“The disease seems in general to come on suddenly. The peculiar symptom is a sudden diminution of secretion of urine, which soon amounts to a complete suspension of it. The affliction is probably at first considered as retention; but the catheter being employed, the bladder is found to be empty… after several days, the patient begins to talk incoherently, and shows a tendency to stupor. This increases gradually to perfect coma, which in a few days more is fatal… ” John Abercombie (1780–1828), “Observations on ischuria renalis” (1)
Acute renal failure (ARF), now increasingly referred to as “acute kidney injury” (AKI), is characterized by sudden (i.e., hours to days) impairment of kidney function. Descriptions of AKI date back to the ancient Greek period (2), when the diagnosis was possible only by observing a reduction in urine volume. The modern day conception of AKI has evolved alongside developments in pathology and clinical biochemistry, which have permitted clinicopathologic correlations and early diagnosis (3). Initial descriptions of AKI from the early 20th century centered around specific conditions, such as crush injuries (4), war nephritis (5), and falciparum malaria (6). Sir William Osler in 1912 described several recognizable causes of AKI under the heading of “acute Bright's disease,” including sepsis, pregnancy, burns, and toxins (7).
AKI is now understood to be an increasingly common and potentially catastrophic complication in hospitalized patients. This review summarizes modern epidemiologic studies of AKI, attempted prevention and treatment strategies, and emerging methods for its early and accurate diagnosis.
Early Cohort Studies of AKI
Hou et al. in 1983 published one of the first prospective cohort studies of AKI (8). They focused on hospital-acquired disease and therefore excluded patients with established AKI on admission. Over a 5-mo period beginning in 1978, a total of 2216 consecutive medical and surgical admissions to Tufts-New England Medical Center were followed for the development of AKI. The definition of AKI in this study was based on an absolute increase in serum creatinine (SCr) depending on the admission SCr: increase in SCr of ≥0.5 mg/dl if admission SCr ≤1.9 mg/dl; increase of ≥1.0 mg/dl for admission SCr of 2.0 to 4.9; or an increase ≥1.5 mg/dl for SCr ≥5.0 mg/dl. Overall, 4.9% of patients met criteria for AKI. The major causes of hospital-acquired AKI were decreased renal perfusion (42%), major surgery (18%), contrast nephropathy (12%), and aminoglycoside antibiotics (7%). The crude in-hospital mortality rate was 32%, and the degree of kidney injury as assessed by change in SCr was noted to be important. In-hospital mortality was 3.8% in patients with an increase in SCr of 0.5 to 0.9 mg/dl, and increased progressively to 75% in patients with a ≥4.0 mg/dl increase who were not treated with renal replacement therapy. This study was also one of the first to establish the association between oliguria and mortality in patients with AKI (52% versus 17% with and without oliguria, P < 0.01).
Shusterman et al. performed a case-control study of hospital-acquired AKI in patients admitted over 1 mo to the Hospital of the University of Pennsylvania in 1981 (9). The definition of AKI was different from that used by Hou et al. 4 yr earlier in the same journal. AKI was defined as a >0.9 mg/dl increase in SCr with baseline SCr <2.0 mg/dl or >2.0 mg/dl increase in SCr with baseline SCr ≥2.0 mg/dl; the incidence was 1.9% among patients on medical, surgical, and gynecologic services. The 34 AKI cases were matched to 57 controls without AKI. From this small group of cases and controls, the authors found volume depletion, aminoglycoside use, septic shock, congestive heart failure, and intravenous contrast administration as risk factors for AKI. They also found a 10-fold increased odds of death and a doubling of the length of stay among patients with AKI.
Nash et al. updated their initial report of hospital-acquired AKI almost two decades later (10). Over a 4-mo period in 1996, they prospectively followed 4622 medical and surgical admissions at Rush Presbyterian-St. Luke's Medical Center for the development of AKI, defined as in their earlier study. They identified 332 patients (7.2% of admissions) who developed AKI, higher than the 4.9% in the original study performed at a different institution. The in-hospital mortality rate of 19.4% was lower, albeit not statistically significantly, than the 25% reported previously. The most common causes of AKI remained decreased renal perfusion (39%; defined broadly to include congestive heart failure, cardiac arrest, as well as volume contraction), nephrotoxin administration (16%), contrast administration (11%), and major surgery (9%).
Multicenter Cohort Studies of AKI
Initial cohort studies of AKI shed important light on the frequency, causes, and mortality associated with hospital-acquired AKI. No matter how carefully conducted, single-center studies are inherently limited in terms of sample size and external validity (i.e., generalizability to AKI at other medical centers). Recognizing this limitation, investigators have launched multicenter epidemiologic investigations of AKI.
Lian[Combining Tilde]o and Pascual conducted a prospective, 9-mo study of all AKI episodes in 13 tertiary-care hospitals in Madrid, Spain, beginning in 1991 (11). They defined AKI as a sudden rise in SCr of more than 2 mg/dl, excluding patients with preexisting chronic kidney disease (CKD) (defined as SCr >3 mg/dl). Unlike the Hou et al. (8) and Nash et al. (10) studies, hospital- and community-acquired cases of AKI were included. Of the 748 episodes of AKI (representing 0.4% of admissions, and 21 per 100,000 population), acute tubular necrosis (ATN) was the most frequent cause (45%, defined to include diverse causes, including surgery, nephrotoxin administration, sepsis, and renal hypoperfusion), followed by prerenal azotemia (21%, defined as the rapid recovery of kidney function following volume administration or restoration of cardiac output), acute onset chronic renal failure (12.7%, not defined), and urinary tract obstruction (10%). The crude in-hospital mortality rate was 45% overall and as high as 65.9% in patients requiring dialysis (which constituted 36% of all cases of AKI). In a follow-up study, Lian[Combining Tilde]o et al. provided more details on the specific differences between AKI in and outside of the intensive care unit (ICU) (12). Compared with non-ICU patients, those admitted to the ICU were younger, more likely to die in-hospital (71.5% versus 31.5%), and more likely to have ATN from sepsis or renal hypoperfusion than nephrotoxin administration.
Brivet et al. focused on AKI occurring in the ICU in a 20-center, prospective, 6-mo study performed in France in 1991 (13). They included all patients with a rise in SCr to at least 3.5 mg/dl and/or blood urea nitrogen (BUN) to at least 100 mg/dl, or a 100% increase with preexisting CKD. Patients with severe CKD (baseline SCr >3.5 mg/dl) were excluded. Overall, 7% of ICU admissions developed AKI or had AKI on ICU admission. The major causes of AKI were attributed to sepsis (48%), hemodynamic alterations (32%), nephrotoxin administration (20%), and prerenal factors (17%). Overall in-hospital mortality was 58% and was higher in those with sepsis (73%) and delayed occurrence of AKI after admission (71%). Another group of French investigators (Guerin et al.) performed a similar prospective observational study beginning in 1996 (14). These authors found a 7.7% incidence of AKI in the ICU, defined as SCr more than 3.4 mg/dl or the need for dialysis (14). Overall in-hospital mortality was 66%, and 81% in patients with AKI that developed 1 wk after admission to the ICU.
The Program to Improve Care in Acute Renal Disease (PICARD) performed a 31-mo-long, prospective observational cohort study of patients at five academic medical centers in the United States from 1999 to 2001 (15). Eligible patients were those in the ICU for whom nephrologic consultation was obtained; AKI was defined as an increase in SCr ≥0.5 mg/dl if baseline ≤1.5 mg/dl, or an increase of ≥1.0 if baseline SCr was between 1.6 and 4.9. Unique to PICARD among AKI epidemiologic studies to date was the extensive clinical detail captured (>800 data elements per patient, including details on dialysis procedures) and limited biologic sample collection.
A total of 618 patients were enrolled in PICARD. One of the most illustrative findings in PICARD was the degree of heterogeneity of patients with AKI across the five medical centers in terms of baseline characteristics, processes of care, and in-hospital mortality. Even across five academic medical centers, in hospital mortality associated with AKI from ATN and nephrotoxins ranged from a low of 24% to a high of 62%. Substantial differences in process of care were also evident across the five sites in terms of dialysis modality. Despite the many differences, however, the presumed etiologies of AKI were relatively similar among institutions. Fully fifty percent of patients were labeled as having ATN with no specified precipitant. The next most common etiologies included nephrotoxin administration (26%), cardiac disease (20%, including myocardial infarction, cardiogenic shock, and congestive heart failure), ATN from hypotension (20%), ATN from sepsis (19%), unresolved prerenal factors (16%), and liver disease (11%). The PICARD cohort has been the subject of subsequent epidemiologic studies to derive prediction rules for mortality (16) and to explore the associations between dialysis modality (17) and timing of initiation and survival (18). The biologic samples from subsets of PICARD participants have been used to study urea volume of distribution (19), insulin resistance (20), cytokine levels (21), and oxidative stress (22) in patients with AKI.
The largest and most inclusive cohort study of AKI to date was conducted by the Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) investigators (23). They prospectively studied patients admitted to 54 ICUs across 23 countries over 15 mo beginning in September 2000. The target population was patients with severe AKI: inclusion criteria were treatment with renal replacement therapy or AKI defined as oliguria (<200 ml in 12 h) or BUN >84 mg/dl. Of 29,269 patients admitted to the ICUs, 1738 (5.7%) had AKI. The most common causes of AKI were septic shock (47.5%), major surgery (34%), cardiogenic shock (27%), hypovolemia (26%), and nephrotoxin administration (19%) (multiple causes were allowed on the data collection form, accounting for total >100%).
The overall in-hospital mortality rate in the BEST Kidney cohort study was 60.2%. As with PICARD, mortality varied widely across centers. Among countries contributing more than 100 patients to the cohort, in-hospital mortality ranged from 50.5% to 76.8%. A multivariable logistic regression model to identify independent correlates of in-hospital mortality yielded several previously identified risk factors also found in PICARD (16) and/or the French Study Group (13), including delayed AKI, age, sepsis, and a generic disease severity score that included BUN and urine output. Follow-up studies from the BEST Kidney multinational database have compared severity scoring systems for AKI-related mortality (24) and investigated the relationship between diuretic administration and mortality (25).
Administrative Database Studies
Medical administrative and claims databases afford investigators the opportunity to study AKI in vast numbers of patients over multiple years admitted to a wide spectrum of hospitals, including those not ordinarily represented in prospective cohort studies. The major limitation of most administrative databases is the lack of detailed clinical and laboratory information. The International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes for ARF (584.x) and renal replacement therapies (39.95) have been shown to be accurate for the identification of patients with severe AKI (defined as AKI requiring dialysis, or AKI-D), but less accurate for AKI not requiring dialysis (26).
