Immunometabolic Inflammation in the Cardiovascular-Kidney-Metabolic Continuum
Article Sidebar
Main Article Content
Abstract
Cardiovascular, kidney, and metabolic disorders are traditionally classified as separate diseases, yet their biological trajectories are tightly coupled. Adiposity, insulin resistance, dyslipidaemia, endothelial dysfunction, chronic kidney disease, and heart failure frequently coexist because they are sustained by shared immunometabolic disturbances rather than by isolated organ failure. This narrative review examines inflammation as an organizing mechanism within the cardiovascular-kidney-metabolic (CKM) continuum. It integrates evidence on adipose-tissue immune remodelling, NLRP3 inflammasome activation, endothelial injury, maladaptive myelopoiesis, clonal haematopoiesis, renal innate immunity, and disturbed resolution pathways. In metabolically stressed tissues, nutrient excess and cellular damage alter macrophage, neutrophil, lymphocyte, endothelial, and parenchymal-cell metabolism. These changes amplify interleukin-1, interleukin-6, tumour-necrosis-factor, reactive-oxygen-species, and extracellular-trap signalling, thereby linking insulin resistance to vascular inflammation, glomerular injury, myocardial fibrosis, and heart failure. The review also evaluates circulating inflammatory indices and emerging tissue-informed biomarkers, emphasizing that association does not automatically establish clinical utility. Sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists demonstrate that therapies developed for metabolic control can improve cardiorenal outcomes, but their anti-inflammatory actions remain only one component of multifactorial benefit. Direct cytokine or inflammasome inhibition is biologically attractive but must be balanced against infection risk, patient heterogeneity, and uncertainty regarding the optimal stage for intervention. A clinically useful CKM framework should therefore combine organ staging with mechanistic phenotyping, longitudinal biomarker validation, and equitable prevention. Understanding when inflammation is causal, compensatory, or merely reflective of tissue injury is essential for translating immunometabolism into precision treatment and advancing Sustainable Development Goal 3.
Article Details
References
1. Sebastian SA, Padda I, Johal G. Cardiovascular-Kidney-Metabolic (CKM) syndrome: A state-of-the-art review. Curr Probl Cardiol. 2024;49(2):102344. doi:10.1016/j.cpcardiol.2023.102344.
2. Gao C, Gao S, Zhao R, Shen P, Zhu X, Yang Y, et al. Association between systemic immune-inflammation index and cardiovascular-kidney-metabolic syndrome. Sci Rep. 2024;14(1):19151. doi:10.1038/s41598-024-69819-0.
3. Kittelson KS, Junior AG, Fillmore N, da Silva Gomes R. Cardiovascular-kidney-metabolic syndrome - An integrative review. Prog Cardiovasc Dis. 2024;87:26-36. doi:10.1016/j.pcad.2024.10.012.
4. Xu Z, Yang S, Tan Y, Zhang Q, Wang H, Tao J, et al. Inflammation in cardiovascular-kidney-metabolic syndrome: key roles and underlying mechanisms-a comprehensive review. Mol Cell Biochem. 2025;480(12):6039-6075. doi:10.1007/s11010-025-05379-9.
5. Carvalho LRRA, Shimari M, Boeder AM, Zhuge Z, Cai M, Leijding C, et al. A novel model of cardiovascular-kidney-metabolic syndrome combining unilateral nephrectomy and high-salt-sugar-fat diet in mice. Lab Anim (NY). 2024;53(11):336-346. doi:10.1038/s41684-024-01457-5.
6. Zhao C, Lin M, Yang Y, Yang H, Gao Z, Yan Z, et al. Association between dietary inflammatory index and cardiovascular-kidney-metabolic syndrome risk: a cross-sectional study. Nutr J. 2025;24(1):60. doi:10.1186/s12937-025-01127-3.
7. Kojta I, Chacińska M, Błachnio-Zabielska A. Obesity, Bioactive Lipids, and Adipose Tissue Inflammation in Insulin Resistance. Nutrients. 2020;12(5). doi:10.3390/nu12051305.
8. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219-46. doi:10.1146/annurev-physiol-021909-135846.
