Non-atherosclerotic Cardiovascular Disease in Chronic Kidney Disease

INTRODUCTION

Chronic Kidney disease (CKD) is a major public health problem; in the U.S., 33.1% of individuals aged over 65 years have prevalent CKD.¹ CVD is the leading cause of death in CKD, with increasing risk of CVD mortality with declining glomerular filtration rates (GFR)² and increasing albuminuria¹ Patients with CKD are six times more likely to die of CVD than to transition to kidney failure.³ In this review, we will discuss non-atherosclerotic CVD in patients with CKD, including heart failure (HF), valvular disease, arrhythmias, and sudden cardiac death. For atherosclerotic CVD in CKD, please refer to a separate review in this collection by Mathew RO et al.

PATHOPHYSIOLOGICAL LINKS BETWEEN CKD AND CVD

The complex interplay between CKD and CVD involves shared mechanisms, like hypertension, diabetes, inflammation and oxidative stress, as well as CKD-specific risk factors, including uremic toxins accumulation, anemia, mineral and bone disorder, volume overload, and endothelial dysfunction.⁴ A key feature of CKD is arterial stiffening, mediated by arteriosclerosis and vascular calcification, which increases left ventricular afterload and promotes left ventricular hypertrophy (LVH), ultimately contributing to heart failure and arrhythmogenesis.⁵ The chronic pro-inflammatory state in CKD, combined with disruptions in bone-mineral metabolism, particularly osteogenic transdifferentiation of vascular smooth muscle cells into osteoblast-like cells, further drive vascular calcification and cause maladaptive cardiac remodeling contributing to CKD associated cardiomyopathy independent of hemodynamic changes described earlier.⁵ Additionally, volume overload and the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) activation augment these deleterious effects. Collectively, these processes establish a bidirectional relationship, where CKD initiates and amplifies cardiovascular pathology, resulting in disproportionately high morbidity and mortality in this population.⁶ Though highly prevalent in older adults,⁷ CKD-associated cardiomyopathy is also observed in children with CKD.⁸

RISK FACTORS FOR CVD in CKD

Traditional Risk Factors for CVD in CKD

Traditional risk factors for CVD such as hypertension, diabetes mellitus, obesity and dyslipidemia are highly prevalent in CKD populations⁹ and though important, are not sufficient to explain the elevated risk of CVD in this group.^4,5 The role of CVD traditional risk factors and their interplay with CKD is well established,⁴ and is summarized in Box 1.

Box 1.

Hypertension:

• Prevalence in CKD 60–90%

• Commonly causes CKD and is exacerbated by sodium retention, volume overload and RAS and SNS activation from CKD

Diabetes Mellitus:

• Risk factor for CKD and CVD

• Co-existing DM and CKD amplify CVD risk due to induction of reactive oxygen species, formation of advanced glycation end products, endothelial dysfunction and hypercoagulability

Obesity:

• Increases risk of CVD7 and ESKD

• Pathogenesis includes inflammation causing atherogenesis and endothelial dysfunction, activation of RAASS and SNS leading to hypertension and myocardial fat accumulation causing fibrosis and arrythmogenicity.

Dyslipidemia:

• Key component of metabolic syndrome leading to cardio-kidney-metabolic syndrome

• Altered lipid metabolism in CKD including deranged VLDL and LDL metabolism and impaired reverse cholesterol transport amplifies atherogenicity.

Non-traditional risk factors for CVD in CKD

Sodium retention and volume overload

CKD is often accompanied by albuminuria, which contains plasmin capable of activating the epithelial sodium channel, contributing to sodium retention and volume overload.¹⁰ The resultant salt-sensitive hypertension, already highly prevalent in CKD is further exacerbated by specific inflammatory pathways. ^10,11

High dietary sodium intake can lead to aldosterone-independent activation of the mineralocorticoid receptor, further promoting sodium retention.^10,12 Sodium accumulation in skin and tissues progressively increases with severity of CKD,¹³ and is associated with LVH.¹⁴ Though osmotically inactive, tissue sodium accumulation activates macrophages and other immune cells,¹⁵ resulting in the upregulation of pro-inflammatory mediators, cardiac fibrosis and vascular inflammation.^16,17 Fluid overload has been linked to endothelial dysfunction,¹⁸ LVH,¹⁹ and increased CVD morbidity and mortality in advanced CKD.²⁰

