Feb 27, 2007 - 10) and noncardiogenic acute lung injury (ALI) (13) account for the high mortality ... REFERENCES. 1. Deng J, Hu X, Yuen PS, Star RA.
Am J Physiol Renal Physiol 293: F28–F29, 2007; doi:10.1152/ajprenal.00159.2007.
Editorial Focus
Distant organ injury following acute kidney injury Alaa S. Awad and Mark D. Okusa Department of Medicine, University of Virginia, Charlottesville, Virginia
(AKI) is associated with unacceptably high mortality that can range from 40 to 60% in some cases (14). The incidence of AKI continues to increase (15, 16) and is associated with a changing spectrum of illnesses, significant comorbid and extrarenal complications (12), and unsatisfactory preventive or treatment strategies (5). The etiology of AKI is diverse, and ischemia constitutes the major cause of this condition. Ischemic AKI is a dynamic process that often coexists with multiple organ failure and involves hemodynamic alteration, inflammation, and direct injury to the tubular epithelium (9). Interestingly, renal failure per se usually is not the cause of death in AKI (7), but rather both cardiogenic (2, 10) and noncardiogenic acute lung injury (ALI) (13) account for the high mortality associated with AKI. These comorbid conditions can explain the failed treatment regimens, especially when mortality is used as a clinical trial end point. Currently, the mortality of combined AKI and ALI is extremely high and may approach 80% (11). Therefore, defining the mechanism by which AKI causes ALI is important if we are to be successful in reducing overall mortality associated with AKI. Experimental studies demonstrated increased pulmonary vascular permeability, lung edema, alveolar hemorrhage, and leukocyte trafficking following ischemic AKI (1, 6, 8). The recent work of Hoke et al. (4) has shed new light on the role of the kidney in lung injury. In their study, they sought to determine the the effect of an acute cessation of kidney function on lung injury. The absence of clearance was achieved by either bilateral nephrectomies or by bilateral renal pedicle clamps. The latter method using bilateral pedicles clamp for 22 min was associated with effects related to ischemia-reperfusion. AKI induced by ischemia-reperfusion or bilateral nephrectomy was associated with a change in level and pattern of serum cytokines. However, lung injury was similar following renal ischemia-reperfusion or bilateral nephrectomies. These results suggest that the absence of kidneys results in lung injury independent of ischemia-reperfusion. By inference, these results indicate a potentially important role that the kidneys play in maintaining serum cytokine balance and pulmonary homeostasis. In this issue of the American Journal of Physiology-Renal Physiology, Hassoun and colleagues (3) addressed the functional and genomic response of the lung following acute renal ischemia-reperfusion injury or bilateral nephrectomies. Interestingly in contrast to the results of Hoke et al. (4), these authors found bilateral renal ischemia-reperfusion injury and bilateral nephrectomies produced disparate effects on lung structure and function. They further correlated these changes with differential lung transcriptome using a global gene expression-profiling model. Global gene expression profiling is a robust tool for identification of diagnostic and mechanism-
ACUTE KIDNEY INJURY
Address for reprint requests and other correspondence: M. D. Okusa, Div. of Nephrology, Box 800133, Univ. of Virginia Health System, Charlottesville, VA 22908. F28
