Urine biomarkers of acute kidney injury and association with brain MRI abnormalities in neonatal hypoxic-ischemic encephalopathy.

OBJECTIVE: Determine whether urine biomarkers NGAL (neutrophil gelatinase-associated lipocalin), KIM-1 (kidney injury molecule 1) and IL-18 (interleukin-18) are associated with abnormal MRI findings in neonates with hypoxic-ischemic encephalopathy (HIE) who underwent therapeutic hypothermia (TH). STUDY DESIGN: Secondary analysis of a multicenter, prospective study of neonates with HIE requiring TH. Urine biomarkers were obtained at 12 and 24 h of life (HOL). Brain MRI was scored per NICHD criteria. Association between biomarkers and MRI stage was determined. RESULTS: In 57 neonates with HIE, only IL-18 at 24 HOL was significantly increased in neonates with MRI Stage 2B or greater, compared to Stage 2A or less (mean 398.7 vs. 182.9 pg/mL, p = 0.024.) A multivariate model including IL-18 at 24 HOL and 5-min Apgar performed best, with an AUC of 0.84 (SE = 0.07, p = 0.02). CONCLUSIONS: Elevated urine IL-18 at 24 HOL was associated with more severe brain MRI abnormalities among neonates with HIE.

Interleukin-18 and Gelsolin Are Associated with Acute Kidney Disease after Cardiac Catheterization.

Patients undergoing cardiac catheterization are at high risk of post-procedure acute kidney injury (AKI) and may experience persistent renal damage after an initial insult, a state known as acute kidney disease (AKD). However, the association between AKD and urinary renal biomarkers has not yet been evaluated in this population. We enrolled 94 patients who underwent elective cardiac catheterization to investigate patterns of urinary renal biomarkers and their associations with post-procedure AKD. Serial urinary renal biomarker levels were measured during pre-procedure, early post-procedure (12-24 h), and late post-procedure (7-10 days) periods. In our investigation, 42.55% of the enrolled patients developed AKD during the late post-procedure period. While the liver-type free-fatty-acid-binding protein level increased sharply during the early post-procedure period, it returned to baseline during the late post-procedure period. In contrast, interleukin-18 (IL-18) levels increased steadily during the post-procedure period. Early post-procedure ratios of IL-18 and gelsolin (GSN) were independently associated with subsequent AKD (odds ratio (95% confidence interval), 4.742 (1.523-14.759) for IL-18 ratio, p = 0.007; 1.812 (1.027-3.198) for GSN ratio, p = 0.040). In conclusion, post-procedure AKD is common and associated with early changes in urinary IL-18 and GSN in patients undergoing cardiac catheterization.

Comparative diagnostic utility of different urinary biomarkers during pre-albuminuric stages of non-hypertensive type 2 diabetic nephropathy.