Dysregulated calcium phosphorus metabolism and vascular calcification

The increase in the FGF23 production by osteocytes in response to hyperphosphatemia occurs early in CKD²¹ and is associated with increased mortality.²² Animal models suggest a direct effect of FGF23 on cardiomyocyte hypertrophy, independent of klotho.^23,24 Serum klotho as a biomarker of LVH has been investigated with inconsistent findings.^25,26

Calciprotein particles (CPP), amorphous complexes of calcium, phosphorus and proteins such as fetuin-A, are associated with vascular calcification in CKD. Increased CPP counts and calcification propensity (T50, time required for transformation of primary to secondary calciprotein particles) associate with vascular remodeling, extracellular matrix remodeling, and ossification in CKD.²⁷ T50 has been associated with higher risk of CVD and all-cause mortality in renal transplant recipients,²⁸ and pre-dialysis CKD in some,²⁹ but not all studies.³⁰ Additionally, low levels of vitamin D, commonly seen in CKD, may increase CVD risk due to loss of vitamin D’s anti hypertrophic and anti-proliferative action on cardiomyocytes.³¹

Chronic Inflammation

Increase in proinflammatory circulating monocytes, activation of innate immune system by uremic toxins, increased levels of circulating endotoxins and their receptors and sympathetic overactivity contribute to the inflammatory state in CKD.³² (NOD)-like protein receptor 3 (NLRP3) inflammasome activates IL-1 which triggers further downstream inflammatory activity.³³ Higher levels of fibrinogen, IL-6 and TNF-α are associated with increased risk of incident CVD in CKD.³⁴

Accumulation of Uremic Toxins

Many compounds, collectively called “uremic toxins” that are normally excreted or metabolized by the kidneys, accumulate in the setting of CKD. High levels of indoxyl sulfate and p-cresol sulfate have been implicated in causing inflammation, increased calcification of blood vessels³⁵ and cardiomyocyte hypertrophy.³⁶ Hippuric acid, trimethylamine N-oxide (TMAO) and asymmetric dimethylarginine (ADMA) have also been associated with a high CVD risk by causing endothelial dysfunction, LVH, NLRP3-driven accelerated atherosclerosis, induction of oxidative stress and inhibition of nitric oxide.

HEART FAILURE (HF) IN CKD

Heart failure (HF) is four times more common in CKD (27.7%) vs. non-CKD (6.4%).^1,37 eGFR and urine albumin-creatinine ratio (UACR) correlate with HF risk.^38,39 The prevalence and hospitalization rates are higher for HF with preserved (HFpEF) than with reduced (HFrEF) ejection fraction, but HFrEF has a stronger association with mortality in CKD.^40,41 Changes in cardiac structure, including myocardial hypertrophy and fibrosis start early in the course of CKD⁴² and the incidence of de novo HF in CKD is estimated to be between 17–21%³⁷. There is a bidirectional amplification of risk between CKD and HF-CKD is common in patients with HF^43,44 with worsened outcomes irrespective of the type of HF. Concentric and eccentric LVH are the most prominent gross findings of HF in CKD while cardiomyocyte hypertrophy, myocardial interstitial fibrosis and coronary microvascular disease are seen on endomyocardial biopsies.⁴⁵ Myocardial fibrosis provides an attractive target for potential therapeutic interventions and is an intense area of research.⁴⁶ Factors contributing to pathogenesis of myocardial fibrosis and heart failure in CKD are depicted in Figure 1.

Figure 1.

Mechanisms of Myocardial Fibrosis and Heart Failure in Chronic Kidney Disease. RAAS– rennin angiotensin aldosterone system, PO4 – phosphate, FGF23 – fibroblast growth factor 23, ADMA –Asymetricdimethyl Arginine, TMAO – Trimethylamine N-oxide

Increases in levels of N-terminal pro-B type natriuretic peptide (NT-pro-BNP), and soluble Suppressor of Tumorigenicity-2 (sST-2), have been associated with increased risk of incident HF in CKD.⁴⁷ Though NT-pro-BNP levels are higher in CKD and cut-offs for significance undefined, higher levels corelate with increased risk of adverse CV events consistently across different stages of kidney disease.⁴⁸ Identifying cutoff points at different eGFR levels remains a key area of investigation. High concentrations of other biomarkers such as high sensitivity troponin T (HsTNT), Galectin-3, and growth differentiation factor-15 (GDF-15), have been associated with increased risk of subclinical⁴⁷ and incident HF.⁴⁹ The combination of high carboxy terminal propeptide of procollagen type-1 (PICP-1) and low carboxy-terminal telopeptide of collagen type-1 to matrix metalloproteinase-1 (CITP:MMP-1) ratio, a marker of myocardial fibrosis and severe diastolic dysfunction, is observed in CKD patients with HFpEF.⁵⁰ PICP-1 correlates with echocardiographic parameters of myocardial fibrosis,⁵¹ and is an independent predictor of mortality in advanced CKD not on dialysis.⁵² Research regarding utility of biomarkers including large scale proteomics in diagnosis and risk stratification is ongoing.⁵³