Two studies to date have used large administrative and/or claims databases to study secular trends in the epidemiology of AKI in the United States. Xue et al. used inpatient claims data from a 5% sample of Medicare beneficiaries to investigate the incidence and mortality of acute renal failure between 1992 and 2001 (27). Waikar et al. used the Nationwide Inpatient Sample (NIS), a nationally representative database of hospital discharges, to study AKI from 1988 and 2002 (28). Using the same ICD-9-CM codes to identify AKI and a similar and partially overlapping study population, the two studies found a marked rise in the incidence and fall in the mortality associated with AKI and AKI-D. Among Medicare beneficiaries, the incidence of AKI rose from 14 to 35 per 1000 discharges between 1992 and 2001; in the NIS, which unlike the Medicare database includes patients under the age of 65, the incidence of AKI rose from 4 to 21 per 1000 discharges between 1988 and 2002. Both studies showed a statistically significant decline in mortality, in contrast to the prevailing wisdom and a recent systematic review, which suggest that mortality rates have remained unchanged over decades (29). Increasing incidence and declining mortality of AKI have also been demonstrated using a large database of critically ill patients admitted to ICUs in Australia and New Zealand (30).
Liangos et al. used the National Hospital Discharge Survey (NHDS), a nationally representative hospital discharge database different from the NIS database used by Waikar et al. (28), to study AKI in patients admitted in 2001 (31). Using the same diagnosis codes, they reported that 19 per 1000 discharges had AKI and that 21.3% died in-hospital, virtually identical to the findings in the NIS.
Both NIS and NHDS studies documented that patients with AKI have a median length of stay of 7 d and that approximately one fourth are discharged to skilled nursing facilities. Costs attributable to AKI were not reported in the NIS, NHDS, or the Medicare analyses. Costs were addressed in a study by Fischer et al. involving administrative data from 23 Massachusetts hospitals (32). They reported that uncomplicated ARF (i.e., excluding patients in the ICU) had the third highest median direct hospital costs ($2600) after acute myocardial infarction and stroke.
The study from the NIS estimated the incidence of AKI at 288 per 100,000 U.S. population in 2002; the incidence of AKI-D was estimated to be 27 per 100,000 population. Other investigators have performed population-based epidemiology studies and estimated AKI-D rates of 45 per 100,000 (Manchester, United Kingdom) (33), 20 per 100,000 (Scotland) (34), and 8 per 100,000 (Australia) (35).
Hsu et al. used a large integrated administrative and laboratory database from Kaiser Permanente Northern California to estimate the community-based incidence of AKI using SCr-based definitions rather than administrative codes (36). They confirmed the finding of a rising incidence of AKI over time: between 1996 and 2003, the incidence of AKI not requiring dialysis increased from 323 to 522 per 100,000, whereas the incidence of AKI-D increased from 20 to 30 per 100,000 in keeping with estimates derived from the nationally representative NIS study (28).
The reasons for increased incidence of AKI are not entirely clear. Differing coding practices (“DRG creep”) have been implicated in describing similar trends for other conditions but probably do not explain the increase in AKI incidence, as AKI requiring dialysis should be less susceptible to overcoding (and a corresponding increase in the incidence of AKI requiring dialysis was consistently observed). Moreover, the study by Hsu et al. (36) defined AKI using changes in SCr without depending on diagnosis codes. Alternatively, increasing severity of illness and comorbidity along with expanded use of invasive procedures in higher-risk patients could have contributed to these trends. Despite a general trend toward more severely and chronically ill patients in hospital, mortality rates associated with AKI have declined. We do not think that differing coding practices can account for the decline in mortality, particularly among individuals with AKI requiring dialysis. Indeed, Waikar et al. demonstrated significant declines in mortality in stratified analysis of concomitant medical conditions (28). Whether better outcomes (perhaps more fairly described as slightly less terrible outcomes) are attributable to improved nephrology care, improved ICU and/or general hospital care, or other factors is unknown and warrants further study.
Epidemiology in Disease-Specific States
Estimates of the incidence of AKI and associated mortality have been performed in numerous conditions, including sepsis, contrast nephropathy, major surgery, and nephrotoxic antibiotic administration. Several of the largest of studies are summarized in Table 1. A striking and consistent finding is the marked increase in mortality associated with the development of AKI. Studies that have identified risk factors for the development of AKI or AKI-D using multivariable regression models are described in Table 2. Attempts at deriving risk factors or prediction rules for AKI-associated mortality are described in Table 3.
Small Changes in Serum Creatinine
In one of the first studies to examine the independent association between AKI and mortality, Levy et al. showed that, in patients undergoing radiocontrast procedures, an increase in SCr of ≥25% to at least 2 mg/dl was associated with a 5.5-fold higher odds of death, after adjustment for comorbid medical conditions (37). Recent studies have explored whether the association between AKI and mortality extends to less severe kidney injury, as assessed by smaller increases in SCr. In a consecutive sample of 19,982 adults admitted to an urban medical center, Chertow et al. found that patients with an increase in SCr of just 0.3 to 0.4 mg/dl had a 70% higher multivariable-adjusted odds of death than patients with little or no change in SCr (38). Other investigators have reported comparable findings in patients with congestive heart failure (39,40) and those undergoing cardiac surgery (41–44). Brown et al. studied 1391 undergoing coronary artery bypass graft to investigate the prognostic significance of varying cutoffs for perioperative increases in SCr (41). Compared with patients with less than 25% change in SCr, those with a 50% to 99% increase in SCr had a 6.6-fold increased risk of death at 90 d, adjusted for age and sex. These authors did not find a significant difference in mortality among patients with a 25% to 49% increase in SCr (hazard ratio = 1.80; 95% confidence interval [CI], 0.73 to 4.44).
In recognition of the potential clinical importance of small changes in kidney function and the need to standardize definitions of AKI for clinical and research purposes, the Acute Dialysis Quality Initiative has proposed the RIFLE criteria for the classification of AKI (45). The RIFLE criteria provide a graded definition of AKI severity, starting at the lowest stage (“Risk,” defined as oliguria for over 6 h or an increase in SCr of at least 50%). Progressively more severe injury, as defined by an increase in SCr or duration and severity of oliguria, is denoted by “Injury” and “Failure.” The final two stages correspond to the provision of renal replacement therapy and its duration for >4 wk (“Loss”) or >3 mo (“ESRD”). The Acute Kidney Injury Network (46) has proposed a similar system that incorporates 3 stages of increasing disease severity. The criteria are identical to the first 3 stages of RIFLE, with the exception of a lower creatinine threshold (≥0.3 mg/dl increase in SCr) for “stage 1” AKI and the requirement that the SCr threshold be reached within 48 h.
Whether the RIFLE or AKIN criteria will be widely adopted in medicine will depend upon the demonstration of their utility and validity. Research has begun on the incidence and prognosis associated with the various stages of RIFLE (47–53). One large study of 5383 ICU admissions at a single center used an integrated database with physiologic and laboratory information to show that more than two-thirds of all patients had some evidence of AKI during admission and that more than one-half of patients with “Risk” progressed; the hazard ratio for in-hospital mortality according to maximum RIFLE classification was NS for “Risk,” of borderline statistical significance for “Injury” (1.40; 95% CI, 1.02 to 1.88) and significant for “Failure” (HR = 2.7; 95% CI, 2.03 to 3.55) (53). The extent to which the RIFLE or AKIN criteria misclassify patients because of the urine output criterion has not been investigated sufficiently and remains to be determined in future studies.
AKI in the Setting of CKD
It is intuitive that an already damaged organ is at heightened risk of acute injury. Indeed, elevated baseline SCr has been consistently observed to be a risk factor for the development of AKI in a number of settings, including radiocontrast administration, cardiac surgery, and sepsis (Table 2). Patients with CKD constitute a large fraction of patients with AKI in cohort studies. One third of patients in the PICARD cohort had CKD stage IV or above (16). Similarly, in the BEST cohort, 30% of patients had impaired kidney function (defined as “any abnormal serum level of creatinine or creatinine clearance before hospitalization”), whereas 15% had unknown baseline kidney function (23). In the cohort study by Nash et al., 151 of 332 patients with AKI had SCr concentrations >1.2 mg/dl at baseline (10). Interestingly, patients with CKD have been reported in some studies to have lower in-hospital mortality than patients without CKD who develop AKI. This finding has been noted in large database studies as well as studies to identify predictors of mortality following AKI. For example, among patients included in the NIS, 22% of patients with CKD and AKI-D died in hospital, compared with 30% of patients without CKD (28). In the PICARD cohort, baseline CKD conferred a 43% (95% CI, 16% to 61%) lower adjusted odds of in-hospital mortality (16); CKD was not associated with lower mortality in the BEST Kidney cohort (23). Used as a continuous variable, higher baseline SCr has also been associated with lower mortality in studies examining outcomes after AKI (16,54). Reasons that may underlie this seemingly paradoxical finding include confounding by malnutrition (and lower SCr values from low muscle mass) and unrecorded differences in disease severity between those with and without CKD who develop AKI. The latter may reflect relatively less severe kidney injury required in patients with CKD to manifest AKI, as currently diagnosed.
The presence or absence of CKD likely influences long-term outcome in survivors of AKI-D. In a population-based surveillance study of AKI from Calgary, among all patients with AKI who required maintenance dialysis 1 yr after hospital admission, 63% had preexisting CKD (median baseline SCr = 2.6 mg/dl) (55).
Because the presence of CKD influences the risk of AKI, its consequences, and the propensity for the development of end-stage renal disease, future studies of AKI epidemiology should use definitions that incorporate baseline CKD stage, as has been suggested by others (56,57). Likewise, prevention and intervention studies of AKI should be stratified on baseline kidney function.
Newer Markers of Glomerular Filtration Rate (GFR)
A reduction in GFR remains the sine qua non for the clinical diagnosis of AKI; however, SCr is an imperfect marker of GFR because of tubular secretion, the need for steady-state determinations for accurate GFR estimates, and the confounding influences of muscle mass and changes in volume of distribution, the latter particularly in the setting of acute illness. Assessment of GFR by gold standards, such as iothalamate or inulin clearance, is cumbersome and impractical in the acute setting. The best studied alternative to SCr as an endogenous GFR marker is cystatin C. Cystatin C is a low molecular weight protein produced by all nucleated cells that is freely filtered by the glomerulus and then reabsorbed and metabolized by the proximal tubule. Several studies in AKI suggest that cystatin C may be superior to SCr for the earlier detection of reduced GFR (58–61). Like any circulating substance, serum levels of cystatin C are dependent not only on clearance but also on production rate and acute changes in the volume of distribution. Higher doses of corticosteroid and hyperthyroidism increase and hypothyroidism decreases serum cystatin C. Although previously a concern, (62), it does not appear that inflammation significantly alters serum cystatin C concentrations (63).
