Cardiac aging is a fundamental contributor to heart failure, arrhythmias, impaired stress tolerance, and reduced cardiovascular resilience in the elderly. While intrinsic myocardial aging has been widely examined, the systemic mechanisms driving age-related cardiac decline are not fully understood. Circulating extracellular vesicles (EVs) have emerged as key mediators of intercellular and inter-organ communication, transferring proteins, lipids, and nucleic acids that modify the phenotypes of recipient cells. Growing evidence indicates that EVs originating from cardiovascular cells as well as distant organs, including the liver, kidney, adipose tissue, lung, and intestine, participate in cardiac aging by influencing senescence-associated signaling, chronic inflammation, mitochondrial and metabolic dysfunction, fibrosis, microvascular remodeling, and contractile function. In this review, we outline the biological basis of circulating EVs in cardiac aging, describe their cellular and inter-organ sources, and examine how they promote progressive myocardial remodeling. We also consider their potential as biomarkers for cardiac aging and age-related heart disease, along with emerging therapeutic strategies such as blocking pathogenic EV signals, using reparative or engineered EVs, and implementing systemic interventions that modulate EV-mediated communication. Key translational challenges are highlighted, including EV heterogeneity, low tissue specificity, methodological inconsistencies, and the need to distinguish physiological cardiac aging from accelerated aging and age-related cardiovascular disease, as EV profiles may reflect systemic comorbidities rather than intrinsic cardiac aging. A deeper understanding of systemic EV crosstalk may offer new insights into the aging heart and support more precise methods for risk stratification, monitoring, and intervention.

Posterior urethral valves (PUV) are rare congenital malformations affecting both the upper and lower urinary tract and can lead to severe long-term complications. Thanks to advances in prenatal diagnostics, neonatal care, and pediatric urological-nephrological management, an increasing number of patients now reach adulthood. Long-term outcomes are primarily determined by the extent of prenatal renal dysplasia as well as the early recognition and targeted management of bladder dysfunction. Care of adult PUV patients remains challenging, as many adult urologists have limited experience and evidence-based guidelines for long-term management are lacking. Adult PUV patients constitute a clearly defined high-risk cohort with characteristic urological and renal sequelae, including persistent or secondary progressive bladder dysfunction with clinically significant lower urinary tract symptoms (LUTS) and an increased risk of progressive chronic kidney disease (CKD) up to end-stage renal disease (ESRD). In cases of ESRD, kidney transplantation may be required; optimized bladder function is crucial to preserve graft function, and reconstructive procedures, such as bladder augmentation, may be necessary.Bladder function evolves throughout life: initially hypertrophic and hyperactive, it may later decompensate, leading to hypocontractility or atony ("myogenic failure"). Adult patients often report voiding difficulties, post-void residual urine, urgency, incontinence, and recurrent urinary tract infections, which can significantly impair quality of life, self-esteem, and sexual self-efficacy. Treatment is guided by the individual urodynamic phenotype and may include conservative, pharmacological, and, when necessary, interventional strategies.Sexual function and fertility are preserved in most patients; limitations primarily occur in advanced CKD or complex bladder management scenarios. Psychosocial burdens related to altered body image, incontinence, catheterization, or concerns regarding partnership and family planning are common and should be addressed early. Optimal care for PUV patients requires lifelong, interdisciplinary follow-up, structured transition from pediatric to adult care, and close coordination between urology, nephrology, pediatric urology/nephrology, and transplant medicine to ensure long-term preservation of renal function, quality of life, and graft survival.

