Extracorporeal Renal Replacement Therapies in the Treatment of Sepsis: Where Are We?

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

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evere sepsis continues to be a major global cause of both mortality and morbidity.1 Encouragingly, 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 syndrome 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 *

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 Children’s Hospital, Rome, Italy. ‡ International Renal Research Institute, Vicenza, Italy. § Department of Nephrology, St Bortolo Hospital, Vicenza, Italy. Financial disclosure and conflict of interest statements: none Address reprint requests to Lui G. Forni, Department of Critical Care, Worthing Hospital Western Sussex Hospitals Trust, Lyndhurst Road, Worthing BN11 2DH, UK. E-mail: [email protected] 0270-9295/ - see front matter & 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semnephrol.2015.01.006

Seminars in Nephrology, Vol 35, No 1, January 2015, pp 55–63

predominantly on source control and the use of antibiotics, 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 antiinflammatory 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 condition. Indeed, more than 20 years ago it was suggested that extracorporeal blood purification techniques may provide an adjunct in treating severe sepsis by removing 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 cytokines 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 indications 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). 55

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L.G. Forni, Z. Ricci, and C. Ronco Convenonal CRRT

High Volume

High Cut-Off

Convecve Therapies RAD

CPFA

Other Therapies

Hybrid Therapies

SCD

Cytosorb

Perfusion/Adsorpve Therapies

PMX Figure 1. Possible potential extracorporeal techniques that could be considered as adjuncts in the treatment of sepsis. RAD, renal tubule cell assist device; SCD, selective cytopheretic devices.

RRT IN SEPSIS AND SEPSIS-ASSOCIATED ACUTE KIDNEY INJURY Treatment Indications The indications for the use of RRT in associated acute kidney injury (AKI) are consistent with the indications for other causes of AKI. Conventionally, these consist of progressive azotemia, intractable volume overload, metabolic acidosis, and severe electrolyte derangements.14 However, in the presence of sepsis, marked azotemia is less prominent and, indeed, creatinine kinetics are somewhat different. As a consequence, under these conditions, some clinicians favor the early application of RRT despite the paucity of supporting evidence. Given the potential confounding effects of sepsis on the more conventional markers, some investigators have suggested other criteria such as prolonged oliguria as sufficient indication to start RRT although, again, the evidence is limited.15,16 With regard to the choice of modality, the use of continuous therapies in sepsis-associated AKI still are preferred. This is owing, in part, to the perceived superior hemodynamic tolerability than, for example, intermittent hemodialysis,17 indeed, there is some evidence to support this view from a prospective randomized trial involving 30 patients with septic shock.18 Advantages from continuous therapies may not just be confined to improved hemodynamic stability: they also provide other advantages compared with

intermittent techniques including temperature regulation and continuous fluid management, thereby avoiding fluid shifts and/or organ edema, which in turn may result in improved function. Of note, new hybrid techniques such as sustained low-efficiency dialysis have been shown to provide excellent clearance of low-molecular-weight solutes as well as hemodynamic stability in critically ill patients, however, their potential use as RRT in patients with severe sepsis and septic shock still is unclear.19,20 Interestingly, a recent retrospective study examining patients undergoing continuous therapies versus extended daily hemofiltration suggested that patients undergoing continuous venovenous hemofiltration (CVVH) had significantly improved renal recovery, although the all-cause mortality rates were similar at 60 days.21 Treatment Timing The optimum time to commence extracorporeal treatment in AKI has yet to be established in any randomized controlled study and in clinical practice the decision regarding whether or not to start early RRT remains a difficult task.22 The differentiation between early and late RRT is based, much like the indications for treatment, on arbitrary thresholds of traditional parameters such as serum urea concentration, serum creatinine concentration, urine output, time from ICU admission, or time from AKI diagnosis.23,24 Although there are

