Mild elevation of urinary biomarkers in prerenal acute kidney injury
2012; Elsevier BV; Volume: 82; Issue: 10 Linguagem: Inglês
10.1038/ki.2012.266
ISSN1523-1755
AutoresKent Doi, Daisuke Katagiri, Kousuke Negishi, S. Hasegawa, Yoshifumi Hamasaki, Toshiro Fujita, Takehiro Matsubara, Takeshi Ishii, Naoki Yahagi, Takeshi Sugaya, Eisei Noiri,
Tópico(s)Trauma, Hemostasis, Coagulopathy, Resuscitation
ResumoPrerenal acute kidney injury (AKI) is thought to be a reversible loss of renal function without structural damage. Although prerenal and intrinsic AKI frequently coexist in clinical situations, serum creatinine and urine output provide no information to support their differentiation. Recently developed biomarkers reflect tubular epithelial injury; therefore, we evaluated urinary biomarker levels in an adult mixed intensive care unit (ICU) cohort of patients who had been clinically evaluated as having prerenal AKI. Urinary L-type fatty acid–binding protein (L-FABP), neutrophil gelatinase–associated lipocalin (NGAL), interleukin-18 (IL-18), N-acetyl-β-D-glucosaminidase (NAG), and albumin in patients with prerenal AKI showed modest but significantly higher concentrations than in patients with non-AKI. We also conducted a proof-of-concept experiment to measure urinary biomarker excretion in prerenal AKI caused by volume depletion. Compared with cisplatinum and ischemia–reperfusion models in mice, volume depletion in mice caused a modest secretion of L-FABP and NGAL into urine with more sensitive response of L-FABP than that of NGAL. Although no histological evidence of structural damage was identified by light microscopy, partial kidney hypoxia was found by pimonidazole incorporation in the volume depletion model. Thus, our study suggests that new AKI biomarkers can detect mild renal tubular damage in prerenal acute kidney injury. Prerenal acute kidney injury (AKI) is thought to be a reversible loss of renal function without structural damage. Although prerenal and intrinsic AKI frequently coexist in clinical situations, serum creatinine and urine output provide no information to support their differentiation. Recently developed biomarkers reflect tubular epithelial injury; therefore, we evaluated urinary biomarker levels in an adult mixed intensive care unit (ICU) cohort of patients who had been clinically evaluated as having prerenal AKI. Urinary L-type fatty acid–binding protein (L-FABP), neutrophil gelatinase–associated lipocalin (NGAL), interleukin-18 (IL-18), N-acetyl-β-D-glucosaminidase (NAG), and albumin in patients with prerenal AKI showed modest but significantly higher concentrations than in patients with non-AKI. We also conducted a proof-of-concept experiment to measure urinary biomarker excretion in prerenal AKI caused by volume depletion. Compared with cisplatinum and ischemia–reperfusion models in mice, volume depletion in mice caused a modest secretion of L-FABP and NGAL into urine with more sensitive response of L-FABP than that of NGAL. Although no histological evidence of structural damage was identified by light microscopy, partial kidney hypoxia was found by pimonidazole incorporation in the volume depletion model. Thus, our study suggests that new AKI biomarkers can detect mild renal tubular damage in prerenal acute kidney injury. In the traditional anatomical flow construct of prerenal, renal, and postrenal causes, prerenal acute kidney injury (AKI) and prerenal azotemia have been recognized as distinct disease conditions from intrinsic AKI and acute tubular necrosis. However, prerenal AKI frequently coexists with acute tubular necrosis in clinical situations. Prerenal azotemia is regarded as a crucial risk factor for ischemic acute tubular necrosis.1.Molitoris B.A. Transitioning to therapy in ischemic acute renal failure.J Am Soc Nephrol. 