A New Clinical Entity Bridging the Cardiovascular System and the Kidney: The Chronic Cardiovascular-Kidney Disorder

The complex relationship between heart and kidney dysfunction has been a subject of medical inquiry since the 19th century by Bright [1], who noted that “In several cases of dropsy, connected with coagulable urine, I have found the heart much enlarged, and the left ventricle particularly thickened. This state of the heart has been so frequently noticed in connection with the disease of the kidney that I cannot but regard it as one of the results of that disease.” Early observations emphasized that diseases affecting one organ often had repercussions on the other, leading to a complex interplay that has intrigued researchers and clinicians alike. A definition of “cardio-renal dysregulation” (not “syndrome”), focusing primarily on the interactions of the heart and the kidney in heart failure (HF), was proposed in 2002 by a group of experts convened by the American Heart Association (AHA). These investigators described the disorder as “… the result of interactions between the kidneys and other circulatory compartments that increase circulating volume and symptoms of heart failure and (exacerbates) disease progression. At its extreme, cardio-renal dysregulation leads to a condition in which therapy to relieve congestive symptoms of heart failure is limited by a further decline in renal function” [2]. This definition suggests that the pathophysiological relationship between renal and cardiac function extends from low/moderate to severe dysfunction and/or damage to the two organs. The AHA experts emphasized that the nature of cardio-renal connections demands that cardiologists and nephrologists establish intensive collaboration to unravel mechanisms underlying this dysregulation.

The term “cardio-renal syndrome” (CRS) was introduced in the early 2000s and has since become a focal point of research, with many studies published on the topic. CRS is typically categorized into five subtypes based on the sequence of cardiovascular and kidney disease events [3]. These subtypes include acute kidney disease or chronic kidney disease (CKD) following heart disease, or vice versa, and systemic conditions causing both heart and kidney dysfunctions. Despite the widespread acceptance of this classification, alternative perspectives on cardio-renal issues exist.

The CRS classification has been instrumental in stimulating clinical research but has limitations. Reliance on the sequence of events – whether heart disease precedes kidney disease or vice versa – is difficult to establish in clinical practice [4, 5]. Furthermore, the chronology of these events has no prognostic bearing [6].

In recent years, understanding the interplay between cardiovascular and renal health has evolved, leading to the proposal of new frameworks that aim to provide a more integrated and holistic view. One such framework is the cardiovascular-kidney-metabolic (CKM) syndrome [7], a conceptualization formulated in early 2023 in a scientific statement of the AHA. This document expands on the concept of metabolic syndrome [8], describing a set of interrelated metabolic risk factors and their effects on the kidneys and cardiovascular system and highlighting the complexity of managing patients with these combined conditions. It identifies several knowledge gaps, including disease mechanisms, clinical phenotype variability, the impact of social determinants on health, and the need for better disease incidence assessment amidst competing risks.

Parallel to the CKM framework, another viewpoint on cardio-renal problems has emerged, advocating a shift from the term “syndrome” to that of “disorder” [4, 5]. The chronic cardiovascular-kidney disorder (CCKD) framework emphasizes that the term “disorder” better captures the chronic and systemic nature of the condition, focusing on the concurrent presence of cardiovascular and kidney problems regardless of their sequence. This perspective argues for a more simplified, conceptually clear approach based on the shared risk factors and pathophysiological pathways between cardiovascular and renal diseases.

The CKM and the CCKD frameworks reflect a growing recognition of the need for a more integrated approach to understanding and managing cardio-renal problems. By moving beyond traditional classifications and embracing a more holistic view, these frameworks aim to improve patient outcomes through better prevention, diagnosis, and treatment strategies.