Background & objectives: Activation of renin-angiotensin system and tubulointerstitial damage might be seen in pre-albuminuria stage of diabetic nephropathy (DN). Here, diagnostic utility of four urinary biomarkers [Angiotensinogen (Angio), Interleukin (IL)-18, Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Cystatin] during pre-albuminuria stages of non-hypertensive type 2 diabetes patients was studied. Methods: A total of 952 type 2 diabetes mellitus (T2DM) patients were screened for nephropathy [estimated glomerular filtration rate (eGFR) ≥120 ml/min and albumin-creatinine ratio (ACR) ≥30], and 120 patients were followed up for one year. At one year, they were classified into hyperfiltration (43), normoalbuminuria (29) and microalbuminuria (48) groups. Another 63 T2DM patients without nephropathy were included as controls. Hypertension, patients on angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, eGFR <60 ml/min/1.73 m2 and all proteinuric conditions were excluded. All were subjected to testing for urine protein, ACR, HbA1C, eGFR, along with urinary biomarkers (IL-18, cystatin-C, NGAL and AGT). Comparative analysis of all the diagnostic tests among different subgroups, correlation and logistic regression was done. Results: Urinary IL-18/Cr, cystatin/creatinine (Cr) and AGT/Cr levels were higher in groups of hyperfiltration (13.47, 12.11 and 8.43 mg/g), normoalbuminuria (9.24, 11.74 and 9.15 mg/g) and microalbuminuria (11.59, 14.48 and 10.24 mg/g) than controls (7.38, 8.39 and 1.26 mg/g), but NGAL/Cr was comparable. The area under receiver operating characteristic curve (AUC) and sensitivity of AGT to detect early CKD were higher than ACR and eGFR (0.91 and 90.4%, 0.6 and 40% and 0.6 and 37%, respectively). AUC values of other biomarkers, namely IL-18/Cr, cystatin/Cr and NGAL/Cr, were 0.65, 0.64 and 0.51, respectively. Angio/Cr and IL-18/Cr showed correlation with log albuminuria (r=0.3, P=0.00, and r=0.28, P=0.00, respectively). NGAL showed correlation with log eGFR (r=0.28 P=0.00). Multivariate logistic analysis showed that odds ratio of developing nephropathy was 7.5 times with higher values of log Angio/Cr. Interpretation & conclusions: Urinary AGT showed a higher diagnostic value than ACR and eGFR followed by IL-18 and cystatin to diagnose DN during pre-albuminuric stages.

Urine Biomarkers for the Assessment of Acute Kidney Injury in Neonates with Hypoxic Ischemic Encephalopathy Receiving Therapeutic Hypothermia.

OBJECTIVE: To evaluate the predictive performance of urine biomarkers for acute kidney injury (AKI) in neonates with hypoxic ischemic encephalopathy (HIE) receiving therapeutic hypothermia. STUDY DESIGN: We performed a multicenter prospective observational study of 64 neonates. Urine specimens were obtained at 12, 24, 48, and 72 hours of life and evaluated for neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), cystatin C, interleukin-18 (IL-18), tissue inhibitor of metalloproteinases 2 (TIMP2), and insulin-like growth factor-binding protein 7 (IGFBP7). Logistic regression models with receiver operating characteristics for area under the curve (AUC) were used to assess associations with neonatal modified KDIGO (Kidney Disease: Improving Global Outcomes) AKI criteria. RESULTS: AKI occurred in 16 of 64 infants (25%). Neonates with AKI had more days of vasopressor drug use compared with those without AKI (median [IQR], 2 [0-5] days vs 0 [0-2] days; P = .026). Mortality was greater in neonates with AKI (25% vs 2%; P = .012). Although NGAL, KIM-1, and IL-18 were significantly associated with AKI, the AUCs yielded only a fair prediction. KIM-1 had the best predictive performance across time points, with an AUC (SE) of 0.79 (0.11) at 48 hours of life. NGAL and IL-18 had AUCs (SE) of 0.78 (0.09) and 0.73 (0.10), respectively, at 48 hours of life. CONCLUSIONS: Urine NGAL, KIM-1, and IL-18 levels were elevated in neonates with HIE receiving therapeutic hypothermia who developed AKI. However, wide variability and unclear cutoff levels make their clinical utility unclear.

Nicorandil Decreases Renal Injury in Patients With Coronary Heart Disease Complicated With Type I Cardiorenal Syndrome.

