Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit
Justin Westhuyzen1,
Zoltan H. Endre2,,
Graham Reece3,
David M. Reith4,
David Saltissi2 and
Thomas J. Morgan3
1 Conjoint Renal Laboratory, Queensland Health Pathology Service,
3 Intensive Care Unit and
2 Department of Renal Medicine, Royal Brisbane Hospital, Brisbane, Australia and
4 Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
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Abstract
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Background. Early detection of acute tubular necrosis (ATN) could permit implementation of salvage therapies and improve patient outcomes in acute renal failure (ARF). The utility of single and combined measurements of urinary tubular enzymes in predicting ARF in critically ill patients has not been evaluated using the receiver-operating characteristic (ROC) plot method.
Methods. In this prospective pilot study, 26 consecutive critically ill adult patients admitted to the intensive-care unit were studied. Urine samples were collected twice daily for up to 7 days. ARF was defined as an increase in plasma creatinine of
50% and
0.15 mmol/l. ROC plot analysis was applied to the tubular marker data to derive optimum cut-offs for ARF.
Results. Four of the 26 study subjects (15.4%) developed ARF. Indexed to urinary creatinine concentration,
glutamyl transpeptidase (
GT), alkaline phosphatase (AP), N-acetyl-glucosaminidase (NAG), and
- and
-glutathione S-transferase (
- and
-GST) but not lactate dehydrogenase (LDH) were higher in the ARF group on admission (P<0.05).
GT, and
- and
-GST remained elevated at 24 h. The onset of ARF based on changes in plasma creatinine varied from 12 h to 4 days (median 36 h). ROC plot analysis showed that
GT,
-GST,
-GST, AP and NAG had excellent discriminating power for ARF (AUC 0.950, 0.929, 0.893, 0.863 and 0.845, respectively). The discriminating strength of creatinine clearance, while lower, was still significant (AUC 0.796). Positive and negative predictive values for ARF on admission were 67/100% for
GT, 67/90% for AP, 60/95% for
-GST, and 67/100% for
-GST indices. Positive and negative predictive values for ARF for creatinine clearance
23 ml/min were 50 and 91%, respectively. Creatinine clearances tended to be lower in ARF than in non-ARF patients on admission (P=0.06) and were significantly lower (P=0.008) after 12 h. Plasma urea and fractional sodium excretion were unhelpful.
Conclusions. Tubular enzymuria on admission to the ICU is useful in predicting ARF. The cheapness and wide availability of automated assays for
GT and AP suggests that estimation of these enzymes in random urine samples may be particularly useful for identifying patients at high risk of ARF.
Keywords: acute renal failure; acute tubular necrosis; alkaline phosphatase; creatinine clearance; creatinine;
-glutamyl transpeptidase; intensive care; tubular markers
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Introduction
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Acute renal failure (ARF) is common in intensive care units (ICU), with a 1030% incidence that is 5-fold higher than among medical ward patients [14]. The mortality rate for hospitalized patients who develop ARF is some five times higher than without ARF [5]. Despite the introduction of continuous renal replacement therapy and biocompatible membranes, the mortality associated with this diagnostic category has improved little over the last 15 years [1,3,4]. Significant improvements in the outcome of these patients seem contingent upon either prevention or the early detection of renal impairment. The routinely available clinical parameters of kidney diseaseplasma creatinine and ureado not in practice provide either a sensitive or specific indication of renal function, and reveal ARF well after the injury inducing ARF has occurred. Clearly, more specific and sensitive markers are desirable for the early detection of an initially occult pathophysiological process.
