The Cardiovascular-Kidney-Metabolic (CKM) syndrome reframes cardiovascular, kidney, and metabolic disease as an integrated continuum, yet its management relies on reactive laboratory markers with substantial resource burdens. Retinal oculomics offers a non-invasive window into this continuum, grounded in structural and functional parallels between the retina and kidney. Their shared vulnerability to metabolic and hemodynamic stressors allows the retina to reflect subclinical CKM injury. Evidence is strongest for cardiovascular endpoints, where retinopathy and quantitative vessel metrics are associated with incident stroke, cardiovascular mortality, and coronary heart disease. Similar associations are reported for new-onset hypertension, diabetes, and incident chronic kidney disease (CKD), although the CKD association attenuates after adjustment for conventional kidney markers. Artificial intelligence (AI) extends retinal analysis beyond categorical grading and predefined vessel metrics by learning latent features from fundus photographs. Systemic biomarker estimation and cardiovascular risk stratification are the most mature, whereas kidney-specific models remain confined to cross-sectional CKD detection and prediction of CKD development. However, retinal AI is supported by evidence that remains largely observational, retrospective, and dependent on cross-sectional surrogates. Albuminuria, sustained decline in estimated glomerular filtration rate, kidney replacement therapy, and kidney-related mortality have not been targeted. Advanced CKD, dialysis, and kidney transplant populations are underrepresented in development and validation cohorts. No retinal model has reported cardiovascular risk prediction in CKD or direct comparison with established kidney risk equations. Discrimination in these models falls in ethnically distinct cohorts, and calibration is infrequently reported. Management-impact trials have not been conducted, and cost-effectiveness remains unevaluated. Algorithmic opacity and imaging standardization remain unresolved. Once these gaps are addressed, retinal AI may support screening, risk stratification, progression monitoring, and treatment prioritization, shifting from screening in early CKM to complementary phenotyping in advanced CKD. Retinal AI would then complement conventional kidney biomarkers as an integrative, low-burden window into CKM injury.

KEY POINTS:The Predicting Risk of Cardiovascular Disease EVENTs score outperformed previous models in prediction of cardio-kidney outcomes. Adding albuminuria to the Predicting Risk of Cardiovascular Disease EVENTs score showed further improvement in patients with CKD. Among East Asian participants, Predicting Risk of Cardiovascular Disease EVENTs provided modest gains in cardiovascular prediction but prominent improvements in predicting kidney outcomes. BACKGROUND:CKD substantially increases cardiovascular disease (CVD) and mortality risks, yet few models account for integrated cardio-kidney outcomes (CKOs). The American Heart Association's Predicting Risk of CVD EVENTs (PREVENT) score incorporates kidney-specific measures; however, its accuracy for CKOs in patients with CKD remains unclear. We aimed to evaluate PREVENT for CKOs against the pooled cohort equation (PCE) and systematic coronary risk evaluation 2 (SCORE2) in two ethnically distinct CKD cohorts: KoreaN Cohort Study for Outcome in Patients With CKD (KNOW-CKD) from South Korea and Chronic Renal Insufficiency Cohort from the United States. METHODS:This study included 4,268 patients with CKD and no known CVD (chronic renal insufficiency cohort: 2,530, KNOW-CKD: 1,738). We compared PREVENT (CVD and atherosclerotic CVD versions) with the PCE and SCORE2. The primary outcome was CKO, a composite of major adverse kidney events (≥50% eGFR decline or kidney failure requiring replacement therapy) and four-point major adverse cardiovascular events (4P-MACEs). Secondary outcomes included individual components and all-cause mortality. RESULTS:The PREVENT-CVD score showed superior predictive accuracy for CKO (Harrell C, 0.688; 95% confidence interval [CI], 0.675 to 0.701) compared with PREVENT-atherosclerotic CVD (delta C [ΔC]=-0.009; 95% CI, -0.011 to -0.007), PCE (ΔC=-0.104; 95% CI, -0.113 to -0.095), and SCORE2 (ΔC=-0.106; 95% CI, -0.114 to -0.097). This superiority was driven by robust prediction for major adverse kidney event, along with significant improvements in reclassification and discrimination for 4P-MACE and all-cause mortality. Although predictive gains for 4P-MACE were attenuated in the KNOW-CKD cohort, adding albuminuria further enhanced predictive performance for primary outcome. CONCLUSIONS:The PREVENT-CVD equation outperformed traditional cardiovascular risk models in predicting integrated CKOs in patients with CKD. Its consistent discrimination across both cardiovascular and kidney events suggests that PREVENT may reflect the shared pathophysiology of cardio-kidney disease and support broader risk stratification in CKD. PODCAST:This article contains a podcast at https://dts.podtrac.com/redirect.mp3//www.asn-online.org/media/podcast/JASN/2026_07_29_KTS_July2026.mp3.