ABSTRACT: Cardiorenal syndrome (CRS) is a group of disorders in which heart or kidney dysfunction worsens each other. This study aimed to explore the improvement effect of nicorandil on cardiorenal injury in patients with type I CRS. Patients with coronary heart disease complicated with type I CRS were enrolled. Based on the conventional treatment, the patients were prospectively randomized into a conventional treatment group and a nicorandil group, which was treated with 24 mg/d nicorandil intravenously for 1 week. Fasting peripheral venous blood serum and urine were collected before and at the end of treatment. An automatic biochemical analyzer and enzyme linked immunosorbent assay were used to detect B-type brain natriuretic peptide (BNP), serum creatinine (Scr) and cystatin C (Cys-C), renal injury index-kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and interleukin-18 (IL-18) levels. The left ventricular ejection fraction was measured by echocardiography. All measurements were not significantly different between the nicorandil and conventional treatment groups before treatment (all P > 0.05), and BNP, Scr, Cys-C, NGAL, KIM-1, and IL-18 were decreased in the 2 groups at the end of treatment (all P < 0.05). Compared with the conventional treatment group, BNP, Scr, Cys-C, NGAL, KIM-1, and IL-18 were more significantly decreased in the nicorandil group (all P < 0.05) and left ventricular ejection fraction was more significantly increased (P < 0.05). Therefore, nicorandil could significantly improve the cardiac and renal function of patients with type I CRS. This may prove to be a new therapeutic tool for improving the prognosis and rehabilitation of type I CRS.

Using urinary Interleukin-18 as a potential marker for early detection of acute kidney injury in intensive care unit.

Acute kidney injury (AKI) is a potentially life-threatening condition. The injury involves the generation of inflammatory mediators which contribute to the recruitment of leukocytes to the site of inflammation. As those inflammatory mediators are secreted directly into the urine, their detection in urine could serve as potential biomarkers for the diagnosis of early kidney injury. This is a prospective cross-sectional descriptive study. Urinary samples were collected from 170 subjects who were admitted to intensive care unit (ICU) at Alkafeel Super Speciality Hospital from September 2017 to June 2018. They were tested for urinary interleukin-18 (IL-18). Among 98 patients, 20 were excluded depending on exclusion criteria. Seventy-two cases in the control group were included. The urine samples were collected at 24, 48, and 72 h after admission to ICU. AKI was diagnosed according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria. The incidence rate of AKI among 78 patients who were admitted to ICU was 38.46%. Most of the patients with AKI belonged to stage 1 (80%) based on KDIGO guidelines2012. Urinary IL-18 levels were significantly higher (P <0.0001) in the AKI group in comparison with the non-AKI group. The result of receiver operating characteristic analysis showed that the higher area under the curve for urinary IL-18 was 0.946 measured at 24 h before development of AKI (P <0.000), with 87.5% sensitivity and 94.4% specificity. In addition, there was no significant difference of urinary IL-18 levels between the different causes of AKI. The results of the study indicate that urinary IL-18 has an excellent performance in predicting AKI in ICU patients.

Augmented transcripts of kidney injury markers and renin angiotensin system in urine samples of overweight young adults.

Obesity has been firmly established as a major risk factor for common disease states including hypertension, type 2 diabetes mellitus, and chronic kidney disease. Increased body mass index (BMI) contributes to the activation of both the systemic and intra-tubular renin angiotensin systems (RAS), which are in turn associated with increased blood pressure (BP) and kidney damage. In this cross-sectional study, 43 subjects of normal or increased body weight were examined in order to determine the correlation of BMI or body fat mass (BFM) with blood pressure, fasting blood glucose (FBG), and urinary kidney injury markers such as interleukin-18 (IL-18), connective tissue growth factor (CTGF), neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 (KIM-1). Our results showed that: (1) subjects with increased body weight showed significantly higher BP, BFM, total body water and metabolic age; (2) BMI was positively correlated to both systolic (R2 = 0.1384, P = 0.01) and diastolic BP (R2 = 0.2437, P = 0.0008); (3) BFM was positively correlated to DBP (R2 = 0.1232, P = 0.02) and partially correlated to urine protein (R2 = 0.047, P = 0.12) and FBG (R2 = 0.07, P = 0.06); (4) overweight young adults had higher urinary mRNA levels of renin, angiotensinogen, IL-18 and CTGF. These suggest that BMI directly affects BP, kidney injury markers, and the activation of the intra-tubular RAS even in normotensive young adults. Given that BMI measurements and urine analyses are non-invasive, our findings may pave the way to developing a new and simple method of screening for the risk of chronic kidney disease in adults.

