Urine Neutrophil Gelatinase-Associated Lipocalin and Kidney Injury Molecule-1 to Detect Pediatric Cisplatin-Associated Acute Kidney Injury

Background: Few studies have described associations between acute kidney injury (AKI) biomarkers, urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), and AKI in cisplatin-treated children. We aimed to describe excretion patterns of urine NGAL and KIM-1 and associations with AKI in children receiving cisplatin. Methods: Participants (n=159) were enrolled between 2013 and 2017 in a prospective cohort study conducted in 12 Canadian pediatric hospitals. Participants were evaluated at early cisplatin infusions (at first or second cisplatin cycle) and late cisplatin infusions (last or second-to-last cycle). Urine NGAL and KIM-1 were measured (1) pre-cisplatin infusion, (2) post-infusion (morning after), and (3) at hospital discharge at early and late cisplatin infusions. Primary outcome: AKI defined by serum creatinine rise within 10 days post-cisplatin based on Kidney Disease: Improving Global Outcomes guidelines criteria (≥stage 1). Results: Of 159 children, 156 (median [interquartile (IQR)] age: 5.8 [2.4-12.0] years; 78 [50%] female) had biomarker data available at early cisplatin infusions and 127 had data at late infusions. Forty-six of 156 (29%) and 22/127 (17%) developed AKI within 10 days of cisplatin administration following early and late infusions, respectively. Urine NGAL and KIM-1 concentrations were significantly higher in patients with vs. without AKI (near hospital discharge of late cisplatin infusion, median [IQR]: NGAL: 76.1 [10.0-232.7] vs. 14.9 [5.4-29.7] ng/mg creatinine; KIM-1: 4415 [2083-9077] vs. 1049 [358-3326] pg/mg creatinine; P<.01). These markers modestly discriminated for AKI (area under receiver-operating characteristic curve (AUC-ROC) range: NGAL: 0.56-0.72; KIM-1: 0.48-0.75). Biomarker concentrations were higher and better discriminated for AKI at late cisplatin infusions (AUC-ROCs range: 0.54-0.75) vs. early infusions (AUC-ROCs range: 0.48-0.65). Conclusions: Urine NGAL and KIM-1 were modest at discriminating for cisplatin-associated AKI. Further research is needed to determine clinical utility and applicability of these markers and late kidney outcomes associations.

Urine neutrophil gelatinase-associated lipocalin (NGAL) measurement is not predictive for ureteral patency in pediatric patients following pyeloplasty: a pilot study

Objective: To evaluate the benefit of urine neutrophil gelatinase-associated lipocalin (NGAL) measurement to predict the ureteral patency in pediatric patients undergoing pyeloplasty. Materials and Methods: Ureteropelvic junction obstruction patients who underwent unilateral dismembered pyeloplasty had urine NGAL measurements taken intraoperatively during pyeloplasty and postoperatively at six months following surgery. All patients were evaluated preoperatively and postoperatively with renal scans. Pairwise comparisons and correlation analyses were performed to determine the dynamics and benefits of urine NGAL measurement. Results: Thirteen patients were included in this pilot study with a mean age of 3.2 years at surgery. Mean intraoperative bladder urine level was 4.43 ng/mL, and median intraoperative renal pelvic urine NGAL level was 3.70 ng/mL. There was no significant difference between these two levels (p-value = 0.76). Six months after pyeloplasty, 9/13 patients demonstrated significant reduction in the bladder urine NGAL level (at least 50% reduction), and 5/13 patients showed ureteral patency based on postoperative renal scan (more than 5% improvement in differential renal function or the conversion of diuretic half time. However, the finding of significant reduction of urine NGAL level did not correlate with ureteral patency (r = -0.50, p-value = 0.08). Conclusion: Although bladder urine NGAL level reduces in most pediatric patients following pyeloplasty, this decline is not reflective of the finding of ureteral patency from renal scanning. The benefits of urine NGAL measurement in this context remain unclear and require further large-scale investigation.