In a single study, cystatin C was compared with proatrial natriuretic peptide (1–98), a circulating prohormone of atrial natriuretic peptide that has been studied as an index of kidney function in patients with heart failure. In 29 critically ill patients with sepsis, Mazul-Sunko et al. reported that pro-ANP (1–98) was superior to cystatin C for the prediction of AKI (64). Confirmatory studies are needed.
The new term AKI heralds a paradigm shift for our conceptualization of the syndrome previously called “acute renal failure.” It is worth considering each of the three terms in turn. “Acute” refers to the temporal nature of the disease process and is designed to exclude the many, usually irreversible, causes of CKD. The recent RIFLE and AKIN classifications specify the time period as “abrupt” and “within 48 h.” Whether the tempo of the rise in serum creatinine (or other biomarkers) is relevant in terms of prognosis of diagnosis remains to be evaluated. “Renal” refers of course to the organ sustaining the damage, but interestingly to only one of the many functions of the kidney, namely, GFR. A reduction in GFR is not always observed in cases of even severe parenchymal injury, as seen in cases of lupus nephritis. Also, reductions in GFR can be observed in cases of no evident pathology, as in some cases of prerenal azotemia. “Failure” refers to organ failure as assessed by a marker of GFR, namely, BUN or creatinine.
The new phrase AKI retains one word, harmlessly substitutes a synonym for another, but replaces “failure” with “injury.” This last substitution may very well redefine the epidemiology of the syndrome. Currently, the diagnosis of “injury” rests on an elevation in serum creatinine, which is understood to be neither perfectly sensitive nor specific. Newer biomarkers under consideration aim in general to identify correlates of cellular (typically tubular cell) injury. Importantly, tubular cell injury may precede or not always lead to a reduction in GFR. The concept that injury to the tubule should cause such a decline in a morphologically and functionally distinct part of the nephron rests upon a series of downstream events, such as tubular obstruction by necrotic debris leading to backflow, creatinine absorption, tubuloglomerular feedback, and intense vasoconstriction from release of inflammatory mediators. What if biomarkers are able to identify tubular injury at a stage even before GFR begins to fall? Would such biomarkers be discarded as nonspecific because they can be elevated without a rise in serum creatinine or another marker of GFR? Perhaps AKI is more common and consequential than currently appreciated on the basis of proxies of GFR, such as SCr, BUN, or cystatin C. Not all cases of AKI, particularly those now identified on the basis of small and transient rises in SCr, reflect structural injury. In other words, markers of GFR may not be true gold standards against which all biomarkers should be judged. In the future, clinical investigators should consider biomarkers of AKI that reflect important consequences of the injury (e.g., death, need for dialysis, hospital length of stay) whether or not they correspond to changes in SCr or other markers of GFR.
Early identification of kidney injury will be critical for future developments in treatment or prevention of AKI. Advances in the care of patients with stroke, myocardial infarction, and sepsis have been made possible by early intervention, which is in turn possible only with early diagnosis.
The earliest sign of ischemic or nephrotoxic AKI may not be a decline in GFR, in much the same way that a decrease in cardiac output or albumin synthesis are not early signs of cardiac or hepatic injury. Time-honored tests, such as urinary microscopy, urine osmolality, and fractional excretion of sodium or urea are nonspecific and insensitive, although careful and large prospective studies evaluating these parameters have not been conducted (65).
The biologic response of kidney tissue to ischemic or nephrotoxic injury may be used as early indicators of AKI. Urine has been investigated as a more promising biologic fluid than serum or plasma to identify the earliest markers of kidney injury. Urinary injury markers may be present in the urine because of impaired tubular reabsorption and catabolism of filtered molecules, release of enzymes or exosomes from tubular cells, and as a response of tubular cells to ischemic or nephrotoxic injury. Table 2 lists several promising urinary biomarkers that have been studied in humans in the context of AKI (not including kidney transplantation).
Neutrophil Gelatinase-Associated Lipocalin (NGAL)
NGAL is one of the best studied urinary biomarkers of AKI to date. Also known as lipocalin-2 or siderocalin, NGAL was first discovered as a protein in granules of human neutrophils; animal studies showed its promise as an early marker of ischemic and nephrotoxic kidney injury (66).
Mishra et al. prospectively obtained serial urine and serum samples from 71 children undergoing cardiopulmonary bypass (CPB) for surgical correction of congenital heart disease (67). Twenty children developed AKI, defined as a 50% increase in SCr. Urinary NGAL at just 2 h after CPB almost perfectly predicted which patients would go on to develop AKI. Two-hour NGAL levels more than 50 mg/L had 100% sensitivity and 98% specificity for the diagnosis of AKI, which was made 24 to 72 h after CPB. A measure of the diagnostic performance characteristics of a test is the area under the receiver operating characteristics curve (AUC-ROC), which ranges from 0.50 (no better than chance alone) to 1.0 (perfect test). In the setting of pediatric patients after CPB, the AUC-ROC for urinary NGAL at 2 h was a remarkable 0.998. In this study, serum NGAL was inferior to urinary NGAL for the identification of AKI. As encouraging as these results were, it should be noted that 29% of eligible patients were excluded because of perioperative use of ibuprofen, angiotensin-converting enzyme inhibitors, gentamicin, or vancomycin.
Other studies showed less impressive results. Wagener et al. reported results on urinary NGAL in 81 adult patients undergoing cardiac surgery; the only exclusion criterion was preexisting end-stage renal disease (68). Sixteen patients developed AKI, defined as a 50% increase in SCr. Urinary NGAL levels were consistently higher immediately postoperatively and at 1, 3, 18, and 24 h postoperatively in patients who went on to develop AKI. However, substantial overlap was noted between patients who did and did not develop AKI. The AUC-ROC for NGAL ranged from 0.67 (immediately after surgery) to 0.80 (18 h following surgery). At 3 h after surgery, urinary NGAL levels more than 213 mg/L had 69% sensitivity and 65% specificity for the diagnosis of AKI. Bachorzewska-Gajewska et al. measured urinary and serum NGAL in 35 patients undergoing elective percutaneous coronary intervention (69). No patient developed contrast nephropathy defined as an increase in SCr. Urinary NGAL was studied in 53 consecutive patients undergoing living or deceased donor kidney transplantation. NGAL levels (normalized to urine creatinine concentration) were significantly higher in deceased donor recipients with delayed graft function (DGF) (n = 10, median 3306 ng/mg creatinine) than after prompt graft function (n = 20, median 756 ng/mg creatinine). A cutoff of 1000 ng/mg creatinine had 90% sensitivity and 83% specificity for the identification of DGF; the AUC-ROC was 0.90. Not reported in this paper was the influence of the normalization of NGAL levels to urine creatinine or the non-normalized NGAL results. Urine creatinine is used as a proxy for urine flow rate to account for differences in the concentration in urine. This normalization approach has been validated in the setting of estimates of 24 h protein or albumin excretion (70), but not in the setting of AKI when the urinary creatinine concentration may decline because of low GFR. Zappitelli et al. studied urinary NGAL in 140 children admitted to the ICU requiring mechanical ventilation (71). Urine was collected daily for 4 d. The authors found on cross-sectional analysis that mean and peak urinary NGAL levels were higher in patients with worsening degrees of AKI (as judged by the pediatric RIFLE criteria (72). At 48 h before the development of AKI, urinary NGAL had an AUC-ROC of 0.79 for the subsequent development of AKI.
IL-18 was found to mediate ischemic AKI and to be detectable in the urine of mice subjected to ischemic kidney injury (73). Urinary IL-18 has been studied by Parikh et al. in a variety of clinical settings, including delayed graft function (74), cardiac surgery (75), and acute respiratory distress syndrome (76) and in patients with and without acute and chronic kidney disease (77). The first AKI study of urinary IL-18 in humans was a cross-sectional comparison of ATN (n = 14), healthy controls (n = 11), prerenal azotemia (n = 8), urinary tract infection (n = 5), CKD (n = 12), and transplant recipients (n = 22) (77). The highest levels of urinary IL-18 were observed in patients with ATN and delayed graft function, with relatively little overlap from patients with prerenal azotemia, urinary tract infections, and CKD. The AUC-ROC from this cross-sectional cohort (for the identification of ATN, including delayed graft function) was 0.95, with a sensitivity of 85% and specificity of 88% at a cutoff of 500 pg IL-18/mg creatinine.
The NIH sponsored Acute Respiratory Distress Syndrome Network trial of low versus high tidal volume ventilation was the source of urine samples in a subsequent study of urinary IL-18 (76). Parikh et al. performed a nested case-control study in 138 of the 861 patients enrolled; exclusion criteria included a baseline SCr more than 1.2 mg/dl. Urinary IL-18 levels were higher in patients who developed AKI (defined as a 50% increase in SCr within 6 d of enrollment), and higher levels were associated with mortality. The AUC-ROC for IL-18 (not normalized to urine creatinine) was 0.73 at 24 h before AKI diagnosis. Parikh et al. also measured IL-18 in urine samples collected in the pediatric cardiac surgery cohort used to study NGAL (67). They measured IL-18 in all 20 cases of AKI and in 35 of the 51 non-AKI cases (matched according to race, gender, and age to AKI cases). Compared with NGAL, which increased 25-fold within 2 h and declined after 6 h of CPB, IL-18 increased at 4 to 6 h and remained elevated up to 48 h after CPB. The reported AUC-ROCs for IL-18 were 0.61 at 4 h, 0.75 at 12 h, and 0.73 at 24 h, lower than the 0.998 reported by Mishra for NGAL at 2 h after CPB. IL-18 was also studied by Washburn et al. (78) in critically ill children requiring mechanical ventilation (identical cohort as studied by Zappitelli et al. for NGAL71). They found on cross-sectional analysis that peak urinary IL-18 levels were higher in patients with worsening degrees of AKI (as judged by the pediatric RIFLE criteria (72)). However, in prospective analysis, IL-18 demonstrated no ability to predict the subsequent development of AKI (AUC-ROC = 0.54). Not surprising for a pro-inflammatory cytokine that plays an important role in sepsis, urinary IL-18 was significantly higher in patients with sepsis than in those without, and limited its diagnostic ability for the early identification of AKI in this cohort.