Acute kidney disease and acute kidney injury biomarkers in coronary care unit patients.

BACKGROUND: Acute kidney disease (AKD) describes acute or subacute damage and/or loss of kidney function for a duration of between 7 and 90 days after exposure to an acute kidney injury (AKI) initiating event. This study investigated the predictive ability of AKI biomarkers in predicting AKD in coronary care unit (CCU) patients. METHODS: A total of 269 (mean age: 64 years; 202 (75%) men and 67 (25%) women) patients admitted to the CCU of a tertiary care teaching hospital from November 2009 to September 2014 were enrolled. Information considered necessary to evaluate 31 demographic, clinical and laboratory variables (including AKI biomarkers) was prospectively recorded on the first day of CCU admission for post hoc analysis as predictors of AKD. Blood and urinary samples of the enrolled patients were tested for neutrophil gelatinase-associated lipocalin (NGAL), cystatin C (CysC) and interleukin-18 (IL-18). RESULTS: The overall hospital mortality rate was 4.8%. Of the 269 patients, 128 (47.6%) had AKD. Multivariate logistic regression analysis revealed that age, hemoglobin, ejection fraction and serum IL-18 were independent predictors of AKD. Cumulative survival rates at 5 years of follow-up after hospital discharge differed significantly (p < 0.001) between subgroups of patients diagnosed with AKD (stage 0A, 0C, 1, 2 and 3). The overall 5-year survival rate was 81.8% (220/269). Multivariate Cox proportional hazard analysis revealed that urine NGAL, body weight and hemoglobin level were independent risk factors for 5-year mortality. CONCLUSIONS: This investigation confirmed that AKI biomarkers can predict AKD in CCU patients. Age, hemoglobin, ejection fraction and serum IL-18 were independently associated with developing AKD in the CCU patients, and urine NGAL, body weight and hemoglobin level could predict 5-year survival in these patients.

Biomarkers of Contrast-Induced Nephropathy:: Which Ones are Clinically Important?

Contrast-induced acute kidney injury (CI-AKI) is a common complication after intravascular injection of iodinated contrast media, and it is associated with a prolonged in-hospital stay and unfavorable outcome. CI-AKI occurs in 5% to 20% among hospitalized patients. Its diagnosis relies on the increase in serum creatinine levels, which is a late biomarker of kidney injury. Novel and early serum and urinary biomarkers have been identified to detect kidney damage before the expected serum creatinine increase.

Longitudinal kidney injury biomarker trajectories in children with obstructive uropathy.

BACKGROUND: Congenital obstructive uropathy (OU) is a leading cause of pediatric kidney failure, representing a unique mechanism of injury, in part from renal tubular stretch and ischemia. Tubular injury biomarkers have potential to improve OU-specific risk stratification. METHODS: Patients with OU were identified in the Chronic Kidney Disease in Children (CKiD) study. "Cases" were defined as individuals receiving any kidney replacement therapy (KRT), while "controls" were age- and time-on-study matched and KRT free at last study visit. Urine and plasma neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18), and liver-type fatty acid-binding protein (L-FABP) levels were measured at enrollment and annually and compared between cases and controls. Urine values were normalized to urine creatinine. RESULTS: In total, 22 cases and 22 controls were identified, with median (interquartile range) ages of 10.5 (9.0-13.0) and 15.9 (13.9-16.9) years at baseline and outcome, respectively. At enrollment there were no differences noted between cases and controls for any urine (u) or plasma (p) biomarker measured. However, the mean pNGAL and uL-FABP/creatinine increased throughout the study period in cases (15.38 ng/ml per year and 0.20 ng/ml per mg/dl per year, respectively, p = 0.01 for both) but remained stable in controls. This remained constant after controlling for baseline glomerular filtration rate (GFR). CONCLUSIONS: In children with OU, pNGAL and uL-FABP levels increased over the 5 years preceding KRT; independent of baseline GFR. Future studies are necessary to identify optimal cutoff values and to determine if these markers outperform current clinical predictors.