Despite numerous studies investigating the effects of antidiabetic medications on cardiovascular outcomes, the optimal second-line oral antidiabetic medication for atrial fibrillation (AF) prevention remains unclear. This study aims to compare the effects of second-line oral antidiabetic medications including sodium-glucose cotransporter 2 (SGLT2) inhibitors, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, or sulfonylureas, on the risk of incident AF in patients with type 2 diabetes. This retrospective study analyzed data from the National Health Insurance Service data on adults with type 2 diabetes who simultaneously initiated metformin and second-line oral antidiabetic medication (SGLT2 inhibitors, thiazolidinediones, DPP-4 inhibitors, or sulfonylureas) between September 2014 and December 2017. Exact matching by sex and age categories was conducted in a 1:1:5:5 ratio corresponding to SGLT2 inhibitor, thiazolidinedione, DPP-4 inhibitor, and sulfonylurea users, with inverse probability of treatment weighting used to balance the baseline characteristics. The primary outcome was incident AF, which was analyzed using a Fine–Gray model treating all-cause mortality as a competing risk. During a mean follow-up of 6.2 years, 774 cases of AF occurred among the 36,744 participants (mean age 55.3 years; 33.6

Blood pressure (BP) control in chronic kidney disease (CKD) remains suboptimal despite renin-angiotensin system (RAS) blockade, contributing to disease progression. This study examined associations of relative aldosterone excess (RAE) with BP control and kidney outcomes in CKD. 745 patients with CKD from the Cardiovascular and Metabolic Disease Etiology Research Center-High Risk (2013-2024) Study were analyzed. BP control status was defined by ambulatory BP: uncontrolled BP (UBP, ≥125/75 mmHg with <3 AHAs or <4 AHAs without diuretics), apparent treatment-resistant hypertension (aTRH, ≥125/75 mmHg with ≥3 AHAs including diuretics or ≥4 AHAs), and controlled BP (CBP, <125/75 mmHg with <4 AHAs). RAE was defined as baseline serum aldosterone ≥ 10 ng/dL with aldosterone to renin ratio ≥30 despite RAS inhibition. The primary kidney outcome was a composite of ≥40% decline in eGFR, new onset eGFR <60 mL/min/1.73 m2, or ESKD. The mean age was 61.5 years, and 53.6% were men. RAE was independently associated with higher odds of uncontrolled hypertension (ABPM ≥ 125/75 mmHg), whereas CBP was associated with lower odds of RAE. Over a median follow-up of 6.9 years, 244 kidney outcomes occurred. In multivariable Cox models, CBP was associated with a reduced risk of kidney outcomes compared to UBP (HR, 0.67; 95% CI, 0.46-0.97), while aTRH was not (HR, 0.88; 95% CI, 0.57-1.37). However, in the interaction model, aTRH with RAE showed a significantly elevated risk of kidney outcomes (HR, 3.04; 95% CI, 1.12-8.24), while the protective effect of CBP was not modified by RAE. Stratified analyses further showed that RAE was associated with the highest risk of kidney outcomes in the aTRH group (HR 2.67, 95% CI 1.2-5.93). Monitoring RAE may help identify high-risk hypertensive CKD patients who could particularly benefit from mineralocorticoid receptor antagonist therapy.

