Chronic kidney disease (CKD) is a complex and progressive condition ultimately leading to premature death. Diabetes is the leading cause of end-stage kidney disease worldwide. Up till 2024, international clinical guidelines have established three therapeutic pillars to delay CKD progression in people with type 2 diabetes (T2D): renin-angiotensin system inhibitors, sodium-glucose cotransporter 2 inhibitors, and the non-steroidal mineralocorticoid receptor antagonist finerenone. With the recent results from the Evaluate Renal Function with Semaglutide Once Weekly study, the glucagon-like peptide-l receptor agonist (GLP-1 RA) class is now considered a new therapeutic pillar in reducing CKD complications in this patient population. In this expert opinion, we identify patient populations at risk of developing new onset or worsening pre-existing CKD to explore optimal therapeutic strategies, introducing GLP-1 RAs. We highlight the important challenges that remain in optimising, sequencing, and combining these four therapeutic pillars. Even though the conventional approach of combining the pillars has been based on the historical emergence of evidence, we discuss the factors that would influence physicians' decision for preferring one pillar over another, and for selecting a certain combination, whether performed simultaneously or sequentially. These factors include the grade of CKD and the level of albuminuria; diabetic control (glycaemia); comorbidities: atherosclerotic cardiovascular disease, heart failure, obesity; concomitant medications; biological variables: potassium serum levels. The efficacy and safety profiles of each pillar, as demonstrated in landmark trials that have clearly shown the nephroprotective effects, along with real-world data, should also be carefully considered when selecting the most appropriate therapeutic option.

AIMS:Antihypertensive therapy (AHT) is usually lifelong. The feasibility of discontinuing AHT in selected individuals is insufficiently studied. The aims are to assess the feasibility of discontinuing AHT in patients on monotherapy or low-dose dual therapy, and identify factors associated with maintaining normotension without treatment for one year. METHODS AND RESULTS:This prospective, multicentre, non-randomized, open-label study assessed stopping AHT in individuals without self-reported cardiovascular risk factors (other than hypertension) or target organ damage, on monotherapy or low-dose dual AHT. The primary endpoint was maintaining normotension (<135/85 mmHg) for one year (with measurements at 1, 3, 6, 9, and 12 months) based on home blood pressure measurements (HBPM). Factors associated with success and failure of maintaining normotension were explored. Among 401 screened individuals, 218 (54.4%) were included after confirmation of controlled blood pressure (BP) by HBPM at baseline and their AHT was discontinued within 3 days. Two hundred three participants had available BP measurements throughout the follow-up and were analysed. Their mean age was 58.2 (±10.1) years, and 47.3% were women. Of these 203, 73 (36%) maintained BP < 135/85 mmHg for one year without AHT while 130 patients (64%) required resumption of their AHT during the follow-up. Baseline HBPM predicted BP values at one year, while office BP or white-coat hypertension did not. Patients with systolic HBPM < 120 mmHg prior to AHT discontinuation had a 60% chance of maintaining normal BP, compared to 23% with systolic HBPM ≥ 120 mmHg. One patient with systolic HBPM > 120 mmHg at baseline experienced an ischaemic stroke. CONCLUSION:About one-third of individuals on monotherapy or low-dose dual AHT who discontinued treatment maintained controlled BP after one year. Discontinuing AHT may be considered in selected individuals with HBPM below 120 mmHg, provided close BP monitoring is performed, particularly within the first year of AHT withdrawal. REGISTRATION:Clinicaltrial.gov registration number: NCT02268071.

