Quantitative Micro-Computed Tomography Imaging of Vascular Dysfunction in Progressive Kidney Diseases

Abstract

Progressive kidney diseases and renal fibrosis are associated with endothelial injury and capillary rarefaction. However, our understanding of these processes has been hampered by the lack of tools enabling the quantitative and noninvasive monitoring of vessel functionality. Here, we used micro-computed tomography (mCT) for anatomical and functional imaging of vascular alterations in three murine models with distinct mechanisms of progressive kidney injury: ischemia-reperfusion (I/R, days 1-56), unilateral ureteral obstruction (UUO, days 1-10), and Alport mice (6-8 weeks old). Contrast-enhanced in vivo mCT enabled robust, noninvasive, and longitudinal monitoring of vessel functionality and revealed a progressive decline of the renal relative blood volume in all models. This reduction ranged from 220% in early disease stages to 261% in late disease stages and preceded fibrosis. Upon Microfil perfusion, high-resolution ex vivo mCT allowed quantitative analyses of three-dimensional vascular networks in all three models. These analyses revealed significant and previously unrecognized alterations of preglomerular arteries: a reduction in vessel diameter, a prominent reduction in vessel branching, and increased vessel tortuosity. In summary, using mCT methodology, we revealed insights into macro-to-microvascular alterations in progressive renal disease and provide a platform that may serve as the basis to evaluate vascular therapeutics in renal disease.

Characterization of the PEGylated Functional Upstream Domain Peptide (PEG-FUD): a Potent Fibronectin Assembly Inhibitor with Potential as an Anti-Fibrotic Therapeutic

“…Administration of a PEGylated FUD variant has the potential of improving FUD penetration into the kidneys by increasing the drug’s circulation time, thus pointing to PEG-FUD as a potential therapeutic for the treatment of renal fibrosis. Recently published work suggesting that structural alterations of peritubular capillaries associated with renal fibrosis allow increased extravasation of solutes as large as albumin (65–70 kDa) and fibrinogen (340 kDa) into the peritubular interstitum (30,31) also present a tantalizing possibility for improved delivery of a long circulating therapeutic with an enhanced molecular weight. Previous successes, combined with this observation, stress the importance of PEG-FUD therapeutic efficacy evaluation in the renal fibrosis context.…”

Renal haemodynamics and oxygenation during and after cardiac surgery and cardiopulmonary bypass

“…35 Hypoxia may also contribute to the progression from AKI to CKD. 36 For example, capillary rarefaction appears to be an early 37 and persistent 38 event after AKI and is common to all forms of CKD. 39,40…”

Endothelial Dysfunction in Renal Interstitial Fibrosis

“…Human kidney biopsies from patients with chronic tubule interstitial disease had a reduction in peritubular capillary density that was associated with tubule atrophy and increased interstitial fibrosis compared to normal kidneys[7]. Mouse models of interstitial fibrosis observed vascular rarefaction occurring as early as day 1 after severe IRI and 3 days after unilateral ureteral obstruction (UUO)[9]. Microvascular loss is apparent at 4 weeks after IRI[10], but can apparently return to sham levels 6 to 9 weeks after IRI when renal function was restored[11].…”