The use of urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin for diagnosis of hepato-renal syndrome in advanced cirrhotic patients.

BACKGROUND: Chronic liver disease is a common and important clinical problem.Hepatorenal syndrome (HRS) is a life threatening complication. Serum creatinine (Cr) remains the only conventional indicator of renal function. However, the interpretation of serum Cr level can be confounded by malnutrition and reduced muscle mass often observed in patients with severe liver disease. Here, we present a cross-sectional study to explore the sensitivity and specificity of other markers as urinary KIM-1 and NGAL for cases of HRS. METHODS: Cross-sectional study was conducted on 88 patients who were admitted to Alexandria main university hospital. Enrolled patients were divided in two groups; group 1: patients with advanced liver cirrhosis (child B and C) who have normal kidney functions while group 2: patients who developed HRS. Stata© version 14.2 software package was used for analysis. RESULTS: Group 1 included 18 males and 26 females compared to 25 males and 19 females in group 2 (p = 0.135). Only the urinary KIM-1 showed a statistically significant difference between both groups in the multivariate logistic regression analysis adjusted for gender, serum bilirubin, serum albumin, INR, serum K, AST and ALT levels. CONCLUSION: In conclusion, our study aligns with prior research, as seen in the consistent findings regarding Urinary NGAL elevation in cirrhotic patients with AKI. Urinary KIM-1, independent of Urinary NGAL, may have a role in precisely distinguishing between advanced liver cirrhosis and HRS and merits further exploration.

Urinary NGAL as a Diagnostic and Prognostic Marker for Acute Kidney Injury in Cirrhosis: A Prospective Study.

INTRODUCTION: Urinary neutrophil gelatinase-associated lipocalin (NGAL) has shown promise in differentiating acute tubular necrosis (ATN) from other types of acute kidney injuries (AKIs) in cirrhosis, particularly hepatorenal syndrome (HRS). However, NGAL is not currently available in clinical practice in North America. METHODS: Urinary NGAL was measured in a prospective cohort of 213 US hospitalized patients with decompensated cirrhosis (161 with AKI and 52 reference patients without AKI). NGAL was assessed for its ability to discriminate ATN from non-ATN AKI and to predict 90-day outcomes. RESULTS: Among patients with AKI, 57 (35%) had prerenal AKI, 55 (34%) had HRS, and 49 (30%) had ATN, with a median serum creatinine of 2.0 (interquartile range 1.5, 3.0) mg/dL at enrollment. At an optimal cutpoint of 244 µg/g creatinine, NGAL distinguished ATN (344 [132, 1,429] µg/g creatinine) from prerenal AKI (45 [0, 154] µg/g) or HRS (110 [50, 393] µg/g; P < 0.001), with a C statistic of 0.762 (95% confidence interval 0.682, 0.842). By 90 days, 71 of 213 patients (33%) died. Higher median NGAL was associated with death (159 [50, 865] vs 58 [0, 191] µg/g; P < 0.001). In adjusted and unadjusted analysis, NGAL significantly predicted 90-day transplant-free survival (P < 0.05 for all Cox models) and outperformed Model for End-Stage Liver Disease score by C statistic (0.697 vs 0.686; P = 0.04), net reclassification index (37%; P = 0.008), and integrated discrimination increment (2.7%; P = 0.02). DISCUSSION: NGAL differentiates the type of AKI in cirrhosis and may improve prediction of mortality; therefore, it holds potential to affect management of AKI in cirrhosis.

Urinary cell cycle arrest biomarker [TIMP-2]·[IGFBP7] in patients with hepatorenal syndrome.

