Cardio–kidney–metabolic syndrome: Underutilized screening and management in primary care settings

Gut–kidney–heart axis and microbial metabolites

Recent mechanistic investigations have elucidated the critical role of gut dysbiosis in CKM syndrome pathophysiology. Dysbiotic microbiota in CKM patients generate altered patterns of microbial metabolites, particularly trimethylamine N-oxide (TMAO) and phenylacetylglutamine, which are absorbed systemically and contribute to endothelial dysfunction, amplified inflammatory burden, and accelerated atherosclerosis progression.^[13,14] The mechanisms underlying TMAO’s pathogenic effects include direct impairment of endothelial nitric oxide production and increased expression of pro-thrombotic molecules. Dysbiotic patterns are further associated with increased intestinal permeability – the “leaky gut” phenomenon – with consequent translocation of lipopolysaccharides and other pathogen-associated molecular patterns that activate toll-like receptors on innate immune cells, perpetuating systemic inflammation.^[15,16] Conversely, short-chain fatty acids, particularly butyrate and propionate generated through microbial fermentation of dietary fiber, exert anti-inflammatory effects through G-protein coupled receptor signaling and histone deacetylase inhibition, promote intestinal barrier integrity, and expand populations of anti-inflammatory regulatory T cells.^[14,17] These mechanistic insights have sparked considerable interest in microbiota-targeted interventions, including dietary manipulation, prebiotic and probiotic supplementation, and selective use of antimicrobial agents, though evidence for clinical efficacy remains preliminary and warrants further investigation.

Cellular senescence as a unifying mechanism

Accumulating evidence suggests that cellular senescence – the permanent cell cycle arrest triggered by telomere shortening, DNA damage, or oncogenic stress – represents a unifying pathophysiological mechanism spanning cardiovascular, renal, and metabolic dysfunction in CKM syndrome.^[18] Senescent cells, which persist in tissues and accumulate with advancing age and chronic disease, produce a constellation of pro-inflammatory and pro-fibrotic factors collectively termed the senescence-associated secretory phenotype (SASP), including TNF-α, IL-6, monocyte chemoattractant protein-1, and transforming growth factor-beta.^[18,19] Recent research demonstrates elevated senescent cell burden in cardiac myocardium, renal parenchyma, and adipose tissue of CKM patients, with accumulation correlating with severity of organ dysfunction.^[18,19] The paracrine effects of senescent cells on neighboring tissues, combined with systemic dissemination of SASP factors, sustain chronic inflammation and promote fibrotic remodeling. An emerging therapeutic frontier involves senolytic agents – compounds that selectively induce apoptosis in senescent cells – with early preclinical evidence demonstrating reversal of age-associated cardiovascular and renal pathology.^[20,21] While translation to clinical practice remains in early stages, this avenue represents a potentially transformative approach to interrupting the senescence-driven progression of CKM syndrome.

Epigenetic modifications and metabolic memory

The phenomenon of metabolic memory – whereby transient metabolic perturbations leave enduring epigenetic imprints that perpetuate organ dysfunction despite restoration of metabolic parameters – has emerged as a critical mechanism in CKM pathophysiology.^[22,23] Accumulating evidence demonstrates that chronic oxidative stress and sustained inflammation in CKM syndrome induce alterations in histone acetylation and DNA methylation patterns, leading to shifts in the transcriptional landscape of metabolic and inflammatory genes.^[22,24] Specifically, hyperglycemia and dyslipidemia suppress histone acetyltransferase activity while enhancing histone deacetylase expression, resulting in reduced acetylation of histone tails and consequent transcriptional silencing of antioxidant and anti-inflammatory genes.^[24]

DNA methyltransferase activity is concomitantly enhanced, leading to hypermethylation of Cytosine-phosphate-Guanine (CpG) islands in promoter regions of genes protective against metabolic and cardiovascular dysfunction.^[22,24] These epigenetic modifications persist even after correction of hyperglycemia or dyslipidemia, explaining the incomplete reversal of cardiovascular and renal pathology despite achievement of glycemic and lipid targets.^[23] Therapeutic targeting of these epigenetic pathways through histone deacetylase inhibitors, DNA methyltransferase inhibitors, and epigenetic “erasers” represents an emerging frontier, though clinical translation remains preliminary.

