2Lecturer of Pediatrics,Faculty of Medicine,Tanta University, Egypt
3MD Medical Microbiology and Immunology, Assistant Professor of Medical Microbiology and Immunology, Faculty of Medicine, Tanta University, Egypt.
Objectives: was to determine NGAL levels in children as early diagnostic and prognostic factor for AKI in critically ill children with sepsis.
Subjects and Methods: The present study was carried out on 120 children with sepsis admitted in Pediatric Intensive care Unit of Tanta University Hospital. They were subdividing into 3 groups, Group (1): 45 sepsis–non-AKI, Group (2): 45 sepsis with AKI. Group (3) 30 non sepsis–non-AKI as controls. Urine samples were collected daily for 5 days from the sepsis patients and urinary NGAL levels were measured by ELISA test for group 1on the admission day and on day 5 after admission while in group 2 on the admission day 24 h before the onset of AKI, and on the day of AKI onset while in group 3, on the admission day.
Results: There was a significant increase in urinary NGAL levels in sepsis patients (groups 1 & 2) when compared with non sepsis patients (14.8 ± 4.2 and 5.5 ± 2.6 ng/ml, respectively; P < 0.001).ROC curve of NGAL reported that in sepsis patients who developed AKI (group 2), urinary NGAL preceded the rise in serum creatinine, and at its cutoff level of 33.1 ng/ml it predicted AKI with an area AUC of 0.96, sensitivity of 99%, and specificity of 85%; at its cutoff level of 48.7 ng/ml, it predicted the need for dialysis with AUC of 0.81, sensitivity of 84%, and specificity of 73%. Urine NGAL could not predict mortality among sepsis patients.
Conclusion: Urinary NGAL can predict AKI well in critically ill septic pediatric patients and can predicted their indication for dialysis.
Keywords: Acute Kidney Injury Prediction; Neutrophil Gelatinase-Associated Lipocalin; Sepsis;
All children admitted in PICU of Tanta university hospitals from November 2016 to November 2017 were included.
Chronic kidney disease was defined on the basis of the definition of National Kidney Foundation as kidney damage or glomerular filtration rate less than 60ml/min/1.73m2 for 3 or more months, irrespective of the cause [18].
Sepsis and septic shock were diagnosed according to the guidelines of the International Sepsis Definitions Conference [19]. AKI was diagnosed according to Risk, Injury, Failure, Loss, and end stage renal disease (ESRD) (RIFLE) criteria. Urine output was closely monitored every hour, and daily assessment of serum creatinine and its change in relation to its baseline levels on admission (if normal) was carried out [20].
• Clinical Examination: included body weight, oedema and vital signs (heart rate, temperature, mean arterial blood pressure) which were assessed for the evaluation of sepsis.
• Laboratory Investigations: which included on admission, baseline serum creatinine and blood urea Nitrogen(BUN) levels, Complete blood counting (CBC), C-reactive protein, 24 hour urinary collection for volume and protein estimation.
• Serum creatinine was assessed in spot blood samples obtained on admission and then reassessed daily at constant intervals (every 24 h) for 5 days in sepsis patients (groups 1 and 2). Simultaneously, urine samples were collected on the day of admission from all involved patients by clean catch mid stream voids or from inserted indwelling Foley catheters. Urine samples were collected daily for 5 days from sepsis patients (groups 1 and 2). In sepsis–AKI patients (group 2) sample collection was stopped at the onset of AKI.
