Taking Aim at Acute Kidney Injury

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A better understanding has led to potential therapeutic targets.

 

Acute kidney injury (AKI) is a complex disorder for which there is no uniform definition. AKI has been reported in up to 7% of hospitalized patients, but epidemiologic studies are sparse and confounded by differences in case definitions and heterogeneity in patient populations.

 

Sepsis is a precipitating factor in up to 50% of patients with AKI, and common predisposing conditions include cardiovascular, metabolic, neoplastic, and neurologic disorders.

 

AKI has a significant impact on mortality, length of stay, and costs in hospitalized patients. An analysis of nearly 20,000 hospitalized adults revealed that AKI (as defined by 0.5 mg/dL or greater increase in serum creatinine level) was associated with 6.5-fold increase in the risk of death, a 3.5-day increase in the length of hospitalization, and a $7,500 increase in hospital costs.1 Risk factors for AKI included older age, lower baseline creatinine clearance, and higher severity of illness.

 

The pathophysiology of ischemic AKI involves a complex interplay between renal hemodynamics, tubular and endothelial cell injury, and inflammatory processes. Despite significant improvements in therapeutics, the morbidity and mortality of AKI remain high. Major reasons for this include a lack of early biomarkers for AKI and a paucity of targets for therapeutic intervention.

 

The recent application of innovative technologies such as functional genomics and proteomics to human and animal models of AKI has led to increased understanding of the pathogenesis of hypoxic renal injury and the identification of promising biomarkers and therapeutic targets in patients with AKI. 

 

Tubular targets

 

The catastrophic breakdown of regulated cellular homeostasis, or cell death, is considered a primary pathogenetic feature of AKI. Hypoxic cell death may occur by apoptosis as well as necrosis, and it may evolve from an apoptotic to a necrotic form depending upon the nature and severity of the insult. It is likely that some common pathways are shared and regulated in the two modes of cell death. Potential therapeutic tubular targets include caspases, interleukin-18 (IL-18), and erythropoietin (EPO).

 

Caspases are intracellular cysteine proteases that play a critical role in the execution or final phase of cell death by cleaving and inactivating various structural and functional intracellular proteins that are essential for cell survival and proliferation. Caspase activation has been implicated in the development of ischemia-reperfusion injury, and evidence is emerging to implicate the caspase pathway in a variety of renal diseases including the pathogenesis of acute renal tubular epithelial cell injury.2

 

Caspase-1 participates in the final degradation of intracellular proteins and mediates inflammation through the activation of the cytokines interleukin-1-beta and IL-18. Increases in caspase-1 have been described in experimental models of ischemic injury to various organs, and inhibition of caspase-1 attenuates the progression of experimental glomerulonephritis and decreases apoptosis and tubular necrosis in ischemic AKI.3 Pharmacologic inhibitors and genetic approaches have been used to inhibit caspases in vivo, and a more precise understanding of the caspase-mediated cell death pathway is emerging.

 

IL-18 is a novel cytokine that plays an important role in T-cell activation and acts as a mediator of ischemic acute tubular necrosis (ATN). IL-18 is synthesized as a biologically inactive precursor molecule which re-quires cleavage by caspase-1 for activation. IL-18 receptor blockade protects caspase-1-deficient mice from ischemic acute renal failure, and neutralization of active IL-18 with IL-18 antiserum protects wild-type mice from ischemic AKI.4 Urinary IL-18 is an early predictive biomarker of AKI after cardiac surgery and predicts mortality in intensive care unit patients.5

 

EPO, originally identified for its critical role in promoting erythrocyte survival and differentiation, recently has been recognized as a multifunctional cytokine that exerts important cytoprotective effects in experimental brain injury and cisplatin-induced nephrotoxicity. Protective effects of EPO demonstrated in various tissues and experimental models of hypoxia- and ischemia-induced AKI include inhibition of apoptotic cell death, enhancement of tubular epithelial regeneration, and promotion of renal functional recovery.6

 

Activation of the EPO receptor with EPO mimetic peptide-1 has been shown to suppress ischemic cell death in cultured neurons by inhibiting glutamate exocytosis.7

 

Inflammatory targets

The inflammatory response is an early event in AKI and thus a po-tential target for therapeutic intervention. Inflammation contributes to the pathophysiology of ischemic AKI by reducing local blood flow with adverse consequences on tubular function and viability. Ischemic AKI involves complement activation, the generation of cytokines and chemokines within the kidney, and infiltration of the kidney by leukocytes. Because of the complex overlapping pathways involved in the inflammatory cascade, blocking single molecules is unlikely to be successful in reducing renal injury.

 

Broadly abrogating the inflammatory response may provide greater success in the treatment and prevention of ischemic AKI. Potential targets include adenosine A (2A) receptors (AA2ARs), neutro-phils, T cells, and macrophages.

 

AA2ARs are members of a family of guanine nucleotide-binding proteins that have become a focus of interest in the treatment of AKI primarily because of their ability to broadly inactivate the inflammatory cascade.8 Agonists of AA2ARs de-crease renal tissue injury in models of ischemia-reperfusion injury in part due to their inhibitory effects on neutrophil adhesion and myeloperoxi-dase activity. A potent selective AA2AR agonist, ATL146e, is being developed for use as both an anti-inflammatory agent and a pharmacological stress agent in cardiac perfusion imaging studies.

