Emerging therapeutic targets of sepsis-associated acute kidney injury

Abstract

Sepsis-associated acute kidney injury (SA-AKI) is linked to high morbidity and mortality. To date, singular approaches to target specific pathways known to contribute to the pathogenesis of SA-AKI have failed. Because of the complexity of the pathogenesis of SA-AKI, a reassessment necessitates integrative approaches to therapeutics of SA-AKI that include general supportive therapies such as the use of vasopressors, fluids, antimicrobials, and target-specific and time-dependent therapeutics. There has been recent progress in our understanding of the pathogenesis and treatment of SA-AKI including the temporal nature of proinflammatory and anti-inflammatory processes. In this review, we discuss the clinical and experimental basis of emerging therapeutic approaches that focus on targeting early proinflammatory and late anti-inflammatory processes, as well as therapeutics that may enhance cellular survival and recovery. Finally, we include ongoing clinical trials in sepsis.

Keywords: Inflammation; cytokines; septic shock; therapeutics.

Figure 1. Immune responsiveness following sepsis

The host response to sepsis and septic shock is an early dysregualted immune response that is mediate via activation of innate immunity followed by a state of immunosuppression. Therapeutics should consider the temporal profile of the immune status. Early blockade of proinflammatory pathways should be followed by late activation of immunity.

Figure 2. Cholinergic Anti-inflammatory Reflex

The cholinergic antiinflammatory reflex regulating immunity is initiated by DAMPs and PAMPS that active the afferent signaling pathway of the vagus nerve to the nucleus tractus solatarius. Neural signals are sent to the hypothalamus and brainstem and efferent signals emanate from the ambiguous and dorsal motor nucleus and travel down the vagus nerve (for a review see). Activation of the adrenergic splenic nerve results in the release of norepinephrine, which binds to adrenergic receptors on nearby CD4⁺ T-cells. This stimulates the production of acetylcholine that binds to α7nAChRs on splenic myeloid cells (macrophages) and results in suppression of the synthesis and release of proinflammatory mediators such as TNF, IL-1, IL-18, HMGB1, chemokines and other cytokines. Nicotine, an a7nAChR agonist, mimics the effect of Ach. A simple US regimen is thought to activate the splenic cholinergic reflex and attenuate kidney IRI. US – ultrasound, NE - norepinephrine, ACh – acetylcholine.

Figure 3. Iron homeostasis and sepsis

Microbes secrete siderophores to capture iron required for their growth and survival. Hosts secrete NGAL to mediate antimicrobial response through iron starvation. Sepsis-associated inflammatory response induces release of antimicrobial peptide, hepcidin, from the liver. Hepcidin downregulates ferroportin to induce reticuloendothelial iron sequestration, which in turn leads to decreased availability of extracellular iron for microbial growth. Iron sequestration in macrophages also results in attenuated pro-inflammatory response to endotoxemia and sepsis. Dysregulated iron homeostasis would result in oxidative stress and worse sepsis-associated end organ injury. Iron chelation might be of therapeutic benefit in decreasing oxidative stress induced damage. NGAL, Neutrophil gelatinase-associated lipocalin.