Search Results (1,349)

COVID-19 perturbs the renin-angiotensin system (RAAS) and inflammatory pathways, shaping disease severity. Soluble ACE2 (sACE2) and angiotensin II (Ang II) are central regulators of vascular and immune homeostasis. We profiled plasma from COVID-19 patients and controls using ELISA, together with 48 cytokine profiling and clinical data. Both sACE2 and Ang II were significantly elevated in patients. Increased Ang II was associated with oxygen supplementation and dyspnea, and negatively correlated with IL-3, whereas sACE2 correlated with IL-13 and FGF. Comorbidities modulated cytokine expression: diabetes mellitus was linked to reduced LIF and MCP-1, hypertension to decreased LIF and increased IP-10, and obesity to elevated IL-12p70. Age correlated with TNF and HGF, and reduced oxygen saturation was associated with lower LIF. These findings reveal that acute COVID-19 disrupts RAAS and amplifies immune dysregulation, with Ang II emerging as a pivotal mediator of respiratory compromise and inflammatory imbalance, underscoring its potential as a biomarker and therapeutic relevance. Full article

Severe full-thickness corneal lacerations disrupt the tight cellular and extracellular matrix (ECM) organization required for corneal transparency. Following injury, an influx of transforming growth factor beta (TGFβ) into the corneal stroma signals the formation of haze-inducing myofibroblasts, resulting in excessive stromal remodeling and corneal haze. We hypothesized that MasR activation using NorLeu³Angiotensin (1-7) (NLE) engages the pro-resolving arm of the renin–angiotensin system (RAS) to minimize fibrotic corneal repair. In this study, 6 mm stellate-shaped, full-thickness corneal lacerations were induced in New Zealand Black (NZB) rabbits and treated with topical vehicle, or 0.1%, 0.3%, or 0.45% NLE. Corneal healing was evaluated using noninvasive corneal imaging, histology, and the gene expression of RAS- and fibrosis-related targets (MasR, AT1R, TGFβR1). Corneal imaging revealed significantly decreased corneal haze (p < 0.05) and increased keratocyte density with 0.1% NLE treatment (p < 0.05). Immunofluorescence showed significantly reduced α-smooth muscle actin (αSMA), indicating decreased myofibroblast formation (p < 0.05). Additionally, 0.1% NLE reduced stromal TGFβR1, suggesting that NLE mediates its activity by disrupting the TGFβ/TGFβR axis. MasR and AT1R gene expression were downregulated, which contributes to a reduction in fibrosis. Collectively, these findings suggest that the NLE activation of MasR modulates RAS and TGFβ/TGFβR signaling to reduce myofibroblast activity and fibrosis following severe corneal trauma. Full article

One of the most critical aspects of post-acute COVID-19 syndrome (PACS) and post-acute COVID-19 vaccination syndrome (PACVS) is the presence of autoantibodies. These autoantibodies are directed against various receptors in the autonomic and cardiovascular systems, including those targeting proteins of the renin–angiotensin system (RAS). The RAS plays a central role in regulating vascular homeostasis, inflammation, and endothelial function. During SARS-CoV-2 infection, the interaction of the spike (S) protein with angiotensin-converting enzyme 2 (ACE2) can alter the balance of the RAS, favoring an imbalance towards the ACE/Angiotensin II/AT1R axis, known for its pro-inflammatory, pro-thrombotic, and vasoconstrictive properties. Similar pathological mechanisms also come into play in response to vaccinations that use the S protein as an antigen. Studies conducted by other groups and us on patients with PACS and PACVS have revealed the presence of autoantibodies directed against these RAS components and the mechanisms by which these antibodies can worsen the clinical situation. In particular, anti-ACE2, presumably formed by the anti-idiotype network or molecular mimicry, is correlated with PACVS symptoms in many patients. Furthermore, the presence of anti-MAS1 antibodies can reduce the efficiency of the ACE2/Angiotensin-(1–7)/MAS1 axis, which normally acts as a counter-regulator. Considering this evidence, an analysis of RAS molecules and the autoantibodies implicated in reactions to them may be useful for evaluating a state of persistent dysregulation associated with post-vaccination symptoms such as asthenia, headache, skin edema and bruising, cardiovascular alterations, and neurovegetative manifestations. Finally, we offer insights into diagnosing these multifaceted syndromes and working hypotheses to guide research into possible therapeutic approaches. Full article

