Expert Guide: Managing Cardiovascular-Kidney-Metabolic Syndrome In Clinical Practice GlobalRPH

Expert Guide Managing Cardiovascular-Kidney-Metabolic Syndrome in Clinical Practice

Introduction

Cardiovascular kidney metabolic syndrome represents one of the most urgent and complex health challenges of the modern era. The global burden of cardiovascular disease continues to rise at an alarming pace, with prevalence increasing from approximately 271 million individuals in 1990 to more than 523 million in 2019. Over the same period, cardiovascular disease related mortality has reached an estimated 18.6 million deaths annually. These trends reflect not only population aging but also the growing impact of metabolic disorders that drive a continuum of cardiovascular and renal pathology.

Also referred to as cardiorenal metabolic syndrome, this condition encompasses a spectrum of interrelated diseases including obesity, type 2 diabetes mellitus, chronic kidney disease, and cardiovascular disease. Rather than occurring in isolation, these disorders are biologically and clinically interconnected through shared pathophysiological mechanisms such as insulin resistance, chronic inflammation, oxidative stress, endothelial dysfunction, and neurohormonal activation. The presence of one condition significantly increases the risk of developing the others. Individuals with diabetes are at substantially higher risk of cardiovascular events and progressive kidney disease, while patients with heart failure frequently experience declining renal function and an increased likelihood of developing glucose dysregulation or overt diabetes. This bidirectional and self reinforcing relationship creates a vicious cycle that accelerates disease progression and worsens clinical outcomes.

Despite improvements in disease specific therapies, the rising prevalence of cardiovascular kidney metabolic syndrome continues to place a significant strain on healthcare systems worldwide. Metabolic syndrome, a central precursor to this condition, is estimated to affect 20 to 30 percent of the adult population globally. While prevalence remains highest in urbanized and high income countries, rates are increasing rapidly across low and middle income regions due to changes in diet, physical activity patterns, and population demographics. The economic consequences are profound. Overweight and obesity related conditions are associated with nearly half a trillion dollars in annual direct healthcare expenditures, alongside an estimated 1.2 trillion dollars in indirect costs attributable to lost productivity, disability, and premature mortality.

In recent years, advances in pharmacotherapy have begun to reshape the management of patients with overlapping cardiovascular, renal, and metabolic disease. Agents such as sodium glucose cotransporter 2 inhibitors, glucagon like peptide 1 receptor agonists, and nonsteroidal mineralocorticoid receptor antagonists have demonstrated benefits that extend beyond glycemic control to include reductions in heart failure hospitalizations, slowing of chronic kidney disease progression, and improvement in cardiovascular outcomes. Finerenone, in particular, has shown efficacy in reducing cardiovascular events and delaying renal decline in patients with type 2 diabetes and chronic kidney disease. While these therapies represent meaningful progress, the overall prognosis for many patients with advanced cardiorenal metabolic disease remains guarded, particularly when diagnosis and intervention occur late in the disease course.

This article reviews the current understanding of the pathophysiology underlying cardiovascular kidney metabolic syndrome, with emphasis on the shared biological pathways that link metabolic dysfunction to cardiovascular and renal injury. It also discusses contemporary diagnostic strategies, including risk stratification and biomarker based assessment, and outlines evidence based management approaches that prioritize early intervention, multidisciplinary care, and integrated treatment strategies. By synthesizing current clinical evidence, this review aims to provide healthcare practitioners with a practical framework for managing this increasingly prevalent and complex patient population.

Defining Cardiovascular-Kidney-Metabolic Syndrome in Clinical Context

The emergence of cardiovascular-kidney-metabolic (CKM) syndrome as a clinical framework marks a pivotal shift in understanding the interrelationship between multiple organ systems. This newly named medical condition affects major organs including the heart, kidneys, brain, and liver, reflecting the complex interactions among previously siloed diseases [1].

CKM vs CRMS: Terminology and Conceptual Evolution

The conceptualization of cardiovascular-kidney-metabolic syndrome represents an evolution from earlier terminologies, primarily the cardiorenal metabolic syndrome (CRMS). This transition reflects growing recognition of the pathophysiological interrelatedness between metabolic risk factors, chronic kidney disease, and cardiovascular disease [2]. The shift from CRMS to CKM highlights an important expansion of the concept beyond just heart-kidney interactions to include metabolic factors more explicitly.

The former approach treated cardiovascular disease, kidney disease, obesity, and Type 2 diabetes as separate clinical entities, often managed independently by different specialists. However, mounting evidence suggests these conditions form an interconnected network where dysfunction in one system frequently cascades into others [3]. As one clinician noted, “The risk associated with having these features together is maybe more than the sum of their parts” [3].

