Perioperative Acute Renal Injury: Revisiting Pathophysiology.

BACKGROUND: Acute renal dysfunction and subsequent acute renal failure after cardiac surgery are associated with high mortality and morbidity. Early therapeutic or preventive intervention is hampered by the lack of an early biomarker for acute renal injury. Recent studies showed that urinary neutrophil gelatinase-associated lipocalin (NGAL or lipocalin 2) is upregulated early (within 1 to 3 h) after murine renal injury and in pediatric acute renal dysfunction after cardiac surgery. The authors hypothesized that postoperative urinary NGAL concentrations are increased in adult patients developing acute renal dysfunction after cardiac surgery compared with patients without acute renal dysfunction. METHODS: After institutional review board approval, 81 cardiac surgical patients were prospectively studied. Urine samples were collected immediately before incision and at various time intervals after surgery for NGAL analysis by quantitative immunoblotting. Acute renal dysfunction was defined as peak postoperative serum creatinine increase by 50% or greater compared with preoperative serum creatinine. RESULTS: Sixteen of 81 patients (20%) developed postoperative acute renal dysfunction, and the mean urinary NGAL concentrations in patients who developed acute renal dysfunction were significantly higher early after surgery (after 1 h, mean ± SD, 4,195 ± 6,520 vs. 1,068 ± 2,129 ng/ml; P < 0.01) compared with patients who did not develop acute renal dysfunction. Mean urinary NGAL concentrations continued to increase and remained significantly higher at 3 and 18 h after cardiac surgery in patients with acute renal dysfunction. In contrast, urinary NGAL in patients without acute renal dysfunction decreased rapidly after cardiac surgery. CONCLUSIONS: Patients developing postoperative acute renal dysfunction had significantly higher urinary NGAL concentrations early after cardiac surgery. Urinary NGAL may therefore be a useful early biomarker of acute renal dysfunction after cardiac surgery. These findings may facilitate the early detection of acute renal injury and potentially prevent progression to acute renal failure.

Novel Finding of Urinary Erythropoietin as an Early Biomarker of Cisplatin-Induced Nephrotoxicity.

Cisplatin is a chemotherapeutic drug used to treat a great variety of solid tumors. Its dose is commonly limited by its nephrotoxicity, manifested as acute kidney injury (AKI). Erythropoietin (Epo) is a glycoprotein hormone that regulates the production of red blood cells. This study was performed to evaluate the presence of endogenous Epo in male Wistar rat urine and to analyse changes in urinary Epo levels in response to cisplatin- induced AKI. Dose-dependent studies and time-dependent experiments were performed to evaluate changes in urea nitrogen and creatinine in plasma as well as Epo, neutrophil gelatinase-associated lipocalin (NGAL), alkaline phosphatase (AP) activity, creatinine and total proteins in urine at 2 days post-dosing. Rats received 2, 5 or 10 mg/kg b.w., i.p. of cisplatin. At 5 mg/kg b.w., i.p. cisplatin, significant increases in urinary Epo were detected. Significant increases in urea nitrogen and creatinine in plasma, NGAL, AP, proteins, and Epo were observed in urine from rats that received 10 mg/kg b.w., i.p. of cisplatin. In the time-dependent experiments, rats were injected with a dose of 5 mg/kg b.w., i.p. of cisplatin, and sampling occurred 2, 4, and 14 days post-dosing. In these animals, there were significant increases in urea nitrogen and creatinine in plasma and total proteins, AP activity, Epo, and NGAL in urine on day 4. Urinary Epo was also detected on day 2. Taken together, these findings provide weight of evidence for urinary Epo as a promising early biomarker of cisplatin-induced AKI in male rats.

Preoperative and postoperative urinary NGAL levels in children with bladder exstrophy.

