Abstract
Key Points
The cardiovascular‑kidney‑metabolic framework encourages routine assessment of cardiovascular risk, metabolic health, and kidney function.
Cardiovascular risk equations should be used in patients with CKD to direct preventive therapies and promote coordination of care to optimize outcomes.
Comprehensive therapy building upon foundational CKD management is essential to minimize treatment gaps and improve cardiovascular‑kidney‑metabolic outcomes.
The recent release of the inaugural AHA/ACC/ADA/ASN Guideline for the Prevention, Detection, Evaluation, and Management of Cardiovascular-Kidney-Metabolic (CKM) Syndrome calls for health care professionals across disciplines to broaden their practice to include the full spectrum of these interconnected disease states. This ASN Kidney Health Guidance aims to unite the nephrology community in this effort, highlighting the central role kidney disease plays in CKM syndrome and providing CKD-specific considerations. CKD is often complicated by comorbid cardiovascular and metabolic diseases, and regular evaluation of patients should include screening and management across disease states. The Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) equation should be integrated along with kidney outcome predictors for routine patient counseling and risk assessment. Lifestyle modifications, including regular physical activity, avoidance of tobacco products, and adoption of a healthy diet and sleep patterns, underpin CKM management. Both renin-angiotensin system inhibitors and sodium-glucose cotransporter 2 inhibitors are foundational therapies in CKD for the prevention of cardiovascular and kidney end points, and glucagon-like peptide-1–based therapies and nonsteroidal mineralocorticoid receptor antagonists may be added according to an individual patient's cardiovascular and metabolic risk profile. CKM therapies may be initiated simultaneously or in rapid sequence according to shared decision making, but therapeutic inertia must be avoided. Cardiovascular disease mitigation should also include lipid management for primary and secondary prevention. Evidence supporting the benefits of CKM treatments in people with glomerulonephritis, those with kidney transplant, those on dialysis with kidney failure treated with maintenance dialysis, pediatric populations, older adults, and those with frailty is limited. However, screening and diagnosis of CKM syndrome are critical, and these cardiokidney protective therapies may be used with shared decision making. Diabetes and obesity are extremely common in people living with kidney disease; both are major contributors to CKD progression. CKD poses a major risk of cardiovascular morbidity and mortality. Hence, nephrology team members should play a vital role in the diagnosis, treatment, and implementation of a holistic and multidisciplinary approach for the well-being of patients with kidney diseases.
Podcast
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Keywords: cardiovascular disease, CKD, clinical nephrology, dialysis, glomerular diseases, kidney transplantation, cardiovascularkidneymetabolic (CKM) syndrome
Introduction
The framework of cardiovascular‑kidney‑metabolic (CKM) syndrome highlights the interconnected relationship between metabolic risk factors, such as obesity and diabetes, CKD, and cardiovascular disease.1 Kidney disease plays a central role in CKM syndrome because it contributes to chronic inflammation and endothelial dysfunction, thereby increasing cardiovascular risk. CKM syndrome is classified into four stages, with all patients with CKD falling within stages 2–4, emphasizing the importance of early identification and timely implementation of evidence-based therapies to improve kidney and cardiometabolic outcomes. The ASN Kidney Health Guidance on the CKM syndrome highlights CKD-specific considerations (Table 1), while the 2026 AHA/ACC/ADA/ASN Guideline for the Prevention, Detection, Evaluation, and Management of Cardiovascular-Kidney-Metabolic Syndrome addresses multiple aspects of CKM management. Together, this clinical guidance emphasizes the critical role nephrologists can play in coordinating and leading the care of patients with multimorbidity and CKM syndrome.2,3
Table 1.
