Neutrophil Gelatinase-associated Lipocalin Excretion Research Articles

Pre-existing renal failure worsens the outcome after intestinal ischaemia and reperfusion in rats

Chronic kidney disease (CKD) serves as a risk factor in the development of acute kidney injury (AKI) requiring renal replacement therapy. Furthermore, superimposed AKI on CKD is associated with an increased mortality and risk of progression to end-stage renal disease. We aim to examine whether CKD increases the morbidity and mortality of AKI induced by intestinal ischaemia and reperfusion (I-I/R). A novel two-stage rat model was developed for CKD induced by 5/6 nephrectomy followed by AKI induced by lethal I-I/R in male rats. All rats initially underwent either 5/6 nephrectomy or sham operation. After 2weeks, half of each group were subjected to clamping of the superior mesenteric artery for 45 min. The rats were placed in metabolic cages for measurements of water intake and urine output. Fourteen days after 5/6 nephrectomy, polyuria, polydipsia, azotaemia and proteinuria were seen. Furthermore, urinary excretion of neutrophil gelatinase-associated lipocalin was increased in rats with CKD. Earlier death was observed in rats with AKI superimposed on CKD compared with rats with AKI superimposed on normal renal function (the average time to death during reperfusion after intestinal ischaemia: 71.0 ± 7.1 vs 112.4 ± 11.0 min, P < 0.05). Shortly after reperfusion of the intestine, mean arterial pressure dropped to pre-shock levels, which were partly compensated, although to a larger extent, in the sham-operated rats compared with the rats with CKD. The results suggest that even mild CKD has a critical impact on survival during the development of multiple organ failure induced by AKI.

Urinary Neutrophil Gelatinase-Associated Lipocalin: A Potential Biomarker for Predicting Rapid Progression of Drug-Induced Chronic Tubulointerstitial Nephritis

IntroductionThe role of urinary biomarkers of kidney injury in the prediction of adverse clinical outcomes in drug-induced chronic tubulointerstitial nephritis (D-CTIN) has not been well described. MethodsA total of 36 patients with D-CTIN were enrolled in the study. The baseline urinary excretion of neutrophil gelatinase-associated lipocalin (NGAL), α1-microglobin (α1-MG), albumin (mAlb) and total protein were measured, and estimated glomerular filtration rate change rates within a period of 6 to 33 (mean: 24months) follow-up months were recorded. ResultsAreas under the receiver-operator characteristic curve of urinary NGAL, α1-MG, mAlb and total protein for predicting deterioration of estimated glomerular filtration rate were 0.707, 0.631, 0.685 and 0.678, respectively. The cutoff points that maximized the combined sensitivity and specificity for NGAL, α1-MG, mAlb and total protein were 37.71 ng/mL, 33.20μg/mL, 6.91mg/L and 60.00mg/L, respectively. At these thresholds, the sensitivity and specificity was 64.7% and 78.9% for NGAL, 66.7% and 50.0% for α1-MG, 80.0% and 50.0% for mAlb and 70.6% and 63.2% for total protein, respectively. The median renal survival time (years) of patients with urinary NGAL level exceeding 37.705 ng/mL was shorter than that of patients with urinary NGAL level below 37.705 ng/mL (1.59 ± 0.79 versus 2.09 ± 0.63, P=0.040, χ2=4.218). ConclusionsIncrease of baseline urinary NGAL was better than α1-MG, mAlb and total protein in predicting renal function deterioration in patients with D-CTIN. This noninvasive approach has potential to serve as a practical tool in D-CTIN prognosis.