Na+/H+ Exchanger Isoform 3 (NHE3)
NHE3 is the most abundant sodium transporter in the renal tubule and is responsible for proximal reabsorption of up to 70% of filtered sodium and bicarbonate. du Cheyron et al. performed a cross-sectional study of 68 patients admitted to the ICU (79). They isolated membrane fractions from the urine and measured NHE3 concentrations using semiquantitative immunoblotting. NHE3 protein was undetectable in patients without AKI (n = 14), detectable at relatively low levels in prerenal azotemia (n = 17) and postrenal obstruction (n = 3), and was significantly elevated in ATN (n = 17; 6.6-fold higher than in prerenal azotemia). The same investigators also measured urinary retinol binding protein (RBP), the primary plasma transport protein for vitamin A, a molecule that gets filtered by the glomerulus and reabsorbed by the proximal tubule. Urinary RBP was significantly higher in patients with ATN than normal controls, but significant overlap was noted, particularly with prerenal azotemia.
Kidney Injury Molecule-1 (KIM-1)
KIM-1 was identified as a markedly upregulated gene in postischemic rat kidney using a polymerase chain reaction-based technique (80). The ectodomain of KIM-1 protein is shed from cells into the urine in rodents and in humans. Han et al. (81) demonstrated marked expression of KIM-1 in kidney biopsy specimens from 6 patients with acute tubular necrosis (ATN), and found elevated urinary levels of KIM-1 in 7 patients with ischemic ATN; urinary levels of KIM-1 were significantly lower in contrast nephropathy (n = 7) although the levels did correlate with severity of contrast-induced injury. Levels of urinary KIM-1 were lower in AKI not due to ATN (n = 9), CKD (n = 9), and were below limits of detection in normal subjects (n = 8). van Timmeren et al. stained for KIM-1 protein in tissue specimens from 102 patients who underwent kidney biopsy for a variety of kidney diseases and 7 patients who underwent nephrectomy for renal cell carcinoma (82). No tissue KIM-1 was found in patients with minimal change disease or in the tumor-free samples of renal cell carcinoma. In all other disease conditions, KIM-1 protein was identified in dedifferentiated proximal tubular cells and correlated with tubulointerstitial fibrosis and inflammation. In the subset of patients who underwent urine collection near the time of biopsy, urinary KIM-1 levels correlated with tissue expression of KIM-1. Urinary KIM-1 may therefore hold promise as a noninvasive assessment of the activity and prognosis of a variety of acute and CKDs. Liangos et al. studied urinary KIM-1 at the time of nephrology consultation in 201 patients with established AKI (83). Because non-AKI controls were not included in this study, diagnostic performance characteristics, such as sensitivity, specificity, or the AUC-ROC curve were not reported. KIM-1 demonstrated prognostic significance: elevated levels were significantly associated with the clinical composite endpoint of death or dialysis requirement, even after adjustment for disease severity or comorbidity. Urinary KIM-1 was also measured by Han et al. (84) in samples from the same pediatric cardiac surgery cohort that was used for prospective studies on urinary NGAL and IL-18. Urinary KIM-1 at 12 h after CPB had an AUC-ROC of 0.83 for the subsequent development of AKI, as defined as an increase in SCr of ≥50%.
Tubular Enzymes and Markers of Tubular Dysfunction
The apical surface of proximal tubular epithelial cells contains numerous microvilli that form the brush border and contain specific proteins to carry out the specialized functions of the proximal tubule. After kidney injury, these tubular enzymes can often be recovered in the urine. Several different classes of enzymes can be found: lysosomal proteins, such as N-acetyl-β-(D)-glucosaminidase (NAG), brush border enzymes, including g-glutamyltransferse (GGT) and alkaline phosphatase, as well as cytosolic proteins, such as α-glutathione s-transferase (GST) and π-GST. Furthermore, when proximal tubular epithelial cells are injured, they may not metabolize cystatin C properly, and intact cystatin may be shed into the urine. Similarly, injured cells may not completely reabsorb low molecular weight proteins that are freely filtered into the urinary space, such as α1 and β2-microglobulin.
In one of the most comprehensive studies performed to date, Westhuyzen et al. (140) compared the predictive value of a number of tubular enzymes for the subsequent development of AKI, defined as a 50% rise in SCr to at least 1.7 mg/dl. Four of 26 subjects developed AKI; baseline levels of GGT, AP, NAG, α-GST, and π-GST were higher in those who developed AKI compared with those who did not. GGT and π-GST had the best predictive value on their own, with AUC-ROC of 0.95 (95% CI, 0.79 to 1.0) and 0.93 (95% CI, 0.74 to 1.0), respectively. Changes in enzyme levels preceded detectable changes in timed creatinine clearance. However, when the authors attempted to develop cutpoints based on this small study and tested the generalizability of their results in a test population of 19 patients (4 of whom developed AKI), the sensitivity and specificity of these biomarkers were significantly reduced. Furthermore, the timing of AKI after study enrollment ranged from 12 h to 4 d in the original study population, so the precise timing of the rise in these markers relative to AKI is also unclear. Further studies are needed to determine how predictive these markers are for AKI in a larger population of patients.
Herget-Rosenthal et al. risk-stratified patients with nonoliguric AKI (defined as a doubling in creatinine from a baseline concentration of <106 μmol/L to at least 115 μmol/L) using tubular enzymes as biomarkers (141). They identified 73 subjects who met prespecified criteria for AKI; 26 of these individuals subsequently required dialysis. They measured urinary excretion of cystatin C, α1 and β2 microglobulin, α-GST, NAG, RBP, GGT, and lactate dehydrogenase on the day of study enrollment. On average, subjects required dialysis 4 d after study enrollment. Cystatin C and α1-microglobulin (markers of abnormal proximal tubule function) had the best predictive value for the need for dialysis, with AUC-ROC curve of 0.92 and 0.86, respectively. Of the tubular enzymes studied, NAG had the best predictive value, with an AUC-ROC of 0.81. Similarly, Chew et al. risk-stratified patients with AKI based on levels of tubular enzymes (142); levels of NAG and alkaline phosphatase were higher in patients with poor outcomes (defined as need for dialysis or death).
Tubular enzymes have been studied as markers of AKI for over two decades, yet they have not been adopted in widespread clinical use either as early diagnostic tests or surrogate endpoints for interventional studies. Some authors have suggested that tubular enzymes are overly sensitive because they tend to rise after injuries such as CPB without an associated rise in SCr (85,86). While tubular enzymes may not prove to be particularly valuable biomarkers, it is unclear that a change in SCr is a satisfactory standard against which to judge their merit. Well-designed and adequately powered clinical studies with appropriately chosen endpoints will be needed to settle these issues.
Keratinocyte-derived chemokine was found in a mouse model of renal ischemia-reperfusion injury to be elevated in serum and urine 3 h after injury (87). These investigators measured urinary levels of a structurally homologous molecule in humans, termed human growth-related oncogene-alpha (Gro-alpha), in a small pilot study of patients (n = 17) undergoing kidney transplantation, and found markedly higher levels among those with DGF following deceased donor transplantation. Zhou et al. have focused on urinary exosomes (small excreted vesicles that contain membrane and cytosolic proteins) as a potential source of novel AKI biomarkers (88). Exosomal fetuin-A was identified in preclinical rodent models of ischemic and cisplatin-induced AKI; a small pilot study in 9 humans showed exosomal fetuin-A to be present in the urine of ICU patients with AKI but not in healthy volunteers or ICU patients without AKI (88).
Availability of Multiple Biomarkers
The various biomarkers under clinical investigation will likely perform differently with respect to disease specificity (e.g., sepsis versus nephrotoxic versus postoperative AKI), time course (early versus late markers), and prognostic characteristics (e.g., markers of incipient AKI versus markers of prognosis in established AKI). Whether a panel of biomarkers would provide complementary information and be practical in use compared with a single biomarker approach remains to be determined. Establishing the optimal test(s) will require prospective validation in large numbers of patients with a variety of causes of AKI. The possibility that injury biomarkers may be superior to SCr or other clearance-based markers for the identification of AKI will require investigators to test the creatinine-independent associations between biomarker levels and exposures (e.g., CPB time, dose of nephrotoxin administration) and outcomes (e.g., not only AKI as defined by change in SCr or cystatin C but mortality, complications, need for dialysis, and length of stay and other outcomes).
Prevention of AKI
Innumerable AKI prevention studies have been conducted over the past three decades, the vast majority of which have targeted persons anticipating exposure to radiocontrast, often persons at above average risk, owing to the presence of diabetes mellitus, with or without underlying CKD. Volume expansion, diuretic agents, vasoactive drugs (including dopamine and related compounds aimed to augment renal blood flow), growth factors, and antioxidants have been the most widely studied, with some clinical trials showing dramatic results: up to a 90% reduction in AKI incidence. However, there are numerous methodologic problems with many of these studies. First, the majority of cases of AKI cannot be anticipated, so that we cannot generalize results obtained in the setting of radiocontrast or antibiotic or chemotherapy exposure to the more common setting of AKI complicating multisystem disease. Second, virtually all prevention studies are underpowered, regardless of the result (89). Thus, our confidence in the results, either negative or positive, is limited. Until we can effectively identify truly high-risk (e.g., ≥20% to 30% incidence of clinically meaningful AKI) subjects, probably using a combination of clinical risk factors and one or more biomarkers (Availability of Multiple Biomarkers), our attention should be focused on studies aimed to reduce the consequences of established AKI.
Treatment of Established AKI
Clinical trials of pharmacologic therapies for established AKI have been uniformly negative to date. These have included reasonably well-designed and executed trials of atrial natiuretic peptide (90) and insulin-like growth factor-1 (91). One of the major design issues with these trials has been delayed enrollment long after the onset of kidney injury. For example, in the Auriculin Anaritide Acute Renal Failure study of atrial natiuretic peptide, the mean SCr at enrollment was greater than 4.5 mg/dl. This delay in study enrollment is likely attributable to our currently limited armamentarium of biomarkers for AKI; SCr, as has been discussed, is a marker of GFR rather than injury per se and therefore reflects severe and established injury.
