Advances in understanding ischemic acute kidney injury

Abstract

Acute kidney injury (AKI) is independently associated with increased morbidity and mortality. Ischemia is the leading cause of AKI, and short of supportive measures, no currently available therapy can effectively treat or prevent ischemic AKI. This paper discusses recent developments in the understanding of ischemic AKI pathophysiology, the emerging relationship between ischemic AKI and development of progressive chronic kidney disease, and promising novel therapies currently under investigation. On the basis of recent breakthroughs in understanding the pathophysiology of ischemic AKI, therapies that can treat or even prevent ischemic AKI may become a reality in the near future.

Figure 1

Renal vascular autoregulation involves three mechanisms: the myogenic reflex (MR), tubuloglomerular feedback (TGF) and a recently discovered third regulatory mechanism (3M). MR refers to the contraction of the smooth muscle in response to stretching forces. TGF is a kidney-specific regulatory mechanism that causes vasoconstriction of the afferent arterioles in response to increased luminal concentration of chloride at the macula densa in the early distal tubule. 3 M takes place chronologically after MR and TGF and was discovered when it was observed that renovascular autoregulation took place well after MR took place and after TGF was inhibited by furosemide administration. (A) Increase in pressure leads to passive stretch. (B) Regulatory mechanisms are activated to maintain renal blood flow via smooth muscle contraction of afferent and efferent arterioles. (C) Three regulatory mechanisms work in concert. MR occurs early and is completed in 10 seconds. TGF and 3 M are late responses, with a delay of 10 to 15 seconds, and take 30 to 60 seconds to complete. (D) Autoregulation maintains constant renal blood flow and glomerular flow rate while systemic blood pressure fluctuates between 80 and 180 mmHg.

Figure 2

Peritubular capillary schematic under two conditions. (A) Cross-section of normal peritubular capillaries with an intact endothelial monolayer anchored by the actin cytoskeleton and covered with the glycocalyx. (B) Endothelial alterations due to acute kidney injury, such as glycocalyx disruption, actin cytoskeleton disruption, detachment of the endothelial monolayer with increased endothelium-leukocyte interaction and expression of intracellular adhesion molecules.