The majority of ARF cases in the ICU are due to acute tubular necrosis (ATN) rather than glomerular dysfunction. In experimental ATN, both proximal (S3 segment) and distal tubule (MTAL) injury occurs, with proximal injury dominating in most purely ischaemic or hypoxic models of injury [6]. However, the site and extent of injury to each of these outer medullary segments is less certain in clinical ARF. The detection of proteins (particularly enzymes) released from damaged tubular cells has been useful in the study of both acute and chronic renal injury in a variety of clinical and experimental situations [79]. In addition to information on the segmental site of injury, the ultrastructural origin of the protein (cytoplasmic, lysosomal or membranous) provides information on the nature and extent of cellular injury. For example, the
- and
-glutathione S-transferase (GST) isomers are cytoplasmic enzymes found in the proximal and distal tubular epithelial cells, respectively [8]. Increased urinary excretion of these proteins implies cellular necrosis. Increased excretion of N-acetyl-glucosaminidase (NAG), a lysosomal enzyme found predominantly in proximal tubules [10], has been reported in a wide variety of conditions such as methotrexate toxicity [11] and contrast-induced toxicity [12]. Increased activity of this enzyme suggests injury to tubular cells but increased concentrations may also indicate increased lysosomal activity without cell disruption [13,14]. However, the majority of the enzymes in tubular urine are brush border enzymes such as alkaline phosphatase (AP),
-glutamyl transpeptidase (
GT) and ala-(leu-gly)-aminopeptidase [7,9]. Increased excretion of these proteins implies injury to the brush border membrane with loss of microvillous structure. Loss of a significant fraction of the microvillus surface area also leads to reduced reabsorption and increased excretion of filtered proteins such as ß2-microglobulin and retinol-binding protein [13].
While the enzymuria described above clearly reflects tubular injury, the usefulness of enzymuria as a marker for either specific segmental injury or of incipient renal failure has been obscured by the low threshold for release of tubular enzymes in response to injury that may not proceed to acute renal failure. For example, in one study almost all patients undergoing coronary bypass surgery demonstrated increased urinary excretion of NAG and adenosine deaminase binding protein although none of these patients developed ARF [15]. Plasma creatinine concentrations increased only slightly (from 0.085 to 0.099 mmol/l at 24 h). This suggests that enzymuria reflects mild injury or injury which is reversible, consistent with the observation that ARF is now relatively infrequent after uncomplicated coronary bypass surgery [16]. The apparent sensitivity of enzymuria to renal injury and the frequency of ARF in the ICU led us to hypothesize that monitoring tubular enzymuria could predict or detect early loss of renal function in this setting, provided that detection sensitivity was selected appropriately. Early detection of ARF or of patients at risk of ARF would permit earlier implementation of renal salvage therapies, more sensitive monitoring of responsiveness to therapy and could improve patient outcome.
We examined this hypothesis by monitoring for enzymuria in patients admitted to a busy general ICU in a large teaching hospital, comparing the results with standard clinical parameters of renal function. Receiver-operating plot (ROC) analysis was used to compare the discriminative power of the tubular marker indices, which were then tested in a second group of partially selected patients. A secondary aim was to identify whether markers of proximal or distal tubular cell injury were more predictive of acute renal failure in the intensive care setting.
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Subjects and methods
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Patients
The Royal Brisbane Hospital's ICU accepts medical and surgical patients and is a referral centre for burns patients. Based on the incidence of renal impairment and the coefficients of variance of NAG and GST, the study was powered for a sample size of 26 patients. Consecutive patients who met the inclusion criteria (that is, adults without exclusion criteria) were recruited into the study. Of 38 consecutive patients, 12 were excluded; the remaining patients were subject to intention-to-treat analysis (Study group, n=26) (Table 1
). Exclusion criteria on admission included anuria (n=0), renal replacement therapy (n=4), established or resolving ARF on admission (n=1), absence of an indwelling urethral catheter (n=3), and contamination of urine with radioactivity or cytotoxics (n=0). Patients predicted to be admitted for only one collection periodsuch as those awakening from drug overdoseswere also excluded (n=4). Four patients (15.4%) developed ARF (Table 2
), defined as an increase in plasma creatinine of
50% baseline and to a concentration
0.15 mmol/l. Ischaemia and sepsis were probable causes of ARF in three patients, and sepsis alone in the fourth. Data on the tubular markers from the study group were analysed using ROC plots to obtain decision thresholds for ARF, as described below. A second group of patients was recruited to obtain preliminary information on the usefulness of the decision thresholds derived from the ROC plot analysis. Patients who were unlikely to remain in ICU for more than 24 h or unlikely to be at risk of ARF on clinical grounds were excluded (in addition to the usual exclusion criteria). Thus a sample more likely to develop ARF on clinical grounds was preferentially selected (n=19). This test group was on average 9.5 years older (P>0.05), included more males (M:F 13:6; P<0.01), and presented with higher median plasma creatinine (0.13 vs 0.08 mmol/l) and plasma urea levels (10.3 vs 6.3 mmol/l) than the study group (both P<0.025). Creatinine clearances on admission were similar to the study group (88±56 SD vs 81±50 ml/min). Four of these patients (21.1%) developed ARF. Ischaemia and sepsis were causally implicated in two patients, sepsis and ischaemia separately in another two patients. Pre-existing chronic disease was defined according to the Acute Physiology and Chronic Health Evaluation (APACHE) II system [17].