The degradation of plastic waste leads to the release of numerous chemical additives, including phthalate plasticizers, which have been implicated in the pathogenesis of metabolic disorders. Di (2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer whose primary metabolite, mono (2-ethyl-5-carboxypentyl) phthalate (MECPP), has been associated with multiple metabolic diseases. In this study, we applied an integrated approach combining network toxicology and molecular docking to systematically investigate the potential mechanistic role of MECPP in metabolic dysregulation. Our strategy included multi-platform target prediction, disease gene association analysis, functional enrichment, protein–protein interaction network construction, and molecular docking analysis. The results suggested that MECPP may be associated with six common core targets, including BCL2, BCL2L1, MAPK14, MMP2, MMP9, and TNFRSF1A, which are mainly involved in apoptosis, inflammatory regulation, and extracellular matrix remodeling. Pathway enrichment analysis further indicated the potential involvement of several disease-overlapping pathways, including insulin resistance, neuroactive ligand–receptor interaction, efferocytosis, advanced glycation end product–receptor for advanced glycation end product (AGE–RAGE) signaling, phospholipase D signaling, and renin secretion. Overall, these findings suggest that MECPP may contribute to metabolic dysregulation through overlapping molecular mechanisms across multiple diseases. This study provides a computational basis for future experimental validation and environmental risk assessment. Full article

Hypertensive nephropathy (HN) is a leading cause of chronic kidney disease and end-stage renal disease worldwide and results from the long-term effects of hypertension on renal structure and function. The pathogenesis of HN is complex and involves haemodynamic disturbances, renal vascular injury, oxidative stress, chronic inflammation, and progressive interstitial fibrosis. In recent years, increasing attention has focused on the role of non-coding RNAs (ncRNAs)—including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs)—as key regulators of gene expression involved in these processes. This review summarises the current understanding of the molecular mechanisms underlying HN, with particular emphasis on the roles of oxidative stress, activation of the renin–angiotensin–aldosterone system, transforming growth factor beta signalling, and inflammatory and fibrogenic pathways. The contribution of dysregulated ncRNAs to endothelial dysfunction, inflammatory responses, apoptosis, angiogenesis, and renal remodelling and fibrosis is also discussed. Particular attention is given to miRNAs and lncRNAs as mediators of disease progression and potential biomarkers, as well as to the emerging role of circRNAs in hypertensive kidney injury, including their involvement in the regulation of redox balance and intercellular communication. Collectively, available evidence indicates that ncRNAs represent a critical link between haemodynamic stimuli and persistent molecular alterations in renal tissue, highlighting their potential as diagnostic markers and therapeutic targets in HN. Full article

Background: Ectopic fat deposition has been demonstrated to play a critical role in the onset and progression of renal dysfunction. However, research on renal parenchymal fat deposition and its association with renal dysfunction in type 2 diabetes mellitus (T2DM) remains limited, particularly regarding its association with early kidney injury. The present study aimed to further investigate the relationship between renal fat fraction (FF) and biomarkers of kidney injury, thereby providing new evidence for the potential link between intrarenal fat accumulation and early renal impairment in T2DM. Methods: This cross-sectional study enrolled 60 patients with T2DM. Renal FF was quantitatively assessed using magnetic resonance imaging (MRI). Clinical characteristics, body composition parameters, and biochemical indices were collected. Levels of kidney injury biomarkers, including tumor necrosis factor receptors 1 (TNF-R1), tumor necrosis factor receptors 2 (TNF-R2), chitinase-3-like protein 1 (YKL-40), and kidney injury molecule-1 (KIM-1), were measured using enzyme-linked immunosorbent assay (ELISA). To evaluate the correlations between fat distribution and inflammatory biomarkers, Pearson correlation analysis was performed. Furthermore, linear regression analysis was conducted to explore the associations between renal FF and kidney injury biomarkers with adjustments for potential confounders such as smoking status, diabetes duration, and visceral fat. Lasso regression was used to screen variables. Results: The results demonstrated that renal FF was significantly positively correlated with serum YKL-40 (r = 0.3, p = 0.021), TNF-R1 (r = 0.246, p = 0.042), and urinary KIM-1 (r = 0.396, p = 0.004), indicating a close association between renal fat accumulation and early kidney injury biomarkers. In regression analyses adjusted for age, sex, and duration of diabetes, the associations between renal FF and these biomarkers remained significant. After further adjustment for potential confounders, including smoking history, alcohol consumption, hypertension, renin-angiotensin-aldosterone system (RAAS) inhibitors, sodium-dependent glucose transporters 2 (SGLT2) inhibitors, glucagon-Like Peptide-1 (GLP-1) receptor agonists, and lipid-lowering drugs, renal FF remained significantly associated with TNF-R1 (β = 0.327, p = 0.015), KIM-1 (β = 0.352, p = 0.021), and YKL-40 (β = 0.275, p = 0.025). Moreover, even after additional adjustment for visceral fat, the associations of renal FF with TNF-R1 and KIM-1 persisted. After using the Benjamini–Hochberg procedure for false discovery rate, the relationship between renal FF and KIM-1 had a significant difference. Variables of age and gender were excluded to build the parsimonious modeling using Lasso regression. It suggested that renal fat accumulation may contribute to kidney injury independently of visceral adiposity. Conclusions: The study systematically demonstrates a significant association between renal FF and early biomarkers of kidney injury in T2DM, which may suggest the potential role of renal fat accumulation in the pathogenesis of diabetic nephropathy. These findings provide clinical data support for the development of a fat-targeted intervention study. Future research should further elucidate the long-term mechanistic role of renal FF in diabetic nephropathy, as well as its potential value in early diagnosis and therapeutic applications. Full article

