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Pathogenesis of Acute Kidney Injury

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Pediatric Nephrology

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Abstract

The rapid loss of kidney function that results from renal ischemia-, sepsis-, toxic-, or toxicant-induced renal cell injury is termed acute kidney injury (AKI). The operative word “injury” initially referred primarily to renal tubule cell injury. However, it has since become clear that the expanse of cellular alterations and injury is broad, affecting other types of cells resident in the kidney that are central to the pathophysiology of AKI. This chapter focuses on the pathophysiology of AKI triggered by an ischemic insult as revealed in experimental models both in vivo and in vitro. How mechanisms of sepsis-induced AKI, a principal cause of AKI in children, overlap with and differ from ischemia-induced AKI is discussed. Included are classical concepts of acute tubular necrosis as well as a contemporary understanding of vascular, cellular, molecular, inflammatory, and metabolic alterations that are associated with renal cell injury. Mechanisms that lead to cell injury and death are addressed along with processes that can result in cellular repair and renal recovery.

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References

  1. Sudhir Shah M, Lieberthal W, Mehta R, Molitoris B, Okusa M, Rabb H, Siegel N, Star R, Venkatachalam MA. American Society of Nephrology renal research report. J Am Soc Nephrol. 2005;16(7):1886–903.

    Article  Google Scholar 

  2. Palevsky PM. Renal angina: right concept…Wrong name? Clin J Am Soc Nephrol. 2014;9(4):633–4.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Thurau K, Boylan JW. Acute renal success. The unexpected logic of oliguria in acute renal failure. Am J Med. 1976;61(3):308–15.

    Article  CAS  PubMed  Google Scholar 

  4. Sutton TA, Fisher CJ, Molitoris BA. Microvascular endothelial injury and dysfunction during ischemic acute renal failure. Kidney Int. 2002;62(5):1539–49.

    Article  CAS  PubMed  Google Scholar 

  5. Siegel NJ, Devarajan P, Van Why S. Renal cell injury: metabolic and structural alterations. Pediatr Res. 1994;36(2):129–36.

    Article  CAS  PubMed  Google Scholar 

  6. Ashworth SL, Molitoris BA. Pathophysiology and functional significance of apical membrane disruption during ischemia. Curr Opin Nephrol Hypertens. 1999;8(4):449–58.

    Article  CAS  PubMed  Google Scholar 

  7. Thadhani R, Pascual M, Bonventre JV. Acute renal failure. N Engl J Med. 1996;334(22):1448–60.

    Article  CAS  PubMed  Google Scholar 

  8. Matthys E, Patton MK, Osgood RW, Venkatachalam MA, Stein JH. Alterations in vascular function and morphology in acute ischemic renal failure. Kidney Int. 1983;23(5):717–24.

    Article  CAS  PubMed  Google Scholar 

  9. Kwon O, Phillips CL, Molitoris BA. Ischemia induces alterations in actin filaments in renal vascular smooth muscle cells. Am J Physiol Renal Physiol. 2002;282(6):F1012–9.

    Article  CAS  PubMed  Google Scholar 

  10. Terry BE, Jones DB, Mueller CB. Experimental ischemic renal arterial necrosis with resolution. Am J Pathol. 1970;58(1):69–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Rabb H, O’Meara YM, Maderna P, Coleman P, Brady HR. Leukocytes, cell adhesion molecules and ischemic acute renal failure. Kidney Int. 1997;51(5):1463–8.

    Article  CAS  PubMed  Google Scholar 

  12. Star RA. Treatment of acute renal failure. Kidney Int. 1998;54(6):1817–31.

    Article  CAS  PubMed  Google Scholar 

  13. Linas S, Whittenburg D, Repine JE. Nitric oxide prevents neutrophil-mediated acute renal failure. Am J Phys. 1997;272(1 Pt 2):F48–54.

    CAS  Google Scholar 

  14. Kelly KJ, Williams WW Jr, Colvin RB, Bonventre JV. Antibody to intercellular adhesion molecule 1 protects the kidney against ischemic injury. Proc Natl Acad Sci U S A. 1994;91(2):812–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Donnahoo KK, Meng X, Ayala A, Cain MP, Harken AH, Meldrum DR. Early kidney TNF-alpha expression mediates neutrophil infiltration and injury after renal ischemia-reperfusion. Am J Phys. 1999;277(3 Pt 2):R922–9.

    CAS  Google Scholar 

  16. Lee SA, Noel S, Sadasivam M, Hamad ARA, Rabb H. Role of immune cells in acute kidney injury and repair. Nephron. 2017;137(4):282–6.

    Article  CAS  PubMed  Google Scholar 

  17. Hollenberg NK, Epstein M, Rosen SM, Basch RI, Oken DE, Merrill JP. Acute oliguric renal failure in man: evidence for preferential renal cortical ischemia. Medicine (Baltimore). 1968;47(6):455–74.

    Article  CAS  Google Scholar 

  18. Oken DE. Acute renal failure (vasomotor nephropathy): micropuncture studies of the pathogenetic mechanisms. Annu Rev Med. 1975;26:307–19.

    Article  CAS  PubMed  Google Scholar 

  19. Basile DP, Anderson MD, Sutton TA. Pathophysiology of acute kidney injury. Compr Physiol. 2012;2(2):1303–53.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Sharma N, Anders HJ, Gaikwad AB. Fiend and friend in the renin angiotensin system: an insight on acute kidney injury. Biomed Pharmacother. 2019;110:764–74.

    Article  CAS  PubMed  Google Scholar 

  21. Molinas SM, Cortes-Gonzalez C, Gonzalez-Bobadilla Y, Monasterolo LA, Cruz C, Elias MM, et al. Effects of losartan pretreatment in an experimental model of ischemic acute kidney injury. Nephron Exp Nephrol. 2009;112(1):e10–9.

    Article  CAS  PubMed  Google Scholar 

  22. Mejia-Vilet JM, Ramirez V, Cruz C, Uribe N, Gamba G, Bobadilla NA. Renal ischemia-reperfusion injury is prevented by the mineralocorticoid receptor blocker spironolactone. Am J Physiol Renal Physiol. 2007;293(1):F78–86.

    Article  CAS  PubMed  Google Scholar 

  23. Regner KR, Zuk A, Van Why SK, Shames BD, Ryan RP, Falck JR, et al. Protective effect of 20-HETE analogues in experimental renal ischemia reperfusion injury. Kidney Int. 2009;75(5):511–7.

    Article  CAS  PubMed  Google Scholar 

  24. Bidani AK, Churchill PC. Aminophylline ameliorates glycerol-induced acute renal failure in rats. Can J Physiol Pharmacol. 1983;61(6):567–71.

    Article  CAS  PubMed  Google Scholar 

  25. Osswald H, Schnermann J. Methylxanthines and the kidney. Handb Exp Pharmacol. 2011;200:391–412.

    Article  CAS  Google Scholar 

  26. Avison MJ, van Waarde A, Stromski ME, Gaudio K, Siegel NJ. Metabolic alterations in the kidney during ischemic acute renal failure. Semin Nephrol. 1989;9(1):98–101.

    CAS  PubMed  Google Scholar 

  27. Lee HT, Xu H, Nasr SH, Schnermann J, Emala CW. A1 adenosine receptor knockout mice exhibit increased renal injury following ischemia and reperfusion. Am J Physiol Renal Physiol. 2004;286(2):F298–306.

    Article  CAS  PubMed  Google Scholar 

  28. Chan L, Chittinandana A, Shapiro JI, Shanley PF, Schrier RW. Effect of an endothelin-receptor antagonist on ischemic acute renal failure. Am J Phys. 1994;266(1 Pt 2):F135–8.

    CAS  Google Scholar 

  29. Kon V, Badr KF. Biological actions and pathophysiologic significance of endothelin in the kidney. Kidney Int. 1991;40(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  30. Kon V, Yoshioka T, Fogo A, Ichikawa I. Glomerular actions of endothelin in vivo. J Clin Invest. 1989;83(5):1762–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Firth JD, Ratcliffe PJ, Raine AE, Ledingham JG. Endothelin: an important factor in acute renal failure? Lancet. 1988;2(8621):1179–82.

    Article  CAS  PubMed  Google Scholar 

  32. Wilhelm SM, Simonson MS, Robinson AV, Stowe NT, Schulak JA. Endothelin up-regulation and localization following renal ischemia and reperfusion. Kidney Int. 1999;55(3):1011–8.

    Article  CAS  PubMed  Google Scholar 

  33. Jerkic M, Miloradovic Z, Jovovic D, Mihailovic-Stanojevic N, Elena JV, Nastic-Miric D, et al. Relative roles of endothelin-1 and angiotensin II in experimental post-ischaemic acute renal failure. Nephrol Dial Transplant. 2004;19(1):83–94.

    Article  CAS  PubMed  Google Scholar 

  34. Gellai M, Jugus M, Fletcher T, DeWolf R, Nambi P. Reversal of postischemic acute renal failure with a selective endothelinA receptor antagonist in the rat. J Clin Invest. 1994;93(2):900–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Inscho EW, Imig JD, Cook AK, Pollock DM. ETA and ETB receptors differentially modulate afferent and efferent arteriolar responses to endothelin. Br J Pharmacol. 2005;146(7):1019–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Piechota M, Banach M, Irzmanski R, Barylski M, Piechota-Urbanska M, Kowalski J, et al. Plasma Endothelin-1 levels in septic patients. J Intensive Care Med. 2007;22(4):232–9.

    Article  PubMed  Google Scholar 

  37. Wang A, Holcslaw T, Bashore TM, Freed MI, Miller D, Rudnick MR, et al. Exacerbation of radiocontrast nephrotoxicity by endothelin receptor antagonism. Kidney Int. 2000;57(4):1675–80.

