Prognostic Role of Ngal In Critically Ill Patients

Acute kidney injury (AKI) is a frequently encountered outcome in critically ill patients, accounting for increased mortality. Neutrophil gelatinase associated lipocalin (NGAL) has been of paramount importance as a novel biomarker of AKI. This study is an attempt to assess the use of NGAL in critically ill patients so that timely interventions can be done to reduce morbidity and mortality in such patients.


MATERIAL
A prospective observational study was conducted at SRN Hospital, Prayagraj from August 1st 2020 to March 15th 2021, which included only critically ill patients with SOFA score>1 and requiring ICU admission. Patients of known renal diseases were excluded from the study. Blood as well as urinary samples for NGAL and other laboratory parameters were collected within 8 hours of admission. Patients who developed renal dysfunction were noted as our cases and the others were noted as controls.


OBSERVATION
The study was done on 125 patients, out of which 67 developed AKI while 58 did not develop AKI. Higher mortality was seen in patients with higher stage of AKI (P- 0.011). The cutoff of serum and urinary NGAL for predicting AKI were >42.3 ng/mL, >40.5 ng/mL respectively (P value <0.001). Hazard Ratio for all cause mortality of raised serum and urinary NGAL was 2.0062 (p value- 0.0001, 95% CI-1.0031 to 1.0092) and 2.0046 (p value-0.0035, 95% CI-1.0015 to 1.0078) respectively. Serum and urinary neutrophil gelatinase associated lipocalin at values >91 and >131 respectively were found to predict requirement of hemodialysis (p value<0.001).


CONCLUSION
A single measurement of NGAL at the time of admission had good predictive ability for AKI. Higher values of NGAL were associated with staging of AKI and thus, correlated with need of hemodialysis. Furthermore, mortality was found to be associated with development of AKI and raised NGAL. Thus, NGAL maybe used to assess the prognosis of ICU patients so that patients at high risk may be managed aggressively, thus reducing mortality.


Background
Acute kidney injury (AKI) is a heterogeneous syndrome that not only affects acute morbidity and mortality, but is also an important risk factor for developing chronic kidney disease (CKD) thus affecting the long-term prognosis of the patient. 1 The most common causes of AKI include sepsis, major surgery such as coronary artery bypass, heart failure and hypovolemia, which are commonly seen in patients admitted in ICUs. 2 AKI is seen in nearly 30%-50% patients admitted in ICU, and may increase in-hospital mortality upto 50% 3 . Thus, there should be a focus on prediction and early detection of AKI, so that timely intervention can be done to decrease morbidity and mortality in patients admitted in ICU patients.
In the past years, NGAL has emerged to be an excellent biomarker for predicting acute kidney injury 4

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However, it is an expensive biomaker and is not used routinely yet. The aim of this study is to evaluate the e ciency of serum and urine NGAL to detect AKI and for early prediction of mortality in critically ill patients.

Materials And Methods
This study was designed as a prospective cohort analysis in patients admitted to various ICUs from 1st August 2020 to 15th March, 2021 at SRN Hospital, Prayagraj. The patients were followed during the hospital stay and their outcomes were noted. Inclusion criteria comprised of age >18 years (male or female), admitted in ICU with SOFA score>1 while patients with raised baseline serum creatinine > 1.3 mg/dl prior to admission or eGFR < 90 ml/min, patients of CKD and on Renal Replacement Therapy and those unwilling for study related diagnostic procedures were excluded. After obtaining ethical committee clearance and informed consent, clinical data and laboratory investigations were collected and noted.
Baseline serum creatinine is de ned as the steady state level of creatinine 4 weeks before admission. If not available, the admission value or the lowest serum creatinine during the hospital stay was used as a surrogate baseline. Blood samples for NGAL were collected within 8 h of admission to ICU aseptically via venipuncture. The rst urine of the day (mid-stream), was collected aseptically into a sterile container and tested for urinary NGAL. NGAL was tested by ELISA kit-ELABSCIENCE® using the sandwich ELISA principle. Serum urea and serum creatinine and other laboratory parameters were measured for three consecutive days, or for the duration of hospital stay, whichever was later. Patients developing AKI during hospital stay were noted and de ned as our cases, while the patients who did not develop AKI were our controls. Staging of AKI was done using AKIN criteria. The primary outcome (development of AKI) and the secondary outcomes (mortality, need of Hemodialysis (HD)) were noted.

