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Objectives: To evaluate urine neutrophil gelatinase-associated lipocalin (uNGAL) concentration and its relation with causes, categories, stages and biochemical indexes of acute kidney injury (AKI) patients.
JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017 STUDY ON THE CONCENTRATION OF URINE NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN IN ACUTE RENAL FAILURE PATIENTS Pham Ngoc Huy Tuan*; Le Viet Thang** SUMMARY Objectives: To evaluate urine neutrophil gelatinase-associated lipocalin (uNGAL) concentration and its relation with causes, categories, stages and biochemical indexes of acute kidney injury (AKI) patients Subjects and methods: A prospective, cross-sectional study in 96 patients with AKI who admitted to General ICU, Trungvuong Hospital, Hochiminh city from 12 - 2013 to 01 - 2017 and a control group of 51 healthy people uNGAL had been done in all 96 patients and healthy people Results: All of the AKI patients (100%) had uNGAL elevation The average concentration of uNGAL in study group (412.26 ng/mL) was significantly higher than in control group (10.74 ng/mL) with p < 0.001 There was no relationship between AKI causes and uNGAL concentration with p > 0.05 The concentration of uNGAL was significantly higher in oliguria group in comparison with non-oliguria group (558.32 ng/mL vs 342.6 ng/mL) with p < 0.005 Patients’ uNGAL concentrations at the time of ICU admission were significantly related to their KDIGO stage (p < 0.001) Urinary NGAL had a moderate positive relationship with serum urea concentration (r = 0.529, p < 0.001) and a strong positive linear relationship with serum creatinine concentration (r = 0.852, p < 0.001) Conclusion: Urinary NGAL elevation was common in AKI patients The concentration of uNGAL depended on category and stage of AKI It had a moderate positive relationship with serum urea and strong positive relationship with creatinine concentration * Keywords: Acute kidney injury; Urine neutrophil gelatinase-associated lipocalin INTRODUCTION Acute kidney injury is a common and devastating problem with in-hospital mortality of 40% to 80% in the intensive care setting [10] The traditional blood (creatinine, blood urea nitrogen) and urine markers of kidney injury (casts, fractional excretion of sodium, urinary concentrating ability) that have been used for decades in clinical studies for diagnosis and prognosis of AKI are insensitive and nonspecific and not directly reflect injury to kidney cells Therefore, early recognition of renal injury is important and may help prevent further renal damage and functional impairment Neutrophil gelatinase-associated lipocalin is a small, 23 kDa protein that is an early biomarker for ischemic, septic or nephrotoxic kidney injury It is normally produced at low levels by the epithelial cells of the kidney, but it is quickly upregulated in the thick ascending limb (TAL) of the loop of Henle and the collecting ducts within three * Trungvuong Hospital ** 103 Military Hospital Corresponding author: Pham Ngoc Huy Tuan (bshuytuantv@yahoo.com.vn) Date received: 12/09/2017 Date accepted: 22/11/2017 170 JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017 hours of tubular epithelial injury Urinary NGAL (uNGAL) has been evaluated as an early biomarker of renal tubular damage in a acute clinical settings such as the operating room, ICU and emergency department, and in high-risk procedures such as cardiac surgery, radio-contrast injection and after adult and pediatric kidney and liver transplantation [1, 6, 7, 8, 9] There is considerable evidence that compared to increases in serum creatinine, NGAL detects early or subclinical kidney injury earlier, and predicts dialysis requirement and mortality better[1] In Vietnam, there are lack of studies on the role of uNGAL in AKI diagnosis and prognogsis in patients admitted to General ICU Therefore, we have conducted this research with the aim: Evaluation of the uNGAL concentration and its relation with causes, categories, stages and some biochemical indexes of AKI patients SUBJECTS AND METHODS Subject The study was conducted with a study group of 96 AKI patients who admitted to General ICU, Trung Vuong