2003; 14: 265-267Crossref PubMed Scopus (94) Google Scholar Acute renal dysfunction indicated by serum creatinine elevation includes both functional loss and structural damage to the kidney. Although the Risk-Injury-Failure-Loss-End stage and Acute Kidney Injury Network criteria enable standardized AKI diagnosis, these criteria provide no clue to differentiate the AKI etiology. Recently, AKI biomarkers have been developed to facilitate early detection, differential diagnosis, and prognosis.2.Murray P.T. Devarajan P. Levey A.S. et al.A framework and key research questions in AKI diagnosis and staging in different environments.Clin J Am Soc Nephrol. 2008; 3: 864-868Crossref PubMed Scopus (87) Google Scholar, 3.Coca S.G. Yalavarthy R. Concato J. et al.Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review.Kidney Int. 2008; 73: 1008-1016Abstract Full Text Full Text PDF PubMed Scopus (528) Google Scholar, 4.Endre Z.H. Pickering J.W. Walker R.J. Clearance and beyond: the complementary roles of GFR measurement and injury biomarkers in acute kidney injury (AKI).Am J Physiol Renal Physiol. 2011; 301: F697-F707Crossref PubMed Scopus (115) Google Scholar, 5.Siew E.D. Ware L.B. Ikizler T.A. Biological markers of acute kidney injury.J Am Soc Nephrol. 2011; 22: 810-820Crossref PubMed Scopus (202) Google Scholar Among them, urinary L-type fatty acid–binding protein (L-FABP), neutrophil gelatinase–associated lipocalin (NGAL), interleukin-18 (IL-18), and kidney injury molecule-1 are regarded as reflecting tubular epithelial cell injury.6.Nguyen M.T. Devarajan P. Biomarkers for the early detection of acute kidney injury.Pediatr Nephrol. 2008; 23: 2151-2157Crossref PubMed Scopus (213) Google Scholar, 7.Parikh C.R. Devarajan P. New biomarkers of acute kidney injury.Crit Care Med. 2008; 36: S159-S165Crossref PubMed Scopus (220) Google Scholar, 8.Waikar S.S. Bonventre J.V. Biomarkers for the diagnosis of acute kidney injury.Curr Opin Nephrol Hypertens. 2007; 16: 557-564Crossref PubMed Scopus (73) Google Scholar, 9.Noiri E. Doi K. Negishi K. et al.Urinary fatty acid-binding protein 1: an early predictive biomarker of kidney injury.Am J Physiol Renal Physiol. 2009; 296: F669-F679Crossref PubMed Scopus (113) Google Scholar Increased urinary secretion of these biomarkers can indicate the presence of tubular damage. To determine whether AKI patients were suffering from prerenal causes, two major features have been examined: fractional excretion of sodium (FENa) and volume responsiveness. Although several limitations exist for FENa, especially in situations of sepsis-associated AKI, AKI with liver failure or congestive heart failure, chronic kidney disease, and use of diuretics,10.Perazella M.A. Coca S.G. Hall I.E. et al.Urine microscopy is associated with severity and worsening of acute kidney injury in hospitalized patients.Clin J Am Soc Nephrol. 2011; 5: 402-408Crossref Scopus (86) Google Scholar FENa is the most sensitive and widely used index among urine indices such as urine-specific gravity, urine osmolality, and the plasma urea/creatinine ratio. Volume responsiveness is another feature of prerenal AKI.11.Himmelfarb J. Joannidis M. Molitoris B. et al.Evaluation and initial management of acute kidney injury.Clin J Am Soc Nephrol. 2008; 3: 962-967Crossref PubMed Scopus (104) Google Scholar When AKI is improved promptly by fluid resuscitation, the patients are categorized as having prerenal AKI. However, reversibility can only be determined by the response to fluid over time, indicating the weakness of retrospective diagnosis. Moreover, fluid resuscitation can endanger volume-unresponsive AKI patients because fluid overload worsens AKI outcomes, including mortality.12.Prowle J.R. Echeverri J.E. Ligabo E.V. et al.Fluid balance and acute kidney injury.Nat Rev Nephrol. 2010; 6: 107-115Crossref PubMed Scopus (322) Google Scholar,13.Bouchard J. Soroko S.B. Chertow G.M. et al.Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury.Kidney Int. 2009; 76: 422-427Abstract Full Text Full Text PDF PubMed Scopus (778) Google Scholar This study was conducted to evaluate urinary AKI biomarkers in prerenal AKI patients treated in a mixed medical–surgical intensive care unit (ICU). Considering the continuum between prerenal AKI and renal AKI, AKI biomarkers can quantify the burden of structural injury in prerenal AKI. Recently, Endre et al.14.Nejat M. Pickering J.W. Devarajan P. et al.Some biomarkers of acute kidney injury are increased in pre-renal injury.Kidney Int. 2012; 81: 1254-1262Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar reported that urinary biomarkers, including NGAL and IL-18, were increased in prerenal AKI, which was defined as recovery within 48h and FENa <1%. In addition, we conducted a proof-of-concept experiment with humanized L-FABP transgenic mice9.Noiri E. Doi K. Negishi K. et al.Urinary fatty acid-binding protein 1: an early predictive biomarker of kidney injury.Am J Physiol Renal Physiol. 2009; 296: F669-F679Crossref PubMed Scopus (113) Google Scholar to demonstrate that mild elevation of urinary L-FABP is detectable in prerenal AKI induced by dehydration. We analyzed 337 adult patients who had been enrolled prospectively in our previous study.15.Doi K. Negishi K. Ishizu T. et al.Evaluation of new acute kidney injury biomarkers in a mixed intensive care unit.Crit Care Med. 2011; 39: 2464-2469Crossref PubMed Scopus (125) Google Scholar Among them, 129 (38.3%) patients were diagnosed as having AKI within 7 days after ICU admission. Fifty-one AKI patients showed recovery within 48h (transient AKI). No transient AKI patient was treated by renal replacement therapy within 1 week after ICU admission. Transient AKI was divided into two groups according to FENa ( 1%). Another 78 nontransient AKI patients were determined as having renal AKI (Figure 1). The clinical characteristics and outcomes of the patients are shown in Table 1. In the transient AKI groups, AKI severity was significantly milder than in the renal AKI group. In the renal AKI group, higher 14-day in-hospital mortality, longer ICU stay, and a higher APACHE II score were observed than in either the transient AKI or the non-AKI group. Although the differences were not statistically significant, the transient AKI groups showed a longer ICU stay and a higher APACHE II score than did the non-AKI group. Taken together, the transient AKI groups appeared to have intermediate severity between the non-AKI and the renal AKI groups.Table 1Baseline clinical data and outcomesTransient AKINon-AKIFENa 1%Renal AKIn=208n=20n=31n=78Age (years)66.0 (53.3–74.0)61.0 (53.5–70.8)70.0 (49.0–74.0)65.5 (57.5–74.0)Male, n (%)132 (63.5)14 (70.0)22 (71.0)54 (69.2)AKI severity Risk, n (%)14 (70.0)25 (80.7)15 (19.2)* Injury, n (%)5 (25.0)6 (19.4)20 (25.6) Failure+RRT, n (%)1 (5.0)0 (0.0)43 (55.1)Sepsis, n (%)30 (14.4)8 (40.0)4 (12.9)23 (29.5)*APACHE II score10.0 (7.0–13.0)14.0 (9.3–17.0)11.0 (8.0–15.0)17.0 (10.0–23.0)**,***ICU stay (days)2.0 (2.0–4.0)3.0 (2.0–5.8)3.0 (2.0–5.0)5.0 (3.0–10.3)**,***14-day mortality, n (%)2 (1.0)0 (0.0)1 (3.2)10 (13.0)*Abbreviations: AKI, acute kidney injury; FENa, fractional excretion of sodium; ICU, intensive care unit; RRT, renal replacement therapy.*P<0.05 by Fisher's exact test; **P<0.05 vs. non-AKI; ***P 1%. Open table in a new tab Abbreviations: AKI, acute kidney injury; FENa, fractional excretion of sodium; ICU, intensive care unit; RRT, renal replacement therapy. *P<0.05 by Fisher's exact test; **P<0.05 vs. non-AKI; ***P 1%. The renal AKI group, and also the transient AKI group, showed significantly higher levels of L-FABP, NGAL, IL-18, N-acetyl-β-D-glucosaminidase (NAG), and albumin than did the non-AKI group (Figure 2). The L-FABP and NGAL, in both absolute concentration and normalized by urinary creatinine, showed significant differences between non-AKI and transient AKI, even after adjusting for age and gender (Supplementary Table S1 online). It is noteworthy that transient AKI with FENa 1% showed significantly lower urinary creatinine levels (Supplementary Figure S1 online). Consequently, all the urinary biomarkers in transient AKI with FENa >1% showed significant