Urine Markers of Kidney Tubule Cell Injury and Kidney Function Decline in SPRINT Trial Participants with CKD.

BACKGROUND AND OBJECTIVES: eGFR and albuminuria primarily reflect glomerular function and injury, whereas tubule cell atrophy and interstitial fibrosis on kidney biopsy are important risk markers for CKD progression. Kidney tubule injury markers have primarily been studied in hospitalized AKI. Here, we examined the association between urinary kidney tubule injury markers at baseline with subsequent loss of kidney function in persons with nondiabetic CKD who participated in the Systolic Blood Pressure Intervention Trial (SPRINT). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 2428 SPRINT participants with CKD (eGFR<60 ml/min per 1.73 m2) at baseline, we measured urine markers of tubule injury (IL-18, kidney injury molecule-1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL]), inflammation (monocyte chemoattractant protein-1 [MCP-1]), and repair (human cartilage glycoprotein-40 [YKL-40]). Cox proportional hazards models evaluated associations of these markers with the kidney composite outcome of 50% eGFR decline or ESKD requiring dialysis or kidney transplantation, and linear mixed models evaluated annualized change in eGFR. RESULTS: Mean participant age was 73±9 (SD) years, 60% were men, 66% were white, and mean baseline eGFR was 46±11 ml/min per 1.73 m2. There were 87 kidney composite outcome events during a median follow-up of 3.8 years. Relative to the respective lowest quartiles, the highest quartiles of urinary KIM-1 (hazard ratio, 2.84; 95% confidence interval [95% CI], 1.31 to 6.17), MCP-1 (hazard ratio, 2.43; 95% CI, 1.13 to 5.23), and YKL-40 (hazard ratio, 1.95; 95% CI, 1.08 to 3.51) were associated with higher risk of the kidney composite outcome in fully adjusted models including baseline eGFR and urine albumin. In linear analysis, urinary IL-18 was the only marker associated with eGFR decline (-0.91 ml/min per 1.73 m2 per year for highest versus lowest quartile; 95% CI, -1.44 to -0.38), a finding that was stronger in the standard arm of SPRINT. CONCLUSIONS: Urine markers of tubule cell injury provide information about risk of subsequent loss of kidney function, beyond the eGFR and urine albumin.

Interleukins and miRNAs intervene in the early stages of diabetic kidney disease in Type 2 diabetes mellitus patients.

Aim: The involvement of proinflammatory interleukins (IL) in diabetic kidney disease of Type 2 diabetes mellitus (DM) patients was studied in relation to a particular miRNA profile. Materials & methods: A total of 117 patients with Type 2 DM and 11 controls were enrolled in a case series study. Serum and urinary ILs and miRNAs were assessed. Results: IL-1α correlated with miRNA21, 124, estimated glomerular filtration rate (eGFR) and negatively with miRNA125a and 192; IL-8 with miRNA21, 124, eGFR and negatively with miRNA125a, 126 and 146a; IL-18 with miRNA21, 124 and negatively with miRNA146a, 192, eGFR. Conclusion: There is an association between specific serum and urinary ILs and serum and urinary miRNAs profiles in the inflammatory response in Type 2 DM patients with diabetic kidney disease.

Angiotensinogen and interleukin 18 in serum and urine of children with kidney cysts.