Neutrophil gelatinase–associated lipocalin as a biomarker of nephropathy in sickle cell disease

Sickle cell nephropathy (SCN) develops via altered hemodynamics and acute kidney injury, but conventional screening tests remain normal until advanced stages. Early diagnostic biomarkers are needed so that preventive measures can be taken. This study evaluates the role of neutrophil gelatinase–associated lipocalin (NGAL) as a biomarker of SCN in steady state and vaso-occlusive crisis (VOC). In this case-control study, 74 sickle cell disease (SCD) patients (37 in steady state and 37 in VOC) and 53 control subjects had hematological and biochemical measurements including plasma and urine NGAL. Univariate and logistic regression analyses were used to find the associations between variables. The receiver operating characteristic (ROC) curve was used to determine the diagnostic performance characteristics of plasma and urine NGAL for detection of VOC. Plasma and urine NGAL, urine microalbumin:creatinine ratio, and urine protein:creatinine ratio were significantly higher in VOC. Microalbuminuria was present in 17.1% steady state and 32.0% VOC patients. Microalbuminuria showed significant correlations with age, plasma NGAL, WBC, and hemolytic parameters. Area under the ROC curve for plasma NGAL was 0.69 (95%CI = 0.567–0.813; p = 0.006) and 0.86 (95%CI = 0.756–0.954; p < 0.001) for urine NGAL. Urine NGAL cut-off value of 12.0 ng/mL had 95% sensitivity and 65% specificity. These results confirm the presence of nephropathy during VOC and suggest that plasma and urine NGAL would be useful in the identification of SCN. Urine NGAL should be used as the screening biomarker, and patients with VOC and urine NGAL > 12.0 ng/mL should be selected for aggressive management to prevent progression of renal damage.

Neutrophil Gelatinase-Associated Lipocalin (NGAL): An Early Dual Biomarker in Diagnosis of Ascitic Fluid Infection and Acute Kidney Injury in Liver Cirrhosis in a Tertiary Centre, Egypt

Background: This study aimed to evaluate the ascitic Neutrophil gelatinase-associated lipocalin (NGAL) as a diagnostic biomarker for bacterial translocation or bactDNA translocation in ascites of cirrhotic patients and to evaluate the urinary NGAL for identifying renal dysfunction in patients with liver cirrhosis. Methods: This study included 44 patients with ascites. Study participants were divided into two groups. Group (1) had 22 patients with neutrocytic ascites and/or positive ascitic fluid (AF) culture while group (2) included 22 patients with culture negative non neutrocytic ascites (CNNNA), recruited as controls. AF and urine samples were collected from all studied participants. ELISA kit was used for measurement of NGAL levels in AF and urine. DNA extraction and PCR were done. Results: Values of NGAL in ascitic fluid were statistically significantly higher in bactDNA positive group. At cutoff 143.9 ng/ml, ascites NGAL had 86.4% sensitivity, 45.5% specificity, 61.3% positive predictive value (PPV) and 76.9% negative predictive value (NPV). When comparing ascites NGAL between bactDNA positive and negative group, NGAL has a sensitivity of 86.2% and a specificity of 46.7%, PPV of 75.8%, NPV of 63.6%. As for urine NGAL, patients with AKI had statistically significant higher levels of NGAL. Urine NGAL achieved sensitivity of 77.3%, specificity of 50%, PPV of 60.7%, NPV of 68.75%. Conclusion: Early and accurate diagnosis of BT or bactDNA translocation can be aided by utilizing NGAL especially in ruling out infection in those reported to have negative culture results, besides, it can help in early detection of complication of cirrhosis and infection especially AKI helping in the improving the prognosis of cirrhotic patients. It is an advantage that a single marker can detect both infection and kidney injury.

Urine NGAL and KIM-1—Tubular Injury Biomarkers in Long-Term Survivors of Childhood Solid Tumors: A Cross-Sectional Study

The deterioration of renal function after childhood solid tumors treatment is the result of using the intensive multimodal therapy. In recent years, urinary kidney injury molecule-1 (KIM-1) and urinary neutrophil gelatinase-associated lipocalin (NGAL) have been introduced as potential promising biomarkers of early kidney damage. The aim of the present study was to determine whether anticancer treatment has any effect on the concentration of KIM-1 and NGAL and its association with renal impairment in survivors of childhood solid tumors. Sixty patients previously treated for solid tumors were involved in this study. The median time after end of treatment was 8.35 years. Urine KIM-1 and NGAL levels were measured using immunoenzymatic ELISA commercial kits. Higher levels of urine NGAL, KIM-1/cr. (creatinine), and NGAL/cr. ratios were found in comparison with healthy controls (p < 0.0001). Among all subjects, 23% were found to have decreased estimated glomerular filtration rate (eGFR). A strong correlation between KIM-1/cr. and a cumulative dose of ifosfamide was observed (r = 0.865, p < 0.05). In addition, a moderate correlation between NGAL/cr. and a cumulative dose of cisplatin was identified (r = 0.534, p < 0.05). The AUC for KIM-1/cr. was 0.52, whereas NGAL/cr. showed a diagnostic profile describing the AUC of 0.67. Univariable regression showed significant associations between NGAL/cr. ratio and subjects after unilateral nephrectomy (coeff. 63.8, p = 0.007), cumulative dose of cisplatin (coeff. 0.111, p = 0.033), and age at diagnosis (coeff. 3.75, p = 0.023). The multivariable model demonstrated only cumulative dose of cisplatin as an independent factor influence on NGAL/cr. ratio. The results of our study showed increased levels of urine KIM-1 and NGAL many years after completion of the childhood solid tumors treatment, which correlated positively with a cumulative dose of ifosfamide and cisplatin. This study also suggests that unilateral nephrectomy could affect the concentration of the studied biomarkers.

