Renal-Cardiac Crosstalk in the Pathogenesis and Progression of Heart Failure

Abstract

Chronic kidney disease (CKD) represents a global health issue with a high socioeconomic impact. Beyond a progressive decline of kidney function, patients with CKD are at increased risk of cardiovascular diseases, including heart failure (HF) and sudden cardiac death. HF in CKD can manifest both as HF with reduced ejection fraction and HF with preserved ejection fraction, with the latter further increasing in relative importance in the more advanced stages of CKD. Typical cardiac remodeling characteristics in uremic cardiomyopathy include left ventricular hypertrophy, myocardial fibrosis, cardiac electrical dysregulation, capillary rarefaction, and microvascular dysfunction, which are triggered by increased cardiac preload, cardiac afterload, and preload and afterload-independent factors. The pathophysiological mechanisms underlying cardiac remodeling in CKD are multifactorial and include neurohormonal activation (with increased activation of the renin-angiotensin-aldosterone system, the sympathetic nervous system, and mineralocorticoid receptor signaling), cardiac steroid activation, mitochondrial dysfunction, inflammation, innate immune activation, and oxidative stress. Furthermore, disturbances in cardiac metabolism and calcium homeostasis, macrovascular and microvascular dysfunction, increased cellular profibrotic responses, the accumulation of uremic retention solutes, and mineral and bone disorders also contribute to cardiovascular disease and HF in CKD. Here, we review the current knowledge of HF in CKD, including the clinical characteristics and pathophysiological mechanisms revealed in animal studies. We also elaborate on the detrimental impact of comorbidities of CKD on HF using hypertension as an example and discuss the clinical characteristics of hypertensive heart disease and the genetic predisposition. Overall, this review aims to increase the understanding of HF in CKD to support future research and clinical translational approaches for improved diagnosis and therapy of this vulnerable patient population.

Keywords: cardiovascular diseases; heart failure; hypertension; inflammation; metabolism.

Figure 1.

KDIGO (Kidney Disease Improving Global Outcomes) classification of chronic kidney disease (CKD) from the 2024 KDIGO guidelines. The table visualizes CKD classification based on glomerular filtration rate (GFR) category (G1–G5) and albuminuria category (A1–A3). Illustration credit: Sceyence Studios. Adapted from the work in reference with permission from Elsevier.

Figure 2.

Increased cardiovascular risk in patients with chronic kidney disease (CKD). Adjusted hazard ratios (HRs) and 95% CIs (shaded areas or whisker plots) of cardiovascular mortality (top row), coronary heart disease (second row), stroke (third row), and heart failure (bottom row) in function of estimated glomerular filtration rate (eGFR; left) and albumin-to-creatinine ratio (ACR; right), combining the combined general population and high-risk cohorts within the database of the CKD Prognosis Consortium. The analysis integrated data from 24 cohorts with data on fatal and nonfatal cardiovascular outcomes and a median follow-up time >4 years. Reference (diamond): eGFR of 95 mL/min per 1.73 m² and ACR of 5 mg/g. Dots represent statistical significance (P<0.05). *Adjustments were for age, sex, race/ethnicity, smoking, systolic blood pressure, antihypertensive drugs, diabetes, total and high-density lipoprotein cholesterol concentrations, and albuminuria (ACR or dipstick) or eGFR, as appropriate. For analyses of eGFR: 629 776 participants for cardiovascular mortality, 144 874 for coronary heart disease, 137 658 for stroke, and 105 127 for heart failure. For analyses of ACR: 120 148 participants for cardiovascular mortality, 91 185 for coronary heart disease, 82 646 for stroke, and 55 855 for heart failure. Illustration credit: Sceyence Studios. Adapted from Matsushita et al with permission from Elsevier.

Figure 3.

Increased risk of cardiovascular disease (CVD) and heart failure (HF) in chronic kidney disease (CKD). A, CKD is a progressive disease and is classified in stages CKD1-5 based on glomerular filtration rate. Patients with CKD show an increased prevalence of CVD and an increased risk of CVD-associated mortality. Increased CVD risk in CKD includes both atherosclerosis-associated CVD and nonatherosclerosis-associated CVD, such as HF. B, HF and sudden cardiac death are increased in patients with (advanced) CKD, with a contribution of both HF with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). A and B, Data based on a, b, c, d, e,^, f,^, and g. Illustration credit: Sceyence Studios. HFmrEF indicates HF with mildly reduced ejection fraction; and LVEF, left ventricular ejection fraction.

Figure 4.

Increased risk of atherosclerosis-associated and nonatherosclerosis-associated cardiovascular disease (CVD) in chronic kidney disease (CKD). A, Patients with CKD display an increased prevalence and progression of atherosclerosis and increased mortality after myocardial infarction. B, Patients with CKD display features of cardiac remodeling, referred to as uremic cardiomyopathy: characteristics, causal factors, and consequences. For more information, see text. Illustration credit: Sceyence Studios.

Figure 5.

Pathophysiological mechanisms underlying cardiac remodeling and heart failure in chronic kidney disease (CKD). The pathophysiological mechanisms underlying cardiac remodeling in CKD are multifactorial. Furthermore, patients with CKD present with comorbidities such as hypertension, metabolic syndrome, and diabetes, which further contribute to cardiovascular pathophysiology and risk. For more information, see text. Illustration credit: Sceyence Studios. MR indicates mineralocorticoid receptor; RAAS, renin-angiotensin-aldosterone system; and SNS, sympathetic nervous system.