Study on the concentration of urinary neutrophil gelatinase - Associated lipocalin in patients occuring acute kidney failure in intensive care unit

Nội dung text: Study on the concentration of urinary neutrophil gelatinase - Associated lipocalin in patients occuring acute kidney failure in intensive care unit

1. Journal of military pharmaco-medicine n o7-2017 STUDY ON THE CONCENTRATION OF URINARY NEUTROPHIL GELATINASE - ASSOCIATED LIPOCALIN IN PATIENTS OCCURING ACUTE KIDNEY FAILURE IN INTENSIVE CARE UNIT Pham Ngoc Huy Tuan*; Nguyen Trung Kien**; Le Viet Thang** SUMMARY Objective: To evaluate urinary neutrophil gelatinase-associated lipocalin (NGAL) 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 121 patients with AKI who admitted to a general Intensive Care Unit (ICU), Trungvuong Hospital, Hochiminh City from 12 - 2013 to 01 - 2017 and a control group of 51 healthy people. Urinary NGAL had done in all 116 patients and healthy people. Results: All of the AKI patients (100%) had urinary NGAL elevation. The average concentration of urinary NGAL in our study group (434.06 ng/mL) was significantly higher than in control group (10.74 ng/mL) with p < 0.001. There was no significant difference in concentration of uNGAL in terms of causes. The concentration of urinary NGAL was significantly higher in oliguria group than non-oliguria group (571.70 ng/mL compared to 355.95 ng/mL) with p < 0.005. Patients’ uNGAL concentration at the time of ICU admission was significantly related to their KDIGO stage (p < 0.001). Urinary NGAL had a moderate positive correlation with serum urea concentration (r = 0.567, p < 0.001) and a strong positive linear correlation with serum creatinine concentration (r = 0.850, p < 0.001). Conclusion: Urinary NGAL elevation was common in AKI patients. The concentration of urinary NGAL depended on category and stage of AKI. It had a moderate positive correlation with serum urea and strong positive correlation with creatinine concentration. * Keywords: Acute kidney injury; Urinary neutrophil gelatinase-associated lipocalin; Intensive care unit. INTRODUCTION prognosis of AKI are insensitive and Acute kidney injury is a common and nonspecific and do not directly reflect devastating problem with in-hospital injury to kidney cells. Therefore, early mortality of 40% to 80% in the intensive recognition of renal injury is important and care setting [10]. The traditional blood may help prevent further renal damage (creatinine, blood urea nitrogen) and urine and functional impairment. markers of kidney injury (casts, fractional Neutrophil gelatinase-associated lipocalin excretion of sodium, urinary concentrating is a small, 23 kDa protein that is an early ability) that have been used for decades biomarker for ischemic, septic, or in clinical studies in diagnosis and nephrotoxic kidney injury. It is normally * 103 Military Hospital ** Trung Vuong Hospital Corresponding author: Pham Ngoc Huy Tuan (bshuytuantv@yahoo.com.vn) Date received: 03/07/2017 Date accepted: 18/07/2017 71
2. Journal of military pharmaco-medicine N o7-2017 produced at low levels by the epithelial 2017 and a control group of 51 healthy cells of the kidney, but it is quickly people. upregulated in the thick ascending limb * Excluding criteria: patients with (TAL) of the loop of Henle and the chronic kidney failure, anuria, did not fit collecting ducts within three hours of with diagnostic criteria, did not have tubular epithelial injury. enough test results or did not agree to Urinary NGAL (uNGAL) has been participate in the study. evaluated as an early biomarker of renal 2. Methods. tubular damage in a acute clinical settings * Study design : A prospective, cross- such as the operating room, ICU and sectional descriptive study. emergency department, and in high-risk procedures such as cardiac surgery, * Urinary NGAL measurement: 24- radio-contrast injection and after adult and hour urine was collected. After that, the pediatric kidney and liver transplantation volume of urine was measured before [1, 6, 7, 8, 9]. There is considerable collecting 1 mL sample for testing evidence that compared to