Several clinical trials have focused on established and severe AKI, such as diuretics to attenuate renal injury and variations in dialysis prescription to improve renal recovery and overall survival. However, it is clear from recent epidemiology studies that even mild AKI is important clinically and that not all individuals with mild AKI progress to severe disease. Other markers of GFR (e.g., cystatin C) or biomarkers of kidney injury and recovery may prove to be predictive tools in the much larger number of individuals with early or less severe AKI and allow for rigorously designed therapeutic trials.
AKI is an increasingly common and potentially catastrophic complication in hospitalized patients. Our understanding of the incidence and consequences of AKI has grown considerably, yet mortality rates remain unacceptably high despite significant advances in the care of the critically ill. The diagnostic approach to AKI has stagnated and rests today on the same biomarkers (BUN, creatinine) used for several decades. To improve the identification of patients at risk of AKI and their care in the years to come, novel approaches for early diagnosis and risk stratification are needed. Prevention and treatment strategies for AKI will be facilitated by ongoing basic and clinical science investigations in this critical field.
Published online ahead of print. Publication date available at www.cjasn.org.
1. Abercrombie J: Observations on ischuria renalis. Edinburgh Med J10 :210– 222,1821
2. Marketos SG, Eftychiadis AG, Diamandopoulos A: Acute renal failure according to ancient Greek and Byzantine medical writers. J R Soc Med86 :290– 293,1993
3. Eknoyan G, Bulger RE, Dobyan DC: Mercuric chloride-induced acute renal failure in the rat: I. Correlation of functional and morphologic changes and their modification by clonidine. Lab Invest46 :613– 620,1982
4. Bywaters EG, Beall D: Crush injuries with impairment of renal function. 1941. J Am Soc Nephrol9 :322– 332,1998
5. Davies FC, Weldon RP: A contribution to the study of “war nephritis.” Lancet2 :118– 120,1917
6. Yorkes W, Nauss RN: The mechanism of the production of suppression of urine in blackwater fever. Ann Trop Med Parasitol12 :287– 312,1911
7. Osler W: The Principles and Practice of Medicine,1912
8. Hou SH, Bushinsky DA, Wish JB, Cohen JJ, Harrington JT: Hospital-acquired renal insufficiency: A prospective study. Am J Med74 :243– 248,1983
9. Shusterman N, Strom BL, Murray TG, Morrison G, West SL, Maislin G: Risk factors and outcome of hospital-acquired acute renal failure: Clinical epidemiologic study. Am J Med83 :65– 71,1987
10. Nash K, Hafeez A, Hou S: Hospital-acquired renal insufficiency. Am J Kidney Dis39 :930– 936,2002
11. Lian[Combining Tilde]o F, Pascual J: Epidemiology of acute renal failure: A prospective, multicenter, community-based study. Madrid Acute Renal Failure Study Group. Kidney Int50 :811– 818,1996
12. Lian[Combining Tilde]o F, Junco E, Pascual J, Madero R, Verde E: The spectrum of acute renal failure in the intensive care unit compared with that seen in other settings: the Madrid Acute Renal Failure Study Group. Kidney Int Suppl66 :S16– S24,1998
13. Brivet FG, Kleinknecht DJ, Loirat P, Landais PJ: Acute renal failure in intensive care units–causes, outcome, and prognostic factors of hospital mortality: A prospective, multicenter study. French Study Group on Acute Renal Failure. Crit Care Med24 :192– 198,1996
14. Guerin C, Girard R, Selli JM, Perdrix JP, Ayzac L: Initial versus delayed acute renal failure in the intensive care unit: A multicenter prospective epidemiological study. Rhone-Alpes Area Study Group on Acute Renal Failure. Am J Respir Crit Care Med161 :872– 879,2000
15. Mehta RL, Pascual MT, Soroko S, Savage BR, Himmelfarb J, Ikizler TA, Paganini EP, Chertow GM: Spectrum of acute renal failure in the intensive care unit: The PICARD experience. Kidney Int66 :1613– 1621,2004
16. Chertow GM, Soroko SH, Paganini EP, Cho KC, Himmelfarb J, Ikizler TA, Mehta RL: Mortality after acute renal failure: Models for prognostic stratification and risk adjustment. Kidney Int70 :1120– 1126,2006
17. Cho KC, Himmelfarb J, Paganini E, Ikizler TA, Soroko SH, Mehta RL, Chertow GM: Survival by dialysis modality in critically ill patients with acute kidney injury. J Am Soc Nephrol17 :3132– 3138,2006
18. Liu KD, Himmelfarb J, Paganini E, Ikizler TA, Soroko SH, Mehta RL, Chertow GM: Timing of initiation of dialysis in critically ill patients with acute kidney injury. Clin J Soc Nephrol1 :915– 919,2006
19. Ikizler TA, Sezer MT, Flakoll PJ, Hariachar S, Kanagasundaram NS, Gritter N, Knights S, Shyr Y, Paganini E, Hakim RM, Himmelfarb J: Urea space and total body water measurements by stable isotopes in patients with acute renal failure. Kidney Int65 :725– 732,2004
20. Basi S, Pupim LB, Simmons EM, Sezer MT, Shyr Y, Freedman S, Chertow GM, Mehta RL, Paganini E, Himmelfarb J, Ikizler TA: Insulin resistance in critically ill patients with acute renal failure. Am J Physiol Renal Physiol289 :F259– F264,2005
21. Simmons EM, Himmelfarb J, Sezer MT, Chertow GM, Mehta RL, Paganini EP, Soroko S, Freedman S, Becker K, Spratt D, Shyr Y, Ikizler TA: Plasma cytokine levels predict mortality in patients with acute renal failure. Kidney Int65 :1357– 1365,2004
22. Himmelfarb J, McMonagle E, Freedman S, Klenzak J, McMenamin E, Le P, Pupim LB, Ikizler TA: The PG: Oxidative stress is increased in critically ill patients with acute renal failure. J Am Soc Nephrol15 :2449– 2456,2004
23. Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Ronco C: Acute renal failure in critically ill patients: A multinational, multicenter study. JAMA294 :813– 818,2005
24. Uchino S, Bellomo R, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Doig GS, Oudemans van Straaten H, Ronco C, Kellum JA: External validation of severity scoring systems for acute renal failure using a multinational database. Crit Care Med33 :1961– 1967,2005
25. Uchino S, Doig GS, Bellomo R, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Nacedo E, Gibney N, Tolwani A, Ronco C, Kellum JA: Diuretics and mortality in acute renal failure. Crit Care Med32 :1669– 1677,2004
26. Waikar SS, Wald R, Chertow GM, Curhan GC, Winkelmayer WC, Liangos O, Sosa MA, Jaber BL: Validity of international classification of diseases, ninth revision, clinical modification codes for acute renal failure. J Am Soc Nephrol17 :1688– 1694,2006
27. Xue JL, Daniels F, Star RA, Kimmel PL, Eggers PW, Molitoris BA, Himmelfarb J, Collins AJ: Incidence and mortality of acute renal failure in Medicare beneficiaries, 1992 to 2001. J Am Soc Nephrol17 :1135– 1142,2006
28. Waikar SS, Curhan GC, Wald R, McCarthy EP, Chertow GM: Declining mortality in patients with acute renal failure, 1988 to 2002. J Am Soc Nephrol17 :1143– 1150,2006
29. Ympa YP, Sakr Y, Reinhart K, Vincent JL: Has mortality from acute renal failure decreased? A systematic review of the literature. Am J Med118 :827– 832,2005
30. Bagshaw SM, George C, Bellomo R: Changes in the incidence and outcome for early acute kidney injury in a cohort of Australian intensive care units. Crit Care11 :R68 ,2007
31. Liangos O, Wald R, O'Bell JW, Price L, Pereira BJ, Jaber BL: Epidemiology and outcomes of acute renal failure in hospitalized patients: a national survey. Clin J Am Soc Nephrol1 :43– 51,2006
32. Fischer MJ, Brimhall BB, Lezotte DC, Glazner JE, Parikh CR: Uncomplicated acute renal failure and hospital resource utilization: a retrospective multicenter analysis. Am J Kidney Dis46 :1049– 1057,2005
33. Hegarty J, Middleton RJ, Krebs M, Hussain H, Cheung C, Ledson T, Hutchison AJ, Kalra PA, Rayner HC, Stevens PE, O'Donoghue DJ: Severe acute renal failure in adults: Place of care, incidence and outcomes. QJM98 :661– 666,2005
34. Metcalfe W, Simpson M, Khan IH, Prescott GJ, Simpson K, Smith WC, MacLeod AM: Acute renal failure requiring renal replacement therapy: Incidence and outcome. QJM95 :579– 583,2002
35. Silvester W, Bellomo R, Cole L: Epidemiology, management, and outcome of severe acute renal failure of critical illness in Australia. Crit Care Med29 :1910– 1915,2001
36. Hsu CY, McCulloch CE, Fan D, Ordonez JD, Chertow GM, Go AS: Community-based incidence of acute renal failure. Kidney Int72 :208– 212,2007
37. Levy EM, Viscoli CM, Horwitz RI: The effect of acute renal failure on mortality: A cohort analysis. JAMA275 :1489– 1494,1996
38. Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW: Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol16 :3365– 3370,2005
39. Gottlieb SS, Abraham W, Butler J, Forman DE, Loh E, Massie BM, O'Connor CM, Rich MW, Stevenson LW, Young J, Krumholz HM: The prognostic importance of different definitions of worsening renal function in congestive heart failure. J Card Fail8 :136– 141,2002
40. Smith GL, Vaccarino V, Kosiborod M, Lichtman JH, Cheng S, Watnick SG, Krumholz HM: Worsening renal function: what is a clinically meaningful change in creatinine during hospitalization with heart failure? J Card Fail9 :13– 25,2003
41. Brown JR, Cochran RP, Dacey LJ, Ross CS, Kunzelman KS, Dunton RF, Braxton JH, Charlesworth DC, Clough RA, Helm RE, Leavitt BJ, Mackenzie TA, O'Connor GT: Perioperative increases in serum creatinine are predictive of increased 90-day mortality after coronary artery bypass graft surgery. Circulation114 :I409– I413,2006
