Fighting Against the Odds: Reducing Cardiovascular Mortality in CKD

Authors

  • MD Medicine - Motilal Nehru Medical College, Allahabad ,MESC, MHFA, MIAE Echocardiology Specialist MBBS - KGMU - King George's Medical University , Diabeto-Cardiologist & Woman Cardiologist, Medical Director - Panacea Hospital Varanasi English Author

Keywords:

Chronic kidney disease, Cardiovascular mortality, Dyslipidemia, Blood pressure management, SGLT2 inhibitors, PCSK9 inhibitors

Abstract

Abstract

Background:
Chronic kidney disease (CKD) is a powerful and independent amplifier of cardiovascular morbidity and mortality. Across all stages of CKD, the risk of cardiovascular death far exceeds the likelihood of progression to end-stage kidney disease, driven by a convergence of traditional risk factors and CKD-specific mechanisms such as chronic inflammation, vascular calcification, oxidative stress, anemia, sympathetic overactivity, and disordered mineral metabolism.

Objective:
To provide a practical, evidence-based overview of contemporary strategies aimed at reducing cardiovascular mortality in CKD, with a focus on lipid modulation, blood pressure optimization, proteinuria reduction, antithrombotic therapy, and emerging cardiometabolic agents.

Methods:
This narrative review synthesizes evidence from landmark randomized controlled trials, meta-analyses, and international guidelines to evaluate the efficacy and safety of established and novel pharmacologic interventions in CKD populations, including nondialysis and dialysis patients.

Results:
Statins remain foundational for cardiovascular risk reduction in early to moderate CKD, while combination therapy with ezetimibe and the introduction of PCSK9 inhibitors address residual atherogenic risk, including elevated lipoprotein(a). High-dose, purified eicosapentaenoic acid has demonstrated promising reductions in cardiovascular events in dialysis patients, redefining the role of omega-3 therapy in this population. Blood pressure management centered on renin–angiotensin system blockade, calcium channel blockers, and vasodilatory beta-blockers improves central aortic pressure and mitigates sympathetic overdrive. Proteinuria reduction through ACE inhibitors, ARBs, mineralocorticoid receptor antagonists, and SGLT2 inhibitors slows CKD progression while conferring cardiovascular protection. Antiplatelet and anticoagulant therapies reduce ischemic events but require individualized risk–benefit assessment due to heightened bleeding risk, particularly in advanced CKD and dialysis.

Conclusion:
Reducing cardiovascular mortality in CKD requires early, aggressive, and individualized intervention targeting dyslipidemia, hypertension, proteinuria, and thrombosis within the context of CKD-specific pathophysiology. Integration of novel lipid-lowering agents, SGLT2 inhibitors, refined antihypertensive strategies, and emerging evidence-based therapies enables a shift from reactive to proactive cardiovascular risk mitigation. Personalized, multidisciplinary care across the cardio–renal interface offers a tangible opportunity to defy the historically poor cardiovascular outcomes associated with chronic kidney disease.

