The relationship between bilirubin levels and diuretic resistance in patients hospitalized with decompansated heart failure

Introduction and Objective: Heart failure (HF), with its chronic and progressive nature, poses a significant burden on healthcare systems due to frequent emergency visits and hospital admissions. Approximately 90% of unplanned hospital admissions in HF patients are attributed to volume overload. Diuretics form the cornerstone of decongestion therapy. Hospital stays are significantly prolonged in patients with diuretic resistance. Recent studies have shown that acetazolamide and sodium-glucose cotransporter-2 inhibitors (SGLT2i) accelerate decongestion in diuretic-resistant patients. Some studies have reported that ultrafiltration and similar therapies increase fluid removal and shorten hospitalization duration. While diuretic resistance may be predictable in patients on long-term high-dose diuretic therapy, it may not be feasible in some cases. Although spot urine sodium levels are a parameter indicating diuretic response, they are not always practical in daily practice. It has been demonstrated that elevated intravenous pressure in patients with right heart failure may contribute to renal tamponade and diuretic resistance. High intravenous pressure is known to affect not only renal function but also cause liver damage. The aim of this study is to investigate the relationship between bilirubin levels at admission and diuretic resistance. Methods: Our study is a retrospective, observational, and cross-sectional study. Patients admitted to Bezmialem Vakif University Coronary Intensive Care Unit with acute decompensated heart failure (ADHF) between February 21, 2024, and October 21, 2024, were included. Patients presenting with ADHF, whose bilirubin levels were measured at admission, and who received diuretic therapy according to European Society of Cardiology guidelines were enrolled. Exclusion criteria included acute myocardial infarction or acute pulmonary edema at presentation, end-stage renal disease requiring dialysis, lack of intake-output monitoring, and absence of spot urine sodium measurement. Demographic characteristics, xiv medications, physical examination findings, and hemodynamic parameters were obtained from nurse and physician records and the e-Nabız Personal Health System. Laboratory results, medications during hospitalization, and clinical events were retrieved from the hospital electronic records. Diuretic resistance was defined as spot urine sodium <50-70 mEq/L at 6 hours and average urine output <100-150 mL/hour over 6 hours. Results: The mean age of the patients was 71.0 ± 11.3 years, and 44 (51.8%) were female. Based on ejection fraction (EF), 38 (44.7%) had preserved EF, 10 (11.8%) had mildly reduced EF, and 37 (43.5%) had reduced EF. Hospital stay was significantly longer in the diuretic resistant group (6.0 ± 4.0 days vs. 3.2 ± 2.0 days, p=0.004). The most common comorbidities were hypertension (72.9%), diabetes mellitus (57.6%), coronary artery disease (56.5%), atrial fibrillation (55.3%), and chronic obstructive pulmonary disease (28.2%). Medications at admission included beta-blockers in 62 (72.9%), renin-angiotensin-aldosterone system (RAAS) inhibitors in 45 (52.9%), mineralocorticoid receptor antagonists (MRA) in 34 (40%), and SGLT2i in 24 (28.2%) patients. Furosemide was used by 69 (81.2%) and thiazides by 21 (24.7%). No significant association was found between diuretic resistance and other medications except MRAs (p>0.05). Diuretic resistance was detected in 12 (14.1%) patients. Spot urine sodium levels were significantly lower in resistant patients (40.92 ± 24.2 mmol/L vs. 98.75 ± 28.79 mmol/L, p<0.001). Univariate analysis identified significant predictors of diuretic resistance: total bilirubin (OR: 11.26, 95% CI: 3.06–41.43; p<0.001), lactate dehydrogenase (LDH) (OR: 1.01, 95% CI: 1.00–1.01; p=0.01), uric acid (OR: 1.36, 95% CI: 1.06–1.74; p=0.02), B-type natriuretic peptide (BNP) (OR: 1.00, 95% CI: 1.00–1.01; p=0.01), spot urine sodium (OR: 0.92, 95% CI: 0.87–0.96; p<0.001), IVC diameter (OR: 1.16, 95% CI: 1.04–1.29; p=0.01), and TAPSE (OR: 0.83, 95% CI: 0.69–0.99; p=0.04). MRA use was inversely associated with diuretic resistance (OR: 0.17, 95% CI: 0.04–0.70; p=0.01). Multivariate analysis revealed only total bilirubin (OR: 8.1, 95% CI: 1.46–45.09; p=0.02) and spot urine sodium (OR: 0.90, 95% CI: 0.83–0.97; p=0.01) as independent predictors. Other variables, including MRA use (p=0.19), LDH (p=0.19), uric acid (p=0.67), BNP (p=0.92), TAPSE (p=0.29), and IVC diameter (p=0.31), lost significance in multivariate analysis. xv Conclusion: A statistically significant association was found between serum total bilirubin levels and diuretic resistance in patients hospitalized for acute decompensated heart failure (ADHF). Our study suggests that elevated total bilirubin levels may serve as a predictive marker for diuretic resistance, enabling early identification of high-risk patients. These results require validation through larger prospective studies. Keywords: bilirubin, diuretic resistance, heart failure, edema, spot urine sodium