Heitham T. Hassoun

The Local and Systemic Inflammatory Transcriptome after Acute Kidney Injury

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.

Organ crosstalk: the role of the kidney.

Purpose of reviewAcute kidney injury (AKI) continues to contribute significantly to morbidity and mortality in the ICU setting, especially when associated with distant organ dysfunction. There is increasing evidence that AKI directly contributes to organ dysfunction in lung, brain, liver, heart and other organs. This review will examine our current understanding of the deleterious organ crosstalk in the critically ill, which can provide a framework for developing novel therapeutics. Recent findingsThe majority of studies correlating AKI with distant organ dysfunction have demonstrated the pathophysiological importance of proinflammatory and proapoptotic pathways as well as oxidative stress and reactive oxygen species (ROS) production. Leukocyte activation and infiltration, changes in levels of soluble factors such as cytokines and chemokines, and regulation of cell death in extra-renal organs are potentially important mechanisms by which AKI modulates multiorgan dysfunction. SummaryThere is increasing knowledge of AKI and deleterious interorgan crosstalk that arises, at least in part, due to the imbalance of immune, inflammatory, and soluble mediator metabolism that attends severe insults to the kidney. Further studies can build on these new mechanistic observations to develop strategies to improve outcomes in the critically ill patient.

Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis

Distant organ effects of acute kidney injury (AKI) are a leading cause of morbidity and mortality. While little is known about the underlying mechanisms, limited data suggest a role for inflammation and apoptosis. Utilizing a lung candidate gene discovery approach in a mouse model of ischemic AKI-induced lung dysfunction, we identified prominent lung activation of 66 apoptosis-related genes at 6 and/or 36 h following ischemia, of which 6 genes represent the tumor necrosis factor receptor (TNFR) superfamily, and another 23 genes are associated with the TNFR pathway. Given that pulmonary apoptosis is an important pathogenic mechanism of acute lung injury (ALI), we hypothesized that AKI leads to pulmonary proapoptotic pathways that facilitate lung injury and inflammation. Functional correlation with 1) terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling and 2) active caspase-3 (aC3) activity, immunoblotting, and immunohistochemistry (IHC) identified kidney IRI-induced pulmonary apoptosis at 24 h, and colocalization studies with CD34 identified predominantly endothelial apoptosis. Mice were treated with the caspase inhibitor Z-VAD-FMK (0.25 mg ip) or vehicle 1 h before and 8 h after sham or kidney IRI, and bronchoalveolar lavage fluid protein was measured at 36 h as a surrogate for lung leak. Caspase inhibition reduced lung microvascular changes after kidney IRI. The pulmonary apoptosis seen in wild-type control mice during AKI was absent in TNFR(-/-) mice. Using an initial genomic approach to discovery followed by a mechanistic approach to disease targeting, we demonstrate that pulmonary endothelial apoptosis is a direct mediator of the distant organ dysfunction during experimental AKI.

Renal ischemia-reperfusion leads to long term infiltration of activated and effector-memory T lymphocytes

It is well-established that significant ischemia-reperfusion injury during kidney transplantation results in increased incidence of long-term fibrosis and rejection. To test for a role of T cell infiltration and activation following ischemic injury, we induced both bilateral and unilateral renal ischemia in mice, followed by reperfusion, and then isolated mononuclear cells. Analysis of these cells by flow cytometry showed that 2 weeks after bilateral ischemia there was a significant increase of CD8(+) T cells. Furthermore, both CD4(+) and CD8(+) T cells infiltrated the injured kidney 6 weeks after unilateral ischemia. These T cells had increased expression of CD69(+) and CD44(hi)CD62L(-), markers of activation and effector-memory, respectively. CD4(+)NK1.1(+) and CD19(+) B cells were decreased in percentage both 6 and 11 weeks after bilateral or unilateral injury. There was a significant upregulation of IL-1beta, IL-6, TNF-alpha, IFN-gamma, MIP-2, and RANTES expression, measured by real-time PCR, 6 weeks after unilateral renal ischemia, further indicating T cell activation. Depletion of CD4(+) and CD8(+) T cells before ischemia caused less medullary damage and reduced kidney IFN-gamma expression, whereas their depletion following ischemia increased kidney IL-1beta; however, depletion of these cells had no effect on histological damage to the kidney. Our study demonstrates that moderate or severe kidney ischemia induces long-term T lymphocyte infiltration and cytokine/chemokine upregulation, leading to kidney structural changes.

Kidney-Lung Crosstalk in the Critically Ill Patient

Despite advances in renal replacement therapy, the mortality of acute kidney injury (AKI) has remained high, especially when associated with distant organ dysfunction such as acute lung injury (ALI). Mortality rates for combined AKI/ALI reach 80% in critically ill patients. While the clinical presentation of AKI-associated ALI is characterized by increased pulmonary edema, a defining feature of the syndrome, the AKI-induced lung effects extend beyond simple volume overload. Furthermore, ALI and associated mechanical ventilation frequently lead to a decline in renal hemodynamics, structure and function. New experimental data have emerged in recent years focusing on the interactive effects of kidney and lung dysfunction, and these studies have highlighted the pathophysiological importance of proinflammatory and proapoptotic pathways as well as the complex nature of interorgan crosstalk. This review will examine our current understanding of the deleterious kidney-lung crosstalk in the critically ill.