9. Dahik VD, Kc P, Materne C, Reydellet C, Lhomme M, Cruciani-Guglielmacci C, et al. ABCG1 orchestrates adipose tissue macrophage plasticity and insulin resistance in obesity by rewiring saturated fatty acid pools. Sci Transl Med. 2024;16(777):eadi6682. doi:10.1126/scitranslmed.adi6682.
10. Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. 2011;17(2):179-88. doi:10.1038/nm.2279.
11. Fuchs A, Samovski D, Smith GI, Cifarelli V, Farabi SS, Yoshino J, et al. Associations Among Adipose Tissue Immunology, Inflammation, Exosomes and Insulin Sensitivity in People With Obesity and Nonalcoholic Fatty Liver Disease. Gastroenterology. 2021;161(3):968-981.e12. doi:10.1053/j.gastro.2021.05.008.
12. Pellegrinelli V, Rodriguez-Cuenca S, Rouault C, Figueroa-Juarez E, Schilbert H, Virtue S, et al. Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance. Nat Metab. 2022;4(4):476-494. doi:10.1038/s42255-022-00561-5.
13. Wu Y, Wu C, Shi T, Cai Q, Wang T, Xiong Y, et al. FAP expression in adipose tissue macrophages promotes obesity and metabolic inflammation. Proc Natl Acad Sci U S A. 2023;120(51):e2303075120. doi:10.1073/pnas.2303075120.
14. Palmer AK, Xu M, Zhu Y, Pirtskhalava T, Weivoda MM, Hachfeld CM, et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell. 2019;18(3):e12950. doi:10.1111/acel.12950.
15. Kong P, Cui ZY, Huang XF, Zhang DD, Guo RJ, Han M. Inflammation and atherosclerosis: signaling pathways and therapeutic intervention. Signal Transduct Target Ther. 2022;7(1):131. doi:10.1038/s41392-022-00955-7.
16. Tang SCW, Yiu WH. Innate immunity in diabetic kidney disease. Nat Rev Nephrol. 2020;16(4):206-222. doi:10.1038/s41581-019-0234-4.
17. Bäck M, Yurdagul A, Tabas I, Öörni K, Kovanen PT. Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat Rev Cardiol. 2019;16(7):389-406. doi:10.1038/s41569-019-0169-2.
18. Ridker PM, Rane M. Interleukin-6 Signaling and Anti-Interleukin-6 Therapeutics in Cardiovascular Disease. Circ Res. 2021;128(11):1728-1746. doi:10.1161/CIRCRESAHA.121.319077.
19. Grebe A, Hoss F, Latz E. NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis. Circ Res. 2018;122(12):1722-1740. doi:10.1161/CIRCRESAHA.118.311362.
20. Fuster JJ, MacLauchlan S, Zuriaga MA, Polackal MN, Ostriker AC, Chakraborty R, et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science. 2017;355(6327):842-847. doi:10.1126/science.aag1381.
21. Gupta A, Singh K, Fatima S, Ambreen S, Zimmermann S, Younis R, et al. Neutrophil Extracellular Traps Promote NLRP3 Inflammasome Activation and Glomerular Endothelial Dysfunction in Diabetic Kidney Disease. Nutrients. 2022;14(14). doi:10.3390/nu14142965.
22. Wang Y, You YK, Guo J, Wang J, Shao B, Li H, et al. C-reactive protein promotes diabetic kidney disease via Smad3-mediated NLRP3 inflammasome activation. Mol Ther. 2025;33(1):263-278. doi:10.1016/j.ymthe.2024.11.018.
23. Wang X, Liu X, Wu W, Liao L, Zhou M, Wang X, et al. Hypoxia activates macrophage-NLRP3 inflammasome promoting atherosclerosis via PFKFB3-driven glycolysis. FASEB J. 2024;38(15):e23854. doi:10.1096/fj.202400283R.
24. Yalcinkaya M, Liu W, Thomas LA, Olszewska M, Xiao T, Abramowicz S, et al. BRCC3-Mediated NLRP3 Deubiquitylation Promotes Inflammasome Activation and Atherosclerosis in Tet2 Clonal Hematopoiesis. Circulation. 2023;148(22):1764-1777. doi:10.1161/CIRCULATIONAHA.123.065344.
