Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Pathophysiology of ischemic acute kidney injury

Abstract

Acute kidney injury (AKI) as a consequence of ischemia is a common clinical event leading to unacceptably high morbidity and mortality, development of chronic kidney disease (CKD), and transition from pre-existing CKD to end-stage renal disease. Data indicate a close interaction between the many cell types involved in the pathophysiology of ischemic AKI, which has critical implications for the treatment of this condition. Inflammation seems to be the common factor that links the various cell types involved in this process. In this Review, we describe the interactions between these cells and their response to injury following ischemia. We relate these events to patients who are at high risk of AKI, and highlight the characteristics that might predispose these patients to injury. We also discuss how therapy targeting specific cell types can minimize the initial and subsequent injury following ischemia, thereby limiting the extent of acute changes and, hopefully, long-term structural and functional alterations to the kidney.

Key Points

  • During ischemic acute kidney injury (AKI), ATP depletion results in cytoskeletal changes in epithelial and endothelial cells, causing disruption of function, and a decrease in glomerular filtration rate

  • Apoptosis and necrosis are major mechanisms of cell death that have important roles in ischemia, with the contribution of each pathway depending on the extent of the injury

  • Under physiological conditions, endothelial cells regulate permeability, vascular tone, coagulation, and inflammation; endothelial cells that are dysfunctional substantially contribute to the extension phase of AKI

  • Inflammation and its mediators orchestrate the extension phase of ischemic AKI, and limit injury to tubular epithelial cells and vascular endothelial cells, thereby promoting repair

  • Complex interactions between epithelial cells, endothelial cells, inflammatory mediators, and cytokines can result in persistent injury during acute tubular necrosis

  • Stem cells, mesenchymal cells, and endothelial progenitor cells contribute to the repair and regeneration of tubular cells and endothelial cells following injury, and could provide attractive targets for therapeutic intervention

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Pathogenesis of ischemic AKI.
Figure 2: Effects of sub-lethal injury to tubular cells and their recovery.
Figure 3: Events in endothelial cell activation, injury, and reduced microvascular flow.

References

  1. 1

    Thakar, C. V., Arrigain, S., Worley, S., Yared, J. P. & Paganini, E. P. A clinical score to predict acute renal failure after cardiac surgery. J. Am. Soc. Nephrol. 16, 162–168 (2005).

    PubMed  Article  PubMed Central  Google Scholar 

  2. 2

    Singh, P., Rifkin, D. E. & Blantz, R. C. Chronic kidney disease: an inherent risk factor for acute kidney injury? Clin. J. Am. Soc. Nephrol. 5, 1690–1695 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  3. 3

    Coca, S. G. Acute kidney injury in elderly persons. Am. J. Kidney Dis. 56, 122–131 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  4. 4

    Harel, Z. & Chan, C. T. Predicting and preventing acute kidney injury after cardiac surgery. Curr. Opin. Nephrol. Hypertens. 17, 624–628 (2008).

    PubMed  Article  PubMed Central  Google Scholar 

  5. 5

    James, M. T. et al. Glomerular filtration rate, proteinuria, and the incidence and consequences of acute kidney injury: a cohort study. Lancet 376, 2096–2103 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  6. 6

    Cruz, D. N., Bagshaw, S. M., Ronco, C. & Ricci, Z. Acute kidney injury: classification and staging. Contrib. Nephrol. 164, 24–32 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  7. 7

    Ricci, Z., Cruz, D. & Ronco, C. The RIFLE criteria and mortality in acute kidney injury: a systematic review. Kidney Int. 73, 538–546 (2008).

    CAS  Article  Google Scholar 

  8. 8

    Molitoris, B. A., Melnikov, V. Y., Okusa, M. D. & Himmelfarb, J. Technology insight: biomarker development in acute kidney injury—what can we anticipate? Nat. Clin. Pract. Nephrol. 4, 154–165 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9

    Molitoris, B. A. Contrast nephropathy: are short-term outcome measures adequate for quantification of long-term renal risk? Nat. Clin. Pract. Nephrol. 4, 594–595 (2008).

    PubMed  Article  PubMed Central  Google Scholar 

  10. 10

    Himmelfarb, J. Acute kidney injury in the elderly: problems and prospects. Semin. Nephrol. 29, 658–664 (2009).

