Renal hypoxia in kidney disease: Cause or consequence?

Abstract

Tissue hypoxia has been proposed as an important factor in the pathophysiology of both chronic kidney disease (CKD) and acute kidney injury (AKI), initiating and propagating a vicious cycle of tubular injury, vascular rarefaction, and fibrosis and thus exacerbation of hypoxia. Here, we critically evaluate this proposition by systematically reviewing the literature relevant to the following six questions: (i) Is kidney disease always associated with tissue hypoxia? (ii) Does tissue hypoxia drive signalling cascades that lead to tissue damage and dysfunction? (iii) Does tissue hypoxia per se lead to kidney disease? (iv) Does tissue hypoxia precede pathology? (v) Does tissue hypoxia colocalize with pathology? (vi) Does prevention of tissue hypoxia prevent kidney disease? We conclude that tissue hypoxia is a common feature of both AKI and CKD. Furthermore, at least under in vitro conditions, renal tissue hypoxia drives signalling cascades that lead to tissue damage and dysfunction. Tissue hypoxia itself can lead to renal pathology, independent of other known risk factors for kidney disease. There is also some evidence that tissue hypoxia precedes renal pathology, at least in some forms of kidney disease. However, we have made relatively little progress in determining the spatial relationships between tissue hypoxia and pathological processes (i.e. colocalization) or whether therapies targeted to reduce tissue hypoxia can prevent or delay the progression of renal disease. Thus, the hypothesis that tissue hypoxia is a "common pathway" to both AKI and CKD still remains to be adequately tested.

Renal oxygenation: From data to insight

“…Firstly, it has been proposed that hypoxia is a final common pathway driving progression of CKD . Thus, hypoxia is seen as both a cause and a consequence of CKD . Secondly, congenital or acquired nephron loss, particularly if it occurs during development of the kidney, greatly increases the risk of subsequent CKD .…”

“…Over the last two decades there has been accumulating evidence for roles of renal hypoxia in the development and progression of both acute kidney injury (AKI) and chronic kidney disease (CKD). [10][11][12][13][14] This has provided a strong impetus for an improved understanding of the factors that regulate kidney oxygenation under physiological conditions and how they are compromised in kidney disease. It is also the problem that brought the authors together, nearly 15 years ago, and continues to drive our collaboration.…”

ExActa HIF prolyl hydroxylase inhibitors—The new lifestyle drug?

“…A resulting epigenetic ‘hypoxic memory’ is discussed as a driver of transition to and progression of CKD . Whether renal hypoxia is rather a cause or a consequence of kidney disease is still a matter of debate . In the context of correcting anaemia in CKD patients, the two most important HIF target genes are EPO and HAMP (hepcidin).…”

“…6 Whether renal hypoxia is rather a cause or a consequence of kidney disease is still a matter of debate. 7 In the context of correcting anaemia in CKD patients, the two most important HIF target genes are EPO and HAMP (hepcidin). PHDis like Roxadustat induce Epo and reduce hepcidin production thereby not only increasing RBC production but also FIGURE 1 The influence of PHDis on erythropoiesis.…”

Probing renal blood volume with magnetic resonance imaging

“…Renal tissue hypoperfusion and hypoxia play a prominent role in the early pathophysiology of AKI and probably also promote its progression to CKD . Hypoxia results from an imbalance between oxygen (O 2 ) delivery and O 2 consumption . Insights into renal oxygenation can be derived from blood oxygenation level–dependent (BOLD) MRI, which offers a non‐invasive in vivo technique .…”