Urine Neutrophil Gelatinase-Associated Lipocalin: An Independent Predictor of Adverse Outcomes in Acute Kidney Injury

Background: Several recent studies have shown that neutrophil gelatinase-associated lipocalin (NGAL) may be a promising biomarker for the early detection of acute kidney injury (AKI), but the role of NGAL in predicting adverse clinical outcomes has not been well addressed. The purpose of this study was to evaluate the usefulness of urine NGAL as outcome predictor in patients with AKI. Methods: This was a prospective cohort study enrolling hospitalized AKI patients. Patients were divided into four groups according to initial urine NGAL excretion quartiles. The primary clinical outcome variables were in-hospital mortality and renal function at 4 weeks. Results: Initial urine NGAL was identified as an independent predictor of in-hospital mortality and persistent loss of renal function. In the analysis of predictive performance of urine NGAL, the AUC was 0.882 and a cutoff value of 298.28 ng/ml predicted loss of renal function with 88.2% sensitivity and 81.0% specificity. Conclusion: This study could suggest that urine NGAL, a new early biomarker might also be served as a reliable clinical outcome predictor in AKI patients.

Predicting Cisplatin-Induced Acute Kidney Injury by Urinary Neutrophil Gelatinase-Associated Lipocalin Excretion: A Pilot Prospective Case-Control Study

Background/Aims: Nephrotoxicity is the major limitation to cisplatin therapy for solid tumors. We aimed at evaluating whether early increases in serum/urine levels of neutrophil gelatinase-associated lipocalin (NGAL), a biomarker of tubular damage and regeneration, predict cisplatin-induced acute kidney injury (AKI). Methods: We compared changes in serum creatinine and serum/urine NGAL levels (ELISA assay) at 1 and 4 h and 1, 2, 3, 7 and 15 days after cisplatin infusion (70–80 mg/m²) versus baseline in 12 consecutive cancer patients (cases) with AKI (>25% serum creatinine increase vs. baseline) and 12 consecutive controls without AKI. Results: Baseline characteristics and posttreatment serum NGAL levels were similar in both groups. Urinary NGAL levels increased significantly more in cases than in controls at 1, 2, 3 and 15 days after cisplatin. The NGAL increase preceded AKI by 4.5 days and the NGAL increase at day 2 after cisplatin independently predicted AKI (p < 0.05). Six cases with residual kidney dysfunction at 15 days showed a trend to earlier and higher increase in urinary NGAL levels compared to cases with renal function recovery. Conclusion: An early increase in urinary NGAL excretion may help in identifying patients at risk of cisplatin-induced AKI who might benefit from innovative treatments to prevent cisplatin nephrotoxicity.

Disease and gender-specific dysregulation of NGAL and MMP-9 in type 1 diabetes mellitus

Neutrophil gelatinase-associated lipocalin (NGAL), a biomarker of renal injury, can bind matrix metalloproteinase-9 (MMP-9) and inhibit its degradation, thereby sustaining MMP-9 proteolytic activity. MMP-9 is produced by renal podocytes, and podocyte MMP production can be modified by high ambient glucose levels. Moreover, dysregulation of MMP-9 activity, gene expression, or urine concentrations has been demonstrated in T2DM-associated nephropathy and in non-diabetic proteinuric renal diseases. Our objective was to determine whether NGAL/MMP-9 dysregulation might contribute to or serve as a biomarker of diabetic nephropathy in type 1 DM (T1DM). Plasma MMP-9, and urine NGAL and MMP-9 concentrations were measured in 121 T1DM and 55 control subjects and examined relative to indicators of glycemia, renal function, and degree of albuminuria. T1DM was associated with a significant increase in urinary excretion of both NGAL and MMP-9, and urine NGAL:Cr (NGAL corrected to urine creatinine) and urine MMP-9:Cr concentrations were highly correlated with each other. Both were also positively correlated with measurements of glycemic control and with albuminuria. Plasma MMP-9, urine MMP-9, and urine NGAL concentrations were significantly higher in females compared to males, and urine MMP-9:Cr concentrations displayed a menstrual cycle specific pattern. Increased urinary excretion of NGAL and MMP-9 supports a role for NGAL/MMP-9 dysregulation in renal dysfunction; moreover, gender-specific differences could support a gender contribution to pathological mechanisms or susceptibility for the development of renal complications in diabetes mellitus.