Background: Patients with hepatorenal syndrome carry a high short-term mortality. Early diagnosis and treatment are essential for patients' outcome. Nevertheless diagnosis of HRS remains difficult. First-line therapy terlipressin is often associated with severe complications. Biomarkers become more on focus for an early diagnosis. Objective: The aim of this study was to test the diagnostic accuracy of urinary [TIMP-2]·[IGFBP7] for HRS patients and prognostic value for therapy responding patients. Material and methods: NephroCheck® measures urinary concentrations of TIMP-2 and IGFBP-7, both indicating stress of renal cells and associated with induction of cell cycle arrest. 22 HRS patients and 30 patients with normal kidney function were included. [TIMP-2]·[IGFBP7] was measured using NephroCheck®. HRS patients receiving terlipressin were also examined. Results: [TIMP-2]·[IGFBP7] values did not differ significantly (1.3 ± 2.09 vs. 1.03 ± 1.03; p = 0.55). Furthermore, there was no significant difference of [TIMP-2]·[IGFBP7] regarding response of terlipressin (1.32 ± 2.39 vs. 0.81 ± 1.05; p = 0.56). Low [TIMP-2]·[IGFBP7] values were significantly associated with higher mortality (p = 0.01). Conclusions: The results of this study suggest that [TIMP-2]·[IGFBP7] is not suitable for diagnostic of HRS and prediction of therapy response, but there might be evidence for prognostic value of [TIMP-2]·[IGFBP7] in regard to mortality of liver cirrhosis patients.

Assessment and prediction of acute kidney injury in patients with decompensated cirrhosis with serum cystatin C and urine N-acetyl-ß-D-glucosaminidase.

BACKGROUND AND AIM: For appropriate management of acute kidney injury (AKI) in cirrhotic patients, accurate differentiation of the types of AKI, prerenal azotemia (PRA), hepatorenal syndrome (HRS), and acute tubular necrosis (ATN) is very important. Urine N-acetyl-ß-D-glucosaminidase (NAG) has been proposed as a good tubular injury marker in many studies, but its efficacy in cirrhosis is unclear. This study was performed to evaluate the usefulness of urine NAG in patients with decompensated cirrhosis. METHODS: In 114 hospitalized patients with decompensated cirrhosis, we assessed serum creatinine, cystatin C, and urine NAG levels as markers for AKI differentiation and development and patient mortality. RESULTS: Thirty patients diagnosed with AKI at baseline had significantly higher serum creatinine and cystatin C levels, urine NAG levels, and Child-Pugh scores than those without AKI. Only urine NAG levels were significantly higher in patients with ATN than those with PRA or HRS (116.1 ± 46.8 U/g vs 39.4 ± 20.2 or 54.0 ± 19.2 U/g urinary creatinine, all P < 0.05). During a median follow up of 6.1 months, AKI developed in 17 of 84 patients: PRA in nine, HRS in six, and ATN in three. Higher serum cystatin C and urine NAG levels were independent predictors of AKI development in patients with decompensated cirrhosis. Survival was significantly associated with low serum cystatin C and urine NAG levels. CONCLUSION: Serum cystatin C and urine NAG levels are useful to differentiate types of AKI and are strong predictors for AKI development and mortality in patients with decompensated cirrhosis.

Gamma-variate plasma clearance versus urinary plasma clearance of 51 Cr-EDTA in patients with cirrhosis with and without fluid retention.

In patients with fluid retention, the plasma clearance of 51 Cr-EDTA (Clexp obtained by multiexponential fit) may overestimate the glomerular filtration rate (GFR). The present study was undertaken to compare a gamma-variate plasma clearance (Clgv) with the urinary plasma clearance of 51 Cr-EDTA (Clu ) in patients with cirrhosis with and without fluid retention. A total of 81 patients with cirrhosis (22 without fluid retention, 59 with ascites) received a quantitative intravenous injection of 51 Cr-EDTA followed by plasma and quantitative urinary samples for 5 h. Clgv was determined from the injected dose relative to the plasma concentration-time area, obtained by a gamma-variate iterative fit. Clexp and Clu were determined by standard technique. In patients without fluid retention, Clgv , Clexp and Clu were closely similar. The difference between Clgv and Clu (Clgv - Clu  = ΔCl) was mean -0·6 ml min-1  1·73 m-2 . In patients with ascites, ΔCl was significantly higher (11·8 ml min-1  1·73 m-2 , P<0·0001), but this value was lower than Clexp - Clu (17·5 mL min-1  1·73 m-2 , P<0·01). ΔCl increased with lower values of GFR (P<0·001). In conclusion, in patients with fluid retention and ascites Clgv and Clexp overestimates GFR substantially, but the overestimation is smaller with Clgv . Although Clu may underestimate GFR slightly, patients with ascites should collect urine quantitatively to obtain a reliable measurement of GFR.