increases in purpose. uNGAL was measured by the serum creatinine, NGAL better detects sandwich ELISA method using NGAL early or subclinical kidney injury, and monoclonal antibody in the NGAL kit. better predicts dialysis requirement and After that, the sample will be analyzed by mortality [1]. Achitech System of Abbott, America to measure uNGAL concentration. In Vietnam, there are lack of studies on the role of uNGAL in AKI diagnosis and * Diagnostic criteria: KDIGO definition prognogsis in patients who admitted to and classification of AKI [5]. general ICU. Therefore, we conducted * Diagnostic criteria for AKI: serum this research for the aim: Evaluation of creatinine ≥ 136.5 µmol/L within 48h. the uNGAL concentration and its relation * AKI degree: with causes, categories, stages and some + AKI stage I: serum creatinine from biochemical indexes of AKI patients. 136.5 - 220 µmol/L. SUBJECTS AND METHODS + AKI stage II: serum creatinine from 220 - 353.6 µmol/L. 1. Subjects. + AKI stage III: ≥ 353.6 µmol/L. The study was conducted with a study group of 121 AKI patients who admitted to * Statistical analysis: a general ICU, Trungvuong Hospital, Statistical analyses were conducted Hochiminh City from 12 - 2013 to 01 - using SPSS 20.0. 72
3. Journal of military pharmaco-medicine n o7-2017 RESULTS AND DISCUSSIONS Table 1: Urinary NGAL concentration in study group. Index Control group (n = 51) Study group (n = 116) p X ± SD 10.74 ± 5.18 434.06 ± 333.14 < 0.001 Urinary NGAL (ng/mL) Max 20.28 1292.38 Min 3.32 69.63 The average concentration of urinary especially unreliable during acute NGAL in our study group was 434.06 ng/mL, changes in kidney function. We identified which was significantly higher than in control uNGAL as one of the most upregulated group (10.74 ng/mL) with p < 0.001. The genes in the kidney soon after ischemic maximum and minimum concentration of injury. NGAL protein was also markedly urianay NGAL was 1292.38 and 69.63 ng/mL induced in kidney tubule cells and easily respectively. With the refference range of detected in the plasma and urine in animal urinary NGAL from 43.62 to 114.66 ng/mL, models of ischemic and nephrotoxic AKI. all of the AKI patients (100%) had urinary The expression of uNGAL protein was NGAL elevation. Study of Au V also showed also dramatically increased in kidney tubules that the mean immediate postoperative of humans with ischemic, septic, and post- transplant AKI. Importantly, NGAL in the urinary NGAL levels in patients who urine was found to be an early predictive developed sustained AKI were 204.8 ng/mL, biomarker of AKI in a variety of acute and significantly higher than those who had clinical settings. Emerging experimental normal renal function (31.9 ± 113 ng/mL) and clinical evidence indicated that in the with p < 0.001 [1]. This result was similar to early phases of AKI from diverse other studies of Geus H.R, Makris K, etiologies, NGAL accumulates within two Zappitelli M: there was a significant higher distinct pools, namely, a renal and a of urinary NGAL concentration in patients systemic pool. Gene expression studies in who submitted AKI compare to non-AKI AKI had clearly demonstrated rapid and patients with p < 0.05 [6, 7, 8]. These massive upregulation of NGAL mRNA in differences in uNGAL concentration are the thick ascending limb of Henle's loop expected because kidney injury associated and the collecting ducts, with resultant with primary renal insults may be more synthesis of NGAL protein in the distal severe than that in most patients included nephron (the renal pool) and secretion in our study. But our patients were probably into the urine where it comprises the more severely ill, with a higher proportion major fraction of urinary NGAL. having sepsis than healthy people. This finding also confirms the need for In current clinical practice, the gold future research to evaluate uNGAL in standard for identification and classification different renal disease subgroups, in of AKI is dependent on serial serum order to understand fully how best to use creatinine measurements, which are uNGAL to diagnose AKI. 73