To assess the impact of functional tricuspid regurgitation (FTR) and transcatheter tricuspid valve repair (TTVR) on sympathetic nerve activity (SNA). Increased SNA is associated with adverse outcomes and reduced survival in patients with valvular heart disease and chronic heart failure (CHF). However, the effect of interventional treatment of FTR on SNA remains unclear. Twenty-eight patients with symptomatic FTR ≥ grade III underwent TTVR (either edge-to-edge repair or direct annuloplasty). Muscle sympathetic nerve activity (MSNA) was assessed via microneurography. While all patients completed the 12-month follow-up, repeated MSNA assessment was feasible in 10. In patients with symptomatic severe FTR, baseline MSNA was markedly elevated (incidence: 192.8 bursts/100 beats; frequency: 167.8 bursts/min). At 12-month follow-up, tricuspid regurgitation severity was significantly reduced (median grade 3 [IQR 3-4] vs. 2 [IQR 1-2]; p < 0.01), accompanied by improved functional status (NYHA class 3 [IQR 3-4] vs. 2 [IQR 1-3], p < 0.01; 53% ≤ NYHA II). NT-proBNP showed a non-significant decline (p = 0.09), while LV function, MR severity, and renal function remained unchanged. MSNA incidence decreased to 72.6 bursts/100 beats (p = 0.01), and frequency to 93.4 bursts/min (p = 0.001). Patients with FTR exhibit markedly increased SNA. TTVR was associated with a significant reduction in MSNA, suggesting a neurophysiological mechanism contributing to clinical improvement beyond hemodynamic relief.

In the United States, kidney transplant candidates are permitted to waitlist at multiple transplant centers to improve their likelihood of transplantation. In March 2021, a distance-based kidney allocation system (KAS250) was implemented, leading to greater geographic organ sharing that might reduce the perceived benefit of multilisting compared to the prior system (KAS). To assess whether the incidence and geographic patterns of multilisting changed after KAS250, we used national registry data to examine adult candidates added to the waitlist before and after KAS250. Among 40 048 candidates waitlisted in KAS and 48 568 in KAS250, the proportion of multilisted candidates was similar (9.5% vs. 9.3%, respectively). Multilisting conferred a greater than twofold increase in two-year adjusted transplant incidence in both KAS and KAS250 (HR 2.02, 2.51, respectively; both p<0.001). Additionally, among multilisted candidates, those whose centers were more than 250 NM apart had a significantly higher adjusted transplant incidence than those whose centers were within 250 NM in both eras (p<0.05). From KAS to KAS250, geographic patterns shifted modestly: cross-DSA multilisting declined slightly (p = 0.035), and median distance between centers increased from 92.5 to 101.6 NM (p = 0.002), with metropolitan and small-town residents traveling farther under KAS250 while rural residents traveled shorter distances. These results demonstrate that multilisting practices have modestly shifted after KAS250 but continue to confer a tremendous advantage regarding transplant receipt. These findings underscore the need for ongoing policy discussions on balancing candidate autonomy with allocation equity.

Diuretic resistance in heart failure and the cardiorenal syndrome is traditionally managed by escalating diuretic doses, yet this approach often fails to address the underlying pathophysiology. Emerging evidence challenges the sodium-centred paradigm and identifies chloride as a key determinant of diuretic responsiveness, tightly interconnected with potassium, magnesium, and acid-base balance. Disturbances in this multi-ionic network promote maladaptive tubular responses, neurohormonal activation, and persistent sodium retention, ultimately leading to diuretic resistance. Clinical and mechanistic data consistently show that hypochloraemia, often accompanied by hypokalaemia and metabolic alkalosis, is associated with impaired natriuretic efficiency and worse outcomes. Through a representative clinical case, we illustrate how a physiology-guided, multi-ionic strategy-focused on identifying and correcting the specific biochemical drivers of resistance rather than intensifying diuretics-can restore diuretic response and achieve effective decongestion. Diuretic resistance should not be viewed as a failure of dose, but as a failure of understanding. A personalized, multi-ionic approach that integrates chloride, potassium, magnesium, and acid-base status offers a more coherent and effective framework for managing congestion in heart failure.