Extracorporeal RRT in sepsis

some retrospective trials that have supported the idea that commencing CVVH early is of benefit,16,25–27 the question of early initiation has been investigated systematically in only one trial to date.28 However, this study was principally surgical, with a low incidence of sepsis and no survival benefit could be shown. As we have outlined, part of the problem is defining what is early initiation of continuous RRT. Interestingly, application of the AKI Network criteria to inform commencement of RRT has been examined retrospectively.29 Early starters were defined as beginning RRT within 24 hours after AKI stage 3 was achieved through both creatinine and urine output criteria. The observed mortality rate was lower in the early RRT group, which persisted even after propensity matching. However, the overall mortality rate was high. Of note, the early group also had a lower duration of mechanical ventilation, time on RRT, and a trend toward a shorter ICU length of stay. The investigators concluded that rather than application of conventional parameters, a time-based approach could be a better parameter to access the association between RRT initiation and outcomes in patients with AKI. These results are in keeping with the observation that excessive delay in commencing RRT has been linked with an increased mortality rate and a decrease in renal function in patients with septic AKI.26 Treatment Dose Early impetus for the use of extracorporeal techniques in sepsis-related AKI was provided by the observation that a higher delivered dose in sepsis was associated with an improved outcome.13 The optimum dose of renal support provided much debate until the publication of two multicenter clinical trials that examined the issue of the optimal RRT dose in critically ill patients as well as the effect of increased intensity of renal support. Unlike several previous studies, the primary end point was mortality.30,31 The RENAL (The RENAL Replacement Therapy Study Investigators) and ATN (Intensity of renal support in critically ill patients with acute kidney injury) studies were designed to compare normal or lessintensive renal support with augmented or intensive therapy. The RENAL study compared 25 mL/kg/h continuous veno-venous hemodiafiltration (CVVHDF) with 40 mL/kg/h CVVHDF, and the ATN study compared 20 mL/kg/h CVVHDF or 3 times/wk intermittent dialysis with 35 mL/kg/h CVVHDF or daily intermittent dialysis. Both studies showed that increases in the intensity of the RRT dose had no beneficial effect on outcomes. However, the definition of a normal dose is open to misinterpretation and should be compared with standard clinical practice.32 This is relevant when one considers the discrepancy between the prescribed dose and the delivered dose of continuous RRT. Treatment time is affected by therapy downtime, premature

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clotting of the circuit, vascular access problems, and prescription errors.33 Thus, the possibility that the delivered dialysis dose might be considerably lower than the prescribed dose should be considered and clinicians should aim to overprescribe RRT with a 25% safety margin, targeting 30 to 35 mL/kg/h to achieve an adequate delivered dose.32 This is particularly pertinent when one considers that overt underdialysis might be harmful in critically ill patients with AKI.

RRT AS TREATMENT IN SEPSIS AND SEPSISASSOCIATED AKI The attraction of extracorporeal circuits in the treatment of sepsis-related AKI resides in the hypothesis that proinflammatory and anti-inflammatory mediators, among other things, when removed from the circulation, may confer a survival benefit.34 Since the conception of that idea many technologic advances have occurred together with modifications of existing technologies, leading to an array of possible therapies (Table 1). Standard RRT Techniques As discussed, the examination of the response to a higher dose of renal replacement failed to show a survival benefit when applied to critically ill patients with AKI. This is disappointing when one considers that modernday, high-flux membranes with an average cut-off value of approximately 30 to 40 kD should be capable of eliminating significant amounts of inflammatory mediators including chemokines and cytokines by convection. However, given the high turnover rates of the respective mediators it has been questioned as to whether the removal of such mediators using conventional techniques ever could achieve a reduction in mediators that would be of clinical significance.35 This was proven by data using CVVH that failed to show any effect on serum levels of several cytokines.11 Interestingly, however, they did show a significant influence on serum cytokine levels resulting from adsorption occurring within the first hour after a new membrane has been placed into the circuit. Furthermore, studies using isovolemic CVVH in patients with severe sepsis without renal failure failed to show changes in serum levels of cytokines or complement in patients treated with a filtration rate of 2 L/h.36 High-Volume RRT Techniques It follows that if standard techniques used in the ICU for treating AKI do not allow sufficient clearances at the convection/filtration rates typically delivered then an increase in dose over and above that conventionally used may be an alternative approach. Thus, highvolume hemofiltration (HVHF) has been prescribed

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L.G. Forni, Z. Ricci, and C. Ronco

Table 1. Currently Available Extracorporeal Blood Purification Technologies Treatment

Principle

Aim

CPFA

Convective with plasma filtration and adsorption

CVVH

Convective

Continuous veno-venous hemodialysis (CVVHD)

Diffusive

CVVHDF

Convective and diffusive

Continuous veno-venous high-flux dialysis (CVVHFD)

Convective and diffusive

HCO for hemofiltration or hemodialysis

Convective or diffusive

Hemoperfusion (HP) HVHF

Adsorption Convective

Pulse HVHF

Convective

Plasma adsorption (PA) Plasma exchange (PEX) Slow continuous ultrafiltration (SCUF) SLED: sustained low efficiency dialysis

