Current Perspectives in Kidney Diseases. Группа авторов

to initiate dialysis is mainly based on the clinical judgment. Indeed, guidelines regarding timing, indication, modality and dose of RRT for S-AKI patients are still lacking. In this part of the review, we will evaluate the clinical and biological effects of different extracorporeal treatments for S-AKI, focusing on timing, dose and modality of RRT. We will consider new therapeutic strategies based on extracorporeal blood purification techniques that may play a role in improving outcomes and in decreasing progression toward CKD in the near future.

      Biological and Clinical Effects of Extracorporeal Treatments

The pathophysiology of sepsis is complex, and renal dysfunction does not simply result from ischemia/hypoperfusion but rather holds a set of inflammation, microcirculatory dysfunction, perfusion deficit, bio-energetic reactions and tubular cell adaptation to injury [34]. The main purpose of blood purification therapies should be to restore homeostasis: as a matter of fact, most sepsis mediators are water-soluble and fall into the “middle-molecular weight” category (about 5–50 kDa) that can be theoretically removed by RRT via convection, diffusion or adsorption. On this basis, we can speculate that RRT can modulate the immune response to sepsis. Furthermore, RRT may have additional clinical benefits including thermal balance, cardiac support achieved by optimization of fluid balance and adequate levels of preload and afterload, protective lung support by the reduction of edema, brain protection with preservation of cerebral perfusion, liver and bone marrow support via the clearance of specific toxins [35].

      Timing

Nowadays, there is no consensus on the optimal timing of RRT initiation. Recent studies showed that an excessive delay in RRT start is associated with higher mortality rates and with the worsening of renal function. Retrospective and observational studies suggested that patients with S-AKI treated with early RRT (defined as urea <35.7 mmol/L, start of RRT ≤24 h after the diagnosis of sepsis or by time from ICU admission/initiation of vasopressor infusion) have better survival [36–38]. Also, recent reviews [40] and a meta-analysis [41] showed that earlier start of RRT in critically ill patients with AKI (before the onset of complications and of fluid overload) may have a beneficial impact on survival; however, the same authors emphasized that this conclusion is based on heterogeneous studies that differed in their definition of early and late initiation. Another retrospective review revealed no significant clinical benefit of early RRT initiation in patients presenting with septic shock and AKI [42]. Furthermore, the recent trial from AKIKI group [43] did not show any significant difference in mortality with delayed or early RRT start. The forthcoming Initiation of Dialysis Early versus Late in the Intensive Care Unit study (IDEAL-ICU) will probably help in defining the optimal timing of RRT in S-AKI. Meanwhile, it is acceptable to start RRT at RIFLE injury/failure level as suggested by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines [44]; early initiation of RRT is indicated when fluid overload is excessive or refractory to diuretics [45].

      Dose

A relevant issue in RRT for S-AKI is the optimal dose of renal support. The “Vicenza study” conducted by Ronco et al. [46] showed a better survival in patients treated with a filtration rate ≥35 mL/kg/h, in particular, in the presence of sepsis. Subsequent evidence from 2 multicenter trials (RENAL – Randomized Evaluation of Normal versus Augmentated Level Renal Replacement Therapy [47] and ATN – Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study) [48], showed no beneficial effects when high-intensity dose RRT was compared to lower doses. On the contrary, in the RENAL study a post-hoc analysis showed a trend toward a reduction in mortality rate in S-AKI patients treated with high-intensity dose (40 mL/kg/h). Subsequently the IVOIRE study [49] compared high-volume hemofiltration (HVHF, 70 mL/kg/h) to standard-volume hemofiltration (35 mL/kg/h) in septic shock patients without finding a survival or clinical benefit.

Currently, the main aim of S-AKI therapy is early source control and appropriate antibiotic therapy. In many of these “high-volume” studies, no correction was made for antibiotic flux and so, patients may have been under-dosed [50]. Additionally, according to the results of the DO-RE-Mi-FA study [26], the actual delivered dose of RRT is approximately 70–90% of the prescription. Thus, prescribing a 25–30 mL/kg/h dose may be more useful in S-AKI, but no strong data support its recommendation. In any case, a particular attention to verify the difference between prescribed versus delivered dose is mandatory.

      Modality

Continuous RRT (CRRT) and intermittent hemodialysis (IHD) represent the mainstays of treatment for S-AKI patients requiring RRT. To date, there is no consensus in choosing CRRT or IHD in these patients, but in the presence of hemodynamic instability it is suggested to favor continuous therapies (level 2B in KDIGO guidelines [44]): indeed, hemodynamically unstable patients treated with CRRT remained significantly less dialysis-dependent [51], and CRRT was associated with a trend towards early reduction of vasopressor support [52]. Furthermore, it has been shown that standard IHD has lower capacity to remove several inflammatory cytokines; however, the use of hybrid therapies such as IHD with high cut-off membranes (HCO) or sustained low-efficiency dialysis (SLED) holds some interesting promises. SLED has been shown to provide good tolerability in critically ill patients, excellent clearance of low molecular weight solutes and reasonable clearance of larger molecules able to modulate immune function [53].

      Anticoagulation Strategies

The most used anticoagulation strategy is still represented by unfractioned or low molecular weight heparins. However, several problems associated with heparin use should be considered when critically ill patients are subjected to RRT. First, heparin and heparinoids may be contraindicated in particular cases (i.e., heparin-induced thrombocytopenia); moreover, in the case of S-AKI, the low levels of antithrombin III (ATIII) and the putative inflammatory effects of heparin may lead to a premature clotting of the circuit. Intravenous administration of ATIII is recommended to maintain levels higher than 60–70%. In accordance with KDIGO guidelines [44], for patients with hemodynamic instability in which continuous therapies represent the treatment of choice, regional citrate anticoagulation (RCA) should be adopted. Several studies demonstrated the advantage of RCA in comparison to heparin in reducing bleeding and increasing circuit lifespan without clotting episodes. A randomized clinical trial by Oudemans Van Straten et al. [54] also revealed a better survival of RRT patients treated with RCA in comparison to heparin; even though these results have not been replicated in other studies, some specific characteristics of citrate should be considered