Key Points Risk of all-cause mortality was significantly lower in KoreaN Cohort Study for Outcome in Patients with CKD group than that in the Chronic Renal Insufficiency Cohort group. Asian cohorts exhibited steeper eGFR decline slopes than that of the Black and White cohorts. Tailored clinical approaches and ethnicity-stratified studies are required to improve CKD management. Background Ethnic differences in CKD progression remain understudied, particularly between Asian and Western populations. Therefore, we aimed to investigate ethnic disparities in CKD progression by comparing nationwide cohorts from South Korea (the KoreaN Cohort Study for Outcome in Patients with CKD [KNOW-CKD]) and the United States (the US Chronic Renal Insufficiency Cohort [CRIC]). Methods A total of 4953 participants were included (69% from CRIC and 31% from KNOW-CKD). The primary outcome was CKD progression, defined as a 50% or greater decline of eGFR or kidney failure requiring KRT. In the secondary outcome analysis, we compared eGFR decline rates and all-cause mortality. Results Of the 4953 participants, CKD progression occurred in 1285 and 570 in the KNOW-CKD and CRIC cohorts, with incidence rates of 67.9 and 41.7 per 1000 person-years, respectively. The hazard ratio for the KNOW-CKD compared with CRIC was 1.66 (95% confidence interval [CI], 1.45 to 1.89). The annual eGFR decline was steeper in KNOW-CKD participants than in CRIC participants (−2.51 versus −1.14 ml/min per 1.73 m 2 ). Asian participants from the CRIC cohort exhibited a similar eGFR slope (95% CIs) (−2.10 [−2.69 to −1.52]) to those from KNOW-CKD (−2.50 [−2.67 to −1.52]), while the slope was −1.47 (−1.61 to −1.33) and −0.81 (−0.92 to −0.70) ml/min per 1.73 m 2 per year for Black and White participants, respectively. However, the risk of mortality was significantly lower in KNOW-CKD participants compared with CRIC participants (hazard ratio, 0.51; 95% CI, 0.38 to 0.68). Conclusions CKD progression was faster in the Korean cohort than in the US cohort, with Asian participants in both cohorts showing similar eGFR decline rates. However, the Korean cohort had a lower risk of mortality, indicating potential ethnic or regional differences in disease progression and survival.

Physical activity is important for health and longevity, but little is known on patients living with chronic kidney disease (CKD). In fact, most studies in patients with CKD have relied on self-reported data, highlighting an unmet need for studies using objective measurements. We investigated the association between device-measured physical activity and adverse outcomes by CKD status. This study included 65,088 participants without CKD and 1170 with CKD, from the UK Biobank, who completed a one-week accelerometer assessment. CKD was defined as either baseline estimated glomerualr filtration rate (eGFR) < 60 mL/min/1.73 m2 or two consecutive eGFR measurements < 60 mL/min/1.73 m2 from primary care data recorded prior to the accelerometer study. The main predictor was device-measured physical activity, categorized into quartiles. The primary outcome was all-cause mortality; secondary outcomes included three-point major adverse cardiovascular events and non-cardiovascular death. We used cause-specific competing risk models adjusting for multiple covariates. Over a median follow-up period of 8.04 years, all-cause mortality occurred in 2028 (3.06

Background: Coronary artery calcification (CAC) is highly prevalent in patients with chronic kidney disease (CKD) and is associated with major adverse cardiovascular events and metabolic disturbances. The triglyceride-glucose index (TyGI), a novel surrogate marker of metabolic syndrome and insulin resistance, is associated with CAC in the general population and in patients with diabetes. This study investigated the association between the TyGI and CAC progression in patients with CKD, which is unknown. Methods: A total of 1,154 patients with CKD (grades 1-5; age, 52.8 +/- 11.9 years; male, 688 [59.6%]) were enrolled from the KNOWCKD (KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease). The TyGI was calculated as follows: ln (fasting triglycerides x fasting glucose/2). Patients were classified into tertiles (low, intermediate, high) based on the TyGI. The primary outcome was annualized percentage change in CAC score [(percent change in CAC score + 1) (12/follow-up months) - 1] of >= 15%, defined as CAC progression. Results: During the 4 -year follow-up, the percentage of patients with CAC progression increased across TyGI groups (28.6%, 37.5%, and 46.2% in low, intermediate, and high groups, respectively; p < 0.001). A high TyGI was associated with an increased risk of CAC progression (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.14-3.88; p = 0.02) compared to the low group. Moreover, a 1 -point increase in the TyGI was related to increased risk of CAC progression (OR, 1.55; 95% CI, 1.06-1.76; p = 0.02) after adjustment. Conclusion: A high TyGI may be a useful predictor of CAC progression in CKD.