As diagnostic modality, electrocardiography (ECG) has low sensitivity in detecting LVH in CKD,⁵⁴ and whether LVH by ECG criteria adds prognostic information to echocardiography diagnosed LVH is unknown.⁵⁵ Advanced cardiac magnetic resonance imaging is helpful in identifying myocardial fibrosis and is a more sensitive indicator of systolic and diastolic dysfunction compared with standard echocardiography.⁵⁵

Quadruple goal directed medical therapy (GDMT) consisting of angiotensin receptor neprilysin inhibitor (ARNI)/ACEI, β adrenergic receptor blockers, mineralocorticoid receptor antagonists (MRAs) and sodium glucose co-transporter 2 inhibitors (SGLT2i) form the cornerstone of treatment for HFrEF in general population. Clinical guidelines suggest the level of care for HF in CKD patients should be equivalent to that offered to those without CKD.³ SGLT2i are also beneficial in HFpEF, and should be used in patients with an eGFR ≥20 mL/min/1.73 m², with or without type 2 diabetes; once initiated, the SGLT2i can be continued at lower levels of eGFR.³More recently, the non-steroidal MRA Finerenone was shown to reduce all-cause mortality, risk of HF hospitalization and composite kidney outcome in patients with cardiovascular-kidney-metabolic syndrome⁵⁶. Unfortunately, patients with advanced CKD were excluded from most of the landmark trials showing benefits of these agents, and observational data indicates that proportion of patients receiving either ARNI/ACEI, β blocker or MRA decreases with increasing severity of renal dysfunction.^57,58 The increase in creatinine and hyperkalemia induced by these drugs is cited as one of the most common reasons for ineffective drug therapy.⁵⁹ Yet, these agents are equally effective for relative risk reduction and even more effective at absolute risk reduction compared to patients without CKD.⁵⁹ Therefore permissive “hypercreatinemia” has been advocated, when clinically appropriate, to avoid therapy de-escalation.⁶⁰.Additionally, newer potassium binding agents such as patiromer are effective in controlling hyperkalemia in the setting of treatment with MRAs, allowing greater adherence to GDMT.⁶¹

VALVULAR HEART DISEASE IN CKD

Valvular calcification occurs early in CKD and is associated with increased CVD and all-cause mortality.⁶² Aortic stenosis was seen in 9.5% of patients with CKD compared with 3.5% of general population, mitral regurgitation in 43% vs 24%, mitral stenosis in 2% vs 1% and aortic regurgitation in 19% vs 10%.⁶³ Aortic stenosis also progresses more rapidly in CKD and has lower survival.⁶³ Furthermore, CKD increases the risk of 30 day mortality, all-cause and CVD mortality and increased risk complications following transcutaneous or surgical aortic⁶⁴ and mitral valve⁶⁵ interventions. Figure 2 summarizes the factors contributing to pathogenesis of valvular disease in CKD.

Figure 2.

Mechanisms of Valvular Injury and Calcification in CKD. TNF-α=Tumor Necrosis Factor α; IL-1β = interleukin 1 β; RANKL= receptor activator of nuclear factor kappa ligand; FGF 23= fibroblast growth factor 23; ROS= reactive oxygen species; BMP-2= bone morphogenic protein 2; ALP= alkaline phosphatase; ADMA= asymmetric dimethylarginine; NO= nitric oxide.

Though a number of biomarkers like ADMA, homocysteine, gamma glutamyl transferase, fetuin A, natriuretic peptides, leptin, CR-reactive protein and osteopontin have been investigated in the diagnosis of calcific aortic stenosis, none has shown consistent value in diagnosis or prognosis.⁶⁶ Screening for gene variants affecting immune cell infiltration of the valve and screening for immune related secretory proteins using bioinformatics approaches and machine learning is a current focus of research.^67,68

Different diagnostic modalities useful for evaluation of valvular heart disease adapted from Baumgartner et al.⁶⁹ are listed in Box 2.