BACKGROUND: Urinary NGAL (neutrophil gelatinase-associated lipocalin) levels have been shown to predict renal damage in various medical conditions. The present study was conducted to study the role of urinary NGAL levels in children with bladder exstrophy-epispadias complex post single-stage total reconstruction (SSTR) as markers of early renal function reduction. METHODS: Urine samples were collected from children with bladder exstrophy before SSTR (Group A, n = 11), 5 years post SSTR (Group B, n = 40) and controls (Group C, n = 41) and stored at - 20 °C. NGAL levels were estimated using double antibody sandwich ELISA. RESULTS: Mean NGAL levels in Groups A, B and C were 1.39, 34.24 and 2.58 ng/ml, respectively. Mean NGAL levels among Group B subjects with glomerular filtration rate (GFR) ≥ 80 ml/min/1.73 m2 body surface area (BSA) was 29.8 ng/ml, while it was 31.74 ng/ml in those with GFR < 80 ml/min. Urine samples were also evaluated 6 months post SSTR. Mean NGAL at 6 months was 6.76 ng/ml, while at 12 months it was 30.3 ng/ml, remaining > 30 ng/ml at 18 and 24 months. Dimercaptosuccinic acid (DMSA) scans did not show any scarring, and GFR on diethylenetriamine pentaacetate (DTPA) scans remained stable. CONCLUSIONS: Increasing levels of urinary NGAL following bladder-exstrophy and epispadias complex repair suggest that NGAL detects the earliest signs of renal damage even before any deterioration is observed in DMSA and/or DTPA-GFR scans. Further studies with an adequate sample size and periodic measurement of NGAL need to be performed before any definitive conclusion can be drawn.

Urinary neutrophil gelatinase-associated lipocalin predicted to contrast-associated acute kidney injury after planned percutaneous coronary intervention in elderly patients.

AIM: To determine the proportion of contrast-associated acute kidney injury (CA-AKI) after percutaneous coronary intervention (PCI) and the predictive value of urine neutrophil gelatinase-associated lipocalin (uNGAL) for CA-AKI in elderly patients with chronic coronary artery disease. METHODS: A total of 509 patients who had planned percutaneous coronary intervention (mean age was 63.58 ± 11.63 years and 63.3% of males) were divided into two groups: group 1 (n = 153; elderly patients) with ≥70 years old and group 2 (n = 356) with <70 years old. Urine NGAL was measured by the ELISA method. Clinical and laboratory data were collected on the day before intervention. CA-AKI was defined based on Kidney Disease: Improving Global Outcomes criteria. RESULTS: The ratio of CA-AKI in group 1 was 23.5% which was higher than that of group 2 (8.7%) with a p-value < 0.001. Urine NGAL level in group 1 was significantly higher than that of group 2 [31.3 (19.16-55.13) ng/ml vs. 19.86 (13.21-29.04) ng/ml, p < 0.001]. At a cut-off value of 44.43 ng/ml, uNGAL had a predictive value for CA-AKI in all patients (AUC = 0.977, p < 0.001). Especially at a cut-off value of 44.14 ng/ml, uNGAL had a predictive value for CA-AKI in elderly patients (AUC = 0.979, p < 0.001). CONCLUSIONS: The rate of CA-AKI after PCI in elderly patients was 23.5%. Urine NGAL before PCI had a good predictive value for CA-AKI in elderly patients with chronic coronary artery disease.

Neutrophil gelatinase-associated lipocalin is elevated in children with acute kidney injury and sickle cell anemia, and predicts mortality.

Urine neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury that has been adapted to a urine dipstick test. However, there is limited data on its use in low-and-middle-income countries where diagnosis of acute kidney injury remains a challenge. To study this, we prospectively enrolled 250 children with sickle cell anemia aged two to 18 years encompassing 185 children hospitalized with a vaso-occlusive pain crisis and a reference group of 65 children attending the sickle cell clinic for routine care follow up. Kidney injury was defined using serial creatinine measures and a modified-Kidney Disease Improving Global Outcome definition for sickle cell anemia. Urine NGAL was measured using the NGAL dipstick and a laboratory reference. The mean age of children enrolled was 8.9 years and 42.8% were female. Among hospitalized children, 36.2% had kidney injury and 3.2% died. Measured urine NGAL levels by the dipstick were strongly correlated with the standard enzyme-linked immunosorbent assay for urine NGAL (hospitalized children, 0.71; routine care reference, 0.88). NGAL levels were elevated in kidney injury and significantly increased across injury stages. Hospitalized children with a high-risk dipstick test (300ng/mL and more) had a 2.47-fold relative risk of kidney injury (95% confidence interval 1.68 to 3.61) and 7.28 increased risk of death (95% confidence interval 1.10 to 26.81) adjusting for age and sex. Thus, urine NGAL levels were found to be significantly elevated in children with sickle cell anemia and acute kidney injury and may predict mortality.