Statistical Analyses
The quantitative data was expressed as mean ± SD. Categorical variables were expressed in number and percentages. Correlation of various parameters are calculated using Spearman's rho correlation coe cient. Receiver operating characteristic (ROC) curves were drawn, and the area under the curve (AUC) was calculated to nd the cut-off points and calculate the threshold speci city, sensitivity and diagnostic accuracy for predicting AKI and mortality outcomes. All statistical analyses were conducted using SPSS version 23.

Results
A total of 140 patients admitted in various ICUs were enrolled in the study, out of which 15 patients were excluded owing to the exclusion criteria (9 patients were newly diagnosed to have CKD while 6 had raised baseline serum creatinine values). Out of 125 patients, 67 (53.6%) developed AKI while 58 (46.4%) did not develop AKI. Table 1 & 2 show the demographic pro le and clinical characteristics of the patients respectively.

Discussion
Renal injury in ICU patients is a common phenomenon and is the consequence of complex interactions between the actual insult and subsequent activation of in ammation and coagulation. Even small changes in serum creatinine concentrations are associated with a substantial increase in the risk of death.
The incidence of AKI in our study group was found to be 53.6%. The AKI patients were distributed in three stages. Nayak et al. 5 studied 102 patients, who were admitted in ICU and AKI was diagnosed based on AKI network criteria and the incidence of AKI was found in 42 patients (41.16%) while the rest, 60 patients did not develop AKI. This is due to patient selection criteria, different criteria applied for diagnosis, epidemiological factors, and associated comorbidities.
At a cutoff of ≥91.3 ng/mL, serum NGAL predicts AKI with a sensitivity of 46% and a speci city of 97%, while the cutoff for urine NGAL for predicting AKI was ≥38.9 ng/mL with sensitivity and speci city of 52% and 90% respectively. Khatami et al. 6 concluded in his study that the sensitivity and speci city of NGAL with cut-off of 22.5 ng/ml were 71.4% and 57.9% in 12 hour urine sample with NPV and PPV of 97.1% and 9.4% respectively for contrast induced nephropathy. The variation in the cutoff value is due to use of various commercial kits available.
NGAL was also found to have a prognostic role in critically ill patients. Hazard Ratio for all cause mortality of raised Serum NGAL was 2.0062 (p value-0.0001, 95% CI-1.0031 to 1.0092) and of raised urinary NGAL was (p value-0.0035, 95% CI-1.0015 to 1.0078). Similar results were seen in the study by Nayak et al. 5 The AUC for serum NGAL and urine NGAL predicting need of hemodialysis was 0.902 (95% CI: 0.84 -0.964) and 0.933 (95% CI: 0.884 -0.983) respectively, which was statistically signi cant (p = <0.001).
Similar results were seen in the study done by Hjortrup et al. 7 who studied 222 patients with severe sepsis. Areas under receiver-operating characteristics curve (AUC) for predicting use of hemodialysis in ICU were 0.70 (95% con dence interval 0.61-0.78) and 0.62 (0.51-0.73) for plasma and urine NGAL, respectively.
The earlier an injurious process to the kidneys can be identi ed, the timelier preventive and supportive measures (removal of the precipitating factor for injury and renal replacement therapy [RRT]) can be initiated.
The study was undertaken as an attempt to reduce ICU mortality. However, the study had few limitations. The number of participants was limited due to the COVID pandemic. Also, it was a single centre study.
Further studies with larger sample sizes are recommended.

Conclusion
A single measurement of NGAL at the time of admission had good predictive ability for AKI. Higher values of NGAL were associated with staging of AKI and thus, correlated with need of hemodialysis. Furthermore, mortality was found to be associated with development of AKI and raised NGAL. Thus, NGAL maybe used to assess the prognosis of ICU patients so that patients at high risk may be managed aggressively, thus reducing mortality. The study was conducted after approval from ethical committee, MLN Medical College, Prayagraj. No harm was perceived from the study.

Consent for publication
Not applicable Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.  Kaplan Meir Survival Curves for Raised NGAL with all cause mortality