**10. Therapeutic Approaches in Septic Patients with AKI**

In the therapeutic approach to AKI in septic critically ill patients, it is essential for clinicians to decide between conservative or invasive measures. The first step is generally the treatment of sepsis by wide-spectrum antimicrobial agents, according to the epidemiologically assumed microbial [30]. Accordingly, there is a need to consider surgical or other intervention to eliminate the potential source of the sepsis. AKI severity, clinical and hemodynamic status as well as metabolic alterations are the basics for RRT or conservative therapy. Many experimental AKI biomarkers including miRNAs have an ancillary role in AKI diagnosis to assist clinicians in decision-making, in primarily preventive approaches. Usually this means dose adjustment of the nephrotoxic agents, stabilization of hemodynamics with controlled volume expansion if needed, preservation of urine output, adequate nutrition and treatment of any metabolic disorder. The crucial use of additive AKI biomarkers besides serum creatinine and urea, are the subject of ongoing research. During the first phase of septic AKI, of clinical importance is optimization of fluid management with adequate fluid resuscitation and avoidance of fluid overload. Physicians have to take into account patient's volume status, urinary output, the type of intravenous fluids and infusion rates [82]. However, fluid overload due to loss of plasmatic proteins and increase in capillary permeability, can lead to fluid accumulation with a worsening of patient clinical status. In the renal parenchyma this increases the renal venous pressure, reduces the renal perfusion pressure and glomerular filtration rate with consequent retention

of salt and water [83]. Fluid resuscitation with hemodynamic stabilization and choice of fluids play an important role in the therapeutic approach to both syndromes—sepsis and AKI. The preferred solutions are saline and balanced crystalloids, whereas hydroxyethyl starches and gelatin solutions can be associated with increased risk of AKI in septic patients. In the presence of septic shock, despite adequate volume resuscitation, there is a need for vasoactive drugs to restore renal parenchymal perfusion. In the case of sepsis, for this reason, commonly used drugs are norepinephrine, dopamine, vasopressin and phenylephrine [84].

With severe AKI, metabolic alterations and worsening hemodynamic instability, there is usually an increased need for RRT initiation in intermittent (IRRT) or continuous (CRRT) form. In physical principle and type of RRT or blood purification techniques, there are dialysis, hemofiltration, hemodiafiltration, hemoadsorption by CytoSorb (for severe sepsis) or plasmapheresis. Some RRT methods can be also combined according to clinical or laboratory findings. Close patient status monitoring and adequate supportive measures in cases with absence for urgent RRT initiation are the basic steps in conservative approaches. Thus, the timing for RRT initiation does not play a substantial role in survival in critically ill patients with AKI, especially in cases where conservative approaches can be successfully used [85]. A more comprehensive view was achieved after termination of the French AKIKI (Artificial Kidney Initiation in Kidney Injury) study (ClinicalTrials.gov NCT 01932190) performed in 620 critically ill patients with acute kidney injury. No significant difference in mortality between early and delayed strategies of RRT initiation with a decrease in need for RRT in the delayed approach was found [86]. Hemoadsorption with CytoSorb can be used predominantly in patients suffering from septic shock with careful decision-making, according to the APACHE II score. The basic principle of these blood purification devices, using more effective membranes or columns incorporated in CRRT, is removal of pro-inflammatory cytokines (e.g., IL-6, IL-8, TNFα) and endotoxins to stabilize the patient's hemodynamics and decrease the need for vasopressor therapy [87]. Preserving adequate fluid balance, net ultrafiltration, treatment dose, nutritional support and antibiotic treatment are a vital component of the therapeutic approach in critically ill septic patients [88].

In patients with septic AKI on any type of RRT treatment, what is crucial is the antimicrobial treatment and therapeutic drug monitoring where possible. Many renally eliminated antimicrobial agents in these circumstances undergo changes in pharmacokinetics/pharmacodynamics parameters, including clearance, volume of distribution, binding to plasma proteins and elimination half-life. The dose adjustment has to be individualized according to serum concentration, to achieve the required pharmacodynamics parameters, drug efficacy and decrease the risk of toxicity [89,90]. Other preventive measures such as antioxidants in the case of antibiotic nephrotoxicity are still under investigation.