In contrast to previous models, the CKM framework encourages clinicians to consider these conditions holistically rather than as isolated pathologies. Furthermore, this perspective acknowledges that CKM syndrome most commonly originates from excess or dysfunctional adipose tissue, particularly visceral adiposity, which secretes proinflammatory and prooxidative products that damage arterial, cardiac, and kidney tissues [2].

AHA Consensus Definition and Patient-Facing Explanation

In 2023, the American Heart Association formally defined CKM syndrome as “a systemic disorder characterized by pathophysiological interactions among metabolic risk factors, CKD, and the cardiovascular system, leading to multiorgan dysfunction and a high rate of adverse cardiovascular outcomes” [2]. This definition established a crucial foundation for both clinical practice and patient education.

The AHA consensus created a staging system to classify the syndrome’s progression:

Stage 0: No risk factors
Stage 1: Excess or dysfunctional adiposity
Stage 2: Metabolic risk factors and chronic kidney disease
Stage 3: Subclinical cardiovascular disease or high-risk chronic kidney disease
Stage 4: Clinical cardiovascular disease with or without kidney failure [4]

Recent data indicates the magnitude of this clinical challenge – approximately 90% of Americans meet criteria for CKM syndrome (stage 1 or higher) [4]. Moreover, a study examining the prevalence between 2011 and 2020 found that 10.6% of US adults met criteria for stage 0, 25.9% for stage 1, 49.0% for stage 2, 5.4% for stage 3, and 9.2% for stage 4 [4]. Consequently, about 15% of US adults had advanced CKM syndrome (stages 3 or 4), with higher prevalence among older individuals, men, and Black adults [4].

For patient-facing explanations, CKM syndrome is described as “a health disorder due to connections among heart disease, kidney disease, diabetes, and obesity leading to poor health outcomes” [3]. This straightforward definition helps patients understand that these conditions are closely connected, potentially worsening each other and leading to serious outcomes like heart attack, stroke, heart failure, and abnormal heart rhythms [3].

The CKM framework notably differs from previous approaches by emphasizing early screening – recommending assessment of both estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) in at-risk individuals [2]. This includes people with obesity, hypertriglyceridemia, metabolic syndrome, diabetes, hypertension, and those with clinical cardiovascular disease [2]. Additionally, the framework acknowledges that social determinants of health play a vital role in the development and progression of CKM syndrome, particularly among disenfranchised populations [2].

Staging the Syndrome: CKM Stage 0 to Stage 4 Explained

The American Heart Association’s novel staging construct for cardiovascular-kidney-metabolic (CKM) syndrome provides clinicians with a framework to stratify risk and guide management decisions. Introduced in 2023, this systematic approach classifies patients based on risk factors and established disease, with stages ranging from 0 (no risk factors) to 4 (established cardiovascular disease) [5]. This structured staging system recognizes CKM syndrome as a progressive condition that commonly begins in early life [6].

Stage 0: No Risk Factors

Stage 0 represents individuals without CKM risk factors, characterized by normal BMI and waist circumference, normoglycemia, normotension, normal lipid profile, and absence of chronic kidney disease (CKD) or subclinical/clinical cardiovascular disease (CVD) [6]. Though increasingly rare, this stage is most commonly encountered among youth and young adults [6]. The focus at this stage is primordial prevention through achievement and maintenance of ideal cardiovascular health according to Life’s Essential 8 recommendations [2]. Screening recommendations include assessment of blood pressure, triglycerides, HDL cholesterol, and blood sugar every three to five years [2]. For children and youth, annual assessments of weight, blood pressure, and mental/behavioral health are recommended starting at age 3 [2].

Stage 1: Excess or Dysfunctional Adiposity

Stage 1 is defined by excess weight (BMI ≥25 kg/m²), abdominal obesity (waist circumference ≥88 cm in women, ≥102 cm in men), or dysfunctional adipose tissue (clinically manifest as impaired glucose tolerance or prediabetes) without other metabolic risk factors or CKD [6]. Lower anthropometric cut points apply for Asian populations (BMI ≥23 kg/m² and waist circumference ≥80 cm in women or ≥90 cm in men) [6]. Pathogenetically, most CKM syndrome factors originate from excess and dysfunction of adipose tissue, especially visceral and ectopic body fat [6]. Screening is recommended every two to three years for blood pressure, triglycerides, cholesterol, and blood sugar [2]. The goal for patients at this stage is a minimum 5% weight loss, along with lifestyle modifications focused on healthy eating and regular physical activity [2].

