Urinary Neutrophil Gelatinase-Associated Lipocalin as Predictor for Development of Hepatorenal Syndrome in Patients with Hepatic Cirrhosis

Background and study aim: Liver cirrhosis has many complications, hepatorenal syndrome (HRS) is one of the most serious complications of it. Neutrophil gelatinase-associated lipocalin (NGAL) is a protein expressed by injured kidney tubular epithelia, urinary NGAL levels rise early in cases of acute kidney impairment before elevation of serum creatinine. The aim of this study is to evaluate NGAL as a biomarker for early detection of HRS in patients with hepatic cirrhosis. Patients and Methods: Seventy five patients were studied and divided into two groups, group (I) 50 patients with liver cirrhosis without impairment of kidney functions and group (II) 25 patients with cirrhosis and impaired kidney functions. Urinary NGAL level were measured by ELISA. Results: The mean value of urinary NGAL level in patients with liver cirrhosis was 50 ± 33 ng/ml while in patients with cirrhosis and HRS was 750 ± 250 ng/ml which showed highly statistically significant difference between both groups of patients. Conclusion: Urinary NGAL increases significantly in patients with liver cirrhosis associated with impairment of kidney function than in those with stable cirrhosis and normal kidney function, so it can be used as a marker for prediction of development of HRS in cirrhotic patients.


INTRODUCTION
Acute kidney injury (AKI) is a common complication in patients admitted to hospital with advanced liver cirrhosis, it is observed in approximately 20% [1].In cirrhosis, AKI include pre-renal azotemia, acute tubular necrosis (ATN), and hepatorenal syndrome (HRS) [2,3].HRS is a dangerous complication, it is functional impairment of kidney function as a result of abnormal hemodynamics leading to splanchnic and systemic vasodilatation associated with renal vasoconstriction [4].Serum creatinine has been the most commonly used marker of AKI, but it is non-specific marker of kidney dysfunction, as it may be normal or near normal in patients with advanced liver cirrhosis despite of diminished kidney function which may be due to muscle cachexy which they suffer from [5], so AKI can develop before change in serum creatinine, therefore investigations of a biomarker for early identification of patients at risk is very important for early diagnosis, because delay in diagnosis not only affect AKI treatment outcome, but it worsens portal pressure elevation in patients with HRS [6,7].

Neutrophil
gelatinase-associated lipocalin (NGAL) is a protein expressed by injured tubular epithelia of the kidney [8,9].Urinary NGAL (NGAL) rises early in AKI, prior to elevation of serum creatinine [8][9][10][11], urinary NGAL is not affected by volume status, diuretic use or pre-renal azotemia [12].Chronic kidney disease (CKD) does not induce NGAL expression [12].Urinary NGAL has been shown to be useful marker in number of clinical settings as predictor of development of AKI and mortality [13,14], but the information on the role of urinary NGAL in cirrhosis and HRS is very few [15,16].
On this background, the aim of this study was to investigate urinary NGAL as early predictor for development of HRS in patients with advanced liver cirrhosis.-Glomerular filtration rate (GFR)was calculated according to Cockcroft-Gault formula [17].-Urine NGAL level by ELISA (BioPorto Diagnostics Hellerup, Denmark).

Definitions Cirrhosis:
The diagnosis of cirrhosis was based on a combination of clinical, biochemical and ultrasonographic findings.

Impairment of Kidney Function:
Impairment of kidney function was diagnosed when serum creatinine concentration was greater than 1.5mg/dL.This value of serum creatinine was chosen because it has been selected in several consensus conferences as cut-off to define impairment of kidney function in

RESULTS
Seventy five patients were included in this study, they were divided into two groups: Group (I): 50 patients with liver cirrhosis without kidney affection (Normal kidney function tests).

DISCUSSION
The result of this study showed that urinary NGAL was significantly higher in patients with liver cirrhosis and impaired kidney functions than in those without impaired kidney function, this result is in agreement with Gungor et al. [18] who found that patients with HRS had significantly higher plasma and urinary NGAL levels compared with stable cirrhosis patients and control subjects.
Also the result in agreement of Verna et al. [16] who evaluated the role of urinary NGAL in determining development of HRS and in patient mortality in patients with liver cirrhosis.Overall, 118 patients (44%) of patients had normal kidney functions while the rest had impaired kidney functions.The result of that study showed that the elevation of urinary NGAL in HRS was intermediate between that of pre-renal azotemia and intrinsic AKI.
The result of current study is in agreement with Nickolas et al. [19] who found urinary NGAL in patients with AKI (416 mg/g creatinine) was significantly higher than in patients with pre-renal azotemia, chronic kidney disease or normal kidney function.But, the result of this study differ than that of Fagundes et al. [20] who found urinary NGAL levels are increased in patients with cirrhosis and ATN compared to those of several other causes as HRS this difference may be due to in the current study patients with impaired kidney functions were divided to HRS and ATN because no kidney biopsies were taken because of short life expectancy and potential bleeding complications due to coagulopathy.
The result of this study also is going with that of Singer et al. [21] who found urinary NGAL was significantly higher (257 ug/L) in patients with AKI compared to patients with pre-renal azotemia and unclassifiable causes (31 and 49 ug/L respectively).
Singer et al. [21] found that a urinary NGAL cutoff level greater than 104 ug/L provided specificity of 0.88 for diagnosis of AKI with high positive likelihood ratio, whereas urinary NGAL cut-off level of 47 ug/L provided a sensitivity of 0.89 and a low negative likelihood ratio for exclusion of AKI.
So, urinary NGAL can be used for early detection of kidney injury in patients with liver cirrhosis for rapid initiation of management and improvement of patient outcomes, which is our primary objective.

Figure 1 :
Figure 1: ROC curve for diagnosis of HRS using urinary NAGL

Table (
* Man Whitney + test student t test $ Fisher's exact test The demographic characteristics of patients are shown in Table 1.Highly significant impairment of kidney function in group II and significant increase in child score and MELD-Na score.