Comparative Evaluation of Two NGAL Automated Immunoassays in Urine and Plasma.

BACKGROUND: Acute kidney injury (AKI), a frequent and serious complication of hospitalized patients, is associated with increased mortality and morbidity. Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker for the early identification of AKI. We report a comparative laboratory verification of the Abbott Diagnostics (ARCHITECT® urine NGAL) and BioPorto Diagnostics (NGAL TestTM) assays including an assessment of the Abbott assay's performance in EDTA plasma. METHODS: Intra-/interbatch imprecision, linearity, recovery, and limit of quantitation (LoQ) were assessed and an interassay comparison performed (n = 51). Between-laboratory agreement was assessed against other laboratories using the Abbott (n = 48) and BioPorto (n = 94) assays. Plasma NGAL (pNGAL) levels were measured in non-AKI patients with a range of estimated glomerular filtration rates (n = 80). RESULTS: Coefficients of variation (CVs) for intra- and interbatch imprecision were 0.7%-12.4% and 1.9%-27.5% for the BioPorto assay, respectively, and 1.4%-6.3%/3.4%-6.8%, respectively, for the Abbott assay. The BioPorto assay exhibited a higher LoQ (27.5 ng/mL vs 1.2 ng/mL). Both assays were linear over the range 5-6000 ng/mL. Recovery of recombinant NGAL was 113.1 ± 7.1% and 96.5 ± 7.8% for the Abbott and BioPorto assays, respectively. On average, the Abbott assay gave results 9.2% lower than the BioPorto assay. Mean differences of 0.2% (Abbott) and 20.2% (BioPorto) were observed in the between-laboratory comparison. In patients without AKI, pNGAL levels were inversely proportional to eGFR. CONCLUSIONS: Performance of the Abbott and BioPorto assays was similar although the latter performed less well at lower NGAL concentrations. The Abbott assay tended to yield lower results, exhibited a lower LoQ and over-recovered NGAL. Although only Conformité Européenne-marked and marketed for use in urine, the Abbott assay demonstrated equivalent performance to the BioPorto assay with EDTA plasma.

Detection of subclinical nephrotoxicity induced by aminoglycosides in critically ill elderly patients using trough levels and urinary neutrophil gelatinase-associated lipocalin.

OBJECTIVES: Early detection of aminoglycoside-induced acute kidney injury (AKI) is crucial in intensive care unit (ICU) patients, but it is not adequately reflected by serum creatinine (SrCr) levels. This study proposed investigating the relationship between amikacin trough levels and the development of nephrotoxicity using both conventional markers and a new biomarker of renal function in critically ill elderly patients. METHODS: Thirty-three critically ill patients aged ≥65 years with normal SrCr who received once-daily amikacin were evaluated. Trough levels of amikacin, creatinine clearance (CrCL) and urinary neutrophil gelatinase-associated lipocalin (uNGAL) were measured during the 10-day study period. The patients were divided into three groups and were compared based on the trough levels on both day 3 and day 7: <3 µg/mL (low trough (LT)), 3-6 µg/mL (moderate trough (MT)) and >6 µg/mL (high trough (HT)). RESULTS: In the LT group, neither CrCL nor uNGAL levels significantly changed from baseline (p=0.364 and p=0.562, respectively). In the MT group, the CrCL level altered significantly over time from baseline (p=0.007), but the uNGAL level did not change significantly over the study period (p=0.916). In the HT group, both CrCL and uNGAL levels significantly changed from baseline during the study period (p=0.002 and p=0.046, respectively). CONCLUSIONS: In critically ill elderly patients with MT, the mean uNGAL level changed at least 4 days earlier than the SrCr level. Instead, the trough level of amikacin demonstrated a potential value for predicting subclinical AKI for implementing necessary interventions. Amikacin trough levels <3 µg/mL in the once-daily dosing regimen appeared safe, even in geriatric patients. Further studies are needed to confirm this finding.