INTRODUCTION:Patients with advanced stages of chronic kidney disease (CKD) and dialysis-dependent kidney failure are at a greater risk of cardiovascular events and mortality than those with early stages of CKD. There are no completed definitive randomized trials on the safety and efficacy of anticoagulant therapy in this patient population. METHODS:Treatment of cardiovascular disease with low-dose Rivaroxaban in Advanced Chronic Kidney disease (TRACK) is a multi-center, randomized, placebo-controlled trial (NCT03969953), designed to enrol 1886 adult participants with CKD stage 4 or 5 (estimated glomerular filtration rate 29 mL/min/1.73 m2) or dialysis-dependent kidney failure and high cardiovascular risk (defined as at least one of the following risk factors; coronary artery disease, non-hemorrhagic non-lacunar stroke, peripheral artery disease [PAD], diabetes mellitus, or age 65 years). Participants are randomized to rivaroxaban 2.5 mg twice daily or matching placebo. The primary efficacy outcome is a composite of cardiovascular death, myocardial infarction, stroke, or PAD event. The primary safety outcome is major bleeding, defined as a composite of fatal bleeding, bleeding leading to hospitalization, or symptomatic bleeding in a critical area or organ. From January 2021 through July 2025, 1458 eligible participants (mean age 63.2 years, 700 [48%] age 65 years, 432 [29.6%] women, 715 [49%] dialysis-dependent kidney failure and 743 [51%] CKD stage 4 or 5, 1125 [77.2%] diabetes mellitus, 674 [46.2%] treated with aspirin at baseline) underwent randomization. CONCLUSION:TRACK will evaluate the effect of low dose rivaroxaban on major adverse cardiovascular events in participants with CKD stages 4 and 5 and dialysis-dependent kidney failure, and elevated cardiovascular risk.

Background Urinary proteomic profiling (UPP) provides insights in disease mechanisms and origin of symptoms. Using UPP, this study aimed at deepening insight in the biology of exercise tolerance. Methods In the HOMAGE trial, 268 patients at risk of heart failure underwent the incremental shuttle walk test (SWT) and UPP by capillary electrophoresis coupled with mass spectrometry at baseline (discovery) and the 9-month final visit (replication). Sequencing of 1498 urinary peptides identified 170 non-collagen and 40 collagen-derived proteins. Ten exercise-related variables, including heart rate and blood pressure responses, symptoms and walking distance were summarised into a single factor, higher values indicating exercise intolerance. In exploratory analyses, exercise intolerance was related to the UPP, first in linear and logistic regression models, considering one peptide at a time, and next by elastic net regression considering the peptides retained in the previous step. Replicated proteins were subjected to pathway analysis. Findings Twenty-nine non-collagen and 31 collagen-derived peptides were associated with reduced exercise capacity with correction for multiple testing. In elastic net regression, exercise intolerance was in >50% of 1000 bootstrap runs associated with the non-collagen proteins FXYD2, GAPDH, HBB, KCNB1, MB, MYOCD, SECTM1, SNX9, TACC3, TMSB4X, and TTN and with collagens COL5A1, COL6A1, COL11A2, and COL28A1. Enriched pathways involved oxygen homoeostasis, oxidative stress regulation, metabolic and developmental processes, and muscle biology. Interpretation In HOMAGE patients, UPP identified parent proteins regulating exercise endurance, which are involved in oxygenation, vascular and muscle structure and function, maintenance of the circulating volume, and protection against oxidative stress. Funding European Union.

