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.

  • Review Article
  • Published:

Kidney physiology and susceptibility to acute kidney injury: implications for renoprotection

Nature Reviews Nephrology volume 17, pages 335–349 (2021)Cite this article

Subjects

Abstract

Kidney damage varies according to the primary insult. Different aetiologies of acute kidney injury (AKI), including kidney ischaemia, exposure to nephrotoxins, dehydration or sepsis, are associated with characteristic patterns of damage and changes in gene expression, which can provide insight into the mechanisms that lead to persistent structural and functional damage. Early morphological alterations are driven by a delicate balance between energy demand and oxygen supply, which varies considerably in different regions of the kidney. The functional heterogeneity of the various nephron segments is reflected in their use of different metabolic pathways. AKI is often linked to defects in kidney oxygen supply, and some nephron segments might not be able to shift to anaerobic metabolism under low oxygen conditions or might have remarkably low basal oxygen levels, which enhances their vulnerability to damage. Here, we discuss why specific kidney regions are at particular risk of injury and how this information might help to delineate novel routes for mitigating injury and avoiding permanent damage. We suggest that the physiological heterogeneity of the kidney should be taken into account when exploring novel renoprotective strategies, such as improvement of kidney tissue oxygenation, stimulation of hypoxia signalling pathways and modulation of cellular energy metabolism.

Key points

  • Rather than a disease entity, acute kidney injury (AKI) comprises a heterogeneous group of conditions that lead to a rapid decline in excretory kidney function.

  • Distinct AKI aetiologies, including sepsis, major surgery, hypovolaemia and inflammatory processes within the kidney, are associated with complex pathophysiological processes that are characterized by distinct changes in gene expression patterns.

  • The unique vascularization of the kidney is associated with regional heterogeneity of oxygen supply, which creates areas at high risk of hypoxia.

  • Tubular segments differ in their ability to use substrates for ATP generation and in their energy demand, which creates further variability in their susceptibility to injury.

  • Emerging renoprotective strategies address these unique susceptibilities and distinct aetiologies to improve oxygen supply, prevent mitochondrial dysfunction or regulate metabolic pathways and oxygen consumption.

  • Over the next few years, pathophysiology-guided strategies are expected to translate into improvements in AKI clinical prevention, diagnosis and therapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Metabolic pathways across nephron segments.
Fig. 2: Susceptibility of different nephron segments to various AKI aetiologies.
Fig. 3: Kidney injury pathways as potential targets for renoprotection.

Similar content being viewed by others

References

  1. Susantitaphong, P. et al. World incidence of AKI: a meta-analysis. Clin. J. Am. Soc. Nephrol. 8, 1482–1493 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Ronco, C., Bellomo, R. & Kellum, J. A. Acute kidney injury. Lancet 394, 1949–1964 (2019).

    Article  CAS  PubMed  Google Scholar 

  3. Hoste, E. A. et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 41, 1411–1423 (2015).

    Article  PubMed  Google Scholar 

  4. Mehta, R. L., Pascual, M. T., Gruta, C. G., Zhuang, S. & Chertow, G. M. Refining predictive models in critically ill patients with acute renal failure. J. Am. Soc. Nephrol. 13, 1350–1357 (2002).

    Article  PubMed  Google Scholar 

  5. Bell, M. et al. Cystatin C is correlated with mortality in patients with and without acute kidney injury. Nephrol. Dialysis Transpl. 24, 3096–3102 (2009).

    Article  CAS  Google Scholar 

  6. Saito, S., Uchino, S., Takinami, M., Uezono, S. & Bellomo, R. Postoperative blood pressure deficit and acute kidney injury progression in vasopressor-dependent cardiovascular surgery patients. Crit. Care 20, 74 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Chen, C. Y., Zhou, Y., Wang, P., Qi, E. Y. & Gu, W. J. Elevated central venous pressure is associated with increased mortality and acute kidney injury in critically ill patients: a meta-analysis. Crit. Care 24, 80 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Uthoff, H. et al. Central venous pressure and impaired renal function in patients with acute heart failure. Eur. J. Heart Fail. 13, 432–439 (2011).

    Article  PubMed  Google Scholar 

  9. Liu, J. et al. Molecular characterization of the transition from acute to chronic kidney injury following ischemia/reperfusion. JCI Insight 2, e94716 (2017).

    Article  PubMed Central  Google Scholar 

  10. Miyazaki, T. et al. Cell-specific image-guided transcriptomics identifies complex injuries caused by ischemic acute kidney injury in mice. Commun. Biol. 2, 326 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Zhang, D. et al. Renal tubules transcriptome reveals metabolic maladaption during the progression of ischemia-induced acute kidney injury. Biochem. Biophys. Res. Commun. 505, 432–438 (2018).