A panel of urinary biochemical markers for the noninvasive detection of kidney dysfunction in HIV-infected patients.

INTRODUCTION: The use of antiretroviral therapy in HIV­infected patients can lead to disturbances in kidney function. Renal dysfunction can also be caused by the direct effects of HIV on the kidneys. The assessment of renal function is needed to monitor these patients for the development of chronic kidney disease. OBJECTIVES: The aim of this study was to identify urinary biochemical parameters for the assessment of kidney dysfunction in HIV­infected patients. PATIENTS AND METHODS: The study included 86 patients with HIV and 34 healthy controls. Spectrophotometry was used to measure the activity of the following enzymes: N­acetyl-ß­D­glucosaminidase (NAG), NAG isoenzyme B (NAG­B), galactosidase, ß­glucuronidase, alanyl aminopeptidase, and γ­glutamyltransferase. An enzyme­linked immunosorbent assay was used to assess the urinary concentrations of low­molecular­weight proteins: kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin, α­glutathione S­transferase, π­glutathione S­transferase, neopterin, ß2­microglobulin (ß2M), and retinol­binding protein (RBP). RESULTS: The urinary levels of all parameters except alanyl aminopeptidase were significantly higher in HIV­infected patients than in the control group. The statistical analysis revealed the following 4 parameters to have the best diagnostic value in: ß2M, NAG, KIM-1, and RBP. CONCLUSIONS: Our results indicate that among selected enzymes and low-molecular proteins, ß2M, NAG, KIM-1, and RBP are the best in assessing renal dysfunction in patients with HIV.

Evaluation of a Diagnostic Test of Serum Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Urine KIM-1 in Contrast-Induced Nephropathy (CIN).

BACKGROUND The aim of this study was to assess changes in serum neutrophil gelatinase-associated lipocalin (NGAL) and urine KIM-1 after percutaneous coronary intervention (PCI). MATERIAL AND METHODS A total of 240 patients receiving coronary stent implantation were selected. All patients were divided into 2 groups: a CIN group (n=25) and a non-CIN group (n=215). The serum creatinine (SCr), NGAL, and urine KIM-1 levels of the patients in both groups were measured before and after surgery, and the sensitivity of serum NGAL and urine KIM-1 in diagnosing CIN in the early stage was assessed by the area under receiver operating characteristic (ROC) curve (ROC-AUC). RESULTS In the CIN group, the serum NGAL and urine KIM-1 levels started to rise at 6 h after surgery. The serum NGAL and urine KIM-1 levels in CIN group were significantly higher than those in the non-CIN group at 6, 12, 24, and 48 h after surgery. However, the SCr levels in the CIN group were not higher than those in the non-CIN group at 6 h after surgery. At 6, 12, and 24 h after PCI, the AUCs for serum NGAL and urine KIM-1 were increased compared with that for SCr, while the AUCs for serum NGAL and urine KIM-1 were decreased at 48 h after PCI compared with that for SCr. CONCLUSIONS Serum NGAL and urine KIM-1 levels in the patients after coronary stent implantation can reflect the changes in renal functions early, thus providing a certain basis for the early diagnosis of CIN.

Urinary neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, uromodulin, and cystatin C concentrations in an experimental rat model of ascending acute kidney injury induced by pyelonephritis.

