Читать книгу Current Perspectives in Kidney Diseases - Группа авторов - Страница 12

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 by injured/activated cells with the aim of modulating the inflammatory response. The immune system is the main source of cytokines, but several other tissues are able to release them. During inflammatory processes, podocytes, TEC and renal endothelium can massively produce IL-18, IL-6 and chemokines such as IL-8 [9, 15]. Several studies have demonstrated the impact of these molecules in S-AKI prognosis; in particular, IL-6 and TNF correlated with AKI severity and with a worse patient survival [16].

Vasoactive Agents and Other Hormones. The release of all the above mentioned molecules coupled with organ dysfunction activates hormones and growth factors involved in homeostasis maintenance. These mediators could only partially counteract tissue injury and promote regeneration processes. However, the excess of signaling of specific stimuli can lead to the development of maladaptive responses. Examples include the massive production of nitric oxide (NO) that induces harmful NO-derived reactive oxygen species, the hyper-activation of the renin-angiotensin-aldosterone system (RAAS) and the sepsis-related catecholamine release that strongly contributes to microvascular vasoconstriction, thrombosis and/or hemorrhage [7, 17].

Immune Products, Activators of Complement and Coagulation Cascades. Cell injury exposes matrix proteins to bloodstream and activates the coagulation cascade. In parallel, complement system is activated by pathogens (mannose pathway), immune complexes (direct pathway) and by downregulation of complement-inhibiting proteins within injured cells (indirect-pathway). Moreover, the loss of glomerular filtration barrier causes proteinuria and exposes complement products to tubular brush border enzymes, thus inducing intra-luminal complement activation [18]. Additionally, activated immune cells release pathogen-killing factors (perforin, granzyme-B, etc.) able to worsen and to perpetuate cell injury [19].

Metabolites and Uremic Toxins. Uremic toxin is an omni-comprehensive term that includes all factors accumulating/upregulated during renal failure that cause any kind of tissue injury. Based on this definition, several molecules included in the previous categories can be defined as uremic toxins (i.e., some cytokines and RAAS). However, the largest part of uremic toxins is constituted by detrimental metabolic products, normally excreted by the kidney. p-Cresol sulfate and indoxyl sulfate are protein-bound metabolites not filtered by glomeruli and secreted by TEC; their accumulation in AKI and CKD is associated with several harmful effects such as endothelial injury and immune dysfunction [20].

Extracellular Vesicles (EV), Apoptotic Bodies and Other Cell Fragments. EV are membrane fragments actively produced to shuttle proteins, nucleic acids, lipids and other metabolites from an origin to a target cell [21]. EV play a key role in cell-to-cell communication processes and are classified as exosomes (30–120 nm in size and released by multi-vesicular bodies) or microvesicles (>120 nm and released by a membrane-sorting process), and they are involved in tissue repair and homeostasis. In the course of sepsis, a significant increase of plasma EV concentration is observed [22]. EV can be released by different cell types including monocytes, platelets and injured endothelial cells. The biological effects of EV may change in relation to the state of activation of the origin cell: this is of particular relevance in S-AKI patients in which plasma EV may represent not only a new biomarker for the early detection of disease, but also a key element in the pathogenic mechanisms of renal damage [22, 23]. Plasma EV are able to modulate NO and prostacyclin endothelial release, activate the coagulation cascade and cytokine production. EV isolated from septic animals and injected in healthy ones were able to induce the same functional and biological alterations observed in the course of the systemic inflammatory response, suggesting that EV can somehow transfer the septic disease to a healthy animal [24]. Moreover, sepsis-induced tissue injury promotes the passive release of other cell fragments such as apoptotic and necrotic bodies that have high DAMP concentrations. Several pathogens may also exploit EV to spread the infection or to transport PAMPs/toxins. Of interest, preliminary data from our research group demonstrated that despite their small size, EV are electrically charged and are not easily removed by standard diffusive and/or convective RRT.