Combination of Cardiovascular, Kidney, and Metabolic Diseases in a Syndrome Named Cardiovascular-Kidney-Metabolic, With New Risk Prediction Equations

Abstract

Associations of chronic kidney disease (CKD) with metabolic syndrome and cardiovascular disease (CVD) have long been recognized. Until recently, such associations were mainly limited to interrelationships between either heart and kidney, heart and metabolic syndrome, or metabolic syndrome and kidney. It is the merit of the American Heart Association (AHA) to have set up a work group of cardiologists, endocrinologists, and nephrologists for the purpose of combining all 3 disorders in a single entity, as an appreciation of their pathophysiological interrelatedness. To this end, they proposed the term cardiovascular-kidney-metabolic (CKM) syndrome, which reflects multidirectional relationships among metabolic risk factors, CKD, and the cardiovascular system. Following a consensus approach in defining CKM with 5 stages, the work group subsequently developed new risk prediction equations, named predicting risk of CVD events (PREVENT) equations, which included estimated glomerular filtration rate (eGFR) and albuminuria as variables in addition to traditional cardiovascular and metabolic factors. Despite several limitations, this development is a major step forward in cardiovascular risk prediction. Its clinical application should translate into earlier, more appropriate treatment and prevention of CKM syndrome. Associations of chronic kidney disease (CKD) with metabolic syndrome and cardiovascular disease (CVD) have long been recognized. Until recently, such associations were mainly limited to interrelationships between either heart and kidney, heart and metabolic syndrome, or metabolic syndrome and kidney. It is the merit of the American Heart Association (AHA) to have set up a work group of cardiologists, endocrinologists, and nephrologists for the purpose of combining all 3 disorders in a single entity, as an appreciation of their pathophysiological interrelatedness. To this end, they proposed the term cardiovascular-kidney-metabolic (CKM) syndrome, which reflects multidirectional relationships among metabolic risk factors, CKD, and the cardiovascular system. Following a consensus approach in defining CKM with 5 stages, the work group subsequently developed new risk prediction equations, named predicting risk of CVD events (PREVENT) equations, which included estimated glomerular filtration rate (eGFR) and albuminuria as variables in addition to traditional cardiovascular and metabolic factors. Despite several limitations, this development is a major step forward in cardiovascular risk prediction. Its clinical application should translate into earlier, more appropriate treatment and prevention of CKM syndrome. It has long been known that CKD is frequently observed in association with metabolic syndrome, CVD, or both. Determining the directionality of the relationship is sometimes easy. As an example, in patients with primary forms of chronic glomerulonephritis, CVD is most often secondary to kidney disease. On the contrary, in patients with metabolic syndrome, diabetes, or CVD, the development of kidney disease is most often a secondary event. However, in many instances the sequence of events is more difficult, if not impossible to establish. In any case, one would always like to know which came first, the egg or the chicken. The answer to this question is of importance not only from a theoretical, pathophysiological point of view, but also from a practical, clinical point of view. Better knowledge can lead to improved individualized disease management. The interrelationship between heart and kidney disease has been named "cardiorenal syndrome." The creation of this term dates back to 2009 when it was first officially defined at a consensus conference of the Acute Dialysis Quality Initiative.1Ronco C. McCullough P.A. Anker S.D. et al.Cardiorenal syndromes: an executive summary from the consensus conference of the Acute Dialysis Quality Initiative (ADQI).Contrib Nephrol. 