Loss of renal function beyond a renal vascular lesion presents a complex challenge to clinicians. This article summarizes current understanding of critical vascular lesions to the kidney and putative mechanisms by which loss of perfusion activates fibrogenic mechanisms in the kidney. The authors emphasize alterations in vasoactive pathways, including disturbed oxidative stress, activation of endothelin, and reduced nitric oxide, which modulate cytokines and inflammatory mediators within the renal parenchyma. Improved understanding of these mechanisms is essential in preventing irreversible interstitial fibrosis and restoring renal perfusion.