Stage 2: Metabolic Risk Factors and CKD

Stage 2 encompasses individuals with metabolic risk factors (hypertriglyceridemia ≥135 mg/dL, hypertension, metabolic syndrome, diabetes) or moderate- to high-risk CKD, or both [6]. This stage represents the most prevalent category, affecting nearly half of adults in Western cohorts [7]. Patients with stage 2 CKM syndrome show pathophysiological changes including endothelial dysfunction, increased inflammation, and prothrombotic alterations [6]. Treatment aims to address these risk factors to prevent progression to cardiovascular disease and kidney failure [2]. Guidelines recommend annual assessment of blood pressure, triglycerides, cholesterol, blood sugar, and kidney function [2].

Stage 3: Subclinical CVD or High-Risk CKD

Stage 3 is characterized by subclinical CVD among individuals with excess/dysfunctional adiposity, metabolic risk factors, or CKD [6]. This includes imaging markers of subclinical atherosclerotic CVD (most commonly an increased coronary artery calcium score) or subclinical heart failure identified through elevated cardiac biomarkers or abnormal cardiovascular structure/function on myocardial imaging [6]. Given the focus on high absolute CVD risk, this stage also includes individuals with high predicted CVD risk through the PREVENT risk calculator or with very high-risk CKD as per the KDIGO heat map [6]. The 10-year risk of total CVD can be calculated using the PREVENT score [8]. Adults in this stage have significantly higher CVD risk compared to those in stages 0-2, with adjusted hazard ratios of 2.74 (95% CI: 2.32, 3.23) in the MESA cohort and 2.18 (95% CI: 1.34, 3.54) in the Rotterdam Study [9].

Stage 4: Clinical CVD with or without Kidney Failure

Stage 4 represents individuals with clinical CVD overlapping with CKM risk factors [6]. It includes patients with established cardiovascular conditions such as coronary heart disease, heart failure, stroke, peripheral artery disease, or atrial fibrillation [6]. This stage is further divided into stage 4a (without kidney failure) and 4b (with kidney failure) [6]. The distinction acknowledges unique management considerations for patients with kidney failure superimposed on CVD [6]. Individuals in stage 4 have substantially reduced life expectancy, losing more than 15.5 years (95% CI: 12.5, 19.8) at age 50 compared to those in stage 0 [10].

The risk of all-cause, cancer, CVD, respiratory, and digestive mortality increases with advancing CKM stages [1]. Compared with Stage 0, the hazard ratio in Stage 4 is 2.34 (95% CI: 2.11–2.58) for all-cause mortality and 10.15 (95% CI: 6.92–14.89) for CVD mortality [1]. Furthermore, younger adults (aged ≤60 years) show stronger associations with all-cause, CVD, cancer, and respiratory events [1].

Pathophysiological Interplay Between Heart, Kidney, and Metabolism

The complex pathophysiology of cardiovascular kidney metabolic (CKM) syndrome stems from interrelated mechanisms that create self-perpetuating cycles of multi-organ dysfunction. At its core lies a network of biological disruptions that connect metabolic disorders, kidney disease, and cardiovascular complications through shared pathways.

Insulin Resistance and Endothelial Dysfunction

Insulin resistance and endothelial dysfunction form a detrimental reciprocal relationship in CKM syndrome. Physiologically, insulin stimulates glucose uptake in skeletal muscle while simultaneously producing vasodilation through nitric oxide (NO) production in the endothelium. Indeed, NO-dependent increases in blood flow account for 25-40% of insulin-stimulated glucose uptake [3]. When insulin resistance develops, it impairs phosphatidylinositol 3-kinase-dependent signaling, causing imbalance between NO production and endothelin-1 secretion [3].

This endothelial dysfunction subsequently worsens insulin resistance, creating a vicious cycle. In metabolic dysfunction, proinflammatory cytokines from adipose tissue suppress endothelial nitric oxide synthase activity and increase expression of adhesion molecules [11]. Clinical studies confirm this relationship – improving endothelial function ameliorates insulin resistance, whereas enhancing insulin sensitivity improves endothelial dysfunction [3].

RAAS and SNS Activation in Obesity

Obesity triggers neurohormonal activation that profoundly affects cardiovascular and renal function. The renin-angiotensin-aldosterone system (RAAS) serves as a central mediator in CKM pathophysiology [12]. Likewise, the sympathetic nervous system (SNS) becomes chronically activated in obesity, contributing to hypertension through multiple mechanisms [13].

In obese individuals, sympathetic activation increases renal norepinephrine spillover, which reduces insulin-mediated glucose uptake [4]. Concurrently, RAAS activation promotes sodium retention, vasoconstriction, and aldosterone secretion, thus worsening hypertension [14]. The neurogenic hypothesis of obesity-related hypertension emphasizes that renal sympathetic activation serves as the “prime mover” in blood pressure elevation [4].