BACKGROUND: The most common disease associated with the presence of kidney cysts in the population is autosomal dominant polycystic kidney disease (ADPKD), which finally leads to end-stage renal disease. METHOD: The study evaluated serum and urinary concentration of angiotensinogen (AGT) and interleukin 18 (IL-18) in a group of 39 children with renal cysts of different aetiology. RESULTS: Serum and urinary AGT concentration in children with renal cysts was higher compared to controls, regardless of the underlying background and gender. Serum IL-18 concentration was lower, in contrast, and the concentration of IL-18 in the urine did not differ between affected and healthy children. Negative correlation between urinary IL-18 concentration and systolic and mean arterial blood pressure was noted. CONCLUSIONS: Higher AGT levels in serum and urine in children with renal cysts may indicate the activation of the renin-angiotensin-aldosterone system, including its intrarenal part, even before the onset of hypertension. Lower serum concentration of IL-18 in children with kidney cysts may indicate the loss of the protective role of this cytokine with the occurrence of hypertension.

The cleavage of gasdermin D by caspase-11 promotes tubular epithelial cell pyroptosis and urinary IL-18 excretion in acute kidney injury.

Inflammation and tubular cell death are the hallmarks of acute kidney injury. However, the precise mechanism underlying these effects has not been fully elucidated. Here we tested whether caspase-11, an inflammatory member of the caspase family, was increased in cisplatin or ischemia-reperfusion-induced acute kidney injury. Caspase-11 knockout mice after cisplatin treatment exhibited attenuated deterioration of renal functional, reduced tubular damage, reduced macrophage and neutrophil infiltration, and decreased urinary IL-18 excretion. Mechanistically, the upregulation of caspase-11 by either cisplatin or ischemia-reperfusion cleaved gasdermin D (GSDMD) into GSDMD-N, which translocated onto the plasma membrane, thus triggering cell pyroptosis and facilitated IL-18 release in primary cultured renal tubular cells. These results were further confirmed in GSDMD knockout mice that cisplatin-induced renal morphological and functional deterioration as well as urinary IL-18 excretion were alleviated. Furthermore, deficiency of GSDMD significantly suppressed cisplatin-induced IL-18 release but not the transcription and maturation level of IL-18 in tubular cells. Thus, our study indicates that caspase-11/GSDMD dependent tubule cell pyroptosis plays a significant role in initiating tubular cell damage, urinary IL-18 excretion and renal functional deterioration in acute kidney injury.

Early Diagnosis and Prognostic Value of Acute Kidney Injury in Critically Ill Patients.

Background and objectives: In hospitalized children, acute kidney injury (AKI) remains to be a frequent and serious condition, associated with increased patient mortality and morbidity. Identifying early biomarkers of AKI and patient groups at the risk of developing AKI is of crucial importance in current clinical practice. Specific human protein urinary neutrophil gelatinase-associated lipocalin (uNGAL) and interleukin 18 (uIL-18) levels have been reported to peak specifically at the early stages of AKI before a rise in serum creatinine (sCr). Therefore, the aim of our study was to determine changes in uNGAL and uIL-18 levels among critically ill children and to identify the patient groups at the highest risk of developing AKI. Materials and methods: This single-center prospective observational study included 107 critically ill children aged from 1 month to 18 years, who were treated in the Pediatric Intensive Care Unit (PICU) of Lithuanian University of Health Sciences Hospital Kauno Klinikos from 1 December 2013, to 30 November 2016. The patients were divided into two groups: those who did not develop AKI (Group 1) and those who developed AKI (Group 2). Results: A total of 68 (63.6%) boys and 39 (36.4%) girls were enrolled in the study. The mean age of the patients was 101.30 ± 75.90 months. The mean length of stay in PICU and hospital was 7.91 ± 11.07 and 31.29 ± 39.09 days, respectively. A total of 32 (29.9%) children developed AKI. Of them, 29 (90.6%) cases of AKI were documented within the first three days from admission to hospital. In all cases, AKI was caused by diseases of non-renal origin. There was a significant association between the uNGAL level and AKI between Groups 1 and 2 both on day 1 (p = 0.04) and day 3 (p = 0.018). Differences in uNGAL normalized to creatinine in the urine (uCr) (uNGAL/uCr) between the groups on days 1 and 3 were also statistically significant (p = 0.007 and p = 0.015, respectively). uNGAL was found to be a good prognostic marker. No significant associations between uIL-18 or Uil-18/uCr and development of AKI were found. However, the uIL-18 level of >69.24 pg/mL during the first 24 hours was associated with an eightfold greater risk of AKI progression (OR = 8.33, 95% CI = 1.39-49.87, p = 0.023). The AUC for uIL-18 was 73.4% with a sensitivity of 62.59% and a specificity of 83.3%. Age of <20 months, Pediatric Index of Mortality 2 (PIM2) score of >2.5% on admission to the PICU, multiple organ dysfunction syndrome with dysfunction of three and more organ systems, PICU length of stay more than three days, and length of mechanical ventilation of >five days were associated with a greater risk of developing AKI. Conclusions: Significant risk factors for AKI were age of <20 months, PIM2 score of >2.5% on admission to the PICU, multiple organ dysfunction syndrome with dysfunction of 3 and more organ systems, PICU length of stay of more than three days, and length of mechanical ventilation of > five days. uNGAL was identified as a good prognostic marker of AKI. On admission to PICU, uNGAL should be measured within the first three days in patients at the risk of developing AKI. The uIL-18 level on the first day was found to be as a biomarker predicting the progression of AKI.