Recent evidence suggests that neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), cystatin C (CysC), uromodulin (UMOD), and some interleukins (IL-6 and IL-18) can be considered as diagnostic markers of acute kidney injury (AKI). The aim of this study was to verify the applicability of four urinary (u) markers, namely uNGAL, uKIM-1, uCysC, and uUMOD, for the diagnosis of ascending AKI induced by bacterial pyelonephritis. The study included 30 female rats that were divided into three groups (n = 10 each) and were inoculated transurethrally with various doses of Escherichia coli to induce isolated pyelonephritis (group 1, 105 CFU/ml), pyelonephritis-induced AKI (group 2, 107 CFU/ml), or AKI and urosepsis (group 3, 109 CFU/ml). The inoculate contained a highly virulent E. coli strain isolated from a patient with pyelonephritis. Urine samples were obtained prior to the inoculation and 7, 14, and 21 days thereafter. The concentrations of all assessed proteins were determined in the urine samples by ELISA. All the study groups showed elevated concentrations of uNGAL and uCysC at all study time points. The concentrations of uKIM-1 in group 1 were the same as that at the baseline, whereas it was elevated in groups 2 and 3 at all study time points. The concentrations of uUMOD in groups 1 and 2 tended to decrease with the time from inoculation, whereas it rapidly increased in group 3 at 21 days postinfection. uKIM-1 seems to be the only marker of ascending AKI associated with urinary tract infection. Elevated concentrations of uNGAL, uCysC, and uUMOD were found in both AKI and isolated pyelonephritis. Thus, it can be concluded that none of these markers can be used as a single diagnostic marker of ascending AKI, as it may produce false-negative results, leading to incorrect diagnosis, lack of adequate treatment, and increased mortality risk.

Iron excretion in urine in patients with acute kidney injury after cardiac surgery.

BACKGROUND: Hemolysis during cardiopulmonary bypass may lead to acute kidney injury caused by an excessive amount of iron. The clinical usefulness of the measurement of total iron concentration in the urine with the use of the atomic absorption spectrometry method for early identification of patients with postoperative acute kidney injury is not well-established. OBJECTIVES: An observational, prospective study was conducted on a group of 88 pre-selected adult patients undergoing a planned coronary artery bypass grafting (CABG) procedure. MATERIAL AND METHODS: The amount and concentrations of total iron, creatinine and neutrophil gelatinaseassociated lipocalin (NGAL) were evaluated in urine samples. A comparative analysis of the evaluated biochemical parameters was performed in regard to the occurrence of acute kidney injury 48 h postoperatively. RESULTS: Patients in the acute kidney injury group presented more advanced age (p = 0.01), preoperative myocardial infarction (p = 0.02), diuresis reduction (p = 0.04), and lower total iron levels in the 48-hour urine sample (p = 0.01). There was no difference when considering iron concentration in single urine samples in the study group. CONCLUSIONS: The sole result of total iron concentration in single urine samples is unreliable for the diagnosis of acute kidney injury after cardiac surgery. Decreased excretion of iron in the urine seems to be an important additional element in the multifactorial pathogenesis of acute postoperative kidney failure.

Effect of Repeated Injection of Iodixanol on Renal Function in Healthy Wistar Rats Using Functional MRI.

PURPOSE: To determine the optimal time interval of repeated intravenous injections of iodixanol in rat model and to identify the injury location and causes of renal damage in vivo. MATERIALS AND METHODS: Rats were randomly divided into Control group, Group 1 with one iodixanol injection, and Group 2 with two iodixanol injections. Group 2 was subdivided into 3 cohorts according to the interval between the first and second iodixanol injections as 1, 3, and 5 days, respectively. Blood oxygen level-dependent (BOLD) imaging and diffusion weighted imaging (DWI) were performed at 1 hour, 1 day, 3 days, 5 days, and 10 days after the application of solutions. RESULTS: Compared with Group 1 (7.2%), Group 2 produced a remarkable R2⁎ increment at the inner stripe of the renal outer medulla by 15.37% (P = 0.012), 14.83% (P = 0.046), and 13.53% (P > 0.05), respectively, at 1 hour after repeated injection of iodixanol. The severity of BOLD MRI to detect renal hypoxia was consistent with the expression of HIF-1α and R2⁎ was well correlated with HIF-1α expression (r = 0.704). The acute tubular injury was associated with urinary NGAL and increased significantly at 1 day. CONCLUSIONS: Repetitive injection of iodixanol within a short time window can induce acute kidney injury, the impact of which on renal damage in rats disappears gradually 3-5 days after the injections.