Oxidative Stress and Inflammatory Pathways

Oxidative stress acts simultaneously as both consequence and amplifier of CKM syndrome progression. Under normal conditions, reactive oxygen species (ROS) are neutralized by endogenous antioxidant systems including superoxide dismutase and catalase [11]. Nevertheless, in CKM syndrome, excessive ROS production overwhelms these defenses, resulting in widespread oxidative damage [11].

Chronic inflammation serves as the foundation for multi-organ dysfunction in CKM syndrome. Excess visceral adipose tissue secretes proinflammatory cytokines including TNF-α and IL-6, creating a state of “meta-inflammation” that damages tissues throughout the body [13]. This inflammatory state contributes to insulin resistance, endothelial dysfunction, and progressive organ damage [15].

Bidirectional Organ Crosstalk: HF to CKD and Vice Versa

The heart-kidney relationship creates a self-reinforcing cycle of organ dysfunction through hemodynamic changes and neurohormonal activation [16]. Heart failure leads to decreased cardiac output and renal hypoperfusion, causing chronic kidney damage [14]. Conversely, CKD contributes to cardiovascular complications through multiple mechanisms, including inflammation, uremic toxins, and vascular calcification [15].

Patients with CKD commonly develop uremic cardiomyopathy, characterized by left ventricular hypertrophy, myocardial fibrosis, and capillary rarefaction [12]. Similarly, heart failure with reduced ejection fraction activates neurohormonal mechanisms that impair renal function [16]. This bidirectional relationship explains why combined cardiac and renal dysfunction produces worse outcomes than either condition alone [8].

The epigenetic regulation imposed by the uremic environment further promotes arteriosclerosis and cardiovascular disease [16], thus completing a complex web of interactions that makes CKM syndrome particularly challenging to manage clinically.

Risk Factors and Progression Drivers in CKM Syndrome

Multiple interrelated risk factors drive the onset and progression of cardiovascular-kidney-metabolic syndrome. Nearly 90% of U.S. adults have at least one risk factor linked to CKM syndrome, including high blood pressure, abnormal cholesterol levels, high blood glucose, excess weight, or reduced kidney function [2]. Each factor amplifies the others, creating a complex cycle that accelerates disease progression through multiple organ systems.

Hypertension and Albuminuria

Hypertension stands out as the most prevalent metabolic risk factor in CKM syndrome progression. Among patients with stage 2 CKM syndrome, hypertension affects 80% of individuals, while its prevalence rises to 95% in those with stage 3 CKM [5]. The impact of hypertension on disease advancement is substantial—individuals with hypertension and stage 2 CKM face a hazard ratio of 3.25 (95% CI: 1.56, 6.80) for progression to stage 4 CKM compared to those with stage 1 CKM [5]. For patients with stage 3 CKM, this risk increases to a hazard ratio of 5.11 (95% CI: 2.05, 12.78) [5].

Albuminuria, meanwhile, serves as both marker and driver of ongoing renal damage. The presence of microalbuminuria represents the first step toward developing overt proteinuria, although only 20% of patients with microalbuminuria progress to proteinuric nephropathy [17]. Hence, detecting albuminuria should prompt aggressive management of all cardiovascular risk factors. For individuals with microalbuminuria, blood pressure targets should be more stringent (≤125/75 mmHg) than standard goals [17].

Type 2 Diabetes and Microvascular Injury

Type 2 diabetes initiates a cascade of microvascular complications through multiple mechanisms. Diabetic nephropathy arises from the interplay between hyperglycemia and hypertension driving glomerular damage [17]. In fact, diabetic nephropathy develops in 30–40% of patients within 25 years of diabetes diagnosis [17].

Microvascular disease progression correlates directly with glycemic control. As demonstrated in landmark studies like UKPDS and DCCT, maintaining HbA1c at or below 6.5% minimizes disease progression [17]. Beyond glycemic control, the management of concomitant risk factors proves essential—patients with established microvascular disease face elevated risks of macrovascular events such as stroke and myocardial infarction [18].

Obesity and Visceral Adiposity

Excess adiposity, particularly visceral fat, initiates the pathophysiological cascade of CKM syndrome. Obesity characteristically features increased expression of adipose tissue with greater representation at visceral sites [1]. At the same time, this metabolically active tissue secretes numerous adipokines involved in regulating blood pressure and vascular tone [1].

Visceral adiposity promotes kidney dysfunction through both direct and indirect mechanisms. The direct pathway involves “obesity-related glomerulopathy,” whereas indirect effects occur through systemic complications including diabetes, hypertension, and atherosclerosis [1]. Chronic inflammation from excess adiposity induces inadequate perfusion and local hypoxia, primarily mediated by HIF-1α, creating a link to increased production of inflammatory cytokines [1].