SERUM NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN (NGAL) AND URINARY NGAL EXCRETION AS A BIOMARKER OF RENAL INJURY IN CHILDREN WITH BETA THALASSEMIA MAJOR

Background Frequent blood transfusions among patients with beta thalassemia major leads to iron overload state and leads to damage of various organs including kidney. Very few studies have explored on Serum and urinary NGAL as a biomarkers of renal injury in thalassemia major children. Therefore, this study is planned to investigate the renal injury in beta thalassemic children by measuring serum and urinary NGAL levels and correlating it with cystatin c and creatinine clearance. Methods: The study was a cross-sectional conducted among 25 patients with β thalassemia major, aged 1-18 years, having undergone regular blood transfusion and chelation therapy. Levels of plasma and urinary NGAL were measured and compared to the standard values of the normal range. Linear regression analysis was done. Results: Mean(SD) serum NGAL value in 1- 5 years of age was 1.6(0.26) , in 5-10 years was 2.15(0.23), in 10- 15 years was 2.6 (0.11) and > 15 years it was 18.11(33.76). ( p value <0.005).Mean (SD) urine NGAL value in 1- 5 years of age was 0.66 (0.11) , in 5-10 years was 1.13(0.13), in 10- 15 years was 1.38 (0.18) and > 15 years it was 1.94(0.25). ( p value <0.005).The mean values of plasma N-GAL, and Urinary N-GAL were significantly higher in our patients as compared to that of standard population values(p<0.05). Conclusions: Serum and urine NGAL values are found to be much higher in those with longer duration of transfusion and chelation. Positive correlation was found between urine NGAL levels and cystatin C. Serum and urine NGAL values are fair markers of renal injury in thalassemia major patients on multiple transfusions.

Urine NGAL and KIM-1: tubular injury markers in acute lymphoblastic leukemia survivors

Introduction Nephrotoxicity is a potential adverse effect of anticancer treatment in childhood. Cytostatics, abdominal radiotherapy, total body irradiation (TBI) and some agents used in supportive care may induce acute kidney injury (AKI) or lead to chronic kidney disease (CKD). The aim of this study was to test the hypothesis whether urinary kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) are increased in acute lymphoblastic leukemia (ALL) survivors. Method The study cohort consisted of 86 patients (42 females) previously treated for ALL. The median time after cessation of treatment was 6.55 (IQR: 1.96–9.93) years and median age at the time of study: 12 (IQR: 6.76–16.00). The control group included 53 healthy peers. Immunoenzymatic ELISA commercial kits were used to measure urine KIM-1 and NGAL levels. Results The median levels of urine uNGAL (p < 0.05), uNGAL/creatinine (cr.) ratio (p < 0.0001) and uKIM-1/creatinine ratio (p < 0.0001) were significantly higher in ALL survivors in comparison with healthy controls. Female patients had significantly higher levels of NGAL and NGAL/cr. than males (mean 8.42 ± 7.1 vs. 4.59 ± 4.5 ng/mL and 86.57 ± 77 vs. 37.7 ± 37 ng/mg, respectively; p < 0.01). Of all the study participants, 11 (13%) presented eGFR below 90 mL/min/1.73 m2. The NGAL/cr. ratio seemed to be the best predictor of decreased eGFR (AUC = 0.65). The cumulative dose of methotrexate and cyclophosphamide did not predict the values of the urine NGAL, NGAL/cr., KIM-1/cr. and eGFR. Five years after the end of treatment, the patients had higher levels of uKIM-1 (1.02 ± 0.8 vs. 0.62 ± 0.6 ng/mL, p < 0.01), uNGAL (7.9 ± 6.7 vs. 4.6 ± 5 ng/mL, p < 0.01) and lower eGFR (114 ± 29 vs. 134 ± 35 mL/min/1.73 m2, p < 0.01) in comparison with ALL survivors with the observation period of less than 5 years. Conclusion We demonstrated that ALL survivors have higher levels of urine NGAL, NGAL/cr. and uKIM-1/cr. ratio as compared to the control group. Further long-term follow-up studies are necessary to assess the significance of the NGAL and KIM-1 and their relationship to kidney damage after anticancer treatment in childhood.