Early postoperative measurement of fibroblast growth factor 23 predicts severe acute kidney injury in infants after cardiac surgery
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AIMS: Acute kidney injury (AKI) occurs in 30 - 40% of children after cardiac surgery (CS) and is associated with poor prognosis. Fibroblast growth factor 23 (FGF23) is a bone-derived hormone with a pivotal role in phosphorus and vitamin D metabolism. We assessed FGF23 as an early marker for severe AKI (sAKI) in infants after CS. MATERIALS AND METHODS: Samples were previously collected in a multicenter observational study from children after CS. Serum FGF23 (n = 41) and urine AKI biomarker levels (n = 35) were assessed 4 - 8 hours after bypass. sAKI was defined as ≥ 100% rise in serum creatinine over baseline. Non-parametric and ROC analyses were used to evaluate the association between FGF23, urine AKI markers, and sAKI in the week after CS. RESULTS: Serum FGF23, urine NGAL, and urine KIM1 were higher in sAKI patients. The AUC-ROC for urine NGAL (0.74, [0.49 - 0.99]), urine KIM1 (0.79, [0.68 - 0.98]), and serum FGF23 (0.74, [0.5 - 0.9]) showed fair prediction of sAKI. CONCLUSION: Early measurement of FGF23 has predictive ability in infants who develop sAKI after CS with cardiopulmonary bypass.
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Salivary Neutrophil Gelatinase-Associated Lipocalin Sampling Feasibility in Acute Renal Colic.

PURPOSE: Neutrophil gelatinase-associated lipocalin (NGAL) levels in the serum and urine are predictive biomarkers of acute kidney injury with correlation to complication and survival in major surgery. Salivary levels of NGAL during acute renal colic may reflect the degree of renal injury as it appears in different compartments encompassing body response in time perspective. Our aim is to evaluate and examine the feasibility and correlation of salivary NGAL with serum and urine levels in acute renal colic event. MATERIALS AND METHODS: A prospective controlled study of all patients presenting to the emergency room with acute renal colic event diagnosed with single ureteral stone obstruction by noncontrast CT. Saliva, urine, and blood samples were collected in patients and a control group during the first morning of admission. RESULTS: The study groups consisted of 44 patients and 13 controls, mean age 47 ± 15 years, body mass index 29 ± 6, mean stone size 6 ± 4 mm, mean creatinine levels 1.3 ± 0.7 mg/dL, mean white blood count 10,900 ± 3100 counts per field, and C-reactive protein 29 ± 55. Serum (190 ± 120 ng/mL vs 81 ± 24; p < 0.001) and predominantly salivary (474 ± 185 vs 328 ± 134 ng/mL; p < 0.05) NGAL levels were significantly elevated in patients compared with controls. CONCLUSIONS: Salivary NGAL sampling is feasible during the acute phase of renal colic. High levels of salivary NGAL are observed in a single sampling during acute ureteral stone obstruction and may advance clinical decision-making.

Urinary Biomarkers to Predict Neonatal Acute Kidney Injury: A Review of the Science.

Acute kidney injury (AKI) occurs in approximately 30% of all infants hospitalized in the neonatal intensive care unit. About 40% of very low-birth-weight infants develop AKI, with an estimated mortality rate of 50% to 80%. Very low-birth-weight survivors have twice the risk of developing chronic renal disease later in life compared with their term counterparts. Current diagnostic modalities for AKI include serum creatinine and urine output; however, recent studies suggest that these measures are imprecise, as they may not change until 25% to 50% of renal function is lost. Urinary biomarkers may more accurately identify infants at risk for early AKI development. The purpose of this review is to discuss current research findings related to neonatal AKI risk factors, provide an overview of short- and long-term outcomes, describe innovative diagnostic approaches, and identify future research direction needed to improve prediction and intervention strategies associated with renal impairment.