Box 2.

Non-invasive techniques:

• 2 Dimensional or 3 Dimensional Echocardiography

  • Screening

  • Assessment of valve morphology and function and of indices of LV size and function

• Stress Testing

  • Unmask objective evidence of symptoms

  • Exercise echocardiography helpful in prognosticating MS and AR

  • Dobutamine stress echocardiography for flow reserve useful in assessing AS severity and operative risk stratification

• Computed Tomography (CT)

  • Multislice CT helpful in assessing AS severity

• Cardiac MRI

  • Helpful when echocardiography technically difficult or yield discrepant results

  • Heps assess severity of valvular lesions, ventricular volumes and systolic function and myocardial fibrosis

Invasive Techniques:

• Cardiac Catheterization:

  • Measurement of pressures and cardiac output and assessment of ventricular performance and valvular regurgitation by ventricular angiography when noninvasive testing is inconclusive or discordant.

LV-left ventricle; MS-mitral stenosis; AR-aortic regurgitation; AS- aortic stenosis; MRI-magnetic resonance imaging

Adapted from ref 69

FATAL AND NONFATAL ARRYTHMIAS in CKD

CKD is associated with a broad spectrum of arrhythmias, including atrial fibrillation/flutter, and ventricular arrhythmias leading to sudden cardiac death (SCD).

Atrial fibrillation (AF) is the most common arrhythmia observed in CKD, with prevalence increasing with severity of CKD and ranging from 16% to 21%.³ Lower eGFR and higher albuminuria are independently associated with an increased risk of incident AF.^3,70 The relationship between AF and CKD is bidirectional, with AF predicting new renal dysfunction or proteinuria.⁷¹ Increased IL-1β levels, atrial fibrosis, and electrical remodeling in CKD create a substrate for AF.⁷²

Non-vitamin K antagonist oral anticoagulants are preferred over vitamin K antagonists for thromboprophylaxis in AF patients with CKD stages 1–4,^3,71 but data are limited and conflicting for CKD stages 5 and 5D.^3,71,73 Except amiodarone, all antiarrhythmic drugs require adjustment for renal function.⁷¹ Radiofrequency ablation is a feasible alternative.⁷¹

Ventricular arrhythmias is estimated to have a prevalence of up to 35% in non-dialyzed CKD patients.⁷⁴ Because of difficulty in capturing ventricular fibrillation (VF) or ventricular tachycardia (VT), premature ventricular contractions,⁷⁵ and nonsustained ventricular tachycardia have been the most recognized ventricular rhythm abnormalities in CKD.^3,76,77 Alterations in the myocardial structure, including hypertrophy and diffuse fibrosis,^78,79 often precede, and are a substrate for ventricular arrhythmia and SCD in CKD.^80,81 CKD is associated with prolonged action potential duration (APD), increased vulnerability to early afterdepolarizations, which can lead to VF/VT. Additionally, hyperkalemia, calcium dysregulation and oxidative stress in CKD contribute to arrhythmogenesis.^82,83 Indoxyl sulfate, kynurenine, and kynurenic acid have been shown to prolong APD and decrease repolarization current densities in cardiomyocytes,⁸⁴ and can trigger fatal ventricular arrythmias.⁸⁵ Despite the recognized burden of ventricular arrhythmias in CKD, data on effective management strategies are limited, with antiarrhythmic drugs carrying an increased potential of toxicity, and implantable cardioverter-defibrillators being ineffective in CKD.^86–88

Bradyarrhythmias, including sinus node dysfunction, atrioventricular block and asystole, may arise from autonomic dysfunction and fibrosis of the conduction system, triggered by electrolyte imbalances, fluid shifts, and the dialysis process itself.⁸⁹ It is estimated that over 25% of ESKD patients experience bradycardia,⁹⁰ which carries a high risk of SCD, particularly during long interdialytic period.⁹¹

Sudden cardiac death (SCD) is significantly more prevalent in patients with CKD compared to the general population due to the increased risk of arrhythmias.^83,92 Compared to <10% in general population, up to 25% of deaths in CKD are attributable to SCD.^86,93–96 Risk factors include race^97,98, sex⁹⁷, underlying CVD^99,100, and various arrhythmia triggers, particularly prolonged QT interval.^99,101

