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.

Diverse Effects of Ischemic Pretreatments on the Long-Term Renal Damage Induced by Ischemia-Reperfusion

“…There were thickened TBM and an enlarged interstitial area, corresponding to increased kidney weight. This finding, as well as other reports [3,13,14,15], indicates that prolonged ischemia may lead to irreversible renal injury. The reason may be the limited repair ability in the kidneys.…”

“…It may occur in several clinical situations including renal transplantation, renal artery and suprarenal aortic surgery, and certain hypotensive states [2]. I/R injury is also an important risk factor for the development of renal interstitial fibrosis [3, 4]. …”

“…Mild or sublethal injury induced by a short period of renal ischemia is reversible because of an innate regenerative process, which depends partly on the integrity of the basement membrane and the number of residual surviving tubular cells [10]. In contrast, it is difficult for the kidney to recover completely from severe I/R injury because of internal architectural disruption [3]. Recent data indicate that most patients, having survived ischemic ARF, cannot recover full renal function [11].…”

Renal Parenchymal Hypoxia, Hypoxia Response and the Progression of Chronic Kidney Disease

“…Basile et al [24] showed that chronic tubulointerstitial disease also leads to depletion of peritubular capillaries, illustrated by microfil infusion into rat kidneys 4–8 weeks after ischemia/reperfusion injury. In this model the capillary volume and perfusion index fall in all renal regions along time, meaning less oxygen supply.…”

“…In this model the capillary volume and perfusion index fall in all renal regions along time, meaning less oxygen supply. Furthermore, evolving fibrosis and the deposition of extracellular matrix interferes with ambient oxygen diffusion [24]. As the peritubular capillaries originate from efferent glomerular arterioles, it is noteworthy that primary glomerular diseases with obliteration of glomerular capillaries also compromise downstream peritubular microcirculation and intensify parenchymal hypoxia [25, 26].…”