increases compared with the non-AKI group, not in absolute concentrations but after correction by the urinary creatinine concentrations (Supplementary Figure S2 online). Download .doc (.05 MB) Help with doc files Supplementary Table 1 Download .ppt (.35 MB) Help with ppt files Supplementary Figures 1 and 2 An animal experiment using human L-FABP transgenic mice was conducted to provide a proof of concept that increased urinary L-FABP and NGAL levels were observable in prerenal AKI. Volume depletion significantly reduced body weight and increased blood urea nitrogen levels, both of which had recovered completely at 7 and 14 days (Figure 3). Urinary L-FABP and NGAL levels were examined in cisplatinum (CDDP) injection, ischemia–reperfusion (IR), and volume depletion models (Figure 4). As described in earlier reports,16.Negishi K. Noiri E. Maeda R. et al.Renal L-type fatty acid-binding protein mediates the bezafibrate reduction of cisplatin-induced acute kidney injury.Kidney Int. 2008; 73: 1374-1384Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar,17.Negishi K. Noiri E. Doi K. et al.Monitoring of urinary L-type fatty acid-binding protein predicts histological severity of acute kidney injury.Am J Pathol. 2009; 174: 1154-1159Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar CDDP injection at the dose of 20mg/kg and IR injury by bilateral 30-min renal artery clamp remarkably induced secretion of L-FABP in urine and increased blood urea nitrogen levels (mean±s.d.; CDDP at 72h, 139.1±21.4mg/dl (n=6); IR at 24h, 94.1±6.3mg/dl (n=6)). However, the urinary L-FABP level in volume depletion was modestly but significantly increased at 24, 48, and 72h, whereas blood urea nitrogen showed significant elevation only at 72h. The levels of urinary L-FABP in CDDP injection and IR models were significantly higher than in the volume depletion model. Urinary NGAL measured at the same time points also showed significant increases in the volume depletion model. However, elevation of urinary NGAL in the volume depletion model was much smaller than in the CDDP injection and IR models. It is noteworthy that urinary L-FABP levels in renal AKI (CDDP and IR) were ∼10–100 times higher than those in prerenal AKI (volume depletion), whereas urinary NGAL levels in renal AKI were more than 100 times higher than in prerenal AKI. Moreover, no significant increase was observed when NGAL was normalized by the urinary creatinine concentration in prerenal AKI.Figure 4Urinary L-type fatty acid–binding protein (L-FABP) and neutrophil gelatinase–associated lipocalin (NGAL) levels in volume depletion (VD), cisplatinum (CDDP) injection, and ischemia–reperfusion (IR) injury models. VD induced significant but modest increases of urinary L-FABP and NGAL compared with CDDP injection and IR injury models. #P<0.05 vs. 0h. Cre, creatinine.View Large Image Figure ViewerDownload (PPT) Light microscopy revealed no histological evidence of tubular injury in the volume depletion model, although CDDP injection and IR injury induced severe acute tubular necrosis in kidney tissues (Supplementary Figure S3 online). Renal hypoxia in the volume depletion model was assessed using pimonidazole incorporation. Reportedly, cellular adduction of pimonidazole shows good correlation with tissue O2 tension.18.Arteel G.E. Thurman R.G. Raleigh J.A. Reductive metabolism of the hypoxia marker pimonidazole is regulated by oxygen tension independent of the pyridine nucleotide redox state.Eur J Biochem. 