Filtration and adsorption Filtration with re-infusion Ultrafiltration Diffusive

Volume removal Purification technique Cytokine removal Volume removal Purification technique Volume removal Purification technique Volume removal Purification technique Volume removal Purification technique Cytokine removal Volume removal Purification technique Purification technique Cytokine removal Volume removal Purification technique Cytokine removal Volume removal Purification technique Cytokine removal Cytokine removal Volume removal Volume removal Purification technique

to try and improve clearance of inflammation mediators.37,38 In keeping with standard convective therapies such as CVVH, HVHF is achieved by convective clearance, in which solutes are transported along with the movement of a solvent in response to positive transmembrane pressure. Although most inflammatory mediators are in the middle-molecular-weight category and theoretically can be removed by hemofiltration, they have, as mentioned previously, very high generation rates. High-volume hemofiltration, defined by a flow rate in excess of 35 mL/kg/h and often as high as 75 to 120 mL/kg/h, may achieve clinically meaningful convective and adsorptive removal of inflammatory mediators. The high RRT dose enabled by HVHF can be delivered either continuously using a constantly high exchange rate or by delivering a pulse (for 6-8 h) of very-high-volume hemofiltration (85-100 mL/kg/h) followed by standard treatment. There have been numerous studies that have reported on the application of HVHF to various patient subgroups. Recently, the use of HVHF in the treatment of sepsis was subject to a Cochrane review.39 Randomized controlled trials and quasirandomized trials comparing HVHF or high-volume hemodiafiltration with standard or usual dialysis therapy and randomized controlled trials and quasirandomized trials comparing HVHF or high-volume hemodiafiltration with no similar dialysis

therapy were selected: 1,282 potential publications were identified, of which only 29 were subject to full-text review. Only three trials were deemed of sufficient quality and, given the small number of studies and participants, it was not possible to combine data or perform subgroup analyses.40–42 The investigators concluded that there were no adverse effects of HVHF reported but that there was insufficient evidence to recommend the use of HVHF in critically ill patients with severe sepsis and/or septic shock except as interventions being investigated in the setting of a randomized clinical trial. Subsequently, a large trial involving the use of HVHF in severe sepsis was reported.43 The IVOIRE (High-volume versus standard-volume haemofiltration for septic shock patients with acute kidney injury) trial was a prospective, randomized, open, multicenter clinical trial conducted in 18 intensive care units and a total of 140 critically ill patients with septic shock and AKI for fewer than 24 hours were enrolled. Patients were randomized to either HVHF at 70 mL/kg/h or standard-volume hemofiltration at 35 mL/kg/h, for a 96-hour period with the primary end point being 28-day mortality. Unfortunately, the trial was stopped prematurely after enrolment of 140 patients because of slow patient accrual (the trial ran from October 2005 to March 2010) and resources no longer being available. A total of 137 patients were

Extracorporeal RRT in sepsis

analyzed, with mortality at 28 days lower than expected, however, no difference was observed between the groups. There were no statistically significant differences in any of the secondary end points either and the investigators concluded that HVHF, as applied in IVOIRE, could not be recommended for the treatment of septic shock complicated by AKI. A subsequent meta-analysis including this study again failed to show any benefit from the use of HVHF in sepsis.44 So why should such a conceptually appealing idea find no evidence to support its clinical use? There are several potential confounders, not least of which was the effects of HVHF on other therapies. We know that timely and appropriate antimicrobial therapy in this patient group is of paramount importance.45,46 It follows that the application of HVHF may cause significantly increased clearance of antimicrobials, leading to subtherapeutic concentrations and hence treatment failure. Moreover, the use of HVHF subjects individuals to increased electrolyte disturbances as well as depletion of micronutrients, which again may lead to a less favorable outcome. However, despite our wishes, perhaps the most plausible explanation is that HVHF may be ineffective at providing adequate mediator clearance at the cellular level rather than in the circulation. High Cut-Off Hemofiltration or Hemodialysis High cut-off (HCO) membranes are porous enough to achieve the removal of larger molecules (approximately 15-60 kD) by diffusion and as such their use in sepsisrelated AKI is logical.47 Moreover, HCO membranes are known to remove cytokines in both in vitro and in vivo models, as well as showing increased survival in experimental models of sepsis.48,49 Several other potential benefits have been attributed to the use of HCO therapy including improved immune cell function, removal of inflammatory cytokines, and a reduction in catecholamine dosage.50,51 A further in vivo study in septic patients examining the elimination of middlesized uremic solutes showed a considerable difference in terms of clearance between a HCO filter and standard techniques, although, as expected, albumin loss was higher using HCO membranes.52 This undesired effect can be attenuated either by albumin replacement or by using HCO membranes in a diffusive, rather than convective, manner while still preserving the effect on cytokine clearance.53 There currently are ongoing prospective adequately powered randomized trials to definitely confirm or negate the clinical efficacy of HCO therapy in the context of septic AKI. Hemoperfusion/Hemoadsorption The techniques of hemoperfusion and hemoadsorption involve the placement of an adsorbent, often resin-