Notably, metabolic risk varies substantially even among individuals with similar weight measurements. Some patients with only modest excess weight develop multiple metabolic risk factors, while others with obesity exhibit few complications beyond excess weight [19]. This heterogeneity reflects differences in ectopic fat distribution and adipose tissue metabolic activity [19].

Environmental and Genetic Modifiers

Environmental factors significantly influence CKM syndrome development and progression. Various environmental exposures contribute to CKD development in “CKD hotspots”—regions with higher-than-average CKD incidence [6]. These factors include exposure to agrochemicals, contaminated drinking water, herbal medicines, and occupational hazards [6].

Genetic predisposition also shapes CKM risk profiles. The apolipoprotein L1 (APOL1) gene demonstrates a clear association with CKD development in African Americans [6]. APOL1 alleles link to various kidney disorders including HIV nephropathy, focal segmental glomerulosclerosis, and hypertension-associated CKD [6].

Gene-environment interactions ultimately determine individual susceptibility to CKM progression. For example, APOL1 genetic risk may manifest differently depending on environmental modifiers such as HIV infection, antiretroviral treatments, or coinfection with non-HIV protective viruses [6]. Such interactions help explain the varying progression patterns observed clinically across different populations with similar risk factor profiles.

Diagnostic Tools and Biomarkers for Early Detection

Early detection of cardiovascular-kidney-metabolic syndrome requires sophisticated biomarkers that can identify subclinical disease before irreversible damage occurs. Clinicians now have access to various diagnostic tools that help detect early organ dysfunction within this complex syndrome.

NT-proBNP and hs-TnT in CKD Populations

NT-proBNP (N-terminal pro-B-type natriuretic peptide) and hs-cTnT (high-sensitivity cardiac troponin T) serve as cornerstone biomarkers for diagnosing acute heart failure and myocardial infarction. For CKM syndrome patients with chronic kidney disease, interpreting these biomarkers becomes challenging, since their baseline levels often exceed thresholds used for acute disease detection in the general population [20].

Research on within-person variability shows that NT-proBNP has median annual changes of 0% (–24.1% to 26.4%), 5.27% (–20.0% to 30.0%), and 3.16% (–16.6% to 28.6%) for those with eGFR ≥60, 45-59, and <45 mL/min/1.73 m², respectively [20]. Similarly, hs-cTnT shows median annual changes of 0% (–5.8% to 4.9%), 0% (–6.8% to 7.3%), and 0.5% (–6.9% to 9.3%) across the same eGFR categories [20]. This stability across kidney function levels suggests baseline values can serve as personalized reference points.

Both biomarkers demonstrate robust predictive capabilities. In non-dialysis-dependent CKD patients, higher quartiles of NT-proBNP and hs-cTnT correlate with increased risk of mortality, major adverse cardiovascular events, and end-stage kidney disease [21]. Combining these biomarkers with traditional risk scores yields the highest prognostic accuracy for mortality prediction (C-statistic: 0.713) [21].

Urine NGAL and FGF-23 for Tubular Injury

Neutrophil gelatinase-associated lipocalin (NGAL) and fibroblast growth factor-23 (FGF-23) provide valuable information about tubular injury in CKM syndrome. NGAL, a 25-KD protein expressed in injured epithelial cells, attenuates apoptosis and promotes proliferation [7]. FGF-23, primarily known for regulating phosphate metabolism, increases rapidly following acute kidney injury [7].

In post-percutaneous coronary intervention patients, serum NGAL and FGF-23 peak one day after the procedure, making them effective early markers of contrast-induced nephropathy [7]. The area under the curve for relative values in serum NGAL reaches 0.899 (95% CI: 0.834–0.964), with an optimum cutoff of 49% (sensitivity=80.0%, specificity=92.4%) [7]. For serum FGF-23, the AUC is 0.814 (95% CI: 0.733–0.894) with a 20% cutoff (sensitivity=73.3%, specificity=87.6%) [7].

Galectin-3 and Subclinical Fibrosis

Galectin-3 (Gal-3), a β-galactoside binding lectin, has emerged as an essential biomarker for cardiac fibrosis and inflammatory pathways in CKM syndrome. Experimental studies confirm Gal-3 as a mediator of cardiac fibrosis, with binding sites located in the myocardial extracellular matrix and cardiac fibroblasts [22].

Clinical studies demonstrate that elevated Gal-3 concentrations correlate with increased fibrosis, poorer prognosis, and higher mortality, with a hazard ratio of 1.38 for all-cause mortality [23]. At a cutoff value of 6.6 ng/ml, Gal-3 shows sensitivity of 82.5% and specificity of 72.8% [24]. Alongside its role in cardiac fibrosis, Gal-3 also correlates with markers of extracellular matrix turnover, supporting its role in collagen metabolism [22].

