Acute kidney injury (AKI) prolongs hospital stay and increases mortality in various clinical settings. Ischaemia-reperfusion injury (IRI), nephrotoxic agents and infection leading to sepsis are among the major causes of AKI. Inflammatory responses substantially contribute to the overall renal damage in AKI. Both innate and adaptive immune systems are involved in the inflammatory process occurring in post-ischaemic AKI. Proinflammatory damage-associated molecular patterns, hypoxia-inducible factors, adhesion molecules, dysfunction of the renal vascular endothelium, chemokines, cytokines and Toll-like receptors are involved in the activation and recruitment of immune cells into injured kidneys. Immune cells of both the innate and adaptive immune systems, such as neutrophils, dendritic cells, macrophages and lymphocytes contribute to the pathogenesis of renal injury after IRI, and some of their subpopulations also participate in the repair process. These immune cells are also involved in the pathogenesis of nephrotoxic AKI. Experimental studies of immune cells in AKI have resulted in improved understanding of the immune mechanisms underlying AKI and will be the foundation for development of novel diagnostic and therapeutic targets. This Review describes what is currently known about the function of the immune system in the pathogenesis and repair of ischaemic and nephrotoxic AKI.

T lymphocytes modulate early ischemia-reperfusion injury in the kidney; however, their role during repair is unknown. We studied the role of TCRbeta(+)CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs), known to blunt immune responses, in repair after ischemia-reperfusion injury to the kidney. Using a murine model of ischemic acute kidney injury we found that there was a significant trafficking of Tregs into the kidneys after 3 and 10 days. Post-ischemic kidneys had increased numbers of TCRbeta(+)CD4(+) and TCRbeta(+)CD8(+) T cells with enhanced pro-inflammatory cytokine production. Treg depletion starting 1 day after ischemic injury using anti-CD25 antibodies increased renal tubular damage, reduced tubular proliferation at both time points, enhanced infiltrating T lymphocyte cytokine production at 3 days and TNF-alpha generation by TCRbeta(+)CD4(+) T cells at 10 days. In separate mice, infusion of CD4(+)CD25(+) Tregs 1 day after initial injury reduced INF-gamma production by TCRbeta(+)CD4(+) T cells at 3 days, improved repair and reduced cytokine generation at 10 days. Treg manipulation had minimal effect on neutrophil and macrophage infiltration; Treg depletion worsened mortality and serum creatinine, while Treg infusion had a late beneficial effect on serum creatinine in bilateral ischemia. Our study demonstrates that Tregs infiltrate ischemic-reperfused kidneys during the healing process promoting repair, likely through modulation of pro-inflammatory cytokine production of other T cell subsets. Treg targeting could be a novel therapeutic approach to enhance recovery from ischemic acute kidney injury.

Kidney ischemia reperfusion injury is a major cause of morbidity in both allograft and native kidneys. Ischemia reperfusion-induced acute kidney injury is characterized by early, allo-antigen independent inflammation. Major components of the innate immune system are activated and participate in the pathogenesis of acute kidney injury, plus prime the allograft kidney for rejection. Soluble members of innate immunity implicated in acute kidney injury include the complement system, cytokines, and chemokines. Toll-like receptors (TLRs) are also important contributors. Effector cells that participate in ACUTE KIDNEY INJURY include the classic innate immune cells, neutrophils and macrophages. Recent data has unexpectedly identified lymphocytes as participants of early acute kidney injury responses. In this review, we will focus on immune mediators that participate in the pathogenesis of ischemic acute kidney injury.

Kidney ischemia-reperfusion injury (IRI) engages both the innate and adaptive immune responses. Cellular mediators of immunity, such as dendritic cells, neutrophils, macrophages, natural killer T, T, and B cells, contribute to the pathogenesis of renal injury after IRI. Postischemic kidneys express increased levels of adhesion molecules on endothelial cells and toll-like receptors on tubular epithelial cells. Soluble components of the immune system, such as complement activation proteins and cytokines, also participate in injury/repair of postischemic kidneys. Experimental studies on the immune response in kidney IRI have resulted in better understanding of the mechanisms underlying IRI and led to the discovery of novel therapeutic and diagnostic targets.

Acute kidney injury (AKI) is being increasingly shown to be a risk factor for chronic kidney disease (CKD), but little is known about the possible mechanistic links. We hypothesized that analysis of the genomic signature in the repair stage after AKI would reveal pathways that could link AKI and CKD. Unilateral renal pedicle clamping for 45 min was performed in male C57BL/6J mice. Mice were euthanized at 3, 10, and 28 days after ischemia-reperfusion injury (IRI). Total RNA was isolated from kidney and analyzed using an Illumina mouse array. Among 24,600 tested genes, 242, 146, and 46 genes were upregulated at days 3, 10, and 28 after IRI, and 85, 35, and 0 genes were downregulated, respectively. Gene ontology analysis showed that gene expression changes were primarily related to immune and inflammatory pathways both early and late after AKI. The most highly upregulated genes late after AKI were hepatitis A virus cellular receptor 1 (Havcr1) and lipocalin 2 (Lcn2), which code for kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), respectively. This was unexpected since they are both primarily potential biomarkers of the early stage of AKI. Furthermore, increases observed in gene expression in amiloride binding protein 1, vascular cell adhesion molecule-1, and endothelin 1 could explain the salt-sensitive hypertension that can follow AKI. These data suggested that 1) persistent inflammation and immune responses late after AKI could contribute to the pathogenesis of CKD, 2) late upregulation of KIM-1 and NGAL could be a useful marker for sustained renal injury after AKI, and 3) hypertension-related gene changes could underlie mechanisms for persistent renal and vascular injury after AKI.

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There is a significant immune response to ischemia-reperfusion injury (IRI), but the role of immunomodulatory natural killer T (NKT) cell subtypes is not well understood. Here, we compared the severity of IRI in mice deficient in type I/II NKT cells (CD1d

Kidney ischemia-reperfusion injury (IRI) is, in part, mediated by immune and inflammatory factors. Since microbial stimuli are known to alter immune and inflammatory responses, we hypothesized that differences in perinatal microbial status would modify renal injury following IRI. We performed bilateral renal IRI on 6-wk-old germ-free and control mice and studied the effects on kidney lymphocyte trafficking, cytokines, function, and structure. Compared with control mice, normal kidneys of germ-free mice exhibited more NKT cells and lower IL-4 levels. Postischemia, more CD8 T cells trafficked into postischemic kidneys of germ-free mice compared with control mice. Renal structural injury and functional decline following IRI were more severe in germ-free mice compared with control mice. When germ-free mice were conventionalized with the addition of bacteria to their diet, the extent of renal injury after IRI became equivalent to age-matched control mice, with similar numbers and phenotypes of T cells and NKT cells, as well as cytokine expression in both normal kidneys and postischemic kidneys of conventionalized germ-free mice and age-matched control mice. Thus microbial stimuli influence the phenotype of renal lymphocytes and the expression of cytokines of normal kidneys and also modulate the outcome of IRI.