Intensive Care Med (2010) 36:1333–1340 DOI 10.1007/s00134-010-1887-4
ORIGINAL
Johan Ma˚rtensson Max Bell Anders Oldner Shengyuan Xu Per Venge Claes-Roland Martling
Neutrophil gelatinase-associated lipocalin in adult septic patients with and without acute kidney injury
Received: 15 September 2009 Accepted: 30 March 2010 Published online: 16 April 2010 Ó Copyright jointly held by Springer and ESICM 2010
Abstract Purpose: To study the impact of inflammation/sepsis on the concentrations of neutrophil gelatinase-associated lipocalin (NGAL) in plasma and urine in adult intensive care unit (ICU) patients and to estimate the predictive properties of NGAL in plasma and urine for early detection of acute kidney injury (AKI) in patients with septic shock. Methods: Sixty-five patients admitted to the general ICU at the Karolinska University Hospital Solna, Sweden, with normal plasma creatinine were assessed for eligibility. Twenty-seven patients with systemic inflammatory response syndrome (SIRS), severe sepsis, or septic shock without AKI and 18 patients with septic shock and concomitant AKI were included in the final analysis. Plasma and urine were analyzed twice daily for plasma NGAL (pNGAL), C-reactive protein (CRP), procalcitonin, myeloperoxidase, plasma cystatin C, plasma creatinine, urine NGAL (uNGAL), urine cystatin C, and urine a1-microglobulin.
Electronic supplementary material The online version of this article (doi:10.1007/s00134-010-1887-4) contains supplementary material, which is available to authorized users.
J. Ma˚rtensson ()) M. Bell A. Oldner C.-R. Martling Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden e-mail:
[email protected] Tel.: ?46-8-51772066 Fax: ?46-8-51775180 S. Xu P. Venge Department of Medical Sciences, Clinical Chemistry, Uppsala University, 751 85 Uppsala, Sweden
Introduction Neutrophil gelatinase-associated lipocalin (NGAL) is a rapidly emerging biomarker for early detection of acute kidney injury (AKI). Seemingly NGAL levels in both plasma and urine can be used to detect AKI days before creatinine, at least when the time of insult to the kidneys is known [1–4].
Results: Of the 45 patients, 40 had elevated peak levels of pNGAL. Peak levels of pNGAL were not significantly different between septic shock patients with and without AKI. Peak levels of uNGAL were below the upper reference limit in all but four patients without AKI. uNGAL was a good predictor (area under ROC 0.86) whereas pNGAL was a poor predictor (area under ROC 0.67) for AKI within the next 12 h in patients with septic shock. Conclusions: pNGAL is raised in patients with SIRS, severe sepsis, and septic shock and should be used with caution as a marker of AKI in ICU patients with septic shock. uNGAL is more useful in predicting AKI as the levels are not elevated in septic patients without AKI. Keywords AKI Cystatin C HNL NGAL RIFLE Sepsis
Released by neutrophils upon activation, NGAL is also a marker of bacterial infection and systemic inflammation [5–7]. As AKI often is associated with sepsis [8, 9] this might hamper the predictive properties of plasma NGAL as a biomarker of AKI, at least in the general intensive care unit (ICU) setting. Whether sepsis affects the specificity of urinary NGAL as an early AKI marker is still unclear.
1334
Few studies have investigated the predictive properties of NGAL as an AKI marker in a general ICU population. In a recent study by Cruz et al. [10] plasma NGAL was a good predictor of AKI. The Cruz study considers many factors that might confound the predictive properties of plasma NGAL. Still, sepsis incidence was almost twice as high in AKI versus non-AKI patients [10]. Similar studies on pediatric ICU patients have shown serum NGAL to be a non-specific predictor [11] and urine NGAL to be a good predictor of AKI [12]. Again, in these two pediatric studies AKI and sepsis coincided to a great extent. This is common in ICU patients and might obstruct the interpretation of elevated NGAL in plasma and urine. Indeed, in a recent study including only AKI patients, both plasma and urine NGAL were higher in septic versus non-septic patients [13]. Before introducing NGAL as an AKI marker in general ICUs it is vital to clarify the impact of infection/ sepsis per se on NGAL in plasma and urine in patients with and without AKI. The present study compares peak concentrations of plasma and urine NGAL and other biomarkers of AKI and sepsis in adult ICU patients with SIRS, severe sepsis, and septic shock without AKI and in patients with septic shock and concomitant AKI. Additionally, we investigate whether the presence of septic shock affects the ability of NGAL in plasma and urine to predict AKI.