Imaging Modalities: CMR and Echocardiography

Cardiac magnetic resonance imaging (CMR) offers superior diagnostic capabilities compared to echocardiography in CKM syndrome patients. Uniquely integrating function with pathology, CMR provides multiparametric information in a single scan [25]. As the gold standard for quantifying myocardial volumes and function, CMR demonstrates lower inter-observer variability than echocardiography in CKD populations [25].

Remarkably, CMR identifies structural heart disease in 25.5% of patients with ventricular arrhythmia who had normal echocardiographic findings [26]. Among patients with completely normal echocardiograms (defined as LVEF ≥55% without regional wall motion abnormalities), 70% still received a diagnosis through CMR [9]. Echocardiography demonstrates 76% sensitivity, 38% specificity, 82% positive predictive value, and only 30% negative predictive value for identifying patients who receive a diagnosis with CMR [9].

Integrated Prevention Strategies Across the Life Course

Prevention of cardiovascular kidney metabolic syndrome requires strategic interventions that address multiple risk factors throughout the lifespan. Evidence-based approaches that target both individual and population-level factors offer the most promising avenues for reducing CKM burden globally.

Lifestyle Interventions: Diet, Exercise, Smoking Cessation

Nonpharmacologic interventions form the foundation of CKM syndrome management across all stages. From primordial prevention in stage 0 to advanced disease management in stage 4, lifestyle modifications help delay progression and improve outcomes [10]. At the earliest stages, treatment focuses on achieving healthy weight, regular physical activity, optimal nutrition, adequate sleep, and tobacco avoidance [27].

For individuals with excess adiposity, attaining at least 5% weight loss represents an important initial goal [10]. In patients with established metabolic risk factors, resistance exercise training demonstrates favorable effects on multiple cardiometabolic parameters, including reductions in blood pressure, triglycerides, and fasting glucose [10]. For those with subclinical cardiovascular disease, exercise training substantially improves exercise capacity, with benefits extending across the spectrum of left ventricular ejection fraction [10].

Population-Level Approaches: PURE and PREDIMED Insights

Large-scale studies provide crucial guidance for population-level prevention strategies. The PREDIMED trial randomized 7,447 high-risk individuals to a Mediterranean diet supplemented with either extra-virgin olive oil, nuts, or a control low-fat diet [28]. After 4.8 years, both Mediterranean diet groups showed a 30% reduction in cardiovascular events compared to the control group [28]. Additionally, the Mediterranean diet with olive oil supplementation reduced incident diabetes by 40% [28].

Similarly, the global PURE study demonstrated that a balanced diet—comprising roughly 54% carbohydrates, 28% fat, and 18% protein—correlated with a 25% lower risk of all-cause mortality [29]. Individuals with the highest-quality diet consumed 8.4 daily servings of fruits and vegetables, 2.5 servings of nuts and legumes, and moderate amounts of dairy and unprocessed meat [29]. This dietary pattern also associated with a 22% lower risk of myocardial infarction and 25% lower risk of stroke [29].

Early Screening in Youth and High-Risk Adults

Screening for CKM risk factors throughout the life course enhances prevention efficacy. For pediatric populations, the American Academy of Pediatrics recommends annual screening for overweight and obesity, along with blood pressure assessments at each clinic visit beginning at age 3 [30]. Mental and behavioral health should undergo at least annual assessment, while lipid panels warrant checking between ages 9-11 and again between 17-21 [30].

For adults, screening intensity should align with CKM stage. Those at stage 0 benefit from cardiovascular risk assessments every 3-5 years, whereas individuals at higher stages require more frequent monitoring [30]. Early identification enables timely intervention—preliminary research indicates that when healthy young adults reduce caloric intake by 12%, CKM syndrome progression may be limited or reversed [31].

Therapeutic Approaches: Pharmacologic and Non-Pharmacologic

Management of cardiovascular-kidney-metabolic syndrome requires a multifaceted approach targeting overlapping pathophysiological mechanisms. Modern therapeutic strategies emphasize personalized treatment plans tailored to individual patient profiles across the CKM spectrum.

SGLT2 Inhibitors and GLP-1 RAs in CKM

SGLT2 inhibitors represent a breakthrough therapy class, delivering benefits beyond glycemic control by reducing heart failure hospitalizations, slowing kidney disease progression, and offering cardiovascular protection even in non-diabetic patients [32]. The DAPA-HF trial demonstrated that dapagliflozin reduced heart failure exacerbations regardless of diabetes status [33], whereas CREDENCE showed canagliflozin lowered the risk of end-stage kidney disease, doubling of serum creatinine, and renal death by 30% [33]. Remarkably, combined GLP-1 receptor agonist and SGLT2 inhibitor therapy showed a 30% lower risk of major adverse cardiovascular events compared with GLP-1 receptor agonists alone [34].

