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]. This trial was prematurely interrupted when the investigators observed a significant reduction of mortality also using a sham cartridge not containing viable tubular cells. Subsequently, they developed the so called selective cytophoretic device (SCD): SCD is similar to RAD but without tubular cells in the second filter. In this case, SCD is able to sequestrate activated leukocytes within the membrane, thus inhibiting the release of harmful mediators. Preliminary studies indicated that SCD reduced mortality and dialysis dependence in S-AKI patients. Interestingly, the outcome improvement was observed only when citrate, and not heparin, was used as an anticoagulant (see paragraph on anticoagulation strategies) [68].
The development of cell therapies associated with RRT may lead to a further improvement of S-AKI. Transplantation of mesenchymal stem cells (MSC) has been shown to reduce mortality and organ failure in experimental models of sepsis. Some reports showed the use of bioreactors that coupled standard RRT with a filter containing viable MSC able to secrete regenerative and immunomodulatory factors [69].
Antibiotic Dosing during RRT
In severe sepsis and septic shock early, appropriate, empiric and broad-spectrum antibiotics are the mainstay of treatment and represent a crucial factor in improving the patient outcome. In septic patients under RRT, the optimization of antibiotic dosing is mandatory but, unfortunately, data to guide dosing in these patients are limited. Patients are at risk of both over- and under-dosing with consequent risk of drug toxicity or treatment failure. When an antibiotic regimen is prescribed in S-AKI patients treated with RRT, several factors have to be considered: pharmacokinetics, patient weight, residual renal function, hepatic function, mode of RRT (membrane and surface area, sieving coefficient, effluent and dialysate rate and blood flow rate), minimum inhibitory concentration, volume overload etc. [70]. Studies that determine the serum antibiotic concentrations are very useful in establishing the correct dosage in critically ill patients, but available data are often based on old RRT modalities resulting in unhelpful/inaccurate dosing recommendations. The application of these older doses in Monte Carlo simulation studies revealed that many of the recommended dosing regimens will never attain pharmacodynamic target [71]. For these reasons, some authors encourage clinicians to prescribe antibiotics, in this vulnerable population, with large loading dose and higher maintenance doses to reach the targets [70, 71].
Conclusions
Sepsis is a serious medical condition frequently associated with the development of multiple organ failure and AKI. The association of sepsis and the loss of renal function determine high incidence of mortality and progression toward CKD. These negative results are possibly due to the lack of human invasive studies (i.e., kidney biopsy) and reliable pathogenic models. However, in recent years, large animal studies and ex vivo human experiments have provided new insights into the pathogenesis of S-AKI. Furthermore, the application of new RRT biotechnologies has opened a new scenario with encouraging clinical data. Despite most of these technologies (i.e., RAD, SCD, polymyxin and CPFA) need to be tested in large phase-3 clinical trials. Some technologies displayed impressive changes in patient mortality (up to 50% for RAD) or were proven to be effective by methanalitic investigations.
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