|Year : 2013 | Volume
| Issue : 4 | Page : 346-352
Urinary neutrophil gelatinase-associated lipocalin as a biomarker for the diagnosis of hepatorenal syndrome in cirrhotic patients
Hanan El-Bassat1, Dina H Ziada1, Atef Taha2, Rasha Alm-Eldin3
1 Department of Tropical Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
3 Department of Microbiology, Faculty of Medicine, Tanta University, Tanta, Egypt
|Date of Submission||23-Jul-2013|
|Date of Acceptance||23-Aug-2013|
|Date of Web Publication||1-Feb-2014|
Dina H Ziada
Ass. Prof. of Tropical Medicine and Infectious Disease Department, Tanta Univeristy, Egypt, Al Gish Street, Tanta Univeristy, Hospital, Tanta
The aim of the study was to assess the usefulness of urinary neutrophil gelatinase-associated lipocalin (uNGAL) as a biomarker for hepatorenal syndrome (HRS) in patients with cirrhosis.
Patients and methods
Eighty-two cirrhotic patients were enrolled in this study. Urinary levels of NGAL were measured using enzyme-linked immunosorbent assay. Ten normal healthy individuals were enrolled as a control group. Group I included 15 cirrhotic patients with normal kidney function. Group II included 52 cirrhotic patients with acute impaired kidney function: 21 with prerenal azotemia, 22 with HRS, and nine with intrinsic acute kidney injury (iAKI). Group III included 15 cirrhotic patients with chronic impaired kidney function. Group IV included 10 healthy normal individuals as control.
In HRS, uNGAL was significantly different from patients with either iAKI or prerenal azotemia. uNGAL levels in patients with prerenal azotemia were low and equivalent to levels in patients with normal kidney function and chronic kidney disease. uNGAL elevation was more prominent in type 1 than in type 2. Serum creatinine was significantly higher in patients with iAKI compared with those with normal kidney function and chronic kidney disease but was statistically similar to those with prerenal azotemia and HRS. Patients with HRS had a significantly higher level of serum creatinine than those with prerenal azotemia, but the level was similar to patients with iAKI. Fractional excretion of sodium was significantly higher in patients with iAKI than in patients with either HRS or prerenal azotemia.
uNGAL levels may be useful in the differential diagnosis of HRS from other causes of acute impairment of kidney function in cirrhosis.
Keywords: Cirrhosis, hepatorenal syndrome, urinary neutrophil gelatinase associated lipocalin
|How to cite this article:|
El-Bassat H, Ziada DH, Taha A, Alm-Eldin R. Urinary neutrophil gelatinase-associated lipocalin as a biomarker for the diagnosis of hepatorenal syndrome in cirrhotic patients. Tanta Med J 2013;41:346-52
|How to cite this URL:|
El-Bassat H, Ziada DH, Taha A, Alm-Eldin R. Urinary neutrophil gelatinase-associated lipocalin as a biomarker for the diagnosis of hepatorenal syndrome in cirrhotic patients. Tanta Med J [serial online] 2013 [cited 2018 Apr 24];41:346-52. Available from: http://www.tdj.eg.net/text.asp?2013/41/4/346/126207
| Introduction|| |
Acute kidney injury (AKI) in patients with cirrhosis is common and lethal. Up to 20% of hospitalized patients with cirrhosis develop AKI , . In cirrhosis, AKI types include prerenal azotemia, hepatorenal syndrome (HRS), and intrinsic acute kidney injury (iAKI), but their mortality risks vary. These types of AKI are difficult to distinguish clinically, as serum creatinine (sCr) poorly discriminates AKI type in cirrhosis ,, .
The International Ascites Club (IAC) classified HRS as a specific form of AKI  . Currently, there is a lack of a kidney function biomarker that both rapidly and accurately discriminates HRS from other forms of AKI. Meanwhile, the discrimination between different AKI type depends on the 48-h diagnostic algorithm proposed by the IAC, which includes diuretic withdrawal and volume administration  . This algorithm not only delays AKI treatment but it potentially worsens portal pressure elevation in patients with HRS ,, . sCr is not a specific marker that can differentiate between different types of kidney dysfunction. It does not completely distinguish the relationship between kidney function and different types of kidney failure or portend different prognoses  . These limitations of sCr highlight the need for improved diagnostic methods to determine AKI type in cirrhosis. Neutrophil gelatinase-associated lipocalin (NGAL) is a protein expressed by injured kidney tubular epithelia  . Urinary neutrophil gelatinase-associated lipocalin (uNGAL) levels rise exponentially early in the course of AKI before sCr elevation , . We aimed at assessing the usefulness of uNGAL in the differential diagnosis of HRS from other causes of acute impairment of kidney function in cirrhosis.