related candidate genes and can also provide insights into mechanisms of gene regulation, evolution, and the etiology of disease. Their data provide clear distinctions of ischemiarelated changes compared with bilateral nephrectomy-related changes in the lung genomic profile. Using bioinformatic analysis, they identified several potentially important genes of an early phase of the immunoinflammatory pathway and a later phase of the apoptotic pathway. These data are scientifically and clinically relevant in defining the complex cross talk between the lung and kidney and will provide insight into human AKI. These new data by Hassoun et al. (3) and Hoke et al. (4) leave unresolved whether organ ischemia-reperfusion injury is necessary to elicit distant lung dysfunction. Different clamp times between the two studies may be responsible for the discrepancy observed in lung injury. Because there was no direct measure of intravascular volume, this factor cannot be excluded as a contributor to acute lung injury. Additional studies will be necessary to carefully address the contribution to lung injury of increased pulmonary capillary pressure. Furthermore, a more detailed analysis of the mechanism of lung injury is necessary including the role of immune cells and other resident cells. Analysis of lung gene profiles in response to kidney injury will be important in identifying novel genes that may contribute to the pathogenesis of distant lung injury. Ultimately, these studies will need to be translated to human AKI with hopes of improving the morbidity and mortality associated with this devastating disorder. GRANTS This work was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grants RO1-DK-56223 and RO1-DK-62324. REFERENCES 1. Deng J, Hu X, Yuen PS, Star RA. Alpha-melanocyte-stimulating hormone inhibits lung injury after renal ischemia/reperfusion. Am J Respir Crit Care Med 169: 749 –756, 2004. 2. Groeneveld AB, Tran DD, van der Meulen J, Nauta JJ, Thijs LG. Acute renal failure in the medical intensive care unit: predisposing, complicating factors and outcome. Nephron 59: 602– 610, 1991. 3. Hassoun HT, Grigoryev DN, Lie ML, Liu M, Cheadle C, Tuder RM, Rabb H. Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy. Am J Physiol Renal Physiol First published February 27, 2007; doi:10.1152/ajprenal.00023.2007. 4. Hoke TS, Douglas IS, Klein CL, He Z, Fang W, Thurman JM, Tao Y, Dursun B, Voelkel NF, Edelstein CL, Faubel S. Acute renal failure after bilateral nephrectomy is associated with cytokine-mediated pulmonary injury. J Am Soc Nephrol 18: 155–164, 2007. 5. Jo SK, Rosner MH, Okusa MD. Pharmacologic treatment of acute kidney injury. Why drugs haven’t worked and what is on the horizon. Clin J Am Soc Nephrol 2: 256 –365, 2007. 6. Kelly KJ. Distant effects of experimental renal ischemia/reperfusion injury. J Am Soc Nephrol 14: 1549 –1558, 2003. 7. Kelly KJ, Molitoris BA. Acute renal failure in the new millennium: time to consider combination therapy. Semin Nephrol 20: 4 –19, 2000. 8. Kramer AA, Postler G, Salhab KF, Mendez C, Carey LC, Rabb H. Renal ischemia/reperfusion leads to macrophage-mediated increase in pulmonary vascular permeability. Kidney Int 55: 2362–2367, 1999.
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Editorial Focus F29 9. Li L, Okusa MD. Blocking the Immune respone in ischemic acute kidney injury: the role of adenosine 2A agonists. Nat Clin Pract Nephrol 2: 432– 444, 2006. 10. Lien J, Chan V. Risk factors influencing survival in acute renal failure treated by hemodialysis. Arch Intern Med 145: 2067–2069, 1985. 11. Mehta RL, Pascual MT, Gruta CG, Zhuang S, Chertow GM. Refining predictive models in critically ill patients with acute renal failure. J Am Soc Nephrol 13: 1350 –1357, 2002. 12. Mehta RL, Pascual MT, Soroko S, Savage BR, Himmelfarb J, Ikizler TA, Paganini EP, Chertow GM. Spectrum of acute renal failure in the intensive care unit: the PICARD experience. Kidney Int 66: 1613–1621, 2004.
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13. Rabb H, Chamoun F, Hotchkiss J. Molecular mechanisms underlying combined kidney-lung dysfunction during acute renal failure. Contrib Nephrol: 41–52, 2001. 14. Star RA. Treatment of acute renal failure. Kidney Int 54: 1817–1831, 1998. 15. Waikar SS, Curhan GC, Wald R, McCarthy EP, Chertow GM. Declining mortality in patients with acute renal failure, 1988 to 2002. J Am Soc Nephrol 17: 1143–1150, 2006. 16. Xue JL, Daniels F, Star RA, Kimmel PL, Eggers PW, Molitoris BA, Himmelfarb J, Collins AJ. Incidence and mortality of acute renal failure in Medicare beneficiaries, 1992 to 2001. J Am Soc Nephrol 17: 1135– 1142, 2006.
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