The chronic hypoxia hypothesis: the search for the smoking gun goes on

摘要

a role for tubulointerstitial hypoxia in the initiation and progression of chronic kidney disease (CKD) was first proposed by Fine and colleagues (6). Since then, a considerable body of evidence has accumulated in support of this concept (14). However, it must also be acknowledged that there is currently no "smoking gun" providing direct evidence of causality (5). At least five lines of evidence are required to assess the validity of the "chronic hypoxia hypothesis." 1) Renal tissue hypoxia should be a common finding in animal models of CKD. This has certainly been the case in nearly all animal models studied to date (13), although recent clinical studies using blood oxygen level-dependent magnetic resonance imaging have been unable to show a strong relationship between renal hypoxia and the severity of CKD (11). 2) Renal hypoxia should activate signaling cascades that drive processes such as inflammation, fibrosis, and capillary rarefaction. There is certainly good evidence for this from in vitro studies (14). There is also good evidence of the development of inflammatory and fibrotic processes, tubular damage, and capillary rarefaction in CKD (14). However, as with any slowly evolving pathology, it has been difficult to show, in the intact animal, whether these processes are driven by hypoxia or vice versa. 3) Renal hypoxia itself should induce CKD. In support of this proposition, Friederich-Persson and colleagues have recently shown that chronic treatment with dinitrophenol (9) or triiodothyro-nine (8) can increase renal oxygen consumption, renal hypoxia, proteinuria, and renal inflammation in the absence of oxidative stress. 4) Hypoxia should precede the development of renal dysfunction in experimental models of CKD. This has been demonstrated in diabetic nephropathy (3) and the remnant kidney model of CKD (10). 5) It should be possible to prevent initiation and progression of CKD by preventing renal hypoxia. This final line of evidence has been the most difficult to generate, chiefly because it has proved difficult to find ways to selectively increase renal oxygenation without introducing a host of confounding factors into the experimental paradigm. However, it arguably represents the best approach for testing the chronic hypoxia hypothesis because such interventions would allow demonstration of a causal relationship between hypoxia and the progression of CKD.