| Patients and methods|| |
After the study protocol had been approved by Tanta University ethical committee, 82 adult patients with cirrhosis were prospectively recruited from the outpatient clinics and inpatient wards of the Departments of Tropical Medicine and Infectious Diseases and Internal Medicine at Tanta University Hospital, Tanta, Egypt, and 10 healthy individuals were recruited as the control group. All participating patients provided informed consent before taking part in the study. Patients were diagnosed as having cirrhosis on the basis of established clinical, laboratory, and/or imaging criteria with ultrasound examination.
The cirrhotic patients were classified as follows:
(1) Group I included 15 cirrhotic patients with normal kidney function.
(2) Group II included 52 cirrhotic patients with acute impaired kidney function.
(a) Twenty-one patients with prerenal azotemia.
(b) Twenty-two patients with HRS.
(c) Nine patients with iAKI.
(4) Group III included 15 cirrhotic patients with chronic impaired kidney function.
(5) Group IV included 10 healthy normal individuals as control.
Exclusion criteria were as follows:
(1) Chronic kidney disease (CKD) under dialysis.
(2) Urinary tract infection.
(3) Patients with urinary obstruction or previous kidney transplantation.
Inclusion criteria were as follows:
(1) Cirrhotic patients with or without infections other than that of the urinary tract.
(2) Measurement of plasma neutrophil gelatinase-associated lipocalin (pNGAL) and uNGAL by enzyme-linked immunosorbent assay (ELISA).
The 24-h urine amount was measured. A volume of 10 ml of urine sample was stored at 80°C until measurement using commercial NGAL (Quantikine; R&D System Inc., Minneapolis, MN USA) ELISA kit in accordance with respective manufacturer's instructions. The t-value of 24-h urinary excretion of NGAL was calculated by multiplying the urine concentration by the urine amount. A volume of 5 ml blood was collected from each patient under complete aseptic condition. The plasma level of NGAL in plasma was estimated using commercially available ELISA kit (036; Bioporto Diagnostics, Gentofte, Denmark).
Calculation of the fractional excretion of Na (FE Na ) was carried out by the following equation  :
where U Na is urine Na, P Na is plasma Na, P Cr is plasma creatinine, and U Cr is urine creatinine. Urinary Na level was estimated by emission flow photometry  , and glomerular filtration rate (GFR) was calculated according to the Cockcroft-Gault formula  .
Definition of kidney disease
Impairment of kidney function was diagnosed when sCr was greater than 1.5 mg/dl. This value was chosen because it has been selected in several consensuses and conferences as a cutoff to define impairment of kidney function in cirrhosis  , Garcia et al., 2004  .
Prerenal azotemia due to volume depletion was considered when patients had a history of fluid loss in the preceding days due to bleeding, diuretic overdose, or other cause. A transient increase in sCr to greater than 1.5 mg/dl with subsequent decrease in sCr to less than 1.5 mg/dl was observed within 48 h of treatment with intravenous hydration. CKD was defined by the evidence of structural kidney abnormalities by imaging and GFR less than 60 ml/min as assessed by the MDRD formula  . HRS type 1 was defined by IAC  as rapidly progressive renal failure with doubling of the initial sCr to a level greater than 2.5 mg/dl in less than 2 weeks in the presence of cirrhosis and ascites that failed to improve after 48 h of diuretic withdrawal and volume expansion in the absence of shock, nephrotoxic medications, and parenchymal kidney disease (proteinuria>500 mg/day, microhematuria>50 red blood cells/high powered field, and abnormal kidney imaging). iAKI was defined as acute elevation in sCr to greater than 1.5 mg/dl, not responding to 48 h of volume resuscitation and not meeting the criteria for HRS  .
Database management and statistical analysis were performed using a statistical software package (SPSS 19). The t-test, the χχ2 -test, and the compare proportion tests were used for comparison between two groups. The Spearman correlation test was used to test correlation between different variables. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated to test the accuracy of uNGAL in the diagnosis of HRS.