Key takeaways from the ASN Kidney Health Guidance on the Cardiovascular‑Kidney‑Metabolic Syndrome
| 1. CKM syndrome highlights the clinical and biological interconnectedness of cardiovascular disease, kidney disease, and metabolic health. Most patients with CKD fall into stages 2–4 CKM, underscoring the need for nephrologists to not only monitor kidney function but also screen for cardiovascular and metabolic health |
| 2. The 2023 AHA PREVENT risk equations should be used for cardiovascular disease risk prediction in those with CKD |
| 3. Several lifestyle changes, including adherence to healthy diet and sleep patterns, regular physical activity, and avoidance of tobacco products, should form the cornerstone of CKM management |
| 4. RASi and SGLT2i are foundational therapies for patients with CKD, particularly for those with diabetes, hypertension, and albuminuria |
| 5. GLP-1–based therapies should be considered for patients who are overweight or have obesity or type 2 diabetes, particularly in those with UACR ≥100 mg/g while taking RASis and SGLT2is. GLP-1–based therapies may be considered in patients on maintenance dialysis to promote weight loss and facilitate eligibility for kidney transplant listing |
| 6. nsMRA therapy should be considered for patients with kidney disease, type 2 diabetes, and persistent albuminuria despite being on RASis |
| 7. Moderate-intensity statins use is suggested for primary prevention in adults aged 40–75 yr with nondialysis stages 3–5 CKD and high-intensity statins with LDL cholesterol targets <55 mg/dl for secondary prevention for established atherosclerotic cardiovascular disease; statin therapy can be considered in stages 1–2 CKD |
| 8. Clinicians should consider early adoption of combination therapies by including RASis, SGLT2is, GLP-1 RAs, and nsMRAs, either through simultaneous initiation or rapid sequencing depending on the patient's underlying cardiometabolic and kidney risk, tolerability, and affordability |
| 9. Special kidney populations, including but not limited to children and adolescents, geriatric/frail individuals, pre/post kidney transplantation, and patients with genetic kidney diseases and/or glomerulonephritis, should be considered for inclusion in the CKM framework of care, despite limited and emerging evidence |
| 10. Implementation, continuation, or restarting of therapeutics should be considered at all patient interactions to minimize unnecessary prolonged gaps in treatment. Nephrologists should be questioning at every opportunity why a patient is not on one or multiple CKM-indicated medications |
| 11. CKM care is a team effort that necessitates collaboration with other medical specialists to optimize care for patients with CKD |
AHA PREVENT, American Heart Association Predicting Risk of Cardiovascular Disease EVENTs; CKM, cardiovascular-kidney‑metabolic; GLP-1, glucagon-like peptide-1; nsMRA, nonsteroidal mineralocorticoid receptor antagonist; RASi, renin-angiotensin system inhibitor; SGLT2i, sodium-glucose cotransporter 2 inhibitor; UACR, urine albumin-creatinine ratio.
Risk Prediction
Cardiovascular disease remains the leading cause of mortality among patients with CKD, underscoring the importance of early detection of subclinical cardiovascular disease in high-risk populations. This includes regular assessment of body mass index and/or waist circumference, along with laboratory evaluation of eGFR, urine albumin-creatinine ratio, hemoglobin A1c, and lipid profile tests at clinical visits. These parameters are essential for comprehensive cardiovascular risk stratification and for estimating the risk of atherosclerotic cardiovascular disease and heart failure in patients with CKD using the Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) equation.4 Nephrologists should use both cardiovascular disease and kidney failure predictive equations and incorporate them into routine patient counseling and risk assessment. Although the predictive performance of the PREVENT equation appears similar across different levels of kidney function, its applicability and predictive accuracy in patients receiving maintenance dialysis and kidney transplant recipients remain uncertain.
Goal-Directed Medical Therapy
Lifestyle modification, including regular physical activity, tobacco avoidance, and adherence to a healthy diet and sleep pattern, forms the cornerstone of CKM management. Renin-angiotensin system inhibitors (RASis) are the foundational therapy for those with CKD, especially in those with albuminuria. After several decades, novel therapies have become available to improve outcomes among CKD patients with and without diabetes. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) exert significant cardiorenal protective effects through multiple mechanisms. Clinical trials have consistently demonstrated their cardiovascular and kidney benefits in patients with and without diabetes, with beneficial effects across the spectrum of eGFR and urine albumin-creatinine ratio.5 Coadministration or rapid sequence prescribing of these two medications should be considered in all high-risk patients. An early, modest decline in eGFR after initiation of SGLT2is, similar to RASis, is expected and should not lead to treatment interruption or discontinuation. Patients should also be counseled regarding potential adverse effects, including genital mycotic infections and the need to temporarily hold this medication during periods of fasting or illness to reduce the risk of ketoacidosis. If CKM medications are held during a hospitalization, it is important to restart them as soon as possible (even before hospital discharge if appropriate) to prevent prolonged discontinuation.
Glucagon-like peptide-1 (GLP-1)–based therapies have demonstrated kidney, cardiovascular, and mortality benefits in those with CKD and type 2 diabetes mellitus, irrespective of the degree of weight loss.6 These medications should be specifically considered in patients with CKD who are overweight or have obesity or type 2 diabetes while on RASis and SGLT2is. Nephrologists should counsel patients regarding potential adverse effects, including gastrointestinal intolerance, and emphasize the importance of lifestyle modification while receiving these therapies. In addition, patients should be encouraged to participate in resistance or strength training and maintain adequate protein intake to minimize the risk of sarcopenia and preserve lean muscle mass.
