Extracorporeal Renal Replacement Therapies in the Treatment of Sepsis: Where Are We? Lui G. Forni, MB, PhD, * Zaccaria Ricci, MD, † and Claudio Ronco, MD ‡,§ Summary: Acute kidney injury (AKI) is common among the critically ill, affecting approximately 40% of patients. Sepsis is the cause of AKI in almost 50% of cases of intensive care patients, however, any evidence-based treatment for sepsis-associated AKI is lacking. Furthermore, the underlying pathophysiology of septic AKI is inadequately understood given the disparity between severe functional changes and limited tubular injury. What is clear is that within this complex interplay leading to septic AKI, the inflammatory response plays a pivotal role and hence modulation of this response may translate to improved outcomes. We outline the use of extracorporeal therapies in the treatment of sepsis and septic AKI. We consider the classic aspects of extracorporeal renal replacement therapy including indications, timing, and delivered dose. The various techniques that currently are used to try and achieve immune homeostasis also are outlined. As well as discussing the evidence accumulated to date, we also suggest possibilities for the future treatment of our patients. Semin Nephrol 35:55-63 C 2015 Elsevier Inc. All rights reserved. Keywords: Extracorporeal circuit, Sepsis, AKI, RRT S evere sepsis continues to be a major global cause of both mortality and morbidity. 1 Encourag- ingly, recent data have implied a reduction in the overall mortality rate from sepsis as shown by the Protocol-Based Care for Early Septic Shock study in which the observed overall mortality rate was lower than that shown 10 years previously. 1,2 However, mortality from severe sepsis in the intensive care unit (ICU) remains one of the most frequent causes of death with little effective targeted therapy. 3 The pathogenesis of sepsis is complex, involving many cellular and biochemical interactions, including endothelial cells, leukocytes, platelets, and the complement system. 4 Moreover, this maelstrom of cellular activity leads to the production of a wide range of inflammatory mediators that propagate the host response, leading to the clinical syndrome of septic shock with multiorgan involvement often distant from the primary source. 5 The development of the multiorgan dysfunction syn- drome consequent to the septic cascade portends a grave prognosis and as intensivists we continue to strive for additions to our armamentarium against the septic process. At present, treatment relies predominantly on source control and the use of anti- biotics, together with organ support when necessary. 6 However, a correlation was observed between the concentrations of circulating inflammatory cytokines and mortality in patients with septic shock. Patients with higher levels of proinflammatory and anti- inflammatory mediators had the highest observed mortality rates. 7–9 Therefore, it is of no great surprise that with the advent of extracorporeal techniques, the hypothesis has been proposed that adequate removal of inflammatory mediators from the circulation may provide a potential therapy for this devastating con- dition. Indeed, more than 20 years ago it was suggested that extracorporeal blood purification techniques may provide an adjunct in treating severe sepsis by remov- ing inflammatory mediators from the plasma of patients with sepsis and improve pulmonary function. 10 Furthermore, subsequent surrogate improvements with the use of hemofiltration were reported in both animal and human studies, showing that inflammatory cyto- kines can be removed from both the circulation of animals and human beings with septic shock, lending more support to this idea. 11,12 This was advanced further when a survival benefit associated with higher dosages of continuous hemofiltration was reported. 13 There are several factors that need to be considered regarding the role and application of extracorporeal renal replacement therapies (RRTs) in the treatment of sepsis. When commencing RRT, the including indica- tions for treatment, timing of the treatment, and the dose used must be considered. Attention should be given to these aspects of replacement therapy regardless of the setting. Second, there is the potential application of these techniques to attempt immunomodulation and immune homeostasis, as well as the application of new technologies to try and improve patient outcomes from this devastating condition (Fig 1). 0270-9295/ - see front matter & 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semnephrol.2015.01.006 Financial disclosure and conflict of interest statements: none * Department of Intensive Care Medicine, Surrey Peri-operative Anaesthesia Critical Care Collaborative Research Group, Royal Surrey County Hospital, and Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK. † Department of Paediatric Cardiac Surgery, Bambino Gesu Chil- dren’s Hospital, Rome, Italy. ‡ International Renal Research Institute, Vicenza, Italy. § Department of Nephrology, St Bortolo Hospital, Vicenza, Italy. Address reprint requests to Lui G. Forni, Department of Critical Care, Worthing Hospital Western Sussex Hospitals Trust, Lynd- hurst Road, Worthing BN11 2DH, UK. E-mail: luiforni@nhs.net Seminars in Nephrology, Vol 35, No 1, January 2015, pp 55–63 55