    Article  CAS  PubMed  Google Scholar 

  38. Peer G, Blum M, Iaina A. Nitric oxide and acute renal failure. Nephron. 1996;73(3):375–81.

    Article  CAS  PubMed  Google Scholar 

  39. Mattson DL, Lu S, Cowley AW Jr. Role of nitric oxide in the control of the renal medullary circulation. Clin Exp Pharmacol Physiol. 1997;24(8):587–90.

    Article  CAS  PubMed  Google Scholar 

  40. Zou AP, Wu F, Cowley AW Jr. Protective effect of angiotensin II-induced increase in nitric oxide in the renal medullary circulation. Hypertension. 1998;31(1 Pt 2):271–6.

    Article  CAS  PubMed  Google Scholar 

  41. Conger JD, Robinette JB, Schrier RW. Smooth muscle calcium and endothelium-derived relaxing factor in the abnormal vascular responses of acute renal failure. J Clin Invest. 1988;82(2):532–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang W, Mitra A, Poole B, Falk S, Lucia MS, Tayal S, et al. Endothelial nitric oxide synthase-deficient mice exhibit increased susceptibility to endotoxin-induced acute renal failure. Am J Physiol Renal Physiol. 2004;287(5):F1044–8.

    Article  CAS  PubMed  Google Scholar 

  43. Basile DP. The endothelial cell in ischemic acute kidney injury: implications for acute and chronic function. Kidney Int. 2007;72(2):151–6.

    Article  CAS  PubMed  Google Scholar 

  44. Raup-Konsavage WM, Gao T, Cooper TK, Morris SM Jr, Reeves WB, Awad AS. Arginase-2 mediates renal ischemia-reperfusion injury. Am J Physiol Renal Physiol. 2017;313(2):F522–F34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hu J, Spina S, Zadek F, Kamenshchikov NO, Bittner EA, Pedemonte J, et al. Effect of nitric oxide on postoperative acute kidney injury in patients who underwent cardiopulmonary bypass: a systematic review and meta-analysis with trial sequential analysis. Ann Intensive Care. 2019;9(1):129.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Lee Y, Mehrotra P, Basile D, Ullah M, Singh A, Skill N, et al. Specific lowering of asymmetric Dimethylarginine by pharmacological Dimethylarginine Dimethylaminohydrolase improves endothelial function, reduces blood pressure and ischemia-reperfusion injury. J Pharmacol Exp Ther. 2021;376(2):181–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science. 1994;265(5180):1883–5.

    Article  CAS  PubMed  Google Scholar 

  48. Noiri E, Peresleni T, Miller F, Goligorsky MS. In vivo targeting of inducible NO synthase with oligodeoxynucleotides protects rat kidney against ischemia. J Clin Invest. 1996;97(10):2377–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gaudio KM, Stromski M, Thulin G, Ardito T, Kashgarian M, Siegel NJ. Postischemic hemodynamics and recovery of renal adenosine triphosphate. Am J Phys. 1986;251(4 Pt 2):F603–9.

    CAS  Google Scholar 

  50. Paller MS, Anderson RJ, editors. Use of vasoactive agents in the therapy of acute renal failure. Philadelphia: WB Saunders; 1983.

    Google Scholar 

  51. Lameire NH, De Vriese AS, Vanholder R. Prevention and nondialytic treatment of acute renal failure. Curr Opin Crit Care. 2003;9:481.

    Article  PubMed  Google Scholar 

  52. Bonventre JV, Zuk A. Ischemic acute renal failure: an inflammatory disease? Kidney Int. 2004;66(2):480–5.

    Article  CAS  PubMed  Google Scholar 

  53. Friedewald JJ, Rabb H. Inflammatory cells in ischemic acute renal failure. Kidney Int. 2004;66(2):486–91.

    Article  PubMed  Google Scholar 

  54. Molitoris BA, Sutton TA. Endothelial injury and dysfunction: role in the extension phase of acute renal failure. Kidney Int. 2004;66(2):496–9.

    Article  PubMed  Google Scholar 

  55. Dagher PC, Herget-Rosenthal S, Ruehm SG, Jo SK, Star RA, Agarwal R, et al. Newly developed techniques to study and diagnose acute renal failure. J Am Soc Nephrol. 2003;14(8):2188–98.

    Article  PubMed  Google Scholar 

  56. Goligorsky MS. Whispers and shouts in the pathogenesis of acute renal ischaemia. Nephrol Dial Transplant. 2005;20(2):261–6.

    Article  PubMed  Google Scholar 

  57. Basile DP, Yoder MC. Renal endothelial dysfunction in acute kidney ischemia reperfusion injury. Cardiovasc Hematol Disord Drug Targets. 2014;14(1):3–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yamamoto T, Tada T, Brodsky SV, Tanaka H, Noiri E, Kajiya F, et al. Intravital videomicroscopy of peritubular capillaries in renal ischemia. Am J Physiol Renal Physiol. 2002;282(6):F1150–5.

    Article  CAS  PubMed  Google Scholar 

  59. Brodsky SV, Yamamoto T, Tada T, Kim B, Chen J, Kajiya F, et al. Endothelial dysfunction in ischemic acute renal failure: rescue by transplanted endothelial cells. Am J Physiol Renal Physiol. 2002;282(6):F1140–9.

    Article  CAS  PubMed  Google Scholar 

  60. Bezemer R, Legrand M, Klijn E, Heger M, Post ICJH, van Gulik TM, et al. Real-time assessment of renal cortical microvascular perfusion heterogeneities using near-infrared laser speckle imaging. Opt Express. 2010;18(14):15054–61.

    Article  CAS  PubMed  Google Scholar 

  61. Singbartl K, Ley K. Leukocyte recruitment and acute renal failure. J Mol Med. 2004;82(2):91–101.

    Article  PubMed  Google Scholar 

  62. Nemoto T, Burne MJ, Daniels F, O’Donnell MP, Crosson J, Berens K, et al. Small molecule selectin ligand inhibition improves outcome in ischemic acute renal failure. Kidney Int. 2001;60(6):2205–14.

    Article  CAS  PubMed  Google Scholar 

  63. Burne MJ, Rabb H. Pathophysiological contributions of fucosyltransferases in renal ischemia reperfusion injury. J Immunol. 2002;169(5):2648–52.

    Article  CAS  PubMed  Google Scholar 

  64. Singbartl K, Forlow SB, Ley K. Platelet, but not endothelial, P-selectin is critical for neutrophil-mediated acute postischemic renal failure. FASEB J. 2001;15(13):2337–44.

    Article  CAS  PubMed  Google Scholar 

  65. Roelofs JJ, Rouschop KM, Leemans JC, Claessen N, de Boer AM, Frederiks WM, et al. Tissue-type plasminogen activator modulates inflammatory responses and renal function in ischemia reperfusion injury. J Am Soc Nephrol. 2006;17(1):131–40.

    Article  CAS  PubMed  Google Scholar 

  66. Collett JA, Corridon PR, Mehrotra P, Kolb AL, Rhodes GJ, Miller CA, et al. Hydrodynamic isotonic fluid delivery ameliorates moderate-to-severe ischemia-reperfusion injury in rat kidneys. J Am Soc Nephrol. 2017;28(7):2081–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Basile DP, Collett JA, Yoder MC. Endothelial colony-forming cells and pro-angiogenic cells: clarifying definitions and their potential role in mitigating acute kidney injury. Acta Physiol (Oxf). 2018;222(2):e12914.

    Article  CAS  Google Scholar 

  68. Lieberthal W, Nigam SK. Acute renal failure. I. Relative importance of proximal vs. distal tubular injury. Am J Phys. 1998;275(5 Pt 2):F623–31.

    CAS  Google Scholar 

  69. Brezis M, Rosen S, Silva P, Epstein FH. Renal ischemia: a new perspective. Kidney Int. 1984;26(4):375–83.

    Article  CAS  PubMed  Google Scholar 

  70. Stein JH, Lifschitz MD, Barnes LD. Current concepts on the pathophysiology of acute renal failure. Am J Phys. 1978;234(3):F171–81.

    CAS  Google Scholar 

  71. Donohoe JF, Venkatachalam MA, Bernard DB, Levinsky NG. Tubular leakage and obstruction after renal ischemia: structural-functional correlations. Kidney Int. 1978;13(3):208–22.

    Article  CAS  PubMed  Google Scholar 

  72. Tsutsui K, Shinya M, Kudo K. Spatiotemporal characteristics of an attacker’s strategy to pass a defender effectively in a computer-based one-on-one task. Sci Rep. 2019;9(1):17260.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Gaudio KM, Ardito TA, Reilly HF, Kashgarian M, Siegel NJ. Accelerated cellular recovery after an ischemic renal injury. Am J Pathol. 1983;112(3):338–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Gaudio KM, Taylor MR, Chaudry IH, Kashgarian M, Siegel NJ. Accelerated recovery of single nephron function by the postischemic infusion of ATP-MgCl2. Kidney Int. 1982;22(1):13–20.

    Article  CAS  PubMed  Google Scholar 

  75. Myers BD, Chui F, Hilberman M, Michaels AS. Transtubular leakage of glomerular filtrate in human acute renal failure. Am J Phys. 1979;237(4):F319–25.

    CAS  Google Scholar 

  76. Gailit J, Colflesh D, Rabiner I, Simone J, Goligorsky MS. Redistribution and dysfunction of integrins in cultured renal epithelial cells exposed to oxidative stress. Am J Phys. 1993;264(1 Pt 2):F149–57.

    CAS  Google Scholar 

  77. Pennica D, Kohr WJ, Kuang WJ, Glaister D, Aggarwal BB, Chen EY, et al. Identification of human uromodulin as the Tamm-Horsfall urinary glycoprotein. Science. 1987;236(4797):83–8.