Urine neutrophil gelatinase-associated lipocalin concentration in healthy newborns during the first three postnatal days

Introduction: Urine neutrophil gelatinase-associated lipocalin (uNGAL) is a biochemical marker significant for early prediction of acute kidney injury in adults. However, it has not been examined sufficiently among the infant population, particularly newborns in terms of reference values. The aim of our study was to determine the concentration of uNGAL in healthy term newborns and to determine if there was a difference in uNGAL concentration according to gender, postnatal age and birth weight. Materials and methods: Our study involved 81 healthy term newborns birth (≥ 37 weeks, Apgar score ≥ 8 in the first minute after birth, CRP < 5 mg/L). Urine NGAL was measured using chemiluminescent microparticle immunoassay (CMIA) within 72 hours after birth, on Architect plus ci8200 analyser (Abbott, Chicago, USA). Data were analysed using Statistica software. Results: The median concentration of uNGAL in the whole study group of healthy term newborns was 27.1 ng/mL (16.5-56.0 ng/mL) (newborn girls, 27.1 ng/mL (15.8-47.9 ng/mL); newborn boys, 27.9 ng/mL (16.5-61.0 ng/mL), P = 0.941). Median uNGAL concentration according to postnatal age expressed in days was 28.2 ng/mL (11.7-57.2 ng/mL) 1st day, 28.9 ng/mL (16.5-64.2 ng/mL ) 2nd day and 23.9 ng/mL (20.2-46.6) 3rd day, P = 0.863. Regarding birth weight for newborns < 3500 g, median concentration was 25.0 ng/mL (16.5-45.4 ng/mL ) and for weight ≥ 3500 g 30.6 ng/mL (16.5-64.2 ng/mL), P = 0.455. Conclusions: There were no significant difference in uNGAL concentration in relation to gender, postnatal age and birth weight.

Urine hepcidin, netrin-1, neutrophil gelatinase-associated lipocalin and C-C motif chemokine ligand 2 levels in multicystic dysplastic kidney

ABSTRACT Introduction: Glomerular hyperfiltration may lead to proteinuria and chronic kidney disease in unilateral multicystic dysplastic kidney (MCDK). We aimed to investigate the urine neutrophil-gelatinase-associated lipocalin (NGAL), netrin-1, hepcidin, and C-C motif chemokine ligand-2 (MCP-1/CCL-2) levels in patients with MCDK. Methods: Thirty-two patients and 25 controls were included. The urine hepcidin, netrin-1, NGAL, and MCP-1/CCL-2 levels were determined by ELISA. Results: The patients had higher serum creatinine (Cr) levels, urine albumin, and netrin-1/Cr ratio with lower GFR. There were positive correlations between urine protein/Cr, MCP-1/CCL-2/Cr, and netrin-1 with NGAL (r = 0.397, p = 0.031; r = 0.437, p = 0.041, r = 0.323, p = 0.042, respectively). Urine netrin-1/Cr was positively correlated with MCP-1/CCL-2/Cr (r = 0.356, p = 0.045). There were positive associations between the presence of proteinuria and netrin-1/Cr, MCP-1/CCL-2/Cr, and NGAL/Cr [Odds ratio (OR): 1.423, p = 0.037, OR: 1.553, p = 0.033, OR: 2.112, p = 0.027, respectively)]. ROC curve analysis showed that netrin-1/Cr, MCP-1/CCL-2/Cr, and NGAL/Cr had high predictive values for determining proteinuria p = 0.027, p = 0.041, p = 0.035, respectively). Urine hepcidin/Cr was negatively correlated with tubular phosphorus reabsorption and was positively correlated with urine NGAL/Cr (r = -0.418, p = 0.019; r = 0.682, p = 0.000; respectively). Conclusions: MCP-1/CCL-2 may play a role in the development of proteinuria in MCDK. Netrin-1 may be a protective factor against proteinuria-induced renal injury. Urine hepcidin/Cr may reflect proximal tubule damage in MCDK. Urine NGAL/Cr may be a predictor of tubule damage by proteinuria.