We found that acute kidney injury, defined by the RIFLE classification, had a high incidence (67.2%) and was associated with an increased risk for hospital mortality compared with those who never developed acute kidney injury. The incidence of almost 70% may appear at odds with the existing literature [5
]. Even when limiting cases to those with RIFLE class F (28%) we found a higher rate for ICU patients than typically reported. Fourteen percent of class F patients received renal replacement therapy, however, leading to a rate of 4–5% among ICU patients, consistent with previous reports [9
]. Indeed, our study highlights the potential for under-reporting when renal replacement therapy is used to 'define' acute kidney injury. Importantly, even milder degrees of kidney dysfunction, RIFLE class R or class I, were still associated with excess mortality compared with patients who maintained normal function. RIFLE provided a well-balanced classification system for determination of patients with different severity of acute kidney injury, at least as far as risk of mortality or need for renal replacement therapy is concerned.
Not surprisingly, the occurrence of acute kidney injury and maximum RIFLE class F were associated with increased baseline severity of illness and older age (Tables and ). Patients developing acute kidney injury were slightly older and had higher APACHE III and SOFA scores, even when kidney dysfunction was not counted. However, the severity within acute kidney injury was not so affected by these factors. Patients progressing to RIFLE class I and class F were no older and their nonrenal SOFA scores no greater than patients remaining in RIFLE class R. Although, Herget-Rosenthal and colleagues have also described the progression of acute kidney injury in a selected cohort of 85 ICU patients [20
], this is to our knowledge the first time that the progression of acute kidney injury has been examined in a large dataset of general ICU patients.
RIFLE class R would appear to be aptly named. More than one-half of the patients of class R progressed to more severe RIFLE classes, yet those that did not were not at increased risk of hospital mortality. Future studies could target this population for prevention. RIFLE class I may also have been fortuitously named, for this is the stage at which risk for hospital mortality increases even after controlling for covariates. It was commonly held until fairly recently that patients die 'with, and not of, acute renal failure'. Medication (for example, erythropoietin and diuretics) and renal replacement therapy were thought to 'replace' the loss of kidney function. It has already been demonstrated in critically ill patients that severe acute renal failure, defined as the need for renal replacement therapy or oliguria, is independently associated with mortality [4
]. In addition, in a cardiothoracic surgery population and in a cohort of hospitalized patients, both with a lower baseline mortality compared with general ICU patients, small changes in serum creatinine were associated with a worse outcome [22
]. In the present study we confirm the association of acute kidney injury with increased hospital mortality in a general ICU population. This is a remarkable finding considering how common this condition appears to be – 55% of all patients had RIFLE class I or class F. Furthermore, there was increasing mortality risk over RIFLE classes, despite the fact that these ICU patients had similar comorbidity, as reflected by the nonrenal SOFA score.
The finding that moderate degrees of kidney dysfunction pose a significant risk of death is particularly notable given that we know very little of why this should be. Acute kidney injury may simply be colinear with unmeasured elements of comorbidity, or it may be causally related to the increased mortality. Future studies should consider exploring whether alternative management of patients with mild degrees of kidney dysfunction could change the outcome. If the problem is actually the kidney, then possible mechanisms underlying the excess mortality associated with acute kidney injury are likely to be found in the pathophysiologic changes resulting from kidney insufficiency and adverse effects of renal replacement therapy [24
]. Salt and water retention resulting in volume overload, hyperkalemia and acid-base derangements [26
], perhaps leading to decreased blood pressure, cardiac output, hepatic and renal blood flow [27
], to insulin resistance and protein breakdown, and even to alterations in innate immunity [28
], all may contribute to the excess mortality in this group of patients. Furthermore, patients with acute kidney injury have a high incidence of infectious complications [29
] and frequently develop anemia. Finally, acute kidney injury itself can lead to a non-infectious, proinflammatory response with activation of leukocytes, secretion of proinflammatory cytokines and recruitment of neutrophils and macrophages with resultant lung injury, as has been demonstrated in animal models of ischemia-reperfusion-induced acute renal failure [32
]. All these changes may occur prior to, or even in, patients never receiving renal replacement therapy. These same mechanisms, however, may explain why patients who are treated with a lower dose of renal replacement therapy have a worse survival [34
Our study has certain limitations. First, we did not attempt to compare RIFLE with other classification systems; nor did we compare urine output and creatinine criteria, but rather used the criteria as proposed by the Acute Dialysis Quality Initiative workgroup, as the worst classification by each criterion. It is possible that urine output and creatinine criteria provide complementary information, which is lost when these criteria are combined.
The Acute Dialysis Quality Initiative recommended the use of a baseline serum creatinine, yet a true baseline is often unknown for patients admitted to the ICU. Several possible baseline values existed for our patients (hospital admission, ICU admission, or a calculated baseline from the MDRD equation). Our use of the lowest of these values for any given patient may have lead to a higher estimate of change and therefore a higher estimate of the incidence of acute kidney injury. Although the MDRD equation was developed and validated on a large number of patients, conflicting results have been published regarding the validation of this equation in different patient populations. We acknowledge that this equation is only a substitute for the actual glomerular filtration rate, but validation of this equation or developing an alternative for the MDRD-derived baseline creatinine was beyond the scope of this study.
We also acknowledge that some members of our research group have contributed to the consensus process by which RIFLE was developed and by which MDRD recommendations were made. In addition, patient follow-up in our study was limited to hospital discharge information.
Some patients may have died shortly after hospital discharge. As shown in Figure , the curves continue to separate, particularly for those in the class F group. Longer follow-up would also be required to examine the RIFLE endpoints 'loss' and 'end-stage disease'. Early renal replacement therapy may theoretically influence the criteria, and patients that would have reached class F could be classified in our study as class R or class I. Only four class I patients were treated with renal replacement therapy, however, and reclassification of these patients to class F does not influence our results.
Although our study is relatively large and included seven ICUs, it was conducted at a single medical center whose case mix and referral patterns may not be representative of other centers. The case mix of this study cohort could have hindered the detection of specific conditions that influence the development of acute kidney injury. Finally, our retrospective study design, using existing medical records, limited our ability to look outside the ICU and to collect information on potential mechanisms of injury. Our design also prohibited the use of more sophisticated measures of kidney function. Indeed, our assessment of time to progression of acute kidney injury may have been artificially lengthened due to daily measurement of creatinine – some patients appeared to skip class R or class I because of this limitation.