Liver-type Fatty Acid Binding Protein Concentration Research Articles

#3937 URINARY EXCRETION OF LIVER-TYPE FATTY ACID-BINDING PROTEIN DETECTS KIDNEY HISTOLOGICAL ALTERATIONS DURING PROGRESSIVE RENAL FIBROSIS

Abstract Background and Aims Subclinical sequelae of acute kidney injury (AKI) are commonly associated with the development of chronic kidney disease (CKD). Despite extensive investigation on AKI to CKD transition on different experimental models, the underlying mechanisms of this transition remain unclear, and there are no known biomarkers monitoring this transition to CKD. The liver-type fatty acid-binding protein (L-FABP) is expressed in the kidney under normal and pathological conditions, and seems to play an important role on kidney injury and repair. We evaluated the efficacy of urinary L-FABP excretion as a prognostic indicator of the progression of renal damage in our AKI to CKD experimental model. Method 8 week old male Wistar rats were divided in two experimental groups: “Control” group (n = 8): SHAM-operated rats, which received saline solution i.p; and Cpt-IR2 group (n = 8): 5 mg/kg cisplatin i.p and 2 weeks after renal function normalization, 60 min ischemia-reperfusion on the left kidney. Blood and urine samples were collected at day 0 (basal), day 4 (AKI development), day 8 (normalized renal function), day 24 (1 day after ischemia), and 2 (M2) and 3 (M3) months after first AKI induction. Renal function was estimated analysing by colorimetric methods plasma and urinary creatinine concentrations (pCr and uCr) and creatinine clearance. Animals were sacrificed at days 56 and 90. Tissue samples were stained with haematoxylin-Eeosin, periodic acid Schiff and Masson's Trichrome for histological analysis. Enzyme-linked immunosorbent assay was used to measure urinary L-FABP concentration. Results Cpt-IR2 rats showed a reduction in renal filtration with respect to control rats even though this decrease does not indicate a severe decline in renal function. This group also presented multiple histological alterations such as fibrosis, loss of brush border membrane, inflammatory infiltrates, basement membrane thickening, tubular dilatation, cellular debris and hyaline casts that worsen markedly from M2 to M3. uL-FABP was greater in Cpt-IR2 rats (52,299 ± 8,407 ng/g uCr M2 and 23,427 ± 4,778 ng/g uCr M3) than in control rats (16,657 ± 2,322 ng/g uCr M2 and 10,636 ± 1,395 ng/g uCr), but this urinary excretion does not correlate with the histological alterations in the last month of the study. Conclusion Urinary L-FABP may be a potential biomarker for the detection of the presence of histological damage although it is not correlated with the extent and degree of the damage in our AKI to CKD transition model. This research was funded by grants from Instituto de Salud Carlos III (ISCIII) PI21/00548 and PI21/01226 co-funded by the European Union and Red de Investigación Renal RICORS2040 (Kidney Disease), RD21/0005/0004 co-funded by the European Union – NextGenerationEU, Mecanismo para la Recuperación y la Resiliencia (MRR). Joana Mercado-Hernández is recipient of a predoctoral fellowship from the Junta de Castilla y Leon (Spain) and the European Social Fund from the European Commission.

Clinical Utility of Urinary Biomarkers for Prediction of Acute Kidney Injury and Chronic Renal Dysfunction After Open Abdominal Aortic Aneurysm Repair.