 

Neutrophils and T-cells play important roles in mediating AKI following ischaemia/reperfusion, but the role of macrophages is less well known. Macrophage depletion has been shown to attenuate renal damage in animal models of ischemic acute renal failure.9 The beneficial effects of macrophage depletion include decreases in inflammation, apoptosis of renal tubular epithelial cells, and the severity of tubular necrosis. Inhibition of nuclear factor-kappa β, a regulator of macrophage functional differentiation, re-orients macrophages so they became profoundly anti-inflammatory in settings where they would normally be classically activated and attenuates glomerular inflammation in vivo.10

 

Vascular targets

Endothelial damage and increased renal vascular permeability are hallmarks of AKI. Recent evidence supports the contribution of altered renal vascular function, especially at the microvascular level, in initiating renal tubular injury. Vascular endothelial cell injury and dysfunction play a vital part in the extension of initial injury. With injury, endothelial cells lose their ability to regulate vascular tone, perfusion, permeability and inflammation/adhesion. This loss of regulatory function has a detrimental impact upon renal function. Potential targets include fractalkine and mesenchymal stem cells (MSC).

 

Fractalkine is a unique chemokine that functions as both a chemoattractant and an adhesion molecule and is expressed on endothelial cells activated by pro-inflammatory cytokines, such as interferon-gamma and tumor necrosis factor-alpha. Soluble fractalkine causes migration of natural killer (NK) cells, cytotoxic T lymphocytes, and macrophages, whereas the membrane-bound form captures and enhances the subsequent migration of these cells in response to secondary stimulation with other chemokines. Accumulating evidence suggests that fractalkine is expressed on endothelial cells during glomerulonephritis and cardiac allograft rejection, as well as on cardiac endothelial cells activated by pro-inflammatory cytokines.

 

The fractalkine receptor, CX3CR1, is expressed on cytotoxic effector lymphocytes, including NK cells and cytotoxic T lymphocytes, and on macrophages. Interstitial and glomerular-infiltrating leukocytes expressing CX3CR1 have been found in a variety of renal diseases including membranous nephropathy, membranoproliferative glomerulo-nephritis, and collapsing glomerulopathy.11 Inhibition of CX3CR1 significantly decreases glomerular leukocyte infiltration and markedly attenuates proteinuria in models of experimental glomerulonephritis.12

 

MSC are non-hematopoietic, non-immunogenic cells that are immunosuppressive, with the ability to inhibit maturation of dendritic cells and suppress the function of naive and memory T cells, B cells and NK cells. In addition to their immuno-modulatory properties, MSC are capable of differentiating into various tissues of mesenchymal and non-mesenchymal origin and migrating to sites of tissue injury and inflammation to participate in tissue repair. The administration of ex vivo expanded bone marrow-derived MSC has proven beneficial in various experimental models of ARI.13

 

References

  1. Chertow GM, Burdick E, Honour M et al. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol. 2005;16:3149-3150.
  2. Kaushal GP. Role of caspases in renal tubular epithelial cell injury. Semin Nephrol. 2003;23:425-431.
  3. Chatterjee PK, Todorovic Z, Sivarajah A, et al. Differential effects of caspase inhibitors on the renal dysfunction and injury caused by ischemia-reperfusion of the rat kidney. Eur J Pharmacol. 2004;503:173-183.
  4. Melnikov VY, Ecder T, Fantuzzi G, et al. Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. J Clin Invest. 2001;107:1145-1152.
  5. Parikh CR, Abraham E, Ancukiewicz M, Edelstein CL. Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit. J Am Soc Nephrol. 2005;16:3046-3052.
  6. Spandou E, Tsouchnikas I, Karkavelas G, et al. Erythropoietin attenuates renal injury in experimental acute renal failure ischaemic/reperfusion model. Nephrol Dial Transplant. 2006;21:330-336.
  7. Kawakami M, Sekiguchi M, Sato K, et al. Erythropoietin receptor-mediated inhibition of exocytotic glutamate release confers neuroprotection during chemical ischemia. J Biol Chem. 2001;276:39469-39475.
  8. Okusa MD. A(2A) adenosine receptor: a novel therapeutic target in renal disease. Am J Physiol Renal Physiol. 2002;282:F10-F18.
  9. Jo SK, Sung SA, Cho WY, et al. Macrophages contribute to the initiation of ischaemic acute renal failure in rats. Nephrol Dial Transplant. 2006;21:1231-1239.
  10. Wilson HM, Chettibi S, Jobin C, et al. Inhibition of macrophage nuclear factor-kappa β leads to a dominant anti-inflammatory phenotype that attenuates glomerular inflammation in vivo. Am J Pathol. 2005;167:27-37.
  11. Segerer S, Hughes E, Hudkins KL, et al. The unique expression of the fractalkine receptor (CX3CR1) in human kidney diseases. Kidney Int. 2002;62:488-495.
  12. Chen S, Bacon KB, Li L, et al. In vivo inhibition of CC and CX3C chemokine-induced leukocyte infiltration and attenuation of glomerulonephritis in Wistar-Kyoto (WKY) rats by vMIP-II. J Exp Med. 1998;188:193-198.
  13. Patschan D, Plotkin M, Goligorsky MS. Therapeutic use of stem and endothelial progenitor cells in acute renal injury; ça ira. Curr Opin Pharmacol. 2006;6:176-183.

Dr. Edelstein is professor of medicine and director of the renal hypertension clinic at the University of Colorado Health Sciences Center in Denver.

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