    PubMed  Article  PubMed Central  Google Scholar 

  11. 11

    Liaño, F. & Pascual, J. Epidemiology of acute renal failure: a prospective, multicenter, community-based study. Madrid Acute Renal Failure Study Group. Kidney Int. 50, 811–818 (1996).

    PubMed  Article  PubMed Central  Google Scholar 

  12. 12

    Nash, K., Hafeez, A. & Hou, S. Hospital-acquired renal insufficiency. Am. J. Kidney Dis. 39, 930–936 (2002).

    Article  Google Scholar 

  13. 13

    Sesso, R., Roque, A., Vicioso, B. & Stella, S. Prognosis of ARF in hospitalized elderly patients. Am. J. Kidney Dis. 44, 410–419 (2004).

    PubMed  Article  PubMed Central  Google Scholar 

  14. 14

    Wencker, D. Acute cardio-renal syndrome: progression from congestive heart failure to congestive kidney failure. Curr. Heart Fail. Rep. 4, 134–138 (2007).

    PubMed  Article  PubMed Central  Google Scholar 

  15. 15

    Wan, L. et al. Pathophysiology of septic acute kidney injury: what do we really know? Crit. Care Med. 36, S198–S203 (2008).

    PubMed  Article  PubMed Central  Google Scholar 

  16. 16

    Himmelfarb, J. et al. Evaluation and initial management of acute kidney injury. Clin. J. Am. Soc. Nephrol. 3, 962–967 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  17. 17

    Fujii, T. et al. The role of renal sympathetic nervous system in the pathogenesis of ischemic acute renal failure. Eur. J. Pharmacol. 481, 241–248 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 18

    Blantz, R. C. The glomerular and tubular actions of angiotensin II. Am. J. Kidney Dis. 10 (Suppl. 1), 2–6 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Kastner, P. R., Hall, J. E. & Guyton, A. C. Control of glomerular filtration rate: role of intrarenally formed angiotensin II. Am. J. Physiol. 246, F897–F906 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Badr, K. F. & Ichikawa, I. Prerenal failure: a deleterious shift from renal compensation to decompensation. N. Engl. J. Med. 319, 623–629 (1988).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21

    Maddox, D. & Brenner, B. M. in The Kidney 6th edn Vol. 1 (eds Brenner, B. M. & Levine, S. A.) 319–374 (W. B. Saunders, Philadelphia, 2000).

    Google Scholar 

  22. 22

    Yared, A., Kon, V. & Ichikawa, I. Mechanism of preservation of glomerular perfusion and filtration during acute extracellular fluid volume depletion. Importance of intrarenal vasopressin-prostaglandin interaction for protecting kidneys from constrictor action of vasopressin. J. Clin. Invest. 75, 1477–1487 (1985).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

    Oliver, J. A., Sciacca, R. R. & Cannon, P. J. Renal vasodilation by converting enzyme inhibition. Role of renal prostaglandins. Hypertension 5, 166–171 (1983).

    CAS  PubMed  Article  Google Scholar 

  24. 24

    Cryer, H. G., Bloom, I. T., Unger, L. S. & Garrison, R. N. Factors affecting renal microvascular blood flow in rat hyperdynamic bacteremia. Am. J. Physiol. 264, H1988–H1997 (1993).

    CAS  PubMed  Google Scholar 

  25. 25

    Molitoris, B. A. & Sutton, T. A. Endothelial injury and dysfunction: role in the extension phase of acute renal failure. Kidney Int. 66, 496–499 (2004).

    PubMed  Article  Google Scholar 

  26. 26

    Oberbauer, R., Rohrmoser, M., Regele, H., Mühlbacher, F. & Mayer, G. Apoptosis of tubular epithelial cells in donor kidney biopsies predicts early renal allograft function. J. Am. Soc. Nephrol. 10, 2006–2013 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Rosenberger, C. et al. Activation of hypoxia-inducible factors ameliorates hypoxic distal tubular injury in the isolated perfused rat kidney. Nephrol. Dial. Transplant. 23, 3472–3478 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28

    Alejandro, V. et al. Mechanisms of filtration failure during postischemic injury of the human kidney. A study of the reperfused renal allograft. J. Clin. Invest. 95, 820–831 (1995).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29

    Ramaswamy, D. et al. Maintenance and recovery stages of postischemic acute renal failure in humans. Am. J. Physiol. Renal Physiol. 282, F271–F280 (2002).