A new viewpoint published alongside the AHA document challenges the existing classification of CRS [4]. This viewpoint applies Occam’s razor principle, suggesting that subtypes 1 and 5 be excluded because acute heart failure [9] and systemic conditions like sepsis and diabetes are, per se, a distinct syndrome [10] and a distinct disease [11], respectively. Therefore, incorporating these conditions into a 5-subtypes classification has no clinical or heuristic gain. The reliance on the sequence of cardiac and kidney events is also questioned as a large-scale epidemiologic study by Halimi et al. [6] shows that the sequence of these events does not influence the risk for adverse kidney or heart outcomes, which is equally high when HF precedes or follows CKD, an issue discussed in detail in an editorial commenting Halimi’s article [12]. The lack of synergic interaction between CKD and HF (Fig. 1) [6] is an important argument for negating cardio-renal problems and the status of the syndrome [12, 13].

The CCKD framework advocates for a terminological shift from “syndrome” to “disorder,” positing that this construct more accurately reflects the systemic disruption caused by concurrent disease states affecting both the heart and kidneys. The term “disorder” is preferred as it underscores the chronic and intertwined nature of these conditions, moving away from the improper definition of “syndrome” applied to cardio-renal problems. This issue will be discussed in some detail in a subsequent section (CKM vs. CCKD). Indeed, the term syndrome applied to cardio-renal problems does not stand the methodological scrutiny needed for using the term syndrome [4, 13]. The diagnostic criteria for CCKD, detailed in Table 1, emphasize the simultaneous presence of cardiovascular and kidney issues, irrespective of which condition manifests first.

The rationale behind this shift is rooted in recognizing shared risk factors and pathophysiological pathways that link cardiovascular disease and CKD. These commonalities include hypertension, diabetes, obesity, and dyslipidemia, which often coexist and exacerbate each other, as well as environmental risk factors, like particulate matter (PM) pollution and cigarette smoking, leading to a vicious cycle of worsening health outcomes. By focusing on the concurrent presence of cardiovascular and kidney problems, the CCKD framework aims to provide a more holistic and integrated approach to diagnosis and treatment.

One key argument for adopting the CCKD terminology is the need for simplification and conceptual clarity. By removing the emphasis on the chronology of disease onset, the CCKD framework allows for a more straightforward and unified approach to understanding and managing these conditions.

Understanding the bidirectional acceleration of disease progression between heart and kidney dysfunction is crucial for developing effective treatment strategies. For instance, HF can lead to reduced renal perfusion and subsequent kidney damage, while CKD can contribute to fluid overload and increased cardiac workload, exacerbating HF. Recognizing these interdependencies is essential for devising therapeutic interventions that simultaneously address cardiovascular and renal health.

Similar to the CKM syndrome framework, the CCKD advocates using a range of pharmacological agents that have shown efficacy in managing cardiovascular and kidney conditions. These include angiotensin-converting enzyme inhibitors, which help reduce blood pressure and protect renal function; sodium-glucose cotransporter-2 (SGLT2) inhibitors, which have been shown to improve cardiovascular outcomes and slow the progression of CKD; and mineralocorticoid receptor antagonists, which can reduce inflammation and fibrosis in both the heart and kidneys.

In addition to pharmacological interventions, the CCKD framework reiterates the importance of lifestyle modifications and comprehensive risk factor management. This includes dietary changes, increased physical activity, smoking cessation, and weight management, all of which are crucial for mitigating the risk factors associated with both CVD and CKD. By adopting a holistic approach that addresses the underlying causes of these conditions, the CCKD framework aims to improve patient outcomes and reduce the burden on healthcare systems.

Furthermore, like the CKM, the CCKD framework calls for a more integrated and interdisciplinary approach to patient care. This involves collaboration between cardiologists, nephrologists, endocrinologists, and primary care providers to ensure that patients receive comprehensive and coordinated care. Such an approach is essential for managing the complex interplay between cardiovascular and renal health and for providing patients with the best possible outcomes.

Inflammation and oxidative stress play a central role in the pathogenesis of CCKD. Chronic low-grade inflammation, often driven by obesity and metabolic syndrome, contributes to endothelial dysfunction, atherosclerosis, and renal injury [14, 15]. Oxidative stress further exacerbates these processes by damaging cellular structures and promoting fibrosis in both the heart and kidneys. Anti-inflammatory therapy targeting pro-inflammatory cytokines is being developed for the prevention of cardiovascular events in patients with atherosclerosis [16] and this intervention has already shown concrete improvements in the risk of cardiovascular events in patients with [17] and without [18, 19] CKD.