42. Lassnigg A, Schmidlin D, Mouhieddine M, Bachmann LM, Druml W, Bauer P, Hiesmayr M: Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: A prospective cohort study. J Am Soc Nephrol15 :1597– 1605,2004
43. Loef BG, Epema AH, Smilde TD, Henning RH, Ebels T, Navis G, Stegeman CA: Immediate postoperative renal function deterioration in cardiac surgical patients predicts in-hospital mortality and long-term survival. J Am Soc Nephrol16 :195– 200,2005
44. Ryckwaert F, Alric P, Picot MC, Djoufelkit K, Colson P: Incidence and circumstances of serum creatinine increase after abdominal aortic surgery. Intensive Care Med29 :1821– 1824,2003
45. Kellum JA, Bellomo R, Ronco C, Mehta R, Clark W, Levin NW: The 3rd International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI). Int J Artif Organs28 :441– 444,2005
46. Molitoris BA, Levin A, Warnock DG, Joannidis M, Mehta RL, Kellum JA, Ronco C, Shah SV: Improving outcomes of acute kidney injury: Report of an initiative. Nat Clin Pract Nephrol3 :439– 442,2007
47. Abosaif NY, Tolba YA, Heap M, Russell J, El Nahas AM: The outcome of acute renal failure in the intensive care unit according to RIFLE: Model application, sensitivity, and predictability. Am J Kidney Dis46 :1038– 1048,2005
48. Bell M, Liljestam E, Granath F, Fryckstedt J, Ekbom A, Martling CR: Optimal follow-up time after continuous renal replacement therapy in actual renal failure patients stratified with the RIFLE criteria. Nephrol Dial Transplant20 :354– 360,2005
49. Guitard J, Cointault O, Kamar N, Muscari F, Lavayssiere L, Suc B, Ribes D, Esposito L, Barange K, Durand D, Rostaing L: Acute renal failure following liver transplantation with induction therapy. Clin Nephrol65 :103– 112,2006
50. Heringlake M, Knappe M, Vargas Hein O, Lufft H, Kindgen-Milles D, Bottiger BW, Weigand MR, Klaus S, Schirmer U: Renal dysfunction according to the ADQI-RIFLE system and clinical practice patterns after cardiac surgery in Germany. Minerva Anestesiol72 :645– 654,2006
51. Kuitunen A, Vento A, Suojaranta-Ylinen R, Pettila V: Acute renal failure after cardiac surgery: Evaluation of the RIFLE classification. Ann Thorac Surg81 :542– 546,2006
52. O'Riordan A, Wong V, McQuillan R, McCormick PA, Hegarty JE, Watson AJ: Acute renal disease, as defined by the RIFLE criteria, post-liver transplantation. Am J Transplant7 :168– 176,2007
53. Hoste EA, Clermont G, Kersten A, Venkataraman R, Angus DC, De Bacquer D, Kellum JA: RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: A cohort analysis. Crit Care10 :R73 ,2006
54. Chertow GM, Christiansen CL, Cleary PD, Munro C, Lazarus JM: Prognostic stratification in critically ill patients with acute renal failure requiring dialysis. Arch Intern Med155 :1505– 1511,1995
55. Bagshaw SM, Laupland KB, Doig CJ, Mortis G, Fick GH, Mucenski M, Godinez-Luna T, Svenson LW, Rosenal T: Prognosis for long-term survival and renal recovery in critically ill patients with severe acute renal failure: a population-based study. Crit Care9 :R700– R709,2005
56. Van Biesen W, Vanholder R, Lameire N: Defining acute renal failure: RIFLE and beyond. Clin J Am Soc Nephrol1 :1314– 1319,2006
57. Mehta RL, Chertow GM: Acute renal failure definitions and classification: Time for change? J Am Soc Nephrol14 :2178– 2187,2003
58. Herget-Rosenthal S, Marggraf G, Husing J, Goring F, Pietruck F, Janssen O, Philipp T, Kribben A: Early detection of acute renal failure by serum cystatin C. Kidney Int66 :1115– 2211,2004
59. Herget-Rosenthal S, Pietruck F, Volbracht L, Philipp T, Kribben A: Serum cystatin C: A superior marker of rapidly reduced glomerular filtration after uninephrectomy in kidney donors compared to creatinine. Clin Nephrol64 :41– 46,2005
60. Villa P, Jimenez M, Soriano MC, Manzanares J, Casasnovas P: Serum cystatin C concentration as a marker of acute renal dysfunction in critically ill patients. Crit Care9 :R139– R143,2005
61. Delanaye P, Lambermont B, Chapelle JP, Gielen J, Gerard P, Rorive G: Plasmatic cystatin C for the estimation of glomerular filtration rate in intensive care units. Intensive Care Med30 :980– 983,2004
62. Knight EL, Verhave JC, Spiegelman D, Hillege HL, de Zeeuw D, Curhan GC, de Jong PE: Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int65 :1416– 1421,2004
63. Singh D, Whooley MA, Ix JH, Ali S, Shlipak MG: Association of cystatin C and estimated GFR with inflammatory biomarkers: The Heart and Soul Study. Nephrol Dial Transplant22 :1087– 1092,2007
64. Mazul-Sunko B, Zarkovic N, Vrkic N, Antoljak N, Bekavac Beslin M, Nikolic Heitzler V, Siranovic M, Krizmanic-Dekanic A, Klinger R: Proatrial natriuretic peptide (1–98), but not cystatin C, is predictive for occurrence of acute renal insufficiency in critically ill septic patients. Nephron Clin Pract97 :c103– c107,2004
65. Bagshaw SM, Langenberg C, Bellomo R: Urinary biochemistry and microscopy in septic acute renal failure: a systematic review. Am J Kidney Dis48 :695– 705,2006
66. Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, Barasch J, Devarajan P: Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol14 :2534– 2543,2003
67. Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, Ruff SM, Zahedi K, Shao M, Bean J, Mori K, Barasch J, Devarajan P: Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet365 :1231– 1238,2005
68. Wagener G, Jan M, Kim M, Mori K, Barasch JM, Sladen RN, Lee HT: Association between increases in urinary neutrophil gelatinase-associated lipocalin and acute renal dysfunction after adult cardiac surgery. Anesthesiology105 :485– 491,2006
69. Bachorzewska-Gajewska H, Malyszko J, Sitniewska E, Malyszko JS, Dobrzycki S: Neutrophil-gelatinase-associated lipocalin and renal function after percutaneous coronary interventions. Am J Nephrol26 :287– 292,2006
70. Ginsberg JM, Chang BS, Matarese RA, Garella S: Use of single voided urine samples to estimate quantitative proteinuria. N Engl J Med309 :1543– 1546,1983
71. Zappitelli M, Washburn KK, Arikan AA, Loftis L, Ma Q, Devarajan P, Parikh CR, Goldstein SL: Urine neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in critically ill children: A prospective cohort study. Crit Care11 :R84 ,2007
72. Akcan-Arikan A, Zappitelli M, Loftis LL, Washburn KK, Jefferson LS, Goldstein SL: Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int71 :1028– 1035,2007
73. Melnikov VY, Ecder T, Fantuzzi G, Siegmund B, Lucia MS, Dinarello CA, Schrier RW, Edelstein CL: Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. J Clin Invest107 :1145– 1152,2001
74. Parikh CR, Jani A, Mishra J, Ma Q, Kelly C, Barasch J, Edelstein CL, Devarajan P: Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation. Am J Transplant6 :1639– 1645,2006
75. Parikh CR, Mishra J, Thiessen-Philbrook H, Dursun B, Ma Q, Kelly C, Dent C, Devarajan P, Edelstein CL: Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery. Kidney Int70 :199– 203,2006
76. Parikh CR, Abraham E, Ancukiewicz M, Edelstein CL: Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit. J Am Soc Nephrol16 :3046– 3052,2005
77. Parikh CR, Jani A, Melnikov VY, Faubel S, Edelstein CL: Urinary interleukin-18 is a marker of human acute tubular necrosis. Am J Kidney Dis43 :405– 414,2004
78. Washburn KK, Zappitelli M, Arikan AA, Loftis L, Yalavarthy R, Parikh CR, Edelstein CL, Goldstein SL: Urinary interleukin-18 is an acute kidney injury biomarker in critically ill children. Nephrol Dial Transplant,23 :566– 572,2008
79. du Cheyron D, Daubin C, Poggioli J, Ramakers M, Houillier P, Charbonneau P, Paillard M: Urinary measurement of Na+/H+ exchanger isoform 3 (NHE3) protein as new marker of tubule injury in critically ill patients with ARF. Am J Kidney Dis42 :497– 506,2003
80. Ichimura T, Bonventre JV, Bailly V, Wei H, Hession CA, Cate RL, Sanicola M: Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem273 :4135– 4142,1998
81. Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV: Kidney Injury Molecule-1 (KIM-1): A novel biomarker for human renal proximal tubule injury. Kidney Int62 :237– 244,2002
82. van Timmeren MM, van den Heuvel MC, Bailly V, Bakker SJ, van Goor H, Stegeman CA: Tubular kidney injury molecule-1 (KIM-1) in human renal disease. J Pathol212 :209– 217,2007
83. Liangos O, Perianayagam MC, Vaidya VS, Han WK, Wald R, Tighiouart H, MacKinnon RW, Li L, Balakrishnan VS, Pereira BJ, Bonventre JV, Jaber BL: Urinary N-acetyl-beta-(D)-glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure. J Am Soc Nephrol18 :904– 912,2007
84. Han WK, Waikar SS, Johnson A, Betensky RA, Dent CL, Devarajan P, Bonventre JV: Urinary biomarkers for detection of acute kidney injury. Kidney Int2008 , in press
85. Eijkenboom JJ, van Eijk LT, Pickkers P, Peters WH, Wetzels JF, van der Hoeven HG: Small increases in the urinary excretion of glutathione S-transferase A1 and P1 after cardiac surgery are not associated with clinically relevant renal injury. Intensive Care Med31 :664– 667,2005
86. Hamada Y, Kanda T, Anzai T, Kobayashi I, Morishita Y: N-acetyl-beta-D-glucosaminidase is not a predictor, but an indicator of kidney injury in patients with cardiac surgery. J Med30 :329– 336,1999
