Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function

Abstract

Acute episodes of severe renal ischemia result in acute renal failure (ARF). These episodes are followed by a characteristic recovery and repair response, whereby tubular morphology and renal function appear completely restored within approximately 1 mo. However, the chronic effects of such an injury have not been well studied. Male rats were subjected to 60-min bilateral ischemia followed by reperfusion, yielding a characteristic injury. Postischemic animals manifested severe diuresis, peaking at 1 wk postinjury (volume: >45 ml/day, ARF vs. 18 ml/day, sham; P < 0.05). Urine flow subsequently declined but remained significantly elevated vs. sham animals for a 40-wk period. The prolonged alteration in urinary concentrating ability was attributable, in part, to a diminished capacity to generate a hypertonic medullary interstitium. By week 16, proteinuria developed in the post-ARF group and progressed for the duration of the study. Histological examination revealed essentially normal tubular morphology at 4 and 8 wk postinjury but the development of tubulointerstitial fibrosis at 40 wk. Transforming growth factor (TGF)-beta1 expression was elevated at 40 wk, but not at 4 and 8 wk postinjury. Microfil analysis revealed an approximately 30-50% reduction in peritubular capillary density in the inner stripe of the outer medulla at 4, 8, and 40 wk in post-ARF groups vs. sham animals. In addition, post-ARF rats manifested a significant pressor response to a low dose of ANG II (15 ng x kg(-1) x min(-1)). We hypothesize that severe ischemic injury results in a permanent alteration of renal capillary density, contributing to a urinary concentrating defect and the predisposition toward the development of renal fibrosis.

Kidney Pericytes: Roles in Regeneration and Fibrosis

“…8,55,56 Capillary rarefaction after kidney injury has been described in a variety of experimental animal models, and in human beings with CKD the decrease of renal capillary density correlates with the severity of fibrosis (Fig. 3).…”

“…3). 56–62 Basile et al 55 previously used silicone rubber injection to show that rats develop a signi-ficant reduction of peritubular capillary density in kidney (cortex, -25%-30%; inner stripe outer medulla, -35%-40%) at 4 to 40 weeks after IRI. Horbelt et al 58 subsequently identified endothelium by immunostaining postischemic mice and also reported a 45% decrease of microvascular density at 30 days after IRI.…”

Renal Endothelial Dysfunction in Acute Kidney Ischemia Reperfusion Injury

“…One possible mechanism relates to the reduction in peritubular capillary density that persists following the otherwise uneventful recovery from AKI [112]. Our laboratory demonstrated that there was a 30-50% reduction of PTC density which was present following the resolution of GFR, RBF and tubular morphology, at 4 weeks post I/R in rats [112, 113]. Similar results have been reported in other species such as mice [114], and in human kidneys following recovery from delayed graft function [115, 116].…”

“…Regardless of the mechanisms of dropout, PTC rarefaction post-AKI appears to be permanent [112] suggesting that the intrinsic regenerative capacity of renal capillaries is profoundly limited. This impaired regenerative response may stem in part from a lack of trophic support following AKI.…”

Defining the Acute Kidney Injury and Repair Transcriptome

“…31 A compromised microvascular density may exacerbate the initial hypoxia and potentially contribute to the progressive development of interstitial fibrosis as in the fibrotic scarring observed in Alzheimers disease. 32 According to the “chronic hypoxia hypothesis”, capillary rarefaction is an important factor driving a final common pathway to end stage renal disease.…”