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based, in direct contact with blood through an extracorporeal circuit. Solutes are attracted to the sorbent and hence eliminated from the circulation through a variety of means.54 Structural manipulation of the solid-phase sorbents results in changes in selectivity through separation based on molecular size and hence the ability to penetrate the network of the sorbent. As was the experience in the early days of hemodialysis, biocompatibility of these sorbents proved an initial problem, however, the addition of a biocompatible outer layer has, for the most part, circumvented this problem. Given the potential to manipulate the sorbent and the high adsorptive capacity of these resins. they ideally are placed as a potential intervention tool in sepsis. Sorbents have been applied in combination with different treatment modalities, including coupled with hemodialysis or coupled with plasma filtration (see later). The choice of modality is based both on the properties of the sorbent as well as the technique used. Perhaps the most extensively studied sorbent is that of polymyxin B (PMX), which is a cyclic cationic polypeptide antibiotic derived from Bacillus polymyxa that has the ability to bind and neutralize endotoxins. However, because of its nephrotoxicity and neurotoxicity on intravenous infusions it is limited as a salvage therapy for gram-negative enterobacteriaceae multidrug-resistant organisms.55 PMX hemoperfusion uses the antibiotic adsorbed to a polystyrene fiber and was developed in Japan in the late 1990s. Since then, a number of small, nonblinded trials have used this technique with promising results. A meta-analysis of studies mainly performed in Japan and Europe where PMX hemoperfusion was used in patients with severe sepsis suggested improvements in hemodynamics as measured by mean arterial pressure as well as oxygenation. However, study quality and sample sizes were such that confirmation of these benefits in larger studies is awaited.56 The Early Use of Polymyxin Hemoperfusion in Abdominal Septic Shock trial reported in 2009 was a randomized nonblinded study of 64 patients in 10 tertiary Italian ICUs.57 Improvements in the primary end points of hemodynamics and organ dysfunction were statistically significant, with the absolute risk of death at 28 days improving from 53% in the conventional therapy group to 32% in the treated group, although the trial was stopped early. In keeping with most studies, endotoxin levels were not measured before enrollment, although patients were selected on the evidence of septic shock from an intra-abdominal source to be more specific regarding patient selection. However, a recent meta-analysis on blood purification techniques and mortality in sepsis did show a reduction in mortality when compared with no blood purification (35.7% versus 50.1%; risk ratio, 0.69; 95% confidence interval, 0.56–0.84; P o .001; 16 trials; n ¼ 827). This

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analysis looked at all potential therapies but the results observed were derived principally from studies on hemoperfusion using PMX principally in Japan. When such studies were excluded no benefit was observed although the control group mortality in some of these studies was high (60%-80%), especially when compared with studies performed elsewhere.58 Also of note were significant regional differences in the management of sepsis given that blood purification techniques are common in some parts of the world and not others.59 Furthermore, there was no standard reporting, with differing end points across trials, however, the investigators concluded that “there may be a role for this form of treatment in a disease that has, so far, eluded effective therapy.”59 Perhaps in answer to these questions we await the results of the first blinded and randomized, controlled, diagnostic-directed trial of a hemoperfusion device: Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock.60 This study differs from previous work in that not only is it a multicenter, placebo-controlled (using a façade hemoperfusion setup), and randomized trial, but it also is a theragnostic trial. Thus, investigations are matched to the treatment. In this case the endotoxin activity assay will be performed and only those individuals with an endotoxin activity assay of 0.6 or greater will be eligible for randomization, with the primary end point being 28day all-cause mortality. Hybrid Technologies: Coupled Plasma Filtration Adsorption Coupled plasma filtration adsorption (CPFA) is a hybrid technology that involves plasma separation followed by an adsorptive step over an activated charcoal sorbent.34 Thus, there is initial plasma filtration with a specific sorbent cartridge placed in series with, but downstream from, the plasma filter. This results in nonspecific removal of larger, soluble inflammatory mediators.61 Early animal experience with CPFA showed promising survival results in a model of endotoxin-induced septic shock and a subsequent clinical study showed hemodynamic improvements.62,63 A subsequent crossover study involving 10 patients with sepsis showed a reduction in norepinephrine requirements although no reduction in measured inflammatory mediators was observed.64 These studies prompted the first randomized but open-label study on CPFA in sepsis.65 In keeping with many studies using extracorporeal therapies for sepsis the results were somewhat disappointing, with no statistical difference observed between groups for the primary end point (mortality at discharge) or indeed secondary outcomes including new