87. Molls RR, Savransky V, Liu M, Bevans S, Mehta T, Tuder RM, King LS, Rabb H: Keratinocyte-derived chemokine is an early biomarker of ischemic acute kidney injury. Am J Physiol Renal Physiol290 :F1187– F1193,2006
88. Zhou H, Pisitkun T, Aponte A, Yuen PS, Hoffert JD, Yasuda H, Hu X, Chawla L, Shen RF, Knepper MA, Star RA: Exosomal Fetuin-A identified by proteomics: A novel urinary biomarker for detecting acute kidney injury. Kidney Int70 :1847– 1857,2006
89. Chertow GM, Palevsky PM, Greene T: Studying the prevention of acute kidney injury: Lessons from an 18th-century mathematician. Clin J Am Soc Nephrol1 :1124– 1127,2006
90. Allgren RL, Marbury TC, Rahman SN, Weisberg LS, Fenves AZ, Lafayette RA, Sweet RM, Genter FC, Kurnik BR, Conger JD, Sayegh MH: Anaritide in acute tubular necrosis: Auriculin Anaritide Acute Renal Failure Study Group. N Engl J Med336 :828– 834,1997
91. Hirschberg R, Kopple J, Lipsett P, Benjamin E, Minei J, Albertson T, Munger M, Metzler M, Zaloga G, Murray M, Lowry S, Conger J, McKeown W, O'Shea M, Baughman R, Wood K, Haupt M, Kaiser R, Simms H, Warnock D, Summer W, Hintz R, Myers B, Haenftling K, Capra W, et al.: Multicenter clinical trial of recombinant human insulin-like growth factor I in patients with acute renal failure. Kidney Int55 :2423– 2432,1999
92. Yegenaga I, Hoste E, Van Biesen W, Vanholder R, Benoit D, Kantarci G, Dhondt A, Colardyn F, Lameire N: Clinical characteristics of patients developing ARF due to sepsis/systemic inflammatory response syndrome: Results of a prospective study. Am J Kidney Dis43 :817– 824,2004
93. Hoste EA, Lameire NH, Vanholder RC, Benoit DD, Decruyenaere JM, Colardyn FA: Acute renal failure in patients with sepsis in a surgical ICU: Predictive factors, incidence, comorbidity, and outcome. J Am Soc Nephrol14 :1022– 1030,2003
94. Neveu H, Kleinknecht D, Brivet F, Loirat P, Landais P: Prognostic factors in acute renal failure due to sepsis: Results of a prospective multicentre study. The French Study Group on Acute Renal Failure. Nephrol Dial Transplant11 :293– 299,1996
95. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP: The natural history of the systemic inflammatory response syndrome (SIRS): A prospective study. JAMA273 :117– 123,1995
96. Marenzi G, Lauri G, Assanelli E, Campodonico J, De Metrio M, Marana I, Grazi M, Veglia F, Bartorelli AL: Contrast-induced nephropathy in patients undergoing primary angioplasty for acute myocardial infarction. J Am Coll Cardiol44 :1780– 1785,2004
97. Mehran R, Aymong ED, Nikolsky E, Lasic Z, Iakovou I, Fahy M, Mintz GS, Lansky AJ, Moses JW, Stone GW, Leon MB, Dangas G: A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: Development and initial validation. J Am Coll Cardiol44 :1393– 1399,2004
98. Rihal CS, Textor SC, Grill DE, Berger PB, Ting HH, Best PJ, Singh M, Bell MR, Barsness GW, Mathew V, Garratt KN, Holmes DR Jr: Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation105 :2259– 2264,2002
99. McCullough PA, Wolyn R, Rocher LL, Levin RN, O'Neill WW: Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality. Am J Med103 :368– 375,1997
100. Mitchell AM, Kline JA: Contrast nephropathy following computed tomography angiography of the chest for pulmonary embolism in the emergency department. J Thromb Haemost5 :50– 54,2007
101. Parfrey PS, Griffiths SM, Barrett BJ, Paul MD, Genge M, Withers J, Farid N, McManamon PJ: Contrast material-induced renal failure in patients with diabetes mellitus, renal insufficiency, or both: A prospective controlled study. N Engl J Med320 :143– 149,1989
102. Cramer BC, Parfrey PS, Hutchinson TA, Baran D, Melanson DM, Ethier RE, Seely JF: Renal function following infusion of radiologic contrast material: A prospective controlled study. Arch Intern Med145 :87– 89,1985
103. Mehta RH, Grab JD, O'Brien SM, Bridges CR, Gammie JS, Haan CK, Ferguson TB, Peterson ED: Bedside tool for predicting the risk of postoperative dialysis in patients undergoing cardiac surgery. Circulation114 :2208– 2216; quiz 2208,2006
104. Thakar CV, Worley S, Arrigain S, Yared JP, Paganini EP: Influence of renal dysfunction on mortality after cardiac surgery: Modifying effect of preoperative renal function. Kidney Int67 :1112– 1119,2005
105. Bove T, Calabro MG, Landoni G, Aletti G, Marino G, Crescenzi G, Rosica C, Zangrillo A: The incidence and risk of acute renal failure after cardiac surgery. J Cardiothorac Vasc Anesth18 :442– 445,2004
106. Ryckwaert F, Boccara G, Frappier JM, Colson PH: Incidence, risk factors, and prognosis of a moderate increase in plasma creatinine early after cardiac surgery. Crit Care Med30 :1495– 1498,2002
107. Chertow GM, Lazarus JM, Christiansen CL, Cook EF, Hammermeister KE, Grover F, Daley J: Preoperative renal risk stratification. Circulation95 :878– 884,1997
108. Mangano CM, Diamondstone LS, Ramsay JG, Aggarwal A, Herskowitz A, Mangano DT: Renal dysfunction after myocardial revascularization: Risk factors, adverse outcomes, and hospital resource utilization. The Multicenter Study of Perioperative Ischemia Research Group. Ann Intern Med128 :194– 203,1998
109. Fowler VG Jr, Boucher HW, Corey GR, Abrutyn E, Karchmer AW, Rupp ME, Levine DP, Chambers HF, Tally FP, Vigliani GA, Cabell CH, Link AS, DeMeyer I, Filler SG, Zervos M, Cook P, Parsonnet J, Bernstein JM, Price CS, Forrest GN, Fatkenheuer G, Gareca M, Rehm SJ, Brodt HR, Tice A, Cosgrove SE: Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med355 :653– 665,2006
110. Bates DW, Su L, Yu DT, Chertow GM, Seger DL, Gomes DR, Dasbach EJ, Platt R: Mortality and costs of acute renal failure associated with amphotericin B therapy. Clin Infect Dis32 :686– 693,2001
111. Wingard JR, Kubilis P, Lee L, Yee G, White M, Walshe L, Bowden R, Anaissie E, Hiemenz J, Lister J: Clinical significance of nephrotoxicity in patients treated with amphotericin B for suspected or proven aspergillosis. Clin Infect Dis29 :1402– 1407,1999
112. Leehey DJ, Braun BI, Tholl DA, Chung LS, Gross CA, Roback JA, Lentino JR: Can pharmacokinetic dosing decrease nephrotoxicity associated with aminoglycoside therapy. J Am Soc Nephrol4 :81– 90,1993
113. Smith CR, Lipsky JJ, Laskin OL, Hellmann DB, Mellits ED, Longstreth J, Lietman PS: Double-blind comparison of the nephrotoxicity and auditory toxicity of gentamicin and tobramycin. N Engl J Med302 :1106– 1109,1980
114. Prinssen M, Verhoeven EL, Buth J, Cuypers PW, van Sambeek MR, Balm R, Buskens E, Grobbee DE, Blankensteijn JD: A randomized trial comparing conventional and endovascular repair of abdominal aortic aneurysms. N Engl J Med351 :1607– 1618,2004
115. Godet G, Fleron MH, Vicaut E, Zubicki A, Bertrand M, Riou B, Kieffer E, Coriat P: Risk factors for acute postoperative renal failure in thoracic or thoracoabdominal aortic surgery: A prospective study. Anesth Analg85 :1227– 1232,1997
116. Davidson CJ, Hlatky M, Morris KG, Pieper K, Skelton TN, Schwab SJ, Bashore TM: Cardiovascular and renal toxicity of a nonionic radiographic contrast agent after cardiac catheterization: A prospective trial. Ann Intern Med110 :119– 124,1989
117. Rich MW, Crecelius CA: Incidence, risk factors, and clinical course of acute renal insufficiency after cardiac catheterization in patients 70 years of age or older: A prospective study. Arch Intern Med150 :1237– 1242,1990
118. Lautin EM, Freeman NJ, Schoenfeld AH, Bakal CW, Haramati N, Friedman AC, Lautin JL, Braha S, Kadish EG, Sprayregen S, et al.: Radiocontrast-associated renal dysfunction: Incidence and risk factors. AJR Am J Roentgenol157 :49– 58,1991
119. Gruberg L, Mehran R, Dangas G, Mintz GS, Waksman R, Kent KM, Pichard AD, Satler LF, Wu H, Leon MB: Acute renal failure requiring dialysis after percutaneous coronary interventions. Catheter Cardiovasc Interv52 :409– 416,2001
120. Chertow GM, Levy EM, Hammermeister KE, Grover F, Daley J: Independent association between acute renal failure and mortality following cardiac surgery. Am J Med104 :343– 348,1998
121. Chawla LS, Abell L, Mazhari R, Egan M, Kadambi N, Burke HB, Junker C, Seneff MG, Kimmel PL: Identifying critically ill patients at high risk for developing acute renal failure: A pilot study. Kidney Int68 :2274– 2280,2005
122. Chertow GM, Lazarus JM, Paganini EP, Allgren RL, Lafayette RA, Sayegh MH: Predictors of mortality and the provision of dialysis in patients with acute tubular necrosis: The Auriculin Anaritide Acute Renal Failure Study Group. J Am Soc Nephrol9 :692– 698,1998
123. Lian[Combining Tilde]o F, Gallego A, Pascual J, Garcia-Martin F, Teruel JL, Marcen R, Orofino L, Orte L, Rivera M, Gallego N, et al: Prognosis of acute tubular necrosis: an extended prospectively contrasted study. Nephron63 :21– 31,1993
124. Paganini EP, Halstenberg WK, Goormastic M: Risk modeling in acute renal failure requiring dialysis: The introduction of a new model. Clin Nephrol46 :206– 211,1996
125. Metnitz PG, Krenn CG, Steltzer H, Lang T, Ploder J, Lenz K, Le Gall JR, Druml W: Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit Care Med30 :2051– 2058,2002
126. Mehta RL, Pascual MT, Gruta CG, Zhuang S, Chertow GM: Refining predictive models in critically ill patients with acute renal failure. J Am Soc Nephrol13 :1350– 1357,2002
