Prevention of Renal Medullary Vascular Congestion is Associated with Reduced Mortality and Preservation of Capillary Density Following Renal Ischemia

The aggregation of red blood cells in the microvascular of the renal medulla is a hallmark of ischemic acute kidney injury (AKI). Our lab has recently shown that pretreatment with low dose lipopolysaccharide (LPS) prior to ischemia‐reperfusion (IR) prevents this vascular congestion. It remains unknown, however, whether prevention of medullary vascular congestion improves recovery from IR. The goal of the current study was to test the hypothesis that ‘prevention of vascular congestion with low dose LPS improves functional recovery of the kidney and attenuates rarefaction of the renal medulla following IR’. Male WKY rats (8 weeks) were implanted with radiotelemetry devices (DSI, St. Paul, MN) and allowed to recover for two weeks prior to beginning blood pressure measurement. Rats were then randomized to receive injections (i.p.) of either low dose LPS (1000µg/kg) (n=4) to prevent vascular congestion or saline control (n=4) once daily for 3 days. 1 day following the 3 rd injection, all rats underwent a 45 minute, warm bilateral IR and were allowed to recover for 7 days. Blood pressure was measured for the duration of the study. Plasma was collected by tail vein pre‐IR and at sacrifice for measurement of creatinine (Cr) and blood urea nitrogen (BUN). Vascular rarefaction was assessed at sacrifice in histological kidney sections via %Threshold Area of CD34+ vascular endothelium (Metamorph). Following recovery of IR, there was a 100% and 50% survival rate in LPS treated and saline control rats, respectively. Saline control rats (with vascular congestion following IR) had a decrease in CD34+ vascular density in the inner stripe of the outer medulla (OM) (Unpaired t‐test, p=0.05) and the inner medulla (Unpaired t‐test, p=0.009), but there were no differences in CD34+ staining in the cortex (Unpaired t‐test, p=0.159) or outer stripe of the OM (Unpaired t‐test, p=0.095) ( Table 1 ). There were no differences in 24 hour mean arterial pressure between groups over the course of the study (two‐way RM ANOVA, p INTERACTION =0.689). At sacrifice, plasma Cr (p INTERACTION =0.249) and BUN (p INTERACTION =0.345) were not different between groups and had recovered to near pre‐IR values. Prevention of vascular congestion in LPS treated rats increased the 7 day survival to 100% following a 45 minute bilateral IR in contrast to control rats which, as expected, had a 50% survival rate. Importantly, this prevention of congestion was associated with preserved capillary density (CD43+) in the renal medulla. These data indicate an important role of vascular congestion to independently drive increased mortality and capillary rarefaction following IR. As renal vascular rarefaction has been implicated as an important factor in the progression to chronic kidney disease following AKI, prevention of vascular congestion may be an important target to prevent this deleterious sequelae.