Recent studies emphasize the role of chronic
hypoxia in the tubulointerstitium as a final common pathway to
end-stage renal failure. When advanced, tubulointerstitial damage is associated with the loss of peritubular capillaries. Associated interstitial
fibrosis impairs
oxygen diffusion and supply to tubular and interstitial cells.
Hypoxia of tubular cells leads to apoptosis or epithelial-mesenchymal transdifferentiation. This in turn exacerbates
fibrosis of the kidney and subsequent chronic
hypoxia, setting in train a vicious cycle whose end point is
ESRD. A number of mechanisms that induce tubulointerstitial
hypoxia at an early stage have been identified. Glomerular injury and vasoconstriction of efferent arterioles as a result of imbalances in vasoactive substances decrease postglomerular peritubular capillary blood flow.
Angiotensin II not only constricts efferent arterioles but, via its induction of oxidative stress, also hampers the efficient utilization of
oxygen in tubular cells. Relative
hypoxia in the kidney also results from increased metabolic demand in tubular cells. Furthermore, renal
anemia hinders
oxygen delivery. These factors can affect the kidney before the appearance of significant pathologic changes in the vasculature and predispose the kidney to tubulointerstitial injury. Therapeutic approaches that target the chronic
hypoxia should prove effective against a broad range of renal diseases. Current modalities include the improvement of
anemia with
erythropoietin, the preservation of peritubular capillary blood flow by blockade of the renin-angiotensin system, and the use of
antioxidants. Recent studies have elucidated the mechanism of
hypoxia-induced transcription, namely that
prolyl hydroxylase regulates
hypoxia-inducible factor. This has given hope for the development of novel therapeutic approaches against this final common pathway.