Marginal zone lymphoma (MZL) is a rare low-grade B-cell lymphoma characterized by its heterogeneous nature and association with chronic antigenic stimulation from infectious agents or autoimmune diseases. Both anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and systemic lupus erythematosus (SLE) are rarely associated with hematologic malignancies, including non-Hodgkin lymphoma. We herein report an 86-year-old man with splenic MZL (SMZL) in whom autopsy revealed the coexistence of microscopic polyangiitis (MPA), SLE, and transthyretin amyloidosis (ATTR). The patient was admitted for rapidly progressive renal dysfunction (serum creatinine (Cr) from 2.04 to 6.77 mg/dL over two months) with general fatigue and loss of appetite. One year previously, SMZL had been diagnosed based on bone marrow biopsy and clinical features. At that time, the patient had renal dysfunction (Cr, 1.77 mg/dL) due to nephrosclerosis. The treatment for SMZL was postponed due to the advanced age and stable condition. On admission, MPA was suspected based on rapidly progressive glomerulonephritis, mononeuritis multiplex, and myeloperoxidase (MPO)-ANCA positivity. Hemodialysis and glucocorticoids improved serum C-reactive protein and MPO-ANCA levels after three weeks, but anuria persisted, and the patient remained dialysis-dependent. Aspiration pneumonia temporarily improved with ceftriaxone sodium hydrate; however, the patient died of sudden deterioration of oxygenation on the 49th hospital day. An autopsy revealed crescentic nephritis complicated by lupus nephritis and ATTR in the lungs and heart. The direct cause of death was cardiac and respiratory failure due to ATTR. This case highlights the potential pathophysiological interplay of multiple immune-mediated and neoplastic conditions in elderly patients, underscoring the importance for clinicians to recognize that patients with SMZL may have coexisting autoimmune diseases such as MPA and SLE. In particular, in elderly patients, the possibility of occult ATTR should also be considered.

ObjectivesTo develop and validate a microsimulation model to estimate the health outcomes and costs of chronic kidney disease (CKD) in type 2 diabetes (T2D) to inform health policies and reduce the burden of CKD.MethodsWe developed a comprehensive model for CKD in type 2 diabetes that assesses the impact of risk factors on the progression of urine albumin-to-creatinine ratio and estimated glomerular filtration rate and their impact on stroke, myocardial infarction (MI), congestive heart failure (CHF), end-stage kidney disease (ESKD), and death without dialysis or transplant using individual-level longitudinal data for T2D populations and summary data from published literature. We internally validated the model using data from the Chronic Renal Insufficiency Cohort (CRIC) of patients with T2D and CKD over 7 y and externally validated the model using the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial data over 3 y.ResultsThe simulated event rates of ESKD, stroke, MI, CHF, and total mortality and the related 95% confidence intervals included the observed event rates in both the internal and external validation cohorts. Using this new model, we showed that lowering the blood pressure target from 140/90 to 120/80 mm Hg in patients with T2D and CKD was cost-saving at the population level.ConclusionThe Michigan Model for Diabetes-Chronic Kidney Disease (MMD-CKD) model provides accurate estimates of disease progression in patients with T2D and CKD. Modeling disease progression in this population will facilitate future assessments of the cost-effectiveness of systematic screening and interventions for CKD, which may reduce the health and economic burden of CKD in T2D. This model can also serve as a tool for predicting the clinical outcomes of individual patients with T2D and CKD. MMD-CKD 1.0 R Shiny app and is publicly available (https://michigandiabetesmodelinggroup.github.io/Software_App).HighlightsWe developed and validated a microsimulation model to simulate kidney disease progression, cardiovascular outcomes, mortality, direct medical costs, and quality of life in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D).This model can be used to evaluate the long-term economic burden of CKD in T2D patients in the United States as well as to assess the costs and benefits associated with specific health policies and interventions.In addition, this model can help inform individual patients of their risk of end-stage kidney disease (ESKD) and cardiovascular events, thereby facilitating shared decision making.