Esaxerenone in Elderly Patients with Hypertension and Chronic Kidney Disease: A Comprehensive Review

Abstract

Esaxerenone, a novel non-steroidal mineralocorticoid receptor antagonist (MRA), has emerged as a promising therapeutic agent for elderly patients with hypertension and chronic kidney disease (CKD). This review critically examines recent PubMed-indexed evidence on the clinical efficacy, safety, and mechanistic rationale for esaxerenone in this high-risk population. We discuss the epidemiology, pathophysiology, and clinical characteristics of hypertension and CKD in the elderly, review diagnostic and therapeutic considerations, highlight recent advances, and synthesize guideline recommendations to provide a practical, evidence-based perspective for healthcare professionals.

Introduction

Hypertension and chronic kidney disease (CKD) are prevalent and frequently coexist in elderly populations, contributing significantly to morbidity, mortality, and health care burden worldwide. Optimal management remains challenging due to age-related physiological changes, polypharmacy, and increased risk of adverse events. Mineralocorticoid receptor antagonists (MRAs) have demonstrated efficacy in blood pressure (BP) control and renal protection, but the use of traditional steroidal MRAs is limited by the risk of hyperkalemia and hormonal side effects. Esaxerenone, a newly approved non-steroidal MRA, offers a favorable safety profile and potent mineralocorticoid receptor blockade, making it a promising option for elderly patients with hypertension and CKD. This article provides a comprehensive review of esaxerenone's role in this patient population, synthesizing current evidence, clinical insights, and guideline-based recommendations.

Epidemiology / Disease Burden

The global burden of hypertension and CKD is rapidly increasing, particularly among the elderly. Epidemiological data indicate that over two-thirds of adults aged 65 years and older have hypertension, and the prevalence of CKD in this demographic exceeds 20%. The coexistence of these conditions exponentially increases the risk of cardiovascular events, heart failure, and progression to end-stage renal disease (ESRD). Elderly patients are especially vulnerable due to cumulative vascular injury, comorbidities, and age-related decline in renal function. The intersection of hypertension and CKD in this group constitutes a major public health challenge, underscoring the need for safe and effective therapeutic strategies.

Pathophysiology

Hypertension and CKD are linked by complex pathophysiological mechanisms. In the elderly, arteriosclerosis, endothelial dysfunction, and increased arterial stiffness contribute to elevated systolic BP and impaired renal autoregulation. Overactivation of the renin-angiotensin-aldosterone system (RAAS) plays a pivotal role, leading to sodium retention, volume expansion, and further renal damage. Aldosterone, acting via mineralocorticoid receptors, induces inflammation, fibrosis, and cardiovascular remodeling. This pathophysiological interplay accelerates renal decline and heightens cardiovascular risk, especially in elderly patients with established CKD.

Risk Factors

Several risk factors predispose elderly patients to hypertension and CKD, including advanced age, genetic predisposition, diabetes mellitus, obesity, metabolic syndrome, and exposure to nephrotoxic agents. Age-related decline in renal function, reduced nephron mass, and increased salt sensitivity further exacerbate BP elevation and renal impairment. Polypharmacy, frequent in this population, can complicate management and increase the risk of drug interactions and adverse effects.

Clinical Features

The clinical presentation of hypertension in elderly CKD patients is often insidious, with many individuals remaining asymptomatic until advanced disease stages. Common findings include elevated systolic BP, widened pulse pressure, and signs of target organ damage such as left ventricular hypertrophy, retinopathy, and proteinuria. CKD may manifest as fatigue, nocturia, edema, or laboratory abnormalities such as elevated serum creatinine and reduced estimated glomerular filtration rate (eGFR). Early detection through routine screening is critical for timely intervention.

Diagnosis

Diagnosis involves accurate BP measurement, assessment of renal function (eGFR, serum creatinine), and evaluation of albuminuria/proteinuria. Additional investigations include urinalysis, renal imaging, and exclusion of secondary causes. Risk stratification and staging of CKD are essential for guiding therapy. In elderly patients, careful consideration of comorbidities and functional status is paramount to avoid overtreatment and iatrogenic complications.

Treatment & Management

Management of hypertension in elderly CKD patients requires a multifaceted approach, targeting BP control, renal protection, and mitigation of cardiovascular risk. Lifestyle modification, including sodium restriction, weight management, and physical activity, forms the cornerstone of therapy. Pharmacologic treatment often includes RAAS inhibitors (ACE inhibitors/ARBs), calcium channel blockers, diuretics, and MRAs. Esaxerenone, as a selective non-steroidal MRA, offers potent BP lowering and antiproteinuric effects with a lower risk of hyperkalemia compared to traditional MRAs. Dose adjustment and monitoring of electrolytes are recommended, especially in advanced CKD.

Recent Advances / Emerging Therapies

Esaxerenone has demonstrated significant efficacy in recent randomized controlled trials (RCTs), including the ESAX-HTN and ESAX-CKD studies, which enrolled elderly Japanese patients with hypertension and CKD. Results showed robust reductions in BP and urinary albumin excretion, with a safety profile comparable to placebo and superior to eplerenone. Esaxerenone\'s unique structure confers high selectivity for mineralocorticoid receptors, minimizing off-target hormonal effects and reducing the incidence of hyperkalemia. Emerging data suggest potential benefits in heart failure and diabetic nephropathy, expanding its therapeutic scope in the elderly CKD population.

Guideline Recommendations

Recent hypertension and CKD management guidelines, including those from the Japanese Society of Hypertension (JSH) and Kidney Disease: Improving Global Outcomes (KDIGO), now recognize the role of non-steroidal MRAs such as esaxerenone in patients intolerant to or inadequately controlled on traditional agents. Recommendations emphasize individualized BP targets, careful monitoring for hyperkalemia, and consideration of comorbidities. Esaxerenone is positioned as a valuable option for elderly CKD patients with persistent proteinuria or resistant hypertension, offering clinical benefits with an improved safety margin.

Conclusion

Esaxerenone represents a significant advance in the pharmacological management of hypertension and CKD in elderly patients. Its selective mechanism of action, favorable efficacy, and improved safety profile address key limitations of traditional MRAs. Ongoing studies and real-world evidence will further clarify its long-term impact on renal and cardiovascular outcomes. Clinicians should consider esaxerenone as part of an individualized, guideline-based treatment strategy for elderly patients with hypertension and CKD while maintaining vigilant monitoring to optimize benefits and minimize risks.