1998; 253: 743-750Crossref PubMed Scopus (149) Google Scholar Pimonidazole incorporation was detected dominantly in the outer stripe of the outer medulla, especially in proximal tubular epithelial cells, in the volume depletion model, although no signal was detected in normal kidney tissue (Figure 5). Download .jpg (.22 MB) Help with files Supplementary Figure 3 The present study evaluated whether new urinary AKI biomarkers are elevated in prerenal AKI, which was previously assumed to cause functional loss with no structural damage. In a cohort of adult mixed ICU patients, modest but significant increases of urinary L-FABP, NGAL, IL-18, NAG, and albumin were observed in AKI patients who had been clinically defined as having prerenal AKI, FENa 1% showed lower urinary creatinine concentration. Therefore, their biomarker levels were significantly higher than those of non-AKI patients when normalized by urinary creatinine (Supplementary Figures S1 and S2 online). These transient AKI patients with FENa >1% might be sufficiently resuscitated or administered with diuretics at ICU admission (i.e., urinary sample correction), and their urinary biomarker elevations can be detected only when corrected by the urinary creatinine concentration. Recently, Ralib et al.19.Ralib A.M. Pickering J.W. Shaw G.M. et al.Test characteristics of urinary biomarkers depend on quantitation method in acute kidney injury.J Am Soc Nephrol. 2012; 23: 322-333Crossref PubMed Scopus (122) Google Scholar reported that normalized concentration of biomarkers can predict AKI development after ICU admission. Consistent with this, we also found a higher frequency of AKI development after ICU admission in transient AKI patients with FENa >1% (21 of 31, 68%), whereas 9 of 20 transient AKI patients with FENa <1% (45%) satisfied the AKI diagnosis criteria after ICU admission (P=0.1073). Animal experiments indicated that modest secretion of L-FABP into urine can be induced by volume depletion, which was accompanied by partial hypoxia in the kidney (Figures 4 and 5). We demonstrated recently that urinary L-FABP levels in AKI showed gradual increases with AKI severity. Urinary L-FABP concentrations in human L-FABP transgenic mice were elevated even after 5-min IR injury and were correlated significantly with the ischemia time (5, 15, 30min) and the histological injury score.17.Negishi K. Noiri E. Doi K. et al.Monitoring of urinary L-type fatty acid-binding protein predicts histological severity of acute kidney injury.Am J Pathol. 2009; 174: 1154-1159Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar Results of the present study demonstrate that simple volume depletion also induced urinary L-FABP secretion, which was significantly lower than those of CDDP injection and IR models. Clinical evaluation of our previous study revealed a gradual increase of urinary L-FABP along with the AKI severity of the Risk-Injury-Failure-Loss-End stage.15.Doi K. Negishi K. Ishizu T. et al.Evaluation of new acute kidney injury biomarkers in a mixed intensive care unit.Crit Care Med. 2011; 39: 2464-2469Crossref PubMed Scopus (125) Google Scholar The present study found that AKI can be regarded clinically as prerenal, showing modest but significant increases of urinary L-FABP compared with non-AKI patients. These findings support the view that prerenal AKI and renal AKI lie on a continuum of renal injury and that L-FABP elevation reflects the severity of structural damage of the kidney. Results of this study also showed a significant increase of urinary NGAL in prerenal AKI. In our clinical cohort of an adult mixed ICU, urinary NGAL in transient AKI patients showed significant elevation compared with that in non-AKI patients (Figure 2 and Supplementary Figure S2 online). A clinical study conducted at an emergency department by Nickolas et al.20.Nickolas T.L. O’Rourke M.J. Yang J. et al.Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury.Ann Intern Med. 2008; 148: 810-819Crossref PubMed Scopus (577) Google Scholar showed an approximately twofold elevation of urinary NGAL in prerenal AKI (defined as FENa <1% and recovered within 3 days) compared with non-AKI (30.1±90.2 vs. 15.5±15.3μg per g creatinine). Singer et al.21.Singer E. Elger A. Elitok S. et al.Urinary neutrophil gelatinase-associated lipocalin distinguishes pre-renal from intrinsic renal failure and predicts outcomes.Kidney Int. 2011; 80: 405-414Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar reported that urinary NGAL