• Urinary NGAL level was assessed by ELISA kit only in selected samples .It was measured in group 1 from samples taken on admission day and on day 5. In group 2,it was measured from samples taken on admission day, from samples collected 24 h before the onset of AKI (1 day before AKI), and from samples taken on the day of AKI onset. In group 3, it was measured from samples taken on the admission day only. [21]
Severity of illness in the first 24 hours of admission was assessed by Pediatric Risk of Mortality score (PRISM III), length of hosoital stay was recorded and the follow up was with the Sequential Organ Failure Assessment (SOFA) score for outcome [22,23]
|
Group 1 |
Group 2 |
Control |
Statistical test |
P value |
Age distribution at time of study (years) |
|||||
range |
1.5-9 years |
2 –10 years |
1.5 –10 years |
ANOVA(F) |
0.05 |
Mean ± SD |
4.47 ± 2.16 |
6.63 ± 2.54 |
4.96 ± 2.72 |
3.135 |
|
Sex distribution |
|||||
Male No (%) |
39(86.7) |
36(80) |
24(80) |
X2=0.316 |
0.85 |
Female No (%) |
6(13.33) |
9(20) |
6(20) |
|
|
Weight in kg |
|||||
Range |
43464 |
13.5-60 |
43432 |
T=turkeys test T1=0.008* |
|
Mean ± SD |
19.57 ± 5.79 |
28,77 ± 11.27 |
18.03 ± 5.35 |
T2=0.858 |
0.001* |
|
|
|
|
T3=0.002* |
|
|
|
|
|
F=8.016 |
|
Urinary volume/24 hr collected urine (ml) |
|||||
Range |
200 -1280 |
200-1200 |
623-1710 |
7.69 |
0.001* |
Mean ± SD |
670.1 ± 382.8 |
653.7 ± 316.2 |
1091 ± 335.9 |
|
|
Blood urea(mg%) |
|||||
Range |
13 - 103 |
31747 |
18 - 32 |
2.724 |
0.77 |
Mean ± SD |
34.9 ± 22.9 |
36.5 ± 20.8 |
22.5 ± 5.31 |
|
|
Serum creatinine(mg%) |
|||||
Range |
0.4-1 |
0.3-0.8 |
0.3-0.7 |
|
|
(Mean ± SD) |
0.58 ± 0.17 |
0.47 ± 0.14 |
0.49 ± 0.11 |
2.83 |
0.07 |
PRISM score |
|||||
Range |
43122 |
43155 |
43178 |
2.7 |
0.25 |
(Mean ± SD) |
9.5 ± 1.79 |
9 ± 1.27 |
9 ± 1.35 |
|
|
Length of PICU stay |
|||||
(Mean ± SD) |
13 ± 8 |
18 ± 10 |
8 ± 5 |
7.69 |
0.001* |
Mortality: No (%) |
16 (35.6) |
20 (44.4) |
4 (13.3) |
2.724 |
0.022 |
** highly Significant difference.
T1=Group 1 versus Group 2
As regard mortality predictive value of uNGAL The multivariate logistic regression analysis of the overall mortality showed that the development of septic shock [51 (35.7%) patients] [P = 0.01, odds ratio (OR): 11, 95% CI: 2.1–91.5] and serum creatinine (P = 0.005, OR: 9, 95% CI: 2.7–101) were the
Urinary NGAL |
Group 1 |
Group 2 |
Groups 1+2 |
ControlII |
P value |
One day before onset of AKI |
- |
40.1 ± 11.7 |
- |
- |
|
On the day of admission |
13.5 ± 4.6 |
16.8± 4.3 |
14.8±4.2. |
5.5 ± 2.6 |
P2=0.32 |
On the day of sepsis |
- |
58.3±14.3 |
- |
- |
- |
5 days after admission |
15.3 ± 3.3 |
- |
- |
- |
|
P value |
P1=0.08 |
P4<0.001 |
- |
- |
- |
Urinary NGAL = Neutrophil Gelatinase-Associated Lipocalin
P1= comparison between NGAL in Group 1 on the day and 5 days after admission
P 2= comparison between NGAL in Groups 1 & 2 on the day of admission
P 3= comparison between NGAL in Group 1 &2 collectively and control group on day of admission
P4=comparison between NGAL in Group 2, one day before, on and 5 days after admission.
|
Sensitivity |
Specificity |
PPV |
NPV |
AUC |
Cut off value ng/mL)) |
As diagnostic |
99 |
85 |
99 |
90 |
0.96 |
33.1 |
As prognostic |
84 |
73 |
99 |
90 |
0.81 |
48.7 |
PPV= Positive Predictive Value
NPV= Negative Predictive Value
|
r |
P value |
Sepsis, no AKI: On admission |
0.35 |
0.026* |
Sepsis, no AKI: 5 days after admission |
0.2 |
0.19 |
Septic AKI: On admission |
0.4 |
0.47 |
Septic AKI: At onset of AKI |
0.56 |
0.06* |
- Mayr VD, Dünser MW, Greil V. Causes of death and determinants of outcome in critically ill patients. Crit Care. 2006; 10(6):R154.
- Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis associated costs of care of incidence, outcome, and. Crit Care Med 2001;29(7):1303–1310.
- Silva E, PedroMde A, Sogayar ACB. Brazilian sepsis epidemiological study (BASES study). Crit Care. 2004;8(4):R251–R260.
- Bennett M, Nehus E, Haffner C. Pediatric reference ranges for acute kidney injury biomarkers. Pediatr Nephrol. 2014;30(4):677-685.
- Russo L, Sandoval R, Campos S. Impaired tubular uptake explains albuminuria in early diabetic nephropathy. J Am Soc Nephrol . 2009;20(3):489-94.
- Zhang Z, Lu B, Ni H. Microalbuminuria can predict the development of acute kidney injury in critically ill septic patients. J Nephrol . 2013;26(4):724-730.
- Hong J and Lim I. Correlation between glomerular filtration rate and urinary N acetyl-beta-D glucosaminidase in children with persistent proteinuria in chronic glomerular disease. Korean J Pediatr. 2012;55(4):136-142.
- Zhou H, Hewitt S, Yuen P. Acute kidney injury biomarkers needs, present status, and future promise. Nephrol Self Assess Program. 2006;5(2):63-71.
- Adiyanti S and Loho T. Acute Kidney Injury (AKI) biomarker. Acta Med Indones 2012; 44(3):246-55.
- Lai C, Chen Y, Chiang W. Cysteine-rich protein 61 plays a proinflammatory role in obstructive kidney fibrosis. PLoS One. 2013;8(2):56481.
- Bignami E, Frati E, Ceriotti F. Urinary neutrophil gelatinaseassociated lipocalin as an early predictor of prolonged intensive care unit stays after cardiac surgery. Ann Card Anaesth. 2012;15(1):13-17.
- Devarajan P. Neutrophil gelatinase-associated lipocalin − an emerging troponin for kidney injury. Nephrol Dial Transplant 2008;23(12):3737–3743.
- Haase M, Bellomo R, Devarajan P, Schlattmann P, Haase-Fielitz A. Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis. 2009; 54(6):1012–1024.
- Briguori C, Quintavalle C, Donnarumma E. Novel biomarkers for contrast-induced acute kidney injury. Biomed Res Int 2014; 2014: 568738.
- Paragas N, Qiu A, Hollmen M. NGAL-Siderocalin in kidney disease. Biochim Biophys Acta. 2012;1823(9):1451-1458.
- Lin H, Lee S, Lin S. Urinary neutrophil gelatinase-associated lipocalin levels predict cisplatin-induced acute kidney injury better than albuminuria or urinary cystatin C levels. Kaohsiung J Med Sci. 2013; 29(6):304-311.
- Nishida M, Kawakatsu H, Okumura Y. Serum and urinary neutronphil-associated lipocalin levels in children with chronic renal disease. Pediatr Int. 2010;52(4):563-568.
- National Kidney Foundation. K/DOQI clinical practice guidelines for kidney disease: evaluation, classification and stratification. Am J Kidney Dis. 2002;39:S1–266.
- Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference.Crit. Care Med 2003;31(4):1250-1256.
- Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, the ADQI Workgroup. Acute renal failure definition, outcome measures, animal models, fluid therapy and information technology needs: Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8(4):204–212.
- Vaidya VS, Waikar SS, Ferguson MA. Urinary biomarkers for sensitive and specific detection of acute kidney injury in humans. Clin Transl Sci. 2008;1(3):200–208.doi.org/10.1111/j.1752-8062.2008.00053
- Castro RA, Angus DC, Hong SY, Lee C, Weissfeld LA. Light and the outcome of the critically ill: an observational cohort study. Crit Care. 2012;16(4): 132.
- Ac-harya SP, Pradhan B, Marhatta MN . Application of thesequential organ failure assessment (SOFA) scores in predicting outcome in ICU patients with SIRS. Kathmandu Univ Med J. 2007;5(4):475-483.