PurposeWe examined the clinical utility of perioperative monitoring of urinary liver-type fatty acid binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), and albumin, for prediction of acute kidney injury (AKI) and prediction of chronic renal dysfunction in patients undergoing open surgical repair (OSR) of an abdominal aortic aneurysm.Patients and MethodsUrine and serum samples were obtained perioperatively from 64 such patients (n=64). Patients in whom OSR-related AKI (defined by the Kidney Disease Improving Global Outcomes criteria) occurred were identified. Renal function was evaluated 3 years after OSR in patients with OSR-related AKI.ResultsThe urinary biomarkers examined increased to maximum levels by 2 hours after aortic cross-clamping (AXC), regardless of whether AKI occurred. Notably, the serum creatinine (Cr) levels increased significantly immediately after OSR in patients with AKI (n=19) (vs that in patients without AKI). In patients with AKI, the increased serum Cr elevation rate, the urinary L-FABP levels 2 hours after AXC and immediately after OSR, and a reduction in eGFR documented 3 years after OSR were significantly greater in patients who underwent suprarenal AXC (n=11) than in those who underwent infrarenal AXC (n=8). Furthermore, urinary L-FABP levels 2 hours after AXC correlated significantly with the reductions in eGFR 3 years after OSR in patients with AKI.ConclusionUrinary L-FABP, NGAL and albumin concentrations 2 hours after AXC may be useful for early detection of OSR-related AKI. Furthermore, the increase in urinary L-FABP 2 hours after AXC may be predictive of chronic renal dysfunction in patients with OSR-related AKI.

Liver-type fatty acid-binding protein and neutrophil gelatinase-associated lipocalin in cats with chronic kidney disease and hyperthyroidism.

BackgroundLiver‐type fatty acid‐binding protein (L‐FABP) and neutrophil gelatinase‐associated lipocalin (NGAL) are candidate biomarkers for the detection of early chronic kidney disease (CKD) in cats.ObjectiveTo evaluate urinary and serum L‐FABP and NGAL concentrations in CKD cats and in hyperthyroid cats before and after radioiodine (131I) treatment.AnimalsNine CKD cats, 45 healthy cats and hyperthyroid cats at 3 time points including before (T0, n = 49), 1 month (T1, n = 49), and 11 to 29 months after (T2, n = 26) 131I treatment.MethodsCross‐sectional and longitudinal study. Serum L‐FABP (sL‐FABP), serum NGAL (sNGAL), urinary L‐FABP (uL‐FABP), and urinary NGAL (uNGAL) were compared between the 3 groups and between hyperthyroid cats before and after treatment. Data are reported as median (min‐max).ResultsCKD cats had significantly higher sL‐FABP (13.50 [3.40‐75.60] ng/ml) and uL‐FABP/Cr (4.90 [0.97‐2139.44] µg/g) than healthy cats (4.25 [1.34‐23.25] ng/ml; P = .01 and 0.46 [0.18‐9.13] µg/g; P < .001, respectively). Hyperthyroid cats at T0 had significantly higher uL‐FABP/Cr (0.94 [0.15‐896.00] µg/g) than healthy cats (P < .001), thereafter uL‐FABP/Cr significantly decreased at T2 (0.54 [0.10‐76.41] µg/g, P = .002). For the detection of CKD, uL‐FABP/Cr had 100% (95% confidence interval [CI], 66.4‐100.0) sensitivity and 93.2% (95% CI, 81.3‐98.6) specificity. There were no significant differences in sNGAL and uNGAL/Cr between the 3 groups.Conclusions and Clinical ImportanceL‐FABP, but not NGAL, is a potential biomarker for the detection of early CKD in cats. Utility of uL‐FABP to predict azotemia after treatment in hyperthyroid cats remains unknown.

Clinical evaluation of urinary liver-type fatty acid-binding protein for the diagnosis of renal diseases in dogs.