normal value for glomerular filtration rate (GFR) (75 mL/ min/1.73 m2) [14, 16]. Patients were classified on a day-to-day basis as having SIRS, severe sepsis, or septic shock according to the definitions of the American College of Chest Physicians/ Society of Critical Care Medicine [17] with SIRS modifications applied by the PROWESS study group [18]. Patients were allocated to one of the cohorts according to the maximum score attained during the study period. Thirty-one patients developed AKI according to the RIFLE or AKIN criteria within 48 h before until 48 h after the study period. Eighteen of these patients had septic shock and were included for biomarker analysis. Twenty-seven out of 34 patients without AKI fulfilled the criteria for SIRS, severe sepsis, or septic shock and were subject to biomarker analysis in the non-AKI cohort (Fig. 1). A total of 509 plasma and 509 urine samples from the 45 patients were analyzed. Biochemical analysis
Samples of blood and urine were collected twice daily until discharge from the ICU or earlier if RRT was initiated. After centrifugation, plasma was analyzed for NGAL (pNGAL), procalcitonin (PCT), C-reactive protein (CRP), myeloperoxidase (MPO), and cystatin C. Urine was analyzed for NGAL (uNGAL), creatinine, cystatin C, and a1-microglobulin. NGAL was measured by the polyclonal antibodybased RIA as described elsewhere [19, 20]. Expected Materials and methods normal pNGAL level was less than 73.5 ng/mL [19]. The Patients upper 97.5 percentile of 101 healthy controls (141 ng/mg creatinine) was used as reference limit for uNGAL This study was approved by the Karolinska Institutet (Venge P and Xu SY, unpublished results). Ethics Committee and written informed consent was obtained before enrollment. Sixty-five patients referred to the general ICU at the Karolinska University Hospital Solna, Sweden, with creatinine clearance greater than 60 mL/min/1.73 m2, estimated by the modification of diet in renal disease (MDRD) equation, and an expected length of stay of more than 24 h were initially included in the study. The study period was the time from the first sample taken until discharge from the ICU or earlier if renal replacement therapy (RRT) was initiated. Patients were classified according to the RIFLE/Acute Kidney Injury Network (AKIN) criteria on a day-to-day basis according to their worst creatinine and/or lowest urine output [14, 15]. Additionally, we evaluated the criteria during the time frame of 48 h before and after the study period based on creatinine levels only. The lowest creatinine level found within 3 months prior to ICU admission was used as baseline for the individual creatinine-based RIFLE classification. When no true preadmission creatinine existed, baseline creati- Fig. 1 Study profile. SIRS systemic inflammatory response synnine was estimated by the MDRD equation using a low drome, AKI acute kidney injury
1335
Statistical analysis
with AKI and septic shock received high-dose steroids. True baseline creatinine was found in 71% of the patients. The presence of a true baseline value was virtually equal among the four study groups. Of 18 patients with AKI and concomitant septic shock, the maximum RIFLE class within 48 h before until 48 h after the study period was class R in 10 patients, class I in 6 patients, and class F in 1 patient who also received RRT. One AKI patient who never met class R reached AKIN stage 1. AKI was first diagnosed within 48 h before the study period in 5 patients, within 48 h after the study period in 1 patient, and during the study period in 12 patients (median second day, IQR 1 day).
Data were analyzed by using STATAÒ for Windows version 10.1 software (Stata Corp., College Station, TX, USA). Continuous variables were expressed as median and interquartile range and categorical variables as n (%). The v2 test and Kruskal–Wallis test (for multiple groups) and Fisher’s exact test and Mann–Whitney test (for two groups) were used for comparison between categorical and continuous values, respectively. Diagnostic characteristics of pNGAL and uNGAL in predicting AKI were assessed by calculation of the area under the receiver operating characteristic curve (AUC-ROC). AUC-ROC analysis was performed by (1) comparing AKI patients with all non-AKI patients, and by (2) comparing AKI patients with those non-AKI patients with septic shock. A p value less than Biomarker levels in plasma 0.05 was considered statistically significant.