    PubMed  PubMed Central  Article  Google Scholar 

  30. 30

    Solez, K., Morel-Maroger, L. & Sraer, J. D. The morphology of “acute tubular necrosis” in man: analysis of 57 renal biopsies and a comparison with the glycerol model. Medicine (Baltimore) 58, 362–376 (1979).

    CAS  Article  Google Scholar 

  31. 31

    Racusen, L. in Acute Renal Failure 1st edn (eds Molitoris, B. A. & Finn, W. F.) 1–12 (W. B. Saunders, Philadelphia, 2001).

    Google Scholar 

  32. 32

    Saikumar, P. & Venkatachalam, M. A. Role of apoptosis in hypoxic/ischemic damage in the kidney. Semin. Nephrol. 23, 511–521 (2003).

    CAS  PubMed  Article  Google Scholar 

  33. 33

    Wagner, M. C. et al. Ischemic injury to kidney induces glomerular podocyte effacement and dissociation of slit diaphragm proteins Neph1 and ZO-1. J. Biol. Chem. 283, 35579–35589 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34

    Molitoris, B. A. Actin cytoskeleton in ischemic acute renal failure. Kidney Int. 66, 871–883 (2004).

    PubMed  Article  Google Scholar 

  35. 35

    Ashworth, S. L., Sandoval, R. M., Tanner, G. A. & Molitoris, B. A. Two-photon microscopy: visualization of kidney dynamics. Kidney Int. 72, 416–421 (2007).

    CAS  PubMed  Article  Google Scholar 

  36. 36

    Molitoris, B. A., Dahl, R. & Hosford, M. Cellular ATP depletion induces disruption of the spectrin cytoskeletal network. Am. J. Physiol. 271, F790–F798 (1996).

    CAS  PubMed  Google Scholar 

  37. 37

    Ashworth, S. L., Sandoval, R. M., Hosford, M., Bamburg, J. R. & Molitoris, B. A. Ischemic injury induces ADF relocalization to the apical domain of rat proximal tubule cells. Am. J. Physiol. Renal Physiol. 280, F886–F894 (2001).

    CAS  PubMed  Article  Google Scholar 

  38. 38

    Ashworth, S. L. et al. ADF/cofilin mediates actin cytoskeletal alterations in LLC-PK cells during ATP depletion. Am. J. Physiol. Renal Physiol. 284, F852–F862 (2003).

    CAS  PubMed  Article  Google Scholar 

  39. 39

    Atkinson, S. J., Hosford, M. A. & Molitoris, B. A. Mechanism of actin polymerization in cellular ATP depletion. J. Biol. Chem. 279, 5194–5199 (2004).

    CAS  PubMed  Article  Google Scholar 

  40. 40

    Chen, J., Doctor, R. B. & Mandel, L. J. Cytoskeletal dissociation of ezrin during renal anoxia: role in microvillar injury. Am. J. Physiol. 267, C784–C795 (1994).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41

    Ashworth, S. L. et al. Renal ischemia induces tropomyosin dissociation-destabilizing microvilli microfilaments. Am. J. Physiol. Renal Physiol. 286, F988–F996 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42

    Molitoris, B. A. & Marrs, J. The role of cell adhesion molecules in ischemic acute renal failure. Am. J. Med. 106, 583–592 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. 43

    Zuk, A., Bonventre, J. V., Brown, D. & Matlin, K. S. Polarity, integrin, and extracellular matrix dynamics in the postischemic rat kidney. Am. J. Physiol. 275, C711–C731 (1998).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. 44

    Molitoris, B. A., Geerdes, A. & McIntosh, J. R. Dissociation and redistribution of Na+, K+-ATPase from its surface membrane actin cytoskeletal complex during cellular ATP depletion. J. Clin. Invest. 88, 462–469 (1991).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45

    Molitoris, B. A. Na+-K+-ATPase that redistributes to apical membrane during ATP depletion remains functional. Am. J. Physiol. 265, F693–F697 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Lieberthal, W., Koh, J. S. & Levine, J. S. Necrosis and apoptosis in acute renal failure. Semin. Nephrol. 18, 505–518 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Bonegio, R. & Lieberthal, W. Role of apoptosis in the pathogenesis of acute renal failure. Curr. Opin. Nephrol. Hypertens. 11, 301–308 (2002).

