced CKD, particularly combined with loop diuretics. Centrally sympatholytic agents represent a valuable alternative. Sodium-glucose cotransporter 2 inhibitors, non-steroidal mineralocorticoid receptor antagonists, and glucagon-like peptide 1 receptor agonists have demonstrated both antihypertensive effects and clear renal and cardiovascular benefits. Dual endothelin receptor antagonist may offer an additional option in patients with resistant hypertension. Renal denervation represents another promising approach. In selected cases of atherosclerotic renovascular disease with high-grade stenosis and clinical risk features, revascularization may provide benefit. Collectively, these developments support a more individualized and evidence-based approach to managing resistant hypertension in CKD.

We investigated on-treatment systolic BP (SBP) with proteinuria both at without proteinuria the relation between lower SBP and WKF was not significant (p = 0.23) at with proteinuria and ESKD from 3.5% (Q1) to 1.6% (Q2) (p = 0.13), 0.7% (Q3) (p = 0.027) and 0.1% in Q4 (p = 0.009). In the patients without proteinuria neither WKF nor ESKD showed statistically significant changes between SBP quartiles. Our data suggest that, compared to SBP ≥ 140 mmHg, on-treatment SBP <130 and 130-139 mmHg was strongly related to nephroprotection in hypertensive patients with proteinuria.