Galectin-3 pharmacological inhibition attenuates early renal damage in spontaneously hypertensive rats.

BACKGROUND: The pharmacological blockade of galectin-3 (Gal-3), a ß-galactoside-binding lectin, reduces renal impairment in acute kidney injury, hyperaldosteronism or nephropathy. We herein investigated the effects of pharmacological Gal-3 inhibition by modified citrus pectin (MCP) in renal damage in spontaneously hypertensive rats (SHRs). METHODS AND RESULTS: Gal-3 inhibition did not modify blood pressure levels in 30-week-old SHR. Kidney weight was higher in SHR, with no effect of MCP treatment (100 mg/kg/day in the drinking water). Plasma creatinine and albuminuria were slightly but significantly increased in SHR and reduced by MCP, as well as plasma and urinary neutrophil gelatinase-associated lipocalin. In kidney from SHR, Gal-3 was upregulated, as well as the fibrotic markers (collagen type I, TGF-ß and connective tissue growth factor) and tubulointerstitial fibrosis. MCP treatment reduced Gal-3 levels and fibrosis. The epithelial-mesenchymal transition (EMT) molecules (fibronectin, α-smooth muscle actin and ß-catenin) were modified in SHR and normalized by Gal-3 inhibition. The inflammatory mediators (monocyte chemoattractant protein-1, osteopontin, cd68, cd80, cd44 and cd45) were elevated in SHR and attenuated by MCP. Renal damage markers (neutrophil gelatinase-associated lipocalin and kidney injury molecule-1) were augmented in SHR and improved by MCP. In renal epithelial normal rat kidney-52E cells, Gal-3 treatment induced EMT markers, whereas Gal-3 silencing attenuated EMT. CONCLUSION: Gal-3 inhibition attenuated early renal damage in SHR as indicated by reduced albuminuria, improved renal function and decreased renal fibrosis, EMT and inflammation, independently of blood pressure levels. These data suggest that Gal-3 could be a potential therapeutic candidate for the prevention of early renal alterations in hypertension.

Early urinary biomarkers of renal tubular damage by a high-salt intake independent of blood pressure in normotensive rats.

Dietary sodium intake has been associated with progression to chronic kidney disease (CKD) as well as hypertension. A high-salt intake causes renal damage independent of hypertension. Because traditional renal biomarkers are insensitive, it is difficult to detect renal injury induced by a high-salt intake, especially in normotensive patients. Here, we investigated whether newly developed renal biomarkers could be detected earlier than traditional biomarkers under a high-salt intake, in normotensive rats. Male Wistar Kyoto rats (WKY) received a regular (0.8% NaCl) or salt-loaded (2, 4, and 8% NaCl) diet from 9 to 17 weeks of age. A urine sample was obtained once a week and urinary vanin-1, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (Kim-1) were measured. At 17 weeks of age, 8% salt-loaded WKY showed histopathological renal tubular damage and elevated Rac1 activity in renal tissues. Although there was no significant increase in serum creatinine, urinary albumin, N-acetyl-ß-D-glucosaminidase (NAG), or Kim-1 during the study period among the groups, urinary vanin-1 and NGAL significantly increased in 8% salt-loaded WKY from 10 to 17 weeks of age. These results suggest that urinary vanin-1 and NGAL, which might be induced by salt per se, are potentially earlier biomarkers for renal tubular damage in normotensive rats under a high-salt intake.

Reference change values of plasma and urine NGAL in cardiac surgery with cardiopulmonary bypass.