    PubMed  Article  Google Scholar 

  48. 48

    Guo, R., Wang, Y., Minto, A. W., Quigg, R. J. & Cunningham, P. N. Acute renal failure in endotoxemia is dependent on caspase activation. J. Am. Soc. Nephrol. 15, 3093–3102 (2004).

    PubMed  Article  Google Scholar 

  49. 49

    Safirstein, R. L. Acute renal failure: from renal physiology to the renal transcriptome. Kidney Int. Suppl. 91, S62–S66 (2004).

    CAS  Article  Google Scholar 

  50. 50

    Nicholson, D. W. From bench to clinic with apoptosis-based therapeutic agents. Nature 407, 810–816 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51

    Edelstein, L. C., Lagos, L., Simmons, M., Tirumalai, H. & Gélinas, C. NF-κB-dependent assembly of an enhanceosome-like complex on the promoter region of apoptosis inhibitor Bfl-1/A1. Mol. Cell. Biol. 23, 2749–2761 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52

    Kelly, K. J., Plotkin, Z., Vulgamott, S. L. & Dagher, P. C. P53 mediates the apoptotic response to GTP depletion after renal ischemia-reperfusion: protective role of a p53 inhibitor. J. Am. Soc. Nephrol. 14, 128–138 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. 53

    Park, K. M., Chen, A. & Bonventre, J. V. Prevention of kidney ischemia/reperfusion-induced functional injury and JNK, p38, and MAPK kinase activation by remote ischemic pretreatment. J. Biol. Chem. 276, 11870–11876 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54

    Scheid, M. P., Schubert, K. M. & Duronio, V. Regulation of bad phosphorylation and association with Bcl-xL by the MAPK/Erk kinase. J. Biol. Chem. 274, 31108–31113 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  55. 55

    Imamura, R. et al. Intravital 2-photon microscopy assessment of renal protection efficacy of siRNA for p53 in experimental rat kidney transplantation models. Cell Transplant. doi:10.3727/096368910X516619.

    PubMed  Article  PubMed Central  Google Scholar 

  56. 56

    Molitoris, B. A. et al. siRNA targeted to p53 attenuates ischemic and cisplatin-induced acute kidney injury. J. Am. Soc. Nephrol. 20, 1754–1764 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57

    Sogabe, K. et al. Calcium dependence of integrity of the actin cytoskeleton of proximal tubule cell microvilli. Am. J. Physiol. 271, F292–F303 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Portilla, D. Role of fatty acid beta-oxidation and calcium-independent phospholipase A2 in ischemic acute renal failure. Curr. Opin. Nephrol. Hypertens. 8, 473–477 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  59. 59

    Galli, F. et al. Oxidative stress and reactive oxygen species. Contrib. Nephrol. 149, 240–260 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 60

    Li, L., Zepeda-Orozco, D., Black, R. & Lin, F. Autophagy is a component of epithelial cell fate in obstructive uropathy. Am. J. Pathol. 176, 1767–1778 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61

    Koesters, R. et al. Tubular overexpression of transforming growth factor-β1 induces autophagy and fibrosis but not mesenchymal transition of renal epithelial cells. Am. J. Pathol. 177, 632–643 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62

    Conger, J. D. & Schrier, R. W. Renal hemodynamics in acute renal failure. Annu. Rev. Physiol. 42, 603–614 (1980).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  63. 63

    Conger, J. D., Robinette, J. B. & Hammond, W. S. Differences in vascular reactivity in models of ischemic acute renal failure. Kidney Int. 39, 1087–1097 (1991).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. 64

    Noiri, E. et al. Oxidative and nitrosative stress in acute renal ischemia. Am. J. Physiol. Renal Physiol. 281, F948–F957 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. 65

    Ling, H. et al. Attenuation of renal ischemia-reperfusion injury in inducible nitric oxide synthase knockout mice. Am. J. Physiol. 277, F383–F390 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Goligorsky, M. S., Brodsky, S. V. & Noiri, E. NO bioavailability, endothelial dysfunction, and acute renal failure: new insights into pathophysiology. Semin. Nephrol. 24, 316–323 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. 67