Objective: The COVID-19 pandemic has strained healthcare systems and has been associated with substantial morbidity and mortality. Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) enters host cells by binding to angiotensin-converting enzyme 2 (ACE2), implicating dysregulation of the renin–angiotensin system (RAS) in COVID-19 pathophysiology. Measurement of circulating RAS components, including ACE and ACE2, may therefore provide an insight into disease severity and underlying mechanisms. Subjects and Methods: In this retrospective cohort study, 224 adults with PCR-confirmed COVID-19 were stratified by World Health Organization disease-severity criteria into asymptomatic, mild, mild-pneumonia, severe, and critical groups. Plasma ACE and ACE2 concentrations were quantified by ELISA. Demographic, clinical, and laboratory data were extracted from electronic medical records. Results and Conclusions: Increasing disease severity was associated with higher mortality, elevated body mass index, and higher viral load estimates. Severe and critical illness was characterized by leukocytosis with neutrophilia, marked lymphopenia, anemia, elevated inflammatory and coagulation markers, renal dysfunction, and hypoalbuminemia. Plasma ACE2 levels declined progressively with increasing severity and were significantly lower in patients with mild-pneumonia, severe, or critical illness compared with asymptomatic or mild cases, showing a strong inverse correlation with severity. In contrast, plasma ACE levels increased significantly with disease severity. The resulting increase in the ACE/ACE2 ratio indicates a progressive shift toward the pro-inflammatory arm of the RAS, providing mechanistic insight into the COVID-19 pathophysiology. Full article

Glucocorticoid-induced hypertension affects over 30% of treated patients, yet its underlying mechanisms remain unclear, particularly how glucocorticoids regulate renin within the renin-angiotensin-aldosterone system (RAAS). Modeling these dynamics is difficult because only four dose-response measurements are available at a single 24-h timepoint (36 observations total), while the system depends on roughly eleven biochemical parameters spanning minutes-long receptor interactions to days-long protein secretion. Classical parameter estimation becomes unreliable in this extremely underdetermined setting, and purely data-driven methods offer limited biological interpretability. In this paper, we introduce a physics-informed neural network (PINN) framework that integrates ELISA measurements from As4.1 juxtaglomerular cells, ordinary differential equations describing glucocorticoid receptor signaling and renin transcription, and automatic differentiation to enforce mechanistic constraints. By systematically tuning synthetic-data weights (SW in {0.2, 0.3, 0.5}), we identify an intermediate value of SW = 0.3 that provides the best overall balance between predictive accuracy, accepted ensemble size, and biologically plausible parameter estimates among the tested configurations. The framework uses adaptive constraint scheduling with a plateau ramp to reduce premature convergence and introduces calibrated plausibility thresholds reflecting experimental noise. The accepted PINN ensemble (n = 5, 50% success rate) achieved R² = 0.803, compared with 0.759 for the SW = 0.5 baseline and −0.220 for the ODE-only baseline, with RMSE = 0.024. Key learned parameters (IC₅₀ = 2.925 ± 0.012 mg/dL, Hill = 1.950 ± 0.009) are biologically plausible within the model assumptions, and the best single accepted model attained R² = 0.891. Information criteria favored the PINN over the ODE model, with improvements of approximately 77× (AIC) and 5.9× (BIC). Despite training on a single timepoint, the PINN also infers full 48-h trajectories and reproduces non-monotonic dose-response behavior. This work presents, to our knowledge, the first PINN framework for glucocorticoid-mediated renin regulation and should be interpreted as a proof-of-concept approach for integrating sparse biomedical data with mechanistic constraints. The inferred parameters and temporal dynamics are best viewed as model-dependent, hypothesis-generating estimates rather than validated biological quantities. Full article