OBJECTIVE: As with any biomarker, interpretation of changes of NGAL concentration must consider its variability in a specific clinical setting. The aim of this study was to calculate the reference change value (RCV) and the index of individuality (II) of plasma and urine NGAL in the context of coronary artery bypass graft surgery with cardiopulmonary bypass, in patients without postoperative acute kidney injury. METHODS: This prospective single-center observational study included patients with a preoperative glomerular filtration rate of >30mlmin-1 1.73m-2, scheduled for elective coronary artery bypass graft with cardiopulmonary bypass and free from postoperative renal injury according to KDIGO criteria during hospital stay or a plasma creatinine Δ<0 (Δ=day1-induction). Plasma and urine NGAL were measured at anesthesia induction, 4h after intensive care admission and on the first and 2nd postoperative day and normalized to plasma proteins or urine creatinine. The RCV was given by the formula: 1.96×√2×√(CVa2+CVi2), were CVi is the intra-individual variability and CVa the reported analytical coefficient of variation of 5%. The II was calculated using the formula II=CVi/CVg for the four previous parameters, where CVg is the inter-individual variability. RESULTS: Of the 100 patients enrolled in the study, 73 or 25 were considered free from acute kidney injury (KDIGO and Δ creatinine criteria, respectively) and included in the analysis. The RCV was 104% and 109% for plasma NGAL and 321% and 608% for urine NGAL. The II was <0.6 for both plasma and urine NGAL. CONCLUSIONS: In patients who underwent coronary artery bypass grafting with normal post-operative kidney function, two-fold change in plasma NGAL and three to six-fold change in urine NGAL occur. In this specific clinical context, pathological variations must consider this biological "noise" for correct interpretation.

The role of oxidative stress in acute renal injury of newborn rats exposed to hypoxia and endotoxin.

Neonatal kidney injury is a frequent pathology, especially among premature infants. The search for effective nephroprotection requires the creation of adequate experimental models of nephropathy in newborns. In this study, we explored the development of acute kidney injury (AKI) in neonatal rats during hypoxia or administration of endotoxin. We found that 2-h hypoxia (8% O2 ) and the intraperitoneal injection of 4 mg·kg-1 lipopolysaccharide (LPS) causes the appearance of AKI markers, such as kidney injury molecule-1 (КIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) in the rat urine after 24 and 72 h of exposure. On the other hand, the levels of blood urine nitrogen under the same conditions rise only slightly. The damaging effects of hypoxia and endotoxin were accompanied by histological changes in the renal tissue and a significant decrease in the proliferation marker, (proliferating cell nuclear antigen). It is revealed that 3 h after the introduction of LPS, levels of reactive oxygen species in the kidney were significantly increased, and the injection of the antioxidant N-acetylcysteine afforded protection from AKI, evaluated by urine КIM-1 and NGAL levels. Thus, the simulation of AKI in newborn rat pups can be employed in screening for potential nephroprotective drugs, particularly among antioxidative compounds to be used in neonatology.

Role of Urinary Neutrophil Gelatinase-Associated Lipocalin for Predicting the Severity of Renal Functions in Patients With Autosomal-Dominant Polycystic Kidney Disease.

BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) has a feature of disruption of tubular integrity with increased cellular proliferation and apoptosis. There are several known tubular membrane proteins in the pathogenesis of ADPKD, and one of these proteins is the neutrophil gelatinase-associated lipocalin (NGAL). NGAL is a protein expressed on renal tubular cells of which production is markedly increased in response to harmful stimuli such as ischemia or toxicity. OBJECTIVE: We aim to study whether urinary NGAL levels could be used as a marker to identify the severity of ADPKD in patients. METHODS: Urinary NGAL levels were measured in 30 patients with ADPKD compared with 30 control patients who were matched by age, gender, and glomerular filtration rate (GFR). All patients with ADPKD were diagnosed by using both phenotypic and genotypic criteria, which showed that all cases of ADPKD were caused by PKD1 gene mutation. The urinary NGAL level was measured using The NGAL Test by Roche, with analytic range of 25-1000 ng/mL. RESULTS: In the ADPKD group, there was significant negative correlation between urinary NGAL and GFR (Pearson r = -0.472; P = .008) and significant positive correlation between urinary NGAL and serum creatinine (Pearson r = 0.718; P < .01). Elevated urinary NGAL was increased as GFR of ADPKD patients was decreased. CONCLUSION: Urinary NGAL might play role in the pathway of renal tubular damage in patients with ADPKD and might be useful in the prediction of the possibility to progress to chronic kidney disease in patients with ADPKD.