    Ogawa, T. et al. Contribution of nitric oxide to the protective effects of ischemic preconditioning in ischemia-reperfused rat kidneys. J. Lab. Clin. Med. 138, 50–58 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. 68

    Mattson, D. L. & Wu, F. Control of arterial blood pressure and renal sodium excretion by nitric oxide synthase in the renal medulla. Acta Physiol. Scand. 168, 149–154 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  69. 69

    Chander, V. & Chopra, K. Renal protective effect of molsidomine and L-arginine in ischemia-reperfusion induced injury in rats. J. Surg. Res. 128, 132–139 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  70. 70

    Sutton, T. A. et al. Injury of the renal microvascular endothelium alters barrier function after ischemia. Am. J. Physiol. Renal Physiol. 285, F191–F198 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  71. 71

    Sutton, T. A. et al. Minocycline reduces renal microvascular leakage in a rat model of ischemic renal injury. Am. J. Physiol. Renal Physiol. 288, F91–F97 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  72. 72

    Van de Wouwer, M., Collen, D. & Conway, E. M. Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation. Arterioscler. Thromb. Vasc. Biol. 24, 1374–1383 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  73. 73

    Gupta, A. et al. Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2. Am. J. Physiol. Renal Physiol. 293, F245–F254 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  74. 74

    Gupta, A., Williams, M. D., Macias, W. L., Molitoris, B. A. & Grinnell, B. W. Activated protein C and acute kidney injury: selective targeting of PAR-1. Curr. Drug Targets 10, 1212–1226 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. 75

    Mizutani, A., Okajima, K., Uchiba, M. & Noguchi, T. Activated protein C reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation. Blood 95, 3781–3787 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Sharfuddin, A. A. et al. Soluble thrombomodulin protects ischemic kidneys. J. Am. Soc. Nephrol. 20, 524–534 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77

    Tajra, L. C. et al. In vivo effects of monoclonal antibodies against rat β2 integrins on kidney ischemia-reperfusion injury. J. Surg. Res. 87, 32–38 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 78

    Singbartl, K., Forlow, S. B. & Ley, K. Platelet, but not endothelial, P-selectin is critical for neutrophil-mediated acute postischemic renal failure. FASEB J. 15, 2337–2344 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  79. 79

    Burne, M. J. & Rabb, H. Pathophysiological contributions of fucosyltransferases in renal ischemia reperfusion injury. J. Immunol. 169, 2648–2652 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  80. 80

    Nemoto, T. et al. Small molecule selectin ligand inhibition improves outcome in ischemic acute renal failure. Kidney Int. 60, 2205–2214 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  81. 81

    Matsukawa, A. et al. Mice genetically lacking endothelial selectins are resistant to the lethality in septic peritonitis. Exp. Mol. Pathol. 72, 68–76 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  82. 82

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

    PubMed  Article  PubMed Central  Google Scholar 

  83. 83

    Basile, D. P. The endothelial cell in ischemic acute kidney injury: implications for acute and chronic function. Kidney Int. 72, 151–156 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  84. 84

    Hörbelt, M. et al. Acute and chronic microvascular alterations in a mouse model of ischemic acute kidney injury. Am. J. Physiol. Renal Physiol. 293, F688–F695 (2007).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  85. 85

    Basile, D. P., Fredrich, K., Chelladurai, B., Leonard, E. C. & Parrish, A. R. Renal ischemia reperfusion inhibits VEGF expression and induces ADAMTS-1, a novel VEGF inhibitor. Am. J. Physiol. Renal Physiol. 294, F928–F936 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  86. 86

    Leonard, E. C., Friedrich, J. L. & Basile, D. P. VEGF-121 preserves renal microvessel structure and ameliorates secondary renal disease following acute kidney injury. Am. J. Physiol. Renal Physiol. 295, F1648–F1657 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87

    Basile, D. P. et al. Impaired endothelial proliferation and mesenchymal transition contribute to vascular rarefaction following acute kidney injury. Am. J. Physiol. Renal Physiol. doi:10.1152/ajprenal.00546.2010.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  88. 88