Liver-type fatty acid-binding protein (L-FABP) is a biomarker for the early detection of renal diseases in humans. L-FABP is a cytotoxic oxidation product secreted from the proximal tubules under ischemic and oxidative stress conditions. First, L-FABP gene expression in the kidney and liver was evaluated. Next, the urinary L-FABP concentrations in dogs with or without renal diseases were measured using a novel enzyme-linked immunosorbent assay kit. Urinary L-FABP was normalized relative to urinary creatinine (uCre) concentrations (µg/g uCre). Finally, the relationships between urinary L-FABP and renal biomarkers used in canine medicine or serum alanine transaminase (ALT) as an indicator of liver damage were examined. Serum and urine samples from 94 client-owned dogs including 23 dogs with renal diseases and 71 dogs without renal diseases were used for analysis. Relative L-FABP gene expression was confirmed both in the liver and kidney. Dogs with renal diseases had a significantly higher urinary L-FABP than those without, and its predictive cutoff value was 26 µg/g uCre. Urinary L-FABP was significantly correlated with serum creatinine (r=0.4674, P<0.01), urea nitrogen (r=0.4907, P<0.01), urine specific gravity (r=−0.5100, P<0.01), and urine protein/creatinine ratio (r=0.7216, P<0.01), but not with serum ALT. Hence, dogs with a high urinary L-FABP value were more likely to have renal diseases.

Evaluation of liver-type fatty acid binding protein (L-FABP) and interleukin 6 in children with renal cysts.

Renal cysts, according to their etiology, can be divided into genetic and acquired cysts. This is of great importance in patients with cystic kidney disease with a possible poor prognosis to identify markers of early kidney damage. The objective of this study was to evaluate the concentration of serum and urine liver-type fatty acid binding protein (L-FABP) and interleukin 6 (IL-6) in children with kidney cysts. The study was conducted on a group of 39 children with kidney cysts including 20 subjects with autosomal dominant polycystic kidney disease (ADPKD). Serum and urine L-FABP concentration in children with renal cysts was significantly higher compared to the controls, regardless of the underlying type of cystic degeneration, number of cysts and gender. Also, serum and urinary IL-6 concentration was significantly higher than in the control group. There was a significant negative correlation between serum L-FABP concentration and standard deviation score (SDS) for diastolic blood pressure (DBP). A significant negative correlation was found between serum IL-6 concentration and systolic blood pressure (SBP), DBP and mean arterial pressure (MAP) values as well as SDS for SBP and DBP. In addition, a significant positive correlation was found between urinary IL-6 concentration and estimated glomerular filtration rate (eGFR). Higher concentration of L-FABP in serum and urine in children with kidney cysts indicates the early damage to the renal parenchyma, detectable before the onset of hypertension and other organ damage. Significantly higher serum and urinary IL-6 levels in children with cystic kidney disease compared to healthy children may suggest the role of this cytokine in chronic kidney disease development.

Screening of Early Diagnostic Markers of Gentamicin-induced Acute Kidney Injury in Canines.

IntroductionThe value of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (Kim-1), and liver-type fatty acid binding protein (L-FABP) was assessed in early diagnosis of gentamicin-induced acute kidney injury (AKI) in dogs.Material and MethodsSubcutaneous gentamicin injection in 16 healthy adult beagles made the AKI model. Blood was sampled every 6 h to detect NGAL, Kim-1, L-FABP, and serum creatinine (SCr) concentrations. Kidney tissue of two dogs was taken before the injection, as soon as SCr was elevated (78 μmol/L), and when it had risen to 1.5 times the baseline, and haematoxylin-eosin staining and transmission electron microscopy (TEM) were used to observe changes.ResultsNGAL, Kim-1, and SCr levels were significantly increased (P < 0.05) at 18, 30, and 78 h post injection, but L-FABP concentration was not associated with renal injury. At the earliest SCr elevation stage, findings were mild oedema, degeneration, and vacuolisation in renal tubular epithelial cells in pathology, and mild cytoplasmic and mitochondrial oedema in TEM. At this time point, NGAL and Kim-1 concentrations were significantly increased (P < 0.05), indicating that these two molecules biomark early kidney injury in dogs. Using receiver operating characteristic curve analysis, their warning levels were > 25.31 ng/mL and > 48.52 pg/mL.ConclusionPlasma NGAL and Kim-1 above warning levels are early indicators of gentamicin-induced AKI in dogs.