2010; 165: 54-67https://doi.org/10.1159/000313745Crossref PubMed Scopus (95) Google Scholar The authors' aim was to characterize and classify the various interrelationships between acute and chronic heart and kidney diseases. The consensus conference defined 5 forms of heart-kidney interaction; including type 1, in which acute heart failure is directly associated with acute kidney injury; type 2, in which chronic heart failure is associated with CKD; type 3, in which acute kidney injury is associated with acute heart failure; type 4, in which the driving factor of CKD is associated with chronic heart failure; and type 5, in which there is concomitant development of both kidney and heart failure. Cardiorenal syndrome has been more recently defined in a simplified way by the North American National Heart, Lung, and Blood Institute, as a result of interactions between the kidneys and other circulatory compartments that increase circulating volume, which exacerbates the symptoms of heart failure and disease progression, encompassing a variety of disorders involving both the heart and kidneys, whereby acute or chronic dysfunction of 1 organ may induce acute or chronic dysfunction in the other organ.2Rangaswami J. Bhalla V. Blair J.E.A. et al.Cardiorenal syndrome: classification, pathophysiology, diagnosis, and treatment strategies: a scientific statement from the American Heart Association.Circulation. 2019; 139: e840-e878https://doi.org/10.1161/CIR.0000000000000664Crossref PubMed Scopus (651) Google Scholar Although the term cardiorenal syndrome has been widely adopted, it is interesting to note that its current classification and even the appropriateness of the term itself have recently been challenged by Zoccali et al.3Zoccali C. Mallamaci F. Halimi J.M. et al.From cardiorenal syndrome to chronic cardiovascular and kidney disorder: a conceptual transition.Clin J Am Soc Nephrol. 2024; 19: 813-820https://doi.org/10.2215/CJN.0000000000000361Crossref Scopus (3) Google Scholar The authors posit that the term "disorder" is more appropriate than the term "syndrome" to describe concomitant cardiovascular and kidney dysfunction and/or damage. Whatever the optimal term to be used, the authors agreed with the appropriateness of this conceptual framework because it builds upon the fact that CVD and CKD share common risk factors and underlying pathophysiologic mechanisms. An interrelationship between metabolic syndrome and kidney disease has been known for at least 20 years.4Chen J. Muntner P. Hamm L.L. et al.The metabolic syndrome and chronic kidney disease in U.S. adults.Ann Intern Med. 2004; 140: 167-174https://doi.org/10.7326/0003-4819-140-3-200402030-00007Crossref PubMed Scopus (1180) Google Scholar, 5Kurella M. Lo J.C. Chertow G.M. Metabolic syndrome and the risk for chronic kidney disease among nondiabetic adults.J Am Soc Nephrol. 2005; 16: 2134-2140https://doi.org/10.1681/ASN.2005010106Crossref PubMed Scopus (595) Google Scholar, 6Bonnet F. Marre M. Halimi J.M. et al.Waist circumference and the metabolic syndrome predict the development of elevated albuminuria in non-diabetic subjects: the DESIR Study.J Hypertens. 2006; 24: 1157-1163https://doi.org/10.1097/01.hjh.0000226206.03560.acCrossref PubMed Scopus (96) Google Scholar In a cross-sectional study of the Third National Health and Nutrition Examination Survey in the US, Chen et al.4Chen J. Muntner P. Hamm L.L. et al.The metabolic syndrome and chronic kidney disease in U.S. adults.Ann Intern Med. 2004; 140: 167-174https://doi.org/10.7326/0003-4819-140-3-200402030-00007Crossref PubMed Scopus (1180) Google Scholar included adult participants in CKD (n = 6217) and microalbuminuria (n = 6125) analyses. Compared with participants without metabolic syndrome, those with the syndrome had multivariate-adjusted odds ratios of CKD and microalbuminuria of 2.60 (95% confidence interval: 1.68–4.03) and 1.89 (95% confidence interval: 1.34–2.67), respectively. In 10,096 nondiabetic individuals with normal baseline kidney function who participated at the Atherosclerosis Risk in Communities study in the US, Kurella et al.5Kurella M. Lo J.C. Chertow G.M. Metabolic syndrome and the risk for chronic kidney disease among nondiabetic adults.J Am Soc Nephrol. 2005; 16: 2134-2140https://doi.org/10.1681/ASN.2005010106Crossref PubMed Scopus (595) Google Scholar reported a multivariable-adjusted odds ratio of developing CKD of 1.43 in participants with metabolic syndrome, compared with participants having no traits of metabolic syndrome. Bonnet et al.6Bonnet F. Marre M. Halimi J.M. et al.Waist circumference and the metabolic syndrome predict the development of elevated albuminuria in non-diabetic subjects: the DESIR Study.J Hypertens. 