Plasma resuscitation restores glomerular hyaluronic acid and mitigates hemorrhage-induced glomerular dysfunction.

Abstract

Acute renal dysfunction following hemorrhagic shock and resuscitation carries significant morbidity and mortality. While shock-induced shedding of the glycocalyx is well described within the pulmonary and splanchnic vasculature, less is known regarding early alterations to the glycocalyx of the renal microcirculation, particularly the glomerulus. We sought to evaluate the impact of hemorrhagic shock and resuscitation modalities on glomerular glycocalyx metabolism and function. We hypothesized that fresh frozen plasma resuscitation would attenuate glomerular glycocalyx shedding and reduce glomerular barrier dysfunction. Male Sprague-Dawley rats were subjected to 60 minutes of hemorrhagic shock to 40% of baseline mean arterial pressure, followed by resuscitation with shed whole blood and either lactated Ringer's or fresh frozen plasma. Experimental groups included the following: ( a ) baseline, ( b ) post-hemorrhagic shock, ( c ) post-lactated Ringer's resuscitation, and ( d ) post-plasma resuscitation. Enzyme-linked immunosorbent assays and immunohistochemistry were used to evaluate alterations of syndecan-1 and hyaluronic acid within the glomerular glycocalyx. Urine protein concentration was measured as a surrogate for glomerular function, and expression of cubilin and megalin was quantified to evaluate renal tubule protein reabsorptive capacity. Despite evidence of systemic glycocalyx shedding, hemorrhagic shock and resuscitation did not alter glomerular synedcan-1 expression. However, shock induced shedding of hyaluronic acid from the glomerular glycocalyx. While hyaluronic acid breakdown was exacerbated by crystalloid resuscitation, plasma utilization restored levels back to baseline. Urine protein concentration drastically increased following hemorrhagic shock and resuscitation with lactated Ringer's. By contrast, plasma administration reduced urine protein levels back to normal. Renal cortex cubilin and megalin expression did not differ among the experimental groups, suggesting that alterations in urine protein were driven by changes in glomerular function. Plasma-based resuscitation appears to reverse shock-induced shedding of glomerular hyaluronic acid and attenuates glomerular barrier dysfunction. Differential shedding of the glomerular glycocalyx may represent a novel pathway in acute kidney injury pathophysiology.