2 α-MSH AKI ALI AP-1 ARDS CNS G-CSF GFAP HSC ICAM-1 IL-1 Il1r2 IRI KC MOF NF-κB Ngp Saa3 SIRS TCR TLR TNFR1 TNFα KC/CXCL1 MIP-2/CXCL-2 Table 1: Abbreviations. α-Melanocyte-stimulating hormone Acute kidney injury Acute lung injury Activator protein-1 Acute respiratory distress syndrome Central nervous system Granulocyte colony-stimulating factor Glial ﬁbrillary acidic protein Hepatic stellate cell Intercellular adhesion molecule-1 Interleukin-1 Interleukin-1 receptor type II Ischemia-reperfusion injury Keratinocyte chemoattractant Keratinocyte-derived chemokine Macrophage inﬂammatory protein Multiple organ failure Nuclear factor-κB Neutrophilic granule protein Serum amyloid A3 Systemic inﬂammatory response syndrome T-cell receptor Toll-like receptor Tumor necrosis factor receptor-1 Tumor necrosis factor-α 2. Ischemic AKI Kidney IRI remains a major cause of AKI in both native and transplanted organs and lacks a speciﬁc treatment aside from renal replacement therapy. The local eﬀects of kidney IRI begin in the most vulnerable regions of the organ, after which a cascade of microvascular inﬂammation propagates. Although 25% of cardiac output contributes to renal blood ﬂow, only a fraction ultimately reaches the vasa recta of the renal medulla, with the majority reaching the renal cortex [7]. Therefore, even slight alterations in total renal blood ﬂow may lead to anoxic injury in the medulla, resulting in tubular dysfunction, salt wasting, and glomerular vasoconstriction through tubuloglomerular feedback [8, 9]. Kidney IRI activates an inﬂammatory response which results in endothelial cell activation, leukocyte adhesion and entrapment, and compromised microvascular blood ﬂow [10]. Inﬂammation in the postischemic kidney triggers the upregulation of leukocyte adhesion molecules, toll-like receptors, and downstream transcription factors, which all contribute to disruption of the integrity of the renal vascular endothelium [11]. Adhesion molecules such as integrins and selectins along with proinﬂammatory cytokines propagate cellular injury not only locally in the renal tubular epithelial cells but also travel to remote organs where genomic markers of injury are upregulated and phenotypic injury occurs [12]. Unfortunately, selective inhibition of cytokines and adhesion International Journal of Nephrology molecules such as tumor necrosis factor-α (TNF-α) and intercellular adhesion molecule (ICAM-1) have failed to demonstrate global attenuation of both local and remote organ injury during experimental models of ischemic AKI [13–16]. However, α-melanocyte-stimulating hormone (α- MSH), a cytokine with broad antiinﬂammatory, anticyto- toxic, and antiapoptotic properties, has demonstrated suc- cess in treating the inﬂammatory phenotype in rodents. In this model, treatment with α-MSH has attenuated both renal and pulmonary injury during ischemic AKI [13, 17]. The largely unsuccessful eﬀort to ameliorate MOF with speciﬁc anti-inﬂammatory therapeutics highlights the complexity of the systemic response to kidney IRI. From these early experimental studies, it is possible that the multiple inﬂammatory pathways activated in each organ system represent a unique response to ischemic AKI. Despite a paucity of data, several diﬀerent pathophysiologic responses to ischemic AKI in remote organs have been identiﬁed (Figure 1). In the heart, increased expression of TNFα and interleukin-1 (IL-1) are associated with myocyte apoptosis. In the brain, increased expression of chemokines including keratinocyte chemoattractant (KC, a brain IL- 8 homologue) and granulocyte colony-stimulating factor (G-CSF) are seen with increased vascular permeability. Additional responses in the lungs, gut, and liver have been discovered, and these individual organ responses will be detailed later in this paper. We will now focus on cellular mediators, speciﬁcally those involved in the innate and adaptive immune system, which may connect local ischemic AKI with distant organ injury. 2.1. Innate Immunity. The innate immune system plays an important role in mediating the inﬂammatory response during ischemic AKI. Traditionally, innate immunity elicits an immediate, preprogrammed response to tissue injury that lacks immunologic memory. It is composed of plasma proteins (complement), cells (neutrophils, macrophages, and natural killer cells), and physical barriers. Proposed initiators of the innate immune response during IRI include the activation of toll-like receptors (TLRs) and the release of reactive oxygen species (nitric oxide and superoxide anion) and mitochondrial products [18]. The complement system, particularly the alternative pathway, is activated, stimulating release of cytokines and subsequent activation of neutrophils, endothelium, and macrophages [19]. TLRs are a family of transmembrane proteins which serve as major pattern recognition receptors, binding to a wide range of microbial products and endogenous ligands released as a consequence of injury. TLR-dependent signaling serves as a rapid response mechanism to local tissue damage and has been implicated in early activation of the innate immune response during kidney IRI [11, 20]. Renal tubular epithelial cells constitutively express TLR2 and TLR4, and IRI results in selective upregulation of these TLRs. Experimental studies of kidney IRI have demonstrated attenuation of renal structural and functional injury in both TLR2−/− and TLR4−/−mice, implicating TLR2 and TLR4 signaling in renal damage [21, 22]. TLR2 may also play a role in transplantation tolerance