In vitro multi-organ crosstalk models

Emerging in vitro platforms, particularly organ-on-chip and multi-organ microphysiological systems, enable unprecedented mechanistic investigation of inter-organ crosstalk relevant to CKM syndrome that cannot be adequately replicated through traditional cell culture or even animal models.^[25-27] These systems recreate the physiological microarchitecture, fluid shear stress, and three-dimensional cellular organization characteristic of native tissues, thereby more faithfully recapitulating organ-level function. Kidney-on-chip platforms can model glomerular ultrafiltration and tubular reabsorption with exquisite physiological fidelity, enabling investigation of how inflammatory mediators or metabolic substrates alter filtration barrier function.^[27] Cardiac-on-chip systems replicate myocardial contractility and can model the response to neurohormonal agonists and pharmacological agents.^[25,26] Multi-organ platforms integrate kidney, heart, and metabolic organ modules into a single system, enabling direct assessment of inter-organ signals and identification of cross-organ synergistic mechanisms driving CKM progression.^[25,27] These platforms hold substantial promise for future mechanistic discovery and accelerated identification of novel therapeutic targets, as well as for personalized medicine applications enabling patient-specific assessment of drug responsiveness.

In conclusion, the pathophysiology of CKM syndrome is a complex and multifaceted process that involves a confluence of inflammatory, neurohormonal, and metabolic pathways. The bidirectional and self-perpetuating nature of this interplay underscores the need for a holistic and integrated approach to management. Interventions that target these core mechanistic pathways, such as SGLT2 inhibitors, which have demonstrated both cardio- and reno-protective effects, hold great promise in breaking the vicious cycle of CKM syndrome and improving patient outcomes.^[9,10,28] A deeper understanding of this intricate pathophysiology is essential for the development of novel therapeutic strategies and the implementation of effective screening and prevention programs in primary care settings.

Universal risk factor-based screening

This foundational approach emphasizes systematic assessment of all patients for the presence of cardinal CKM risk factors, including obesity or dysfunctional adiposity (elevated waist circumference, elevated body mass index), hypertension, dysglycemia (pre-diabetes or diabetes), or reduced kidney function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m² or albuminuria). The primary advantages of this approach include conceptual simplicity, widespread applicability across diverse healthcare settings from well-resourced academic centers to resource-constrained primary care facilities, seamless alignment with existing preventive care paradigms and periodic health examination frameworks, and potential for direct translation into clinical practice without substantial informatics infrastructure. Furthermore, universal screening captures disease burden across the entire population spectrum, ensuring that no individuals are overlooked due to perceived low-risk status. Conversely, significant disadvantages include potential for substantial over-detection in very low-risk populations (e.g., younger individuals without obesity or cardiometabolic risk factors), considerable resource demands in settings with limited laboratory capacity or specialist access, and risk of unnecessary downstream testing and referrals that may generate patient anxiety or financial burden.

Stage-based targeted screening (AHA CKM framework)

The AHA staging approach prioritizes risk stratification, with screening intensity and intervention scale tailored to individual risk profiles. Key advantages of this methodology include a structure that facilitates integration into clinical workflows, provision of a discrete taxonomy enabling longitudinal tracking of disease progression and assessment of intervention efficacy, and potential for optimized resource allocation through risk-stratified intensity of investigation and specialist consultation. The five-stage framework provides clinically intuitive guidance that can inform patient education and shared decision-making regarding risk level and intervention necessity. However, substantial disadvantages include considerable operational complexity requiring accurate and complete data collection across multiple risk factor domains, the need for robust informatics support and decision algorithms to facilitate implementation, potential for paradoxical delay in recognition of highest-risk individuals if intermediate staging causes false reassurance, and training burden imposed on PCPs to understand staging criteria and their clinical implications. In resource-constrained settings, the informatics infrastructure required to support systematic staging may be prohibitive.