    Article  CAS  PubMed  Google Scholar 

  12. Xu, K. et al. Unique transcriptional programs identify subtypes of AKI. J. Am. Soc. Nephrol. 28, 1729–1740 (2017).

    Article  CAS  PubMed  Google Scholar 

  13. Mar, D. et al. Heterogeneity of epigenetic changes at ischemia/reperfusion- and endotoxin-induced acute kidney injury genes. Kidney Int. 88, 734–744 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Brezis, M. & Rosen, S. Hypoxia of the renal medulla–its implications for disease. N. Engl. J. Med. 332, 647–655 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Zhang, B. et al. Application of noninvasive functional imaging to monitor the progressive changes in kidney diffusion and perfusion in contrast-induced acute kidney injury rats at 3.0 T. Abdom. Radiol. 43, 655–662 (2018).

    Article  Google Scholar 

  16. Friederich-Persson, M., Persson, P., Hansell, P. & Palm, F. Deletion of Uncoupling Protein-2 reduces renal mitochondrial leak respiration, intrarenal hypoxia and proteinuria in a mouse model of type 1 diabetes. Acta Physiol. 223, e13058 (2018).

    Article  CAS  Google Scholar 

  17. Harrois, A., Grillot, N., Figueiredo, S. & Duranteau, J. Acute kidney injury is associated with a decrease in cortical renal perfusion during septic shock. Crit. Care 22, 161 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Lyu, Z. et al. PPARγ maintains the metabolic heterogeneity and homeostasis of renal tubules. EBioMedicine 38, 178–190 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hirakawa, Y. et al. Intravital phosphorescence lifetime imaging of the renal cortex accurately measures renal hypoxia. Kidney Int. 93, 1483–1489 (2018).

    Article  PubMed  Google Scholar 

  20. Cantow, K., Flemming, B., Ladwig-Wiegard, M., Persson, P. B. & Seeliger, E. Low dose nitrite improves reoxygenation following renal ischemia in rats. Sci. Rep. 7, 14597 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Evans, R. G. & Ow, C. P. C. Heterogeneity of renal cortical oxygenation: seeing is believing. Kidney Int. 93, 1278–1280 (2018).

    Article  PubMed  Google Scholar 

  22. Ngo, J. P. et al. Diffusive shunting of gases and other molecules in the renal vasculature: physiological and evolutionary significance. Am. J. Physiol. Regul. Integr. Comp. Physiol. 311, R797–R810 (2016).

    Article  PubMed  Google Scholar 

  23. Edwards, A., Palm, F. & Layton, A. T. A model of mitochondrial O2 consumption and ATP generation in rat proximal tubule cells. Am. J. Physiol. Renal Physiol. 318, F248–F259 (2020).

    Article  CAS  PubMed  Google Scholar 

  24. Schiffer, T. A., Gustafsson, H. & Palm, F. Kidney outer medulla mitochondria are more efficient compared with cortex mitochondria as a strategy to sustain ATP production in a suboptimal environment. Am. J. Physiol. Renal Physiol. 315, F677–F681 (2018).

    Article  CAS  PubMed  Google Scholar 

  25. Chen, J., Layton, A. T. & Edwards, A. A mathematical model of O2 transport in the rat outer medulla. I. Model formulation and baseline results. Am. J. Physiol. Renal Physiol. 297, F517–F536 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kriz, W. & Lever, A. F. Renal countercurrent mechanisms: structure and function. Am. Heart J. 78, 101–118 (1969).

    Article  CAS  PubMed  Google Scholar 

  27. Olof, P., Hellberg, A., Källskog, O. & Wolgast, M. Red cell trapping and postischemic renal blood flow. Differences between the cortex, outer and inner medulla. Kidney Int. 40, 625–631 (1991).

    Article  CAS  PubMed  Google Scholar 

  28. Sendeski, M. M. et al. Functional characterization of isolated, perfused outermedullary descending human vasa recta. Acta Physiol. 208, 50–56 (2013).

    Article  CAS  Google Scholar 

  29. Crislip, G. R., O’Connor, P. M., Wei, Q. & Sullivan, J. C. Vasa recta pericyte density is negatively associated with vascular congestion in the renal medulla following ischemia reperfusion in rats. Am. J. Physiol. Renal Physiol. 313, F1097–F1105 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Lankadeva, Y. R. et al. Strategies that improve renal medullary oxygenation during experimental cardiopulmonary bypass may mitigate postoperative acute kidney injury. Kidney Int. 95, 1338–1346 (2019).

    Article  PubMed  Google Scholar 

  31. Lankadeva, Y. R. et al. Effects of fluid bolus therapy on renal perfusion, oxygenation, and function in early experimental septic kidney injury. Crit. Care Med. 47, e36–e43 (2019).

    Article  PubMed  Google Scholar 

  32. Heyman, S. N. et al. Near-drowning: new perspectives for human hypoxic acute kidney injury. Nephrol. Dial. Transpl. 35, 206–212 (2020).

    CAS  Google Scholar 

  33. Lankadeva, Y. R., Kosaka, J., Evans, R. G., Bellomo, R. & May, C. N. Urinary Oxygenation as a surrogate measure of medullary oxygenation during angiotensin II therapy in septic acute kidney injury. Crit. Care Med. 46, e41–e48 (2018).