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Table 2. Clinical data for study group who developed ARF in the ICU compared to the remaining patients (controls)a
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Laboratory methods
For all patients admitted to the study, blood and urine samples were collected twice daily (at 0600 and 1800) for up to 7 days while in the ICU. Creatinine clearances were measured on 4-h urine samples collected from 0400 to 0800 and from 1600 to 2000 h. Creatinine clearances were standardized to body surface area (1.73 m2). Urinary alkaline phosphatase (AP),
-glutamyl transpeptidase (
GT), lactate dehydrogenase (LDH), urinary and plasma sodium (Na+) and creatinine were measured by standard laboratory methods using the Hitachi 747 autoanalyzer. N-acetyl-glucosaminidase (NAG; E.C. 3.2.1.30) was measured by colorimetry [14] after column chromatography.
- and
-Glutathione S-transferase (
- and
-GST) were measured by ELISA (kits supplied by Biotrin Ltd, Dublin, Ireland). To correct for variations in urine flow, enzyme activities (U/l, mmol/l, or µg/l as applicable) were normalized to urinary creatinine (mmol/l) concentration and given as an index [U/mmol creatinine, (no units), or µg/mmol creatinine], respectively.
Statistical analyses
Subjects were assigned to the ARF or Control group based on observed changes in plasma creatinine. ARF was defined as an increase in plasma creatinine of
50% baseline and to a concentration
0.15 mmol/l. Groups were compared using Student's t-test or MannWhitney rank sum test for parametric and non-parametric data as appropriate. A probability value P<0.05 was considered significant.
ROC plots were used to compare the discriminative power of the tubular marker indices [18]. The ROC plot graphically presents all possible sensitivity/specificity pairs for a particular test, and is useful for comparing the ability of tests to discriminate between alternative states of health. The areas under the curve (AUC) of the ROC plots range from 1.0 (perfect separation of test values into two groups) to 0.5 (no distributional difference). An AUC >0.7 indicates a discriminating strength of statistical significance; an AUC >0.8 indicates excellent discriminating power for the test [18]. Comparisons between AUCs and between no distributional difference (represented by a value of 0.5) were performed using confidence interval analysis. The 95% confidence intervals (CI) were calculated using the standard errors for the AUCs, calculated according to the method of DeLong [19] and using Stata software (College Station, TX, USA).
The optimal decision threshold was determined according to the numbers of patients correctly classified at each possible cut-off point. The point at which the maximum number of patients was correctly classified was used as the decision threshold for the test to be positive or negative. The presence of interaction effects between the variables was explored using backward stepwise logistic regression. Two new outcome variables (one for additive effect and the other for a multiplicative effect) were generated from the individual variables. Three new variables,
-GSTx
-GST,
GTxAP and
GTx
-GST, were retained by their respective models.
The decision thresholds were used to calculate sensitivity and specificity of the tests, and the predictive values. Sensitivity (the true-positive fraction) was defined as the number of true test positive (TP) results divided by the sum of the number of true-positive (TP) and false-negative test (FN) results. Specificity (the ability of a test to correctly exclude the presence of the disease) was defined as the number of true negative (TN) results divided by the sum of the number of true-negative (TN) and false positive (FP) results. Positive and negative predictive values were calculated: TP divided by TP+FP for positive predictive value; TN divided by FN+TN for the latter.