Trained immunity is the long-term functional reprogramming of innate immune cells, which results in altered responses toward a secondary challenge. Despite indoxyl sulfate (IS) being a potent stimulus associated with chronic kidney disease (CKD)-related inflammation, its impact on trained immunity has not been explored. Here, we demonstrate that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production. Mechanistically, the aryl hydrocarbon receptor (AhR) contributes to IS-trained immunity by enhancing the expression of arachidonic acid (AA) metabolism-related genes such as arachidonate 5-lipoxygenase (ALOX5) and ALOX5 activating protein (ALOX5AP). Inhibition of AhR during IS training suppresses the induction of IS-trained immunity. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and after 6 days training, they exhibit enhanced TNF-α and IL-6 production to lipopolysaccharide (LPS). Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-α and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-α after in vivo and ex vivo LPS stimulation compared to that of control mice. These results provide insight into the role of IS in the induction of trained immunity, which is critical during inflammatory immune responses in CKD patients.

Background A high medication burden is associated with adverse outcomes. Although patients with ESKD have a substantial medication burden, the relationship between the number of medications in use and clinical outcomes in these patients remains unclear. Hence, this study aimed to investigate the prognostic implications of medication burden regarding adverse outcomes in patients with ESKD on maintenance hemodialysis. Methods We analyzed 29,690 patients receiving maintenance hemodialysis who participated in the Periodic Hemodialysis Quality Assessment conducted by the Health Insurance Review and Assessment Service. The exposure of interest was the number of routinely prescribed oral medications. The main outcome was a composite of nonfatal cardiovascular events (nonfatal myocardial infarction, coronary revascularization, nonfatal stroke, or hospitalization for heart failure) or all-cause death (major adverse cardiac and cerebrovascular events [MACCEs]). The secondary outcomes were the individual components of the primary outcome. Results During a follow-up period of 146,749 person-years (median, 6.0 years), MACCEs occurred in 17,573 patients (59.2%). Higher medication burden was associated with progressively higher incidence of MACCEs (84.7, 107.2, 130.2, and 168.9 events per 1000 person-years in Q1-Q4, respectively). In a multivariable Cox proportional hazard model, the adjusted hazard ratios (95% confidence intervals) for the second, third, and highest quartiles were 1.05 (1.00 to 1.10), 1.12 (1.07 to 1.17), and 1.27 (1.21 to 1.33), respectively, compared with the lowest quartile. In continuous modeling, each increase in the number of medication was associated with a 1.03-fold (95% confidence interval, 1.03 to 1.04) higher risk of the primary outcome. Conclusion A high medication burden was independently associated with higher risk of adverse cardiovascular outcomes and all-cause death in patients receiving maintenance hemodialysis. These findings suggest that a high medication burden could be a useful indicator of adverse clinical outcomes in patients undergoing hemodialysis.

