From cardiorenal to cardiovascular–kidney–metabolic syndromes

Connections between the heart and the kidneys were repeatedly mentioned in ancient times, including the Egyptian ‘Book of the Dead’ and the Old Testament.1 They were brought into focus in 1836 by Richard Bright, an English pathologist who described cardiac enlargement in patients with advanced renal diseases who might have been hypertensive.2 This finding was confirmed repeatedly, and in 1913, Thomas Lewis, another Englishman, was the first to use the term ‘cardiorenal patients.’3 By the mid-20th century when both cardiovascular and renal functions were measurable, it was noted that some patients with heart failure (HF) had impaired estimated renal glomerular filtration rates (eGFR). While the mechanisms responsible for this renal dysfunction were hotly debated, it now appears that elevated renal venous pressure plays a dominant role, while impaired renal perfusion in patients with a reduced cardiac output may also be involved, but of lesser importance. In 1998, the US National Kidney Foundation published a detailed monograph on this subject that emphasized three points: (i) an inverse association exists between eGFR and adverse cardiac events; (ii) patients with chronic kidney disease (CKD) are at high risk of developing atherosclerotic cardiovascular disease (ATCVD), and/or HF; and (iii) evaluation of patients with or at risk of cardiovascular disease (CVD) should include measurements of eGFR and of the urine albumin/creatinine ratio.4 In an effort to explore further this bidirectional interplay between the two organ systems, the National Heart, Lung and Blood Institute established a ‘Working Group on Cardiorenal Connections’ and the American Heart Association (AHA) a ‘Council on the Kidney in Cardiovascular Disease.’ In 2004, the combination of the disorders was termed the ‘cardiorenal syndrome’ (CRS) by Heywood,5 who defined it as a ‘moderate or greater renal dysfunction that exists or develops in patients with HF.’ Ronco et al.6 subdivided CRS into five subgroups, identifying the precipitating organ (heart or kidney) and the temporal pattern (acute or chronic) (Table 1). Treatment of CRS consists of the guideline-directed management of HF and is discussed below.7 Subdivisions of cardiorenal diseasea aDerived from Ronco et al.6 Subdivisions of cardiorenal diseasea aDerived from Ronco et al.6 Contemporary research on CRS includes the identification of novel markers of early renal injury; the use of plasma proenkephalin concentration in predicting acute kidney injury in patients with acute coronary syndrome8; the detection of novel circulating proteins as mediators of HF in patients with CKD; the development of renal assist devices for the management of acute CRS; and the development of a new animal model in which HF was created by coronary artery ligation in spontaneously hypertensive rats. Overall, the breadth and complexity of CRS requires the knowledge and skills of both nephrology and cardiology, hence the need for nephrocardiologists (or cardionephrologists).9 It is well established that patients with CRS are more likely to die of a cardiac event than from kidney failure, and the severity of CRS is influenced by the presence of additional underlying conditions. The most frequent of these, type 2 diabetes (T2D), which assumed pandemic proportions in the last quarter of the 20th century, greatly increased the risk of the development and severity of cardiac and renal disorders as well as of their combination in CRS.10,11 Other common risk factors that occur in both CVD and CKD include visceral obesity, which has also become pandemic,12 the metabolic syndrome, dyslipidaemias, hypertension, and prothrombotic phenotypes. These metabolic disorders (MetS) can cause oxidative stress, endothelial dysfunction, inflammation, arterial plaques, and thrombosis. Given the importance of these MetS, in 2023, the AHA expanded CV and kidney risk factors into a new group of syndromes, the cardiovascular–kidney–metabolic (CKM) syndromes. These interrelated syndromes have been defined as ‘systemic disorders characterized by pathophysiologic interactions among MetS, CKD and CVD leading to multiorgan dysfunction and a high rate of adverse CV outcomes’13; the latter include both ATCVD and HF. Cardiovascular–kidney–metabolic syndrome has been divided into five stages, which progressively increase the risk of developing or worsening CVD (Table 2). In addition, adverse social determinants of health are also important risk factors for CKM.13 Approximately 90% of US adults are in Stages 1 to 4.14 While individuals in Stages 1 and 2 are asymptomatic, 15% of US