Inflammatory Mechanisms of Organ Crosstalk during Ischemic Acute Kidney Injury

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.

Multiple treatment algorithms for successful outcomes in venous thoracic outlet syndrome

BACKGROUNDnWe sought to determine the outcomes in patients presenting with venous thoracic outlet syndrome.nnnMETHODSnProspectively collected data from 67 patients between October 2003 and December 2007. The average age was 31 years (range, 16-54); the 37 males and 30 females presented on average 9.2 months (range, 1 month-6 years) after acute thrombosis. Four treatment algorithms were utilized.nnnRESULTSnIn group 1, 3 patients presented with acute occlusion and received tissue plasminogen activator (tPA) and immediate first rib resection with scalenectomy (FRRS). One vein rethrombosed and was treated by intravenous tPA postoperatively. In group 2, 39 patients presented with stenotic subclavian veins an average of 22 weeks after their initial thrombosis, all of whom underwent FRRS followed by a venogram 2 weeks postoperatively: 25 had a tight stenosis and underwent venoplasty with anticoagulation; 13 had patent, nonstenotic subclavian veins, and 1 patient required tPA and venoplasty owing to rethrombosis. Two patients had their subclavian vein thrombose after venoplasty and were treated with anticoagulation, tPA, and venoplasty. In group 3, 11 patients presented with intermittent venous obstruction without thrombosis and underwent FRRS; 3 underwent venograms because of concerns of residual stenosis, 2 of whom required venoplasty postoperatively. Finally, in group 4, 14 patients presented with occluded subclavian veins and underwent FRRS with long-term anticoagulation. Eleven have recanalized at an average of 6 months (range, 2-12).nnnCONCLUSIONnOverall, 64 of 67 patients have patent subclavian veins after a median follow-up of 10 months, and all patients are asymptomatic for a success rate of 96%. Tailored treatment algorithms including FRRS, postoperative venograms with or without intervention, and the use of long-term anticoagulation seems to be required in this complicated group of young patients to achieve optimal results.

Surgical sepsis and organ crosstalk: the role of the kidney.

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 preclinical 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).

Interactive Effects of Mechanical Ventilation and Kidney Health on Lung Function in an In Vivo Mouse Model

We hypothesized that the influence of acute kidney injury (AKI) on the sensitivity of the lung to an injurious process varies with the severity of the injurious process. Thus, we thought that AKI would exacerbate lung injury from low degrees of lung trauma but attenuate lung injury from higher degrees of lung trauma. C57BL/6 mice underwent AKI (30-min kidney ischemia) or sham surgery, followed at 24 h by 4 h of spontaneous breathing (SB), mechanical ventilation with low tidal volume (7 ml/kg, LTV), or mechanical ventilation with high tidal volume (30 ml/kg, HTV). Compared with LTV, median bronchoalveolar lavage (BAL) protein leak was significantly lower with SB and greater with HTV in both sham and AKI mice. Compared with LTV, median Evans blue dye-labeled albumin extravasation in lungs (L-EBD) was also significantly lower with SB and greater with HTV. L-EBD showed a significant interaction between ventilatory mode and kidney health, such that AKI attenuated the L-EBD rise seen in HTV vs. LTV sham mice. An interaction between ventilatory mode and kidney health could also be seen in BAL neutrophil number (PMN). Thus, AKI attenuated the BAL PMN rise seen in HTV vs. LTV sham mice. These data support the presence of a complex interaction between mechanical ventilation and AKI in which the sensitivity of the lung to trauma varies with the magnitude of the trauma and may involve a modification of pulmonary neutrophil activity by AKI.

Effects of acid aspiration-induced acute lung injury on kidney function

Acute lung injury (ALI) in combination with acute kidney injury carries a mortality approaching 80% in the intensive care unit. Recently, attention has focused on the interaction of the lung and kidney in the setting of ALI and mechanical ventilation (MV). Small animal models of ALI and MV have demonstrated changes in inflammatory mediators, water channels, apoptosis, and function in the kidney early in the course of injury. The purpose of this investigation was to test the hypothesis that ALI and injurious MV cause early, measurable changes in kidney structure and function in a canine HCl aspiration model of ALI when hemodynamics and arterial blood gas tensions are carefully controlled. Intratracheal HCl induced profound ALI as demonstrated by increased shunt fraction and airway pressures compared with sham injury. Sham-injured animals had similar mean arterial pressure and arterial Pco(2) and HCO(3) levels compared with injured animals. Measurements of renal function including renal blood flow, urine flow, serum creatinine, glomerular filtration rate, urine albumin-to-creatinine ratio, and kidney histology scores were not different between groups. With maintenance of hemodynamic parameters and alveolar ventilation, ALI and injurious MV do not alter kidney structure and function early in the course of injury in this acid aspiration canine model. Kidney injury in large animal models may be more similar to humans and may differ from results seen in small animal models.