- Khothari CR . Research methodology, methods and techniques. (2nd edn). New Age International, New Delhi, 2012; p: 95-97.
- Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the US from 1979 through 2000. N Engl J Med. 2003;348(16):1546–1554.
- Brun-Buisson C, Meshaka P, Pinton P, Vallet B .EPISEPSIS Study Group. EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Med. 2004;30(4):580–588.
- Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med. 2013;41(5):1167–1174.
- Case J, Khan S, Khalid R, Khan A. Epidemiology of Acute Kidney Injury in the Intensive Care Unit. Crit Care Res Pract. 2013; 2013:479730.
- Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, et al. Acute renal failure in critically ill patients: a multinational, multicenter study.JAMA. 2005;294(7):813–818.
- Hoste EA, Lameire NH, Vanholder RC, Benoit DD, Decruyenaere JM, Colardyn FA. Acute renal failure in patients with sepsis in a surgical ICU: predictive factors, incidence, comorbidity, and outcome. J Am Soc Nephrol. 2003;14(4):1022–1030.
- Bagshaw SM, George C, Bellomo R, ANZICS Database Management Committee. Early acute kidney injury and sepsis: a multicentre evaluation. Crit Care. 2008;12(2):R47.
- Bagshaw SM, Uchino S, Bellomo R, Morimatsu H, Morgera S, Schetz M, et al. Beginning, ending supportive therapy for the kidney (BEST kidney) investigators. Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Clin J Am Soc Nephrol. 2007;2(3):431–439.
- Suh SH, Kim CS, Choi JS, Bae EH, Ma SK, Kim SW. Acute kidney injury in patients with sepsis and septic shock: risk factors and clinical outcomes. Yonsei Med J. 2013;54(4):965–972.
- Oppert M, Engel C, Brunkhorst FM, Bogatsch H, Reinhart K, Frei U, et al. German Competence Network Sepsis (Sepnet): ARF in patients with severe sepsis and septic shock – a significant independent risk factor for mortality: results from the German Prevalence Study. Nephrol Dial Transplant. 2008;23(3):904–909.
- Mehta RL, Kellum JA, Shah SV, Molitoris BA, Levin A. Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31.
- Devarajan P. Neutrophil gelatinase-associated lipocalin (NGAL): a new marker of kidney disease. Scand J Clin Lab Invest 2008;241:89–94.
- Star RA. Treatment of acute renal failure. Kidney Int 1998; 54:1817–1831.
- Doi K, Yuen PS, Eisner C, Hu X, Leelahavanichkul A. Reduced production of creatinine limits its use as marker of kidney injury in sepsis. J Am Soc Nephrol. 2009;20(6):1217–1221.
- Lima RS, Marques CN, Silva Junior GB. Comparison between early and delayed AKI secondary to infectious disease in the intensive care unit. Int Urol Nephrol. 2008;40(3):731–739.
- Sood MM, Shafer LA, Ho J, Reslerova M, Martinka G, Keenan S, et al. Early reversible acute kidney injury is associated with improved survival in septic shock. J Crit Care. 2014;29(5):711–717.
- Mishra J, Mori K, Ma Q, Kelly C, Barasch J, Devarajan P, et al. Neutrophil gelatinase-associated lipocalin: a novel early urine biomarker for cisplatin nephrotoxicity. Am J Nephrol. 2004;24(3):307–315.
- Kuwabara T, Mori K, Mukoyama M. Urine NGAL levels reflect damage to glomeruli, proximal tubules, and distal nephrons. Kidney Int. 2009;75(3):285–294.
- Wan L, Bagshaw SM, Langenberg C, Saotome T, May C, Bellomo R. Pathophysiology of septic acute kidney injury: what do we really know? Crit Care Med. 2008;36(4):198–S203.
- Glassford NJ, Schneider AG, Eastwood G, Bellomo R. Neutrophil gelatinase-associated lipocalin has a stronger association with serum creatinine than C-reactive protein in patients without sepsis; this relationship is lost in septic patients. Crit Care. 2011;15(3):P9.