Biomarker-intensive screening

Comprehensive biomarker panel approaches incorporate both traditional markers of organ dysfunction (eGFR, urine albumin-to-creatinine ratio [UACR], N-terminal pro-B-type natriuretic peptide [NT-proBNP]) and emerging biomarkers of cellular and systemic injury (hs-cTn, Lp(a), circulating TMAO levels, proteomic signatures). The principal advantage resides in the potential for enhanced precision phenotyping and personalized risk prediction through multi-dimensional biomarker integration and machine-learning derived algorithms. Biomarker-intensive approaches may identify subclinical organ dysfunction before clinical manifestations emerge, potentially enabling earlier intervention. However, formidable barriers to implementation include substantial cost implications of comprehensive biomarker panels, limited availability of novel biomarker assays in resource-constrained or low-income countries, unclear guidance regarding the interpretation and clinical significance of biomarker results in primary care settings, and insufficient evidence that biomarker-driven screening and intervention strategies produce superior patient outcomes compared to conventional approaches. Furthermore, the multiplicity of biomarker results can create interpretive confusion for PCPs and generate unnecessary alarm or therapeutic inertia.

Recommended approach

Evidence synthesis suggests that optimal screening strategies employ hybrid approaches combining risk factor assessment, selective biomarker testing informed by risk stratification, and clinical judgment regarding individual patient context. For Stage 0–1 patients in well-resourced settings, universal assessment for cardinal risk factors with selective biomarker testing (eGFR, UACR, hemoglobin A1c [HbA1c]) is appropriate. For Stage 2–3 patients, more intensive biomarker panels including NT-proBNP, lipid subfractions, and inflammatory markers are justified. In resource-constrained settings, prioritization of eGFR and UACR testing combined with clinical risk assessment provides maximal value at minimal cost. Provider education regarding staging criteria and appropriate biomarker interpretation is essential for implementation success across all contexts.

eGFR and UACR

The dual assessment of eGFR and UACR is the cornerstone of CKD screening and is strongly recommended by the Kidney Disease: Improving Global Outcomes guidelines.^[12] However, studies have consistently shown that UACR testing is significantly underutilized in primary care, particularly in patients with hypertension and even in those with diabetes, where it is strongly indicated. This represents a critical gap in care, as albuminuria is not only a marker of kidney damage but also a potent and independent predictor of cardiovascular events.

NT-proBNP

This biomarker is a sensitive indicator of myocardial wall stress and is a valuable tool for the early detection of asymptomatic heart failure. The American Diabetes Association recommends NT-proBNP screening in patients with diabetes to identify those at high risk for heart failure.^[31] However, its use in primary care remains limited, often due to a lack of awareness and uncertainty about its interpretation.

High-sensitivity troponin (hs-cTn)

High-sensitivity troponins are markers of myocyte injury and can detect subclinical myocardial damage. Elevated levels of hs-cTn are associated with an increased risk of future cardiovascular events and can be used for risk stratification in patients with CKM syndrome. However, like NT-proBNP, its use in the primary care setting is not yet widespread.

Lipoprotein(a) (Lp[a])

Lp(a) is a genetically determined and independent risk factor for atherosclerotic CVD. The 2018 American College of Cardiology/AHA guideline on the management of blood cholesterol recommends considering Lp(a) measurement in selected individuals to refine risk assessment.^[32] However, its routine use in primary care is still uncommon.