A receiver operator characteristic analysis was used to determine the optimum cutoff value for the studied marker. Significance was adopted at P-value less than 0.05 for interpretation of the results of tests of significance.
| Results|| |
Clinical and laboratory data of all groups are shown in [Table 1]. In 21 patients with prerenal azotemia, volume depletion was due to diuretic overdose in 11, gastrointestinal bleeding in four, and diarrhea in six. Abnormal ultrasound appearance of the kidneys was present in 10 patients with CKD and a combination of low GFR with hypertension and diabetes mellitus. The remaining five patients were diagnosed by kidney biopsy, which showed chronic interstitial nephritis in three, membranous glomerulopathy in one, and hypertensive nephropathy in one patient. Of the 22 patients with HRS, 12 had type 1 and 10 had type 2. Infections were present in seven patients: spontaneous bacterial peritonitis in four, chest infections in two, and cellulitis in one patient. There was a significantly higher level of serum bilirubin in patients with cirrhosis compared with control (P = 0.001). In the patients with four categories of renal impairment, serum bilirubin levels were significantly higher compared with those with normal kidney function. Serum albumin, sodium, and GFR were significantly lower in patients with cirrhosis compared with control (P = 0.001, 0.03, and 0.001, respectively). FE Na was significantly higher in patients with iAKI compared with other types of renal impairment, patients with normal kidney function, and control (P = 0.0001). Urinary sodium levels were significantly low in patients with HRS compared with other types of AKI (P = 0.0001).
[Table 2] shows the comparison between HRS patients with and without infections with respect to kidney parameters. Patients with HRS type 1 had significantly higher values of uNGAL than type 2 (131 + 13.5 vs. 105 + 30.5; P = 0.001).
[Table 3] shows kidney function biomarkers in the cirrhotic groups with and without renal impairment. Patients with impaired kidney function had significantly higher uNGAL levels compared with those with normal kidney function and healthy control (P = 0.001). Patients with HRS had significantly higher level of uNGAL compared with those with prerenal azotemia (P = 0.01), CKD (P ≤ 0.05), or cirrhotic patients with normal kidney function (P = 0.01). The highest values of uNGAL were detected in patients with iAKI (P = 0.001). sCr level was significantly higher in patients with HRS compared with those with prerenal azotemia, but the level was similar to patients with iAKI. FE Na was significantly higher in patients with iAKI than in patients with either HRS or prerenal azotemia.
|Table 3: Kidney function biomarkers in the different types of renal impairment and normal kidney function|
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[Table 4] shows uNGAL and pNGAL in cirrhotic patients with and without renal impairment including and excluding infection. pNGAL and uNGAL levels were significantly higher in cirrhotic patients with impaired kidney function either with or without infection compared with those with normal kidney function (P = 0.001). There was no significant difference between different types of AKI with respect to pNGAL levels (P > 0.05). Patients without infections had lower values of urinary and pNGAL; yet, the difference did not reach statistical significance (P > 0.05).
|Table 4: Urinary and plasma NGAL levels in patients with renal impairment including and excluding infections|
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A cutoff value of 110 ng/ml uNGAL had sensitivity, specificity, PPV, NPV, and accuracy of 90.2, 67.9, 79.0, 91, and 88.75%, respectively, to diagnose HRS [Table 5].
|Table 5: Sensitivity, specificity, PPV, NPV and accuracy of uNGAL in diagnosis of HRS|
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Positive correlation was found between uNGAL and sCr (r =0.462, P = 0.042), whereas no correlation was detected with pNGAL (r = 0.203, P = 0.39; [Table 6]).
| Discussion|| |
In patients with cirrhosis, the differential diagnosis of acute renal impairment of kidney function is further complicated by the fact that they may develop HRS , . HRS is characterized by markedly reduced GFR in the setting of preserved tubular function , . Nevertheless, there is some evidence of the presence of renal parenchymal lesions in these patients. NGAL is secreted into urine by the thick ascending limb of Henle and collecting ducts of the kidney. Thus, urinary excretion of NGAL is increased in AKI but not in functional AKI  .
Although sCr levels were elevated in patients with impaired kidney function, sCr poorly differentiated AKI type. sCr was significantly higher in patients with HRS compared with those with prerenal azotemia but was similar to patients with iAKI. sCr was significantly higher in patients with iAKI compared with those with normal kidney function and CKD but was statistically similar to those with prerenal azotemia and HRS. These findings are similar to those reported by Verna et al.  , who found that sCr was not different between patients with iAKI and HRS. In addition, FE Na was significantly higher in patients with iAKI than in patients with either HRS or prerenal azotemia. FE Na levels did not discriminate patients with HRS from those with prerenal azotemia. These findings are in accordance with those of Verna and colleagues , .
This study revealed that patients with impaired kidney function had significantly higher uNGAL levels compared with those without impairment of kidney function and healthy controls. This is in accordance with the study by Verna and colleagues , .