    Article  CAS  PubMed  Google Scholar 

  78. Goligorsky MS, DiBona GF. Pathogenetic role of Arg-Gly-Asp-recognizing integrins in acute renal failure. Off. Proc Natl Acad Sci U S A. 1993;90(12):5700–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Noiri E, Gailit J, Sheth D, Magazine H, Gurrath M, Muller G, et al. Cyclic RGD peptides ameliorate ischemic acute renal failure in rats. Kidney Int. 1994;46(4):1050–8.

    Article  CAS  PubMed  Google Scholar 

  80. Weinberg JM. The cell biology of ischemic renal injury. Kidney Int. 1991;39(3):476–500.

    Article  CAS  PubMed  Google Scholar 

  81. Stromski ME, Cooper K, Thulin G, Gaudio KM, Siegel NJ, Shulman RG. Chemical and functional correlates of postischemic renal ATP levels. Proc Natl Acad Sci U S A. 1986;83(16):6142–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Finn WF, Chevalier RL. Recovery from postischemic acute renal failure in the rat. Kidney Int. 1979;16(2):113–23.

    Article  CAS  PubMed  Google Scholar 

  83. Van Why SK, Mann AS, Thulin G, Zhu XH, Kashgarian M, Siegel NJ. Activation of heat-shock transcription factor by graded reductions in renal ATP, in vivo, in the rat. J Clin Invest. 1994;94(4):1518–23.

    Article  PubMed  PubMed Central  Google Scholar 

  84. van Why SK, Kim S, Geibel J, Seebach FA, Kashgarian M, Siegel NJ. Thresholds for cellular disruption and activation of the stress response in renal epithelia. Am J Phys. 1999;277(2 Pt 2):F227–34.

    Google Scholar 

  85. Funk JA, Schnellmann RG. Persistent disruption of mitochondrial homeostasis after acute kidney injury. Am J Physiol Renal Physiol. 2012;302(7):F853–64.

    Article  PubMed  Google Scholar 

  86. Funk JA, Schnellmann RG. Accelerated recovery of renal mitochondrial and tubule homeostasis with SIRT1/PGC-1alpha activation following ischemia-reperfusion injury. Toxicol Appl Pharmacol. 2013;273(2):345–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Andreoli SP. Reactive oxygen molecules, oxidant injury and renal disease. Pediatr Nephrol. 1991;5(6):733–42.

    Article  CAS  PubMed  Google Scholar 

  88. McKelvey TG, Hollwarth ME, Granger DN, Engerson TD, Landler U, Jones HP. Mechanisms of conversion of xanthine dehydrogenase to xanthine oxidase in ischemic rat liver and kidney. Am J Phys. 1988;254(5 Pt 1):G753–60.

    CAS  Google Scholar 

  89. Paller MS. Hemoglobin- and myoglobin-induced acute renal failure in rats: role of iron in nephrotoxicity. Am J Phys. 1988;255(3 Pt 2):F539–44.

    CAS  Google Scholar 

  90. Himmelfarb J, McMonagle E, Freedman S, Klenzak J, McMenamin E, Le P, et al. Oxidative stress is increased in critically ill patients with acute renal failure. J Am Soc Nephrol. 2004;15(9):2449–56.

    Article  CAS  PubMed  Google Scholar 

  91. Perianayagam MC, Liangos O, Kolyada AY, Wald R, MacKinnon RW, Li L, et al. NADPH oxidase p22phox and catalase gene variants are associated with biomarkers of oxidative stress and adverse outcomes in acute renal failure. J Am Soc Nephrol. 2007;18(1):255–63.

    Article  CAS  PubMed  Google Scholar 

  92. Arnold PE, Lumlertgul D, Burke TJ, Schrier RW. In vitro versus in vivo mitochondrial calcium loading in ischemic acute renal failure. Am J Phys. 1985;248(6 Pt 2):F845–50.

    CAS  Google Scholar 

  93. Weinberg JM. Oxygen deprivation-induced injury to isolated rabbit kidney tubules. J Clin Invest. 1985;76(3):1193–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kribben A, Wieder ED, Wetzels JF, Yu L, Gengaro PE, Burke TJ, et al. Evidence for role of cytosolic free calcium in hypoxia-induced proximal tubule injury. J Clin Invest. 1994;93(5):1922–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ogata M, Iwamoto T, Tazawa N, Nishikawa M, Yamashita J, Takaoka M, et al. A novel and selective Na+/Ca2+ exchange inhibitor, SEA0400, improves ischemia/reperfusion-induced renal injury. Eur J Pharmacol. 2003;478(2–3):187–98.

    Article  CAS  PubMed  Google Scholar 

  96. Yamashita J, Kita S, Iwamoto T, Ogata M, Takaoka M, Tazawa N, et al. Attenuation of ischemia/reperfusion-induced renal injury in mice deficient in Na+/Ca2+ exchanger. J Pharmacol Exp Ther. 2003;304(1):284–93.

    Article  CAS  PubMed  Google Scholar 

  97. Cheng CW, Rifai A, Ka SM, Shui HA, Lin YF, Lee WH, et al. Calcium-binding proteins annexin A2 and S100A6 are sensors of tubular injury and recovery in acute renal failure. Kidney Int. 2005;68(6):2694–703.

    Article  CAS  PubMed  Google Scholar 

  98. Cummings BS, McHowat J, Schnellmann RG. Phospholipase A(2)s in cell injury and death. J Pharmacol Exp Ther. 2000;294(3):793–9.

    CAS  PubMed  Google Scholar 

  99. Humes HD, Nguyen VD, Cieslinski DA, Messana JM. The role of free fatty acids in hypoxia-induced injury to renal proximal tubule cells. Am J Phys. 1989;256(4 Pt 2):F688–96.

    CAS  Google Scholar 

  100. Zager RA, Burkhart KM, Conrad DS, Gmur DJ, Iwata M. Phospholipase A2-induced cytoprotection of proximal tubules: potential determinants and specificity for ATP depletion-mediated injury. J Am Soc Nephrol. 1996;7(1):64–72.

    Article  CAS  PubMed  Google Scholar 

  101. Cummings BS, McHowat J, Schnellmann RG. Role of an endoplasmic reticulum Ca(2+)-independent phospholipase A(2) in oxidant-induced renal cell death. Am J Physiol Renal Physiol. 2002;283(3):F492–8.

    Article  CAS  PubMed  Google Scholar 

  102. Zager RA, Kalhorn TF. Changes in free and esterified cholesterol: hallmarks of acute renal tubular injury and acquired cytoresistance. Am J Pathol. 2000;157(3):1007–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Zager RA, Burkhart KM, Johnson AC, Sacks BM. Increased proximal tubular cholesterol content: implications for cell injury and “acquired cytoresistance”. Kidney Int. 1999;56(5):1788–97.

    Article  CAS  PubMed  Google Scholar 

  104. Molitoris BA. New insights into the cell biology of ischemic acute renal failure. J Am Soc Nephrol. 1991;1(12):1263–70.

    Article  CAS  PubMed  Google Scholar 

  105. Molitoris BA. Putting the actin cytoskeleton into perspective: pathophysiology of ischemic alterations. Am J Phys. 1997;272(4 Pt 2):F430–3.

    CAS  Google Scholar 

  106. Atkinson SJ, Hosford MA, Molitoris BA. Mechanism of actin polymerization in cellular ATP depletion. J Biol Chem. 2004;279(7):5194–9.

    Article  CAS  PubMed  Google Scholar 

  107. Madara JL, Barenberg D, Carlson S. Effects of cytochalasin D on occluding junctions of intestinal absorptive cells: further evidence that the cytoskeleton may influence paracellular permeability and junctional charge selectivity. J Cell Biol. 1986;102(6):2125–36.

    Article  CAS  PubMed  Google Scholar 

  108. Kashgarian M, Van Why SK, Hildebrand F, et al., editors. Regulation of expression and polar distribution of Na,K ATPase in renal epithelium during recovery from ischemic injury. New York: The Rockefeller University Press; 1991.

    Google Scholar 

  109. Molitoris BA, Dahl R, Hosford M. Cellular ATP depletion induces disruption of the spectrin cytoskeletal network. Am J Phys. 1996;271(4 Pt 2):F790–8.

    CAS  Google Scholar 

  110. Ashworth SL, Sandoval RM, Hosford M, Bamburg JR, Molitoris BA, Ischemic injury induces ADF. Relocalization to the apical domain of rat proximal tubule cells. Am J Physiol Renal Physiol. 2001;280(5):F886–94.

    Article  CAS  PubMed  Google Scholar 

  111. Ashworth SL, Southgate EL, Sandoval RM, Meberg PJ, Bamburg JR, Molitoris BA. ADF/cofilin mediates actin cytoskeletal alterations in LLC-PK cells during ATP depletion. Am J Physiol Renal Physiol. 2003;284(4):F852–62.

    Article  CAS  PubMed  Google Scholar 

  112. Ashworth SL, Wean SE, Campos SB, Temm-Grove CJ, Southgate EL, Vrhovski B, et al. Renal ischemia induces tropomyosin dissociation-destabilizing microvilli microfilaments. Am J Physiol Renal Physiol. 2004;286(5):F988–96.

    Article  CAS  PubMed  Google Scholar 

  113. Gopalakrishnan S, Hallett MA, Atkinson SJ. Marrs JA. aPKC-PAR complex dysfunction and tight junction disassembly in renal epithelial cells during ATP depletion. Am J Physiol Cell Physiol. 2007;292(3):C1094–102.

    Article  CAS  PubMed  Google Scholar 

  114. Racusen L, editor. The morphologic basis of acute renal failure. Philadelphia: W. B. Saunders Company; 2001.

    Google Scholar 

  115. Levine JWL, editor. Terminal pathways to cell death. Philadelphia: W. B. Saunders Company; 2001.

    Google Scholar 

  116. Jaffe R, Ariel I, Beeri R, Paltiel O, Hiss Y, Rosen S, et al. Frequent apoptosis in human kidneys after acute renal hypoperfusion. Exp Nephrol. 1997;5(5):399–403.

