Study on the concentration of urine neutrophil gelatinase - associated lipocalin in acute renal failure patients

Nội dung text: Study on the concentration of urine neutrophil gelatinase - associated lipocalin in acute renal failure patients

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