Abstract
Acute kidney injury (AKI) is one of the most common sepsis complications, and AKI development increases the risk of sepsis episodes by affecting host immune competence. The concomitance of these 2 clinical syndromes is associated with an extremely poor prognosis with mortality rates ranging from 50 to 70%. These unacceptable outcomes reflect the poor knowledge of the underlying pathogenic mechanisms and the lack of appropriate diagnostic and therapeutic methodologies as well as of appropriate experimental models. However, in recent years new insights have revolutionized the scientific and clinical approach to sepsis-induced AKI (S-AKI) leading to encouraging results. The aim of this paper is to review the extracorporeal treatment of S-AKI with a focus on the most promising experimental techniques and the underlying molecular mechanisms.
© 2017 S. Karger AG, Basel
Introduction
Sepsis and acute kidney injury (AKI) are 2 acute clinical syndromes that are tightly connected. From one side, AKI represents one of the most common complications of sepsis and on the other, sepsis risk is significantly increased by AKI development [1]. The concomitance of these 2 clinical syndromes, or sepsis-associated AKI (S-AKI), is related to an extremely poor prognosis with 28-day mortality rate ≥50% and a high risk of progression toward chronic kidney disease (CKD) in survivors, with increased healthcare costs [2, 3]. Nowadays, sepsis therapy is based on antibiotic administration and on a complex network of supportive cares that do not target the mechanisms of tissue injury: for this reason, several clinical trials aimed at selectively blocking “the magic bullet” involved in sepsis-associated tissue injury failed [4]. Furthermore, classical renal replacement therapies (RRTs) are not associated with an improvement of renal recovery rate, and have a questioned impact on patient survival in randomized clinical trials with a large number of patients.
However, in last years the scientific and clinical approaches to S-AKI have been deeply revolutionized. The 2001 sepsis definition was focused on the interplay between pathogens and immune cells and the consequent Systemic Inflammatory Response Syndrome (SIRS). Subsequently, large observational studies clearly demonstrated that several septic episodes are not simply related to SIRS and that SIRS detection has a poor clinical utility [5]. Indeed, different tissues implement aberrant responses to infections independently from the immune system. Based on these considerations, in 2016 sepsis was re-defined as “a life-threatening organ dysfunction caused by a dysregulated host response to infection” [5]. Moreover, in the recent years new insights have changed the scientific and clinical approaches to S-AKI, leading to some encouraging results. In particular, “Omic” technologies (i.e. genomics, transcriptomics, proteomics and metabolomics) allowed the development of new biomarkers of outcome and tissue injury. In addition, biotechnology advances in the field of extracorporeal techniques lead to the improvement of treatments aimed to remove the circulating inflammatory mediators involved in the pathogenesis of S-AKI.
The aim of this paper is to review the current extracorporeal therapies available for the treatment of S-AKI, with a particular focus on the most promising techniques known to interfere with the molecular mechanisms involved in renal microvascular derangement and tubular epithelial cell (TEC) injury, key features of S-AKI at cell biology and molecular level.
S-AKI: Novel Pathogenic Mechanisms, Biomarkers of Tissue Injury and Promising Therapeutic Targets
A complex network of pathogenic elements sustains the strong relationship between sepsis and kidney dysfunction. The systemic hemodynamic failure occurring during sepsis has been ascribed for decades as the main or the sole cause of AKI. However, recent experimental and clinical studies clearly demonstrated that the hemodynamic resuscitation of septic patients rarely reverts renal failure and that a significant number of S-AKI episodes are not associated with evident hemodynamic changes [3, 6]. Indeed, AKI may develop in the presence of a normal or even increased renal blood flow, suggesting a dissociation between perfusion and kidney function [7]. On this basis, the mechanisms of kidney injury seem to be related not only to ischemia, but also to other causes that have a toxic and/or immunologic nature. Indeed, an increasing body of evidence demonstrated the pivotal role of harmful circulating mediators (in particular, middle molecules), upregulated during S-AKI and potentially removed by extracorporeal therapies [8, 9]. These detrimental factors may reach the kidney by different ways: (1) some molecules can be freely filtered by glomeruli reaching tubular lumen, thus modulating the biological activities of epithelial cells at this level; (2) the same or other molecules directly act on endothelial cells located in the peritubular capillaries inducing a microvascular derangement that leads to alterations of tubular function at the basolateral compartment. These inflammatory mediators finally lead to bioenergetic alteration, loss of cell polarity, apoptosis, enhanced senescence, and fibroblast differentiation of TECs [10].
Several detrimental molecules are known to be potentially involved in renal cell dysfunction (Figure 1) and are classified in the following categories:
Pathogen-Associated Molecular Patterns (PAMPs). This first family includes molecules produced by pathogens that may have a direct cytotoxic effect or are sensed by tissues as an alarm signal after binding to specific receptors. The most studied PAMP is obviously represented by lipopolysaccharide (LPS) that can directly interact with the Toll-like receptor 4 (TLR-4) on immune cells, kidney resident TECs and endothelial cells. Other highly pathogenic PAMPs include porins, mannose-containing glycoproteins, lipoteichoic acid, flagellin, double-strain RNA and quorum sensing molecules. All these elements are able to alter kidney microcirculation, induce apoptosis and functional alterations of tubular cells and concomitantly modulate the immune response in septic patients [3, 11, 12].
Damage-Associated Molecular Patterns (DAMPs). DAMPs are endogenous molecules released by injured or necrotic cells: RNA, single/double strain DNA, ATP, histones and high-mobility group box 1 (HMGB-1). Also, these molecules activate specific receptors located on the surface of both immune and renal cells (i.e., P2Xr for ATP or TLR-2 for HMGB-1) and have physiological roles in spreading “the alert signal,” inducing the recruitment of activated immune cells: indeed, the over-activation of DAMP pathways is a further source of renal damage trough direct and indirect (immune-mediated) effects [13, 14].
Fig. 1. Modulation of sepsis-associated acute kidney injury by extracorporeal therapies. ADMA, asymmetric dimethylarginine; ATP, adenosine tri-phosphate; DAMPs, damage-associated molecular pathways; HMGB-1, high-mobility group box 1; LPS, lipopolysaccharide; NO, nitric oxide; RAD, renal assist device.
Inflammatory Cytokines and Chemokines. Cytokines/chemokines are actively produced