Current Perspectives in Kidney Diseases. Группа авторов
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.
References
1 Clark E, Bagshaw SM: Long-term risk of sepsis among survivors of acute kidney injury. Crit Care 2014;18:103.
2 Mehta RL, Bouchard J, Soroko SB, Ikizler TA, Paganini EP, Chertow GM, et al: Sepsis as a cause and consequence of acute kidney injury: program to improve care in acute renal disease. Intensive Care Med 2011;37:241–248.
3 Dellepiane S, Marengo M, Cantaluppi V: Detrimental cross-talk between sepsis and acute kidney injury: new pathogenic mechanisms, early biomarkers and targeted therapies. Crit Care 2016;20:61.
4 Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, et al: Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 2012;366:2055–2064.
5 Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al: The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 2016;315:801–810.
6 Murugan R, Karajala-Subramanyam V, Lee M, Yende S, Kong L, Carter M, et al: Acute kidney injury in non-severe pneumonia is associated with an increased immune response and lower survival. Kidney Int 2010;77:527–535.
7 Di Giantomasso D, Morimatsu H, May CN, Bellomo R: Intrarenal blood flow distribution in hyperdynamic septic shock: effect of norepinephrine. Crit Care Med 2003;31:2509–2513.
8 Mariano F, Cantaluppi V, Stella M, Romanazzi GM, Assenzio B, Cairo M, et al: Circulating plasma factors induce tubular and glomerular alterations in septic burns patients. Crit Care 2008;12:R42.
9 Cantaluppi V, Quercia AD, Dellepiane S, Ferrario S, Camussi G, Biancone L: Interaction between systemic inflammation and renal tubular epithelial cells. Nephrol Dial Transplant 2014;29:2004–2011.
10 Peng ZY, Zhou F, Kellum JA: Cross-species validation of cell cycle arrest markers for acute kidney injury in the rat during sepsis. Intensive Care Med Exp 2016;4:12.
11 Gupta RK, Chhibber S, Harjai K: Quorum sensing signal molecules cause renal tissue inflammation through local cytokine responses in experimental UTI caused by Pseudomonas aeruginosa. Immunobiology 2013;218:181–185.
12 Opal SM, Laterre PF, Francois B, LaRosa SP, Angus DC, Mira JP, et al: Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA 2013;309:1154–1162.
13 Chen J, Hartono JR, John R, Bennett M, Zhou XJ, Wang Y, et al: Early interleukin 6 production by leukocytes during ischemic acute kidney injury is regulated by TLR4. Kidney Int 2011;80:504–515.
14 Solini A, Usuelli V, Fiorina P: The dark side of extracellular ATP in kidney diseases. J Am Soc Nephrol 2015;26:1007–1016.
15 Gerritsma JS, Hiemstra PS, Gerritsen AF, Prodjosudjadi W, Verweij CL, Van Es LA, et al: Regulation and production of IL-8 by human proximal tubular epithelial cells in vitro. Clin Exp Immunol 1996;103:289–294.
16 Panacek EA, Marshall JC, Albertson TE, Johnson DH, Johnson S, MacArthur RD, et al: Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab')2 fragment afelimomab in patients with severe sepsis and elevated