can distinguish intrinsic from prerenal AKI. However, 26% of AKI patients were categorized as having an unclassifiable diagnosis. Their urinary NGAL values were between prerenal and renal AKI. Although animal experiments using NGAL reporter mice showed no increase of NGAL expression in the kidney by volume depletion,22.Paragas N. Qiu A. Zhang Q. et al.The Ngal reporter mouse detects the response of the kidney to injury in real time.Nat Med. 2011; 17: 216-222Crossref PubMed Scopus (331) Google Scholar we detected a modest but significant increase of urinary NGAL in the volume depletion model (Figure 4). It is noteworthy that Paragas et al.22.Paragas N. Qiu A. Zhang Q. et al.The Ngal reporter mouse detects the response of the kidney to injury in real time.Nat Med. 2011; 17: 216-222Crossref PubMed Scopus (331) Google Scholar evaluated NGAL expression in the reporter mice, not using enzyme-linked immunosorbent assay but using the luciferase-based fluorescence imaging technique, whereas we measured urine NGAL using the enzyme-linked immunosorbent assay method, which is assumed to be more sensitive than fluorescence imaging. In addition, the relative increases of urinary L-FABP and NGAL in prerenal AKI (volume depletion) compared with renal AKI (CDDP and IR) differed; urinary L-FABP in prerenal AKI increased by ∼10% of that in renal AKI, whereas urinary NGAL in prerenal AKI was elevated by ∼1% of that in renal AKI. This result suggests that L-FABP responds more sensitively to volume depletion than NGAL. What stimulates urinary biomarker secretion into urine in prerenal AKI patients? Reduced renal blood flow is the most frequent cause of prerenal AKI. Because of the anatomical structure of the kidney, the outer medullary region can be exposed easily to hypoxia by low blood flow in the peritubular capillary. The promoter region of the L-FABP gene has a hypoxia-responsive element. Therefore, the L-FABP gene is responsive to hypoxic stress.9.Noiri E. Doi K. Negishi K. et al.Urinary fatty acid-binding protein 1: an early predictive biomarker of kidney injury.Am J Physiol Renal Physiol. 2009; 296: F669-F679Crossref PubMed Scopus (113) Google Scholar We observed a mild but significant increase of urinary L-FABP with evidence of renal hypoxia in volume depletion. These results suggest that urinary L-FABP in prerenal AKI can be increased by transient renal hypoxia. We also observed increased urinary NGAL excretion in the prerenal AKI of both clinical data and animal experiments. However, the degrees of NGAL elevations were milder than those of L-FABP as described above. L-FABP and NGAL are expressed, respectively, in renal proximal and distal tubular epithelial cells. Hypoxia examined by hypoxic probe in the animal volume depletion model was predominantly detected in proximal tubules (Figure 5). Gobe et al.23.Gobe G. Zhang X.J. Willgoss D.A. et al.Relationship between expression of Bcl-2 genes and growth factors in ischemic acute renal failure in the rat.J Am Soc Nephrol. 2000; 11: 454-467PubMed Google Scholar reported the relative resistance to hypoxic injury of distal tubules. Taken together, the evidence shows that L-FABP might respond to hypoxia caused by volume depletion more sensitively than NGAL because of its regulation (hypoxia-responsive element) and localization (proximal tubules) of expression in the kidney. In our adult mixed ICU cohort examined in the present study, we also found significant elevation of urinary IL-18, NAG, and albumin concentrations in transient AKI compared with those in non-AKI. Although hypoxic injury caused by volume depletion or renal hypoperfusion might have a dominant role in prerenal AKI, prerenal AKI in clinical situations is assumed to be complicated frequently with inflammatory conditions such as sepsis. NGAL and IL-18 can be upregulated by inflammation, whereas urinary NAG and albumin can be increased in renal tubular injury by various different etiologies.24.Han W.K. Waikar S.S. Johnson A. et al.Urinary biomarkers in the early diagnosis of acute kidney injury.Kidney Int. 2008; 73: 863-869Abstract Full Text Full Text PDF PubMed Scopus (465) Google Scholar,25.Ware L.B. Johnson A.C. Zager R.A. Renal cortical albumin gene induction and urinary albumin excretion in response to acute kidney injury.Am J Physiol Renal Physiol. 