The lung–kidney axis forms an important physiologically integrated system which controls multiple essential functions of the body. An important observation of this interaction is tissue oxygenation and erythropoiesis, a vital process that involves erythropoietin (EPO) release by the kidney to bring red cell production into the bone, while pulmonary gas exchange ensures adequate oxygen delivery to the cells. Subsequently, the lung–kidney activation of the renin angiotensin system (RAS) influences vascular tone, blood pressure, and tissue perfusion, influencing the delivery of oxygen and the body’s requirement for erythropoietin. Additionally, beyond oxygen sensing, studies have evidenced the role of hypoxia-inducible factors (HIFs), inflammatory mediators, endothelial signaling pathways and iron availability. These modulate erythropoietin production, which enhances the process of erythropoiesis and arterial oxygen balance. Localized variations in renal oxygen levels together with hemodynamic control mechanisms enable the body to produce erythropoietin independently from systemic hypoxia conditions. This concept emerged to include the renal oxygen extraction fraction (OFE) and intrarenal microvascular shunting with perfusion oxygen coupling in governing EPO production. The present review refines the traditional knowledge to further expand our understanding of the lung–kidney axis regulating the process of erythropoiesis and arterial oxygen content. The integrative framework demonstrates that pulmonary arterial oxygenation and renal oxygen sensing together with bone hematopoietic responses operate as a unified system which maintains both oxygen equilibrium and hematopoietic balance throughout the body. Full article

Background: Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) were historically considered contraindicated in severe aortic stenosis (AS) due to theoretical haemodynamic risks. Contemporary evidence increasingly challenges this paradigm, yet data on preoperative use and postoperative outcomes remain limited. We examined the association between preoperative ACEi/ARB use and mortality following aortic valve replacement. Methods: We conducted a retrospective cohort study of 198 consecutive patients undergoing transcatheter (TAVI) or surgical aortic valve replacement (SAVR) at a single tertiary centre between May 2020 and March 2025. Complete one-year follow up was available for 185 patients (93%). The primary outcome was one-year all-cause mortality. Multivariable logistic regression adjusted for age, sex, hypertension, diabetes, LVEF, and procedure type. Results: Of 198 patients, 80 (40%) were receiving ACEi/ARB therapy preoperatively. ACEi/ARB users had a higher prevalence of hypertension (82% vs. 53%, p < 0.001) and diabetes (48% vs. 27%, p = 0.005) but similar age, valve area, and ejection fraction. Unadjusted one-year mortality was lower in the ACEi/ARB group (7% vs. 19%; odds ratio [OR] 0.33, 95% CI 0.12–0.91, p = 0.030). After multivariable adjustment for confounders including age, diabetes, and hypertension, the association did not reach statistical significance (adjusted OR 0.33, 95% CI 0.10–1.12, p = 0.075). Among diabetic patients, unadjusted one-year mortality was numerically lower in the ACEi/ARB group (12% vs. 35%, p = 0.038); however, six subgroup comparisons were performed and this result would not survive Bonferroni correction (threshold p < 0.008). This exploratory finding should be interpreted with caution given the small sample size and absence of adjustment for confounders. Conclusions: Preoperative ACEi/ARB use was associated with lower unadjusted one-year mortality, but this association did not reach statistical significance after multivariable adjustment and residual confounding cannot be excluded. ACEi/ARB use was not associated with increased mortality in this cohort. These hypothesis-generating findings from a single-centre observational study require confirmation in adequately powered prospective trials. Full article