4. Journal of military pharmaco-medicine N o7-2017 Table 2: Relation between urinary NGAL concentration and the causes of AKI. Causes n % Serum NGAL (ng/mL) Sepsis (1) 67 57.8 447.28 ± 321.45 Dehydration (2) 18 15.5 341.75 ± 312.55 Cirrhosis (3) 7 6.0 690.17 ± 467.48 Shock (4) 11 9.5 451.19 ± 339.97 Toxic (5) 4 3.45 187.48 ± 98.69 Urinary obstruction (4) 5 4.3 259.29 ± 285.91 Others (7) 4 3.45 597.91 ± 330.90 p > 0.05 In our study, sepsis was the most ligands which are linked to tubular common causes with the proportion of epithelial TLR activation are responsible 57.8%. There was no significant difference for the increased uNGAL concentrations between these causes with p > 0.05. Our that we observed in patients who had result was similar to study of Vaidya D.S: sepsis, but showed no increases in their there was no significant difference between serum creatinine levels. However, recent urinary NGAL concentration and several studies in patients with sepsis, septic causes of AKI in these studies (p > 0.05) shock, and systemic inflammatory response [10], but was different with other studies syndrome had reported contradictory of Di Nardo M and Geus H.R (there was a findings. A possible explanation for this significant higher concentration of urinary difference is the variability of the subject NGAL in septic AKI patients than non- inclusion time (up to 48 h after ICU septic AKI patients with p < 0.001 [4, 6]. admission). Intensive resuscitation and Lipoproteins also have strong affinity for the administration of antibiotics may have Toll-like receptors (TLRs) that trigger an already occurred before study inclusion, innate immune response. Therefore, it therefore most likely inducing rapid could be postulated that these circulating changes of uNGAL values. Table 3: Relation between urinary NGAL concentration and AKI category. Categories n % Urinary NGAL (ng/mL) Non-anuria 74 63.8 355.95 ± 302.05 Anuria 42 36.2 571.70 ± 344.14 p < 0.005 In our study, category of anuria occupied in 36.2% of all AKI patients. The concentration of urinary NGAL was significantly higher in anuria group than non-anuria group (571.70 ng/mL compared with 355.95 ng/mL) with p < 0.005. Our findings highlight the mechanistic insights of NGAL levels based on the specimens being measured. 74
5. Journal of military pharmaco-medicine n o7-2017 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 urinary NGAL was directly related to the renal tubule injury in AKI patients as well as urine excretion ability. Table 4: Relation between serum NGAL concentration and stage of AKI. AKI stages (KDIGO) n % Urinary NGAL (ng/mL) 1 81 69.8 244.07 ± 156.79 2 26 22.4 818.01 ± 153.01 3 9 7.8 1034.83 ± 160.49 < 0.001 pANOVA p1-2, p 1-3 < 0.001, p 2 -3 < 0.005 Following to the KDIGO classification, epithelial neogenesis, and in iron the stage 1 AKI in our study made up the chelation and delivery after ischemic or highest proportion (69.8%). Stage 2 and 3 toxic insults to the renal tubular occupied smaller proportion (22.4% and epithelium. After kidney injury, NGAL is 7.8%, respectively). Our results also pointed rapidly expressed on the apical epithelial that patients’ uNGAL concentrations at membranes of the distal nephron. the time of ICU admission were significantly NGAL is excreted in the urine through related to their KDIGO stage (p < 0.001). exocytosis and has local bacteriostatic This result was similar to the study of and proapoptotic effects. Therefore, Geus H.R (p < 0.0001) and Zapittelli M (p uNGAL concentration had a positive < 0.0002) when research on the relation relation with the level of renal damage between uNGAL and RIFFLE stage [6, 8]. which exhibited throughout the high stage NGAL fulfills a central role in regulating of KDIGO classification. Table 5: Correlation between serum NGAL and urea, creatinine concentration. Serum NGAL Indexes Correlation equation r p Urea 0.567 < 0.001 uNGAL = 18,89*urea + 165.63 Creatinine 0.850 < 0.001 uNGAL = 2.63*creatinine - 142.30 In our study, urinary NGAL had a + 165.63; uNGAL = 2.63*creatinine - moderate positive correlation with serum 142.30). Boglignano D also pointed that a urea concentration (r = 0.567, p < 0.001) significant correlation was also found and a strong positive linear correlation between serum creatinine and uNGAL with serum creatinine concentration (r = 0.399, p < 0.001) [2]. NGAL has (r = 0.850, p < 0.001). The correlation mainly been studied in the setting of acute equation was created (uNGAL = 18,89*Urea renal failure. Patients who experienced 75