Hospital, Hochiminh city from 12 - 2013 to 01 - 2017 and a control group of 51 healthy people * Excluding criteria: Patients with chronic kidney failure, did not fit with diagnostic criteria, did not enough test results, anuria patients or did not agree to participate in the study Methods * Study design: A cross-sectional descriptive study * uNGAL measurement: 24-hour urine was collected After that, the volume of urine was measured before collecting mL sample for testing purpose uNGAL was measured by the sandwich ELISA method using NGAL monoclonal antibody in the NGAL kit After that, the sample will be analyzed by Achitech System of Abbott, America to measure uNGAL concentration * Diagnostic criteria: KDIGO definition and classification of AKI [5] - Diagnostic criteria for AKI: Serum creatinine increases ≥ 0.3 mg/dL (26.4 μmol/L compared to basic creatinine within 48 h or urine volum < 0.6 mL/kg BW/hour at least hours - AKI degree: + AKI degree 1: serum creatinine from < 220 μmol/L + AKI degree 2: serum creatinine from 220 - 353.6 μmol/L + AKI degree 3: ≥ 353.6 μmol/L * Statistical analysis: Statistical analyses were conducted using SPSS 20.0 RESULTS AND DISCUSSIONS Table 1: uNGAL concentration in study group Control group (n = 51) Study group (n = 96) p X ± SD 10.74 ± 5.18 412.26 ± 324.91 < 0.001 Max 20.28 1292.38 Min 3.32 69.63 Index uNGAL (ng/mL) The average concentration of uNGAL in study group was 412.26 ng/mL which was significantly higher than in control group (10.74 ng/mL) with p < 0.001 The maximum 171 JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017 and minimum concentration of uNGAL was 1292.38 and 69.63 ng/mL, respectively With the range of urinary NGAL from 43.62 to 114.66 ng/mL, all of the AKI patients (100%) had uNGAL elevation Study by Au V also showed that the mean immediate postoperative uNGAL levels in patients who developed sustained AKI were 204.8 ng/mL, and significantly higher than those who had normal renal function (31.9 ± 113 ng/mL) with p < 0.001 [1] This result was similar to other studies by Geus H.R, Makris K, Zappitelli M: there was a significant higher of uNGAL concentration in patients who diagnosed AKI compared with non-AKI patients with p < 0.05 [6, 7, 8] These differences in uNGAL concentration were expected because kidney injury associated with primary renal insults may be more severe than that in most patients included in our study, but our patients were probably more severely ill In current clinical practice, the gold standard for identification and classification of AKI is dependent on serial serum creatinine measurements, which are especially unreliable during acute changes in kidney function We identified uNGAL as one of the most upregulated genes in the kidney soon after ischemic injury NGAL protein was also markedly induced in kidney tubule cells and easily detected in the plasma and urine in animal models of ischemic and nephrotoxic AKI The expression of uNGAL protein was also dramatically increased in kidney tubules of humans with ischemic, septic, and post-transplant AKI Importantly, NGAL in the urine was found to be an 172 early predictive biomarker of AKI in a variety of acute clinical settings Emerging experimental and clinical evidence indicated that in the early phases of AKI from diverse etiologies, NGAL accumulates within two distinct pools, namely, a renal and a systemic pool Gene expression studies in AKI have clearly demonstrated rapid and massive upregulation of NGAL mRNA in the thick ascending limb of Henle's loop and the collecting ducts, with resultant synthesis of NGAL protein in the distal nephron (the renal pool) and secretion into the urine where it comprises the major fraction of uNGAL This finding also confirms the need for future research to evaluate uNGAL in different renal disease subgroups in order to understand fully how best to use uNGAL to diagnose AKI Table 2: Relation between urine NGAL concentration and the causes of AKI (n = 96) Causes n Urine NGAL (ng/mL) Sepsis (1) 58 415.25 ± 312.44 Bleeding, dehydration (2) 19 388.24 ± 332.46 Cirrhosis (3) 614.87 ± 458.23 Shock, heart failure (4) 349.58 ± 260.33 Toxic (5) 187.48 ± 98.69 p (1), (2), (3), (4) > 0.05 (5) and others < 0.01 In our