tubules become necrotic as well.10 Distal nephron involvement in these animal experiments is minimal, unless medullary oxygenation is specifically targeted.11 Although these animals develop severe ARF, as noted by Rosen and Heyman, not much else resembles the clinical syndrome in humans.12 Indeed these authors correctly point out that the term ‘‘acute tubular necrosis does not accurately reflect the morphological changes in this condition’’.12 Instead, the term ATN is used to describe a clinical situation in which there is adequate renal perfusion to largely maintain tubular integrity, but not http://www.kidney-international.org chapter 1.1 & 2012 KDIGO Kidney International Supplements (2012) 2, 13–18 13 to sustain glomerular filtration. Data from renal biopsies in patients with ATN dating back to the 1950s13 confirm the limited parenchymal compromise in spite of severe organ dysfunction.12 Thus, the syndrome of ATN has very little to do with the animal models traditionally used to study it. More recently, investigators have emphasized the role of endothelial dysfunction, coagulation abnormalities, systemic inflammation, endothelial dysfunction, and oxidative stress in causing renal injury, particularly in the setting of sepsis.14,15 True ATN does, in fact, occur. For example, patients with arterial catastrophes (ruptured aneurysms, acute dissection) can suffer prolonged periods of warm ischemia just like animal models. However, these cases comprise only a small fraction of patients with AKI, and ironically, these patients are often excluded from studies seeking to enroll patients with the more common clinical syndrome known as ATN. ARF In a recent review, Eknoyan notes that the first description of ARF, then termed ischuria renalis, was by William Heberden in 1802.16 At the beginning of the twentieth century, ARF, then named Acute Bright’s disease, was well described in William Osler’s Textbook for Medicine (1909), as a consequence of toxic agents, pregnancy, burns, trauma, or operations on the kidneys. During the First World War the syndrome was named ‘‘war nephritis’’,17 and was reported in several publications. The syndrome was forgotten until the Second World War, when Bywaters and Beall published their classical paper on crush syndrome.18 However, it is Homer W. Smith who is credited for the introduction of the term ‘‘acute renal failure’’, in a chapter on ‘‘Acute renal failure related to traumatic injuries’’ in his textbook The kidney-structure and function in health and disease (1951). Unfortunately, a precise biochemical definition of ARF was never proposed and, until recently, there was no consensus on the diagnostic criteria or clinical definition of ARF, resulting in multiple different definitions. A recent survey revealed the use of at least 35 definitions in the literature.19 This state of confusion has given rise to wide variation in reported incidence and clinical significance of ARF. Depending on the definition used, ARF has been reported to affect from 1% to 25% of ICU patients and has lead to mortality rates from 15–60%.7,20,21 RIFLE criteria The Acute Dialysis Quality Initiative (ADQI) group developed a system for diagnosis and classification of a broad range of acute impairment of kidney function through a broad consensus of experts.22 The characteristics of this system are summarized in Figure 1. The acronym RIFLE stands for the increasing severity classes Risk, Injury, and Failure; and the two outcome classes, Loss and End-Stage Renal Disease (ESRD). The three severity grades are defined on the basis of the changes in SCr or urine output where the worst of each criterion is used. The two outcome criteria, Loss and ESRD, are defined by the duration of loss of kidney function. AKI: acute kidney injury/impairment Importantly, by defining the syndrome of acute changes in renal function more broadly, RIFLE criteria move beyond ARF. The term ‘‘acute kidney injury/impairment’’ has been proposed to encompass the entire spectrum of the syndrome from minor changes in markers of renal function to requirement for renal replacement therapy (RRT).23 Thus, the concept of AKI, as defined by RIFLE creates a new paradigm. AKI is not ATN, nor is it renal failure. Instead, it encompasses both and also includes other, less severe conditions. Indeed, as a syndrome, it includes patients without actual damage to the kidney but with functional impairment relative to physiologic demand. Including such patients in the classification of AKI is conceptually attractive because these are precisely the patients that may benefit from early intervention. However, it means that AKI includes both injury and/or impairment. Rather than focusing exclusively on patients with renal failure or on those who receive dialysis or on those that have a clinical syndrome defined by pathology, which is usually absent (ATN), the strong association of AKI with hospital mortality demands that we change the way we think about this disorder. In a study by Hoste et al.,2 only 14% of patients reaching RIFLE ‘‘F’’ received RRT, yet these patients experienced a hospital mortality rate more than five times that of the same ICU population without AKI. Is renal support underutilized or delayed? Are there other supportive measures that should be employed for these patients? Sustained AKI leads to profound alterations in fluid, electrolyte, acid-base and hormonal regulation. AKI results