Results Patient characteristics The basal characteristics for patients with SIRS, severe sepsis, and septic shock with and without AKI are shown in Table 1. The four groups were equally distributed regarding basic characteristics and mortality. There was no significant difference between the groups in time elapsed from ICU admission until the first urine or plasma sample was obtained. Patients with SIRS had a shorter length of stay than patients with severe sepsis and patients with septic shock with and without AKI. A total of 14 patients (31%) received steroids, the majority of whom had septic shock and concomitant AKI. Twelve patients received low-dose steroids (a daily dose of less than 300 mg hydrocortisone or equivalent), and two patients
Peak pNGAL and MPO levels occurred early after ICU admission in most patients (median second day, IQR 2 days for both pNGAL and MPO). Patients with septic shock—irrespective of AKI status—had significantly higher peak levels of MPO, PCT, and CRP compared to patients with SIRS (Table 2). There was a stepwise increase in peak levels of pNGAL with increasing sepsis severity, and concomitant AKI raised the peak levels further (Fig. 2a; Table 2). However, difference in peak pNGAL levels between septic shock patients with and without AKI was non-significant (p = 0.06). Patients with AKI had a significantly higher change in plasma creatinine relative to baseline than non-AKI patients. Plasma cystatin C also showed significantly higher peak levels in patients with septic shock and concomitant AKI as compared to non-AKI patients. This difference was not seen for absolute creatinine levels (Table 2).
Table 1 Clinical characteristics of non-AKI patients with SIRS, severe sepsis, and septic shock and AKI patients with septic shock
Age, years (IQR) Male gender, n (%) Caucasian, n (%) APACHE II score (IQR) ICU length of stay, days (IQR) Time of admission enrolled, h (IQR) True baseline creatinine available, n (%) ICU mortality, n (%) 30-day mortality, n (%)
SIRS (n = 10)
Severe sepsis (n = 10)
Septic shock (n = 7)
Septic shock ? AKI (n = 18)
40 6 9 15 3.0 9.8 6 0 1
57 8 10 15 4.5 20.8 7 1 2
40 4 7 17 10 9.6 5 0 1
55 11 18 20 7 9.2 14 3 5
(30) (60) (90) (15) (2.0) (9.8) (60) (0) (10)
Values are expressed as median (IQR interquartile range) or as n (%) SIRS systemic inflammatory response syndrome, AKI acute kidney injury, APACHE II acute physiology and chronic health evaluation II
a b c
(11) (80) (100) (6) (2.0)a (47.3) (70) (10) (20)
(46) (57) (100) (6) (9.0)a, (6.3) (71) (0) (14)
b
p \ 0.05 compared with SIRS p \ 0.05 compared with severe sepsis p \ 0.05 compared with septic shock without AKI
(29) (61) (100) (10) (7)a (29.3) (78) (17) (28)
1336
Table 2 Peak biomarker levels in plasma and urine in non-AKI patients with SIRS, severe sepsis, and septic shock and in AKI patients with septic shock
Biomarkers in plasma NGAL (ng/mL) MPO (ng/mL) PCT (ng/mL) CRP (mg/L) Cystatin C (mg/L) Creatinine (lmol/L) Creatinine change relative to baseline (%) Biomarkers in urine NGAL (ng/mg creatinine) a1-microglobulin (mg/g creatinine) Cystatin C (mg/g creatinine)
SIRS (n = 10)
Severe sepsis (n = 10)
Septic shock (n = 7)
111 108 0.54 112 0.8 93.5 12.9
116 198 1.4 251 1.0 84.5 2.1
134 216 2.8 185 1.4 94.0 22.7
(67.8) (34.0) (1.3) (126) (0.3) (29.0) (27.6)
24.4 (34.4) 96.6 (78.1) 0.35 (0.22)
Values are expressed as median (interquartile range) SIRS systemic inflammatory response syndrome, AKI acute kidney injury
(27.6) (115)a (2.8) (120)a (0.5) (21.0) (28.4)
47.7 (29.1) 138 (111) 0.86 (1.86)a a b c
(72.7)b (502)a (10.3)a (137)a (0.4)a (52.0) (18.7)