study, sepsis was the most common cause with the proportion of 60.4% There was no significant difference between these causes with p > 0.05 Our result was similar to study by Vaidya D.S: there was no significant difference between uNGAL concentration and several causes JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017 of AKI in these studies (p > 0.05) [10], but was different with studies by Di Nardo M and Geus H.R (there was a significant higher concentration of uNGAL in septic AKI patients than non-septic AKI patients with p < 0.001 [4, 6] Lipoproteins also have strong affinity that trigger an innate immune response Therefore, it could be postulated that these circulating ligands that are linked to tubular epithelial TLR activation are responsible for the increased uNGAL concentrations, which we observed in patients with sepsis However, there were no increases in their SCr levels However, recent studies in patients with sepsis, septic shock, and systemic inflammatory response syndrome has reported contradictory findings A possible explanation for this difference is the variability of the subject inclusion time (up to 48 h after ICU admission) Intensive resuscitation and the administration of antibiotics may have already occurred before study inclusion, therefore most likely inducing rapid changes of uNGAL values Table 3: Relation between urine NGAL concentration and AKI category (n = 96) Categories n % Urine NGAL (ng/mL) Non-anuria 65 67.7 342.60 ± 284.68 Anuria 31 32.3 558.32 ± 358.95 p < 0.01 In our study, category of anuria occupied 32.3% all of AKI patients The concentration of uNGAL was significantly higher in anuria group compared with non-anuria group (558.32 ng/mL compared with 342.6 ng/mL) with p < 0.01 Our findings highlight the mechanistic insights of NGAL levels based on the specimens being measured Urine NGAL is proposed to derive predominantly from local renal synthesis of NGAL in the thick ascending limb of the loop of Henle and the collecting ducts when under inflammatory and oxidative stress Therefore, the concentration of uNGAL was directly related to the renal tubule injury in AKI patients as well as urine excretion ability Table 4: Relation between uNGAL concentration and stage of AKI (n = 96) AKI stages (KDIGO) n % Urine NGAL (ng/mL) 68 70.8 230.58 ± 146.29 21 21.9 796.92 ± 147.77 7.3 1023.20 ± 179.70 pAnova < 0.001 p1-2, p1-3 < 0.001, p2-3 = 0.002 According to the KDIGO classification, the stage AKI in our study made up the highest proportion (70.8%) Stage and occupied smaller proportion (21.9% and 7.3%, respectively) Our results also pointed that patients’ uNGAL concentrations at the time of ICU admission were significantly related to their KDIGO stage (p < 0.001) This result was similar to the study by Geus H.R (p < 0.0001) and Zapittelli M (p < 0.0002) when research on the relation between uNGAL and RIFFLE stage [6, 8] NGAL fulfills a central role in regulating epithelial neogenesis, and in iron chelation and delivery after ischemic or toxic insults to the renal tubular epithelium After kidney injury, NGAL is rapidly expressed on the apical epithelial membranes of the distal nephron NGAL is excreted in the urine 173 JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017 through exocytosis and has local bacteriostatic and proapoptotic effects Therefore, uNGAL concentration had a positive relation with the level of renal damage which exhibited throughout the high stage of KDIGO classification Table 5: Correlation between uNGAL and serum urea, creatinine concentration (n = 96) uNGAL Indexes Correlation equation r p Urea 0.529 < 0.001 uNGAL = 17.304*urea + 169.141 Creatinine 0.852 < 0.001 uNGAL = 2.616*creatinine - 150.730 In our study, uNGAL had a moderate positive relationship with serum urea concentration (r = 0.529, p < 0.001) and a strong positive linear relationship with serum creatinine concentration (r = 0.852, p < 0.001) Boglignano D also pointed that a significant correlation was also found between serum creatinine and uNGAL (r = 0.399, p < 0.001) [2] NGAL has mainly been studied in the setting of acute renal failure Patients who experienced acute renal dysfunction showed a marked increase in uNGAL levels, which preceded