Vascular Remodeling with Reduced Renal Mass

Abstract

Maintenance of vascular anatomy is critical for the kidneys to perform their chief function of blood filtration. It is then no surprise that compromises in kidney vascular anatomy and function are associated with chronic kidney disease (CKD), which afflicts >15% of the US population. Rat renal remnant models of CKD, including 1/3 and 5/6 nephrectomies (1/3NX, 5/6NX, respectively), recapitulate many elements of human CKD. We have observed from prior studies that remnant kidneys of 5/6NX rats spontaneously undergo remarkable hypertrophic remodeling, and by 10 weeks post NX are, on average, larger than Sham NX, intact kidneys. In contrast, the 1/3NX remnant kidney (2/3 of mass excised with contralateral kidney intact) atrophies over time. These disparate observations of whole‐organ remodeling must occur concomitantly with commensurate differences in vascular remodeling. Careful examination of differences in vascular remodeling in these two CKD models may uncover important molecular pathways and mechanisms underlying alterations in renal function. The first step toward realization of this goal, and the primary aim of this study, was to anatomically characterize the vasculature of the remnant kidneys from 1/3NX and 5/6NX rats.Methods1/3NX, 5/6NX, and Sham surgeries were performed on 10 week old male Sprague Dawley rats. Gross vascular anatomy was assessed 10 weeks post NX using two approaches. The first was in‐vivo assessment of major renal vessels with using Doppler ultrasound imaging of the short axis. The second was morphometric analysis of microfil kidney vascular cast photos.ResultsDoppler imaging revealed a reduction in renal blood flow through large vessels in the 1/3NX remnant kidney. The 5/6NX rats demonstrated pronounced vascular remodeling, with both increased diameter of larger vessels and turbulent flow. Quantitative analysis of microfil photos indicates that 1/3NX remnant kidneys have, on average, reduced vessel‐area fraction (FAV, area of photo occupied by vessels/area of tissue) compared to Sham (0.96 ± 0.2 vs. 0.53 ± 0.15; mean ± SEM), and that 5/6NX kidneys have reduced FAV compared to 1/3NX remnant kidneys (0.24 ± 0.06). Sham animal microfil casts extended to the capsule, while the mean distance from the most superficial casted vessels was greater in 1/3NX remnant kidney (0.20 ± 0.13 mm) and much greater in 5/6NX kidneys (1.57 ± 0.32 mm).ConclusionThese observations demonstrate pronounced anatomical differences between 1/3, 5/6, and Sham NX rat kidney vasculature, including apparent differences in peripheral vessel density. These anatomical differences were accompanied by functional differences in blood flow. Thus, these rat models of CKD appear to recapitulate elements of the vessel rarefaction/injury of human CKD, which is associated with hypoxia, fibrosis, tubular damage, and functional loss. Improved understanding of these anatomical changes and underlying molecular pathways may reveal novel treatment approaches.Support or Funding Information1R01HL128332‐01A1Figure 1