    Article  PubMed  Google Scholar 

  34. Ngo, J. P. et al. Factors that confound the prediction of renal medullary oxygenation and risk of acute kidney injury from measurement of bladder urine oxygen tension. Acta Physiol. 227, e13294 (2019).

    Article  CAS  Google Scholar 

  35. Lee, C. J., Gardiner, B. S., Evans, R. G. & Smith, D. W. Analysis of the critical determinants of renal medullary oxygenation. Am. J. Physiol. Renal Physiol. 317, F1483–F1502 (2019).

    Article  CAS  PubMed  Google Scholar 

  36. Wang, Z. et al. Specific metabolic rates of major organs and tissues across adulthood: evaluation by mechanistic model of resting energy expenditure. Am. J. Clin. Nutr. 92, 1369–1377 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. O’Connor, P. M. Renal oxygen delivery: matching delivery to metabolic demand. Clin. Exp. Pharmacol. Physiol. 33, 961–967 (2006).

    Article  PubMed  CAS  Google Scholar 

  38. Darawshi, S. et al. Biomarker evidence for distal tubular damage but cortical sparing in hospitalized diabetic patients with acute kidney injury (AKI) while on SGLT2 inhibitors. Ren. Fail. 42, 836–844 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Curthoys, N. P. & Moe, O. W. Proximal tubule function and response to acidosis. Clin. J. Am. Soc. Nephrol. 9, 1627–1638 (2014).

    Article  CAS  PubMed  Google Scholar 

  40. Zager, R. A., Johnson, A. C. & Becker, K. Renal cortical pyruvate depletion during AKI. J. Am. Soc. Nephrol. 25, 998–1012 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Jang, C. et al. Metabolite exchange between mammalian organs quantified in pigs. Cell Metab. 30, 594–606.e3 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rabelink, T. J. & Giera, M. New insights into energy and protein homeostasis by the kidney. Nat. Rev. Nephrol. 15, 596–598 (2019).

    Article  PubMed  Google Scholar 

  43. Zacchia, M., Tian, X., Zona, E., Alpern, R. J. & Preisig, P. A. Acid stimulation of the citrate transporter NaDC-1 requires Pyk2 and ERK1/2 signaling pathways. J. Am. Soc. Nephrol. 29, 1720–1730 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Uchida, S. & Endou, H. Substrate specificity to maintain cellular ATP along the mouse nephron. Am. J. Physiol. 255, F977–983 (1988).

    CAS  PubMed  Google Scholar 

  45. Bagnasco, S., Good, D., Balaban, R. & Burg, M. Lactate production in isolated segments of the rat nephron. Am. J. Physiol. 248, F522–F526 (1985).

    CAS  PubMed  Google Scholar 

  46. Chen, Y., Fry, B. C. & Layton, A. T. Modeling glucose metabolism and lactate production in the kidney. Math. Biosci. 289, 116–129 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Heyman, S. N., Brezis, M., Epstein, F. H., Spokes, K. & Rosen, S. Effect of glycine and hypertrophy on renal outer medullary hypoxic injury in ischemia reflow and contrast nephropathy. Am. J. Kidney Dis. 19, 578–586 (1992).

    Article  CAS  PubMed  Google Scholar 

  48. Heyman, S. N., Brezis, M., Greenfeld, Z. & Rosen, S. Protective role of furosemide and saline in radiocontrast-induced acute renal failure in the rat. Am. J. Kidney Dis. 14, 377–385 (1989).

    Article  CAS  PubMed  Google Scholar 

  49. Lan, R. et al. Mitochondrial pathology and glycolytic shift during proximal tubule atrophy after ischemic AKI. J. Am. Soc. Nephrol. 27, 3356–3367 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Smith, J. A., Stallons, L. J. & Schnellmann, R. G. Renal cortical hexokinase and pentose phosphate pathway activation through the EGFR/Akt signaling pathway in endotoxin-induced acute kidney injury. Am. J. Physiol. Renal Physiol. 307, F435–F444 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gugliucci, A. Formation of fructose-mediated advanced glycation end products and their roles in metabolic and inflammatory diseases. Adv. Nutr. 8, 54–62 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Andres-Hernando, A. et al. Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice. Nat. Commun. 8, 14181 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ejaz, A. A. et al. The role of uric acid in acute kidney injury. Nephron 142, 275–283 (2019).

    Article  CAS  PubMed  Google Scholar 

  54. Rabelink, T. J. & Carmeliet, P. Renal metabolism in 2017: glycolytic adaptation and progression of kidney disease. Nat. Rev. Nephrol. 14, 75–76 (2018).

    Article  PubMed  Google Scholar 

  55. Gonzalez, A., Hall, M. N., Lin, S. C. & Hardie, D. G. AMPK and TOR: the yin and yang of cellular nutrient sensing and growth control. Cell Metab. 31, 472–492 (2020).

