Metabolic Serum Profiles for Patients Receiving Allogeneic Stem Cell Transplantation: The Pretransplant Profile Differs for Patients with and without Posttransplant Capillary Leak Syndrome

Table 2

The biological functions of the seven metabolites showing the largest difference when comparing pretransplant serum levels for patients with and without posttransplant capillary leak syndrome (random forest analysis, see Figure 1): a summary of known effects on endothelial cells, renal function, and vascular permeability.

Metabolite; (main class)	Biological functions relevant for fluid and electrolyte balance
Homocitrulline; (amino acid)	Homocitrulline and ornithine are linked together in the urea cycle, and genetic defects in ornithine transport into mitochondria cause increased systemic homocitrulline levels [16]. Homocitrulline is also a product derived from carbamylation, a nonenzymatic posttranslational protein modification with binding of isocyanic acid to ε-amino groups of lysine, and serum/plasma homocitrulline levels may reflect the overall carbamylation process including carbamylation of tissue proteins [17]. Serum homocitrulline levels and carbamylation seem important for vascular biology, and high plasma citrulline is associated with severe coronary artery disease [17], risk of cardiovascular death [18], and increased mortality in renal failure [19]. It is not known whether homocitrulline/carbamylation is important for regulation of vascular permeability or regulation of paracellular or transendothelial transport, but carbamylation of low density lipoprotein induces endothelial cell dysfunction [20].
1-Methylhistidine; (amino acid)	Anserine (beta-alanyl-1-methyl-L-histidine) is present in many kinds of vertebrate muscles but not in human muscles; 1-methylhistidine is derived from metabolism of anserine and may thus reflect the nutritional status of the patients [21].
Betaine; (amino acid)	Betaine is found in many foods including spinach and wheat, and it accumulates in renal medullary cells during adaptation to hypertonic stress [22]. The primary role of betaine in the kidney seems to be osmoprotection; intracellular accumulation is then mediated by the betaine/GABA transporter. Thus, betaine seems to be involved in renal regulation of fluid balance.
Methoxytyramine; (amino acid)	This is the O-methylated metabolite of dopamine [23] and recent studies suggest that it can be used as a marker for dopamine-producing tumors [24]. Dopamine is involved in renal regulation of body fluid and electrolyte balance; these effects are mediated through binding to specific dopamine receptors that regulate the function of Na^+/K^+-ATPase [25]. Animal studies suggest that altered dopamine-induced signaling is important for fluid retention in nephrotic syndrome [26]. Thus, the increased methoxytyramine levels may reflect altered dopamine metabolism that contributes to fluid retention through a renal mechanism. Dopamine may also be important for fluid extravasation in other vascular beds [27].
Methionine sulfone; (amino acid)	Methionine can be oxidized to methionine sulfone during food processing; this metabolite seems to reduce the effectiveness of gut proteases to digest dietary proteins and its plasma/serum levels may reflect the nutritional status [28, 29].
Caffeine; (xenobiotics)	Serum caffeine levels are not only determined by the intake but are rather determined by several additional factors, including physical activity, the fat mass, and carbohydrate intake (i.e., nutritional status) [30, 31].
N^δ-Acetylornithine; (amino acid)	This is a nonprotein amino acid found in various plants [32]; its level may thus be related to the nutritional status.