International Journal of Nephrology 5 Underlying mechanisms: (i) Alveolar cell apoptosis (ii) Fluid pressure (iii) Dysregulated Na+, water channels (iv) Increased vascular permeability Acute lung injury Mediators: (i) Oxidative stress (ii) Cytokines/chemokines (iii) Activated leukocytes (iv) Uremic toxins Pathological axis between AKI and ALI Mediators: (i) Hypoxia (ii) Hypercapnia (iii) PEEP (iv) Biotrauma Acute kidney injury Underlying mechanisms: (i) Decreased renal perfusion (ii) Blood-gas disturbances (iii) Inﬂammation/apoptosis Figure 2: Pathological Axis between AKI and ALI. AKI induces pathophysiologic eﬀects on the lung via cellular and soluble mediators. ALI, in turn, exacerbates kidney dysfunction through metabolic and biochemical derangements. [53]. In a rodent model, our laboratory has characterized caspase-dependent pulmonary apoptosis which is abrogated by the administration of a broad-spectrum caspase inhibitor. Not only did caspase inhibition attenuate the pulmonary functional injury, but the proapoptotic response to ischemic AKI appears to be mediated via a TNF receptor-1 (TNF-R-1) dependent pathway [54]. Our research has also demonstrated T-cell-dependent pulmonary apoptosis during ischemic AKI. Along with iden- tiﬁcation of activated T cells traﬃcking to the lungs during ischemic AKI, we have found that pulmonary apoptosis was subsequently attenuated in T-cell-deﬁcient animals [33]. Further pursuit of the speciﬁc pathway for T cell and TNFR1- dependent pulmonary apoptosis remains an active focus of future investigation in our research laboratory. 3.2. Kidney Crosstalk with Other Distant Organs. Cardio- vascular collapse is one of the most common causes of death in the setting of AKI, yet the mechanisms involved are not entirely understood [55]. Kelly has demonstrated left ventricular dilation, increased left ventricular end diastolic and end systolic diameter, increased relaxation time, and decreased fractional shortening in an experimental model of ischemic AKI [56]. Mechanisms of cardiac injury during ischemic AKI include cardiac myocyte apoptosis and neu- trophil inﬁltration, which have been attributed to increased cardiac and systemic TNFα, IL-1, and ICAM-1 expression [56, 57]. When kidney ischemic time is decreased, cardiac IL-1 and ICAM expression, along with myocyte necrosis, decreased correspondingly [56]. Eﬀects of ischemic AKI on the central nervous system (CNS) are evident clinically when mental status changes develop. Of note, renal replacement therapy fails to fully cor- rect this CNS manifestation of renal failure [58]. Uremic tox- ins certainly contribute to many symptoms of encephalopa- thy; however, cellular and soluble inﬂammatory mediators have also been implicated. Preclinical data identiﬁed an increase of KC, G-CSF, and glial ﬁbrillary acidic protein (GFAP) in the cerebral cortex and hippocampus of the brain, which may serve to recruit neutrophils to sites of neuronal damage [59]. This may result from either increased local neuronal production or an alteration of the blood-brain barrier; further research is required to delineate the source. A cell-mediated proinﬂammatory response has also been iden- tiﬁed with activation of microglial cells (brain macrophages) during ischemic AKI [59]. Ischemic AKI is also implicated in oxidative stress, inﬂammation, apoptosis, and tissue damage in hepatocytes. Hepatic stellate cells (HSCs) regulate leukocyte traﬃcking and the secretion of chemokines such as IL-8, and crosstalk between HSCs likely occurs via a c-Jun N-terminal kinase pathway [60]. Oxidative stress during ischemic AKI causes hepatic malondialdehyde, an index of lipid peroxidation, to increase while total glutathione, an antioxidant, decreases [61]. Proinﬂammatory cytokine TNFα expression and hepatic cellular apoptosis is also evident during ischemic AKI [61].