Since traditional CVD risk factors poorly predict SCD in CKD,^102,103 research has focused on understanding the role of myocardial fibrosis and hypertrophy,^83,92 and uremic toxins, such as ADMA in arrhythmogenesis.^84,104 Prevention of SCD is challenging, and current ACC/AHA, and Heart Rhythm Society guidelines suggest that the decision to implant an ICD should be individualized, considering the patient’s overall health status and comorbidities.¹⁰⁵

FUTURE DIRECTIONS

Effective clinical care models require a multidisciplinary approach to address the complex interaction between CVD and CKD.^3,106 Early referral to specialists, individualized patient care, and adherence to evidence-based therapies been shown to be cost-effective and improve outcomes.¹⁰⁷ Investing in technologies for continuous remote monitoring of cardiovascular metrics, including blood pressure, arrhythmias, and fluid status, will facilitate earlier intervention and improve management.

Future research should focus on elucidating the mechanisms and identifying novel therapeutic targets to prevent and treat heart failure, valvular heart disease and arrhythmias in CKD.

SUMMARY

Patients with CKD face a markedly increased risk of non-atherosclerotic CVD phenotypes, including heart failure, arrhythmias, valvular disease, and sudden death. These conditions, driven by unique pathophysiological mechanisms, contribute significantly to the high cardiovascular morbidity and mortality. Early recognition and stratification of cardiovascular risk are critical, and emerging research into novel biomarkers and improved imaging modalities hold promise for improving early detection and mitigate the burden of non-atherosclerotic cardiovascular disease in CKD.

Clinics Care Points.

• KDIGO recommends that all individuals with CKD be considered at increased risk for CVD.³

• Use a multidisciplinary approach, involving both cardiologists and nephrologists, to optimize the management of nonatherosclerotic CVD in CKD patients.

  Prevention should include interventions targeting traditional cardiovascular, and CKD-specific risk factors including inflammation, volume overload, electrolytes abnormalities, mineral bone disorder and anemia.

• KDIGO 2024 guidelines¹⁰⁸ recommend (2A) systolic blood pressure target of less than 120 mm Hg using standardized office measurements, when tolerated, in adults with high BP and CKD, based mainly on evidence from the SPRINT trial,¹⁰⁹ to reduce CVD events and mortality.¹¹⁰

• ADA/KDIGO consensus recommends the use of SGLT2 inhibitors and finerenone in patients with type 2 diabetes and CKD to reduce CVD events and slow CKD progression.^123,111

• The level of care for heart failure in CKD patients should be equivalent to that offered to those without CKD.³

Key Points.

• Non-atherosclerotic cardiovascular disease including heart failure, often with preserved ejection fraction, arrhythmias, valvular disease, and sudden cardiac death significantly contributes toto morbidity and mortality in chronic kidney disease (CKD),.

• CKD-specific risk factors including anemia, volume overload, metabolic bone disease, accumulation of uremic toxins, and sympathetic overactivity, exacerbate arteriosclerosis, vascular calcification, endothelial dysfunction, and metabolic cardiac remodeling.

• Left ventricular hypertrophy, observed in up to 70–80% of patients with advanced CKD, is driven by increased arterial stiffness and volume overload, and is a major risk factor for heart failure.

• Up to 25% of deaths in CKD are attributable to sudden cardiac death, which is due primarily to ventricular arrythmias. Myocardial fibrosis, a known substrate for ventricular arrythmias, is proportional to CKD severity and integral to sudden cardiac death pathogenesis.

• Research targeting anti-inflammatory strategies and interventions to reduce uremic toxin levels in the setting of CKD is ongoing.

Synopsis.

Non-atherosclerotic cardiovascular disease (CVD) in chronic kidney disease (CKD) is highly prevalent and involves distinct pathophysiological mechanisms. Arteriosclerosis, characterized by medial arterial layer thickening and fibrosis, leads to increased arterial stiffness and vascular calcification, driven by disordered bone mineral metabolism. Clinical manifestations of non-atherosclerotic CVD include left ventricular hypertrophy (LVH), which occurs in up to 70–80% of patients with advanced CKD, heart failure (often with preserved ejection fraction), valvular heart disease, and both fatal and nonfatal arrhythmias. These conditions are exacerbated by CKD-specific factors such as volume overload, anemia, and sympathetic overactivity, contributing to high cardiovascular morbidity and mortality