Reduction in urinary excretion of neutrophil gelatinase-associated lipocalin by angiotensin receptor blockers in hypertensive patients

Reduction in urinary excretion of neutrophil gelatinase-associated lipocalin by angiotensin receptor blockers in hypertensive patients

Urinary neutrophil gelatinase–associated lipocalin as a biomarker of nephritis in childhood‐onset systemic lupus erythematosus

Renal involvement in systemic lupus erythematosus (SLE) is associated with poor prognosis. Currently available renal biomarkers are relatively insensitive and nonspecific for diagnosing SLE nephritis. Previous research suggests that neutrophil gelatinase-associated lipocalin (NGAL) is a high-quality renal biomarker of acute kidney injury, while its usefulness in SLE is unclear. We undertook this study to determine the relationship between urinary NGAL excretion and SLE disease activity or damage, with a focus on nephritis. A cohort of 35 patients diagnosed as having SLE prior to age 16 years (childhood-onset SLE) was assessed for disease activity (using the Systemic Lupus Erythematosus Disease Activity Index 2000 update) and damage (using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology SLE Damage Index) in a double-blind, cross-sectional study. Information on current markers of renal function and disease was obtained and compared with NGAL levels (ng/mg of urinary creatinine) measured by enzyme-linked immunosorbent assay. Eight children with juvenile idiopathic arthritis (JIA) served as controls. NGAL levels did not differ with the age, weight, height, sex, or race of the patients. Patients with childhood-onset SLE had significantly higher NGAL levels than did those with JIA (P < 0.0001). NGAL levels were strongly to moderately correlated with renal disease activity and renal damage (Spearman's r >/= 0.47, P < 0.0001 for both comparisons), but not with extrarenal disease activity or extrarenal damage. NGAL levels of >0.6 ng/mg urinary creatinine were 90% sensitive and 100% specific for identifying childhood-onset SLE patients with biopsy-proven nephritis. Urinary NGAL is a promising potential biomarker of childhood-onset SLE nephritis. The results of the current study require validation in a larger cohort to more accurately delineate urinary NGAL excretion in relation to the diverse SLE phenotypes.

Neutrophil Gelatinase-Associated Lipocalin: A Novel Early Urinary Biomarker for Cisplatin Nephrotoxicity

Background: Cisplatin is one of the most widely used chemotherapeutic agents, but the risk of nephrotoxicity frequently hinders the use of higher doses to maximize its antineoplastic effects. The lack of early biomarkers has impaired our ability to initiate potential therapeutic or preventive interventions in cisplatin nephrotoxicity in a timely manner. In this study, we have explored the expression and urinary excretion of neutrophil gelatinase-associated lipocalin (NGAL) in a mouse model of cisplatin-induced nephrotoxic injury. Methods: Mice were subjected to intraperitoneal injections of 20 mg/kg (high dose) or 5 mg/kg (low dose) cisplatin. The expression of NGAL was measured in the kidney and urine by Western analysis and immunofluorescence, and compared to changes in serum creatinine and urinary N-acetyl-β-D-glucosaminidase (NAG). Results: Cisplatin resulted in tubule cell necrosis and apoptosis following the high dose, but not the low dose. By Western analysis, NGAL protein was rapidly induced in the kidney within 3 h of high-dose cisplatin. By immunofluorescence, NGAL was induced predominantly in proximal tubule cells in a punctate cytoplasmic distribution, reminiscent of a secreted protein. NGAL was easily detected in the urine by Western analysis within 3 h of cisplatin administration in a dose- and duration-dependent manner. By comparison, changes in urinary NAG or serum creatinine were not evident until 96 h after cisplatin. Using defined concentrations of purified recombinant NGAL, urinary NGAL excretion following cisplatin administration was quantified to be in the 20–80 ng/ml range. Conclusion: The results indicate that NGAL represents an early and quantitative urinary biomarker for cisplatin nephrotoxicity.