6. Journal of military pharmaco-medicine N o7-2017 acute renal dysfunction showed a marked serve as a very early marker of worsening increase in urinary NGAL levels, which renal function. Urinary (or plasma) NGAL preceded the increase in serum creatinine levels could therefore be used to adjust by a day. In a single case of acute tubular therapy, to anticipate and possibly necrosis due to heart failure induced prevent expected renal injury, even before hypotension, NGAL tubular expression a peak in serum creatinine occurs. This was reported to be strongly increased [3]. potential of NGAL needs to be explored Hence, measurements of NGAL may further in future studies. uNGAL = 18.89*Urea + 165.63 2000 1500 1000 uNGAL 500 0 0 20 40 60 80 Urea Chart 1: Correlation between urinary NGAL and urea concentration. uNGAL = 2,63*creatinine - 142.30 2500 2000 1500 1000 uNGAL 500 0 0 200 400 600 800 1000 Creatinine Chart 2: Correlation between urinary NGAL and creatinine concentration. CONCLUSIONS group compared to non-oliguria group In our study, all of the AKI patients (571.70 ng/mL compared to 355.95 (100%) had urinary NGAL elevation. The ng/mL) with p < 0.005. Patients’ uNGAL average concentration of urinary NGAL in concentrations at the time of ICU our study group (434.06 ng/mL) was admission were significantly related to significantly higher than that in control their KDIGO stage (p < 0.001). Urinary group (10.74 ng/mL) with p < 0.001. NGAL had a moderate positive correlation There was no significant difference in with serum urea concentration (r = 0.567, concentration of uNGAL in terms of p < 0.001) and a strong positive linear causes. The concentration of urinary correlation with serum creatinine NGAL was significantly higher in oliguria concentration (r = 0.850, p < 0.001). 76
7. Journal of military pharmaco-medicine n o7-2017 REFFERENCES 6. Geus H. R. H. D et al. Neutrophil gelatinase-associated lipocalin at ICU 1. Au V et al. Urinary neutrophil gelatinase- associated lipocalin distinguishes sustained admission predicts for acute kidney injury in from transient acute kidney injury after adult patients . American Journal of Respiratory general surgery. KI reports. 2016, 1 (1), pp.3- and Critical Care Medicine. 2011, 183 (7), 9. pp.907-914. 2. Bolignano D.et al. Neutrophil gelatinase- 7. Makris K et al. Urinary neutrophil associated lipocalin as a marker of kidney gelatinase-associated lipocalin as an early damage . American Journal of Kidney marker of acute kidney injury in critically ill Diseases. 2008, 52 (3), pp.595-605. multiple trauma patients. Clinical Chemistry 3. Damman K et al. Urinary neutrophil and Laboratory Medicine. 2009, p.79. gelatinase associated lipocalin (NGAL), a 8. Zappitelli M et al. Urine neutrophil marker of tubular damage, is increased in gelatinase-associated lipocalin is an early patients with chronic heart failure . European marker of acute kidney injury in critically ill Journal of Heart Failure. 2008, 10 (10), children: a prospective cohort study. Critical pp.997-1000. Care. 2007, 11 (4), p.R84. 4. Di Nardo M et al. Impact of severe sepsis on serum and urinary biomarkers of 9. Chertow G.M et al. Acute kidney injury, acute kidney injury in critically Ill children: An mortality, length of stay, and costs in observational study . Blood Purification. 2013, hospitalized patients. J Am Soc Nephrol. 35 (1-3), pp.172-176. 2005, 16 (11), pp.3365-3370. 5. Disease, K. Improving global outcomes 10. Vaidya V.S et al. Urinary biomarkers (KDIGO) acute kidney injury work group: for sensitive and specific detection of acute KDIGO clinical practice guideline for acute kidney injury in humans. Clin Transl Sci. 2008, kidney injury. Kidney Int Suppl. 2012, 2, pp.1-138. 1 (3), pp.200-208. 77