Importance:Approximately 10% to 15% of patients with advanced chronic kidney disease (CKD) experience a fatal or nonfatal cardiovascular event annually. The effects of antithrombotic therapies on cardiovascular events in patients with advanced CKD are unknown. Objective:To determine whether low-dose rivaroxaban reduces rates of adverse cardiovascular events compared with placebo in patients with advanced CKD. Design, Setting, and Participants:Randomized, double-blind, placebo-controlled trial conducted at 90 centers in 12 countries. Eligible participants were adults with CKD stage 4 or 5 and patients with dialysis-dependent kidney failure. Participants had a history of either coronary artery disease; nonhemorrhagic, nonlacunar stroke; peripheral artery disease; diabetes; or were 65 years or older. Enrollment occurred between January 2021 and July 2025. The trial was stopped early on August 7, 2025, for lack of efficacy. Final follow-up occurred on October 30, 2025. Statistical analyses were conducted in February and March 2026. Interventions:Patients were randomized 1:1 to receive rivaroxaban 2.5 mg twice daily or placebo. Main Outcomes and Measures:The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, stroke, or a peripheral artery disease event. The primary safety outcome was major bleeding. Results:Of 1458 randomized patients (mean [SD] age, 63.2 [11.6] years, 432 [29.6%] female), 1360 (93.3%) completed follow-up. During a median follow-up of 1.7 years, the primary outcome occurred in 164 patients (22.6%) in the low-dose rivaroxaban group and 151 (20.7%) in the placebo group (13.0 vs 11.8 events per 100 person-years; hazard ratio, 1.09 [95% CI, 0.87-1.36]; P = .46). Major bleeding occurred in 64 patients (8.8%) receiving low-dose rivaroxaban and 44 (6.0%) receiving placebo (5.1 vs 3.4 events per 100 person-years; hazard ratio, 1.51 [95% CI, 1.02-2.22]; P = .04). Conclusions and Relevance:In patients with advanced CKD at high cardiovascular risk, low-dose rivaroxaban did not reduce the risk of a composite cardiovascular outcome. Major bleeding rates were significantly higher in the low-dose rivaroxaban group compared with the placebo group. Trial Registration:ClinicalTrials.gov Identifier: NCT03969953.

BACKGROUND:Identifying early pathobiological mechanisms associated with the onset and progression of heart failure (HF) could guide development of preventive strategies. OBJECTIVE:To elucidate molecular pathways driving HF pathogenesis and identify potential therapeutic targets by profiling plasma microRNAs (miRNAs). METHODS:Multicenter study including 799 elderly patients from HOMAGE. Incident HF was defined as the first hospitalization for HF. A panel of miRNAs implicated in HF was analyzed using RT-qPCR. Two machine learning-based feature selection methods were employed to identify contributors for HF onset. Associations between miRNA targets and HF were explored using publicly available datasets. Bioinformatic analyses were performed using the intersected targets, including functional and single-cell enrichment analyses and drug-gene interaction assessment. RESULTS:After adjusting for confounders, four miRNAs (miR-21-5p, miR-24-3p, miR-132-3p, miR-221-3p) were significantly associated with incident HF in univariate analyses (FDR < 0.05). The feature selection process identified miR-21-5p, miR-24-3p and miR-221-3p as the most informative miRNAs linked to HF onset. The predicted targetome of these miRNAs encompassed 1293 transcripts, of which 32 demonstrated cardiac expression and differential levels between HF cases and controls across six different datasets. Pathway enrichment analysis revealed five key biological processes associated with HF progression: i) calcium homeostasis and signaling; ii) cell proliferation; iii) stress response and remodeling; iv) metabolic dysregulation; and v) neurohormonal activation. Drug-gene interaction analysis identified five FDA-approved agonists of the target GABBR2. CONCLUSIONS:The identified miRNAs provide a rationale for future longitudinal and mechanistic studies and potentially inform the development of novel strategies for HF prevention.

Loop diuretics are first-line therapy for hypervolemia. They block the sodium-potassium-2-chloride cotransporter type 1 on the renal afferent arteriole that mediates vasoconstriction and the sodium-potassium-2-chloride cotransporter type 2 on the macula densa cells that mediates the tubuloglomerular feedback response and raises intrarenal pressure that inhibits the myogenic response. These should reduce afferent arteriolar vasoconstriction and increase the glomerular filtration rate; however, more often, the glomerular filtration rate is reduced. This has been attributed to diuretic-induced extracellular volume depletion that activates a systemic neurohormonal response. Accordingly, a fall in glomerular filtration rate can lead to strategies to restore body fluid volumes while reducing the diuretic dosage. Here, we review the regulation of renal hemodynamics during loop diuretic therapy. We propose that a passive, obstructive component of reduced renal blood flow combines with activation of renal afferent nerves, macula densa-derived renin release with intrarenal Ang II (angiotensin II) formation, and generation of vasoconstrictor prostaglandins and thromboxane to provide intrarenal mechanisms of passive and active increases in renal vascular resistance that together can reduce the glomerular filtration rate. The hypothesis that a reduction in the glomerular filtration rate with loop diuretics can derive from intrarenal mechanisms of vasoconstriction rather than from volume depletion suggests novel approaches to manage diuretic resistance and worsening renal function in heart failure.