RAAS Blockade and Finerenone in Diabetic CKD

RAAS inhibitors remain essential for blood pressure control and organ protection. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, offers additional benefits through potent anti-inflammatory and antifibrotic effects [15]. The FIDELIO-DKD trial revealed that finerenone reduced the primary kidney composite outcome by 18% [3] and cardiovascular events by 14% [35] across the CKD spectrum.

Statins and Lipid Management in CKD

Statin therapy demonstrates clear benefits for non-dialysis CKD patients, reducing major cardiovascular events by approximately 20% [36]. For patients with severe CKD (eGFR <30 ml/min/1.73 m²), KDIGO guidelines recommend specific maximal daily doses: simvastatin ≤40 mg, pravastatin 40 mg, rosuvastatin 10 mg, and pitavastatin 2 mg [36]. Nonetheless, atorvastatin and fluvastatin require no adjustment regardless of CKD stage [36].

Bariatric Surgery and Renal Replacement Therapies

Bariatric surgery offers substantial benefits for patients with obesity and kidney disease, producing excess weight loss ranging from 29.8% to 72.8% [37]. Among patients with end-stage renal disease, this intervention reduced all-cause mortality at 5 years (25.6% vs. 39.8%) [38] and increased kidney transplant rates (33.0% vs. 20.4%) [38]. Sleeve gastrectomy improves comorbidities including diabetes and hypertension while enabling transplant listing for previously ineligible patients [37].

Future Directions: Precision Medicine and AI in CKM Care

The next frontier in cardiovascular-kidney-metabolic syndrome management involves tailored therapeutic approaches based on individual patient characteristics. As medicine evolves beyond conventional treatment algorithms, innovative technologies offer unprecedented opportunities for personalized intervention strategies.

AI-Based Risk Prediction Models

Artificial intelligence has begun transforming risk assessment in CKM syndrome through enhanced predictive analytics. Unlike traditional statistical models, AI-based approaches can identify complex patterns across diverse datasets, potentially improving early detection and treatment allocation. Yet, these advances face substantial challenges—calibration reporting occurs in only 24% of models [39], while both data and algorithmic biases remain common concerns. The CKM2S2-BAG score exemplifies progress in this area, demonstrating good-to-excellent discrimination for total cardiovascular disease risk using routine clinical data [4]. Future AI applications may integrate multiple polygenic risk scores alongside appropriate biomarkers and imaging studies to enhance outcome-specific predictions [40].

Proteomic and Genomic Biomarkers

Molecular biomarker discovery represents a critical advancement in CKM syndrome management. Recent analyzes have identified over 3,000 biomarkers used across 2,600 diseases [13], with specific proteins demonstrating causal links to CKM components. Machine learning approaches now automatically classify biomarkers according to measurement methodologies, enabling computation of disease specificity indices [13]. Research utilizing Mendelian randomization has identified 22 circulating proteins causally linked to adult type 2 diabetes and 11 proteins associated with youth-onset diabetes [41]. Among these, growth differentiation factor 15 (GDF15) appears particularly promising as both an incidence and prevalence biomarker [42].

Emerging Therapies: IL-1β Inhibitors and NLRP3 Blockers

The NLRP3 inflammasome has emerged as a pivotal therapeutic target for CKM syndrome. NodThera has pioneered clinical-stage small-molecule NLRP3 inhibitors, including NT-0796, which crosses the blood-brain barrier [43]. In clinical trials, NT-0796 demonstrated reductions in inflammation markers comparable to injectable monoclonal antibodies [43]. This approach shows particular promise for obesity treatment—in mouse models, NT-0796 reduced body weight, inflammation, and neuroinflammation while resetting multiple endocrine hormones [43]. The company currently conducts two Phase 2 clinical trials (RESOLVE-1 and RESOLVE-2) evaluating NT-0796 for obesity, with results expected in 2026’s second quarter [43].

Conclusion

Cardiovascular-kidney-metabolic syndrome represents a paradigm shift in understanding the interrelationships between multiple organ systems. This reconceptualization moves beyond treating obesity, diabetes, cardiovascular disease, and chronic kidney disease as isolated conditions toward recognizing their shared pathophysiological mechanisms and bidirectional relationships. The American Heart Association’s staging system now provides clinicians with a structured framework for risk stratification and targeted interventions across the disease spectrum.

Evidence clearly demonstrates how insulin resistance, RAAS activation, sympathetic nervous system overactivity, and chronic inflammation create self-perpetuating cycles of organ dysfunction. These pathways explain why patients with one component of CKM syndrome frequently develop others, thus necessitating early intervention before irreversible damage occurs. Biomarkers such as NT-proBNP, hs-TnT, NGAL, and galectin-3 offer valuable tools for detecting subclinical disease, while advanced imaging modalities like cardiac MRI provide superior diagnostic capabilities compared to conventional echocardiography.