Clinical significance of urinary L-FABP in the emergency department

BackgroundThis study’s aim is to measure liver-type fatty acid-binding protein (L-FABP) levels in urine using a rapid semiquantitative assay kit in the emergency department and to investigate whether the onset of acute kidney injury (AKI) after hospitalization can be predicted.MethodsThis was a prospective observation study. Patients transferred to the emergency and critical care center were divided into two groups: urinary L-FABP negative and positive groups. The status and severity of AKI were evaluated for the respective patients based on the Kidney Disease: Improving Global Outcome (KDIGO) classification. We compared the proportion of AKI patients in the two groups.ResultsIn the urine L-FABP-positive group, many patients had a significant onset of AKI (p < 0.001). After excluding patients who were diagnosed as AKI for creatinine level at admission, urinary L-FABP could predict the onset of AKI after admission (p < 0.001).ConclusionBy measuring urinary L-FABP concentration using a rapid semiquantitative assay kit, there is the possibility that the onset of AKI after admission can be predicted from immediately after a patient is transported by ambulance.

The renoprotective effect of the dipeptidyl peptidase-4 inhibitor sitagliptin on adenine-induced kidney disease in rats

We assessed the effect of treatment with the dipeptidyl peptidase-4 inhibitor, sitagliptin, on adenine-induced chronic kidney disease (CKD). Six equal groups of rats were given either normal food or food mixed with adenine (0.25% w/w for five weeks) to induce CKD. Some of these groups were also simultaneously treated with sitagliptin (2.5 and 10 mg/kg/day, by gavage). Rats given adenine showed elevation of blood pressure, decreased body weight and increased relative kidney weight. Adenine also significantly increased plasma urea, creatinine, cystatin C, liver-type fatty acid–binding protein concentrations and neutrophil gelatinase-associated lipocalin activity by 404%, 354%, 667%, 91% and 281% respectively and reduced plasma α-Klotho by 50%. In addition, adenine significantly increased albumin/creatinine ratio and N-acetyl-β-d-glucosaminidase activity by 3553% and 400% respectively and reduced creatinine clearance by 91%. Adenine feeding also significantly elevated the plasma concentration of inflammatory cytokines (plasma tumor necrosis factor-alpha, interleukin-1beta and transforming growth factor beta-1) and significantly reduced antioxidant indices (catalase, glutathione reductase and superoxide dismutase). Histopathologically, adenine caused renal fibrosis, inflammation and atrophy. When given concomitantly with adenine, sitagliptin ameliorated all the measured adenine-induced physiological and biochemical changes but not the histopathological changes. Sitagliptin (10 mg/kg/day) reduced plasma urea and creatinine by 32% and 25% respectively and increased creatinine clearance by 248%. These findings suggest a renoprotective action of sitagliptin on adenine-induced CKD.

L-FABP and IL-6 as markers of chronic kidney damage in children after hemolytic uremic syndrome.

Hemolytic-uremic syndrome (HUS) is a form of thrombotic microangiopathy, in the course of which some patients may develop chronic kidney disease (CKD). From a clinical point of view, it is important to search for markers that allow for early identification of patients at risk of a poor prognosis. The study evaluated the serum and urine levels of liver-type fatty acid binding protein (L-FABP) and interleukin 6 (IL-6). The study was conducted in 29 children with a history of HUS. The relationship between L-FABP and IL-6 and anthropometric measurements, the value of estimated glomerular filtration rate (eGFR) and albuminuria were additionally evaluated. In children after HUS, L-FABP and IL-6 concentration in both serum and urine was significantly higher in comparison to the control group. No differences in L-FABP and IL-6 concentration in serum and urine depending on the type of HUS and gender were noted. Correlation between L-FABP and IL-6 in serum and urine with eGFR and urine albumin-creatinine ratio (ACR) in the total group of patients after HUS was not detected. In the group of children after 6 month observation after HUS, a negative correlation of L-FABP concentration with eGFR was found. The results indicate that the higher concentration of L-FABP in serum and urine of children with a history of HUS can be the result of protracted injury initiated during the acute phase of the disease. Lack of correlation of L-FABP concentration with the ACR may be associated with a short (less than 6 months) observation after acute renal failure or merely temporary renal tubular damage in the acute phase of the disease. In contrast, higher levels of IL-6 in serum and urine in children after HUS compared to healthy children and the negative correlation of L-FABP concentration and eGFR in children after 6 month observation after HUS may confirm their participation in CKD. Thus, L-FABP and IL-6 seem to be good biomarkers of chronic kidney damage in survivors of the acute phase of HUS.