Serum uric acid

Hyperuricemia is associated with an increased risk of hypertension, metabolic syndrome, CKD, and CVD. While the causal role of uric acid in the pathogenesis of these conditions is still being debated, it may serve as a valuable and inexpensive biomarker for risk stratification in CKM syndrome.^[33]

Novel metabolomic and proteomic profiles

Advances in omics technologies have led to the identification of novel metabolic and proteomic signatures that may provide a more granular assessment of CKM risk. These emerging biomarkers hold promises for personalized medicine approaches but are not yet ready for routine clinical use.

Systemic barriers

These include the lack of integrated and user-friendly EHR decision support tools that can automate risk assessment and prompt providers to order appropriate tests. The fragmented nature of healthcare, with a lack of seamless communication between primary care and specialty services, also contributes to the problem.

Provider-level barriers

Many PCPs report a lack of time and resources to conduct comprehensive CKM screening. There is also a need for ongoing education and training to keep up with the rapidly evolving evidence-based and clinical guidelines. Uncertainty about the interpretation of biomarkers and the appropriate referral pathways can also be a significant barrier.

Patient-level barriers

Patient-related factors such as lack of awareness about CKM syndrome, financial constraints, and competing health priorities can also contribute to low screening rates.

In conclusion, the underutilization of effective screening and diagnostic strategies for CKM syndrome in primary care represents a significant public health challenge.^{[2,4,5,12,29,30,34,35]} Overcoming these barriers will require a multi-pronged approach that includes the development of simplified and risk-based screening protocols, the integration of decision support tools into EHRs, the promotion of interdisciplinary collaboration, and the empowerment of patients through education and shared decision-making. By bridging the gap between evidence and practice, we can unlock the full potential of early detection and intervention to improve the lives of millions of individuals affected by CKM syndrome.

Weight management

Excess or dysfunctional adiposity, characterized by enlarged and metabolically dysfunctional adipocytes and expanded visceral fat depots, represents a primary driver of systemic inflammation and CKM syndrome initiation and progression. Intentional weight reduction, even modest decrements of 5–10% of baseline body weight, has been convincingly demonstrated to improve multiple pathophysiological parameters including glycemic control (reductions in HbA1c of 0.5–1.5%), reduce systemic blood pressure (reductions of 5–8 mmHg systolic pressure per 10% weight loss), improve dyslipidemia (reductions in triglycerides and increases in high-density lipoprotein [HDL] cholesterol), and reduce 10-year cardiovascular event risk. Strategies for achieving weight loss include comprehensive dietary modification programs emphasizing caloric restriction (typically 500–750 kcal daily deficit), augmented physical activity, structured behavioral therapy incorporating motivational interviewing and cognitive-behavioral techniques to address maladaptive eating behaviors and enhance adherence, and in carefully selected individuals with body mass index [BMI] >35 kg/m² or BMI >30 kg/m² with obesity-related comorbidities refractory to medical management, consideration of pharmacological adjuncts (including glucagon-like peptide-1 [GLP-1] receptor agonists used for weight management independent of glycemic benefits) or bariatric surgical interventions.

Dietary modification

A heart-healthy and kidney-friendly dietary pattern is essential for the prevention and management of CKM syndrome. The Dietary Approaches to Stop Hypertension diet and Mediterranean dietary patterns, both of which are rich in fruits, vegetables, whole grains, legumes, and lean protein sources while limiting processed foods, saturated fat, and sodium, have been rigorously evaluated in prospective randomized trials and consistently demonstrate beneficial effects on blood pressure (reductions of 8–14 mmHg),^[37] lipid levels (reductions in low-density lipoprotein [LDL]-cholesterol and triglycerides, increases in HDLcholesterol), glycemic control, and inflammatory markers. The Mediterranean diet, which emphasizes olive oil as the primary fat source, fish consumption 2–3 times weekly, and abundant plant-derived foods, has demonstrated particular cardioprotective benefits in landmark trials.^[38] Sodium restriction to <2,300 mg daily (with further reduction to 1,500 mg daily in hypertensive individuals) is critical for blood pressure control and management of fluid overload in patients with heart failure and advanced CKD. Implementation of dietary interventions is optimized through collaboration with registered dietitians who provide personalized dietary counseling, recipe modifications, food selection guidance, and behavioral support to sustain long-term dietary adherence.^[39]