Therapeutic approaches must address multiple risk factors simultaneously. SGLT2 inhibitors and GLP-1 receptor agonists have emerged as cornerstone therapies due to their pleiotropic effects across heart, kidney, and metabolic parameters. Finerenone offers additional cardio-renal protection through anti-inflammatory and antifibrotic mechanisms. Lifestyle modifications remain fundamental regardless of CKM stage, with evidence from PURE and PREDIMED studies confirming the substantial benefits of optimal nutrition patterns.

Future management will likely become more personalized through artificial intelligence, genomic profiling, and novel inflammatory pathway inhibitors. The development of AI-based risk prediction models and identification of causal protein biomarkers shows promise for earlier detection and more precise therapeutic targeting. Emerging therapies targeting the NLRP3 inflammasome pathway could potentially address multiple components of CKM syndrome simultaneously.

Medical practice must evolve accordingly, with increased emphasis on early screening and multidisciplinary collaboration. Primary care physicians, cardiologists, nephrologists, endocrinologists, and other specialists need to coordinate care across traditional boundaries. Most importantly, clinicians should view CKM syndrome as a preventable and potentially reversible condition when appropriate interventions occur early in its course. This integrated approach ultimately offers the best hope for reducing the substantial health and economic burden of this increasingly prevalent syndrome.

Key Takeaways

Understanding cardiovascular-kidney-metabolic syndrome requires recognizing it as an interconnected disease process rather than separate conditions, enabling more effective prevention and treatment strategies.

CKM syndrome affects 90% of US adults across five progressive stages, from no risk factors to clinical cardiovascular disease with kidney failure
Early intervention is crucial – the syndrome commonly begins with excess adiposity and creates self-perpetuating cycles of organ dysfunction through shared pathways
SGLT2 inhibitors and GLP-1 receptor agonists provide breakthrough therapy by targeting multiple organ systems simultaneously, reducing heart failure and kidney disease progression
Biomarkers like NT-proBNP and galectin-3 enable early detection of subclinical disease before irreversible damage occurs, improving patient outcomes
Lifestyle modifications remain fundamental across all stages, with Mediterranean diet patterns showing 30% reduction in cardiovascular events in high-risk patients

The key insight is that CKM syndrome represents a paradigm shift toward treating interconnected organ dysfunction holistically rather than managing isolated diseases separately. This approach, combined with emerging AI-based risk prediction and novel anti-inflammatory therapies, offers unprecedented opportunities for personalized prevention and treatment strategies that could significantly reduce the global health burden of this increasingly prevalent condition.

Frequently Asked Questions:

FAQs

Q1. What is cardiovascular-kidney-metabolic syndrome? Cardiovascular-kidney-metabolic syndrome is a complex health disorder characterized by the interconnected relationships between obesity, diabetes, chronic kidney disease, and cardiovascular disease. It represents a systemic condition where dysfunction in one organ system can cascade into others, leading to multiorgan complications and increased cardiovascular risk.

Q2. How is cardiovascular-kidney-metabolic syndrome diagnosed? Diagnosis involves assessing multiple risk factors and biomarkers. Key indicators include excess weight or abdominal obesity, high blood pressure, abnormal cholesterol levels, elevated blood glucose, and reduced kidney function. Advanced diagnostic tools like cardiac MRI and biomarkers such as NT-proBNP and galectin-3 can help detect subclinical disease before irreversible damage occurs.

Q3. What are the main treatment approaches for cardiovascular-kidney-metabolic syndrome? Treatment typically involves a combination of lifestyle modifications and pharmacological interventions. Key approaches include achieving at least 5% weight loss, adopting a Mediterranean-style diet, regular physical activity, and medications such as SGLT2 inhibitors and GLP-1 receptor agonists. These therapies aim to address multiple risk factors simultaneously across heart, kidney, and metabolic parameters.

Q4. Can cardiovascular-kidney-metabolic syndrome be prevented? Yes, prevention is possible through early intervention and lifestyle modifications. Maintaining a healthy weight, regular exercise, optimal nutrition, adequate sleep, and avoiding tobacco use are crucial preventive measures. Early screening, especially in high-risk individuals and youth, can help identify and address risk factors before the syndrome progresses.

Q5. What future developments are expected in managing cardiovascular-kidney-metabolic syndrome? Future management is likely to become more personalized through artificial intelligence, genomic profiling, and novel therapies. AI-based risk prediction models and proteomic biomarkers show promise for earlier detection and precise treatment targeting. Emerging therapies like NLRP3 inflammasome inhibitors could potentially address multiple components of the syndrome simultaneously, offering new hope for more effective management.

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