Background: Increase in arterial stiffness is associated with increase in cardiovascular events and mortality. Although studies have shown an association between arterial stiffness and chronic kidney disease (CKD), the association between CKD progression and arterial stiffness has not been clearly defined. The aim of this study is to investigate the association between brachial-ankle pulse wave velocity and chronic kidney disease progression in CKD patients with hypertension. Methods: A total of 717 CKD (stage 3 to 5) patients with hypertension were enrolled from the prospective observational cohort of CMERC-HI (Cardiovascular and Metabolic Disease Etiology Research Center-High Risk). Patients were classified into tertile based on brachial-ankle PWV: low, intermediate, high. Primary outcome was progression of CKD, which was composite of at least 50% decrease in estimated glomerular filtration rate (eGFR) from baseline or end stage kidney disease requiring dialysis. Results: The mean age of study subjects was 60.7 ± 11.8 years and 404 (56.3%) were male. During a median follow-up of 42.5 months, CKD progression occurred in 213 (29.7%). There were statistically significant differences in age (54.0 ± 12.1, 61.0 ± 11.1, 67.1 ± 8.2 in low, intermediate, high group, respectively, P < 0.001) among brachial-ankle PWV tertile groups. In multivariate Cox analysis, brachial-ankle PWV above the median value was related to increased risk of CKD progression (HR, 2.29; 95% CI, 1.33–3.94, P = 0.003) compared to subjects with brachial-ankle PWV below the median. In addition, when the study population was divided into tertiles, the intermediate and high brachial-ankle PWV group were associated with progressively increased risk of CKD progression (HR, 2.03; 95% CI, 1.09–3.77, P = 0.03, HR, 2.51: 95% CI, 1.27–4.96, P = 0.008) compared to low brachial-ankle PWV group after adjusting for confounding factors. The Kaplan-Meier analysis also showed statistically significant association between brachial-ankle PWV and CKD progression. In contrast, there was no statistically significant association between CKD progression and femoral-ankle PWV, an index for peripheral arterial stiffness, which suggests that increase in central arterial stiffness is associated with CKD progression. Conclusions: High brachial-ankle pulse wave velocity may be an independent predictor of CKD progression in CKD patients with hypertension.

Short-term blood pressure variability (BPV) measured with ambulatory blood pressure (BP) monitoring has been demonstrated to be significant in predicting various clinical outcomes. Short-term BPV is distinguished from long-term BPV based on the time interval in which BP fluctuations are measured. Increased short-term BPV has been linked to detrimental effects on the microvascular structure and contributes to subclinical organ damage in the heart, blood vessels, and kidneys, regardless of the average 24-h BP levels. Short-term BPV can be defined by various measures, including calculated metrics (standard deviation, coefficient of variation, average real variability, weighted standard deviation, variability independent of the mean) or dipping patterns. Nevertheless, the additional role of short-term BPV beyond the predictive value of average 24-h BPs or established risk factors for cardiovascular disease and kidney disease remains unclear. In particular, longitudinal studies that evaluate the association between short-term BPV and kidney function impairment are limited and no conclusive data exist regarding which short-term BPV indicators most accurately reflect the prognosis of kidney disease. The issue of how to treat BPV in clinical practice is another concern that is frequently raised. This paper presents a review of the evidence for the prognostic role of short-term BPV in kidney outcomes. Additionally, this review discusses the remaining concerns about short-term BPV that need to be further investigated as an independent risk modifier.

Background: Ankle-brachial index (ABI) used for diagnosis of peripheral vascular disease is related to endothelial dysfunction. Previous studies showed the relationship between endothelial dysfunction and chronic kidney disease (CKD). Therefore, we aimed to investigate the association between ankle-brachial index and CKD progression in patients with hypertension. Methods: A total of 2,429 patients with hypertension were enrolled from the prospective observational cohort of CMERC-HI (Cardiovascular and Metabolic Disease Etiology Research Center-High Risk). Patients were classified into quartile based on ABI (A1: ABI < 1.11, A2: ABI 1.11 to 1.17, A3: ABI 1.17 to 1.23, A4: ABI> 1.23). Primary outcome was progression of CKD, which was composite of at least 50% decrease in estimated glomerular filtration rate (eGFR) from baseline or end stage kidney disease requiring dialysis, or incident CKD which was defined as eGFR < 60 ml/min/1.73m 2 . Results: The mean age of study subjects was 60.1 ± 11.3 years and 1,346 (55.4%) were male. There were statistically significant differences in DM status (40.1%, 41.1%, 43.7%, 51.7% in A1, A2, A3, A4 group, respectively, P < 0.001) among ABI quartile groups. During a median follow-up of 42.5 months, the primary outcome met the pre-specified CKD progression in 490 (20.2%). In multivariate Cox analysis, A1 and A3 group were associated with increased risk of CKD progression (HR, 2.28; 95% CI, 1.30–4.00, P = 0.004, HR, 2.22: 95% CI, 1.27–3.90, P = 0.005) compared to A2 group. Moreover, low ABI showed increased risk of CKD progression (HR, 1.57; 95% CI, 1.04–2.38; P = 0.03) after adjusting confounding factors. Conclusions: Ankle-brachial index may be an independent predictor of renal outcome in patients with hypertension.