Few studies have reported the usefulness of uNGAL in the differential diagnosis of impairment of kidney functions. The results of this study showed that patients with HRS had significantly higher levels of uNGAL compared with those with prerenal azotemia, CKD, or cirrhotic patients with normal kidney function. To further assess the relationship between uNGAL levels and HRS, we divided the patients with HRS into type 1 and type 2. In patients with classical HRS, those with type 1 had significantly higher values of uNGAL than those with HRS type 2. This was in agreement with the study by Verna and colleagues , . In patients with prerenal azotemia, uNGAL levels showed no significant difference compared with those with CKD and normal kidney function. Our findings were in agreement with those of Verna et al.  but were in contrast to the study by Fagundes et al.  in which it was reported that uNGAL levels in patients with CKD were not significantly different from those with HRS type 2 or prerenal azotemia. They reported that patients with classical type 1 HRS had significantly higher levels of uNGAL than those with type 2 HRS, CKD, or prerenal azotemia due to volume depletion. This was not surprising considering that no acute injury of tubular cells is known to exist in these conditions.
The mechanisms by which patients with HRS have high level of uNGAL remain uncertain. HRS physiology is classically thought to be an extreme prerenal state , with severe renovascular vasoconstriction and decreased GFR but normal intrinsic kidney function. Kidney function can return to normal after improvement of hepatic hemodynamics or after transplantation of the kidney into a recipient with normal hepatic function , . However, pathologic investigations have reported subtle kidney tubular and glomerular damage in HRS kidneys, some seen only with electron microscopy , . Perhaps these results from cellular changes associated with chronic activation of angiotensin-aldosterone signaling  . It is conceivable that profound renovascular constriction may cause subclinical tubular damage in at least a subset of nephrons, not detectable by urinary sodium, which is not sensitive enough to detect mild or patchy tubular epithelial damage. These findings were supported by Cavallin et al.  , who reported that type 1 HRS could not be entirely functional in nature but may be associated with tubular damage. This fact may affect to some extent the response of this complication to treatment with terlipressin and albumin in patients with advanced cirrhosis.
This study revealed that patients with HRS associated with active bacterial infection had levels of uNGAL none significantly higher compared with those with HRS in the absence of infections. This was in agreement with the study by Verna et al.  . In contrast, other studies demonstrated significantly higher levels of uNGAL in patients with HRS and infection than those without infection ,, . Patients with urinary tract infections were not excluded in these studies. These findings suggest the existence of some degree of tubular injury in patients with HRS associated with active bacterial infection. Fagundes et al.  reported statistically nonsignificant differences in uNGAL between patients with HRS in the presence of infections other than urinary tract infection and those without infections.
In contrast to uNGAL levels, the pNGAL were not helpful in the differential diagnosis of impaired kidney function. Patients with all types of impairment of kidney function showed higher levels of pNGAL than those with normal kidney function. These findings were in accordance with Gerbes et al.  . However, when patients were categorized into different types of renal impairment, there were no significant differences in pNGAL across groups. These results suggest the absence of correlation between uNGAL and pNGAL. This supports the hypothesis that uNGAL originates from renal tubules. Studies on experimental animals have demonstrated convincingly an increased expression of uNGAL in the renal tubules in conditions of ischemia or toxicity , . In addition to the kidney tubules, NGAL may be expressed in the polymorphonuclear cells and macrophages as a result of activation of the innate immunity through a pathway that involves Toll-like receptor 4 and interleukin 1-b.
No correlation was detected between urinary and pNGAL, which was similar to the findings of Fagundes et al.  , whereas there was a positive correlation between uNGAL and sCr. This finding was in agreement with the result of Haase et al.  , who reported an increase in uNGAL several days before increase in sCr.
At a cutoff value of 110 ng/ml, uNGAL had sensitivity, specificity, PPV, NPV, and accuracy of 90.2, 67.9, 79.0, 91, and 88.75%, respectively, to diagnose HRS. These were close to the findings of Verna et al.  , where they diagnosed this level for non-pre-renal AKI. Other studies reported a cutoff value greater than 150 ng/ml to diagnose AKI in noncirrhotic patients ,,, .
| Conclusion|| |
uNGAL can be used to differentiate HRS from other types of AKI in cirrhotic patients, with 90.2% sensitivity and 67.9% specificity at a cutoff value of 110 ng/ml. Significantly higher levels were detected in type 1 HRS than in type 2. There was no correlation between urinary and pNGAL in cirrhotic patients with impaired kidney function.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]