Hepatorenal dysfunction in sepsis: epidemiological, clinical and laboratory aspects.

UNLABELLED: The major impact of sepsis-induced multiple organ dysfunction on healthcare system in the European Union was estimated at 90.4 cases per 100000 inhabitants, compared to 58 per 100000 for breast cancer. The association of organ dysfunctions in terms of both the number of dysfunctions and the degree of organ dysfunction is the most powerful predictor of death in sepsis. AIM: To find medical and statistical correlations in hepatorenal dysfunction in sepsis patients. MATERIAL AND METHODS: This retrospective study included 117 patients diagnosed with sepsis at the Iasi Infectious Diseases Hospital, patients who presented liver/renal and other organ dysfunctions. The clinical, etiological, and laboratory data, and APACHE II prognostic scores were analyzed. The data were processed using SPSS version 16.0. RESULTS: The etiological agents were Gram positive as well as Gram negative bacteria, and 40% of sepsis patients with hepatic/kidney dysfunction presented hepatorenal syndrome. CONCLUSIONS: Over one-third of patients with sepsis-related hepatorenal dysfunction had a creatinine clearance of less than 30 ml/min, and we found statistical correlations between serum creatinine and APACHE II score. There were no statistically significant differences between the survival curves of patients with hepatorenal syndrome and those with sepsis-related hepatorenal dysfunction.

Neutrophil gelatinase-associated lipocalin in prediction of mortality in patients with hepatorenal syndrome: a prospective observational study.

BACKGROUND & AIMS: Hepatorenal syndrome (HRS) is a severe complication of cirrhosis which is characterized by renal dysfunction and associated with poor survival. Neutrophil gelatinase-associated lipocalin (NGAL) is a troponin-like biomarker for human acute kidney injury. We aimed to investigate levels of plasma and urine NGAL in HRS and predictive ability of these markers for all-cause mortality, in HRS, stable cirrhosis and control subjects. METHODS: A total of 64 patients with cirrhosis (8 patients with type 1 HRS, 22 with type 2 HRS, and 34 without HRS) and 23 control subjects were included in the study. Blood and urine samples were measured with Human NGAL sandwich ELISA. Patients were followed up prospectively. RESULTS: Patients with type 1 and type 2 HRS had significantly higher plasma and urine NGAL levels compared with stable cirrhosis and control subjects. Cox regression analysis showed that plasma NGAL and MELD-Na scores were independent predictors of mortality. ROC-curve analysis showed that the plot of the plasma NGAL, urine NGAL, MELD-Na and Child-Turcot-Pugh score could predict all-cause mortality in cirrhotic patients' area under the curve (AUC 0.819, 0.686, 0.807 and 0.795 respectively). CONCLUSIONS: NGAL could predict mortality in patients with HRS independent of other commonly used risk factors.

High age and low sodium urine concentration are associated with poor survival in patients with hepatorenal syndrome.

BACKGROUND: Combination therapy with terlipressin and albumin substitution is considered a widely accepted treatment regimen for patients with hepatorenal syndrome (HRS). However, only half of the patients respond to treatment and to date albumin substitution and terlipressin therapy are among the most expensive medical treatments available for patients with liver diseases. Thus, we aimed to identify clinical and etiological parameters to predict treatment response and overall mortality in patients with HRS. MATERIAL AND METHODS: We retrospectively evaluated 21 patients, 13 male/8 female, aged 43-72 years with HRS. Four patients were transplanted after following combination treatment. Terlipressin was administered by continuous intravenous perfusion (2-6 mg/d) and albumin drips (50 mg) were given daily. Treatment response was defined by a decrease in serum creatinine level to ≤ 1.5 mg/dL or by a ≥ 50% reduction of the baseline concentration. RESULTS: 57% of the patients responded to treatment, which was associated with improved survival at day 60, compared to non-responders. However, the overall mortality was not different between the two groups. Median age of 63 years was a significant negative predictor for therapy response. High baseline urinary sodium levels were of prognostic value for survival. The Model of End stage Liver Disease score (MELD score) did not correlate with therapy response. CONCLUSION: In conclusion high age is a predictor of non-response. Low urinary sodium before treatment is associated with poor survival. Terlipressin and albumin co-treatment is associated with increased two-months survival rate. This seemingly moderate extension in survival rate can, however, be decisive for obtaining liver transplantation.

Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis.

BACKGROUND & AIMS: Impairment of kidney function is common in cirrhosis but differential diagnosis remains a challenge. We aimed at assessing the usefulness of neutrophil gelatinase-associated lipocalin (NGAL), a biomarker of tubular damage, in the differential diagnosis of impairment of kidney function in cirrhosis. METHODS: Two-hundred and forty-one patients with cirrhosis, 72 without ascites, 85 with ascites, and 84 with impaired kidney function, were studied. Urinary levels of NGAL were measured by ELISA. RESULTS: Patients with impaired kidney function had higher urinary NGAL levels compared to patients with and without ascites. Patients with urinary tract infection (n=25) had higher uNGAL values than non-infected patients. Patients with acute tubular necrosis (ATN) had uNGAL levels markedly higher (417µg/g creatinine (239-2242) median and IQ range) compared to those of patients with pre-renal azotemia due to volume depletion 30 (20-59), chronic kidney disease (CKD) 82 (34-152), and hepatorenal syndrome (HRS) 76 (43-263) µg/g creatinine (p<0.001 for all). Among HRS patients, the highest values were found in HRS-associated with infections, followed by classical (non-associated with active infections) type-1 and type-2 HRS (391 (72-523), 147 (83-263), and 43 (31-74) µg/g creatinine, respectively; p<0.001). Differences in uNGAL levels between classical type 1 HRS and ATN on the one hand and classical type 1 HRS and CKD and pre-renal azotemia on the other were statistically significant (p<0.05). CONCLUSIONS: uNGAL levels may be useful in the differential diagnosis of impairment of kidney function in cirrhosis. Urinary tract infections should be ruled out because they may increase uNGAL excretion.

Aquaporin-1 and aquaporin-2 urinary excretion in cirrhosis: Relationship with ascites and hepatorenal syndrome.

Several experimental models of cirrhosis have shown dysregulation of renal aquaporins in different phases of liver disease. We investigated the urinary excretion of both aquaporin-1 and aquaporin-2 in patients with cirrhosis at different stages of the disease. Twenty-four-hour urine was collected from 11 healthy volunteers, 13 patients with compensated cirrhosis (without ascites), and 20 patients with decompensated cirrhosis (11 with ascites without renal failure and 9 with hepatorenal syndrome). Aquaporin-1 and aquaporin-2 excretion was analyzed by immunoblotting. Urinary aquaporin-2 excretion was reduced in patients with cirrhosis compared to healthy subjects. A progressive decrease in urinary aquaporin-2 excretion was observed as the severity of cirrhosis increased, from compensated cirrhosis to cirrhosis with ascites and hepatorenal syndrome. Patients with hyponatremia had lower urinary aquaporin-2 excretion than patients without hyponatremia. Vasopressin plasma level did not correlate with aquaporin-2 excretion. There were no differences between healthy subjects and patients with cirrhosis with or without ascites in urinary excretion of aquaporin-1, but urinary aquaporin-1 excretion of those with hepatorenal syndrome was extremely low. In conclusion, patients with cirrhosis appear to exhibit a decreased abundance of renal aquaporin-2 and therefore lower water permeability in the collecting tubules. This may represent an adaptive renal response to sodium retention, with expansion of extracellular fluid volume and dilutional hyponatremia observed in those who have cirrhosis with ascites. Finally, aquaporin-1 does not appear to play a role in the progressive dysregulation of extracellular fluid volume in cirrhosis.

Beneficial effects of terlipressin in hepatorenal syndrome: a prospective, randomized placebo-controlled clinical trial.

