The Local and Systemic Inflammatory Transcriptome after Acute Kidney Injury

Abstract

Studies in humans and animal models have demonstrated that acute kidney injury (AKI) has a significant effect on the function of extrarenal organs. The combination of AKI and lung dysfunction is associated with 80% mortality; the lung, because of its extensive capillary network, is a prime target for AKI-induced effects. The study presented here tested the hypothesis that AKI leads to a vigorous inflammatory response and produces distinct genomic signatures in the kidney and lung. In a murine model of ischemic AKI, prominent global transcriptomic changes and histologic injury in both kidney and lung tissues were identified. These changes were evident at both early (6 h) and late (36 h) timepoints after 60-min bilateral kidney ischemia and were more prominent than similar timepoints after sham surgery or 30 min of ischemia. The inflammatory transcriptome (109 genes) of both organs changed with marked similarity, including the innate immunity genes Cd14, Socs3, Saa3, Lcn2, and Il1r2. Functional genomic analysis of these genes suggested that IL-10 and IL-6 signaling was involved in the distant effects of local inflammation, and this was supported by increased serum levels of IL-10 and IL-6 after ischemia-reperfusion. In summary, this is the first comprehensive analysis of concomitant inflammation-associated transcriptional changes in the kidney and a remote organ during AKI. Functional genomic analysis identified potential mediators that connect local and systemic inflammation, suggesting that this type of analysis may be a useful discovery tool for novel biomarkers and therapeutic drug development. Clinical studies have revealed a strong association between AKI and dysfunction of extrarenal organs, and more recently animal research has shown a significant causal effect of AKI on distant organ dysfunction. [1][2][3][4][5][6][7] Since the availability of dialysis, AKIassociated distant organ dysfunction constitutes the major cause of death in these patients, with the mortality rate still in the 50% range. Despite this frustrating outcome, little is known about the potential pathophysiological interactions between the kidney and extrarenal organs in critically ill patients. Numerous recent studies have demonstrated that outcomes of AKI are heavily dependent upon the severity of comorbid conditions. 8 -10 Isolated AKI has a much better prognosis than AKI associated with multiple organ failure, 11,12 and the presence of renal insufficiency continues to be a sensitive marker for poor outcome in the hospitalized patient. 13 Thus, there is an urgent need to study the systemic effects of AKI, and modern discovery tools have the potential to unveil novel diagnostic and therapeutic targets.Inflammation is a major component of the initiation and exacerbation of kidney injury during AKI, 14,15 and local inflammation of kidney tissues could be a source of the development of inflamma-

Delayed Graft Function and the Risk for Death with a Functioning Graft

“…[12][13][14][15] These adverse effects may partially contribute to the poor long-term survival observed in patients who have AKI and eventually recover renal function. 16,17 Similar to AKI, DGF in KTR is associated with the modulation of leukocyte/endothelial function, upregulation of cytokines/adhesion molecules, and increase in markers of oxidative stress.…”

Sepsis and Acute Kidney Injury

“…21 Several pro-inflammatory cytokines contribute to the development of sepsis, and others may be identifiable from other kinds of genetic screens. 22 For instance, administration of recombinant IL-1 or TNF-␣ induces many of the features observed after lipopolysaccharide exposure or sepsis itself. 18,19 Furthermore, anti-TNF monoclonal antibodies have beneficial effects in several animal models of sepsis.…”

Neutrophil Gelatinase Associated Lipocalin (NGAL) as a Biomarker. Does It Apply in Abdominal Aortic Aneurysms? A Review of Literature

“…More specifically, as far as open AAA repair and NGAL level changes are concerned, an increase in serum NGAL (75.21±55.83 vs. 46.37±21.60 ng/ml, p>0.05) and significantly elevated plasma NGAL levels at 2 h (91.54±76.54 vs. baseline, p<0.05), 12 h (100.78±44.92 vs. baseline, p<0.05), and 24 h (89.46±94.18 vs. baseline, p<0.05) after clamp release and reperfusion were found [33,34].…”

“…In cases of open AAA repair, it is shown that after clamp removal, NGAL washes out from the lower extremities, which become ischemic during aneurysm repair [33]. Additionally, AAA surgery triggers an inflammatory reaction and thus the increase of NGAL, which is known to be an acute-phase reactant produced by some immune cells [33].…”

“…In cases of open AAA repair, it is shown that after clamp removal, NGAL washes out from the lower extremities, which become ischemic during aneurysm repair [33]. Additionally, AAA surgery triggers an inflammatory reaction and thus the increase of NGAL, which is known to be an acute-phase reactant produced by some immune cells [33]. NGAL has further been widely studied as an individual marker of acute kidney injury (AKI) induced by the AAA repair surgery, and it has been shown to increase due to decreased GFR with subsequent clearance impairment per se [34,35].…”