Renal Tissue Hypoxia in Kidney Diseases

Abstract

Tissue hypoxia has been implicated in the pathogenesis of various kidney diseases. Yet, because of technical limitations, temporal and spatial aspects of tissue hypoxia in the pathogenesis of kidney disease have received little attention. The recent development of the oxygen telemeter allowed for the possibility for the investigation into the contribution of tissue hypoxia in the progression of kidney diseases over long periods of time. We validated and established that the inherent offset in the telemeter was stable throughout the implantation period after a 5 day ‘bedding in’ period. The primary aim of this PhD project was to utilize the recently developed oxygen telemeter; the Clark electrode and pimonidazole adduct immunohistochemistry to determine both the temporal and spatial distribution of tissue hypoxia in the subacute phase of acute kidney injury induced by renal ischemia reperfusion injury. The tissue damage in response to an hour of anoxia was vast, such that tubular elements were often observed to be riddled with intraluminal casts, cellular sloughing and thinning of the epithelium. Interestingly, despite the extensive cellular damage, we could not detect tissue hypoxia at 24 h and 5 days after reperfusion of the kidney in both the cortex and the medulla using the oxygen telemeter and the Clark electrode. In contrast, the widespread staining pattern of pimonidazole adduct suggest otherwise i.e. cellular hypoxia was prominent in the subacute phase of ischemia reperfusion injury. A large proportion of these stained adducts was associated with tissue damage. Thus, the presence of these adducts was likely artifactual and is not reflective of ‘true hypoxia’. The absence of tissue hypoxia was likely contributed by the marked reduction of renal oxygen consumption and well maintained renal oxygen delivery. In conclusion, the absence of tissue hypoxia in the acute and subacute phase of ischemia reperfusion injury indicates that tissue hypoxia may not be an important driver of the pathogenesis of ischemia reperfusion injury. However, tissue damage in the subacute phase may lead to tissue hypoxia in the chronic phase of ischemia reperfusion injury. This line of inquiry could be investigated by instrumenting rats with the oxygen telemeter for weeks following recovery from ischemia surgery. Using Clark electrodes, we directly quantified tissue PO2 in rats with advanced polycystic kidney disease. There was extensive tissue hypoxia in both the renal parenchyma and within the cysts. Renal tissue hypoxia in these rats was driven by a greater reduction in renal oxygen delivery than renal oxygen consumption. The data presented in this thesis reinforce the need to consider both spatial and temporal aspects of tissue hypoxia in various forms of kidney disease in order to verify the importance of tissue hypoxia in driving the pathogenesis of kidney diseases.