Why do urinary angiotensinogen concentrations increase in acute heart failure?

Why Urinary Angiotensinogen Concentrations Increase in Acute Heart Failure

Urinary angiotensinogen (uAGT) concentrations increase in acute heart failure primarily due to activation of the intrarenal renin-angiotensin-aldosterone system (RAAS) and venous congestion that impairs renal perfusion pressure. This elevation reflects the pathophysiological mechanisms underlying the cardiorenal syndrome that develops during acute heart failure episodes.

Pathophysiological Mechanisms

Venous Congestion as Primary Driver

The primary mechanism responsible for increased uAGT in acute heart failure is venous congestion, which:

• Decreases the arteriovenous pressure gradient across the kidney, reducing effective renal perfusion pressure (calculated as the difference between mean arterial pressure and central venous pressure) 1
• Increases hydrostatic pressure in the kidney, reducing the pressure gradient across Bowman's capsule and impairing glomerular filtration 2
• Creates a vicious cycle where congestion leads to kidney dysfunction, which further worsens fluid retention and congestion 2

RAAS Activation

Acute heart failure triggers significant neurohormonal responses:

• Reduced cardiac output decreases renal perfusion, activating the RAAS 1
• The sympathetic nervous system is activated in response to decreased cardiac output 1
• These systems promote sodium and water retention, vasoconstriction, and increased angiotensin II production 1
• Intrarenal RAAS activation is reflected by increased production and excretion of angiotensinogen in the urine 3

Clinical Significance of Urinary Angiotensinogen

Biomarker for Acute Kidney Injury

• uAGT serves as an early predictor of acute kidney injury (AKI) in patients with acute decompensated heart failure 4
• In a prospective two-stage study, uAGT levels peaked on the first hospital day in patients who subsequently developed AKI 4
• The highest quartile of uAGT on admission was associated with a 50-fold increased risk of AKI compared to the lowest quartile 4

Correlation with Heart Failure Status

• uAGT levels significantly decrease between admission and discharge as clinical status improves 3
• Changes in uAGT correlate with changes in NT-proBNP levels, a well-established biomarker of heart failure severity 3
• uAGT can predict 1-year mortality and rehospitalization risk in acute decompensated heart failure patients 4

Therapeutic Implications

Understanding the relationship between uAGT and acute heart failure has important therapeutic implications:

• Diuretic therapy, which is the mainstay of congestion management, affects RAAS activation 5
• Continuous infusion of furosemide and ultrafiltration are associated with greater increases in plasma renin activity compared to bolus diuretic administration 5
• RAAS inhibitors (ACE inhibitors, ARBs) should be used cautiously in patients with marginal cardiac output as they may significantly reduce glomerular filtration 1
• A GDMT-centered (Guideline-Directed Medical Therapy) approach to decongestion that addresses the underlying pathophysiology may be more effective than a purely diuretic-centered approach 1

Clinical Monitoring Considerations

When managing patients with acute heart failure:

• Monitor for signs of congestion (jugular venous distention, peripheral edema, pulmonary rales) 2
• Track renal function parameters, as worsening renal function is defined as a 25% increase in baseline creatinine, an absolute increase of 26.4 μmol/L, or a 20% decrease in eGFR 2
• Consider uAGT as a potential biomarker for risk stratification and monitoring treatment response 4, 3
• Target a near-zero fluid balance to reduce complications 2

Conclusion

The increase in urinary angiotensinogen concentrations in acute heart failure reflects the complex interplay between cardiac dysfunction, venous congestion, and neurohormonal activation. This biomarker not only indicates the severity of heart failure but also predicts the development of acute kidney injury and long-term outcomes, making it a potentially valuable tool for clinical monitoring and risk stratification.