adults meet criteria for the advanced stages, i.e. 3 and 4. Cardiovascular–kidney–metabolic disorders are responsible for more than a million annual deaths in the USA (29% of the total). The principal goal of CKM assessment is to reduce adverse CV events and multiorgan dysfunction, improve the quality of life, and ultimately prevent premature mortality of both individuals and populations. Since CKM crosses several subspecialties, a secondary goal is to unify several clinical practice guidelines. Stages of cardiac–kidney–metabolic syndromea CVD, cardiovascular disease; CKD, chronic kidney disease; MetS, metabolic disorders. aDerived from Ndumele et al.13 Stages of cardiac–kidney–metabolic syndromea CVD, cardiovascular disease; CKD, chronic kidney disease; MetS, metabolic disorders. aDerived from Ndumele et al.13 The AHA has also developed and validated equations for ‘Predicting Risk of CVD Events (PREVENT).’15 These equations are based on data derived from 6.6 million US adults, 30–79 years of age, who were followed for an average of 4.8 years. These equations were based on traditional risk factors that are routinely available, which include age, sex, body mass index, cholesterol, T2D, smoking status, eGFR, urinary albumin/creatinine ratio, and treatment with antihypertensive and/or cholesterol-lowering medications. The outcomes of the PREVENT equations are total CVD and all-cause mortality at both 10 and 30 years after baseline measurements, with a median C statistic of 7.85. Screening for CKM should begin in childhood to identify obesity and should be carried out on a regular basis in adults in whom it should include measurement of systolic blood pressure, lipids, glucose, creatinine, and urinary albumin/creatinine ratio. The goal for individuals in Stage 0 is to follow the guidelines for primordial prevention.16 During the last decade, three new drug classes that improve clinical outcomes in both CRS and CKM have become available. Sodium–glucose cotransporter 2 inhibitors (SGLT2i),17 introduced as glucosuric agents for the treatment of T2D, were found, unexpectedly, to be both effective in the management of HF across ejection fraction classes and CKD.18 These agents are currently administered to patients with one, two, or all three components of CKM. Incretin hormones, including the glucagon-like peptide 1 (GLP-1) receptor agonists, like SGLT2i, were introduced as antidiabetic agents, but lower blood glucose concentration by a different mechanism, i.e. stimulating the secretion of insulin and reducing the secretion of glucagon. They also act on the brain to reduce appetite and slow gastric emptying, thereby lowering body weight, properties which have made these agents very popular. Semaglutide, a GLP-1 agonist with anti-inflammatory and antifibrotic properties, also improves outcomes in patients with HF with preserved ejection fraction19 and slows the progression of CKD.20 GIP, a glucose-dependent insulinotropic polypeptide receptor agonist, also increases insulin secretion and sensitivity. Dual GLP-1/GIP receptor agonists are more potent than GLP-1 alone. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist can also reduce the risk of progressive CKD in patients with T2D, as well as in patients with HF and mildly reduced or preserved ejection fraction.21 In a prespecified pooled analysis of almost 19 000 patients enrolled in three placebo-controlled trials, finerenone significantly reduced all-cause mortality, HF hospitalization, and adverse kidney outcomes.22 All three of these relatively new drug classes have been approved by regulatory bodies and are well tolerated with few side effects, many of which can be controlled by dose adjustments. They are potent additions to the therapeutic armamentarium for large segments of the population who may require prolonged, perhaps lifetime, administration. Fortunately, since their mechanisms of action differ, they can be administered together and appear to have additive effects. The combination of the blockers of the renin–angiotensin system and these three new drug classes has been referred to as the ‘four pillars of treatment for cardiorenal protection.’7 What began in ancient times as hints of connections between the heart and kidneys1 has evolved into CRS and CKM, two common and related syndromes. While both can be recognized and often treated, much more must be learned about these syndromes and their prevention is now an important goal. The author reports grant support through his institution from AstraZeneca, Daiichi Sankyo, Merck, and Novartis and consulting fees from Bristol Myers Squibb, Boehringer Ingelheim/Lilly, Cardurion, Edgewise, and Verve.