2011; 300: F628-F638Crossref PubMed Scopus (84) Google Scholar Urinary IL-18 in prerenal AKI was higher than in healthy control subjects in a cross-sectional study (155±68 vs. 23±9μg per g creatinine).26.Parikh C.R. Jani A. Melnikov V.Y. et al.Urinary interleukin-18 is a marker of human acute tubular necrosis.Am J Kidney Dis. 2004; 43: 405-414Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar Recently, Endre et al.14.Nejat M. Pickering J.W. Devarajan P. et al.Some biomarkers of acute kidney injury are increased in pre-renal injury.Kidney Int. 2012; 81: 1254-1262Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar reported that urinary kidney injury molecule-1, cystatin C, and IL-18 were significantly greater in prerenal AKI than in non-AKI patients. In the cohorts of postcardiac surgery AKI, in which renal hypoperfusion is assumed to be a dominant cause of renal injury, modest elevation of urinary NAG was observed.27.Han W.K. Wagener G. Zhu Y. et al.Urinary biomarkers in the early detection of acute kidney injury after cardiac surgery.Clin J Am Soc Nephrol. 2009; 4: 873-882Crossref PubMed Scopus (319) Google Scholar,28.Katagiri D. Doi K. Honda K. et al.Combination of two urinary biomarkers predicts acute kidney injury after adult cardiac surgery.Ann Thorac Surg. 2012; 93: 577-583Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar Considering the continuum between prerenal AKI and renal AKI, these biomarkers might reflect structural injury in prerenal AKI. In addition, the duration of injury must be evaluated because it also has a considerable impact on the biomarker profile. Endre et al.29.Endre Z.H. Pickering J.W. Walker R.J. et al.Improved performance of urinary biomarkers of acute kidney injury in the critically ill by stratification for injury duration and baseline renal function.Kidney Int. 2011; 79: 1119-1130Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar reported that the urinary biomarker performance was improved by stratifying AKI patients based on the time after probable renal insult. Although transient AKI showed recovery within 48h, information related to AKI duration before ICU admission is lacking in this study. Further evaluation is necessary to clarify what other factors in prerenal AKI affect these urinary biomarker elevations. Several limitations might affect the results obtained in this study. First, we studied adult patients at a single ICU. Evaluation should be conducted at multicenter ICUs to confirm our findings. Second, no data related to the usage of diuretics, which might have a significant impact on FENa, were available for this study. Actually, we determined prerenal AKI as FENa 1 or <1%). Renal AKI was defined as non-transient AKI, i.e., no recovery was observed within 48h, irrespective of FENa. Volume depletion, CDDP injection, and IR models were used, respectively, to mimic prerenal (volume depletion) and renal AKI (CDDP and IR). Male heterozygous human L-FABP transgenic mice (C57BL/6 background) weighing 25–35g were provided food and water ad libitum and were kept in glass-shielded metabolic cages (Metabolica; Sugiyama-gen Iriki, Tokyo, Japan). Simple volume depletion was induced by water intake restriction (n=6). The degree of dehydration was evaluated using body weight measurements recorded every 24h. CDDP (generously provided by Nippon Kayaku, Tokyo, Japan) at the dosage of 20mg/kg was administered by intraperitoneal injection (n=6). An ischemia–reperfusion model induced by 30-min bilateral renal artery clamp was produced as described in a previous report (n=6).17.Negishi K. Noiri E. Doi K. et al.Monitoring of urinary L-type fatty acid-binding protein predicts histological severity of acute kidney injury.Am J Pathol. 