The data from the second group of patients (test group) was also examined to determine the sensitivity, specificity, and positive and negative predictive values for each variable using the decision thresholds derived from the first group of patients.
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Results
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While in the ICU, four of the 26 study patients developed ARF based on changes in plasma creatinine concentration. Peak plasma creatinine concentrations ranged from 0.15 to 0.30 mmol/l (median 0.21). The ARF was resolved in only one of these patients (on day 6); in the remainder, plasma creatinine remained above 0.15 mmol/l (median 0.21) at the time of their departure from the ICU. However, none required dialysis. The median stay for all these patients was 4 days, range 28 days. There were no differences in age, gender ratio, APACHE II score, the duration of stay in the ICU, or in the proportion of subjects with sepsis, systemic inflammatory response syndrome or treatment with aminoglycoside antibiotics between the ARF group and the remaining patients (controls, P>0.05) (Table 3
). Five subjects exhibited plasma creatinine concentrations >0.12 mmol/l on admission. Two of these patients (40.0%) subsequently developed ARF, compared to three (21.9%) of those with plasma creatinine <0.12 mmol/l on admission (P=0.79).
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Table 3. Markers of renal function and tubular injury for the study group on admission to the ICU and after 12 and 24 h [Means±SEM or medians (range)]
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The changes in standard laboratory measures of renal function and tubular markers in the ARF and control patients during the first 24 h are summarized in Table 3
. There were no differences between the groups for plasma urea, urinary creatinine or fractional sodium excretion on ICU admission or during the next 24 h. Lower plasma creatinine concentrations were evident after 12 h (P=0.031). Creatinine clearances tended to be lower in the ARF group on admission (P=0.057) and became significantly lower after 12 (P=0.008) and 24 h (P=0.042). Indexed to urinary creatinine, all of the enzymic tubular markers (
GT, AP, NAG, and
- and
-GST) except LDH were higher in the ARF group on admission (P<0.05);
GT,
- and
-GST indices remained significantly higher at 24 h (Table 3
). Absolute urinary concentrations of AP,
GT and
- and
-GST were higher on admission, with
- and
-GST higher at 12 h, and
-GST at 24 h.
ROC plots for creatinine clearance and the indexed tubular markers determined on admission are shown in Figure 1
. At high specificities,
GT and
-GST indices showed the highest sensitivities for detecting ARF, followed by
-GST, AP, NAG, and LDH indices. The ROC plot for creatinine clearance showed less displacement from the line of identity than all the indexed tubular markers except LDH. The confidence interval analysis (Table 4
) indicates that for all the tests except LDH index, there was a statistically significant difference between the AUC and that of no distributional difference. For
-GST,
GT and the compound variables (but not creatinine clearance), the lower 95% CI was greater than 0.7, indicating that these tests had statistically significant discriminating strength. There was no statistically significant difference between the AUCs of the tests in the present study.


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Fig. 1. Non-parametric plots of creatinine clearance (calculated in the reciprocal) and urinary enzymes (indexed to creatinine) for predicting ARF in patients admitted to the ICU. The true positive fraction (sensitivity) was plotted against the true negative fraction (1-specificity). Each point on the graph represents a sensitivity/specificity pair as the cut-off point is varied. Tests with the high sensitivity and high specificity are most likely to be useful. The greater the displacement above and to the left of the line of identity, the greater the likelihood that raised values of the test will identify the condition (in this case ARF).
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Table 4. AUC and 95% confidence interval for ROC analysis of creatinine clearance (CrCl) and urinary enzymes (indexed to creatinine) in the study group (n=26)
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The sensitivity (true positives) and specificity (true negatives) for each marker are summarized in Table 5
. Results for the small test sample are presented for comparison. For the study group, sensitivities were highest for
GT, NAG and
-GST (100%), followed by
-GST (75.0 %). Creatinine clearance was not a sensitive test for ARF (50.0% for values <23 ml/min); however, the specificity of creatinine clearance at 91% was comparable with most of the individual tubular markers (range 81% for NAG to 100% for LDH). Sensitivities and specificities of the compound variables (
-GSTx
-GST,
GTxAP and
GTx
-GST) were similar to the individual indices (Table 5
). By comparison, sensitivities were generally lower in the test group, with the exception of AP (which was only 50%), and
GTxAP (100%). Specificities were lower for AP,
GT, NAG and
-GST, but higher for
-GST, creatinine clearance, and the compound variables (
-GSTx
-GST,
GTxAP, and
GTx
-GST).