    Article  CAS  PubMed  Google Scholar 

  56. Fantus, D., Rogers, N. M., Grahammer, F., Huber, T. B. & Thomson, A. W. Roles of mTOR complexes in the kidney: implications for renal disease and transplantation. Nat. Rev. Nephrol. 12, 587–609 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hallows, K. R., Mount, P. F., Pastor-Soler, N. M. & Power, D. A. Role of the energy sensor AMP-activated protein kinase in renal physiology and disease. Am. J. Physiol. Renal Physiol. 298, F1067–F1077 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Cunningham, J. T. et al. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 450, 736–740 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Mihaylova, M. M. & Shaw, R. J. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat. Cell Biol. 13, 1016–1023 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mount, P. F. et al. Acute renal ischemia rapidly activates the energy sensor AMPK but does not increase phosphorylation of eNOS-Ser1177. Am. J. Physiol. Renal Physiol. 289, F1103–F1115 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Jager, S., Handschin, C., St-Pierre, J. & Spiegelman, B. M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc. Natl Acad. Sci. USA 104, 12017–12022 (2007).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  62. Funk, J. A. & Schnellmann, R. G. Persistent disruption of mitochondrial homeostasis after acute kidney injury. Am. J. Physiol. Renal Physiol. 302, F853–F864 (2012).

    Article  PubMed  Google Scholar 

  63. Tran, M. et al. PGC-1alpha promotes recovery after acute kidney injury during systemic inflammation in mice. J. Clin. Invest. 121, 4003–4014 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Safirstein, R. L. Acute renal failure: from renal physiology to the renal transcriptome. Kidney Int. 66 (Suppl. 91), S62–S66 (2004).

    Article  Google Scholar 

  65. Arany, I., Megyesi, J. K., Kaneto, H., Tanaka, S. & Safirstein, R. L. Activation of ERK or inhibition of JNK ameliorates H(2)O(2) cytotoxicity in mouse renal proximal tubule cells. Kidney Int. 65, 1231–1239 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. di Mari, J. F., Davis, R. & Safirstein, R. L. MAPK activation determines renal epithelial cell survival during oxidative injury. Am. J. Physiol. 277, F195–F203 (1999).

    PubMed  Google Scholar 

  67. Heyman, S. N., Rosenberger, C. & Rosen, S. Experimental ischemia-reperfusion: biases and myths-the proximal vs. distal hypoxic tubular injury debate revisited. Kidney Int. 77, 9–16 (2010).

    Article  PubMed  Google Scholar 

  68. Mathia, S. et al. A dual role of miR-22 in rhabdomyolysis-induced acute kidney injury. Acta Physiol. 224, e13102 (2018).

    Article  CAS  Google Scholar 

  69. Fähling, M., Seeliger, E., Patzak, A. & Persson, P. B. Understanding and preventing contrast-induced acute kidney injury. Nat. Rev. Nephrol. 13, 169–180 (2017).

    Article  PubMed  Google Scholar 

  70. Desanti De Oliveira, B. et al. Molecular nephrology: types of acute tubular injury. Nat. Rev. Nephrol. 15, 599–612 (2019).

    Article  CAS  PubMed  Google Scholar 

  71. Heyman, S. N., Reichman, J. & Brezis, M. Pathophysiology of radiocontrast nephropathy: a role for medullary hypoxia. Invest. Radiol. 34, 685–691 (1999).

    Article  CAS  PubMed  Google Scholar 

  72. Heyman, S. N., Rosen, S., Fuchs, S., Epstein, F. H. & Brezis, M. Myoglobinuric acute renal failure in the rat: a role for medullary hypoperfusion, hypoxia, and tubular obstruction. J. Am. Soc. Nephrol. 7, 1066–1074 (1996).

    Article  CAS  PubMed  Google Scholar 

  73. Harvig, B., Engberg, A. & Ericsson, J. L. Effects of cold ischemia on the preserved and transplanted rat kidney. Structural changes of the loop of Henle, distal tubule and collecting duct. Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 34, 173–192 (1980).

    Article  CAS  PubMed  Google Scholar 

  74. Goldfarb, M. et al. Acute-on-chronic renal failure in the rat: functional compensation and hypoxia tolerance. Am. J. Nephrol. 26, 22–33 (2006).

    Article  PubMed  Google Scholar 

  75. Rosenberger, C. et al. Acute kidney injury in the diabetic rat: studies in the isolated perfused and intact kidney. Am. J. Nephrol. 28, 831–839 (2008).

    Article  PubMed  Google Scholar 

  76. Rosenberger, C., Rosen, S. & Heyman, S. N. Renal parenchymal oxygenation and hypoxia adaptation in acute kidney injury. Clin. Exp. Pharmacol. Physiol. 33, 980–988 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Schmitz, C. et al. Megalin deficiency offers protection from renal aminoglycoside accumulation. J. Biol. Chem. 277, 618–622 (2002).

    Article  CAS  PubMed  Google Scholar 

  78. Servais, H. et al. Renal cell apoptosis induced by nephrotoxic drugs: cellular and molecular mechanisms and potential approaches to modulation. Apoptosis 13, 11–32 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Prozialeck, W. C. & Edwards, J. R. Mechanisms of cadmium-induced proximal tubule injury: new insights with implications for biomonitoring and therapeutic interventions. J. Pharmacol. Exp. Ther. 343, 2–12 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Gburek, J. et al. Renal uptake of myoglobin is mediated by the endocytic receptors megalin and cubilin. Am. J. Physiol. Renal Physiol. 285, F451–F458 (2003).