    Okusa, M. D., Chertow, G. M. & Portilla, D. for the Acute Kidney Injury Advisory Group of the American Society of Nephrology. The nexus of acute kidney injury, chronic kidney disease, and World Kidney Day 2009. Clin. J. Am. Soc. Nephrol. 4, 520–522 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  89. 89

    Akcay, A., Nguyen, Q. & Edelstein, C. L. Mediators of inflammation in acute kidney injury. Mediators Inflamm. 2009, 137072 (2009).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  90. 90

    Gluba, A. et al. The role of Toll-like receptors in renal diseases. Nat. Rev. Nephrol. 6, 224–235 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  91. 91

    Wu, H. et al. TLR4 activation mediates kidney ischemia/reperfusion injury. J. Clin. Invest. 117, 2847–2859 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92

    Burne-Taney, M. J. & Rabb, H. The role of adhesion molecules and T cells in ischemic renal injury. Curr. Opin. Nephrol. Hypertens. 12, 85–90 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  93. 93

    Burne-Taney, M. J. et al. B cell deficiency confers protection from renal ischemia reperfusion injury. J. Immunol. 171, 3210–3215 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  94. 94

    de Vries, B. et al. Complement factor C5a mediates renal ischemia-reperfusion injury independent from neutrophils. J. Immunol. 170, 3883–3889 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95

    Riedemann, N. C., Guo, R. F. & Ward, P. A. The enigma of sepsis. J. Clin. Invest. 112, 460–467 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96

    Huber-Lang, M. S. et al. Protective effects of anti-C5a peptide antibodies in experimental sepsis. FASEB J. 15, 568–570 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  97. 97

    Thurman, J. M. et al. C3a is required for the production of CXC chemokines by tubular epithelial cells after renal ishemia/reperfusion. J. Immunol. 178, 1819–1828 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  98. 98

    Thurman, J. M. et al. Altered renal tubular expression of the complement inhibitor Crry permits complement activation after ischemia/reperfusion. J. Clin. Invest. 116, 357–368 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99

    Zheng, X. et al. Protection of renal ischemia injury using combination gene silencing of complement 3 and caspase 3 genes. Transplantation 82, 1781–1786 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  100. 100

    Kinsey, G. R., Li, L. & Okusa, M. D. Inflammation in acute kidney injury. Nephron Exp. Nephrol. 109, e102–e107 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101

    Tsuboi, N. et al. Roles of toll-like receptors in C-C chemokine production by renal tubular epithelial cells. J. Immunol. 169, 2026–2033 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102

    El-Achkar, T. M. et al. Sepsis induces changes in the expression and distribution of Toll-like receptor 4 in the rat kidney. Am. J. Physiol. Renal Physiol. 290, F1034–F1043 (2006).

    CAS  PubMed  Article  Google Scholar 

  103. 103

    El-Achkar, T. M., Plotkin, Z., Marcic, B. & Dagher, P. C. Sepsis induces an increase in thick ascending limb Cox-2 that is TLR4 dependent. Am. J. Physiol. Renal Physiol. 293, F1187–F1196 (2007).

    CAS  Article  Google Scholar 

  104. 104

    El-Achkar, T. M. et al. Tamm-Horsfall protein protects the kidney from ischemic injury by decreasing inflammation and altering TLR4 expression. Am. J. Physiol. Renal Physiol. 295, F534–F544 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. 105

    Rusai, K. et al. Toll-like receptors 2 and 4 in renal ischemia/reperfusion injury. Pediatr. Nephrol. 25, 853–860 (2010).

    PubMed  Article  Google Scholar 

  106. 106

    Day, Y. J., Huang, L., Ye, H., Linden, J. & Okusa, M. D. Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: role of macrophages. Am. J. Physiol. Renal Physiol. 288, F722–F731 (2005).

    CAS  PubMed  Article  Google Scholar 

  107. 107

    Jo, S. K., Bajwa, A., Awad, A. S., Lynch, K. R. & Okusa, M. D. Sphingosine-1-phosphate receptors: biology and therapeutic potential in kidney disease. Kidney Int. 73, 1220–1230 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. 108

    Bajwa, A. et al. Activation of sphingosine-1-phosphate 1 receptor in the proximal tubule protects against ischemia-reperfusion injury. J. Am. Soc. Nephrol. 21, 955–965 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. 109

    Dong, X. et al. Resident dendritic cells are the predominant TNF-secreting cell in early renal ischemia-reperfusion injury. Kidney Int. 71, 619–628 (2007).