Cardiovascular disease (CVD) is highly prevalent in patients receiving hemodialysis and is the leading cause of mortality in this population. Cardiovascular randomized clinical trials frequently exclude patients with kidney failure or on hemodialysis for a variety of reasons, and the current practice is generally to apply guidelines for the management of CVD in patients without kidney failure to patients on hemodialysis. However, the benefits seen in patients without kidney failure have not always translated to those receiving hemodialysis, because the etiology of vascular disease differs, drug metabolism varies, the risk for individual outcomes is different, and the patients are subject to higher all-cause mortality risk. There are several barriers to conduct cardiovascular outcome trials in patients receiving hemodialysis and more efforts are needed to bridge the evidence gap for this population. In this narrative review, we discuss the current state of cardiovascular outcome trials in patients receiving hemodialysis, the barriers that have hindered clinical trial conduct, the potential opportunities in studying this population, and the solutions as well as future directions to improve the evidence derived from clinical trials in patients on hemodialysis.

The Kidney Disease: Improving Global Outcomes (KDIGO) 2026 Clinical Practice Guideline for the Management of Anemia in Chronic Kidney Disease (CKD) represents an update to the guideline published in 2012. Its scope includes diagnosis and evaluation of anemia; use of iron to treat iron deficiency and anemia in CKD; use of erythropoiesis-stimulating agents and hypoxia-inducible factor-prolyl hydroxylase inhibitors to treat anemia in CKD; and red blood cell transfusions to treat anemia in CKD. The guideline has been developed with patient partners, healthcare providers, and researchers around the world, with the goal to generate a useful resource for healthcare providers and patients by providing actionable recommendations. The development of this guideline followed an explicit process of evidence review and appraisal based on systematic reviews. The certainty of evidence and strength of recommendations follows the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. The guideline also provides practice points that provide clinical advice but are not supported by a systematic review. Limitations of the evidence are discussed. Research recommendations to address gaps in knowledge, and implications for policy and payment, are provided. The guideline targets a broad audience of healthcare providers, affected individuals, and stakeholders involved in the various aspects of anemia and CKD care.

INTRODUCTION AND OBJECTIVES:Maintaining or improving quality of life (QoL) is an important therapeutic goal. QoL may be impaired before clinical onset of heart failure (HF). This study aims to describe changes in health status and the effect of spironolactone in people at risk of developing HF. METHODS:The Heart 'OMics' in AGEing (HOMAGE) trial randomized participants to spironolactone or usual care over a maximum follow-up of 9 months. Health status was assessed as a post-hoc secondary outcome using EQ-5D-3L (and derived EQ index), EQ-VAS and HOMAGE patient-reported symptom questionnaire. RESULTS:Health status was available on 98% of the 527 trial participants. The median age was 73 years, 25% were women. The EQ index ranged from 0.18 to 1; 42% of participants had an index of 1 (best possible health status). Participants with poorer health status (EQ index <1) were predominantly women, had obesity, exertional breathlessness and lived alone. Independent baseline associations of deteriorating health status included: breathlessness on moderate exertion, smoking, higher serum galectin-3, higher E/e' and higher left ventricular mass index at baseline. Left ventricular systolic function was associated with worse baseline QoL, but not with changes in EQ index or EQ-VAS during follow-up. Spironolactone did not influence health status during follow-up. CONCLUSIONS:In people at risk of developing HF, obesity was associated with poorer health status. Worsening health status was more likely in patients with exertional breathlessness, echocardiographic signs of raised left ventricular filling pressures, and elevated galectin-3 levels at baseline. Spironolactone did not influence health status.