Arsenic, cadmium, lead, and chromium in well water, rice, and human urine in Sri Lanka in relation to chronic kidney disease of unknown etiology.

Chronic kidney disease of unknown etiology (CKDu) is spreading gradually in Sri Lanka. In the current research, 1,435 well water samples from all 25 districts of Sri Lanka, 91 rice samples, and 84 human urine samples from both CKDu-endemic and non-endemic areas in Sri Lanka were analyzed for arsenic, cadmium, lead, and chromium to detect whether toxic elements could be a cause of CKDu. The liver-type fatty acid binding protein (L-FABP) concentration and arsenic, cadmium, lead, and chromium concentrations of the urine samples were analyzed to determine the relation of L-FABP with arsenic, cadmium, lead, and chromium. High concentrations of arsenic, cadmium, lead, and chromium were not detected in the well water samples from CKDu-endemic areas. Arsenic, cadmium, and lead contents in the rice samples from both CKDu-endemic and non-endemic areas were well below the Codex standard. There were no relationships between the L-FABP concentration and concentrations of arsenic, cadmium, lead, and chromium in urine. In addition, arsenic, cadmium, lead, and chromium concentrations in human urine samples from CKDu-endemic areas were not significantly different from those from non-endemic areas. These findings indicated that arsenic, cadmium, lead, and chromium could not cause CKDu.

Associations between Deceased-Donor Urine Injury Biomarkers and Kidney Transplant Outcomes.

Assessment of deceased-donor organ quality is integral to transplant allocation practices, but tools to more precisely measure donor kidney injury and better predict outcomes are needed. In this study, we assessed associations between injury biomarkers in deceased-donor urine and the following outcomes: donor AKI (stage 2 or greater), recipient delayed graft function (defined as dialysis in first week post-transplant), and recipient 6-month eGFR. We measured urinary concentrations of microalbumin, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), IL-18, and liver-type fatty acid binding protein (L-FABP) from 1304 deceased donors at organ procurement, among whom 112 (9%) had AKI. Each biomarker strongly associated with AKI in adjusted analyses. Among 2441 kidney transplant recipients, 31% experienced delayed graft function, and mean±SD 6-month eGFR was 55.7±23.5 ml/min per 1.73 m(2) In analyses adjusted for donor and recipient characteristics, higher donor urinary NGAL concentrations associated with recipient delayed graft function (highest versus lowest NGAL tertile relative risk, 1.21; 95% confidence interval, 1.02 to 1.43). Linear regression analyses of 6-month recipient renal function demonstrated that higher urinary NGAL and L-FABP concentrations associated with slightly lower 6-month eGFR only among recipients without delayed graft function. In summary, donor urine injury biomarkers strongly associate with donor AKI but provide limited value in predicting delayed graft function or early allograft function after transplant.

