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  • Review Article
  • Published:

The suffocating kidney: tubulointerstitial hypoxia in end-stage renal disease

Nature Reviews Nephrology volume 6, pages 667–678 (2010)Cite this article

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Abstract

Chronic kidney disease (CKD) is characterized by irreversible pathological processes that result in the development of end-stage renal disease (ESRD). Accumulating evidence has emphasized the important role of chronic hypoxia in the tubulointerstitium in the final common pathway that leads to development of ESRD. The causes of chronic hypoxia in the tubulointerstitium are multifactorial and include mechanisms such as hemodynamic changes and disturbed oxygen metabolism of resident kidney cells. Epidemiological studies have revealed an association between CKD and systemically hypoxic conditions, such as chronic obstructive pulmonary disease and sleep apnea syndrome. In addition to tubulointerstitial hypoxia, glomerular hypoxia can occur and is a crucial factor in the development of glomerular disorders. Chemical compounds, polarographic sensors, and radiographical methods can be used to detect hypoxia. Therapeutic approaches that target chronic hypoxia in the kidney should be effective against a broad range of kidney diseases. Amelioration of hypoxia is one mechanism of inhibiting the renin–angiotensin system, the current gold standard of CKD therapy. Future therapeutic approaches include protection of the vascular endothelium and appropriate activation of hypoxia-inducible factor, a key transcription factor involved in adaptive responses against hypoxia.

Key Points

  • Tubulointerstitial hypoxia is a final step that is common to the development of end-stage renal disease (ESRD) in a variety of kidney diseases

  • A number of mechanisms are involved in the development of tubulointerstitial hypoxia

  • Chronic hypoxia mediates the progression of kidney injury even from the early stages of disease

  • Chronic hypoxia and tubulointerstitial injury form a vicious cycle that leads to ESRD

  • The development of tools to detect hypoxia in the human kidney is a matter of high priority

  • Therapeutic approaches that target hypoxia should be effective in a variety of kidney diseases

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Figure 1: Tolerance of the kidney to hypoxia.
Figure 2: Vasculature of the kidney.
Figure 3: The arterial-to-venous oxygen shunt.
Figure 4: Mechanism of chronic hypoxia in the kidney.
Figure 5: HIF–HRE interactions.
Figure 6: The vicious cycle that leads to end-stage renal disease.
Figure 7: Demonstration of hypoxia of the kidney in hypoxia-sensing transgenic animals.
Figure 8: Graph showing the high prevalence of CKD among patients with sleep apnea.

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Acknowledgements

Studies described in this Review were supported by Grants-in-Aids for Scientific Research from the Japan Society for the Promotion of Science (2139,036) to M. Nangaku. We appreciate the invaluable advice from members of our group and our collaborators, particularly R. Inagi, T. Miyata and T. Tanaka. We thank A. Jo from our laboratory for drawing the original for Figure 5. Initial drafts of this manuscript were edited by G. Harris from Digital Medical Communications, Japan; this editorial assistance was funded by a government grant to M. Nangaku.

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  1. Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo ku, 113 8655, Tokyo, Japan

    Imari Mimura & Masaomi Nangaku

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  1. Imari Mimura
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I. Mimura and M. Nangaku contributed equally to all aspects of this manuscript.

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Correspondence to Masaomi Nangaku.

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Mimura, I., Nangaku, M. The suffocating kidney: tubulointerstitial hypoxia in end-stage renal disease. Nat Rev Nephrol 6, 667–678 (2010). https://doi.org/10.1038/nrneph.2010.124

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