Physical activity prescription

Regular physical activity is a powerful and evidence-supported tool for improving cardiovascular and metabolic health and for slowing CKM progression. The AHA recommends a minimum of 150 min of moderate-intensity aerobic activity (such as brisk walking, cycling, or swimming) or 75 min of vigorous-intensity aerobic activity per week, combined with muscle-strengthening activities performed on two or more days per week. Physical activity produces multiple beneficial effects, including improvements in insulin sensitivity (measurable within 2–4 weeks of exercise initiation), reduction in blood pressure and heart rate, improvements in lipid profiles, enhancements in endothelial function, and reductions in circulating inflammatory markers. The cardiovascular event risk reduction associated with regular physical activity is substantial, with meta-analyses documenting 20–30% reductions in cardiovascular mortality.^[40] Supervised exercise programs delivered through rehabilitation centers or primary care settings, with guidance from exercise physiologists, enhances initial program efficacy and adherence. Progressive intensity advancement, incorporation of both aerobic and resistance training components, and flexible exercise modalities accommodating individual preferences and physical limitations optimize adherence and long-term sustainability.

Smoking cessation

Cigarette smoking represents a major modifiable risk factor for CVD and is independently associated with accelerated progression of CKD and enhanced cardiovascular mortality in CKM patients. Smoking cessation is among the most impactful lifestyle modifications available for individuals with CKM syndrome, with cardiovascular benefits accruing within weeks to months of cessation. Comprehensive smoking cessation support should incorporate behavioral counseling (including individual counseling, group programs, and telephone quit-lines), pharmacological adjuncts including varenicline (which blocks nicotinic acetylcholine receptors and reduces craving and withdrawal symptoms) and bupropion (an antidepressant with nicotine antagonism properties), and nicotine replacement therapy strategies. Combination pharmacological approaches (e.g., varenicline plus nicotine replacement) often achieve superior quit rates compared with monotherapy.

Structured behavioral and psychological support

Adherence to comprehensive lifestyle modification represents a formidable challenge in clinical practice, with long-term adherence to diet and exercise recommendations often exceeding 50% discontinuation rates within 6–12 months. Contemporary evidence demonstrates that structured psychological support substantially enhances both short-term and long-term adherence. Cognitive-behavioral therapy specifically adapted for chronic disease management, motivational interviewing techniques designed to enhance intrinsic motivation for behavioral change, and ongoing counseling by trained behavioral health specialists produce adherence rates 2–3 fold higher than standard advice alone. Emerging evidence supports digital health interventions, including mobile health applications, telemedicine-delivered behavioral counseling, and virtual support groups as effective adjuncts or alternatives to in-person counseling, particularly for patients in geographic or transportation-limited circumstances.

Multidisciplinary lifestyle program structure

Optimal delivery of comprehensive lifestyle interventions occurs through structured, multidisciplinary programs involving registered dietitians, exercise physiologists, behavioral health specialists, and PCPs working collaboratively. Programs should include systematic baseline assessment of dietary patterns, physical activity capacity, and psychosocial barriers; individualized goal-setting incorporating patient preferences and circumstances; regular follow-up visits at intervals of 2–4 weeks during intensive intervention phases; and ongoing contact at progressively lengthened intervals (monthly to quarterly) for maintenance and relapse prevention. Evidence-based program models such as the Diabetes Prevention Program, adapted for broader CKM populations, produce sustained weight loss of 5–10% at 3 years and substantial reductions in incident diabetes in prediabetic populations.^[41]

SGLT2 inhibitors

SGLT2 inhibitors have emerged as a game-changer in the management of CKM syndrome. These agents, which were initially developed for the treatment of T2Ds, have been shown to have profound cardiovascular and renal protective effects, independent of their glucose-lowering effects. Large randomized controlled trials have demonstrated that SGLT2 inhibitors reduce the risk of cardiovascular death, hospitalization for heart failure, and progression of CKD in patients with and without T2Ds.^[9,10]

The mechanisms underlying these benefits are multifactorial and include their effects on glomerular hemodynamics, natriuresis, blood pressure, and cardiac metabolism.