2006; 24: 1157-1163https://doi.org/10.1097/01.hjh.0000226206.03560.acCrossref PubMed Scopus (96) Google Scholar studied 2738 subjects from the Epidemiological Study on the Insulin Resistance Syndrome cohort without microalbuminuria or diabetes at baseline. At 6 years of follow-up, they found that 254 individuals (9.3%) had developed albuminuria ≥ 20 mg/l, which was significantly and positively associated with waist circumference (reflecting abdominal adiposity) and blood pressure, although not with fasting glucose, lipids or body mass index (BMI) in either sex.6Bonnet F. Marre M. Halimi J.M. et al.Waist circumference and the metabolic syndrome predict the development of elevated albuminuria in non-diabetic subjects: the DESIR Study.J Hypertens. 2006; 24: 1157-1163https://doi.org/10.1097/01.hjh.0000226206.03560.acCrossref PubMed Scopus (96) Google Scholar Given the steadily increasing rate of overweight, obesity, and type 2 diabetes worldwide, although with marked discrepancies between geographical regions, the coexistence of these conditions with heart failure and CKD is striking.7Al-Chalabi S. Syed A.A. Kalra P.A. Sinha S. Mechanistic links between central obesity and cardiorenal metabolic diseases.Cardiorenal Med. 2024; 14: 12-22https://doi.org/10.1159/000535772Crossref Scopus (0) Google Scholar It clearly needs special attention and multidisciplinary approaches. In this vein, as an extension beyond the cardiorenal and metabolic-renal connections, the American Heart Association (AHA) has recently proposed a broader concept in the form of a unifying syndrome. On behalf of the AHA, Ndumele et al.8Ndumele C.E. Neeland I.J. Tuttle K.R. et al.A synopsis of the evidence for the science and clinical management of cardiovascular-kidney-metabolic (CKM) syndrome: a scientific statement from the American Heart Association.Circulation. 2023; 148: 1636-1664https://doi.org/10.1161/CIR.0000000000001186Crossref PubMed Scopus (28) Google Scholar named this entity CKM syndrome, as an appreciation of the pathophysiological interrelatedness of the following: (i) metabolic risk factors such as obesity and diabetes, (ii) CKD, and (iii) CVD. In Figure 1, we show a conceptual diagram for CKM syndrome with its pathophysiological consequences reflecting multidirectional relationships among metabolic risk factors, CKD, and the cardiovascular system. The reason for creating the new term is that CKM syndrome proposes an integrated staging system. The staging encompasses individuals at risk for CVD due to the presence of metabolic risk factors, hypertension, diabetes, or CKD, or a combination of these; as well as individuals with existing CVD that is potentially related to or complicates metabolic risk factors or CKD.9Sebastian S.A. Padda I. Johal G. Cardiovascular-kidney-metabolic (CKM) syndrome: a state-of-the-art review.Curr Probl Cardiol. 2024; 49102344https://doi.org/10.1016/j.cpcardiol.2023.102344Crossref Scopus (3) Google Scholar Individuals who do not present CKM health risk factors are classified as stage 0. Those with excess and/or dysfunctional adiposity are classified as stage 1, those with metabolic risk factors and CKD as stage 2, those with subclinical CVD in CKM as stage 3, and those with clinical CVD in CKM as stage 4. The complete definitions of CKM health stages 0 through 4 are outlined in Table 1.Table 1Definitions of CKM health stagesCKM health stagesDefinitionStage 0: No CKM health risk factorsIndividuals without overweight/obesity, metabolic risk factors (hypertension, hypertriglyceridemia, MetSaMetS is defined by the presence of 3 or more of the following: (i) waist circumference ≥ 88 cm for women and ≥102 cm for men (≥80 cm for women and ≥90 cm for men if of Asian ancestry); (ii) HDL cholesterol < 40 mg/dl for men and <50 mg/dl for women; (iii) triglycerides ≥ 150 mg/dl; (4) elevated blood pressure (systolic blood pressure ≥ 130 mm Hg or diastolic blood pressure ≥ 80 mm Hg and/or use of antihypertensive medications); and (5) fasting blood ≥ CKD, or and/or dysfunctional with overweight/obesity, abdominal obesity, or dysfunctional without the presence of other metabolic risk factors or ≥ if Asian circumference cm in if Asian cm in blood mg/dl or between and with diabetes should for Metabolic