    CAS  PubMed  Google Scholar 

  117. Lieberthal W, Menza SA, Levine JS. Graded ATP depletion can cause necrosis or apoptosis of cultured mouse proximal tubular cells. Am J Phys. 1998;274(2 Pt 2):F315–27.

    CAS  Google Scholar 

  118. Dong Z, Saikumar P, Weinberg JM, Venkatachalam MA, Internucleosomal DNA. Cleavage triggered by plasma membrane damage during necrotic cell death. Involvement of serine but not cysteine proteases. Am J Pathol. 1997;151(5):1205–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Hagar H, Ueda N, Shah SV. Endonuclease induced DNA damage and cell death in chemical hypoxic injury to LLC-PK1 cells. Kidney Int. 1996;49(2):355–61.

    Article  CAS  PubMed  Google Scholar 

  120. Kelly KJ, Sandoval RM, Dunn KW, Molitoris BA, Dagher PC. A novel method to determine specificity and sensitivity of the TUNEL reaction in the quantitation of apoptosis. Am J Physiol Cell Physiol. 2003;284(5):C1309–18.

    Article  CAS  PubMed  Google Scholar 

  121. Padanilam BJ. Cell death induced by acute renal injury: a perspective on the contributions of apoptosis and necrosis. Am J Physiol Renal Physiol. 2003;284(4):F608–27.

    Article  CAS  PubMed  Google Scholar 

  122. Nogae S, Miyazaki M, Kobayashi N, Saito T, Abe K, Saito H, et al. Induction of apoptosis in ischemia-reperfusion model of mouse kidney: possible involvement of Fas. J Am Soc Nephrol. 1998;9(4):620–31.

    Article  CAS  PubMed  Google Scholar 

  123. Feldenberg LR, Thevananther S, del Rio M, de Leon M, Devarajan P. Partial ATP depletion induces Fas- and caspase-mediated apoptosis in MDCK cells. Am J Phys. 1999;276(6 Pt 2):F837–46.

    CAS  Google Scholar 

  124. Del Rio M, Imam A, DeLeon M, Gomez G, Mishra J, Ma Q, et al. The death domain of kidney ankyrin interacts with Fas and promotes Fas-mediated cell death in renal epithelia. J Am Soc Nephrol. 2004;15(1):41–51.

    Article  PubMed  Google Scholar 

  125. Hamar P, Song E, Kokeny G, Chen A, Ouyang N, Lieberman J. Small interfering RNA targeting Fas protects mice against renal ischemia-reperfusion injury. Proc Natl Acad Sci U S A. 2004;101(41):14883–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Green DR, Reed JC. Mitochondria and apoptosis. Science. 1998;281(5381):1309–12.

    Article  CAS  PubMed  Google Scholar 

  127. Kroemer G, Dallaporta B, Resche-Rigon M. The mitochondrial death/life regulator in apoptosis and necrosis. Annu Rev Physiol. 1998;60:619–42.

    Article  CAS  PubMed  Google Scholar 

  128. Zamzami N, Susin SA, Marchetti P, Hirsch T, Gomez-Monterrey I, Castedo M, et al. Mitochondrial control of nuclear apoptosis. J Exp Med. 1996;183(4):1533–44.

    Article  CAS  PubMed  Google Scholar 

  129. Castedo M, Hirsch T, Susin SA, Zamzami N, Marchetti P, Macho A, et al. Sequential acquisition of mitochondrial and plasma membrane alterations during early lymphocyte apoptosis. J Immunol. 1996;157(2):512–21.

    Article  CAS  PubMed  Google Scholar 

  130. Antonsson B, Conti F, Ciavatta A, Montessuit S, Lewis S, Martinou I, et al. Inhibition of Bax channel-forming activity by Bcl-2. Science. 1997;277(5324):370–2.

    Article  CAS  PubMed  Google Scholar 

  131. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science. 1998;281(5381):1322–6.

    Article  CAS  PubMed  Google Scholar 

  132. Saikumar P, Dong Z, Patel Y, Hall K, Hopfer U, Weinberg JM, et al. Role of hypoxia-induced Bax translocation and cytochrome c release in reoxygenation injury. Oncogene. 1998;17(26):3401–15.

    Article  CAS  PubMed  Google Scholar 

  133. Wei Q, Alam MM, Wang MH, Yu F, Dong Z. Bid activation in kidney cells following ATP depletion in vitro and ischemia in vivo. Am J Physiol Renal Physiol. 2004;286(4):F803–9.

    Article  CAS  PubMed  Google Scholar 

  134. Dagher PC. Apoptosis in ischemic renal injury: roles of GTP depletion and p53. Kidney Int. 2004;66(2):506–9.

    Article  CAS  PubMed  Google Scholar 

  135. Wei Q, Yin XM, Wang MH, Dong Z. Bid deficiency ameliorates ischemic renal failure and delays animal death in C57BL/6 mice. Am J Physiol Renal Physiol. 2006;290(1):F35–42.

    Article  CAS  PubMed  Google Scholar 

  136. Castaneda MP, Swiatecka-Urban A, Mitsnefes MM, Feuerstein D, Kaskel FJ, Tellis V, et al. Activation of mitochondrial apoptotic pathways in human renal allografts after ischemiareperfusion injury. Transplantation. 2003;76(1):50–4.

    Article  CAS  PubMed  Google Scholar 

  137. Schwarz C, Hauser P, Steininger R, Regele H, Heinze G, Mayer G, et al. Failure of BCL-2 up-regulation in proximal tubular epithelial cells of donor kidney biopsy specimens is associated with apoptosis and delayed graft function. Lab Investig. 2002;82(7):941–8.

    Article  CAS  PubMed  Google Scholar 

  138. Salahudeen AK, Huang H, Joshi M, Moore NA, Jenkins JK. Involvement of the mitochondrial pathway in cold storage and rewarming-associated apoptosis of human renal proximal tubular cells. Am J Transplant. 2003;3(3):273–80.

    Article  CAS  PubMed  Google Scholar 

  139. Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell. 1996;86(1):147–57.

    Article  CAS  PubMed  Google Scholar 

  140. Zou H, Henzel WJ, Liu X, Lutschg A, Wang X. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell. 1997;90(3):405–13.

    Article  CAS  PubMed  Google Scholar 

  141. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997;91(4):479–89.

    Article  CAS  PubMed  Google Scholar 

  142. Periyasamy-Thandavan S, Jiang M, Schoenlein P, Dong Z. Autophagy: molecular machinery, regulation, and implications for renal pathophysiology. Am J Physiol Renal Physiol. 2009;297(2):F244–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Rabb H, Griffin MD, McKay DB, Swaminathan S, Pickkers P, Rosner MH, et al. Inflammation in AKI: current understanding, key questions, and knowledge gaps. J Am Soc Nephrol. 2016;27(2):371–9.

    Article  CAS  PubMed  Google Scholar 

  144. Kinsey GR, Li L, Okusa MD. Inflammation in acute kidney injury. Nephron Exp Nephrol. 2008;109(4):e102–7.

    Article  CAS  PubMed  Google Scholar 

  145. Kato N, Yuzawa Y, Kosugi T, Hobo A, Sato W, Miwa Y, et al. The E-selectin ligand basigin/CD147 is responsible for neutrophil recruitment in renal ischemia/reperfusion. J Am Soc Nephrol. 2009;20(7):1565–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Burne-Taney MJ, Rabb H. The role of adhesion molecules and T cells in ischemic renal injury. Curr Opin Nephrol Hypertens. 2003;12(1):85–90.

    Article  CAS  PubMed  Google Scholar 

  147. Billups KL, Palladino MA, Hinton BT, Sherley JL. Expression of E-selectin mRNA during ischemia/reperfusion injury. J Lab Clin Med. 1995;125(5):626–33.

    CAS  PubMed  Google Scholar 

  148. Patarroyo M. Leukocyte adhesion in host defense and tissue injury. Clin Immunol Immunopathol. 1991;60(3):333–48.

    Article  CAS  PubMed  Google Scholar 

  149. Grams ME, Rabb H. The distant organ effects of acute kidney injury. Kidney Int. 2012;81(10):942–8.

    Article  PubMed  Google Scholar 

  150. Fuggle SV, Koo DD. Cell adhesion molecules in clinical renal transplantation. Transplantation. 1998;65(6):763–9.

    Article  CAS  PubMed  Google Scholar 

  151. Skott M, Norregaard R, Birke-Sorensen H, Palmfeldt J, Kwon TH, Frokiaer J, et al. Acute kidney injury in rats with or without pre-existing chronic kidney disease: cytokine/chemokine response. Nephrology (Carlton). 2014;19(7):410–9.

    Article  CAS  Google Scholar 

  152. Lee DW, Faubel S, Edelstein CL. Cytokines in acute kidney injury (AKI). Clin Nephrol. 2011;76(3):165–73.

    CAS  PubMed  Google Scholar 

  153. Huang Y, Rabb H, Womer KL. Ischemia-reperfusion and immediate T cell responses. Cell Immunol. 2007;248(1):4–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Huang Y, Zhou F, Xiao Y, Shen C, Liu K, Zhao B. TLR7 mediates increased vulnerability to ischemic acute kidney injury in diabetes. Rev Assoc Med Bras. 2019;65(8):1067–73.

    Article  PubMed  Google Scholar 

  155. Lee JW, Kim SC, Ko YS, Lee HY, Cho E, Kim MG, et al. Renoprotective effect of paricalcitol via a modulation of the TLR4-NF-kappaB pathway in ischemia/reperfusion-induced acute kidney injury. Biochem Biophys Res Commun. 2014;444(2):121–7.

    Article  CAS  PubMed  Google Scholar 

  156. Zhang B, Ramesh G, Uematsu S, Akira S, Reeves WB. TLR4 signaling mediates inflammation and tissue injury in nephrotoxicity. J Am Soc Nephrol. 2008;19(5):923–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Leemans JC, Stokman G, Claessen N, Rouschop KM, Teske GJ, Kirschning CJ, et al. Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney. J Clin Invest. 2005;115(10):2894–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Gould SE, Day M, Jones SS, Dorai H. BMP-7 regulates chemokine, cytokine, and hemodynamic gene expression in proximal tubule cells. Kidney Int. 2002;61(1):51–60.

    Article  CAS  PubMed  Google Scholar 

  159. Okusa MD. The changing pattern of acute kidney injury: from one to multiple organ failure. Contrib Nephrol. 2010;165:153–8.

    Article  PubMed  Google Scholar 

  160. Li X, Hassoun HT, Santora R, Rabb H. Organ crosstalk: the role of the kidney. Curr Opin Crit Care. 2009;15(6):481–7.

    Article  PubMed  Google Scholar 

  161. Rabb H. The promise of immune cell therapy for acute kidney injury. J Clin Invest. 2012;122(11):3852–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Linfert D, Chowdhry T, Rabb H. Lymphocytes and ischemia-reperfusion injury. Transplant Rev (Orlando). 2009;23(1):1–10.

    Article  Google Scholar 

  163. Savransky V, Molls RR, Burne-Taney M, Chien CC, Racusen L, Rabb H. Role of the T-cell receptor in kidney ischemia-reperfusion injury. Kidney Int. 2006;69(2):233–8.

    Article  CAS  PubMed  Google Scholar 

  164. Burne-Taney MJ, Ascon DB, Daniels F, Racusen L, Baldwin W, Rabb H. B cell deficiency confers protection from renal ischemia reperfusion injury. J Immunol. 2003;171(6):3210–5.

    Article  CAS  PubMed  Google Scholar 

  165. Faubel S, Shah PB. Immediate consequences of acute kidney injury: the impact of traditional and nontraditional complications on mortality in acute kidney injury. Adv Chronic Kidney Dis. 2016;23(3):179–85.

    Article  PubMed  Google Scholar 

  166. Bhargava R, Altmann CJ, Andres-Hernando A, Webb RG, Okamura K, Yang Y, et al. Acute lung injury and acute kidney injury are established by four hours in experimental sepsis and are improved with pre, but not post, sepsis administration of TNF-alpha antibodies. PLoS One. 2013;8(11):e79037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Ahuja N, Andres-Hernando A, Altmann C, Bhargava R, Bacalja J, Webb RG, et al. Circulating IL-6 mediates lung injury via CXCL1 production after acute kidney injury in mice. Am J Physiol Renal Physiol. 2012;303(6):F864–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Grigoryev DN, Liu M, Hassoun HT, Cheadle C, Barnes KC, Rabb H. The local and systemic inflammatory transcriptome after acute kidney injury. J Am Soc Nephrol. 2008;19(3):547–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Bai M, Zhang L, Fu B, Bai J, Zhang Y, Cai G, et al. IL-17A improves the efficacy of mesenchymal stem cells in ischemic-reperfusion renal injury by increasing Treg percentages by the COX-2/PGE2 pathway. Kidney Int. 2018;93(4):814–25.

    Article  CAS  PubMed  Google Scholar 

  170. Martina MN, Noel S, Bandapalle S, Hamad AR, Rabb H. T lymphocytes and acute kidney injury: update. Nephron Clin Pract. 2014;127(1–4):51–5.

    Article  CAS  PubMed  Google Scholar 

  171. Huang Y, Johnston P, Zhang B, Zakari A, Chowdhry T, Smith RR, et al. Kidney-derived stromal cells modulate dendritic and T cell responses. J Am Soc Nephrol. 2009;20(4):831–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Kinsey GR, Okusa MD. Expanding role of T cells in acute kidney injury. Curr Opin Nephrol Hypertens. 2014;23(1):9–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Fayyazi A, Scheel O, Werfel T, Schweyer S, Oppermann M, Gotze O, et al. The C5a receptor is expressed in normal renal proximal tubular but not in normal pulmonary or hepatic epithelial cells. Immunology. 2000;99(1):38–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Ortiz A, Lorz C, Egido J. The Fas ligand/Fas system in renal injury. Nephrol Dial Transplant. 1999;14(8):1831–4.

    Article  CAS  PubMed  Google Scholar 

  175. Laurence J, Mulvey JJ, Seshadri M, Racanelli A, Harp J, Schenck EJ, et al. Anti-complement C5 therapy with eculizumab in three cases of critical COVID-19. Clin Immunol. 2020;108555:219.

    Google Scholar 

  176. Castellano G, Franzin R, Stasi A, Divella C, Sallustio F, Pontrelli P, et al. Complement activation during ischemia/reperfusion injury induces pericyte-to-myofibroblast transdifferentiation regulating peritubular capillary lumen reduction through pERK signaling. Front Immunol. 2018;9:1002.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. de Vries B, Kohl J, Leclercq WK, Wolfs TG, van Bijnen AA, Heeringa P, et al. Complement factor C5a mediates renal ischemia-reperfusion injury independent from neutrophils. J Immunol. 2003;170(7):3883–9.

    Article  PubMed  Google Scholar 

  178. Thurman JM, Ljubanovic D, Edelstein CL, Gilkeson GS, Holers VM. Lack of a functional alternative complement pathway ameliorates ischemic acute renal failure in mice. J Immunol. 2003;170(3):1517–23.

    Article  CAS  PubMed  Google Scholar 

  179. Paladino JD, Hotchkiss JR, Rabb H. Acute kidney injury and lung dysfunction: a paradigm for remote organ effects of kidney disease? Microvasc Res. 2009;77(1):8–12.

    Article  CAS  PubMed  Google Scholar 

  180. Hassoun HT, Grigoryev DN, Lie ML, Liu M, Cheadle C, Tuder RM, et al. Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy. Am J Physiol Renal Physiol. 2007;293(1):F30–40.

    Article  CAS  PubMed  Google Scholar 

  181. Kieran NE, Rabb H. Immune responses in kidney preservation and reperfusion injury. J Investig Med. 2004;52(5):310–4.

    Article  CAS  PubMed  Google Scholar 

  182. Hoste EA, Bagshaw SM, Bellomo R, Cely CM, Colman R, Cruz DN, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015;41(8):1411–23.

    Article  PubMed  Google Scholar 

  183. Kashani K, Rosner MH, Haase M, Lewington AJP, O’Donoghue DJ, Wilson FP, et al. Quality improvement goals for acute kidney injury. Clin J Am Soc Nephrol. 2019;14(6):941–53.

    Article  PubMed  PubMed Central  Google Scholar 

  184. Kolhe NV, Stevens PE, Crowe AV, Lipkin GW, Harrison DA. Case mix, outcome and activity for patients with severe acute kidney injury during the first 24 hours after admission to an adult, general critical care unit: application of predictive models from a secondary analysis of the ICNARC Case Mix Programme database. Crit Care. 2008;12(Suppl 1):S2.

    Article  PubMed  PubMed Central  Google Scholar 

  185. Mishra SK, Choudhury S. Experimental protocol for cecal ligation and puncture model of polymicrobial sepsis and assessment of vascular functions in mice. Methods Mol Biol. 2018;1717:161–87.

    Article  CAS  PubMed  Google Scholar 

  186. Bellomo R, Kellum JA, Ronco C, Wald R, Martensson J, Maiden M, et al. Acute kidney injury in sepsis. Intensive Care Med. 2017;43(6):816–28.

    Article  CAS  PubMed  Google Scholar 

  187. Choi HM, Jo SK, Kim SH, Lee JW, Cho E, Hyun YY, et al. Glucocorticoids attenuate septic acute kidney injury. Biochem Biophys Res Commun. 2013;435(4):678–84.

    Article  CAS  PubMed  Google Scholar 

  188. Williams DL, Ha T, Li C, Kalbfleisch JH, Ferguson DA Jr. Early activation of hepatic NFkappaB and NF-IL6 in polymicrobial sepsis correlates with bacteremia, cytokine expression, and mortality. Ann Surg. 1999;230(1):95–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Browder W, Ha T, Chuanfu L, Kalbfleisch JH, Ferguson DA Jr, Williams DL. Early activation of pulmonary nuclear factor kappaB and nuclear factor interleukin-6 in polymicrobial sepsis. J Trauma. 1999;46(4):590–6.

    Article  CAS  PubMed  Google Scholar 

  190. Bagshaw SM, Uchino S, Bellomo R, Morimatsu H, Morgera S, Schetz M, et al. Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Clin J Am Soc Nephrol. 2007;2(3):431–9.

    Article  PubMed  Google Scholar 

  191. Denning NL, Aziz M, Gurien SD, Wang P. DAMPs and NETs in sepsis. Front Immunol. 2536;2019:10.

    Google Scholar 

  192. Kakihana Y, Ito T, Nakahara M, Yamaguchi K, Yasuda T. Sepsis-induced myocardial dysfunction: pathophysiology and management. J Intensive Care. 2016;4:22.

    Article  PubMed  PubMed Central  Google Scholar 

  193. Emlet DR, Shaw AD, Kellum JA. Sepsis-associated AKI: epithelial cell dysfunction. Semin Nephrol. 2015;35(1):85–95.

    Article  PubMed  Google Scholar 

  194. Eleftheriadis T, Pissas G, Liakopoulos V, Stefanidis I, Lawson BR. Toll-like receptors and their role in renal pathologies. Inflamm Allergy Drug Targets. 2012;11(6):464–77.

    Article  CAS  PubMed  Google Scholar 

  195. Scindia Y, Wlazlo E, Leeds J, Loi V, Ledesma J, Cechova S, et al. Protective role of hepcidin in polymicrobial sepsis and acute kidney injury. Front Pharmacol. 2019;10:615.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Gan Y, Tao S, Cao D, Xie H, Zeng Q. Protection of resveratrol on acute kidney injury in septic rats. Hum Exp Toxicol. 2017;36(10):1015–22.

    Article  CAS  PubMed  Google Scholar 

  197. Brochner AC, Dagnaes-Hansen F, Hojberg-Holm J, Toft P. The inflammatory response in blood and in remote organs following acute kidney injury. APMIS. 2014;122(5):399–404.

    Article  CAS  PubMed  Google Scholar 

  198. Ramesh G, Zhang B, Uematsu S, Akira S, Reeves WB. Endotoxin and cisplatin synergistically induce renal dysfunction and cytokine production in mice. Am J Physiol Renal Physiol. 2007;293(1):F325–32.

    Article  CAS  PubMed  Google Scholar 

  199. Liu JX, Yang C, Zhang WH, Su HY, Liu ZJ, Pan Q, et al. Disturbance of mitochondrial dynamics and mitophagy in sepsis-induced acute kidney injury. Life Sci. 2019;116828:235.

    Google Scholar 

  200. Matsuda N, Yamamoto S, Takano K, Kageyama S, Kurobe Y, Yoshihara Y, et al. Silencing of Fas-associated death domain protects mice from septic lung inflammation and apoptosis. Am J Respir Crit Care Med. 2009;179(9):806–15.

    Article  CAS  PubMed  Google Scholar 

  201. Thakar CV, Zahedi K, Revelo MP, Wang Z, Burnham CE, Barone S, et al. Identification of thrombospondin 1 (TSP-1) as a novel mediator of cell injury in kidney ischemia. J Clin Invest. 2005;115(12):3451–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Lee SA, Cozzi M, Bush EL, Rabb H. Distant organ dysfunction in acute kidney injury: a review. Am J Kidney Dis. 2018;72(6):846–56.

    Article  PubMed  PubMed Central  Google Scholar 

  203. Calzavacca P, May CN, Bellomo R. Glomerular haemodynamics, the renal sympathetic nervous system and sepsis-induced acute kidney injury. Nephrol Dial Transplant. 2014;29(12):2178–84.

    Article  CAS  PubMed  Google Scholar 

  204. Ishikawa K, May CN, Gobe G, Langenberg C, Bellomo R. Pathophysiology of septic acute kidney injury: a different view of tubular injury. Contrib Nephrol. 2010;165:18–27.

    Article  PubMed  Google Scholar 

  205. Langenberg C, Bagshaw SM, May CN, Bellomo R. The histopathology of septic acute kidney injury: a systematic review. Crit Care. 2008;12(2):R38.

    Article  PubMed  PubMed Central  Google Scholar 

  206. Bellomo R, Bagshaw S, Langenberg C, Ronco C. Pre-renal azotemia: a flawed paradigm in critically ill septic patients? Contrib Nephrol. 2007;156:1–9.

    PubMed  Google Scholar 

  207. Maiden MJ, Otto S, Brealey JK, Finnis ME, Chapman MJ, Kuchel TR, et al. Structure and function of the kidney in septic shock. A prospective controlled experimental study. Am J Respir Crit Care Med. 2016;194(6):692–700.

    Article  PubMed  Google Scholar 

  208. Xu D, Shen L, Zhou L, Sha W, Yang J, Lu G. Upregulation of FABP7 inhibits acute kidney injury-induced TCMK-1 cell apoptosis via activating the PPAR gamma signalling pathway. Mol Omics. 2020;16(6):533–42.

    Article  CAS  PubMed  Google Scholar 

  209. Elshazly S, Soliman E. PPAR gamma agonist, pioglitazone, rescues liver damage induced by renal ischemia/reperfusion injury. Toxicol Appl Pharmacol. 2019;362:86–94.

    Article  CAS  PubMed  Google Scholar 

  210. Chen DZ, Chen LQ, Lin MX, Gong YQ, Ying BY, Wei DZ, Esculentoside A. Inhibits LPS-induced acute kidney injury by activating PPAR-gamma. Microb Pathog. 2017;110:208–13.

    Article  CAS  PubMed  Google Scholar 

  211. Swaminathan S, Rosner MH, Okusa MD. Emerging therapeutic targets of sepsis-associated acute kidney injury. Semin Nephrol. 2015;35(1):38–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Sun J, Zhang J, Tian J, Virzi GM, Digvijay K, Cueto L, et al. Mitochondria in sepsis-induced AKI. J Am Soc Nephrol. 2019;30(7):1151–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Kaushal GP, Shah SV. Autophagy in acute kidney injury. Kidney Int. 2016;89(4):779–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Parikh SM, Yang Y, He L, Tang C, Zhan M, Dong Z. Mitochondrial function and disturbances in the septic kidney. Semin Nephrol. 2015;35(1):108–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Stallons LJ, Funk JA, Schnellmann RG. Mitochondrial homeostasis in acute organ failure. Curr Pathobiol Rep. 2013;1(3):169.

    Article  Google Scholar 

  216. Lameire N, Van Biesen W, Vanholder R. Acute renal failure. Lancet. 2005;365(9457):417–30.

    Article  CAS  PubMed  Google Scholar 

  217. Fekete A, Treszl A, Toth-Heyn P, Vannay A, Tordai A, Tulassay T, et al. Association between heat shock protein 72 gene polymorphism and acute renal failure in premature neonates. Pediatr Res. 2003;54(4):452–5.

    Article  CAS  PubMed  Google Scholar 

  218. Vasarhelyi B, Toth-Heyn P, Treszl A, Tulassay T. Genetic polymorphisms and risk for acute renal failure in preterm neonates. Pediatr Nephrol. 2005;20(2):132–5.

    Article  PubMed  Google Scholar 

  219. Lu JC, Coca SG, Patel UD, Cantley L, Parikh CR. Searching for genes that matter in acute kidney injury: a systematic review. Clin J Am Soc Nephrol. 2009;4(6):1020–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Basile DP, Donohoe D, Cao X, Van Why SK. Resistance to ischemic acute renal failure in the Brown Norway rat: a new model to study cytoprotection. Kidney Int. 2004;65(6):2201–11.

    Article  CAS  PubMed  Google Scholar 

  221. Basile DP, Dwinell MR, Wang SJ, Shames BD, Donohoe DL, Chen S, et al. Chromosome substitution modulates resistance to ischemia reperfusion injury in Brown Norway rats. Kidney Int. 2013;83(2):242–50.

    Article  CAS  PubMed  Google Scholar 

  222. Devarajan P, Mishra J, Supavekin S, Patterson LT, Steven Potter S. Gene expression in early ischemic renal injury: clues towards pathogenesis, biomarker discovery, and novel therapeutics. Mol Genet Metab. 2003;80(4):365–76.

    Article  CAS  PubMed  Google Scholar 

  223. Kurella M, Hsiao LL, Yoshida T, Randall JD, Chow G, Sarang SS, et al. DNA microarray analysis of complex biologic processes. J Am Soc Nephrol. 2001;12(5):1072–8.

    Article  CAS  PubMed  Google Scholar 

  224. Higgins JP, Wang L, Kambham N, Montgomery K, Mason V, Vogelmann SU, et al. Gene expression in the normal adult human kidney assessed by complementary DNA microarray. Mol Biol Cell. 2004;15(2):649–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Schwab K, Patterson LT, Aronow BJ, Luckas R, Liang HC, Potter SS. A catalogue of gene expression in the developing kidney. Kidney Int. 2003;64(5):1588–604.

    Article  CAS  PubMed  Google Scholar 

  226. Liang M, Cowley AW Jr, Hessner MJ, Lazar J, Basile DP, Pietrusz JL. Transcriptome analysis and kidney research: toward systems biology. Kidney Int. 2005;67(6):2114–22.

    Article  PubMed  Google Scholar 

  227. Bonventre JV, Yang L. Kidney injury molecule-1. Curr Opin Crit Care. 2010;16(6):556–61.

    Article  PubMed  Google Scholar 

  228. Singer E, Marko L, Paragas N, Barasch J, Dragun D, Muller DN, et al. Neutrophil gelatinase-associated lipocalin: pathophysiology and clinical applications. Acta Physiol (Oxf). 2013;207(4):663–72.

    Article  CAS  Google Scholar 

  229. Cullen MR, Murray PT, Fitzgibbon MC. Establishment of a reference interval for urinary neutrophil gelatinase-associated lipocalin. Ann Clin Biochem. 2012;49(Pt 2):190–3.

    Article  CAS  PubMed  Google Scholar 

  230. Sprenkle P, Russo P. Molecular markers for ischemia, do we have something better then creatinine and glomerular filtration rate? Arch Esp Urol. 2013;66(1):99–114.

    PubMed  Google Scholar 

  231. Pennemans V, Rigo JM, Faes C, Reynders C, Penders J, Swennen Q. Establishment of reference values for novel urinary biomarkers for renal damage in the healthy population: are age and gender an issue? Clin Chem Lab Med. 2013;51(9):1795–802.

    Article  CAS  PubMed  Google Scholar 

  232. Fujigaki Y, Goto T, Sakakima M, Fukasawa H, Miyaji T, Yamamoto T, et al. Kinetics and characterization of initially regenerating proximal tubules in S3 segment in response to various degrees of acute tubular injury. Nephrol Dial Transplant. 2006;21(1):41–50.

    Article  CAS  PubMed  Google Scholar 

  233. Bonventre JV. Dedifferentiation and proliferation of surviving epithelial cells in acute renal failure. J Am Soc Nephrol. 2003;14(Suppl 1):S55–61.

    Article  PubMed  Google Scholar 

  234. Gobe GC, Johnson DW. Distal tubular epithelial cells of the kidney: potential support for proximal tubular cell survival after renal injury. Int J Biochem Cell Biol. 2007;39(9):1551–61.

    Article  CAS  PubMed  Google Scholar 

  235. Nover L, editor. Heat shock response. Boca Raton: CRC Press; 1991.

    Google Scholar 

  236. Emami A, Schwartz JH, Borkan SC. Transient ischemia or heat stress induces a cytoprotectant protein in rat kidney. Am J Phys. 1991;260(4 Pt 2):F479–85.

    CAS  Google Scholar 

  237. Van Why SK, Hildebrandt F, Ardito T, Mann AS, Siegel NJ, Kashgarian M. Induction and intracellular localization of HSP-72 after renal ischemia. Am J Phys. 1992;263(5 Pt 2):F769–75.

    Google Scholar 

  238. Aufricht C, Lu E, Thulin G, Kashgarian M, Siegel NJ, Van Why SK. ATP releases HSP-72 from protein aggregates after renal ischemia. Am J Phys. 1998;274(2 Pt 2):F268–74.

    CAS  Google Scholar 

  239. Riordan M, Sreedharan R, Wang S, Thulin G, Mann A, Stankewich M, et al. HSP70 binding modulates detachment of Na-K-ATPase following energy deprivation in renal epithelial cells. Am J Physiol Renal Physiol. 2005;288(6):F1236–42.

    Article  CAS  PubMed  Google Scholar 

  240. Van Why SK, Mann AS, Ardito T, Thulin G, Ferris S, Macleod MA, et al. Hsp27 associates with actin and limits injury in energy depleted renal epithelia. J Am Soc Nephrol. 2003;14(1):98–106.

    Article  PubMed  Google Scholar 

  241. Riordan M, Garg V, Thulin G, Kashgarian M, Siegel NJ. Differential inhibition of HSP72 and HSP25 produces profound impairment of cellular integrity. J Am Soc Nephrol. 2004;15(6):1557–66.

    Article  CAS  PubMed  Google Scholar 

  242. Sreedharan R, Riordan M, Thullin G, Van Why S, Siegel NJ, Kashgarian M. The maximal cytoprotective function of the heat shock protein 27 is dependent on heat shock protein 70. Biochim Biophys Acta. 2011;1813(1):129–35.

    Article  CAS  PubMed  Google Scholar 

  243. Chen SW, Kim M, Song JH, Park SW, Wells D, Brown K, et al. Mice that overexpress human heat shock protein 27 have increased renal injury following ischemia reperfusion. Kidney Int. 2009;75(5):499–510.

    Article  CAS  PubMed  Google Scholar 

  244. Kim M, Park SW, Chen SW, Gerthoffer WT, D’Agati VD, Lee HT. Selective renal overexpression of human heat shock protein 27 reduces renal ischemia-reperfusion injury in mice. Am J Physiol Renal Physiol. 2010;299(2):F347–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Gaudio KM, Thulin G, Mann A, Kashgarian M, Siegel NJ. Role of heat stress response in the tolerance of immature renal tubules to anoxia. Am J Phys. 1998;274(6 Pt 2):F1029–36.

    CAS  Google Scholar 

  246. Vicencio A, Bidmon B, Ryu J, Reidy K, Thulin G, Mann A, et al. Developmental expression of HSP-72 and ischemic tolerance of the immature kidney. Pediatr Nephrol. 2003;18(2):85–91.

    Article  PubMed  Google Scholar 

  247. Sreedharan R, Riordan M, Wang S, Thulin G, Kashgarian M, Siegel NJ. Reduced tolerance of immature renal tubules to anoxia by HSF-1 decoy. Am J Physiol Renal Physiol. 2005;288(2):F322–6.

    Article  CAS  PubMed  Google Scholar 

  248. Sreedharan R, Chen S, Miller M, Haribhai D, Williams CB, Van Why SK. Mice with an absent stress response are protected against ischemic renal injury. Kidney Int. 2014;86:515–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Soifer NE, Van Why SK, Ganz MB, Kashgarian M, Siegel NJ, Stewart AF. Expression of parathyroid hormone-related protein in the rat glomerulus and tubule during recovery from renal ischemia. J Clin Invest. 1993;92(6):2850–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Ichimura T, Bonventre JV. Growth factors, signaling, and renal injury and repair. In: Bruce Molitoris WFF, editor. Acute renal failure: a companion to Brenner & Rector’s the kidney. 6th ed. Philadelphia: Elsevier Health Sciences; 2001. p. 101–18.

    Google Scholar 

  251. Gobe G, Zhang XJ, Willgoss DA, Schoch E, Hogg NA, Endre ZH. Relationship between expression of Bcl-2 genes and growth factors in ischemic acute renal failure in the rat. J Am Soc Nephrol. 2000;11(3):454–67.

    Article  CAS  PubMed  Google Scholar 

  252. Christov M, Neyra JA, Gupta S, Leaf DE. Fibroblast growth factor 23 and klotho in AKI. Semin Nephrol. 2019;39(1):57–75.

    Article  CAS  PubMed  Google Scholar 

  253. Tanaka H, Terada Y, Kobayashi T, Okado T, Inoshita S, Kuwahara M, et al. Expression and function of Ets-1 during experimental acute renal failure in rats. J Am Soc Nephrol. 2004;15(12):3083–92.

    Article  PubMed  Google Scholar 

  254. Terada Y, Tanaka H, Okado T, Shimamura H, Inoshita S, Kuwahara M, et al. Expression and function of the developmental gene Wnt-4 during experimental acute renal failure in rats. J Am Soc Nephrol. 2003;14(5):1223–33.

    Article  CAS  PubMed  Google Scholar 

  255. Villanueva S, Cespedes C, Gonzalez A, Vio CP. bFGF induces an earlier expression of nephrogenic proteins after ischemic acute renal failure. Am J Physiol Regul Integr Comp Physiol. 2006;291(6):R1677–87.

    Article  CAS  PubMed  Google Scholar 

  256. Sharples EJ, Patel N, Brown P, Stewart K, Mota-Philipe H, Sheaff M, et al. Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion. J Am Soc Nephrol. 2004;15(8):2115–24.

    Article  CAS  PubMed  Google Scholar 

  257. Fiaschi-Taesch NM, Santos S, Reddy V, Van Why SK, Philbrick WF, Ortega A, et al. Prevention of acute ischemic renal failure by targeted delivery of growth factors to the proximal tubule in transgenic mice: the efficacy of parathyroid hormone-related protein and hepatocyte growth factor. J Am Soc Nephrol. 2004;15(1):112–25.

    Article  CAS  PubMed  Google Scholar 

  258. Gupta S, Verfaillie C, Chmielewski D, Kim Y, Rosenberg ME. A role for extrarenal cells in the regeneration following acute renal failure. Kidney Int. 2002;62(4):1285–90.

    Article  PubMed  Google Scholar 

  259. Kale S, Karihaloo A, Clark PR, Kashgarian M, Krause DS, Cantley LG. Bone marrow stem cells contribute to repair of the ischemically injured renal tubule. J Clin Invest. 2003;112(1):42–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Lin F, Cordes K, Li L, Hood L, Couser WG, Shankland SJ, et al. Hematopoietic stem cells contribute to the regeneration of renal tubules after renal ischemia-reperfusion injury in mice. J Am Soc Nephrol. 2003;14(5):1188–99.

    Article  PubMed  Google Scholar 

  261. Duffield JS, Park KM, Hsiao LL, Kelley VR, Scadden DT, Ichimura T, et al. Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow-derived stem cells. J Clin Invest. 2005;115(7):1743–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Fang TC, Alison MR, Cook HT, Jeffery R, Wright NA, Poulsom R. Proliferation of bone marrow-derived cells contributes to regeneration after folic acid-induced acute tubular injury. J Am Soc Nephrol. 2005;16(6):1723–32.

    Article  CAS  PubMed  Google Scholar 

  263. Humphreys BD, Czerniak S, DiRocco DP, Hasnain W, Cheema R, Bonventre JV. Repair of injured proximal tubule does not involve specialized progenitors. Proc Natl Acad Sci U S A. 2011;108(22):9226–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Lin F, Moran A, Igarashi P. Intrarenal cells, not bone marrow-derived cells, are the major source for regeneration in postischemic kidney. J Clin Invest. 2005;115(7):1756–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Poulsom R, Forbes SJ, Hodivala-Dilke K, Ryan E, Wyles S, Navaratnarasah S, et al. Bone marrow contributes to renal parenchymal turnover and regeneration. J Pathol. 2001;195(2):229–35.

    Article  CAS  PubMed  Google Scholar 

  266. Togel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol. 2005;289(1):F31–42.

    Article  PubMed  CAS  Google Scholar 

  267. Togel F, Weiss K, Yang Y, Hu Z, Zhang P, Westenfelder C. Vasculotropic, paracrine actions of infused mesenchymal stem cells are important to the recovery from acute kidney injury. Am J Physiol Renal Physiol. 2007;292(5):F1626–35.

    Article  CAS  PubMed  Google Scholar 

  268. Stokman G, Leemans JC, Claessen N, Weening JJ, Florquin S. Hematopoietic stem cell mobilization therapy accelerates recovery of renal function independent of stem cell contribution. J Am Soc Nephrol. 2005;16(6):1684–92.

    Article  CAS  PubMed  Google Scholar 

  269. Iwasaki M, Adachi Y, Minamino K, Suzuki Y, Zhang Y, Okigaki M, et al. Mobilization of bone marrow cells by G-CSF rescues mice from cisplatin-induced renal failure, and M-CSF enhances the effects of G-CSF. J Am Soc Nephrol. 2005;16(3):658–66.

    Article  CAS  PubMed  Google Scholar 

  270. Togel FE, Westenfelder C. Kidney protection and regeneration following acute injury: progress through stem cell therapy. Am J Kidney Dis. 2012;60(6):1012–22.

    Article  PubMed  Google Scholar 

  271. Swaminathan M, Stafford-Smith M, Chertow GM, Warnock DG, Paragamian V, Brenner RM, et al. Allogeneic mesenchymal stem cells for treatment of AKI after cardiac surgery. J Am Soc Nephrol. 2018;29(1):260–7.