Urinary Fatty Acids and Liver-Type Fatty Acid Binding Protein in Diabetic Nephropathy

Background: The aims of this clinical study were to investigate the associations of urinary free fatty acid (FFA) levels with tubulointerstitial damage, and to determine the clinical significance of urinary liver-type fatty acid binding protein (L-FABP) in diabetic nephropathy. Methods: Fifteen patients with nephrotic syndrome due to diabetic nephropathy and 12 patients with minimal-change nephrotic syndrome (MCNS) were studied. Urinary and serum FFA concentrations (palmitic, oleic, linoleic, and arachidonic acids) were measured by gas chromatography, and urinary L-FABP levels were quantified using an ELISA technique. Tubulointerstitial damage was assessed using renal biopsy specimens. Results: The levels of urinary linoleic and arachidonic acids were significantly elevated in diabetic nephropathy compared to MCNS patients, though serum FFA levels were lower in diabetic nephropathy than MCNS patients. The degree of tubulointerstitial damage was significantly severer in the patients with diabetic nephropathy than MCNS. Urinary L-FABP and 8-OHdG (8-hydroxydeoxyguanosine) concentrations were significantly higher in the diabetic nephropathy subjects. Conclusion: Elevated urinary excretion of FFA may be a reflection of FFA overload in the proximal tubules, and FFA may be an important promoter of tubulointerstitial damage in diabetic nephropathy patients. Urinary L-FABP levels may reflect the stress induced by FFA to the proximal tubules, leading to severe tubulointerstitial damage.

Combined effect of pioglitazone and simvastatin on urinary liver-type fatty acid-binding protein concentration in diabetic patients with microalbuminuria.

The first author of this paper has informed us that the patients and data reported in this article were fabricated and that the third author does not exist. Dr Ma has been contacted and states that he had no knowledge of this paper. Kagawa University had no knowledge of this submission. We further note that the same authors, real and fictitious, have recently published in other journals, whose Editors have been informed. Diabetologia DOI 10.1007/s00125-007-0703-3

Cigarette Smoking Affects Urinary Liver-Type Fatty Acid–Binding Protein Concentration in Patients With Early Diabetic Nephropathy

Cigarette smoking causes a decrease in the glomerular filtration rate in diabetic patients with normal renal function, independent of confounding factors including severe proteinuria (1). It increases the risk of microalbuminuria and accelerates the progression from microalbuminuria to overt proteinuria as well as the progression of renal failure in patients with type 2 diabetes (2). It is widely accepted that the rate of functional decline correlates with the degree of renal tubulointerstitial fibrosis. Previous studies have shown …

Effect of pioglitazone on urinary liver‐type fatty acid‐binding protein concentrations in diabetes patients with microalbuminuria

Urinary liver-type fatty acid-binding protein (L-FABP) is a useful marker for renal tubulointerstitial injury. Pioglitazone is reported to be effective in early diabetic nephropathy. The aim of the present study was to determine whether pioglitazone affects urinary L-FABP levels in diabetic nephropathy patients with microalbuminuria. Sixty-eight patients with type 2 diabetes and microalbuminuria were randomized to a 12-month treatment with pioglitazone (30 mg/d, n = 17), glibenclamide (5 mg/d, n = 18), voglibose (0.6 mg/d, n = 17), or nateglinide (270 mg/d, n = 16). Pre- and posttreatment urinary albumin excretion (UAE) and urinary L-FABP concentrations were compared between the four treatment groups and 40 age-matched healthy subjects. Pretreatment UAE and urinary L-FABP levels differed little between the four groups. UAE and urinary L-FABP levels were significantly greater in the diabetes patients than in the healthy subjects (UAE: p < 0.001; L-FABP: p < 0.01). After 6 and 12 months, UAE and urinary L-FABP were significantly lower in the pioglitazone treatment group than in the other treatment groups (UAE: 6 months, p < 0.01 and 12 months, p < 0.001; L-FABP: 6 months, p < 0.05 and 12 months, p < 0.01). Pioglitazone, but not glibenclamide, voglibose, or nateglinide, appears to be effective in reducing UAE and the urinary L-FABP level, suggesting that pioglitazone has a specific role in ameliorating both glomerular and tubulointerstitial lesions associated with early diabetic nephropathy.