25. Libby P, Buring JE, Badimon L, Hansson GK, Deanfield J, Bittencourt MS, et al. Atherosclerosis. Nat Rev Dis Primers. 2019;5(1):56. doi:10.1038/s41572-019-0106-z.
26. Libby P. The changing landscape of atherosclerosis. Nature. 2021;592(7855):524-533. doi:10.1038/s41586-021-03392-8.
27. Speer T, Dimmeler S, Schunk SJ, Fliser D, Ridker PM. Targeting innate immunity-driven inflammation in CKD and cardiovascular disease. Nat Rev Nephrol. 2022;18(12):762-778. doi:10.1038/s41581-022-00621-9.
28. Pasupuleti SK, Ramdas B, Burns SS, Palam LR, Kanumuri R, Kumar R, et al. Obesity-induced inflammation exacerbates clonal hematopoiesis. J Clin Invest. 2023;133(11). doi:10.1172/JCI163968.
29. Wu Q, Yao Q, Hu T, Yu J, Jiang K, Wan Y, et al. Dapagliflozin protects against chronic heart failure in mice by inhibiting macrophage-mediated inflammation, independent of SGLT2. Cell Rep Med. 2023;4(12):101334. doi:10.1016/j.xcrm.2023.101334.
30. Preda A, Montecucco F, Carbone F, Camici GG, Lüscher TF, Kraler S, et al. SGLT2 inhibitors: from glucose-lowering to cardiovascular benefits. Cardiovasc Res. 2024;120(5):443-460. doi:10.1093/cvr/cvae047.
31. Girardi ACC, Polidoro JZ, Castro PC, Pio-Abreu A, Noronha IL, Drager LF. Mechanisms of heart failure and chronic kidney disease protection by SGLT2 inhibitors in nondiabetic conditions. Am J Physiol Cell Physiol. 2024;327(3):C525-C544. doi:10.1152/ajpcell.00143.2024.
32. Cowie MR, Fisher M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol. 2020;17(12):761-772. doi:10.1038/s41569-020-0406-8.
33. Rayego-Mateos S, Rodrigues-Diez RR, Fernandez-Fernandez B, Mora-Fernández C, Marchant V, Donate-Correa J, et al. Targeting inflammation to treat diabetic kidney disease: the road to 2030. Kidney Int. 2023;103(2):282-296. doi:10.1016/j.kint.2022.10.030.
34. Sandsdal RM, Juhl CR, Jensen SBK, Lundgren JR, Janus C, Blond MB, et al. Combination of exercise and GLP-1 receptor agonist treatment reduces severity of metabolic syndrome, abdominal obesity, and inflammation: a randomized controlled trial. Cardiovasc Diabetol. 2023;22(1):41. doi:10.1186/s12933-023-01765-z.
35. Ussher JR, Drucker DJ. Glucagon-like peptide 1 receptor agonists: cardiovascular benefits and mechanisms of action. Nat Rev Cardiol. 2023;20(7):463-474. doi:10.1038/s41569-023-00849-3.
36. Mehdi SF, Pusapati S, Anwar MS, Lohana D, Kumar P, Nandula SA, et al. Glucagon-like peptide-1: a multi-faceted anti-inflammatory agent. Front Immunol. 2023;14:1148209. doi:10.3389/fimmu.2023.1148209.
37. Ndumele CE, Rangaswami J, Chow SL, Neeland IJ, Tuttle KR, Khan SS, et al. Cardiovascular-kidney-metabolic health: a presidential advisory from the American Heart Association. Circulation. 2023;148(20):1606-1635. doi:10.1161/CIR.0000000000001184.
38. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119-1131. doi:10.1056/NEJMoa1707914.
39. Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019;381(26):2497-2505. doi:10.1056/NEJMoa1912388.
40. Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ, et al. Colchicine in patients with chronic coronary disease. N Engl J Med. 2020;383(19):1838-1847. doi:10.1056/NEJMoa2021372.