Update on mechanisms of ischemic acute kidney injury.

A cute renal failure (ARF), classically defined as an abrupt decrease in kidney function that leads to accumulation of nitrogenous wastes such as blood urea nitrogen and creatinine, is a common clinical problem with increasing incidence, serious consequences, unsatisfactory therapeutic options, and an enormous financial burden to society (1–5). ARF may be classified as prerenal (functional response of structurally normal kidneys to hypoperfusion), intrinsic renal (involving structural damage to the renal parenchyma), and postrenal (urinary tract obstruction). This review focuses on intrinsic ARF, which has emerged as the most common and serious subtype in hospitalized patients and can be associated pathologically with acute tubular necrosis (ATN). Consequently, it still is common clinical practice to use the terms intrinsic ARF and ATN interchangeably. Despite decades of pioneering basic research and important technical advances in clinical care, the prognosis for patients with intrinsic ARF remains poor, with a mortality rate of 40 to 80% in the intensive care setting. Two major problems have plagued the field and hindered progress. First, well over 20 definitions for ARF have been used in published studies, ranging from dialysis requirement to subtle increases in serum creatinine (6). In an attempt to standardize the definition and reflect the entire spectrum of the condition, the term acute kidney injury (AKI) has been proposed (4). AKI refers to a complex disorder that comprises multiple causative factors and occurs in a variety of settings with varied clinical manifestations that range from a minimal but sustained elevation in serum creatinine to anuric renal failure. Prerenal azotemia and other fully reversible causes of acute renal insufficiency are specifically excluded from the spectrum of AKI. An inherent shortcoming of this term is the continued reliance on serum creatinine measurements, and the definition of AKI undoubtedly will undergo enhancements as novel early biomarkers for the identification of ARF before the rise in serum creatinine come to light (7). This review avoids the term ATN and uses the expressions AKI and intrinsic ARF transposably. The second problem is an incomplete understanding of the cellular and molecular mechanisms that underlie AKI. This review updates the reader on current advances in basic and translational research that hold promise in human ischemic AKI. Classic concepts are mentioned briefly as founding principles but expanded on only if contemporary findings substantiate or refute them. The reader is referred to recent publications that address the mechanisms that underlie other causes of intrinsic AKI, such as sepsis (8) and nephrotoxins (9). However, from the clinical viewpoint, it is acknowledged that AKI is frequently multifactorial, with concomitant ischemic, nephrotoxic, and septic components and with overlapping pathogenetic mechanisms.