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Table 5. Sensitivity, specificity and predictive values (with 95% CI) of creatinine clearance (CrCl) and urinary enzymes (indexed to creatinine) for predicting acute renal failure in patients admitted to ICU: comparison of study patients and test groups
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The ability of tubular enzymuria indexed to creatinine to predict renal outcome correctly was analysed by calculating both positive and negative predictive values (Table 5
). For the study group, positive predictive values for ARF were highest for LDH (100%), followed by
-GSTx
-GST and
GTx
-GST (both 75%), AP,
GT and
-GST (all 67%); creatinine clearance was 50%. Negative predictive values for ARF were much higher, ranging from 100% for
GT,
-GST and NAG, followed by LDH (96%),
-GST,
-GSTx
-GST and
GTx
-GST (95%). The positive predictive value of creatinine clearance (<23 ml/min) was only 50%, but the negative predictive value was 91%.
Unlike sensitivity and specificity, predictive values change markedly as the proportion of subjects with and without the condition (ARF) are tested. Although the test group excluded patients unlikely to develop ARF in the short term, the percentage of subjects developing ARF was not dissimilar to the study group (21.1 vs 15.4%, respectively). Individual positive predictive values were generally lower (except creatinine clearance), but the compound variables had higher predictive values. Similarly, negative predictive values were generally lower, with the exception of AP (essentially no change at 90%) and
GTxAP (100%).
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Discussion
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While previous studies have demonstrated that enzymuria can detect tubular injury [7], the present study demonstrates for the first time that relatively simple urinary indices can identify those patients in a high risk group who will develop acute renal failure. Importantly for the ICU population, indices had high negative predictive values: 100% for
GT and
-GST, 96% for LDH and 90% for AP in the study group. The
GT and
-GST indices also correctly identified two of three patients on admission who developed ARF in the ICU. In contrast, the detection of ARF based on changes in plasma creatinine ranged from 12 h to 1, 2 or 4 days for the four study patients. Creatinine clearance did not distinguish ARF and control groups until 12 h after admission to the ICU. This latter observation is not surprising since during and immediately after the development of ARF, plasma and urine creatinine concentrations are not stable and it is doubtful whether creatinine clearance is a meaningful measure of glomerular filtration rate under non-equilibrium conditions. These observations highlight the difficulty in diagnosing ARF in clinical practice until it is revealed by a rising plasma creatinine with or without oliguria. Depending on the definition of ARF, this usually takes at least 24 h and this time frame compares very unfavourably with the diagnosis of the equivalent state of ischaemic myocardial injury.
The high frequency of sepsis/SIRS in our patients (>70%) is to be expected, since sepsis is an exceedingly common feature of ARF, especially in ICU patients. While some observers suggest that ARF never occurs without sepsis, our ARF patients (with admittedly milder degrees of ARF) included one patient with an ischaemic insult in the absence of sepsis.