RAAS inhibitors

RAAS inhibitors, including angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), have long been the cornerstone of therapy for hypertension, heart failure, and CKD. These agents have been shown to reduce blood pressure, decrease albuminuria, and slow the progression of CKD. The combination of a RAAS inhibitor with an SGLT2 inhibitor has been shown to have additive cardio-renal protective effects.

GLP-1 receptor agonists

GLP-1 receptor agonists are another class of glucose-lowering agents that have demonstrated significant cardiovascular benefits. These agents have been shown to reduce the risk of major adverse cardiovascular events in patients with T2Ds. The mechanisms underlying these benefits are thought to be related to their effects on weight loss, blood pressure, and inflammation.

Mineralocorticoid receptor antagonists (MRAs)

Non-steroidal MRAs, such as finerenone, have been shown to have renal and cardiovascular benefits in patients with T2Ds and CKD. Finerenone has been shown to reduce the risk of CKD progression and cardiovascular events in this patient population.^[10]

Systematic monitoring and surveillance protocols for CKM syndrome

Effective CKM syndrome management requires systematic and coordinated monitoring of key clinical and biochemical parameters at intervals informed by disease stage and therapeutic response. Evidence-based monitoring protocols enhance detection of disease progression, facilitate timely therapeutic intensification, and enable early identification of adverse drug effects [Supplementary Table 4].

Glycemic control

For patients with T2DM, quarterly HbA1c assessments are recommended until glycemic targets (generally HbA1c <7% for most patients, with individualization based on age, comorbidities, and hypoglycemia risk) are achieved, after which transition to semi-annual monitoring is appropriate. Quarterly monitoring enables rapid detection of inadequate glycemic control and provides an opportunity for therapeutic intensification before substantial hyperglycemia-related complications accrue. Home glucose monitoring or continuous glucose monitoring systems provide additional granularity for assessment of glycemic patterns and identification of periods of hypo- or hyperglycemia.

Blood pressure monitoring

Systematic blood pressure assessment is essential at each clinical encounter, with careful documentation of office readings, home blood pressure telemetry when available, and consideration of ambulatory blood pressure monitoring in patients with apparent treatment-resistant hypertension. For patients in CKM stages 2–3 not yet at target blood pressure (<130/80 mmHg per current guidelines), quarterly office visits with home blood pressure monitoring between visits enable detection of inadequate control and timely medication adjustments. Once the target blood pressure is achieved and sustained, monitoring frequency can be reduced to semi-annual or annual intervals.

Renal function parameters:

Assessment of serum creatinine and eGFR, combined with quantification of albuminuria through UACR, should be performed annually in patients with Stage 2 CKM syndrome, and at a minimum semi-annually in those with albuminuria or progressive CKD. A decline in eGFR exceeding 5 mL/min/1.73m² per year constitutes a rapid decline. It should prompt urgent specialist evaluation, intensification of RAAS inhibition and SGLT2 inhibitor therapy if tolerated, and careful assessment for alternative etiologies of CKD progression, including uncontrolled hypertension, medication-induced nephrotoxicity, and superimposed acute kidney injury.

Cardiovascular assessment

Regular assessment for heart failure symptoms, including exertional dyspnea, orthopnea, paroxysmal nocturnal dyspnea, peripheral edema, and exercise intolerance, should be systematized at each clinical encounter. For asymptomatic high-risk patients (Stage 3 CKM with diabetes and/or albuminuria), consideration of BNP or NT-proBNP measurement can identify subclinical ventricular dysfunction, potentially enabling early therapeutic intervention with ACE inhibitors, ARBs, or SGLT2 inhibitors before symptomatic heart failure develops.^[42]

Multidisciplinary coordination and specialist consultation

Patients with CKM syndrome Stage 3–4 warrant systematic collaboration between primary care, cardiology, nephrology, and endocrinology specialists. Formalized referral criteria and consultation protocols, with clearly defined responsibility for specific management domains and transparent communication regarding medication adjustments and monitoring results, optimize care coordination and reduce duplication or gaps in management.