Background/Objectives: The renin–angiotensin–aldosterone (RAA) system is a key regulator of cardiovascular homeostasis. Recent evidence suggests that Angiotensin II (Ang II) can trigger ferroptosis, an iron-dependent form of cell death. We previously demonstrated that periodontitis induces neurovascular dysfunction, and our preliminary observations indicate that this oral inflammatory model is associated with elevated blood pressure. However, the mechanism by which Ang II impaired nitrergic vasodilation and triggered ferroptosis in cerebral arteries remains unclear. This study investigates the functional effects of electrical and chemical nerve stimulation in adult spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Methods: Endothelium-denuded basilar arterial (BA) rings from SHRs and WKYs were used to assess the impact of Ang II on neurogenic relaxation via wire myography. Results: Vascular relaxation responses to nicotine and transmural nerve stimulation (TNS) were significantly diminished in SHRs compared to WKYs. This impairment was reversed by both acute preincubation and chronic treatment with losartan (an AT1 receptor antagonist). In WKY BAs, exogenous Ang II pretreatment inhibited relaxation responses to nicotine, TNS, and isoproterenol. Importantly, this inhibition was effectively reversed by marimastat (MMP inhibitor), catalase (antioxidant), and ferrostatin-1 (ferroptosis inhibitor). Conclusions: Our findings indicate that Ang II induces functional alterations in neurovascular signaling patterns by triggering ferroptosis within nerve terminals. This process leads to a functional imbalance between sympathetic and parasympathetic influences, ultimately impairing neurogenic nitrergic dilation in the BAs of SHRs. These results suggest that targeting Ang II-induced ferroptosis may alleviate the neuroinflammation and cognitive decline associated with hypertension-related cerebrovascular dysfunction. Full article

Endocrine disorders are increasingly recognized as major contributors to secondary cardiomyopathies, leading to profound alterations in cardiac structure and function. This comprehensive review synthesizes current evidence on the genetic basis of cardiomyopathies associated with endocrine conditions, including primary aldosteronism, Cushing’s syndrome, pheochromocytoma/paraganglioma, acromegaly, thyroid disorders, hyperparathyroidism, and diabetic cardiomyopathy. We examine the contribution of somatic and germline mutations, genetic polymorphisms, shared molecular pathways transforming growth factor-β (TGF-β)/SMAD (TGF-β/SMAD signaling, the renin–angiotensin–aldosterone system, oxidative stress, and calcium handling), sarcomeric gene modifiers, ion channel variants, and epigenetic mechanisms to disease pathogenesis. We propose a conceptual framework distinguishing three major categories of genetic involvement: (i) variants causing the primary endocrinopathy; (ii) genetic modifiers of myocardial susceptibility under conditions of hormonal excess; and (iii) direct pleiotropic effects, whereby single gene variants independently cause both endocrine and cardiac phenotypes. In addition, we discuss genotype–phenotype correlations, ethnic and population differences in genetic susceptibility, the emerging role of polygenic risk scores, and precision medicine approaches. Overall, this review provides an integrated perspective on the complex genetic architecture of endocrine-related cardiomyopathies and outlines practical considerations for genetic testing aimed at improving patient management and clinical outcomes. Full article

Background: The prognostic value of discharge renin–angiotensin–aldosterone system inhibitor (RASi) therapy in contemporary PCI-treated acute myocardial infarction (AMI) survivors with preserved or mildly reduced left ventricular ejection fraction (LVEF) remains uncertain. Methods: A retrospective cohort study of 2530 AMI patients (2019–2022) stratified by RASi use. Exclusion criteria were in-hospital mortality, LVEF < 40%, contraindications to the use of RASis or no percutaneous coronary intervention (PCI). Primary endpoints included heart failure (HF) events, recurrent acute coronary syndrome (ACS), and all-cause mortality. Kaplan–Meier analyses and inverse probability of treatment weighting (IPTW)-weighted Cox models were applied. Results: Over a mean follow-up of 49 months, discharge RASi therapy was not associated with all-cause mortality overall, but was associated with fewer HF rehospitalizations (HR 0.62, 95% CI 0.40–0.95; p = 0.03). Mortality associations differed by AMI type and hypertension status, particularly for NSTEMI (HR 0.36, 95% CI 0.14–0.91; p = 0.03; p for interaction = 0.02) and hypertension (HR 0.36, 95% CI 0.15–0.84; p = 0.02; p for interaction = 0.04). Conclusions: In this single-center observational cohort of PCI-treated AMI survivors with LVEF ≥ 40%, discharge RASi therapy was associated with fewer HF rehospitalizations but not with lower overall mortality. Exploratory subgroup analyses suggested potential heterogeneity according to NSTEMI status and hypertension, but these findings should be considered hypothesis-generating and require confirmation. Full article

