The potential effect of albumin replacement on immune modulation and sphingosine 1-phosphate dynamics.

Hypoalbuminemia is common in critically ill patients, yet albumin replacement remains controversial. Beyond volume regulation, albumin transports sphingosine 1-phosphate (S1P), a key modulator of immunity and endothelial stability. This study investigates how human albumin (HA) affects S1P distribution between high-density lipoprotein (HDL-cholesterol, HDL) and serum albumin (SA) and its impact on lymphocyte migration and vascular integrity ex vivo. Between March 2022 and February 2023, a prospective observational cohort study (AlbuS1P Study) was conducted in an intensive care unit (ICU). A total of 47 patients were enrolled and stratified based on baseline SA levels: Group A (normal SA, untreated control), Group B (low SA, untreated control) and Group C (low SA, treated with 180 g HA over three days). Blood samples were collected at multiple time points for laboratory analyses, including S1P quantification, immune cell assessments, ApoM ELISA and flow-induced dispersion analysis (FIDA) to determine S1P binding to SA or HDL. In this cohort study of 42 ICU patients with hypoalbuminemia, HA administration increased SA-levels (+ 0.7 g/dL, + 40%) but had no effect on free plasma S1P levels. HA treatment tended to shift S1P binding from HDL to SA in vivo and coincided with lower CD4⁺ T cell and CD19⁺ B cell counts, a finding that could be consistent with, but does not prove, reduced S1P-driven immune cell migration. In contrast, ex vivo assays showed no significant effects of HA-treated plasma on endothelial barrier function or S1P-mediated lymphocyte chemotaxis. These findings are consistent with the notion that HA treatment may modulate S1P distribution in vivo in patients, potentially influencing immune cell dynamics without evidence of impaired vascular stability. HA redistributed S1P from HDL to SA without altering total plasma S1P levels. This shift may correlate with immune modulation and had no negative effect on endothelial stability or cell migration ex vivo. Future studies should identify patient endotypes and subgroups, such as those with low HDL or hyperinflammation, who may benefit from HA’s immunomodulatory effects.