Steroidal mineralocorticoid receptor antagonists have traditionally been recommended for patients with resistant hypertension and/or heart failure; however, their use in patients with CKD is frequently complicated by hyperkalemia and AKI. Nonsteroidal MRAs (nsMRAs) have demonstrated the ability to reduce kidney disease progression and improve cardiovascular outcomes in patients with CKD, with a lower incidence of hyperkalemia compared with steroidal mineralocorticoid receptor antagonists.7 These agents have also shown benefits in patients with heart failure with preserved ejection fraction and should be used in patients with albuminuric CKD and type 2 diabetes. Furthermore, nsMRAs have demonstrated reductions in albuminuria in patients with type 1 diabetes mellitus, which provides an alternative to patients with concerns for diabetic ketoacidosis with SGLT2is. More recent data suggest the kidney protective effects of nsMRA among CKD patients without diabetes.8
Combination Therapies
Randomized control studies on the beneficial effects and safety profiles of combinations of newer medications in CKD are somewhat limited. However, significant albuminuria reduction has been shown in a dedicated combination therapy trial.9 Thus, therapies may be initiated simultaneously in appropriate patients or in a traditional, rapid sequence and accelerated risk-based approach for patients who might be at higher risk of side effects.10,11 Typically, starting two medications simultaneously in a high-risk patient, with potential to add a third in a short period, requires frequent monitoring for changes in serum creatinine and potassium levels as well as other side effects. Patient tolerability, treatment preferences, and affordability (insurance coverage, copay, etc.) should be carefully considered, and the nephrology community should work to identify and expand patient assistance and support programs that facilitate equitable access and adoption of these therapies.
Other Treatment Options
In addition to these therapies, lipid-lowering therapies should be used for primary and secondary treatment of atherosclerotic cardiovascular disease in patients with stages 3–5 (nondialysis) CKD. Nephrologists should also align with cardiologists to manage other common cardiovascular complications including atrial fibrillation, endocrinologists and dietitians for optimal glycemic control, and liver specialists if metabolic dysfunction–associated steatohepatitis is present. Given the complexity of the comorbid illnesses of patients with CKD, a multidisciplinary team–based approach is preferred when logistically feasible.
Special Considerations
Nephrologists are the main caregivers for patients with glomerulonephritis, patients on maintenance dialysis, and kidney transplant recipients. Kidney disease is also present among a wide spectrum of ages, from children to older adults, and those with frailty. Transplant and glomerulonephritis pose additional risks of immunosuppression-related side effects, infection risks, and interactions between multiple pharmacotherapies. The population on dialysis sustains a very high cardiovascular mortality, and evidence for treatment of CKM with novel therapies is limited in this population. However, given the urgency to treat cardiovascular risk, these agents should be considered with shared decision making after discussing risks/benefits. It is suggested, at a minimum, to proactively screen, diagnose, and manage CKM risk factors across the lifespan of all patients with kidney disease regardless of etiology or eGFR.
Conclusion
As the interconnected nature of cardiovascular, kidney, and metabolic diseases becomes increasingly clear, these risks must be addressed together. Nephrologists should use an interdisciplinary approach that includes early screening, lifestyle modification, and timely initiation of foundational and combination therapies, especially for high-risk patients. Managing CKD alone is not enough; care should also address heart failure, atherosclerotic cardiovascular disease, diabetes, and lipid disorders in a manner that leverages the expertise of relevant care teams. Broad adoption of the CKM care model has the potential to improve patient outcomes.
Supplementary Material
Acknowledgments
The following statement is specific to ASN KHG. The content of this article reflects the personal experience and views of the authors and should not be considered medical advice or recommendation. This ASN KHG is intended to reflect current practice and is intended as a resource and concise point of reference geared toward clinicians caring for people with kidney diseases. The guidance should not preclude clinical judgment and must be applied in the context of the specific patient, with adjustments for patient preferences, comorbidities, and other factors.
Footnotes
See related ASN Kidney Health Guidance, “ASN Kidney Health Guidance on the Cardiovascular-Kidney-Metabolic Syndrome,” on pages 2282–2305.
Disclosures
Disclosure forms, as provided by each author, are available with the online version of the article at https://links.lww.com/JSN/F980.
Author Contributions
Conceptualization: Amy K. Mottl, Sankar D. Navaneethan, Brian Rifkin.
Supervision: Sankar D. Navaneethan.
Writing – original draft: Amy K. Mottl, Sankar D. Navaneethan, Brian Rifkin.
Writing – review & editing: Amy K. Mottl, Sankar D. Navaneethan, Brian Rifkin.
Funding
None.
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