Role of Renal Hypoxia in the Progression From Acute Kidney Injury to Chronic Kidney Disease

Abstract

Over the past 20 years, there has been an increased appreciation of the long-term sequelae of acute kidney injury (AKI) and the potential development of chronic kidney disease (CKD). Several pathophysiologic features have been proposed to mediate AKI to CKD progression including maladaptive alterations in tubular, interstitial, inflammatory, and vascular cells. These alterations likely interact to culminate in the progression to CKD. In this article we focus primarily on evidence of vascular rarefaction secondary to AKI, and the potential mechanisms by which rarefaction occurs in relation to other alterations in tubular and interstitial compartments. We further focus on the potential that rarefaction contributes to renal hypoxia. Consideration of the role of hypoxia in AKI to CKD transition focuses on experimental evidence of persistent renal hypoxia after AKI and experimental maneuvers to evaluate the influence of hypoxia, per se, in progressive disease. Finally, consideration of methods to evaluate hypoxia in patients is provided with the suggestion that noninvasive measurement of renal hypoxia may provide insight into progression in post-AKI patients.

Keywords: Fibrosis; inflammation; peritubular capillaries; renal hypoxia.

Figure 1.. Hypothesized role of renal hypoxia in the progression of acute kidney injury to chronic kidney disease.

Acute kidney injury is associated with damage to both tubular and vascular compartments. Tubular injury results in increased expression of profibrotic cytokines and growth factors and decreased expression of vascular factors such as VEGF in tubular cells may lead to renal microvascular loss. The reduction of peritubular capillaries restricts downstream blood flow from glomerular capillaries and contributes to the development of renal hypoxia, while also being associated with activation of pericytes toward a fibrogenic myofibroblast phenotype. Hypoxia influences pro-fibrotic and inflammatory activity of tubular and inflammatory cells. Myofibroblast profibrotic signaling is influenced by factors produced from hypoxic tubules or inflammatory cells or may be influenced directly by hypoxia (?). Progressive interstitial fibrosis exacerbates renal hypoxia by increasing oxygen diffusion distance between peritubular capillaries and parenchyma forming a pathological cycle promoting progressive chronic kidney disease.

Figure 2.. Micrographs of Microfil®- perfused kidney sections processed from rats kidney at 4 weeks after sham-operation (A) or post ischemia reperfusion injury (B).

Note, renal capillaries are filled with Microfil which appears as bright yellow against a dark background. In post ischemic kidneys, capillary density is reduced in both the cortex and the medulla. Cortex (c), outer stripe of the outer medulla (os), inner stripe of the outer medulla (is), and inner medulla (im) are shown. Images were reproduced from Basile et al. with permission.