Both brush border enzymes (especially
GT with AUC of 0.95) and the cytoplasmic enzymes
- and
-GST (AUC 0.893 and 0.929) were useful in predicting ARF at the time of admission to ICU. Both the S3 segment of the proximal tubule and the thick ascending limb of Henle's loop are closely located in the outer stripe of the outer medulla. Both these segments are sensitive to hypoxic injury in experimental models [20]; however, proximal tubular injury appears to dominate in both experimental and clinical ARF in vivo [8]. This selectivity may result from increased survival gene (Bc1-2 and Bcl-x(L)) expression in surviving distal tubular cells [21, 22]. These cells showed increased expression of growth factors (EGF and IGF1), suggesting that surviving distal tubular cells produce autocrine and paracrine promoters of survival and regeneration of the distal cells and convoluted tubular cells [21, 22]. While this suggests that proximal tubular enzymes are likely to predominate in urine in clinical ARF, the distal tubular marker
-GST showed identical sensitivity, specificity and positive and negative predictive values to the best proximal tubular marker,
GT (Table 5
). There is therefore evidence for both proximal and distal tubular injury in the early stages of clinical ATN. While both
- and
-GST were useful markers, these enzymes need to be assayed using expensive ELISA tests, which militates against their wider use. Apart from cost, ELISA assays are generally batched and results are not instantly available. Thus, while the
- and
-GST indices remain useful as a research tool, the widely available markers
GT and AP indices appear more practical. In either case, the ability to assay the enzymes indexed to creatinine in random samples of urine provides a simple method for early detection of ARF in a high-risk population. Interestingly, in patients presenting to renal units with ARF, higher urinary enzyme levels (particularly AP and NAG indexed to creatinine) were found in those with poor outcomes (death in hospital or requiring long-term renal replacement therapy) [9]. Using a lower cut-off value for AP than ours (>12 U/g or >1.3 U/mmol creatinine) and a higher cut-off for NAG (>100 U/g or >11 U/mmol creatinine), the positive predictive values for a poor prognosis were 100% (5 of 5 deaths) and 66%, respectively. The urinary
GT-to-creatinine ratio has also been explored as an early indicator of aminoglycoside-induced nephrotoxicity in dogs, with promising results [23].
To what extent does the declining urinary creatinine excretion in ARF contribute to specificity and sensitivity? Lower urinary creatinine concentrations have the effect of raising the ratio value for the urinary enzyme indexed to creatinine, which in turn may increase the likelihood of individual patients exceeding the threshold for detection of ARF by this criterion. Pursuing this line of thought, it may well be that the combination of urinary enzymes and the act of linking the concentration to urinary creatinine, may have enhanced the sensitivity (rate of true positives) and specificity (rate of true negatives) for these measurements than either used separately. Thus, linking to urinary creatinine appears to enhance the utility of the tubular markers. In contrast, there does not appear to be any benefit in expressing the tubular markers as the fractional excretion. In the case of an enzyme excreted only by direct leakage from damaged tubular cells into urine, say
- and
-GST, the indexed value is equivalent to the fractional excretion (although the actual value will be less since dividing the urine creatinine by the plasma creatinine concentration is simply dividing by a constant). Fractional excretion also requires measurement of the plasma enzymes or plasma creatinine concentrations.
On the basis of our results, we suggest that further clinical studies of patients at high risk of developing ARF be undertaken to explore the utility of these markers. Early identification of these patients may allow further diagnostic evaluation that is not usually undertaken at this stage, for example ultrasonography, nuclear studies or even biopsy to diagnose ATN positively rather than by exclusion. Since the enzyme tests only require a random urine specimen, which can be analysed rapidly and accurately on modern high-throughput analysers, clinicians should have the information within a few hours of admission. Further trials are required to ascertain whether screening is warranted in clinical settings where the risk of ARF is lower. However, much larger numbers of patients will be needed.
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Conclusions
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These studies demonstrated that monitoring tubular enzymuria in patients admitted to the ICU detected ARF on admission and 12 h to 4 days earlier than standard parameters of renal function. The cheapness and wide availability of automated assays for
GT and AP suggests that the detection of these enzymes in random urine samples may be particularly useful clinically for identifying patients at high risk of ARF. Further studies are required to evaluate the usefulness of this method in high- and low-risk hospital populations of patients.
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Acknowledgments
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The authors would like to thank the staff of the ICU, Royal Brisbane Hospital and Chemical Pathology, Queensland Health Pathology Service, for their assistance during this study.
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Notes
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Correspondence and offprint requests to: Z. Endre, Associate Professor, Department of Medicine, Clinical Sciences Building, Royal Brisbane Hospital, Herston 4029, Queensland, Australia. Email: Z.Endre{at}medicine.herston.uq.edu.au 
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Received for publication: 9.10.01
Accepted in revised form: 9.10.02