The SPRINT trial suggests that markers of tubule cell function in the urine associate with risk of subsequent acute kidney injury while injury markers elevate after the injury.

Urine markers can quantify tubular function including reabsorption (α-1 microglobulin [α1m]) and ß-2-microglobulin [ß2m]) and protein synthesis (uromodulin). Individuals with tubular dysfunction may be less able to compensate to insults than those without, despite similar estimated glomerular filtration rate (eGFR) and albuminuria. Among Systolic Blood Pressure Intervention Trial (SPRINT) participants with an eGFR under 60 ml/min/1.73m2, we measured urine markers of tubular function and injury (neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule-1 [KIM-1], interleukin-18 [IL-18], monocyte chemoattractant protein-1, and chitinase-3-like protein [YKL-40]) at baseline. Cox models evaluated associations with subsequent acute kidney injury (AKI) risk, adjusting for clinical risk factors, baseline eGFR and albuminuria, and the tubular function and injury markers. In a random subset, we remeasured biomarkers after four years, and compared changes in biomarkers in those with and without intervening AKI. Among 2351 participants, 184 experienced AKI during 3.8 years mean follow-up. Lower uromodulin (hazard ratio per two-fold higher (0.68, 95% confidence interval [0.56, 0.83]) and higher α1m (1.20; [1.01, 1.44]) were associated with subsequent AKI, independent of eGFR and albuminuria. None of the five injury markers were associated with eventual AKI. In the random subset of 947 patients with repeated measurements, the 59 patients with intervening AKI versus without had longitudinal increases in urine NGAL, IL-19, and YKL-40 and only 1 marker of tubule function (α1m). Thus, joint evaluation of tubule function and injury provided novel insights to factors predisposing to AKI, and responses to kidney injury.

IL-18, VCAM-1 and P-selectin as early biomarkers in normoalbuminuric Type 2 diabetes patients.

Aim: To investigate the pathophysiological role of different biomarkers in diabetic kidney disease (DKD) among normoalbuminuric patients with a low-estimated glomerular filtration rate (eGFR). Methods: In this cross-sectional study of 200 normoalbuminuric Type 2 diabetes patients, 28 patients (14%) had a low eGFR. Results: The IL-18, VCAM-1 and P-selectin levels were significantly higher at a low eGFR. On analyzing the area under the receiver operating characteristic curve, these biomarkers had significant diagnostic value and have important pathophysiological role in the progression of DKD. Conclusion: Among normoalbuminuric Type 2 diabetes patients, IL-18, VCAM-1 and P-selectin may play a significant role in the prediction of early DKD. Further prospective studies need to be conducted to confirm this observation.

Urinary and Serum Biomarkers for Prediction of Acute Kidney Injury in Patients Undergoing Liver Transplantation.

