The 2021 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for the management of glomerular diseases recommends using loop diuretics as first-line therapy for treating edema in nephrotic syndrome. In patients with a serum albumin less than 2 g/dL who failed to respond to maximal dosing of intravenous (IV) diuretics, either alone or in combination, the panel recommends the addition of IV albumin to IV diuretic therapy to improve intravascular volume, diuresis, and natriuresis. Albumin can be administered either as a premixed solution with a loop diuretic or by giving 25 to 50 grams of albumin solution 30 to 60 minutes before administering a loop diuretic. It should be noted that in patients with nephrotic syndrome, most of the administered albumin will be rapidly excreted in the urine, and the effect on plasma albumin will be transient. [1]
Review articles have mentioned the lack of clinical evidence for the use of albumin as a treatment for nephrotic syndrome. In patients presenting with edema in severe nephrotic syndrome refractory to diuretics, albumin may enhance diuresis. However, meta-analyses reported conflicting results on the use of albumin alone or in combination with furosemide. Despite this, a 2020 review article recommends human albumin in two settings of nephrotic syndrome: intravascular hypovolemia and severe diuretic refractory edema. Recommended dosing includes human albumin 20% 0.5 to 1 g/kg over 3-4 hours for intravascular hypovolemia, followed by 0.5 to 1 mg/kg intravenous furosemide administration. Refractory edema patients may receive a higher dose of 1 g/kg over 3-4 hours followed by 2 mg/kg of furosemide. A 20% undiluted solution may be given but should not exceed a 2-4 mL/min infusion rate. Albumin may also be diluted to 5% with normal saline to administer a higher infusate volume. The authors recommend repeat doses of albumin in severe cases and monitoring for worsening hypertension, pulmonary edema, congestive heart failure, and anaphylactic reaction in patients. [2], [3]
A 2014 meta-analysis analyzing the combination of albumin plus furosemide for diuretic resistance in hypoalbuminemia presents a subgroup analysis of patients with nephrotic syndrome. Based on three clinical studies (N= 23, nephrotic syndrome due to primary renal disease were excluded), the summarized differences for the outcomes of urinary volume at <8 hours in nephrotic syndrome patients who received combination therapy versus those who did not was 378.4 mL (95% confidence interval [CI] 103.4 to 653.4 mL) and urinary volume at 24 hours was 420.5 mL (120.8 to 720.2 mL). Both outcomes are deemed statistically significant. In contrast, urinary sodium at <8 and 24 hours did not observe a statistically significant difference (24.2 mEq and 34.9 mEq respectively). [4]
A 2022 systematic review (5 studies; N= 54) compared the efficacy of furosemide alone versus furosemide with albumin in the treatment of nephrotic edema in adults and children with nephrotic syndrome. The review excluded patients with hypoalbuminemia of non-renal origin and severe chronic kidney disease (CKD) with a glomerular filtration rate below 30 mL/min/1.74 m2. The results showed greater urine excretion with furosemide and albumin compared to furosemide alone (standardized mean difference [SMD] 0.85; 95% CI 0.33 to 1.38). The results for sodium excretion were deemed inconclusive (SMD 0.37; 95% CI -0.28 to 1.02). Among included studies, published between 1995 to 2011, one study showed high risk of bias while other three were assessed to have some concerns. Given the suboptimal quality of evidence and small sample size in each respective study, the accumulated evidence was not sufficient to suggest definitive conclusions regarding the role of albumin in treating nephrotic edema. [5]
An attempt at a 2019 Cochrane meta-analysis was only able to locate one quality randomized controlled study investigating the use of human albumin for the treatment of edema in patients with nephrotic syndrome. The study consisted of 26 pediatric patients and compared albumin with furosemide. The authors reported no difference in weight loss up to 10 days between albumin and furosemide. However, due to inconsistent values, the outcomes remained uncertain. This uncertainty extends to the secondary outcome of effect on serum sodium, systolic blood pressure, and diastolic blood pressure. The quality is further questioned by the unreported allocation concealment and potential risk of bias. Cross-over studies were also excluded from the meta-analysis. [6]
A 2015 article observing albumin use to improve edema in nephrotic syndrome also reported conflicting evidence within the literature. Specifically, the combination of albumin and furosemide have observed improved diuresis and weight loss whether patients also present with hypoalbuminemia or not. But other studies with different outcome parameters observed a modest or little benefit. The heterogeneity between low-quality studies make it difficult to assess where combination therapy may be most effective and a definitive recommendation cannot be provided. [7]