risk factors and with metabolic risk factors hypertension, or CVD in or subclinical among individuals with other metabolic risk factors, or to be by by also by elevated ≥ ≥ for women and for for women and for or by with combination of subclinical CKD or CKD or risk CVD CVD in CVD heart heart among individuals with other metabolic risk factors, or no kidney kidney failure cardiovascular body mass CKD, chronic kidney CVD, cardiovascular heart failure; metabolic and is defined by the presence of 3 or more of the following: (i) waist circumference ≥ 88 cm for women and ≥102 cm for men (≥80 cm for women and ≥90 cm for men if of Asian ancestry); (ii) HDL cholesterol < 40 mg/dl for men and <50 mg/dl for women; (iii) triglycerides ≥ 150 mg/dl; (4) elevated blood pressure (systolic blood pressure ≥ 130 mm Hg or diastolic blood pressure ≥ 80 mm Hg and/or use of antihypertensive medications); and (5) fasting blood ≥ Individuals with diabetes should for in a new cardiovascular body mass CKD, chronic kidney CVD, cardiovascular heart failure; metabolic and The underlying a variety of S.A. Padda I. Johal G. Cardiovascular-kidney-metabolic (CKM) syndrome: a state-of-the-art review.Curr Probl Cardiol. 2024; 49102344https://doi.org/10.1016/j.cpcardiol.2023.102344Crossref Scopus (3) Google Scholar factors of the of and dysfunction with chronic and potentially to Ndumele et al.8Ndumele C.E. Neeland I.J. Tuttle K.R. et al.A synopsis of the evidence for the science and clinical management of cardiovascular-kidney-metabolic (CKM) syndrome: a scientific statement from the American Heart Association.Circulation. 2023; 148: 1636-1664https://doi.org/10.1161/CIR.0000000000001186Crossref PubMed Scopus (28) Google Scholar CKM syndrome most from excess or dysfunctional or with an of and in to and of the cardiovascular and the kidney, and can also and organ in heart and kidney, and and Neeland I.J. and cardiovascular an PubMed Scopus Google Scholar, I.J. et and and a 2019; PubMed Scopus Google Scholar, C. et and blood pressure and the heart PubMed Scopus Google Scholar, C. et integrated of and in kidney PubMed Scopus Google Scholar In Table 2, we show a of factors for CKM C.E. J. et a from the American Heart Association.Circulation. 2023; 148: PubMed Scopus Google Scholar an of factors for CKM conditions Asian of health disorders and disorders risk diabetes in stage of < 40 of disorders of for mg/l, if of kidney failure; of of with from in a new of with from The pathophysiological consequences of these are including of as well as and kidney dysfunction and these the development of and kidney disease. can be classified as and knowledge the of disease the of clinical the of various health and risk factors, as well as the of disease in the of as by Ndumele et al.8Ndumele C.E. Neeland I.J. Tuttle K.R. et al.A synopsis of the evidence for the science and clinical management of cardiovascular-kidney-metabolic (CKM) syndrome: a scientific statement from the American Heart Association.Circulation. 2023; 148: 1636-1664https://doi.org/10.1161/CIR.0000000000001186Crossref PubMed Scopus (28) Google Scholar The authors that CKM syndrome and related are also by and which are to by appropriate in and Although to that the term CKM would be to that of CKM syndrome, in with the term cardiorenal C. Mallamaci F. Halimi J.M. et al.From cardiorenal syndrome to chronic cardiovascular and kidney disorder: a conceptual transition.Clin J Am Soc Nephrol. 2024; 19: 813-820https://doi.org/10.2215/CJN.0000000000000361Crossref Scopus (3) Google Scholar the concept of this new entity should to be for both clinical management and the the in CKM syndrome of the 2 major of kidney glomerular filtration rate and is an to a mainly of by into CKD with its increase in cardiovascular in heart and as major risk is an addition to the risk by CVD in the C. Mallamaci F. M. et in chronic kidney a from the and of the 2023; PubMed Scopus Google Scholar It is that in patients with kidney a of risk factors to the of cardiovascular and including and of a of and a variety of C. Mallamaci F. M. et in chronic kidney a from the and of the 2023; PubMed Scopus Google Scholar, Atherosclerosis in from the Nephrol. 