    Article  PubMed  Google Scholar 

  81. Zhou, J. et al. Myoglobin-induced apoptosis: two pathways related to endoplasmic reticulum stress. Ther. Apher. Dial. 16, 272–280 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Moore, K. P. et al. A causative role for redox cycling of myoglobin and its inhibition by alkalinization in the pathogenesis and treatment of rhabdomyolysis-induced renal failure. J. Biol. Chem. 273, 31731–31737 (1998).

    Article  CAS  PubMed  Google Scholar 

  83. 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).

    Article  CAS  PubMed  Google Scholar 

  84. Lelubre, C. & Vincent, J. L. Mechanisms and treatment of organ failure in sepsis. Nat. Rev. Nephrol. 14, 417–427 (2018).

    Article  PubMed  Google Scholar 

  85. Yuen, P. S., Jo, S. K., Holly, M. K., Hu, X. & Star, R. A. Ischemic and nephrotoxic acute renal failure are distinguished by their broad transcriptomic responses. Physiol. Genomics 25, 375–386 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Evans, R. G. et al. Haemodynamic influences on kidney oxygenation: clinical implications of integrative. Physiol. Clin. Exp. Pharmacol. Physiol. 40, 106–122 (2013).

    Article  CAS  PubMed  Google Scholar 

  87. Ferenbach, D. A. & Bonventre, J. V. Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat. Rev. Nephrol. 11, 264–276 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bhargava, P. & Schnellmann, R. G. Mitochondrial energetics in the kidney. Nat. Rev. Nephrol. 13, 629–646 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Anders, H. J. Necroptosis in acute kidney injury. Nephron 139, 342–348 (2018).

    Article  CAS  PubMed  Google Scholar 

  90. Wang, Y., Cai, J., Tang, C. & Dong, Z. Mitophagy in acute kidney injury and kidney repair. Cells 9, 338 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  91. Rodger, C. E., McWilliams, T. G. & Ganley, I. G. Mammalian mitophagy — from in vitro molecules to in vivo models. FEBS J. 285, 1185–1202 (2018).

    Article  CAS  PubMed  Google Scholar 

  92. Hall, A. M., Unwin, R. J., Parker, N. & Duchen, M. R. Multiphoton imaging reveals differences in mitochondrial function between nephron segments. J. Am. Soc. Nephrol. 20, 1293–1302 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Darmon, M. et al. Acute respiratory distress syndrome and risk of AKI among critically ill patients. Clin. J. Am. Soc. Nephrol. 9, 1347–1353 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Passmore, M. R. et al. Evidence of altered haemostasis in an ovine model of venovenous extracorporeal membrane oxygenation support. Crit. Care 21, 191 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Upadhyaya, V. D. et al. Management of acute kidney injury in the setting of acute respiratory distress syndrome: review focusing on ventilation and fluid management strategies. J. Clin. Med. Res. 12, 1–5 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Yang, Y., Ma, J. & Zhao, L. High central venous pressure is associated with acute kidney injury and mortality in patients underwent cardiopulmonary bypass surgery. J. Crit. Care 48, 211–215 (2018).

    Article  PubMed  Google Scholar 

  97. McCoy, I. E., Montez-Rath, M. E., Chertow, G. M. & Chang, T. I. Central venous pressure and the risk of diuretic-associated acute kidney injury in patients after cardiac surgery. Am. Heart J. 221, 67–73 (2020).

    Article  PubMed  Google Scholar 

  98. Abu-Saleh, N. et al. Increased intra-abdominal pressure induces acute kidney injury in an experimental model of congestive heart failure. J. Card. Fail. 25, 468–478 (2019).

    Article  PubMed  Google Scholar 

  99. Juul, T., Palm, F., Nielsen, P. M., Bertelsen, L. B. & Laustsen, C. Ex vivo hyperpolarized MR spectroscopy on isolated renal tubular cells: a novel technique for cell energy phenotyping. Magn. Reson. Med. 78, 457–461 (2017).

    Article  CAS  PubMed  Google Scholar 

  100. Lankadeva, Y. R. et al. Dexmedetomidine reduces norepinephrine requirements and preserves renal oxygenation and function in ovine septic acute kidney injury. Kidney Int. 96, 1150–1161 (2019).

    Article  CAS  PubMed  Google Scholar 

  101. Osawa, E. A. et al. Effect of furosemide on urinary oxygenation in patients with septic shock. Blood Purif. 48, 336–345 (2019).

    Article  CAS  PubMed  Google Scholar 

  102. Sendeski, M., Patzak, A. & Persson, P. B. Constriction of the vasa recta, the vessels supplying the area at risk for acute kidney injury, by four different iodinated contrast media, evaluating ionic, nonionic, monomeric and dimeric agents. Invest. Radiol. 45, 453–457 (2010).