63.5 (133)a 159 (155) 1.73 (7.31)a
Septic shock ? AKI (n = 18) 216 243 11.2 270 1.7 116.5 78.2
(364)a,b (139)a (20.5)a,b (101)a (0.9)a,b,c (45.0)b (57.1)a,b,c
319 (1,933)a,b,c 296 (415) 5.57 (42.7)a,b
p \ 0.05 compared with SIRS p \ 0.05 compared with severe sepsis p \ 0.05 compared with septic shock without AKI
Biomarker levels in urine Peak levels for uNGAL occurred early after ICU admission (median second day, IQR 4 days) and were significantly higher in AKI patients as compared to nonAKI patients (Table 2; Fig. 2b). Other biomarkers of acute tubular injury (cystatin C and a1-microglobulin in urine) are shown in Table 2. Peak urine cystatin C levels were significantly lower in patients with SIRS as compared to patients with severe sepsis and septic shock with and without AKI. The difference in peak urine cystatin C levels between septic shock patients with and without AKI did not reach significance (p = 0.18). Although there was a trend towards higher peak levels with increasing sepsis severity and the presence of AKI, no overall significant difference in peak urinary a1-microglobulin levels were found between the four groups (p = 0.08). Diagnostic characteristics of pNGAL and uNGAL in predicting AKI The kinetics for pNGAL, uNGAL, and MPO relative to the timepoint when AKI was first diagnosed (AKI day 0) is shown in Fig. 3. For comparison, non-AKI patients are included in Fig. 3. For non-AKI patients, the biomarker concentrations obtained from the fifth consecutive sample were arbitrarily chosen to represent AKI day 0. In nonAKI patients, values for pNGAL, uNGAL, and MPO were virtually unchanged during these 4 days. Twelve hours prior to AKI diagnosis both pNGAL and uNGAL were raised in AKI patients compared with non-AKI patients. At AKI day 0 pNGAL and uNGAL decreased but peaked again at AKI day 1. MPO was higher in AKI
Fig. 2 Peak levels of pNGAL (a) and uNGAL (b) in non-AKI patients with SIRS, severe sepsis, and septic shock and in AKI patients with septic shock. The horizontal lines indicate the upper reference limits for pNGAL and uNGAL, respectively. SIRS systemic inflammatory response syndrome, AKI acute kidney injury
patients as compared to non-AKI patients at 2 days prior to AKI day 0 and thereafter showed values similar to the non-AKI patients. Both pNGAL and uNGAL were good
Mean pNGAL, ng/mL
1337
350 300 250 200 150 100 50
1400 1200 1000
Mean MPO, ng/mL
Mean uNGAL, ng/mg creatinine
0
800 600 400 200 0
600 500 400 300 200 100 0 AKI day −2
AKI day −1
AKI day 0
AKI day 1
AKI day 2
Fig. 3 Mean plasma NGAL (upper), urine NGAL (middle), and MPO (lower) levels at various timepoints in AKI patients with septic shock (solid squares) and in non-AKI patients with SIRS, severe sepsis, or septic shock (empty squares). AKI day 0 represents the time when AKI was first classified according to the RIFLE or AKIN criteria. For non-AKI patients, consecutive plasma and urine samples are shown where AKI day 0 represents the time when the fifth sample was obtained. Error bars are SEM. MPO myeloperoxidase, AKI acute kidney injury
predictors for AKI within the next 12 h when comparing AKI patients in septic shock with non-AKI patients with SIRS, severe sepsis, and septic shock using the optimal cutoff values of 120 ng/mL and 68 ng/mg creatinine for pNGAL and uNGAL, respectively (Table 3). The predictive property of uNGAL to detect AKI was preserved when comparing patients with septic shock with and without AKI. When comparing pNGAL among septic shock patients with and without AKI, sensitivity was preserved but specificity decreased, yielding an AUCROC of 0.67 (CI 0.39–0.94).
