Specific Extracorporeal Therapies for S-AKI
Blood purification therapies able to remove inflammatory substances from the circulation of septic patients include: diffusion-based hemodialysis, convection-based hemofiltration, mixed diffusive-convective therapies (hemodiafiltration), plasma-filtration and adsorption, hemoperfusion and some combinations of them. Nowadays, a consensus on the optimal extracorporeal treatment for S-AKI is still lacking and many randomized clinical trials only reported an improvement of hemodynamics without any positive effect on outcome. Standard RRT therapies using high-flux membranes or adsorptive membranes include continuous veno-venous hemofiltration (CVVH), continuous veno-venous hemodialysis and continuous veno-venous hemodiafiltration have been evaluated for S-AKI treatment. The high-flux membranes have an average cut-off of 30–40 kDa and are able to eliminate significant amounts of inflammatory mediators including chemokines and cytokines. Other types of membranes such as polymethylmethacrylate and AN69ST are capable of adsorbing inflammatory mediators that are known to play a key role in the pathogenic mechanisms of S-AKI; this is the case of HMGB-1 which, despite small size (26 kDa), is not removed by convection but exclusively by adsorption [55]. However, we must emphasize that these inflammatory mediators have a very high generation rate: for this reason, many studies using RRT failed to show any significant modulation of plasma levels of different cytokines [56]. These standard RRT strategies may also adopt the use of HCO, which are porous enough to remove large molecules (approximately 15–60 kDa). Several studies showed clinical benefits associated with the use of HCO membranes: improved immune cell function and removal of inflammatory cytokines, with a decreased dose of norepinephrine in S-AKI patients [57]. An undesired effect of HCO is represented by albumin loss, which can be attenuated by albumin replacement or by using HCO membranes in a diffusive rather than a convective manner [58].
Convection-based high-volume therapies (HVHF) are defined by a flow rate of more than 35 mL/kg/h. To achieve HVHF, it is necessary to use a high permeability membrane with a large surface area and a sieving coefficient close to 1 for a wide spectrum of molecules. HVHF has been shown to improve hemodynamic and survival in patients with refractory septic shock [46]. On the contrary, a recent Cochrane review [59], comparing HVHF with standard dialysis, did not show any improvements in patients’ outcome. Furthermore, the use of HVHF may potentially cause increased clearance of antimicrobial agents, electrolyte disturbances and depletion of micronutrients.
Hemoperfusion, hemoadsorption and plasma adsorption are techniques in which a sorbent is placed in an extracorporeal circuit in direct contact with blood or plasma, respectively. Polymyxin B (PMX-B) is a cationic polypeptide antibiotic with known activity directed to gram-negative bacteria and high affinity to endotoxin. The intravenous use of PMX-B is avoided in consideration of its nephrotoxicity and neurotoxicity. PMX-B has been fixed and immobilized onto polystyrene fiber in a hemoperfusion column cartridge that allows LPS removal without the above mentioned toxic effects [36]. The main mechanism of PMX-B action is the removal of circulating endotoxin, although its effects are likely pleiotropic including the aspecific entrapment of inflammatory cells. A preliminary study of PMX-B hemoperfusion added to conventional therapy showed an improvement of hemodynamics, less organ dysfunction and reduced 28-day mortality in patients with severe sepsis or septic shock from abdominal origin [60]. A recent multicenter randomized study did not demonstrate a significant difference in mortality or improvement in organ failure comparing PMX-B hemoperfusion with conventional treatments in patients with septic shock induced by peritonitis [61]. The first randomized, controlled, diagnostic-directed and theragnostic trial named “Evaluating the Use of PMX-B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock” (EUPHRATES) is still ongoing in the US and Canada [62]. However, meta-analysis showed that PMX-B treatment is the only adsorption strategy to impact patient’s mortality [63]. Moreover, the PMX-B-associated improvement of the SOFA score has been reported and experimental studies showed that after hemoperfusion, the pro-apoptotic effect of septic plasma on cultured human kidney-derived TECs was significantly decreased. These clinical and experimental results suggest that PMX-B hemoperfusion remove from the bloodstream LPS and other potential mediators of S-AKI [64].
Among other emerging adsorption strategies, CytoSorb is a biocompatible polymer, able to aspecifically adsorb inflammatory cytokines from the bloodstream. Kellum et al. [65] demonstrated, in experimental models of sepsis, that this sorbent is able to modulate chemokine gradients between infected tissue and healthy organs, thus directing leukocyte trafficking in the sites of tissue injury [41]. An increasing number of evidences based on clinical cases suggested that CytoSorb is efficient in removing septic mediators, bilirubin and myoglobin.
Coupled plasma filtration adsorption (CPFA) is based on aspecific adsorption of inflammatory mediators onto a sorbent located after a plasma filter: CPFA can be integrated with a standard RRT circuit. Experimental studies showed that CPFA is able to prevent microvascular failure with a consequent improvement of hemodynamic instability, respiratory parameters and a decreased use of vasopressors. The COMPACT study demonstrated that high volumes of plasma exchange using CPFA are mandatory to obtain a clinical benefit and the biological effects of protection against microvascular endothelial cell damage and immunoparalysis [66]. The randomized controlled trial COMPACT-2 is still ongoing in different Italian ICUs.
Last, conventional extracorporeal blood purification techniques remove toxic factors by plasma through filtration, thus mimicking kidney glomerular but not tubular function. Indeed, renal parenchyma contributes to metabolite clearance with tubular secretion (essential for protein-bound molecules) and releases several trophic factors such as erythropoietin and vitamin D. Based on this assumption, Dr. Humes group [67] implemented a standard RRT circuit with a polysulfone filter containing living kidney TECs. This renal assist device (RAD) was at first validated in large animal sepsis models: treated animals maintained reabsorption of K+, HCO3− and glucose, excretion of ammonia and normal levels of 1,25-OH-vitamin D3 [67]. Moreover, the authors found a significant reduction of inflammatory cytokines only in RAD-treated animals; interestingly, RAD was also able to regulate both the early inflammatory cytokines (e.g., IL-6) and the late-phase cytokines involved in post-septic immune-paralysis (IL-10 and G-CSF) [67]. Encouraged by these results, the same group performed a randomized controlled trial and showed a 50% reduction of 180-day mortality in patients treated with RAD compared to standard CVVH [67].