127. Lins RL, Elseviers MM, Daelemans R, Arnouts P, Billiouw JM, Couttenye M, Gheuens E, Rogiers P, Rutsaert R, Van der Niepen P, De Broe ME: Re-evaluation and modification of the Stuivenberg Hospital Acute Renal Failure (SHARF) scoring system for the prognosis of acute renal failure: An independent multicentre, prospective study. Nephrol Dial Transplant19 :2282– 2288,2004
128. Nakamura T, Sugaya T, Node K, Ueda Y, Koide H: Urinary excretion of liver-type fatty acid-binding protein in contrast medium-induced nephropathy. Am J Kidney Dis47 :439– 444,2006
129. Fujisaki K, Kubo M, Masuda K, Tokumoto M, Hirakawa M, Ikeda H, Matsui R, Matsuo D, Fukuda K, Kanai H, Hirakata H, Iida M: Infusion of radiocontrast agents induces exaggerated release of urinary endothelin in patients with impaired renal function. Clin Exp Nephrol7 :279– 283,2003
130. Takeda M, Komeyama T, Tsutsui T, Mizusawa T, Go H, Hatano A, Tanikawa T: Changes in urinary excretion of endothelin-1-like immunoreactivity in patients with testicular cancer receiving high-dose cisplatin therapy. Am J Kidney Dis24 :12– 16,1994
131. Boldt J, Brenner T, Lang J, Kumle B, Isgro F: Kidney-specific proteins in elderly patients undergoing cardiac surgery with cardiopulmonary bypass. Anesth Analg97 :1582– 1589,2003
132. Jorres A, Kordonouri O, Schiessler A, Hess S, Farke S, Gahl GM, Muller C, Djurup R: Urinary excretion of thromboxane and markers for renal injury in patients undergoing cardiopulmonary bypass. Artif Organs18 :565– 569,1994
133. Fauli A, Gomar C, Campistol JM, Alvarez L, Manig AM, Matute P: Pattern of renal dysfunction associated with myocardial revascularization surgery and cardiopulmonary bypass. Eur J Anaesthesiol20 :443– 450,2003
134. Westhuyzen J, McGiffin DC, McCarthy J, Fleming SJ: Tubular nephrotoxicity after cardiac surgery utilising cardiopulmonary bypass. Clin Chim Acta228 :123– 132,1994
135. Boldt J, Brenner T, Lehmann A, Suttner SW, Kumle B, Isgro F: Is kidney function altered by the duration of cardiopulmonary bypass? Ann Thorac Surg75 :906– 912,2003
136. Ikeda H, Nagashima K, Okumura H, Takahashi A, Matsuyama S, Nagamachi Y: Urinary excretion of beta 2-microglobulin and N-acetyl-beta-D-glucosaminidase in advanced neuroblastoma patients receiving cis-diamminedichloroplatinum(II). Eur J Surg Oncol14 :17– 20,1988
137. Verplanke AJ, Herber RF, de Wit R, Veenhof CH: Comparison of renal function parameters in the assessment of cis-platin induced nephrotoxicity. Nephron66 :267– 272,1994
138. Goren MP, Wright RK, Horowitz ME: Cumulative renal tubular damage associated with cisplatin nephrotoxicity. Cancer Chemother Pharmacol18 :69– 73,1986
139. Diener U, Knoll E, Langer B, Rautenstrauch H, Ratge D, Wisser H: Urinary excretion of N-acetyl-beta-D-glucosaminidase and alanine aminopeptidase in patients receiving amikacin or cis-platinum. Clin Chim Acta112 :149– 157,1981
140. Westhuyzen J, Endre ZH, Reece G, Reith DM, Saltissi D, Morgan TJ: Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit. Nephrol Dial Transplant18 :543– 551,2003
141. Herget-Rosenthal S, Poppen D, Husing J, Marggraf G, Pietruck F, Jakob HG, Philipp T, Kribben A: Prognostic value of tubular proteinuria and enzymuria in nonoliguric acute tubular necrosis. Clin Chem50 :552– 558,2004
142. Chew SL, Lins RL, Daelemans R, Nuyts GD, De Broe ME: Urinary enzymes in acute renal failure. Nephrol Dial Transplant8 :507– 511,1993
143. Etherington C, Bosomworth M, Clifton I, Peckham DG, Conway SP: Measurement of urinary N-acetyl-b-d-glucosaminidase in adult patients with cystic fibrosis: Before, during and after treatment with intravenous antibiotics. J Cyst Fibros6 :67– 73,2007
144. Glass S, Plant ND, Spencer DA: The effects of intravenous tobramycin on renal tubular function in children with cystic fibrosis. J Cyst Fibros4 :221– 225,2005
145. Nix DE, Thomas JK, Symonds WT, Spivey JM, Wilton JH, Gagliardi NC, Schentag JJ: Assessment of the enzymuria resulting from gentamicin alone and combinations of gentamicin with various beta-lactam antibiotics. Ann Pharmacother31 :696– 703,1997
146. Kang HK, Kim DK, Lee BH, Om AS, Hong JH, Koh HC, Lee CH, Shin IC, Kang JS: Urinary N-acetyl-beta-D-glucosaminidase and malondialdehyde as a markers of renal damage in burned patients. J Korean Med Sci16 :598– 602,2001
147. Win A, Aye K, Tin W, San K, Thin Thin H: Urinary NAG as an early indicator of renal damage in Russell's viper bite envenomation. Trans R Soc Trop Med Hyg90 :169– 172,1996
148. Fink JC, Cooper MA, Burkhart KM, McDonald GB, Zager RA: Marked enzymuria after bone marrow transplantation: A correlate of veno-occlusive disease-induced “hepatorenal syndrome.” J Am Soc Nephrol6 :1655– 1660,1995
149. Jung K, Kirschner P, Wille A, Brien G: Excretion of urinary enzymes after extracorporeal shock wave lithotripsy: A critical reevaluation. J Urol149 :1409– 1413,1993
150. Assimos DG, Boyce WH, Furr EG, Espeland MA, Holmes RP, Harrison LH, Kroovand RL, McCullough DL: Selective elevation of urinary enzyme levels after extracorporeal shock wave lithotripsy. J Urol142 :687– 690,1989
151. Sakamoto W, Kishimoto T, Nakatani T, Ameno Y, Ohyama A, Kamizuru M, Yasumoto R, Maekawa M: Examination of aggravating factors of urinary excretion of N-acetyl-beta-D-glucosaminidase after extracorporeal shock wave lithotripsy. Nephron58 :205– 209,1991
152. Roberts DS, Haycock GB, Dalton RN, Turner C, Tomlinson P, Stimmler L, Scopes JW: Prediction of acute renal failure after birth asphyxia. Arch Intern Med65 :1021– 1028,1990
153. Carraro M, Malalan F, Antonione R, Stacul F, Cova M, Petz S, Assante M, Grynne B, Haider T, Palma LD, Faccini L: Effects of a dimeric vs a monomeric nonionic contrast medium on renal function in patients with mild to moderate renal insufficiency: A double-blind, randomized clinical trial. Eur Radiol8 :144– 147,1998
154. Carraro M, Mancini W, Artero M, Stacul F, Grotto M, Cova M, Faccini L: Dose effect of nitrendipine on urinary enzymes and microproteins following non-ionic radiocontrast administration. Nephrol Dial Transplant11 :444– 448,1996
155. Donadio C, Tramonti G, Lucchesi A, Giordani R, Lucchetti A, Bianchi C: Tubular toxicity is the main renal effect of contrast media. Ren Fail18 :647– 656,1996
156. Nicot GS, Merle LJ, Charmes JP, Valette JP, Nouaille YD, Lachatre GF, Leroux-Robert C: Transient glomerular proteinuria, enzymuria, and nephrotoxic reaction induced by radiocontrast media. JAMA252 :2432– 2434,1984
157. Cavaliere G, Arrigo G, D'Amico G, Bernasconi P, Schiavina G, Dellafiore L, Vergnaghi D: Tubular nephrotoxicity after intravenous urography with ionic high-osmolal and nonionic low-osmolal contrast media in patients with chronic renal insufficiency. Nephron46 :128– 133,1987
158. Pai MP, Norenberg JP, Telepak RA, Sidney DS, Yang S: Assessment of effective renal plasma flow, enzymuria, and cytokine release in healthy volunteers receiving a single dose of amphotericin B desoxycholate. Antimicrob Agents Chemother49 :3784– 3788,2005
159. Tolkoff-Rubin NE, Thompson RE, Piper DJ, Hansen WP, Bander NH, Cordon-Cardo C, Finstad CJ, Klotz LH, Old LJ, Rubin RH: Diagnosis of renal proximal tubular injury by urinary immunoassay for a proximal tubular antigen, the adenosine deaminase binding protein. Nephrol Dial Transplant2 :143– 148,1987
160. Goren MP, Wright RK, Horowitz ME: Increased levels of urinary adenosine deaminase binding protein in children treated with cisplatin or methotrexate. Clin Chim Acta160 :157– 161,1986
161. Goren MP, Wright RK, Horowitz ME, Pratt CB: Cancer chemotherapy-induced tubular nephrotoxicity evaluated by immunochemical determination of urinary adenosine deaminase binding protein. Am J Clin Pathol86 :780– 783,1986
162. Sarica K, Suzer O, Yaman O, Kupeli B, Baltaci S, Bilaloglu E, Tasman S: Leucine aminopeptidase enzymuria: Quantification of renal tubular damage following extracorporeal shock wave lithotripsy. Int Urol Nephrol28 :621– 626,1996
163. Schiavon M, Di Landro D, Baldo M, De Silvestro G, Chiarelli A: A study of renal damage in seriously burned patients. Burns Incl Therm Inj14 :107– 112,1988
164. da Silva Magro MC, de Fatima Fernandes Vattimo M: Does urinalysis predict acute renal failure after heart surgery? Ren Fail26 :385– 392,2004
165. Cressey G, Roberts DR, Snowden CP: Renal tubular injury after infrarenal aortic aneurysm repair. J Cardiothorac Vasc Anesth16 :290– 293,2002
166. Arici M, Usalan C, Altun B, Erdem Y, Yasavul U, Turgan C, Kes S, Caglar S: Radiocontrast-induced nephrotoxicity and urinary alpha-glutathione S-transferase levels: Effect of amlodipine administration. Int Urol Nephrol35 :255– 261,2003
167. Gupta KL, Kalra OP, Malik N, Ganguly NK: Quantitative enzymuria following aorto-renal angiography. J Assoc Physicians India47 :189– 191,1999
168. Hartmann HG, Braedel HE, Jutzler GA: Detection of renal tubular lesions after abdominal aortography and selective renal arteriography by quantitative measurements of brush-border enzymes in the urine. Nephron39 :95– 101,1985
169. Blaikley J, Sutton P, Walter M, Lapsley M, Norden A, Pugsley W, Unwin R: Tubular proteinuria and enzymuria following open heart surgery. Intensive Care Med29 :1364– 1367,2003