Discussion Recent studies on NGAL as an early AKI marker show promising results in various settings [1–4, 21, 22]. NGAL levels rises in plasma and urine days before the RIFLE or AKIN criteria are met. The origin of plasmatic and urinary NGAL in these patients is, however, not fully
understood. Possible sources include (a) extrarenal production and release by neutrophils or epithelial cells into the bloodstream with subsequent glomerular filtration and spillover to the urine, (b) increased production by tubular epithelial cells, or (c) production by granulocytes sequestered in the tubular lumen. Considering that NGAL is released by activated neutrophils [19, 23] is a reason for concern about its specificity as an AKI marker in the ICU where sepsis might be a contributing cause in 50% of patients with AKI [8, 9]. To study the impact of systemic inflammation per se to NGAL levels in plasma and urine we selected patients with SIRS, severe sepsis, and septic shock with no AKI according to the RIFLE or AKIN criteria. For comparison, we included patients with septic shock and concomitant AKI. The APACHE II score was generally low in this study as compared to the PROWESS study [18]. This is explained by the absence of severe AKI and hence less organ failure on ICU admission in patients eligible for inclusion in our study. The distribution of CRP and PCT levels between patients with SIRS, severe sepsis, and septic shock in this study was in accordance to other findings [24, 25]. We found that pNGAL was elevated above normal not only in patients with severe sepsis and septic shock but also in patients with SIRS. The same was true for MPO, a protein preferentially released by neutrophils. This may reflect that the inflammatory response as such in critically ill patients affects activation of neutrophils with subsequent release of NGAL into the bloodstream. We used MPO as a reference marker of neutrophil activation, the rationale being that MPO is a large molecule (118 kDa) not cleared by the kidney. MPO levels in plasma are hence unaffected by alterations in glomerular filtration rate (GFR). In contrast, NGAL is a mid-sized molecule (22.5–45 kDa) that escapes freely over the intact glomerular filter. Therefore, pNGAL might rise when GFR falls. This may explain the early rise in pNGAL in patients with AKI seen in other studies [1, 3, 4, 26, 27]. In this study peak MPO levels were significantly higher in septic as compared to non-septic patients. However, patients with septic shock had significantly higher peak levels of pNGAL but not of MPO compared to patients with severe sepsis. The presence of concomitant AKI and septic shock raised pNGAL levels further, almost reaching significance (p = 0.06). Septic shock, even without AKI, also seemed to affect the levels of plasma cystatin C, another mid-sized molecule (13 kDa) easily cleared by glomerular filtration, with significantly higher levels in septic shock as compared to SIRS patients. This might indicate that some non-AKI patients with septic shock in this study actually had an impaired GFR overlooked by the RIFLE and AKIN criteria. Indeed, three out of seven patients in the non-AKI, septic
1338
Table 3 Diagnostic characteristics of pNGAL and uNGAL to predict AKI within the next 12 h Variables
Cutoff value
Compared to all non-AKI patients pNGAL [120 ng/mL uNGAL [68 ng/mg creatinine Compared to non-AKI patients with septic shock pNGAL [120 ng/mL uNGAL [68 ng/mg creatinine
AUC-ROC
Sensitivity
Specificity
0.85 (0.67–1.0) 0.86 (0.68–1.0)
0.83 (0.34–1.0) 0.71 (0.29–0.96)
0.86 (0.64–0.97) 1.0 (0.85–1.0)
0.67 (0.39–0.94) 0.86 (0.68–1.0)
0.83 (0.36–1.0) 0.71 (0.29–0.96)
0.50 (0.12–0.88) 1.0 (0.54–1.0)
Values are expressed as mean (95% CI) AKI acute kidney injury, AUC-ROC area under the receiver operating characteristic curve