    CAS  PubMed  Article  Google Scholar 

  110. 110

    Gandolfo, M. T. et al. Foxp3+ regulatory T cells participate in repair of ischemic acute kidney injury. Kidney Int. 76, 717–729 (2009).

    CAS  Article  Google Scholar 

  111. 111

    Kinsey, G. R., Huang, L., Vergis, A. L., Li, L. & Okusa, M. D. Regulatory T cells contribute to the protective effect of ischemic preconditioning in the kidney. Kidney Int. 77, 771–780 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112

    Kinsey, G. R. et al. Regulatory T cells suppress innate immunity in kidney ischemia-reperfusion injury. J. Am. Soc. Nephrol. 20, 1744–1753 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113

    Li, L. et al. NKT cell activation mediates neutrophil IFN-γ production and renal ischemia-reperfusion injury. J. Immunol. 178, 5899–5911 (2007).

    CAS  Article  Google Scholar 

  114. 114

    Gupta, A. et al. Distinct functions of activated protein C differentially attenuate acute kidney injury. J. Am. Soc. Nephrol. 20, 267–277 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115

    Liu, M. et al. Effect of T cells on vascular permeability in early ischemic acute kidney injury in mice. Microvasc. Res. 77, 340–347 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  116. 116

    Savransky, V. et al. Role of the T-cell receptor in kidney ischemia-reperfusion injury. Kidney Int. 69, 233–238 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  117. 117

    Kelly, K. J. Distant effects of experimental renal ischemia/reperfusion injury. J. Am. Soc. Nephrol. 14, 1549–1558 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  118. 118

    Kramer, A. A. et al. Renal ischemia/reperfusion leads to macrophage-mediated increase in pulmonary vascular permeability. Kidney Int. 55, 2362–2367 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  119. 119

    Rabb, H. et al. Acute renal failure leads to dysregulation of lung salt and water channels. Kidney Int. 63, 600–606 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  120. 120

    Liu, M. et al. Acute kidney injury leads to inflammation and functional changes in the brain. J. Am. Soc. Nephrol. 19, 1360–1370 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. 121

    Pratschke, J. et al. Influence of donor brain death on chronic rejection of renal transplants in rats. J. Am. Soc. Nephrol. 12, 2474–2481 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Pinsky, M. R. Pathophysiology of sepsis and multiple organ failure: pro- versus anti-inflammatory aspects. Contrib. Nephrol. 144, 31–43 (2004).

    PubMed  Article  PubMed Central  Google Scholar 

  123. 123

    Kelly, K. J. Stress response proteins and renal ischemia. Minerva Urol. Nefrol. 54, 81–91 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Paller, M. S., Weber, K. & Patten, M. Nitric oxide-mediated renal epithelial cell injury during hypoxia and reoxygenation. Ren. Fail. 20, 459–469 (1998).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  125. 125

    Hill-Kapturczak, N., Chang, S. H. & Agarwal, A. Heme oxygenase and the kidney. DNA Cell Biol. 21, 307–321 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  126. 126

    Inguaggiato, P. et al. Cellular overexpression of heme oxygenase-1 up-regulates p21 and confers resistance to apoptosis. Kidney Int. 60, 2181–2191 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  127. 127

    Kapturczak, M. H. et al. Heme oxygenase-1 modulates early inflammatory responses: evidence from the heme oxygenase-1-deficient mouse. Am. J. Pathol. 165, 1045–1053 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. 128

    Stromski, M. E. et al. Chemical and functional correlates of postischemic renal ATP levels. Proc. Natl Acad. Sci. USA 83, 6142–6145 (1986).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  129. 129

    Spiegel, D. M., Wilson, P. D. & Molitoris, B. A. Epithelial polarity following ischemia: a requirement for normal cell function. Am. J. Physiol. 256, F430–F436 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Ichimura, T. et al. Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells. J. Clin. Invest. 118, 1657–1668 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. 131

    Li, B. et al. The melanoma-associated transmembrane glycoprotein Gpnmb controls trafficking of cellular debris for degradation and is essential for tissue repair. FASEB J. 24, 4767–4781 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132

    Lin, S. L. et al. Macrophage Wnt7b is critical for kidney repair and regeneration. Proc. Natl Acad. Sci. USA 107, 4194–4199 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  133. 133

    Matsumoto, M. et al. Induction of renoprotective gene expression by cobalt ameliorates ischemic injury of the kidney in rats. J. Am. Soc. Nephrol. 14, 1825–1832 (2003).

