Biomarkers of Intravascular and Extravascular Volume Overload: Associations with Parameters of Cardio-Renal Dysfunction

Background Volume overload is a major driver of symptoms and organ dysfunction in heart failure. Although we typically focus on intravascular volume overload, the majority of fluid and sodium actually reside in extravascular spaces. The kidney regulates both intravascular and extravascular sodium and fluid stores. As such, markers of extravascular fluid overload may provide important cardio-renal information. Natriuretic peptides have emerged as the prototype biomarker of intravascular overload, released primarily in response to ventricular stretch. The use of carbohydrate antigen 125 (CA-125) in heart failure has also gained popularity. CA-125 is a glycoprotein produced largely from serosal epithelium such as pleura, pericardium, and peritoneum, and its increased circulation can be the result of extravascular volume retention and likely inflammation of these tissues. The goal of this analysis was to better understand the relative importance of intravascular vs. extravascular markers of volume overload on cardio-renal parameters. Methods Plasma NT-proBNP and CA-125 were measured in 199 outpatients presenting to the Yale Transition Care Center for evaluation and treatment of volume overload. Urine samples were collected before and after administration of loop diuretics, in addition to a timed urine collection. Diuretic efficiency was defined as sodium excretion per doubling of loop diuretic dose. Results The median level of CA-125 was 78 U/ml (IQR 28-187 U/ml) and the median NT-proBNP was 1860 pg/ml (IQR 607-4670 pg/ml). There was a modest correlation between these markers (r=0.40, p Conclusion Between the markers of intravascular volume overload (NT-proBNP) and extravascular volume overload (CA-125), we found that signals of intravascular volume overload appeared to have much more important effects on cardio-renal dysfunction. Additional research is warranted to better understand if this is related to the limitations of the biomarkers or the greater importance of intravascular fluid overload on cardio-renal function.