The primary difference between the AHA document on CKM and the concept of CCKD lies in terminology (syndrome vs. disorder) and the delineation of risk factors. The CKM framework retains the term “syndrome” and focuses on the cardio-renal impact of a cluster of metabolic factors prevalent in the general population. In contrast, the CCKD framework defines the occurrence of simultaneous cardiovascular and kidney problems as a disorder rather than a syndrome. The term “metabolic syndrome” has faced criticism from the American Diabetes Association and the European Association for the Study of Diabetes [20], and this criticism extends to the terms “cardio-renal syndrome” and “cardiovascular and kidney syndrome.” An important element why the term syndrome is inappropriate is the observation that like the combined risk for death from excess abdominal circumference, hypertriglyceridemia, low HDL cholesterol and hypertension, is simply additive rather than more than additive or multiplicative as one would expect in the presence of synergism of these risk factors [20] the combined death risk of cardiac and renal problems is less than additive [6, 12] (Fig. 1). The CCKD framework, in addition to metabolic risk factors, emphasizes other established, actionable common risk factors for cardiovascular and kidney disease, such as exposure to environmental pollutants like PM2.5, PM10, nitrogen oxides, black carbon, and environmental noise (Fig. 2).

Both CKM and CCKD share common pathophysiological mechanisms and risk factors, including hypertension, diabetes, obesity, and dyslipidemia. These conditions often coexist and interact, leading to a cycle of worsening health outcomes. Inflammation and oxidative stress are central to the pathogenesis of both CKM and CCKD. Chronic low-grade inflammation, often driven by obesity and metabolic syndrome, contributes to endothelial dysfunction, atherosclerosis, and renal injury [14, 15]. Oxidative stress further exacerbates these processes by damaging cellular structures and promoting fibrosis in both the heart and kidneys.

Managing both CKM and CCKD requires a comprehensive approach that addresses the underlying risk factors and pathophysiological mechanisms. Lifestyle modifications, such as dietary changes, increased physical activity, and weight loss, are fundamental to reducing the burden of metabolic disorders. Pharmacological interventions, including antihypertensive agents, statins, and antidiabetic medications, are essential for controlling blood pressure, lipid levels, and glucose metabolism.

Emerging therapies, such as SGLT2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, have shown promise in improving cardiovascular and renal outcomes in patients with CKM and CCKD. These agents lower blood glucose levels and have beneficial effects on weight, blood pressure, and inflammation. Despite differences in terminology, the CKM and CCKD concepts align on several points, including (a) emphasis on metabolic disorders, hypertension, diabetes, and obesity; (b) understanding the impact of social determinants of health on disease prevalence and management; (c) recognition of interconnected pathophysiology; (d) acknowledgment of the complexity of managing patients with coexisting cardiovascular and kidney issues necessitating multifaceted approaches; (e) need for comprehensive research into the common mechanisms underlying these conditions; and (f) innovative treatment strategies addressing multiple facets simultaneously.

The CCKD viewpoint posits at center stage the use of cardio-renal composite endpoints in clinical trials [4, 5], incorporating various combinations of cardiovascular death, death secondary to kidney failure, major acute cardiac events, HF hospitalization, end-stage kidney disease, need for renal replacement therapy, and sustained decline of eGFR. These composite endpoints have been successfully adopted in trials testing renin inhibitors and SGLT2 inhibitors like in the “Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation” (CREDENCE) trial [21].