    Article  PubMed  Google Scholar 

  103. Goto, Y. et al. Influence of contrast media on renal function and outcomes in patients with sepsis-associated acute kidney injury: a propensity-matched cohort study. Crit. Care 23, 249 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Gorelik, Y., Bloch-Isenberg, N., Yaseen, H., Heyman, S. N. & Khamaisi, M. Acute kidney injury after radiocontrast-enhanced computerized tomography in hospitalized patients with advanced renal failure: a propensity-score-matching analysis. Invest. Radiol. 55, 677–687 (2020).

    Article  CAS  PubMed  Google Scholar 

  105. Su, X. et al. Comparative effectiveness of 12 treatment strategies for preventing contrast-induced acute kidney injury: a systematic review and Bayesian network meta-analysis. Am. J. Kidney Dis. 69, 69–77 (2017).

    Article  CAS  PubMed  Google Scholar 

  106. John, S., Schneider, M. P., Delles, C., Jacobi, J. & Schmieder, R. E. Lipid-independent effects of statins on endothelial function and bioavailability of nitric oxide in hypercholesterolemic patients. Am. Heart J. 149, 473 (2005).

    Article  PubMed  CAS  Google Scholar 

  107. Ridker, P. M. et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N. Engl. J. Med. 344, 1959–1965 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. Wagner, A. H., Köhler, T., Rückschloss, U., Just, I. & Hecker, M. Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler. Thromb. Vasc. Biol. 20, 61–69 (2000).

    Article  CAS  PubMed  Google Scholar 

  109. Quintavalle, C. et al. Impact of a high loading dose of atorvastatin on contrast-induced acute kidney injury. Circulation 126, 3008–3016 (2012).

    Article  CAS  PubMed  Google Scholar 

  110. Fishbane, S. N-acetylcysteine in the prevention of contrast-induced nephropathy. Clin. J. Am. Soc. Nephrol. 3, 281–287 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. Mason, J., Joeris, B., Welsch, J. & Kriz, W. Vascular congestion in ischemic renal failure: the role of cell swelling. Miner. Electrolyte Metab. 15, 114–124 (1989).

    PubMed  Google Scholar 

  112. Kapitsinou, P. P. & Haase, V. H. Molecular mechanisms of ischemic preconditioning in the kidney. Am. J. Physiol. Renal Physiol. 309, F821–834 (2015).

    Article  CAS  Google Scholar 

  113. Johnsen, M. et al. The integrated RNA landscape of renal preconditioning against ischemia-reperfusion injury. J. Am. Soc. Nephrol. 31, 716–730 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Veighey, K. V. et al. Early remote ischaemic preconditioning leads to sustained improvement in allograft function after live donor kidney transplantation: long-term outcomes in the REnal Protection Against Ischaemia-Reperfusion in transplantation (REPAIR) randomised trial. Br. J. Anaesth. 123, 584–591 (2019).

    Article  PubMed  Google Scholar 

  115. Roubille, F. et al. Effects of remote ischemic conditioning on kidney injury in at-risk patients undergoing elective coronary angiography (PREPARE study): a multicenter, randomized clinical trial. Sci. Rep. 9, 11985 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Zwaag, J. et al. Remote ischaemic preconditioning does not modulate the systemic inflammatory response or renal tubular stress biomarkers after endotoxaemia in healthy human volunteers: a single-centre, mechanistic, randomised controlled trial. Br. J. Anaesth. 123, 177–185 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Schödel, J. & Ratcliffe, P. J. Mechanisms of hypoxia signalling: new implications for nephrology. Nat. Rev. Nephrol. 15, 641–659 (2019).

    Article  PubMed  Google Scholar 

  118. Eckardt, K. U. et al. Role of hypoxia in the pathogenesis of renal disease. Kidney Int. Suppl. (99), S46–S51 (2005).

  119. Rosenberger, C. et al. Up-regulation of HIF in experimental acute renal failure: evidence for a protective transcriptional response to hypoxia. Kidney Int. 67, 531–542 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. He, K. et al. Lipopolysaccharide-induced cross-tolerance against renal ischemia-reperfusion injury is mediated by hypoxia-inducible factor-2α-regulated nitric oxide production. Kidney Int. 85, 276–288 (2014).

    Article  CAS  PubMed  Google Scholar 

  121. Stoyanoff, T. R. et al. Erythropoietin attenuates LPS-induced microvascular damage in a murine model of septic acute kidney injury. Biomed. Pharmacother. 107, 1046–1055 (2018).

    Article  CAS  PubMed  Google Scholar 

  122. Schaalan, M. F. & Mohamed, W. A. Determinants of hepcidin levels in sepsis-associated acute kidney injury: Impact on pAKT/PTEN pathways? J. Immunotoxicol. 13, 751–757 (2016).

    Article  CAS  PubMed  Google Scholar 

  123. Rosenberger, C. et al. Expression of hypoxia-inducible factor-1alpha and -2alpha in hypoxic and ischemic rat kidneys. J. Am. Soc. Nephrol. 13, 1721–1732 (2002).

