Background Acute kidney injury (AKI) is a common and often catastrophic complication in hospitalized patients, however the impact of AKI in surgical sepsis remains unknown. We utilized RIFLE (Risk-Injury-Failure-Loss-End stage) consensus criteria to define the incidence of AKI in surgical sepsis and characterize the impact of AKI on patient morbidity and mortality. Methods Our prospective, Institutional Review Board-approved sepsis research database was retrospectively queried for the incidence of AKI by RIFLE criteria, excluding those with chronic kidney disease. Patients were grouped into sepsis, severe sepsis and septic shock by refined consensus criteria. Data including demographics, baseline biomarkers of organ dysfunction (BOD), and outcomes were compared by Student's t test and χ2 test. Multivariable regression analysis was performed for the effect of AKI on mortality adjusting for age, gender, African-American race, elective surgery, APACHE II score, septic shock vs. severe sepsis, and sepsis source. Results During the 36-month study period ending December 2010, 246 patients treated for surgical sepsis were evaluated. AKI occurred in 67% of all patients and 59%, 60%, and 88% of patients with sepsis, surgical sepsis, and septic shock, respectively. AKI was associated with Hispanic ethnicity, several baseline BODs, and a greater severity of illness. Patients with AKI had fewer ventilator-free and ICU-free days and a decreased likelihood of discharge to home. Morbidity and mortality increased with severity of AKI, and AKI of any severity was found to be a strong predictor of hospital mortality (OR 10.59, 95% CI 1.28-87.35, p=0.03) in surgical sepsis. Conclusion AKI frequently complicates surgical sepsis, and serves as a powerful predictor of hospital mortality in severe sepsis and septic shock. Level of Evidence Level III

Despite advancements in renal replacement therapy, the mortality rate for acute kidney injury (AKI) remains unacceptably high, likely due to remote organ injury. Kidney ischemia-reperfusion injury (IRI) activates cellular and soluble mediators that incite a distinct pulmonary proinflammatory and proapoptotic response. Tumor necrosis factor receptor 1 (TNFR1) has been identified as a prominent death receptor activated in the lungs during ischemic AKI. We hypothesized that circulating TNF-α released from the postischemic kidney induces TNFR1-mediated pulmonary apoptosis, and we aimed to elucidate molecular pathways to programmed cell death. Using an established murine model of kidney IRI, we characterized the time course for increased circulatory and pulmonary TNF-α levels and measured concurrent upregulation of pulmonary TNFR1 expression. We then identified TNFR1-dependent pulmonary apoptosis after ischemic AKI using TNFR1-/- mice. Subsequent TNF-α signaling disruption with Etanercept implicated circulatory TNF-α as a key soluble mediator of pulmonary apoptosis and lung microvascular barrier dysfunction during ischemic AKI. We further elucidated pathways of TNFR1-mediated apoptosis with NF-κB (Complex I) and caspase-8 (Complex II) expression and discovered that TNFR1 proapoptotic signaling induces NF-κB activation. Additionally, inhibition of NF-κB (Complex I) resulted in a proapoptotic phenotype, lung barrier leak, and altered cellular flice inhibitory protein signaling independent of caspase-8 (Complex II) activation. Ischemic AKI activates soluble TNF-α and induces TNFR1-dependent pulmonary apoptosis through augmentation of the prosurvival and proapoptotic TNFR1 signaling pathway. Kidney-lung crosstalk after ischemic AKI represents a complex pathological process, yet focusing on specific biological pathways may yield potential future therapeutic targets.

Acute kidney injury (AKI) is a common complication during inpatient hospitalization, and clinical outcomes remain poor despite advancements in renal replacement therapy. AKI in the setting of multiple organ failure (MOF) remains a formidable challenge to clinicians and incurs an unacceptably high mortality rate. Kidney ischemia-reperfusion injury (IRI) incites a proinflammatory cascade and releases cellular and soluble mediators with systemic implications for remote organ injury. Evidence from preclinical models cites mechanisms of organ crosstalk during ischemic AKI including the expression of cellular adhesion molecules, lymphocyte trafficking, release of proinflammatory cytokines and chemokines, and modification of the host innate and adaptive immune response systems. In this paper, the influence of kidney IRI on systemic inflammation and distant organ injury will be examined. Recent experimental data and evolving concepts of organ crosstalk during ischemic AKI will also be discussed in detail.

Acute kidney injury (AKI) is a common complication of hospitalized patients, and clinical outcomes remain poor despite advances in renal replacement therapy. The accepted pathophysiology of AKI in the setting of sepsis has evolved from one of simple decreased renal blood flow to one that involves a more complex interaction of intra-glomerular microcirculatory vasodilation combined with the local release of inflammatory mediators and apoptosis. Evidence from pre-clinical AKI models suggests that crosstalk occurs between kidneys and other organ systems via soluble and cellular inflammatory mediators, and that this involves both the innate and adaptive immune systems. These interactions are reflected by genomic changes and abnormal rates of cellular apoptosis in distant organs including the lungs, heart, gut, liver, and central nervous system. The purpose of this article is to review the influence of AKI, particularly sepsis-associated AKI, on inter-organ crosstalk in the context of systemic inflammation and multiple organ failure (MOF).