Importance: Approximately 10% to 15% of patients with advanced chronic kidney disease (CKD) experience a fatal or nonfatal cardiovascular event annually. The effects of antithrombotic therapies on cardiovascular events in patients with advanced CKD are unknown. Objective: To determine whether low-dose rivaroxaban reduces rates of adverse cardiovascular events compared with placebo in patients with advanced CKD. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled trial conducted at 90 centers in 12 countries. Eligible participants were adults with CKD stage 4 or 5 and patients with dialysis-dependent kidney failure. Participants had a history of either coronary artery disease; nonhemorrhagic, nonlacunar stroke; peripheral artery disease; diabetes; or were 65 years or older. Enrollment occurred between January 2021 and July 2025. The trial was stopped early on August 7, 2025, for lack of efficacy. Final follow-up occurred on October 30, 2025. Statistical analyses were conducted in February and March 2026. Interventions: Patients were randomized 1:1 to receive rivaroxaban 2.5 mg twice daily or placebo. Main Outcomes and Measures: The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, stroke, or a peripheral artery disease event. The primary safety outcome was major bleeding. Results: Of 1458 randomized patients (mean [SD] age, 63.2 [11.6] years, 432 [29.6%] female), 1360 (93.3%) completed follow-up. During a median follow-up of 1.7 years, the primary outcome occurred in 164 patients (22.6%) in the low-dose rivaroxaban group and 151 (20.7%) in the placebo group (13.0 vs 11.8 events per 100 person-years; hazard ratio, 1.09 [95% CI, 0.87-1.36]; P = .46). Major bleeding occurred in 64 patients (8.8%) receiving low-dose rivaroxaban and 44 (6.0%) receiving placebo (5.1 vs 3.4 events per 100 person-years; hazard ratio, 1.51 [95% CI, 1.02-2.22]; P = .04). Conclusions and Relevance: In patients with advanced CKD at high cardiovascular risk, low-dose rivaroxaban did not reduce the risk of a composite cardiovascular outcome. Major bleeding rates were significantly higher in the low-dose rivaroxaban group compared with the placebo group. Trial Registration: ClinicalTrials.gov Identifier: NCT03969953.

Aims Cardiovascular (CV) trials have yielded neutral results in haemodialysis. A better understanding of patient profiles is needed to personalize treatment strategies in order to improve CV outcomes in this setting. This study sought to identify biological phenotypes based on proteomic data using machine learning approaches in patients undergoing haemodialysis.Methods and results A clustering analysis using 253 plasma protein biomarkers was performed in 382 patients (machine learning derivation analysis) from the AURORA trial, which tested the effect of rosuvastatin on CV outcomes in patients on haemodialysis. A decision tree was subsequently constructed to predict cluster membership and assess its association with CV outcomes in another subset of the trial (n = 389 patients, validation analysis). Four phenotypes were identified, namely 'cytokine storm signalling', 'toll-like receptors (TLRs) signalling', 'multiple pathways related to inflammation and fibrosis' phenotypes, as well as a 'reference phenotype' which exhibited the least biological abnormalities. In multivariable analysis of the validation study, after adjusting for key prognostic factors, the TLRs phenotype was significantly associated with CV death, all-cause mortality, and MACE (HR = 1.65 [1.13-2.41], 1.43 [1.03-1.98], and 1.48 [1.04-2.10], respectively).Conclusion Using unsupervised machine learning on proteomic data, we identified four mechanistic biological phenotypes involving cytokine storm and TLRs signalling, inflammation and fibrosis. These biological phenotypes may contribute to CV prognosis and pave the way for personalized therapy in haemodialysis.