Fighting Against the Odds: Reducing Cardiovascular Mortality in CKD A Practical, Modern Guide to Lipids, Drugs, and Disease Modulation Dr. Ashutosh Mishra MBBS, MD (Medicine), IMS BHU Fellowship in Diabetes (DFID), CMC Vellore DMSc (Endocrinology), University of South Wales, UK Consultant Endocrinologist, Panacea Hospital Navigating the Cardiovascular Challenge in Chronic Kidney Disease Chronic kidney disease (CKD) presents one of the most formidable challenges bridging nephrology and cardiology. Over 650 million people worldwide live with CKD, and its prevalence is rising rapidly, fueled by demographic changes and the increasing burden of diabetes and hypertension. Unlike many chronic diseases, cardiovascular mortality among CKD patients dramatically eclipses the risk of progressing to kidney failure requiring dialysis. Scientific evidence shows that patients with moderate to advanced CKD face cardiovascular mortality rates two to four times higher than age-matched individuals without kidney impairment. The reasons behind this heightened risk are complex and multifactorial. Traditional risk factors common in CKD such as hypertension, diabetes, and dyslipidemia are compounded by “kidney-specific” mechanisms including persistent anemia, non-traditional inflammation, oxidative stress, disturbed mineral metabolism, and widespread vascular calcification. These factors contribute to arterial stiffening, left ventricular hypertrophy, and microvascular dysfunction—effectively transforming the vascular system into a “calcified battlefield.” The cardiovascular system, in turn, imposes stress on residual renal function, creating a vicious cycle accelerating both cardiovascular disease and kidney failure. Yet this bleak outlook is not immutable. Recent advances in understanding CKD’s unique pathophysiology, alongside emerging therapeutic options, offer practical avenues for intervention. Smarter dyslipidemia management, innovative therapies targeting inflammation and sympathetic overdrive, and refined strategies to control blood pressure and proteinuria are reshaping care pathways. The key lies in early, individualized, and evidence-driven interventions that address the full spectrum of risks to blunt cardiovascular mortality. This comprehensive review synthesizes modern knowledge about lipid targets, novel therapeutics including PCSK9 inhibitors and high-dose fish oils, optimal blood pressure management, sympathetic regulation, and antithrombotic strategies in CKD patients. It offers clinicians an actionable framework to improve survival outcomes amidst the cardio-kidney convergence. The Cardio-Kidney Crossroads: Why CKD Patients Face Steep Cardiovascular Mortality Odds The interplay of kidney dysfunction and cardiovascular risk is unrelenting. Patients with CKD—especially stages 3 through 5—are burdened with an elevated incidence of coronary artery disease, heart failure, arrhythmias, and stroke. Epidemiological data reveal that cardiovascular disease accounts for approximately 40 to 50 percent of deaths in advanced CKD patients, far exceeding mortality risks from progression to dialysis. Traditional risk factors—hypertension, diabetes—are highly prevalent yet insufficient alone to explain this excess risk. CKD-specific factors such as persistent low-grade inflammation, accumulation of uremic toxins, altered calcium-phosphate metabolism leading to vascular calcification, anaemia-induced hypoxia, and increased oxidative stress aggravate endothelial dysfunction and promote atherosclerosis. Notably, arterial stiffness and microvascular mismatch impair organ perfusion, and left ventricular hypertrophy develops early, predisposing patients to heart failure and sudden cardiac death. CKD also amplifies the risk of arrhythmias through electrolyte imbalance and sympathetic overactivity. Importantly, these cardiovascular risks manifest early in CKD, occasionally even during mild to moderate kidney insufficiency, and worsen with disease progression. Dialysis patients face unique challenges including fluid shifts and electrolyte changes that precipitate arrhythmic events, making tailored cardiovascular risk mitigation a clinical imperative. Beyond the Basics: Rethinking Lipid Management in CKD Lipid abnormalities in CKD differ significantly from the general population. Though LDL cholesterol promotes atherosclerosis across CKD stages, characteristic dyslipidaemia in CKD also involves elevated triglycerides, reduced HDL cholesterol, and increased small, dense LDL particles—all highly atherogenic. Statins continue to form the mainstay for lipid management in early to moderate CKD (stages 1-4), reducing myocardial infarction, stroke, and cardiovascular interventions. High-intensity statins such as atorvastatin or rosuvastatin are preferred except in cases of intolerance. However, clinical trials like SHARP have demonstrated that initiating statins at dialysis onset does not confer significant benefits in primary cardiovascular prevention, although continuing pre-existing statins during dialysis transition may reduce events. For patients who fail to reach LDL cholesterol targets or cannot tolerate statins, addition of ezetimibe is endorsed. This agent works by inhibiting intestinal cholesterol absorption and synergizes with statins effectively. A revolutionary development in lipid therapy has been PCSK9 inhibitors, which profoundly reduce LDL cholesterol by up to 60 percent and also reduce lipoprotein(a), a potent residual cardiovascular risk factor frequently elevated in CKD. Meta-analyses affirm their safety and efficacy in both advanced CKD and dialysis patients, though renal dosing and long-term safety require continued monitoring. Omega-3 Polyunsaturated Fatty Acids: The Fish Oil Comeback in CKD Unlike previous neutral or disappointing omega-3 studies, emerging evidence with high-purity, high-dose eicosapentaenoic acid (EPA) formulations has demonstrated striking cardiovascular risk reduction in dialysis patients. The PISCES trial reported a substantial decrease in myocardial infarction, cardiac death, and major vascular events with daily 4g fish oil supplementation in haemodialysis patients. While the mechanistic basis, possibly linked to anti-inflammatory effects, triglyceride lowering, and plaque stabilization, is not fully elucidated, these findings redefine fish oil as a cornerstone adjunctive therapy for cardiovascular protection in haemodialysis, prompting revaluation of supplementation guidelines for this high-risk group. Blood Pressure Management: Central Aortic Pressure and Sympathetic Overdrive in CKD Hypertension in CKD is complicated by arterial stiffness and frequent white coat or masked hypertension. Current evidence points to central aortic pressure as a more relevant measure than traditional brachial readings, as it directly reflects load on the heart and brain. Vasodilating beta-blockers such as carvedilol and nebivolol favourably reduce central aortic pressure, offering possibly better stroke and cardiovascular event prevention compared to older beta-blockers. Dihydropyridine calcium channel blockers are effective at volume control and blood pressure reduction, especially useful in volume-overloaded haemodialysis patients. ACE inhibitors and ARBs remain fundamental for both blood pressure and proteinuria reduction. CKD also features profound sympathetic nervous system activation, aggravating hypertension and cardiac remodelling. Beta-blockers cross the blood-brain barrier to attenuate sympathetic hyperactivity, reducing morbidity and mortality, particularly in diabetic nephropathy and CKD-associated heart failure. Combination antihypertensive regimens are typical, with beta-blockers, RAAS inhibitors, and CCBs forming the cornerstone, complemented by diuretics where needed. Careful balance is essential to manage electrolyte disturbances and optimize outcomes. Managing Proteinuria: The Therapeutic Window in CKD Proteinuria is both a marker and driver of CKD progression and cardiovascular risk. Even modest reductions in proteinuria correlate with improved outcomes. ACE inhibitors and ARBs offer the strongest evidence for proteinuria reduction and delay kidney decline. Mineralocorticoid receptor antagonists, such as finer none, demonstrate additional proteinuria reduction and cardiovascular protection, although hyperkalaemia risk warrants caution. Non-dihydropyridine calcium channel blockers provide adjunctive benefit for proteinuria in select cases. SGLT2 inhibitors have recently emerged as powerful agents in reducing albuminuria and improving kidney outcomes in diabetic CKD. Antiplatelet and Antithrombotic Strategies: Navigating Risk and Benefit In CKD, antiplatelet use for secondary prevention of cardiovascular events remains important but must be balanced against increased bleeding risks, particularly in advanced stages and dialysis patients. Aspirin remains first-line unless contraindicated, while P2Y12 inhibitors like clopidogrel are used after acute coronary syndromes or percutaneous interventions. Newer agents improve outcomes but increase bleeding risk and must be carefully selected. Oral anticoagulation in CKD is nuanced, with warfarin and apixaban preferred options based on kidney function. Revolutionary Agents: SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Emerging Therapies SGLT2 inhibitors have transformed CKD and cardiovascular disease outcomes by slowing kidney function decline, reducing heart failure hospitalization, and lowering cardiovascular mortality across diabetic and nondiabetic CKD populations. Trials such as CREDENCE, DAPA-CKD, and EMPA-KIDNEY support their early use. GLP-1 receptor agonists provide complementary metabolic and vascular benefits, including weight loss and improved albuminuria control, offering additional protection in eligible patients. The Unique Landscape of Dialysis Patients: Tailored Cardiovascular Care In dialysis populations, cardiovascular risk management must consider altered pharmacokinetics and heightened bleeding risks. Statins are rarely initiated at dialysis start but should generally continue if previously established. PCSK9 inhibitors and high-dose EPA fish oil have emerging evidence supporting use and safety in dialysis. Blood pressure control emphasizes volume management, with beta-blockers and calcium channel blockers playing central roles. Antiplatelet and anticoagulant agents require judicious use to balance haemorrhagic complications. Conclusion: Cardiovascular mortality drives the grim prognosis of chronic kidney disease, underscoring the need for aggressive and tailored prevention strategies. The complex interplay of traditional risk factors, CKD-specific pathophysiology, and therapeutic challenges demands comprehensive, multidisciplinary management founded on robust evidence. Advances in lipid management—from statins through PCSK9 inhibitors and high-dose omega-3 fatty acids—offer unprecedented gastroprotection, even in advanced stages of kidney disease. Progressive refinement in blood pressure control, emphasizing central aortic pressure and sympathetic modulation with beta-blockers and other agents, further improve outcomes. Targeting proteinuria with renin-angiotensin-aldosterone system blockers and SGLT2 inhibitors slows kidney disease progression and cardiovascular complications. Antiplatelet and anticoagulant therapies must be individualized to balance ischemic and bleeding risks, particularly in dialysis patients. Emerging trial data endorse the early and combined application of these therapies, moving from reactive to proactive cardiovascular risk mitigation in CKD. Personalization based on patient comorbidities, kidney function, and life goals is paramount. By integrating novel therapeutics and evidence-based clinical strategies, clinicians can defy the odds imposed by CKD, substantially reducing cardiovascular mortality and enhancing patient quality of life. The future holds promise as evolving research broadens the therapeutic toolkit and deepens understanding of cardio-renal interactions. References: 1. Jankowski J, et al. cardiovascular disease in chronic kidney disease. Circulation. 2021; Abstract and Figure data. 2. Ahmad E, et al. Trends in cardiovascular mortality in patients with CKD. J Am Heart Assoc. 2025. 3. Xie K, et al. Global burden of CKD. Lancet. 2025. 4. Feldman H, et al. PCSK9 inhibitors in CKD patients. J Am Soc Nephrol. 2025. 5. Medscape Reports. Fish Oil Reduces Cardiovascular Events in Dialysis Patients. 2025. 6. SGLT2i Trials CREDENCE, DAPA-CKD, EMPA-KIDNEY. NEJM and Lancet 2020-2023. 7. ESC Guidelines 2023. Management of Hypertension in CKD. 8. Frontiers Cardiovasc Med. Antiplatelet strategies in CKD. 2025.

Downloads

Published

2025-11-15

Issue

Vol. 3 No. 2 (2025): Fighting Against the Odds: Reducing Cardiovascular Mortality in CKD

Section

Articles

How to Cite

Fighting Against the Odds: Reducing Cardiovascular Mortality in CKD . (2025). Diabzen, 3(2), 31-34. https://www.thediabzen.com/index.php/d/article/view/16

Most read articles by the same author(s)