Despite advances in renal replacement therapy, the mortality rate for acute kidney injury (AKI) remains unacceptably high, likely owing to extrarenal organ dysfunction. Kidney ischemia–reperfusion injury (IRI) activates cellular and soluble mediators that facilitate organ crosstalk and induce caspase-dependent lung apoptosis and injury through a TNFR1-dependent pathway. Given that T lymphocytes mediate local IRI in the kidney and are known to drive TNFR1-mediated apoptosis, we hypothesized that T lymphocytes activated during kidney IRI would traffic to the lung and mediate pulmonary apoptosis during AKI. In an established murine model of kidney IRI, we identified trafficking of CD3+ T lymphocytes to the lung during kidney IRI by flow cytometry and immunohistochemistry. T lymphocytes were primarily of the CD3+CD8+ phenotype; however, both CD3+CD4+ and CD3+CD8+ T lymphocytes expressed CD69 and CD25 activation markers during ischemic AKI. The activated lung T lymphocytes did not demonstrate an increased expression of intracellular TNF-α or surface TNFR1. Kidney IRI induced pulmonary apoptosis measured by caspase-3 activation in wild-type controls, but not in T cell-deficient (Tnu/nu) mice. Adoptive transfer of murine wild-type T lymphocytes into Tnu/nu mice restored the injury phenotype with increased cellular apoptosis and lung microvascular barrier dysfunction, suggesting that ischemic AKI-induced pulmonary apoptosis is T cell dependent. Kidney–lung crosstalk during AKI represents a complex biological process, and although T lymphocytes appear to serve a prominent role in the interorgan effects of AKI, further experiments are necessary to elucidate the specific role of activated T cells in modulating pulmonary apoptosis.

Kidney ischemia-reperfusion injury (IRI) activates cellular and soluble mediators that drive lung inflammatory cascades, tumor necrosis factor receptor 1 (TNFR1)-mediated programmed cell death, and microvascular barrier dysfunction, leading to acute lung injury. We hypothesized that lung microvascular endothelial cells (ECs), with their integral role in maintaining the lung-semipermeable barrier, were key cellular targets of TNFR1-mediated apoptosis during ischemic AKI. Male C57/BL6 mice and Sprague-Dawley rats underwent 60 min of bilateral renal pedicle occlusion (IRI) or sham laparotomy (sham) and were killed at 4 or 24 h. Colocalization with TUNEL, DAPI, and CD34 was performed to identify EC-specific apoptosis. Mouse ECs (CD45/CD31) isolated with novel tissue digestion techniques and magnetic microbead sorting underwent quantitative real-time polymerase chain reaction SuperArray analysis with 84 apoptosis-related genes. In parallel, rat lung microvascular ECs grown to confluence were treated with serum from rats obtained following sham or kidney IRI. Rat lung microvascular ECs treated +/- etanercept, a TNF-α/TNFR1 signaling inhibitor, underwent custom real-time polymerase chain reaction analysis for proapoptotic and TNF superfamily transcriptional events, and apoptosis was identified with caspase 3 and poly(ADP-ribose) polymerase activity assays. In vivo, TUNEL-positive cells colocalized with CD34 in whole-lung tissue and isolated lung ECs demonstrated a proapoptotic transcriptome during ischemic AKI. In vitro, ischemic AKI incited proapoptotic (FasL, Dapk1, Bcl10) and TNF superfamily (TNFR1, TNFR2, TNF-α) gene activation and increased caspase 3 and poly(ADP-ribose) polymerase activity at 24 h versus sham. Compared with vehicle, treatment of rat lung microvascular ECs with etanercept inhibited proinflammatory gene activation (E-selectin, intercellular adhesion molecule 1, interleukin 6, RhoB) and apoptosis during ischemic AKI. Ischemic AKI drives distinct proinflammatory and proapoptotic changes in the pulmonary EC transcriptome with TNFR1-dependent caspase activation and programmed cell death. Further investigation of potential EC mechanisms of kidney-lung crosstalk during AKI may identify potential therapeutic targets for this deadly disease.

We developed a lower-extremity activity scale and validated that it was an effective instrument for the assessment of patients' actual activity levels. It is easy to apply and interpret, and it is valid and ready for use in the clinical setting. This scale will allow more accurate analysis and prediction of outcomes. Consequently, it will become a useful, practical adjunct to objective clinical decision-making and intervention for patients undergoing arthroplasty.

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