Immune modulation of acute kidney injury.

A cute kidney injury (AKI), inclusive of clinical terms such as acute renal failure, acute tubular necrosis, and delayed graft function, is being defined as functional or structural abnormalities or markers of kidney damage, including abnormalities in blood, urine, or tissue tests or imaging studies present for 3 months (Acute Kidney Injury Network group proposed consensus definition; personal communication, Mehta R., University of California San Diego, January 16, 2006). AKI occurs in 5 to 10% of patients in tertiary care hospitals and in virtually all patients early after kidney transplantation (1). The leading cause of AKI is ischemia reperfusion injury (IRI), while nephrotoxins and obstruction are other common etiologies. AKI in the native kidney is associated with high mortality rates, while AKI in transplants is associated with increased frequency of rejection and decreased short-term and long-term allograft function (2). The lack of specific therapies for AKI has led to intense investigation of the pathophysiology with the promise that targeted therapies will emerge. The role of innate immunity in acute tissue injury is well established, with engagement of complement, cytokines, and neutrophils. However, studies examining blockade of neutrophils in experimental AKI, unlike in acute injury to heart or gut, led to mixed results, whereas blockade of leukocyte adhesion molecules in experimental AKI models, supposedly targeting neutrophils, were usually highly protective (reviewed in 3). This seeming inconsistency led to the consideration that leukocyte adhesion molecule blockade was working through nonneutrophil leukocytes that expressed these receptors, like lymphocytes and macrophages. Although unexpected according to traditional immune models, lymphocytes, particularly CD4 T cells, have been found to directly mediate AKI as well as IRI injury to liver, lung, and intestine (4–8). Lymphocytes have recently been implicated in the pathogenesis of cardiac ischemia and stroke (9,10). The recognition of this important finding was delayed by limited data on early lymphocyte infiltration soon after kidney injury, plus absence of a conceptual model to explain how lymphocytes could be involved in acute, alloantigen-independent, tissue injury. However, studies performed 30 yr ago on human AKI biopsies demonstrated mononuclear leukocytes rather than neutrophils (11). Subsequent studies in humans have shown that these mononuclear leukocytes include CD3 cells in the vasa recta (12). While pursuing the identify of pathogenic lymphocytes in experimental kidney IRI in mice, a surprise finding was that not only were IFN producing T cells injurious, but lymphocytes producing Th2 cytokines, including IL-4, were protective (13). A complex model began to emerge where lymphocytes could not only be deleterious, but also have some protective properties in kidney IRI—now more consistent with classic immunologic models of balancing roles for lymphocytes in disease. Similar finding of both deleterious and potentially protective lymphocytes were found in a model of liver IRI (14). Thus, a model of a modulatory role of the lymphocyte in IRI has emerged, rather than a purely pathogenic one. In the context of this work, Fiorina and colleagues at Harvard have studied the role of the CXC chemokine receptor 3 (CXCR3) in kidney IRI in mice (15). CXCR3 is mainly expressed on activated Th1 T cells and mediates recruitment of T cells to sites of inflammation, adhesion and activation. In a unilateral clamp model of kidney IRI, an early increase in the CXCR3 ligands IP-10/CXCL10 and MIG/CXCL9 in postischemic tissue was observed using real-time PCR, but little expression of another ligand-ITAC. CXCR3 expression was observed at 6 h of clamping, but not later, demonstrating the importance of studying very early times after ischemia reperfusion to kidney. A marked attenuation of kidney dysfunction, tubular injury, and mortality was observed in the CXCR3-deficient mouse compared with age-, sex-, and strain-matched controls. However, actual littermate controls were not used and controls derived in different environments could have other factors that alter response to injury. Given that CXCR3 could be mediating AKI through nonlymphocyte cells, an important mechanistic experiment was performed: Adoptively transferring purified CD3 cells into CXCR3 deficient mice before induction of IRI, which restored the expression of kidney injury and mortality. Thus, CXCR3 was indeed mediating AKI through T cells. To evaluate whether CXCR3 deficiency was protective via polarizing lymphocytes toward a “protective” Th2 phenotype, kidney infiltrating CD4 cells were extracted, and Th2 producing anti-inflammatory IL-4 and IL-10 were enhanced in CXCR3-deficient mice. Furthermore, enhanced protective genes superoxide dismutase and heme oxygenase, additional candidate mediators of the protected phenotype, were found in CXCR3 / mice. The important role for CXCR3 in kidney IRI is consistent with its recently described role in experimental lower limb IRI (16). The study by Fiorina et al. provides strong additional data supporting the role for immune cells as modulators of AKI; Published online ahead of print. Publication date available at www.jasn.org.