    Article  CAS  PubMed  Google Scholar 

  124. Schley, G. et al. Hypoxia-inducible transcription factors stabilization in the thick ascending limb protects against ischemic acute kidney injury. J. Am. Soc. Nephrol. 22, 2004–2015 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. 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).

    Article  PubMed  Google Scholar 

  126. Hill, P. et al. Inhibition of hypoxia inducible factor hydroxylases protects against renal ischemia-reperfusion injury. J. Am. Soc. Nephrol. 19, 39–46 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kapitsinou, P. P. et al. Endothelial HIF-2 mediates protection and recovery from ischemic kidney injury. J. Clin. Invest. 124, 2396–2409 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Bernhardt, W. M. et al. Preconditional activation of hypoxia-inducible factors ameliorates ischemic acute renal failure. J. Am. Soc. Nephrol. 17, 1970–1978 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Bernhardt, W. M. et al. Donor treatment with a PHD-inhibitor activating HIFs prevents graft injury and prolongs survival in an allogenic kidney transplant model. Proc. Natl Acad. Sci. USA 106, 21276–21281 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Weidemann, A. et al. HIF activation protects from acute kidney injury. J. Am. Soc. Nephrol. 19, 486–494 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ito, M. et al. Prolyl hydroxylase inhibition protects the kidneys from ischemia via upregulation of glycogen storage. Kidney Int. 97, 687–701 (2020).

    Article  CAS  PubMed  Google Scholar 

  132. Yang, Y. et al. Hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) protects against cisplatin-induced acute kidney injury. Clin. Sci. 132, 825–838 (2018).

    Article  CAS  Google Scholar 

  133. Schindler, K. et al. Preconditioned suppression of prolyl-hydroxylases attenuates renal injury but increases mortality in septic murine models. Nephrol. Dialysis Transpl. 31, 1100–1113 (2016).

    Article  CAS  Google Scholar 

  134. Wang, Z. et al. The protective effect of prolyl-hydroxylase inhibition against renal ischaemia requires application prior to ischaemia but is superior to EPO treatment. Nephrol. Dial. Transpl. 27, 929–936 (2012).

    Article  CAS  Google Scholar 

  135. Shu, S. et al. Hypoxia and hypoxia-inducible factors in kidney injury and repair. Cells 26, 860–867 (2019).

    Google Scholar 

  136. Dhillon, S. Roxadustat: first global approval. Drugs 79, 563–572 (2019).

    Article  CAS  PubMed  Google Scholar 

  137. Tsubakihara, Y. et al. A 24-week anemia correction study of daprodustat in Japanese dialysis patients. Ther. Apher. Dial. 24, 108–114 (2020).

    Article  CAS  PubMed  Google Scholar 

  138. Markham, A. Vadadustat: first approval. Drugs 80, 1365–1371 (2020).

    Article  PubMed  CAS  Google Scholar 

  139. Tran, M. T. et al. PGC1alpha drives NAD biosynthesis linking oxidative metabolism to renal protection. Nature 531, 528–532 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Poyan Mehr, A. et al. De novo NAD+ biosynthetic impairment in acute kidney injury in humans. Nat. Med. 24, 1351–1359 (2018).

    Article  CAS  PubMed  Google Scholar 

  141. Kong, X. et al. Sirtuin 3, a new target of PGC-1alpha, plays an important role in the suppression of ROS and mitochondrial biogenesis. PLoS ONE 5, e11707 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Guan, Y. et al. Nicotinamide mononucleotide, an NAD+ precursor, rescues age-associated susceptibility to AKI in a sirtuin 1-dependent manner. J. Am. Soc. Nephrol. 28, 2337–2352 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Morigi, M. et al. Sirtuin 3-dependent mitochondrial dynamic improvements protect against acute kidney injury. J. Clin. Invest. 125, 715–726 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Lempiainen, J., Finckenberg, P., Levijoki, J. & Mervaala, E. AMPK activator AICAR ameliorates ischaemia reperfusion injury in the rat kidney. Br. J. Pharmacol. 166, 1905–1915 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Liu, S., Soong, Y., Seshan, S. V. & Szeto, H. H. Novel cardiolipin therapeutic protects endothelial mitochondria during renal ischemia and mitigates microvascular rarefaction, inflammation, and fibrosis. Am. J. Physiol. Renal Physiol. 306, F970–F980 (2014).

    Article  CAS  PubMed  Google Scholar 

  146. Galluzzi, L. et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 25, 486–541 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Linkermann, A. et al. Two independent pathways of regulated necrosis mediate ischemia-reperfusion injury. Proc. Natl Acad. Sci. USA 110, 12024–12029 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Mulay, S. R. et al. Mitochondria permeability transition versus necroptosis in oxalate-induced AKI. J. Am. Soc. Nephrol. 30, 1857–1869 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Fähling, M. et al. Cyclosporin a induces renal episodic hypoxia. Acta Physiol. 219, 625–639 (2017).