    Article  PubMed  Google Scholar 

  272. Briggs JD, Kennedy AC, Young LN, Luke RG, Gray M. Renal function after acute tubular necrosis. Br Med J. 1967;3(5564):513–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Lewers DT, Mathew TH, Maher JF, Schreiner GE. Long-term follow-up of renal function and histology after acute tubular necrosis. Ann Intern Med. 1970;73(4):523–9.

    Article  CAS  PubMed  Google Scholar 

  274. Bonomini V, Stefoni S, Vangelista A. Long-term patient and renal prognosis in acute renal failure. Nephron. 1984;36(3):169–72.

    Article  CAS  PubMed  Google Scholar 

  275. Lowe KG. The late prognosis in acute tubular necrosis; an interim follow-up report on 14 patients. Lancet. 1952;1(6718):1086–8.

    Article  CAS  PubMed  Google Scholar 

  276. Finkenstaedt JT, Merrill JP. Renal function after recovery from acute renal failure. N Engl J Med. 1956;254(22):1023–6.

    Article  CAS  PubMed  Google Scholar 

  277. Alon US. Neonatal acute renal failure: the need for long-term follow-up. Clin Pediatr (Phila). 1998;37(6):387–9.

    Article  CAS  Google Scholar 

  278. Polito C, Papale MR, La Manna A. Long-term prognosis of acute renal failure in the full-term neonate. Clin Pediatr (Phila). 1998;37(6):381–5.

    Article  CAS  Google Scholar 

  279. Shaw NJ, Brocklebank JT, Dickinson DF, Wilson N, Walker DR. Long-term outcome for children with acute renal failure following cardiac surgery. Int J Cardiol. 1991;31(2):161–5.

    Article  CAS  PubMed  Google Scholar 

  280. Askenazi DJ, Feig DI, Graham NM, Hui-Stickle S, Goldstein SL. 3-5 year longitudinal follow-up of pediatric patients after acute renal failure. Kidney Int. 2006;69(1):184–9.

    Article  CAS  PubMed  Google Scholar 

  281. Chawla LS, Kimmel PL. Acute kidney injury and chronic kidney disease: an integrated clinical syndrome. Kidney Int. 2012;82(5):516–24.

    Article  PubMed  Google Scholar 

  282. Coca SG, Singanamala S, Parikh CR. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int. 2012;81(5):442–8.

    Article  PubMed  Google Scholar 

  283. Basile DP, Bonventre JV, Mehta R, Nangaku M, Unwin R, Rosner MH, et al. Progression after AKI: understanding maladaptive repair processes to predict and identify therapeutic treatments. J Am Soc Nephrol. 2016;27(3):687–97.

    Article  CAS  PubMed  Google Scholar 

  284. Pagtalunan ME, Olson JL, Tilney NL, Meyer TW. Late consequences of acute ischemic injury to a solitary kidney. J Am Soc Nephrol. 1999;10(2):366–73.

    Article  CAS  PubMed  Google Scholar 

  285. Torres R, Velazquez H, Chang JJ, Levene MJ, Moeckel G, Desir GV, et al. Three-dimensional morphology by multiphoton microscopy with clearing in a model of cisplatin-induced CKD. J Am Soc Nephrol. 2016;27(4):1102–12.

    Article  CAS  PubMed  Google Scholar 

  286. Geng H, Lan R, Wang G, Siddiqi AR, Naski MC, Brooks AI, et al. Inhibition of autoregulated TGFbeta signaling simultaneously enhances proliferation and differentiation of kidney epithelium and promotes repair following renal ischemia. Am J Pathol. 2009;174(4):1291–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  287. Yang L, Besschetnova TY, Brooks CR, Shah JV, Bonventre JV. Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med. 2010;16(5):535–43, 1p following 143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  288. Venkatachalam MA, Griffin KA, Lan R, Geng H, Saikumar P, Bidani AK. Acute kidney injury: a springboard for progression in chronic kidney disease. Am J Physiol Renal Physiol. 2010;298(5):F1078–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  289. Cianciolo Cosentino C, Skrypnyk NI, Brilli LL, Chiba T, Novitskaya T, Woods C, et al. Histone deacetylase inhibitor enhances recovery after AKI. J Am Soc Nephrol. 2013;24(6):943–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  290. Kirita Y, Wu H, Uchimura K, Wilson PC, Humphreys BD. Cell profiling of mouse acute kidney injury reveals conserved cellular responses to injury. Proc Natl Acad Sci U S A. 2020;117(27):15874–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  291. Ullah MM, Basile DP. Role of renal hypoxia in the progression from acute kidney injury to chronic kidney disease. Semin Nephrol. 2019;39(6):567–80.

    Article  PubMed  PubMed Central  Google Scholar 

  292. Leonard EC, Friedrich JL, Basile DP. VEGF-121 preserves renal microvessel structure and ameliorates secondary renal disease following acute kidney injury. Am J Physiol Renal Physiol. 2008;295(6):F1648–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  293. Basile DP, Yoder MC. Circulating and tissue resident endothelial progenitor cells. J Cell Physiol. 2014;229(1):10–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  294. Chade AR, Tullos NA, Harvey TW, Mahdi F, Bidwell GL 3rd. Renal therapeutic angiogenesis using a bioengineered polymer-stabilized vascular endothelial growth factor construct. J Am Soc Nephrol. 2016;27(6):1741–52.

    Article  CAS  PubMed  Google Scholar 

  295. Matsumoto M, Makino Y, Tanaka T, Tanaka H, Ishizaka N, Noiri E, et al. Induction of Renoprotective gene expression by cobalt ameliorates Ischemic injury of the kidney in rats. J Am Soc Nephrol. 2003;14(7):1825–32.

    Article  PubMed  Google Scholar 

  296. Kapitsinou PP, Jaffe J, Michael M, Swan CE, Duffy KJ, Erickson-Miller CL, et al. Preischemic targeting of HIF prolyl hydroxylation inhibits fibrosis associated with acute kidney injury. Am J Physiol Renal Physiol. 2012;302(9):F1172–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  297. Liu M, Reddy NM, Higbee EM, Potteti HR, Noel S, Racusen L, et al. The Nrf2 triterpenoid activator, CDDO-imidazolide, protects kidneys from ischemia-reperfusion injury in mice. Kidney Int. 2014;85(1):134–41.

    Article  CAS  PubMed  Google Scholar 

  298. Wu J, Liu X, Fan J, Chen W, Wang J, Zeng Y, et al. Bardoxolone methyl (BARD) ameliorates aristolochic acid (AA)-induced acute kidney injury through Nrf2 pathway. Toxicology. 2014;318(0):22–31.

    Article  CAS  PubMed  Google Scholar 

  299. Humphreys BD, Lin SL, Kobayashi A, Hudson TE, Nowlin BT, Bonventre JV, et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol. 2010;176(1):85–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  300. Broekema M, Harmsen MC, van Luyn MJ, Koerts JA, Petersen AH, van Kooten TG, et al. Bone marrow-derived myofibroblasts contribute to the renal interstitial myofibroblast population and produce procollagen I after ischemia/reperfusion in rats. J Am Soc Nephrol. 2007;18(1):165–75.

    Article  CAS  PubMed  Google Scholar 

  301. Basile DP, Leonard EC, Beal AG, Schleuter D, Friedrich J. Persistent oxidative stress following renal ischemia-reperfusion injury increases ANG II hemodynamic and fibrotic activity. Am J Physiol Renal Physiol. 2012;302(11):F1494–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  302. Kinsey GR. Macrophage dynamics in AKI to CKD progression. J Am Soc Nephrol. 2014;25(2):209–11.

    Article  PubMed  Google Scholar 

  303. Mehrotra P, Collett JA, McKinney SD, Stevens J, Ivancic CM, Basile DP. IL-17 mediates neutrophil infiltration and renal fibrosis following recovery from ischemia reperfusion: compensatory role of natural killer cells in athymic rats. Am J Physiol Renal Physiol. 2017;312(3):F385–F97.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Indiana University School of Medicine, Indianapolis, IN, USA

    David P. Basile

  2. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA

    Rajasree Sreedharan & Scott K. Van Why

  3. Department of Pediatrics, Emory School of Medicine, Atlanta, GA, USA

    Rajit K. Basu

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  1. David P. Basile
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  2. Rajasree Sreedharan
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  3. Rajit K. Basu
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  4. Scott K. Van Why
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Correspondence to Scott K. Van Why .

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Editors and Affiliations

  1. Division of Nephrology, Bambino Gesù Children’s Hospital –, ROMA, Roma, Italy

    Francesco Emma

  2. Division of Nephrology and Hypertension The Heart Institute, University of Cincinnati Cincinnati Children’s Hospital Medical C, Cincinnati, OH, USA

    Stuart Goldstein

  3. Division of Nephrology, All India Institute of Medical Sciences, Ansari Nagar East, Delhi, India

    Arvind Bagga

  4. Division of Pediatric Nephrology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA

    Carlton M. Bates

  5. Renal Unit, Graet Ormond Street Hospital, London, UK

    Rukshana Shroff

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Basile, D.P., Sreedharan, R., Basu, R.K., Van Why, S.K. (2021). Pathogenesis of Acute Kidney Injury. In: Emma, F., Goldstein, S., Bagga, A., Bates, C.M., Shroff, R. (eds) Pediatric Nephrology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-27843-3_56-2

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  1. Latest

    Pathogenesis of Acute Kidney Injury
    Published:
    29 October 2021

    DOI: https://doi.org/10.1007/978-3-642-27843-3_56-2

  2. Original

    Pathogenesis of Acute Kidney Injury
    Published:
    19 November 2014

    DOI: https://doi.org/10.1007/978-3-642-27843-3_56-1

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