Addressing the issue of differing weight among cardiovascular and kidney components in composite endpoints is crucial. The win ratio allows investigators to prioritize components based on clinical importance [22]. For example, in a recent trial comparing the potassium binder patiromer vs. placebo for treating hyperkalemia in HF with reduced ejection fraction [23], two win-ratios were considered secondary endpoints within a hierarchical testing strategy. Post hoc analyses of a trial testing an SGLT2 inhibitor showed that this approach is feasible and produces cogent results [24]. However, the hierarchical ranking of events may be challenging when combining cardiovascular and kidney outcomes instead of ranking either a set of cardiac or renal outcomes in isolation. The win ratio cannot address the potential for heterogeneity of treatment effects across the kidney and cardiovascular components of the composite. Investigators and methodologists agree that a combined cardio-renal endpoint should be adopted only when an investigational therapy can plausibly influence both heart and kidney outcomes concordantly [25]. An alternative to a composite cardio-renal outcome is planning a hierarchical analysis encompassing either a primary kidney endpoint and a secondary cardiovascular endpoint, as implemented in the Dapagliflozin in Patients with Chronic Kidney Disease (DAPA-CKD) trial, or vice versa. A composite cardio-kidney endpoint in a single trial may have been a reasonable alternative to the FIGARO and FIDELIO trials, which had separate cardiac and kidney endpoints but showed similar cardiac and renal benefits with finerenone [26].

The future of managing concomitant CVD and kidney disorders lies in an integrative approach that considers individual patient phenotypes and broader population health dynamics [26, 27]. This approach involves embracing both precision medicine – tailoring interventions to individual genetic, environmental, and lifestyle factors – and public health strategies that address social determinants and prevent disease at a community level. An interdisciplinary model of care that bridges cardiology, nephrology, endocrinology, and primary care is essential [28] as there is the need to train next-generation specialists in cardio-renal and metabolic medicine [29]. This model should be supported by robust clinical guidelines that are flexible enough to accommodate rapidly evolving evidence from omics research and clinical trials focusing on composite endpoints. Both the CKM and CCKD concepts underscore the necessity for an integrated approach to research, prevention, and management strategies to mitigate the burden of this integrated condition on patients and healthcare systems.

Public health strategies are crucial in preventing and managing CKM and CCKD at the population level. These strategies include promoting healthy lifestyles [30], reducing exposure to environmental risk factors [31], and addressing social determinants of health [32]. For example, initiatives to reduce the consumption of processed foods high in sugar, salt, and unhealthy fats can help prevent obesity, diabetes, and hypertension, thereby reducing the burden of CKM and CCKD.

Efforts to reduce air pollution and environmental noise can also significantly impact cardiovascular and renal health. Policies aimed at improving access to healthcare, education, and economic opportunities can help address the social determinants of health that contribute to the development and progression of CKM and CCKD.

An interdisciplinary model of care that bridges cardiology, nephrology, endocrinology, and primary care is essential for effectively managing CKM and CCKD [33]. This model should be supported by robust clinical guidelines that are flexible enough to accommodate rapidly evolving evidence from omics research and clinical trials focusing on composite endpoints. Interdisciplinary care teams can provide comprehensive, patient-centered care that addresses the complex interplay between cardiovascular, metabolic, and renal health.

Funding agencies and policymakers should prioritize research on CKM and CCKD, including studies on the underlying mechanisms, novel biomarkers, and therapeutic targets. Patient education and engagement [34] are critical to effective CKM and CCKD management. Patients should be empowered with the knowledge and tools to manage their conditions and make informed decisions about their care. Healthcare providers should engage patients in shared decision-making and provide personalized education and support to help them achieve their health goals.

The CKM and CCKD frameworks offer valuable perspectives on managing cardio-renal problems. While the CKM emphasizes the interconnectedness of metabolic risk factors and their impact on cardiovascular and kidney health, the CCKD advocates for a simplified, disorder-focused approach highlighting the importance of shared risk factors and pathophysiological pathways. Both frameworks underscore the need for comprehensive, interdisciplinary care models and innovative treatment strategies to address the complex interplay between cardiovascular and kidney diseases.

Carmine Zoccali is a scientific consultant for Fresenius Medical Care Europe.

This study was not supported by any sponsor or funder.

C.Z. conceived and wrote the manuscript.