Acute kidney injury (AKI) is a frequent and serious complication of orthotopic liver transplantation (OLT), with a significant impact on mortality, graft survival, and chronic kidney disease. Currently, the diagnosis of AKI is based on changes in serum creatinine, which is a late marker, usually rising when there is already significant damage to the renal parenchyma. During the last 2 decades, various biomarkers have been studied in many clinical situations, mostly after cardiac surgery, in drug-induced AKI, or in sepsis. The present article summarizes the data on those biomarkers that have been evaluated for the prediction of AKI in patients undergoing OLT.

Biomarkers of Drug-Induced Kidney Toxicity.

Blood urea nitrogen and serum creatinine are imperfect markers of kidney function because they are influenced by many renal and nonrenal factors independent of kidney function. A biomarker that is released directly into the blood or urine by the kidney in response to injury may be a better early marker of drug-induced kidney toxicity than blood urea nitrogen and serum creatinine. Urine albumin and urine protein, as well as urinary markers kidney injury molecule-1 (KIM-1), ß2-microglobulin (B2M), cystatin C, clusterin, and trefoil factor-3 (TFF-3) have been accepted by the Food and Drug Administration and European Medicines Agency as highly sensitive and specific urinary biomarkers to monitor drug-induced kidney injury in preclinical studies and on a case-by-case basis in clinical trials. Other biomarkers of drug-induced kidney toxicity that have been detected in the urine of rodents or patients include IL-18, neutrophil gelatinase-associated lipocalin, netrin-1, liver-type fatty acid-binding protein (L-FABP), urinary exosomes, and TIMP2 (insulin-like growth factor-binding protein 7)/IGFBP7 (insulin-like growth factor-binding protein 7), also known as NephroCheck, the first Food and Drug Administration-approved biomarker testing platform to detect acute kidney injury in patients. In the future, a combined use of functional and damage markers may advance the field of biomarkers of drug-induced kidney toxicity. Earlier detection of drug-induced kidney toxicity with a kidney-specific biomarker may result in the avoidance of nephrotoxic agents in clinical studies and may allow for earlier intervention to repair damaged kidneys.

Assessing urinary levels of IL-18, NGAL and albumin creatinine ratio in patients with diabetic nephropathy.

AIMS: Diabetic nephropathy (DN) is a serious microvascular complication of a longstanding hyperglycemia. This study aims to evaluate whether urinary neutrophil gelatinase-associated lipocalin (NGAL) and urinary Interleukin-18 possess a better diagnostic value than albumin creatinine ratio in assessing the severity of nephropathy in patients with type 2 diabetes mellitus (T2DM). MATERIAL & METHODS: Ninety participants diagnosed with T2DM were recruited and they were divided into three study groups according to their albumin/creatinine ratio (ACR): (Normoalbuminuria group, Microalbuminuria group, and Macroalbuminuria group). A matching of Ninety healthy subjects were included as controls. Blood and urine samples were collected to measure various markers of glycemic control and kidney function. RESULTS: IL-18 levels were not changed significantly between all study groups (P > 0.05), despite a significant positive correlation between IL-18 and urinary albumin levels. NGAL levels were significantly increased in Microalbuminuria group and Macroalbuminuria group as compared to the control and Normoalbuminuria groups. NGAL was also positively correlated with urinary albumin and ACR, but negatively correlated with the age and body mass index. Receiver Operating Characteristic curves revealed that for early detection of DN, the best cutoff values to discriminate DN and diabetic without nephropathy groups were ˃ 21.4 ng/ml for NGAL (94.67 sensitivity, 26.67% specificity), ≤0.34 pg/mL for IL-18 (72% sensitivity, 53.33% specificity), and ˃29.8 mg/g for ACR (80% sensitivity, 100% specificity). CONCLUSION: We conclude that the urinary ACR is a more accurate individual biomarker of DN when compared to both NGAL and IL-18.