2010; PubMed Scopus Google Scholar, et kidney disease and cardiovascular and PubMed Scopus Google Scholar It has been known for that increasing CKD with a increase in the of cardiovascular et Chertow G.M. C.E. kidney disease and the of cardiovascular and J Med. 2004; PubMed Scopus Google Scholar 20 years that patients with an of to stage had a increase in of cardiovascular events as compared to an ≥ stages and a increase at < stage In Figure 2, we the increase by kidney and a increase in and In with the study by et Chertow G.M. C.E. kidney disease and the of cardiovascular and J Med. 2004; PubMed Scopus Google Scholar a in more than individuals from and this in that was associated with of including risk of kidney failure kidney cardiovascular acute kidney any heart heart and J. et for the CKD glomerular filtration and an 2023; Scopus Google Scholar albuminuria in the of CKM is as In the a on more than individuals from that more ratio was associated with of all J. et for the CKD glomerular filtration and an 2023; Scopus Google Scholar The increase of all these with of both and albuminuria has found an in the for the and of CKD for the and of 2024; PubMed Scopus Google Scholar as in Figure risk and prevention more or on to disease such as CVD, diabetes, hypertension, metabolic syndrome, or kidney disease. and most been by or are without an In the US, the most of for Risk and were in the years to on cohort The were to the management of blood et for the and management of blood pressure in executive a of the American of Heart Association On PubMed Scopus Google Scholar the management of et on the management of blood executive a of the American of Heart Association on 2019; 139: PubMed Scopus Google Scholar the primary prevention of et on the primary prevention of cardiovascular executive a of American of Heart Association on 2019; in in PubMed Scopus Google Scholar and the management of heart P.A. et for the management of heart executive a of the American of Heart Association on clinical PubMed Scopus Google Scholar The American Association of the use of cohort for the of CVD risk among individuals with G. et cardiovascular disease and risk of in 2023; PubMed Scopus Google Scholar The American Association of developed for the management of patients with diabetes in of on to with clinical of health P. et association of clinical consensus type 2 diabetes management 2023; in in 2023; PubMed Scopus Google Scholar for the of patients with obesity were developed by the American Association of of and the American of of in et of the obesity clinical American association of clinical and of clinical for of patients with PubMed Scopus Google Scholar of heart failure risk were developed to predict risk of heart failure in the 2 from the Atherosclerosis Risk in Communities study clinical or with or without the both et of heart failure in the Atherosclerosis Risk in Communities Heart PubMed Scopus Google Scholar The of on CVD prevention and CKD as and CVD risk on traditional cardiovascular risk factors, that diabetes, hypertension, and it developed risk 2 and risk 2 in to predict CVD It included or albuminuria in its The authors subsequently developed and an to CKD and into these a The with CKD improved CVD risk prediction beyond risk 2 and risk 2 in S. et of chronic kidney disease to cardiovascular risk prediction by and J Cardiol. 2023; Scopus Google Scholar As as CKD is and have been The most clinical for the and management of CKD has been by the CKD in CKD for the and of 2024; PubMed Scopus Google Scholar The work group developed an from the on CKD, associations between CKD staging by and with for common in multivariable-adjusted and treatment and on of Following its consensus approach in defining CKM with its 5 stages, the to new risk prediction equations, including and albuminuria as variables in addition to traditional cardiovascular and metabolic development was because of in the of risk factors such as use and in in such as a more use of antihypertensive and the risk of CVD with cohort J. et prediction for risk of cardiovascular disease cardiovascular-kidney-metabolic a scientific statement from the American Heart Association.Circulation. 