shock group had a peak rise in creatinine relative to baseline above 25% indicating a mild kidney dysfunction. This is consistent with the elevation in urine cystatin C and a-1-microglobulin in this group. This may further explain elevated pNGAL levels in patients with septic shock and no AKI according to the RIFLE or AKIN criteria in this study. Alternatively, pNGAL and plasma cystatin C levels are affected by other non-renal factors such as the inflammatory state itself. A similar hypothesis was discussed by Bell et al. [28] after finding that cystatin C levels correlated with mortality in ICU patients with no signs of AKI measured by creatinine. High-dose steroid treatment can contribute to a rise in plasma cystatin C [29–31]. This is an unlikely explanation to the elevated plasma cystatin C levels seen in septic shock patients with and without AKI in this study. Among the non-AKI patients with septic shock none received steroids and among AKI patients only two received high-dose steroids. These two patients had relatively low peak plasma cystatin C levels (1.40 and 1.65 mg/L, respectively). The RIFLE criteria are recommended when staging AKI in clinical studies. However, the classification has inherent limitations. First, it is based on relative changes in serum or plasma creatinine. Partly due to varying extrarenal clearance, creatinine is a late and unreliable responder to GFR alterations. Second, creatinine is a small molecule (113 Da) and may pass the glomerular filter freely even when glomerular pores are moderately narrowed and the passage of bigger molecules such as NGAL and cystatin C is hindered [32]. Third, baseline creatinine needs to be known in order to prevent misclassification. When true creatinine is lacking the baseline level needs to be estimated. Using the MDRD formula for baseline creatinine estimation, one could overestimate baseline, especially in patients with a low muscle mass and habitually low creatinine. These patients might never reach a 50% increase in plasma creatinine relative to an estimated baseline despite a great increase in plasma creatinine relative to their true baseline. Even so, relying on MDRD as baseline estimator for the RIFLE classification renders less misclassification and is more robust in predicting outcome than the AKIN classification [33]. Although the majority of non-AKI patients had elevated peak pNGAL, their peak uNGAL levels were within
the normal reference range (\141 ng/mg creatinine) in all but four patients. In contrast, the AKI patients had a fivefold increase in peak uNGAL that differed significantly from the non-AKI patients. This finding challenges the theory that high uNGAL is a mere result of spillover from plasma. In our study both pNGAL and uNGAL were good predictors of AKI within the next 12 h. However, the ability of pNGAL to predict AKI in patients with septic shock was poor with an AUC-ROC (0.67) similar to the AUC-ROC (0.68) found in pediatric patients [11]. The ability of uNGAL to predict AKI was less affected by the presence of septic shock. The magnitude to which AKI per se contributes to NGAL levels in plasma might be clouded by the systemic activation of neutrophils due to sepsis with subsequent release of NGAL into the bloodstream. This is a possible explanation of why uNGAL performed better as an AKI predictor in this subgroup of patients. The expression of uNGAL seemed to follow a bimodal pattern around the development of AKI with an early peak preceding AKI followed by a second peak after AKI was established (Fig. 3). Since we used a polyclonal antibody-based assay (RIA) to measure NGAL it is likely that all possible forms of NGAL were detected. We speculate that the early expression seen in Fig. 3 is the result of excretion from neutrophils sequestered in the tubular lumen whereas the second peak might represent other forms of NGAL released after upregulation in the tubular cells themselves. In fact, in a recent study, different molecular forms of uNGAL were found at different timepoints after cardiac surgery [20]. The present study has some important limitations. Only a small number of patients were included which merely reflects the difficulty in selecting critically ill patients with severe sepsis and septic shock and no signs of AKI. In fact, our findings may suggest that we did not completely succeed in selecting patients without AKI in the non-AKI, septic shock group. Also, the septic state often begins outside the ICU and there is often a time delay from admission to the ICU until the first urine and plasma sample is obtained. Since NGAL has a short halflife its peak values could be missed [34].
1339
Conclusion