2009; 174: 1154-1159Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar,30.Yamamoto T. Noiri E. Ono Y. et al.Renal L-type fatty acid-binding protein in acute ischemic injury.J Am Soc Nephrol. 2007; 18: 2894-2902Crossref PubMed Scopus (278) Google Scholar Urine and blood samples were collected at 0, 24, 48, and 72h after initiation of water restriction, at 0 and 72h after CDDP injection, and at 0 and 24h after IR injury. Animals were killed at 72h (volume depletion and CDDP) and 24h (IR) for histological analyses. Blood urea nitrogen and urinary creatinine levels were measured as described previously.17.Negishi K. Noiri E. Doi K. et al.Monitoring of urinary L-type fatty acid-binding protein predicts histological severity of acute kidney injury.Am J Pathol. 2009; 174: 1154-1159Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar,31.Doi K. Noiri E. Maeda-Mamiya R. et al.Urinary L-type fatty acid-binding protein as a new biomarker of sepsis complicated with acute kidney injury.Crit Care Med. 2010; 38: 2037-2042Crossref PubMed Scopus (72) Google Scholar Urinary human L-FABP and mouse NGAL were measured using sandwich enzyme–linked immunosorbent assay kits (CMIC, Tokyo, Japan and BioPorto Diagnositics, Gentofte, Denmark, respectively). For histological examination, the kidneys were resected from the mice after perfusion with phosphate-buffered saline. Paraffin sections (3μm thick) were stained with periodic acid–Schiff. Evaluation of renal hypoxia by pimonidazole immunohistochemistry was conducted as described previously.30.Yamamoto T. Noiri E. Ono Y. et al.Renal L-type fatty acid-binding protein in acute ischemic injury.J Am Soc Nephrol. 2007; 18: 2894-2902Crossref PubMed Scopus (278) Google Scholar, 32.Tanaka T. Doi K. Maeda-Mamiya R. et al.Urinary L-type fatty acid-binding protein can reflect renal tubulointerstitial injury.Am J Pathol. 2009; 174: 1203-1211Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 33.Yasuda H. Yuen P.S. Hu X. et al.Simvastatin improves sepsis-induced mortality and acute kidney injury via renal vascular effects.Kidney Int. 2006; 69: 1535-1542Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar For this study, data were expressed as medians (interquartile range) and compared using the Wilcoxon rank-sum test or Steel–Dwass test for individual comparison. Categorical variables were described as proportions and were compared using Fisher's exact tests. To adjust age and gender in comparison of transient AKI with non-AKI, a likelihood ratio test in a multiple logistic regression model was performed, where the dependent variable was either non-AKI or transient AKI. These calculations were carried out using the software JMP 9.0 (SAS Institute, Cary, NC). The null hypothesis was rejected for P<0.05. We thank Dr Yutaka Yamomi, Dr Tatsuo Shimosawa, and Ms Mami Haba (The University of Tokyo) for their support. This work was supported by KAKEN-HI no. 23790931, MEXT, Japan (KD), KAKEN-HI no. 22790780, MEXT, Japan (KN), the Takeda Science Foundation, Japan (KD), and Asahi Kasei Kuraray Medical. Table S1. Adjustment of age and gender by likelihood ratio test in logistic regression model. Figure S1. Urinary sodium (A) and creatinine (B) concentrations measured at intensive care unit (ICU) admission are shown in each acute kidney injury (AKI) category (non-AKI (n=208), transient AKI + fractional excretion of sodium (FENa) 1 (n=31), renal AKI (n=78)). Figure S2. Urinary biomarkers measured at intensive care unit (ICU) admission are shown in each acute kidney injury (AKI) category (non-AKI (n=208), transient AKI + fractional excretion of sodium (FENa) 1 (n=31), renal AKI (n=78)). Figure S3. Renal histology of volume depletion (VD), cisplatinum (CDDP) injection, and ischemia–reperfusion (IR) injury models. Supplementary material is linked to the online version of the paper at http://www.nature.com/ki
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