L.G. Forni, Z. Ricci, and C. Ronco

organ failures or ICU-free days. However, this is not the whole story given that the study was terminated early on the grounds of futility but on subsequent analysis many of the patients were deemed to be undertreated and also many patients were excluded because of the narrow time window used for inclusion of such a relatively complex technique. Other Technologies A technique that has attracted some attention is that of the renal tubule cell assist device in which nonautologous human renal tubule cells are grown along hollow fibers within a extracorporeal cartridge. The ultrafiltrate is pumped through this, which eliminates mediators from the circuit, in part mimicking the role of the kidney.66 This now has been applied to critically ill patients with an observed improvement in mortality.67 In addition to the removal of inflammatory mediators, the possibility that activated leukocytes also may be removed from the circulation of septic patients has been shown, and has been explored as a potential cytopheretic modality.68 Another area of considerable recent interest is that of the use of polymer-based sorbents, which have been introduced into the clinical practice of extracorporeal therapies. Originally designed to remove β2 microglobulin in addition to high-flux dialyzers in chronic dialysis patients, these sorbents were applied successfully to remove cytokines from the septic patient in hemoperfusion mode.69 Because of improved biocompatibility these cartridges (CytoSorb CytoSorbents Corporation and CytoSorbents Medical Inc., New Jersey, United States) could be placed in direct contact with blood, increasing the efficiency of the adsorption process. These CytoSorb beads are composed of a highly adsorptive and biocompatible polymer that has the potential to remove multiple inflammatory mediators from the bloodstream. Indeed, this has been shown in case reports in which dramatic effects on a patient’s IL-6 levels, for example, were observed.70,71 Furthermore, animal studies have shown that therapeutic apheresis using CytoSorb beads have shown beneficial effects on chemokine gradients, which may restore chemokine gradients toward infected tissue and away from healthy organs through leukocyte trafficking control.72 Where Are We With Extracorporeal Therapies? Clearly, renal replacement techniques have advanced dramatically since their early primitive description more than 40 years ago. Modern-day machines are designed to permit safe and reliable therapy and are equipped with user-friendly interfaces that allow for easy performance and monitoring. Practical considerations such as self-loading circuits or cartridges that

Extracorporeal RRT in sepsis

include the filter, the blood, and dialysate lines are commonplace. Priming is now automatic and these new machines permit all continuous RRT methodologies to be performed by programming flows and fluid exchanges easily at the beginning of the session. Thus, the critical care nephrologist has an array of tools available and furthermore our understanding of the pathophysiology of acute kidney injury evolves. The demand for earlier markers of AKI over and above urine output has lead to an explosion of new biomarkers, some of which show promise for early detection but perhaps more importantly have shed light on the underlying pathophysiology. However, where are we with the use of extracorporeal therapies in the treatment of sepsis? We have discussed the techniques available and the paucity of hard data supporting the global adoption of techniques such as hemoperfusion. However, perhaps the fault lies not with the technique but in our application of it. There are a myriad of articles written on the pathophysiology of sepsis and one could be lead to believe that our existing knowledge regarding the immune status of the septic host is so well defined that we should be able to reduce the observed mortality associated with this condition significantly. However, as shown, sequential failures of clinical studies using extracorporeal blood purification aiming to modulate the immune response of the septic host have failed. This probably reflects the fact that the septic response is characterized by marked heterogeneity from one patient to another and that also the site of sepsis may provoke a different response. For example, high mobility group box 1 (HMGB1), an intracellular protein that is secreted by some immune cells as a cytokine mediator of inflammation, shows differing kinetics dependent on infection type. In severe sepsis secondary to pneumonia, peak circulating levels of HMGB1 are found in patients as early as at the time of admission, whereas in acute pyelonephritis peak levels of HMGB1 are seen in serum 3 days after admission.73 Furthermore, hopefully in the very near future novel specific pathology biomarkers and/or the identification of specific genotypes will help clinicians to identify accurately and effectively the optimal time to start treatment and finally tailor extracorporeal therapies delivered to septic critically ill patients with AKI.74,75 This may well be even more effective when treatment is started before the development of the multiorgan dysfunction syndrome, in which the patient’s homeostasis is so disrupted that no intervention could be effective.

CONCLUSIONS In conclusion, we believe that blood purification techniques may have a future a role in the management

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of severe sepsis. However, therapy will have to be targeted to the individual in terms of technique as well as mediator(s) that wish to be removed or restored to pre-septic levels. A targeted, specific treatment may well herald a new dawn for these therapies and a brighter outlook for our patients.

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