Kinetics of SuPAR hemoadsorption in critical COVID-19 patients on renal replacement therapy

SARS-CoV-2 viral infection is associated with a rapid and vigorous systemic inflammatory response syndrome. Innate and adaptive immunity responses may take up a month to fully mature, in some cases being harmful in the development process [1‐3]. These responses are associated with an increase in pro-inflammatory cytokines, sometimes causing a deranged response, i.e. “cytokine storm”, which has been shown as a potential factor worsening the clinical outcome [4‐6]. One of the treatments advocated to regulate the hyper-inflammatory response is hemoadsorption [7‐9]. This blood purification technique is most often carried out by integrating the adsorber in the extracorporeal circuit. It has been reported that levels of various pro-inflammatory cytokines are diminished during the first 24 hours of the therapy [9].

One of the novel inflammatory biomarkers is suPAR, soluble urokinase-type plasminogen activator receptor. This molecule is expressed in the membranes of various immune cells, associated both with innate and adaptive immunity: endothelial cells, macrophages, neutrophils and activated T-cells. During the immune response, this molecule is released into the circulation, showing either an ongoing chronic inflammation or an acute process and may be measured and evaluated in a quantitative manner [10, 11]. SuPAR has been recently reported as the predictor of the acute kidney injury in COVID-19 patients [12]. This biomarker has been described before as a potential starting mechanism of the acute kidney injury, being not only indicative of the damage, but also the cause of it. Furthermore, higher levels of suPAR have been associated with higher admission rates to the ICU, mechanical ventilation and prolonged stay in the hospital [13, 14]. In these studies, the suPAR is reported as a pro-inflammatory cytokine, propagating the deranged immune response [15‐17].

There are no clinical trials conducted concerning the hemoadsorption of suPAR. One of the reasons is the size of the suPAR molecule, which is measured from 20 to 50 kDa, depending on the degree of glycosylation and proteolytic cleavage form its membrane form. Therefore, it is unclear to what extent suPAR can be removed during the hemoadsorption procedure. There is a case report, showing that suPAR levels can be diminished up to 27% during the hemoadsorption procedure [18]. However, it is unclear whether this clearance can be sustained during the whole procedure and produce a substantial drop in systemic suPAR concentration. Therefore, the aim of this study is to determine the kinetics of suPAR clearance during hemoadsorption in COVID-19 patients.

One of the main findings of our study is that suPAR molecule can be effectively removed with hemoadsorber. In the beginning of the session almost 30% of the incoming suPAR was removed, these results are concordant to the clearance reported in other studies [18]. Also, the degree of clearance reported in our study is similar to other the molecules, which are comparable in size, polarity and ionization [19]. In the ending of the session where was a significant drop of adsorber capacity, plummeting to 7.2%. There is a number of reasons why this decrease could have happened, both conventional and specific to our study. Conventional reasons mainly comprise of saturation of the adsorber membranes, clotting and clogging [20, 21]. Reasons specific to our study are SARS-CoV-2 induced coagulopathy, microthrombosis and length of the procedure [22]. To express the importance of the procedure length, linear regression analysis was performed, linking hours of hemoadsorption with capacity of the adsorbed, showing that clearance capacity decreased by 2.4% per every hour. However, since increment of the regression curve is extrapolated from the samples taken after the 16 hours of the procedure, we cannot say whether there was some sort of non-linear drop of capacity during the first hours of the procedure. All these assumptions and results should be taken into consideration, in this particular time generating more questions rather than answers.

Second finding in our study was no change in systemic suPAR concentration in the beginning and ending of the session. The overall suPAR concentration was rather high in the beginning of the hemoadsorbtion procedure, 8.71 ng/ml. Comparing to the studies of COVID-19 patients the concentration measured in our study was high, indicating an active inflammatory process [12]. However, there are no studies showing suPAR concentrations in COVID-19 patients treated in the ICU, therefore we can not compare our results. After the first session the concentration decreased slightly, only about 5.6%, with no statistical significance, which is comparable to other studies dealing with hemoadsorption. However, there are some insights to be considered. Firstly, the blood flow during extracorporeal circuit in our study was selected to be 100 - 150 ml per minute, providing a high volume of liters perfused via adsorber per day. Adding an average clearance of 5.6% per hour form out study it would let us assume that if suPAR would not be produced during the session it would have been cleared to the minimum. Therefore, even though the overall concentration of suPAR is not being reduced, we can evidently state that a substantial amount is cleared. On the other hand, the concentration of 7.35 ng/ml after the session is still substantially increased, propagating the SIRS and organ failure. This would be expected, since most of the patients in our study were enrolled during their second week of COVID-19 disease, with an ongoing SIRS [23].

There are some limitations to our study. Our results demonstrate the kinetics of suPAR molecule during one hemoadsorption session. It is evident that adsorbers can clear the circulating suPAR molecules effectively, but clinical implementations of these findings are scarce. Firstly, the rate of suPAR production during SIRS, especially in COVID-19 patients is unknow. Form our study we can see that despite clearing a substantial amount of suPAR we did not achieve a lower concertation, suggesting an ongoing active production, which negates the amount cleared. Secondly, the measurements and sampling in our study were done in cross-sectional manner in the beginning and ending of the session, creating a static model, stagnant in representing real clinical cases. Furthermore, the sample size was small, complicating the statistical analysis and leaving the assumptions what would have been if large sample was enrolled. Finally, it is still unknown if stabilizing or lowering the concentration of suPAR would help to achieve better clinical outcomes.

This study concluded that in the beginning of the hemoadsorption procedure significant amount of suPAR is removed from the circulation. However, in the end of the procedure there is a substantial drop in adsorbed capacity. Furthermore, despite a substantial amount of suPAR cleared there is no significant difference in systemic suPAR concentrations before and after the hemoadsorption procedure.