Multidisciplinary teams

The management of CKM syndrome often requires the expertise of a multidisciplinary team, including PCPs, cardiologists, nephrologists, endocrinologists, dietitians, and pharmacists. A team-based approach can ensure that patients receive comprehensive and coordinated care.

Care coordination mechanisms

Structured care coordination platforms, including shared EHRs, regular multidisciplinary case conferences, and clear protocols for inter-provider communication, enhance care quality and efficiency.

Patient engagement and shared decision-making

Effective CKM syndrome management is predicated on active patient engagement and shared decision-making. Patients should be educated about their condition, empowered to participate in treatment decisions, and supported in achieving lifestyle goals through accessible resources and support networks.

Telemedicine and remote monitoring

Telemedicine and remote monitoring technologies can play a valuable role in the management of CKM syndrome, particularly for patients in rural or underserved areas. These technologies can be used to facilitate virtual consultations with specialists, monitor key biometric data, and provide ongoing education and support to patients.

Prevention-focused and risk-based screening

Rather than a one-size-fits-all approach, screening for CKM syndrome should be tailored to the individual patient’s risk profile. This can be achieved through the use of risk-based algorithms that are integrated into the EHR and that can automatically identify patients who are at high risk for CKM syndrome. This approach would allow for the more efficient use of resources and would ensure that screening is targeted to those who are most likely to benefit.

Integrated and collaborative management

The management of CKM syndrome requires a collaborative approach that bridges the gap between primary care and specialty services. This can be facilitated through the use of co-management agreements, e-consultations, and telemedicine, which can provide PCPs with timely access to specialist expertise. A team-based approach, which includes pharmacists, dietitians, and other allied health professionals, can also help to provide patients with comprehensive and coordinated care.

Patient-centered and technology-enabled engagement

Patients must be active partners in the management of their CKM syndrome. This requires a patient-centered approach that is based on shared decision-making and that empowers patients with the knowledge and tools they need to manage their own health. Technology can play a valuable role in this process through the use of mobile health applications, remote monitoring devices, and online patient portals.

Implementation science

There is a critical need for research on the most effective strategies for implementing CKM screening and management protocols in real-world primary care settings. This includes research on the development and validation of EHR-based decision support tools, the evaluation of different care delivery models, and the identification of strategies for overcoming provider- and patient-level barriers to care.

Biomarker development and validation

While we have several established biomarkers for CKM syndrome, there is a need for novel biomarkers that can provide a more granular assessment of risk and that can be used to guide personalized medicine approaches. The development of point-of-care tests for key CKM biomarkers could also help to facilitate more timely and efficient screening in primary care.

Health economics and outcomes research

There is a need for more real-world data on the cost-effectiveness of different CKM screening and management strategies. This includes research on the long-term clinical and economic outcomes of interventions such as SGLT2 inhibitors and integrated care models. This research will be critical for informing policy decisions and for making the business case for investing in more comprehensive CKM care.

Health equity

CKM syndrome disproportionately affects individuals from racial and ethnic minority groups and those from lower socioeconomic backgrounds.^[43] There is a critical need for research on the social determinants of health that contribute to these disparities and for the development of culturally tailored interventions that can help to reduce health inequities.

In conclusion, the challenge of CKM syndrome is immense, but so too is the opportunity for improvement. By embracing a more holistic and integrated approach to care, by investing in innovative care delivery models, and by addressing the critical knowledge gaps through targeted research, we can transform the management of CKM syndrome and improve the lives of millions of individuals worldwide.