used with caution as the only measure of AKI in the clinical setting. A panel of different biomarkers of AKI in We conclude that pNGAL is raised in critically ill patients plasma and urine might bring the AKI diagnosis forward. with SIRS, severe sepsis, and septic shock with no apparent AKI and that elevated pNGAL levels coincide Acknowledgments The authors thank Ola Friman, A˚sa Bengtsson, Jenny Svedlund for their assistance with urine and plasma with the activation of neutrophil granulocytes. uNGAL is and collections, data collection, and help with patient recruitment. We probably a more robust marker of AKI than pNGAL in also thank Lena Moberg and Kerstin Lindblad for their technical patients with septic shock since uNGAL levels remain assistance. within normal limits even when plasma levels are high and signs of AKI are absent. The RIFLE criteria should be
References 7. Mori K, Lee HT, Rapoport D, Drexler 1. Mishra J, Dent C, Tarabishi R, IR, Foster K, Yang J, Schmidt-Ott KM, Mitsnefes MM, Ma Q, Kelly C, Ruff Chen X, Li JY, Weiss S, Mishra J, SM, Zahedi K, Shao M, Bean J, Mori K, Cheema FH, Markowitz G, Suganami Barasch J, Devarajan P (2005) T, Sawai K, Mukoyama M, Kunis C, Neutrophil gelatinase-associated D’Agati V, Devarajan P, Barasch J lipocalin (NGAL) as a biomarker for (2005) Endocytic delivery of lipocalinacute renal injury after cardiac surgery. siderophore-iron complex rescues the Lancet 365:1231–1238 kidney from ischemia-reperfusion 2. Wagener G, Jan M, Kim M, Mori K, injury. J Clin Invest 115:610–621 Barasch JM, Sladen RN, Lee HT (2006) 8. Uchino S, Kellum JA, Bellomo R, Doig Association between increases in GS, Morimatsu H, Morgera S, Schetz urinary neutrophil gelatinase-associated M, Tan I, Bouman C, Macedo E, lipocalin and acute renal dysfunction Gibney N, Tolwani A, Ronco C (2005) after adult cardiac surgery. Acute renal failure in critically ill Anesthesiology 105:485–491 patients: a multinational, multicenter 3. Hirsch R, Dent C, Pfriem H, Allen J, study. JAMA 294:813–818 Beekman RH 3rd, Ma Q, Dastrala S, 9. Bagshaw SM, Uchino S, Bellomo R, Bennett M, Mitsnefes M, Devarajan P Morimatsu H, Morgera S, Schetz M, (2007) NGAL is an early predictive Tan I, Bouman C, Macedo E, Gibney N, biomarker of contrast-induced Tolwani A, Oudemans-van Straaten nephropathy in children. Pediatr HM, Ronco C, Kellum JA (2007) Septic Nephrol 22:2089–2095 acute kidney injury in critically ill 4. Bachorzewska-Gajewska H, Malyszko patients: clinical characteristics and J, Sitniewska E, Malyszko JS, Pawlak outcomes. Clin J Am Soc Nephrol K, Mysliwiec M, Lawnicki S, 2:431–439 Szmitkowski M, Dobrzycki S (2007) Could neutrophil-gelatinase-associated 10. Cruz DN, de Cal M, Garzotto F, Perazella MA, Lentini P, Corradi V, lipocalin and cystatin C predict the Piccinni P, Ronco C (2010) Plasma development of contrast-induced neutrophil gelatinase-associated nephropathy after percutaneous lipocalin is an early biomarker for acute coronary interventions in patients with kidney injury in an adult ICU stable angina and normal serum population. Intensive Care Med creatinine values? Kidney Blood Press 36:444–451 Res 30:408–415 11. Wheeler DS, Devarajan P, Ma Q, 5. Xu SY, Pauksen K, Venge P (1995) Harmon K, Monaco M, Cvijanovich N, Serum measurements of human Wong HR (2008) Serum neutrophil neutrophil lipocalin (HNL) discriminate gelatinase-associated lipocalin (NGAL) between acute bacterial and viral as a marker of acute kidney injury in infections. Scand J Clin Lab Invest critically ill children with septic shock. 55:125–131 Crit Care Med 36:1297–1303 6. Fjaertoft G, Foucard T, Xu S, Venge P 12. Zappitelli M, Washburn KK, Arikan (2005) Human neutrophil lipocalin AA, Loftis L, Ma Q, Devarajan P, (HNL) as a diagnostic tool in children Parikh CR, Goldstein SL (2007) Urine with acute infections: a study of the neutrophil gelatinase-associated kinetics. Acta Paediatr 94:661–666 lipocalin is an early marker of acute kidney injury in critically ill children: a prospective cohort study. Crit Care 11:R84