BACKGROUND AND AIM: Hepatorenal syndrome (HRS) occurs in about 18% of cirrhotic patients with ascites and is characterized by intense renal vasoconstriction, low glomerular filtration rate and preserved tubular function and normal renal histology. The aim of the present study was to examine the effects of terlipressin on renal function, systemic hemodynamics and clinical outcome in patients with HRS. METHODS: The study was a randomized controlled single-blind trial. We randomly assigned 24 consecutive patients with HRS to treatment with terlipressin 1 mg i.v. at 12-h intervals (group A; n = 12) or placebo at 12-h intervals (group B; n = 12). The end-point of the study was improvement in renal functions defined as reversal of HRS and survival at 15 days. RESULTS: The two groups were comparable at baseline. After treatment with terlipressin, urine output significantly (P < 0.05) increased progressively in group A (day 4, 960 +/- 40 mL/24 h; day 8, 1068 +/- 56 mL/24 h) compared with group B (day 4, 451 +/- 40 mL/24 h; day 8, 291 +/- 45 mL/24 h). Creatinine clearance improved (P < 0.05) in group A (day 4, 20.2 +/- 2.1 mL/min; day 8, 35 +/- 2.8 mL/min) compared with group B (day 4, 11.3 +/- 1.3 mL/min; day 8, 9.3 +/- 1.7 mL/min). Serum creatinine decreased in group A but not in group B (day 8, 1.6 +/- 0.01 compared with 3.9 +/- 0.26, P < 0.05). Mean arterial pressure increased significantly (P < 0.05) in group A. Terlipressin administration was associated with transient self-limiting side-effects including crampy abdominal pain in two patients and cardiac arrhythmias in three patients. Five of the 12 patients survived in group A compared with none in group B at day 15 (P < 0.05) and all survivors had reversal of HRS. CONCLUSION: In patients with HRS, terlipressin significantly improved renal functions and systemic hemodynamics, and showed a trend towards better clinical outcome. The drug merits further evaluation with different dosages and longer schedules.

Circulatory disturbance and renal dysfunction in liver disease and in obstructive jaundice.

The appearance of hepatorenal syndrome in a patient with acute or chronic liver disease is associated with a dismal outcome. Thus, management of HRS remains a formidable challenge to the aggressiveness and perseverance of the physician. The best treatment for HRS remains prevention based on avoidance of circulating volume contraction or the use of nephrotoxic drugs. Treatment for established HRS remains a frustrating experience with recovery being rare. A successful liver transplantation is currently the only definitive treatment that can reverse HRS. As this procedure is being performed with increasing frequency and encouraging results, a new window of hope has been opened for these patients.

Increased production of cysteinyl leukotrienes in hepatorenal syndrome.

The cysteinyl leukotrienes C4 and D4 are potent renal vasoconstrictors which may modulate glomerular function in vivo, and may therefore be important in the pathogenesis of hepatorenal syndrome. Urinary leukotriene E4, the major metabolite of leukotrienes C4 and D4, was elevated in patients with hepatorenal syndrome (17.8 ng/h) when compared with normal controls (5.1 ng/h) or subjects with renal failure alone (1.9 ng/h). Urinary leukotriene E4 was also elevated in subjects with decompensated liver disease (cirrhosis with ascites 28.6 ng/h, severe hepatocellular dysfunction 57.5 ng/h), but normal in compensated liver disease (6.7 ng/h). In the early stages of hepatorenal syndrome, leukotriene E4 excretion rate was up to 100-fold higher (560 ng/h) than in normals, and fell in parallel with creatinine clearance, indicative of the glomerular filtration rate-dependent renal excretion. Following correction for creatinine clearance, leukotriene E4, excretion was considerably higher in hepatorenal syndrome (54.1 pg/ml creatinine clearance) compared with normals (1.0 pg/ml creatinine clearance), chronic renal failure (3.2 pg/ml creatinine clearance), decompensated liver disease (ascites 7.7 pg/ml creatinine clearance, and severe hepatocellular dysfunction 11.0 pg/ml creatinine clearance), and compensated liver disease (1.9 pg/ml creatinine clearance). To interpret the significance of these findings, we determined renal clearance and endogenous metabolism of the cysteinyl leukotrienes by infusion of [3H]leukotriene C4 into a single subject with hepato-renal syndrome and two control subjects. Renal clearance of leukotriene E4, was reduced in hepatorenal syndrome (2.4 ml/min) compared with controls (greater than 17 ml/min) which together with the increased excretion rate of leukotriene E4 demonstrates that there is increased cysteinyl leukotriene production in hepatorenal syndrome. This may be one of the factors involved in its pathogenesis.