BACKGROUND:Myeloperoxidase (MPO), a neutrophil-derived enzyme, is associated with oxidative stress and inflammation, which contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Bioactive MPO causes vascular dysfunction and accumulation of serum uric acid (SUA). We investigated the association of plasma MPO and SUA with echocardiographic variables in a populational setting. METHODS:This was a cross-sectional analysis of the fourth visit of the STANISLAS cohort (N=1677 participants, age 49±14 years, 48% male), a population of initially healthy individuals. Participants were divided into four groups according to median plasma MPO and SUA levels. Adjusted linear regression models were used to assess the relationship of plasma MPO and SUA with echocardiographic markers. RESULTS:Participants with high MPO and high SUA were older, had more diabetes, a higher body mass index, lower estimated glomerular filtration rate and higher systolic blood pressure. In multivariable regression analyses, compared with patients with low MPO and low SUA, they had decreased left atrial reservoir strain (mean±SE=-1.43±0.62, p=0.022), decreased mitral annular e' velocity (mean±SE=-0.60±0.16, p<0.001) and more impaired left ventricular systolic global longitudinal strain (mean±SE=0.50±0.23, p=0.029). In contrast, high MPO with low SUA was not associated with impaired diastolic function. CONCLUSIONS:In a population setting, high MPO and SUA, indicative of high bioactive MPO, were associated with early markers of diastolic dysfunction, suggesting a potential role of the MPO pathway in the early development of HFpEF.

In the DIAMOND (Patiromer for the Management of Hyperkalaemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure) trial, the potassium binder patiromer enabled optimization of renin–angiotensin–aldosterone system inhibitors (RAASi) for patients with heart failure and a reduced ejection fraction (HFrEF) and current or recent hyperkalaemia. In this post-hoc analysis, we evaluated the effect of patiromer-enabled RAASi optimization on N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, an established surrogate endpoint for clinical outcomes in HFrEF. During screening, 539 (61.4%) of the 878 subsequently randomized patients had NT-proBNP ≥1000 pg/ml, measured prior to a 12-week run-in period on single-blinded patiromer during which RAASi were optimized. Among these patients, 165/266 (62%) in the patiromer and 172/273 (63%) in the placebo arm had follow-up NT-proBNP. For these 337 patients, we evaluated the change in NT-proBNP from screening to week 18 after randomization. NT-proBNP declined by −53% (95% confidence interval −59% to −46%; p < 0.001) in both arms combined (median absolute change: −731 [−1832, 107] pg/ml), with no significant difference between the two arms ( p = 0.135). A >30% NT-proBNP reduction was observed in 93/165 (56%) patiromer and 88/172 (51%) placebo patients ( p = 0.38), whereas 60/165 (36%) and 53/172 (31%), respectively, achieved NT-proBNP levels <1000 pg/ml at week 18 ( p = 0.30). In this post-hoc analysis of DIAMOND, patients with HFrEF and elevated (>1000 ng/ml) NT-proBNP at screening experienced clinically meaningful NT-proBNP reductions following a RAASi optimization strategy that included patiromer during the run-in phase, with no significant differences observed between patiromer and placebo groups during the randomized withdrawal phase.

High consumption of ultra-processed food (UPF) is associated with an increased risk of developing chronic diseases. Inflammation may be one of the underlying mechanisms behind this association. However, only a limited number of studies have investigated the association between UPF consumption and a few selected inflammation biomarkers, yielding inconsistent results. This study aimed to assess the cross-sectional association between UPF consumption (as a whole and 10 sub-categories), and 78 circulating proteins related to inflammation. The present study included 1594 adult participants from the STANISLAS cohort. UPF consumption was estimated using the NOVA classification, and linear regression models were used to assess their association with circulating proteins. UPFs accounted for 28