2023; 148: PubMed Scopus Google Scholar Although risk of both CVD and heart failure with from CKM stage 0 to stage 3 more optimal for risk and primary prevention had to be set all the more because a of have for all 3 CKM in et et and of the American Heart 2024; in PubMed Scopus Google Scholar developed and and risk equations, named equations, among to who are without known CVD. The development was on a of from with 3 participants and by an in 3 participants from were included if they were and had on the 5 risk factors of blood pressure, and on the the CVD risk of and respectively. as a risk and for risk of other CKM factors such as and of The in for CVD were and and the and in and respectively. but in was observed when and index were in was observed when was to the among those with marked In Figure 4, we show the estimated risk of CVD, CVD, and heart failure by and The development of the is a major step et et and of the American Heart 2024; in PubMed Scopus Google Scholar several of the risk prediction to and including by and the authors which may have of and of and for they with clinical of blood pressure, and HDL or However, they that secondary risk associations between risk factors and CVD and the long baseline of the included more than 3 have to in risk factor and treatment However, secondary to the of in directionality and of ratios between and from one to the the authors for development as the have to the this they that they the risk of CVD risk factor at baseline and for risk of to any risk of health were not in all of such among and may lead to improved risk prediction. a variety of of were not included in the As and as of as a of and as a of disease were The for this were their in present for primary and limited in clinical of was for CVD and its in the development of that an may 1 or more of these the risk for is than the of its It may be in to risk factors. In addition to the by et et and of the American Heart 2024; in PubMed Scopus Google Scholar the have other which from in the Although the present a they are only for individuals to years in the to be for and North recently, an study the and of CKM syndrome stages, but it was from the the National Health and Nutrition Examination Survey et M. of cardiovascular-kidney-metabolic syndrome stages in 2024; Scopus (0) Google Scholar found that of the for CKM syndrome 1 or and for stages, of which improved between and the of in to concomitant and of risk factors The use of as the obesity is as not the importance of obesity have as an in disease The index has a potentially in the of The of index is on waist and It with of it individuals with normal body but like with obesity, present with a of cardiovascular risk factors including and J. and adiposity index are for the PubMed Scopus Google Scholar study that index were associated with an risk of heart and diastolic C. S. et adiposity index and the risk of heart and function in J Cardiol. 2023; Scopus (4) Google Scholar other variables be in of reflecting more either CVD, metabolic syndrome, or CKD, and reflecting 2 or all 3 of variables diastolic blood pressure, and and of and and C. Mallamaci F. M. et in chronic kidney a from the and of the 2023; PubMed Scopus Google Scholar a more point of view, in the it may be more appropriate to use the term of the term to describe the interrelationship between and kidney in to the for the proposed of the term "cardiorenal C. Mallamaci F. Halimi J.M. et al.From cardiorenal syndrome to chronic cardiovascular and kidney disorder: a conceptual transition.Clin J Am Soc Nephrol. 2024; 19: 813-820https://doi.org/10.2215/CJN.0000000000000361Crossref Scopus (3) Google Scholar The of CKD is often in the of the disease. The new CKM staging if should lead to of CKD in individuals at risk for hypertension, CVD, metabolic syndrome, and diabetes because it both and as as at stage individuals at that stage are by the presence of obesity or dysfunctional without evidence for of CKD should earlier, more of disease progression, and result in improved and health It also lead to an treatment of patients with new that kidney, and metabolic disorders such as 2 and The development of CKM syndrome with its integrated of health stages is a extension from defined of the between and kidney diseases. The subsequently developed may a application for primary prevention in with CKM syndrome. are on and such as CKD, obesity, and Despite the outlined the development of is a major step at for a of the It to be to which the and risk of translate into earlier, more appropriate treatment and prevention of CKM factors in clinical at to may be more

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