Background: Secondary pseudohypoaldosteronism (PHA) is a rare, transient condition caused by renal tubular resistance to aldosterone, most commonly associated with urinary tract infection (UTI) and/or congenital anomalies of the kidney and urinary tract (CAKUT). It mimics primary adrenal disorders, presenting with life-threatening electrolyte disturbances in early infancy. Case Presentation: We report a male infant admitted twice within the first four months of life with severe dehydration, hyponatremia, hyperkalemia, metabolic acidosis, and acute kidney injury (AKI). Urine cultures grew Klebsiella pneumoniae and later Escherichia coli. Imaging studies demonstrated obstructive CAKUT, including posterior urethral valves, bilateral megaureters, hydronephrosis, and bladder diverticulosis. Congenital adrenal hyperplasia was excluded. Further evaluation showed markedly elevated plasma renin and aldosterone levels, confirming secondary PHA. The patient was successfully treated with intravenous fluids, electrolyte correction, and antibiotic therapy. Subsequently, oral sodium chloride and bicarbonate supplementation were added. Stepwise surgical correction of the urinary tract anomalies was initiated. Conclusions: Secondary PHA should be considered in infants presenting with failure to thrive, dehydration, hyponatremia, and hyperkalemia, particularly in the presence of UTI or CAKUT. Early recognition and differentiation from primary adrenal disorders are essential to prevent life-threatening complications. Prompt correction of electrolyte imbalance and management of the underlying urinary tract pathology are crucial for favorable outcomes. Full article

Background: The prognosis of chronic kidney disease (CKD) typically requires longitudinal estimated glomerular filtration rate (eGFR) data, making risk stratification difficult at initial consultation. Furthermore, eGFR-based clinical decisions often overlook the critical factor of patient age. This study aimed to establish a simplified predictive model for progressive CKD and quantify the impact of clinical interventions. Methods: Utilizing a historical dataset (1988–2003) from the pre-renin-angiotensin system inhibitor (RASi) and pre-sodium-glucose cotransporter 2 inhibitor (SGLT2i) era, we developed heatmaps to predict the probability of reaching eGFR < 30 mL/min/1.73 m² by age 80 years. The model also estimated the risk reduction from smoking cessation and pharmacological therapies. The predictive performance for age + eGFR was assessed using standard calibration and discrimination metrics, and clinical utility was evaluated using decision curve analysis across a range of threshold probabilities. Risk reclassification analyses compared age +eGFR-based categories with conventional eGFR-based stratification. Results: Regarding the risk of eGFR < 30 mL/min/1.73 m² by age 80 years, simulations confirmed a correlation between age and eGFR. At age 40 years, an eGFR of ~57 mL/min/1.73 m² indicated a 50% probability of progressing to CKD stage 4 by age 80 years. This threshold decreases to 53 and 48 mL/min/1.73 m² at 50 and 60 years of age, respectively. Calibration and discrimination analyses demonstrated acceptable agreement between predicted and observed risks. Decision curve analysis showed that an age + eGFR threshold of approximately 115 primarily provided a net benefit at lower threshold probabilities, supporting intensified surveillance strategies, whereas an age +eGFR of 100 showed a positive net benefit across a broader range of thresholds, comparable to the conventional eGFR < 45 mL/min/1.73 m² criterion. While proteinuria markedly increased risk, smoking cessation provided a 9.4–11.2% risk reduction. Combined RASi and SGLT2i treatment showed the greatest impact, reducing progression probability by 31.2–40.0% (e.g., reducing a 50.0% baseline risk to 32.1% in 40-year-old men). Conclusions: The age + eGFR rule represents a simple, clinically interpretable heuristic for age-adjusted risk stratification based on a single eGFR measurement and may offer potential clinical utility for guiding surveillance intensity and consideration of earlier intervention strategies. However, external validation is required before clinical application. Full article