the increase in serum creatinine by a day In a single case of acute tubular necrosis due to heart failure induced hypotension, NGAL tubular expression was reported to be strongly increased [3] Hence, measurements of NGAL may serve as a very early marker of worsening renal function Urinary (or plasma) NGAL levels could therefore be used to adjust therapy, to anticipate and possibly prevent expected renal injury, even before a peak in serum creatinine occurs This potential of NGAL needs to be explored further in future studies uNGAL = 17.304 x ure + 169.141 1800 1600 1400 uNGAL 1200 1000 800 600 400 200 0 10 20 30 40 50 60 70 Ure Chart 1: Correlation between urine NGAL and urea concentration 174 80 JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017 uNGAL = 2.616 x creatinin - 150.730 2500 uNGAL 2000 1500 1000 500 0 100 200 300 400 500 Serum creatinin 600 700 800 900 Chart 2: Correlation between urine NGAL and creatinine concentration CONCLUSIONS In our study, all of the AKI patients (100%) had urine NGAL elevation The average concentration of uNGAL in our study group (412.26 ng/mL) was significantly higher than in control group (10.74 ng/mL) with p < 0.001 There was no significant difference between AKI causes and uNGAL concentration with p > 0.05 The concentration of uNGAL was significantly higher in oliguria group compared with non-oliguria group (558.32 ng/mL compared with 342.6 ng/mL) with p < 0.005 Patients’ uNGAL concentrations at the time of ICU admission were significantly related to their KDIGO stage (p < 0.001) Urinary NGAL had a moderate positive relationship with serum urea concentration (r = 0.529, p < 0.001) and a strong positive linear relationship with serum creatinine concentration (r = 0.852, p < 0.001) REFFERENCES Au V et al Urinary neutrophil gelatinaseassociated lipocalin (NGAL) distinguishes sustained from transient acute kidney injury after general surgery KI reports 2016, (1), pp.3-9 Bolignano D et al Neutrophil gelatinaseassociated lipocalin (NGAL) as a marker of kidney damage American Journal of Kidney Diseases 2008, 52 (3), pp.595-605 Damman K et al Urinary neutrophil gelatinase associated lipocalin (NGAL), a marker of tubular damage, is increased in patients with chronic heart failure European Journal of Heart Failure 2008, 10 (10), pp.997-1000 175 JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017 Di Nardo M et al Impact of severe sepsis on serum and urinary biomarkers of acute kidney injury in critically Ill children: An observational study Blood purification 2013, 35 (1-3), pp.172-176 Disease K Improving global outcomes (KDIGO) acute kidney injury work group: KDIGO clinical practice guideline for acute kidney injury Kidney Int Suppl 2012, 2, pp.1-138 Geus H.R.H.D et al Neutrophil gelatinaseassociated lipocalin at ICU admission predicts for acute kidney injury in adult patients American Journal of Respiratory and Critical Care Medicine 2011, 183 (7), pp.907-914 Makris K et al Urinary neutrophil gelatinase-associated lipocalin (NGAL) as an 176 early marker of acute kidney injury in critically ill multiple trauma patients, in Clinical Chemistry and Laboratory Medicine 2009, p.79 Zappitelli M et al Urine neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in critically ill children: a prospective cohort study Critical Care 2007, 11 (4), p.R84 Chertow G.M et al Acute kidney injury, mortality, length of stay, and costs in hospitalized patients J Am Soc Nephrol 2005, 16 (11), pp.3365-3370 10 Vaidya V.S et al Urinary biomarkers for sensitive and specific detection of acute kidney injury in humans Clin Transl Sci 2008, (3), pp.200-208 ... creatinin 600 700 800 900 Chart 2: Correlation between urine NGAL and creatinine concentration CONCLUSIONS In our study, all of the AKI patients (100%) had urine NGAL elevation The average concentration. .. stress Therefore, the concentration of uNGAL was directly related to the renal tubule injury in AKI patients as well as urine excretion ability Table 4: Relation between uNGAL concentration and... mainly been studied in the setting of acute renal failure Patients who experienced acute renal dysfunction showed a marked increase in uNGAL levels, which preceded the increase in serum creatinine