    PubMed  PubMed Central  Article  Google Scholar 

  134. 134

    Vannay, A. et al. Divergence of renal vascular endothelial growth factor mRNA expression and protein level in post-ischaemic rat kidneys. Exp. Physiol. 89, 435–444 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  135. 135

    Ichimura, T. & Bonventre, J. V. in Acute Renal Failure 1st edn (eds Molitoris, B. A. & Finn, W. F.) 101–118 (W. B. Saunders, Philadelphia, 2001).

    Google Scholar 

  136. 136

    Gupta, S. et al. Isolation and characterization of kidney-derived stem cells. J. Am. Soc. Nephrol. 17, 3028–3040 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  137. 137

    Bussolati, B. et al. Isolation of renal progenitor cells from adult human kidney. Am. J. Pathol. 166, 545–555 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. 138

    De Broe, M. E. Tubular regeneration and the role of bone marrow cells: 'stem cell therapy'—a panacea? Nephrol. Dial. Transplant. 20, 2318–2320 (2005).

    PubMed  Article  PubMed Central  Google Scholar 

  139. 139

    Lange, C. et al. Administered mesenchymal stem cells enhance recovery from ischemia/reperfusion-induced acute renal failure in rats. Kidney Int. 68, 1613–1617 (2005).

    PubMed  PubMed Central  Article  Google Scholar 

  140. 140

    Tögel, F., Zhang, P., Hu, Z. & Westenfelder, C. VEGF is a mediator of the renoprotective effects of multipotent marrow stromal cells in acute kidney injury. J. Cell. Mol. Med. 13, 2109–2114 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  141. 141

    Humphreys, B. D. & Bonventre, J. V. Mesenchymal stem cells in acute kidney injury. Annu. Rev. Med. 59, 311–325 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  142. 142

    Humphreys, B. D. et al. Intrinsic epithelial cells repair the kidney after injury. Cell Stem Cell 2, 284–291 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  143. 143

    Cantley, L. G. Adult stem cells in the repair of the injured renal tubule. Nat. Clin. Pract. Nephrol. 1, 22–32 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  144. 144

    Reinders, M. E., Rabelink, T. J. & Briscoe, D. M. Angiogenesis and endothelial cell repair in renal disease and allograft rejection. J. Am. Soc. Nephrol. 17, 932–942 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  145. 145

    Tongers, J. & Losordo, D. W. Frontiers in nephrology: the evolving therapeutic applications of endothelial progenitor cells. J. Am. Soc. Nephrol. 18, 2843–2852 (2007).

    PubMed  Article  PubMed Central  Google Scholar 

  146. 146

    Becherucci, F. et al. The role of endothelial progenitor cells in acute kidney injury. Blood Purif. 27, 261–270 (2009).

    PubMed  Article  PubMed Central  Google Scholar 

  147. 147

    Li, B. et al. Mobilized human hematopoietic stem/progenitor cells promote kidney repair after ischemia/reperfusion injury. Circulation 121, 2211–2220 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

A. A. Sharfuddin and B. A. Molitoris contributed equally to researching data for the article, discussion of the content, writing and reviewing/editing of the manuscript before submission.

Corresponding author

Correspondence to Bruce A. Molitoris.

Ethics declarations

Competing interests

B. A. Molitoris has worked as a consultant for and received grant/research support from Eli Lilly and Quark Pharmaceuticals. He is also a patent holder/applicant with Eli Lilly. A. A. Sharfuddin declares no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sharfuddin, A., Molitoris, B. Pathophysiology of ischemic acute kidney injury. Nat Rev Nephrol 7, 189–200 (2011). https://doi.org/10.1038/nrneph.2011.16

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing