Furosemide, a highly protein-bound organic acid, promotes free water clearance and natriuresis by entering the proximal tubules of the kidneys and blocking the sodium-potassium-chloride co-transporters in the thick ascending loop of Henle, thus inhibiting the reabsorption of sodium and chloride.1 It is a potent loop diuretic commonly used for the management of fluid overload. However, diuretic resistance, defined as the failure to achieve the desired level of diuresis despite maximal doses of diuretics, can occur in certain clinical situations.2
Hypoalbuminemia resulting from co-morbidities such as nephrotic syndrome, malnutrition, and cirrhosis has been associated with diuretic resistance stemming from decreased tubular secretion of furosemide into the urine.3–5 Other causes of diuretic resistance include vasoconstriction of kidney blood vessels, resulting in decreased delivery of diuretics and compensatory tubular sodium reabsorption in congestive heart failure (CHF) and impaired tubular secretion of diuretics in chronic kidney disease (CKD).2
Although the co-administration of albumin and furosemide in cases of diuretic resistance has been proposed to enhance the diuretic effect by restoring plasma oncotic pressure and facilitating the renal distribution and efficacy of furosemide, the clinical impact of this approach remains a topic of ongoing debate and may vary depending on the underlying cause of diuretic resistance.6-8 We review the evidence for and against the use of albumin to enhance the diuretic effect of furosemide.
Albumin Enhances the Diuretic Effect of Furosemide
You take over the care of a 67-year-old man with known CHF and stage 3 CKD, who was admitted to the hospital two days ago with worsening dyspnea. On admission, he had significant bilateral lower extremity edema, pulmonary crackles, and jugular venous distension. His labs revealed a creatinine level of 1.5 mg/dL and a serum albumin level of 2.1 g/dL. Initial treatment with intravenous furosemide 80 mg twice daily has been ineffective, and the patient has had minimal urine output with progressive weight gain and persistent dyspnea.
You suspect diuretic resistance, which is exacerbated by hypoalbuminemia, and administer 30 g of intravenous albumin followed by a 100 mg bolus of intravenous furosemide. The patient has a substantial increase in urine output and a decrease in dyspnea over the next 12 hours. You decide to continue intravenous albumin followed by furosemide twice daily until the patient is euvolemic.
Albumin Does Not Enhance the Diuretic Effect of Furosemide and May Have Harmful Effects
You take over the care of a 67-year-old man with known CHF who was admitted to the hospital two days ago with worsening dyspnea. On admission, he had significant bilateral lower extremity edema, pulmonary crackles, and jugular venous distension. His labs revealed a creatinine level of 1.1 mg/dL and a serum albumin level within normal range. Initial treatment with intravenous furosemide 80 mg twice daily has been ineffective, and the patient has had minimal urine output with progressive weight gain and persistent dyspnea.
You suspect diuretic resistance and administer 30 g of intravenous albumin followed by a 100 mg bolus of intravenous furosemide, hoping to enhance the diuretic response. The patient continues to have minimal urine output with progression of dyspnea and edema over the next 24 hours despite albumin administration.
Discussion
Diuretic resistance presents a common clinical challenge in hospitalized patients and has been associated with prolonged hospital stays, increased readmission rates, and elevated mortality rates.9,10 Co-administration of albumin and furosemide in cases of diuretic resistance has been proposed to enhance diuresis.
A 2021 meta-analysis evaluating the efficacy of furosemide and albumin co-administration found increased diuretic effect with co-administration of high-dose albumin (> 30 g; P = .02) and furosemide.6 Urine output increased by an average of 31.45 mL/hour (95% confidence interval [CI], 19.30 to 43.59) compared to furosemide treatment alone. However, the administered doses of albumin varied widely among the included studies, ranging from 6 g to 40 g, or weight-based dosing at 0.5 g/ kg.6 Patients with impaired renal function, particularly those with baseline creatinine level greater than 1.2 mg/dL (P = .07) or an estimated glomerular filtration rate of less than 60 ml/min/1.73m2 (P = .10), tended to exhibit a better response to the co-administration of albumin and furosemide, but without statistical significance. Increase in urine output was mainly observed within 12 hours of albumin infusion (P = .01), which is an ideal interval for a convenient twice-daily dosing regimen in the hospital.6 Additionally, there was significant heterogeneity among the included studies, characterized by limited participant enrollment and varying treatment responses. These factors contribute to uncertainty in the clinical application of these findings, as demonstrated by the observed difference in urine output, which, although statistically significant, is likely without meaningful clinical impact. Another meta-analysis of 10 studies also showed that administering albumin with furosemide led to a significant increase in the amount of urine volume (231 mL; 95% CI, 135.5 to 326.5) and sodium excretion (15.9 mEq; 95% CI, 4.9 to 26.8) in eight hours. However, these differences were not significant at 24 hours.11
Notably, in low albumin states (<2.5 g/dL; P = .04) like nephrotic syndrome, cirrhosis, or severe malnutrition, co-administration of high-dose albumin and furosemide improved urine output and sodium excretion.6 However, the beneficial effect of plasma albumin is transient due to rapid urinary loss of the infused albumin. The Kidney Disease: Improving Global Outcomes, or KDIGO, guideline states that in nephrotic patients, most administered albumin is rapidly excreted, and any effect on plasma albumin is short-lived.6,7 Similarly, in patients with cirrhosis, an open-label, randomized, controlled trial using albumin with furosemide to help augment diuresis did not significantly increase the diuretic effect.12
Another potentially beneficial application of the co-administration of albumin and furosemide is in critically ill patients, where combination therapy may aid in achieving the desired levels of fluid removal while maintaining hemodynamic stability by providing colloidal volume support alongside diuresis.13,14 In addition to hemodynamic stabilization, this approach may improve oxygenation in patients with hypoproteinemia and acute lung injury.14 However, a non-blinded, prospective, randomized trial demonstrated no significant increase in urine output when albumin was used with furosemide for diuresis in critically ill patients with hypoalbuminemia.15 Additionally, the efficacy of edema resolution remains unclear.6
Finally, albumin administration is not without potential risks. Albumin is a colloid derived from human plasma, which can rapidly increase intravascular volume and acutely worsen hypertension, lead to pulmonary edema, or exacerbate acute heart failure in patients who are not truly hypovolemic or in those with renal and cardiac dysfunction.7,16,17 As with any blood-derived product, there is a risk of allergic reactions, especially in those with IgA deficiency, anaphylaxis, or transmission of infectious agents, although these are rare with highly purified modern preparations.18 Albumin is also expensive and limited in supply compared to other evidence-based strategies to address diuretic resistance, such as dual nephron blockade with the addition of either a thiazide-like diuretic (e.g., metolazone) or a carbonic anhydrase inhibitor (e.g., acetazolamide).19,20 Moreover, sodium-glucose co-transporter 2 inhibitors (e.g., empagliflozin or dapagliflozin) can be added to help augment diuresis along with diuretic dose escalation guided by spot urine sodium measurements.19,20
Growing evidence cautions against the routine use of furosemide-albumin co-administration, as literature evaluating the effects of albumin as an adjunct to diuresis is primarily limited to low-quality, heterogeneous studies that have observed conflicting results. Several meta-analyses have concluded that the co-administration of albumin and furosemide has a marginal and short-lived increase in urine output and sodium excretion in select populations with hypoalbuminemia or CKD.6,8,11,21,22 Yet other studies have failed to demonstrate a consistent or clinically meaningful benefit of using albumin with furosemide compared to furosemide alone. Given the potential risks and increased costs associated with the addition of albumin, its routine use should be reserved for clinical situations with established treatment guidelines where its benefit is well-established, such as volume expansion after large-volume paracentesis or in spontaneous bacterial peritonitis with cirrhosis. However, co-administration of albumin and furosemide may be appropriate in certain diuretic-resistant patients with hypoalbuminemia or CKD who have exhausted all other treatment options. The clinical effectiveness of co-administration of albumin and furosemide to overcome diuretic resistance remains controversial, and further large-scale, randomized, controlled trials are needed to definitively assess its efficacy and safety in diuretic-resistant clinical settings.
Dr. Khalighi
Dr. Ackermann
Dr. Khalighi is a clinical associate professor of medicine at the University of Washington and director of the preoperative medicine consult clinic at the VA Puget Sound Health Care System, both in Seattle. Dr. Ackermann is a hospitalist and clinical associate professor of medicine at Thomas Jefferson University Hospital in Philadelphia.
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