Analysis of cysteinyl leukotrienes in human urine: enhanced excretion in patients with liver cirrhosis and hepatorenal syndrome.

The cysteinyl leukotrienes, comprising leukotriene C4 and its metabolites, are biologically most active mediators, eliminated from the blood circulation by the liver and the kidneys. The urine of normal subjects and of patients with hepatic and/or renal failure was analysed for endogenous cysteinyl leukotrienes. The leukotriene metabolites were separated by reversed-phase high-performance liquid chromatography and subsequently quantified by radioimmunoassay. Leukotriene E4 was detected in all urine samples analysed. Its mean concentration increased from 0.3 nmol l-1 in healthy subjects to 0.8 nmol l-1 in patients with liver cirrhosis. In patients with hepatorenal syndrome leukotriene E4 averaged 7.8 nmol l-1; in addition, N-acetyl-leukotriene E4 was detected in an average amount of 1.5 nmol l-1. The mean leukotriene E4/creatinine ratio in urine increased from 0.02 in healthy subjects to 0.11 in patients with liver cirrhosis and to 1.2 mumol leukotriene E4 mol-1 creatinine in patients with hepatorenal syndrome. These results indicate that cysteinyl leukotrienes may play an important role in the mediator network responsible for the development of the hepatorenal syndrome in patients with severe liver disease.

Immunohistochemical distribution of renal prostaglandin endoperoxide synthase and prostacyclin synthase: diminished endoperoxide synthase in the hepatorenal syndrome.

To evaluate possible causes of the diminished prostaglandin production in advanced hepatorenal syndrome, prostaglandin endoperoxide synthase and prostacyclin synthase were localized and semiquantitated by immunofluorescence in postmortem, biopsy and nephrectomy renal tissues. In normal kidneys, antiprostacyclin synthase serum caused intense staining in peritubular capillaries, in the adjacent renal interstitial cells and in glomerular mesangial regions. Antiprostaglandin endoperoxide synthase serum caused staining of collecting duct epithelial cells, cells of the thin ascending limb and possibly glomerular mesangial cells. Prostacyclin synthase-positive staining was graded 5+ (scale of 0+ to 5+) in all kidney samples. Medullary collecting tubule prostaglandin endoperoxide synthase-positive staining was graded 4+ or 5+ in kidney samples from patients with acute tubular necrosis or acute tubulointerstitial nephritis and from patients with liver failure without the hepatorenal syndrome. However, prostaglandin endoperoxide synthase-positive staining was markedly diminished or absent (average 1+) in patients with the hepatorenal syndrome. These data suggest that loss of the medullary prostaglandin endoperoxide synthase is the cause of diminished urinary prostaglandin E2 excretion in the hepatorenal syndrome.

Analysis of serum and urinary retinol binding protein in hepato-renal syndrome.

Retinol binding protein (RBP) was analyzed in the sera and urines of 5 patients with hepato-renal syndrome (HRS), 4 with acute tubular necrosis (ATN), 20 liver cirrhosis patients with normal kidney function (NKF), 14 chronic renal failure (CRF) patients, and 19 healthy adults. All renal failure patients had high mean urine RBP (URBP): HRS, 8 mg/L; ATN, 11 mg/L; CRF, 8 mg/L respectively; p less than 0.001 vs the rest. Those with ATN and CRF had high mean serum RPB (SRBP): 146 and 149 mg/L, respectively, p less than 0.001 compared to the other groups. In HRS, in spite of renal failure, SRBP was very low (mean = 12 mg/L). The cirrhotics with NKF averaged less than 50% of the SRBP values of the healthy controls (16 vs 41 mg/L RBP, p less than 0.001); their RBP excretion was normal (mean URBP of 0.1 vs 0.06 mg/L in the control group). RBP analyses before and during HRS in two patients showed a marked increase in urine RBP during HRS (35- and 600-fold respectively) with practically unchanged serum levels. Impaired hepatic production and/or release is proposed to explain the low serum RBP in HRS, and a renal tubular injury or dysfunction to account for its high excretion. The RBP urinary loss could further compromise an already abnormal RBP metabolism and its serum levels. This combination (of low serum and high urine RBP), in the context of renal failure occurring in alcoholic liver cirrhosis, could help in the recognition of HRS.