13. Bagshaw SM, Bennett M, Haase M, Haase-Fielitz A, Egi M, Morimatsu H, D’Amico G, Goldsmith D, Devarajan P, Bellomo R (2010) Plasma and urine neutrophil gelatinase-associated lipocalin in septic versus non-septic acute kidney injury in critical illness. Intensive Care Med 36:452–461 14. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P (2004) Acute renal failure: definition, outcome measures, animal models, fluid therapy and information technology needs: the second international consensus conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 8:R204–R212 15. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, Levin A (2007) Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 11:R31 16. Kellum JA, Bellomo R, Ronco C (2008) Definition and classification of acute kidney injury. Nephron Clin Pract 109:c182–c187 17. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis The ACCP/SCCM consensus conference committee. American College of Chest Physicians/ Society of Critical Care Medicine. Chest 101:1644–1655 18. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, LopezRodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699–709 19. Xu SY, Petersson CG, Carlson M, Venge P (1994) The development of an assay for human neutrophil lipocalin (HNL)—to be used as a specific marker of neutrophil activity in vivo and vitro. J Immunol Methods 171:245–252
1340
20. Cai L, Borowiec J, Xu S, Han W, Venge P (2009) Assays of urine levels of HNL/NGAL in patients undergoing cardiac surgery and the impact of antibody configuration on their clinical performances. Clin Chim Acta 403:121–125 21. Nickolas TL, O’Rourke MJ, Yang J, Sise ME, Canetta PA, Barasch N, Buchen C, Khan F, Mori K, Giglio J, Devarajan P, Barasch J (2008) Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury. Ann Intern Med 148:810–819 22. Makris K, Markou N, Evodia E, Dimopoulou E, Drakopoulos I, Ntetsika K, Rizos D, Baltopoulos G, Haliassos A (2009) Urinary neutrophil gelatinaseassociated lipocalin (NGAL) as an early marker of acute kidney injury in critically ill multiple trauma patients. Clin Chem Lab Med 47:79–82 23. Xu SY, Carlson M, Engstrom A, Garcia R, Peterson CG, Venge P (1994) Purification and characterization of a human neutrophil lipocalin (HNL) from the secondary granules of human neutrophils. Scand J Clin Lab Invest 54:365–376
24. Brunkhorst FM, Wegscheider K, Forycki ZF, Brunkhorst R (2000) Procalcitonin for early diagnosis and differentiation of SIRS, sepsis, severe sepsis, and septic shock. Intensive Care Med 26(Suppl 2):S148–S152 25. Luzzani A, Polati E, Dorizzi R, Rungatscher A, Pavan R, Merlini A (2003) Comparison of procalcitonin and C-reactive protein as markers of sepsis. Crit Care Med 31:1737–1741 26. Dent CL, Ma Q, Dastrala S, Bennett M, Mitsnefes MM, Barasch J, Devarajan P (2007) Plasma neutrophil gelatinaseassociated lipocalin predicts acute kidney injury, morbidity and mortality after pediatric cardiac surgery: a prospective uncontrolled cohort study. Crit Care 11:R127 27. Tuladhar SM, Puntmann VO, Soni M, Punjabi PP, Bogle RG (2009) Rapid detection of acute kidney injury by plasma and urinary neutrophil gelatinase-associated lipocalin after cardiopulmonary bypass. J Cardiovasc Pharmacol 53:261–266 28. Bell M, Granath F, Martensson J, Lofberg E, Ekbom A, Martling CR (2009) Cystatin C is correlated with mortality in patients with and without acute kidney injury. Nephrol Dial Transplant 24:3096–3102 29. Risch L, Herklotz R, Blumberg A, Huber AR (2001) Effects of glucocorticoid immunosuppression on serum cystatin C concentrations in renal transplant patients. Clin Chem 47:2055–2059
30. Poge U, Gerhardt T, Bokenkamp A, Stoffel-Wagner B, Klehr HU, Sauerbruch T, Woitas RP (2004) Time course of low molecular weight proteins in the early kidney transplantation period—influence of corticosteroids. Nephrol Dial Transplant 19:2858–2863 31. Bokenkamp A, Laarman CA, Braam KI, van Wijk JA, Kors WA, Kool M, de Valk J, Bouman AA, Spreeuwenberg MD, Stoffel-Wagner B (2007) Effect of corticosteroid therapy on low-molecular weight protein markers of kidney function. Clin Chem 53:2219–2221 32. Strevens H, Wide-Swensson D, Grubb A, Hansen A, Horn T, Ingemarsson I, Larsen S, Nyengaard JR, Torffvit O, Willner J, Olsen S (2003) Serum cystatin C reflects glomerular endotheliosis in normal, hypertensive and pre-eclamptic pregnancies. BJOG 110:825–830 33. Joannidis M, Metnitz B, Bauer P, Schusterschitz N, Moreno R, Druml W, Metnitz PG (2009) Acute kidney injury in critically ill patients classified by AKIN versus RIFLE using the SAPS 3 database. Intensive Care Med 35:1692– 1702 34. Axelsson L, Bergenfeldt M, Ohlsson K (1995) Studies of the release and turnover of a human neutrophil lipocalin. Scand J Clin Lab Invest 55:577–588