    Article  CAS  Google Scholar 

  150. Chung, K. W. et al. Mitochondrial damage and activation of the STING pathway lead to renal inflammation and fibrosis. Cell Metab. 30, 784–799.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Maekawa, H. et al. Mitochondrial damage causes inflammation via cGAS-STING signaling in acute kidney injury. Cell Rep. 29, 1261–1273.e6 (2019).

    Article  CAS  PubMed  Google Scholar 

  152. Ishikawa, H., Ma, Z. & Barber, G. N. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788–792 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Ishikawa, H. & Barber, G. N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455, 674–678 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Ablasser, A. et al. cGAS produces a 2’-5’-linked cyclic dinucleotide second messenger that activates STING. Nature 498, 380–384 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Luft, F. C. Biomarkers and predicting acute kidney injury. Acta Physiol. 231, e13479 (2020).

    Google Scholar 

  156. Bowers, S. L. K. et al. Inhibition of fibronectin polymerization alleviates kidney injury due to ischemia-reperfusion. Am. J. Physiol. Renal Physiol. 316, F1293–F1298 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Devarajan, P. The current state of the art in acute kidney injury. Front. Pediatr. 8, 70 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Andrade-Oliveira, V. et al. Gut bacteria products prevent AKI induced by ischemia-reperfusion. J. Am. Soc. Nephrol. 26, 1877–1888 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Yang, J. et al. Intestinal microbiota controls acute kidney injury severity by immune modulation. Kidney Int. 98, 932–946 (2020).

    Article  CAS  PubMed  Google Scholar 

  160. Andrianova, N. V. et al. Microbiome-metabolome signature of acute kidney injury. Metabolites 10, 142 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  161. Nakade, Y. et al. Gut microbiota-derived D-serine protects against acute kidney injury. JCI Insight 3, e97957 (2018).

    Article  PubMed Central  Google Scholar 

  162. Sekine, T. & Endou, H. in Seldin and Giebisch’s The Kidney 5th edn. Ch. 6 (eds Alpern, R. J., Moe, O. W. & Caplan, M. J.) 143–175 (Academic, 2013).

  163. Huang, H. et al. Gentamicin-induced acute kidney injury in an animal model involves programmed necrosis of the collecting duct. J. Am. Soc. Nephrol. 31, 2097–2115 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Niendorf, T., Frydman, L., Neeman, M. & Seeliger, E. Google maps for tissues: Multiscale imaging of biological systems and disease. Acta Physiol. 228, e13392 (2020).

    Article  CAS  Google Scholar 

  165. Gardiner, B. S., Smith, D. W., Lee, C. J., Ngo, J. P. & Evans, R. G. Renal oxygenation: from data to insight. Acta Physiol. 228, e13450 (2020).

    Article  CAS  Google Scholar 

  166. Olsen, T. S. & Hansen, H. E. Ultrastructure of medullary tubules in ischemic acute tubular necrosis and acute interstitial nephritis in man. APMIS 98, 1139–1148 (1990).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), Project-ID 394046635 — SFB 1365, and acknowledge the secretarial assistance of C. Neubert in the preparation of this manuscript before submission.

Author information

Authors and Affiliations

  1. Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

    Holger Scholz, Felix J. Boivin, Kai M. Schmidt-Ott, Sebastian Bachmann, Kai-Uwe Eckardt, Ute I. Scholl & Pontus B. Persson

  2. Molecular and Translational Kidney Research, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

    Felix J. Boivin & Kai M. Schmidt-Ott

Authors
  1. Holger Scholz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Felix J. Boivin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kai M. Schmidt-Ott
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sebastian Bachmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kai-Uwe Eckardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ute I. Scholl
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pontus B. Persson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.S., F.J.B., K.M.S.-O., S.B., U.I.S. and P.B.P. researched data for the article. All authors made substantial contributions to discussions of the content, wrote the manuscript, and reviewed or edited the manuscript before submission.

Corresponding author

Correspondence to Pontus B. Persson.

Ethics declarations

Competing interests

K.-U.E. reports personal fees from Akebia, Astellas and Bayer, grants from Astra Zeneca, Bayer and Vifor. P.B.P. advises for Bayer regarding renal safety and has received funding from Bayer. The other authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Nephrology thanks R. Evans, S. Heyman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Diffusional equilibrium

A condition of balanced oxygen distribution (that is, lack of partial pressure of oxygen (pO2) heterogeneities) within a tissue.

Arterial–venous shunting

The diffusion of oxygen from arteries to veins in blood vessels that are arranged in a countercurrent.

Vascular congestion

In the context of acute kidney injury, vascular congestion describes reduced kidney perfusion in critical regions due to low blood flow and erythrocyte aggregation.

Rheological measures

Treatment protocols aimed at improving intrarenal haemodynamics and, thus, excretory kidney function.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Scholz, H., Boivin, F.J., Schmidt-Ott, K.M. et al. Kidney physiology and susceptibility to acute kidney injury: implications for renoprotection. Nat Rev Nephrol 17, 335–349 (2021). https://doi.org/10.1038/s41581-021-00394-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41581-021-00394-7

This article is cited by

Search

Advanced 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