Urinary liver-type fatty acid binding protein is a biomarker reflecting renal damage and the ameliorative effect of drugs at an early stage of histone-induced acute kidney injury.

AIM: Circulated histones play a crucial role in the pathogenesis of infectious diseases and severe trauma, and it is one of the potential molecular targets for therapeutics. Recently, we reported that histone is one of the causative agents for urinary L-FABP increase. However, the mechanism is still unclear, especially in severe cases. We further investigated the mechanism of urinary L-FABP increase using a more severe mouse model with histone-induced kidney injury. This study also aims to evaluate the therapeutic responsiveness of urinary L-FABP as a preliminary study. METHODS: Human L-FABP chromosomal transgenic mice were administrated 30 mg/kg histone from a tail vein with a single dose. We also performed a comparative study in LPS administration model. For the evaluation of the therapeutic responsiveness of urinary L-FABP, we used heparin and rolipram. RESULTS: The histological change with cast formation as a characteristic of the models was observed in proximal tubules. Urinary L-FABP levels were significantly elevated and these levels tended to be higher in those with more cast formation. Heparin and rolipram had the ameliorative effect of the cast formation induced by histone and urinary L-FABP levels significantly decreased. CONCLUSION: Histone is one of the causative agents for the increase of urinary L-FABP at an early stage of AKI. In addition, it suggested that urinary L-FABP may be useful as a subclinical AKI marker reflecting kidney damage induced by histone. Furthermore, urinary L-FABP reflected the degree of the damage after the administration of therapeutic agents such as heparin and PDE4 inhibitor.

Urinary liver-type fatty acid binding protein is increased in the early stages of the disease with a risk of acute kidney injury induced by histone.

AIM: Urinary liver-type fatty acid binding protein (L-FABP) has potential utility as an early prognostic biomarker ahead of traditional severity scores in coronavirus disease 2019 and sepsis, however, the mechanism of elevated urinary L-FABP in the disease has not been clearly elucidated. We investigated the background mechanisms of urinary L-FABP excretion through non-clinical animal model focusing on histone, which is one of the aggravating factors in these infectious diseases. METHODS: Male Sprague-Dawley rats were placed in central intravenous catheters, and these rats were given a continuous intravenous infusion of 0.25 or 0.5 mg/kg/min calf thymus histones for 240 min from caudal vena cava. RESULTS: After the administration of histone, urinary L-FABP and gene expression of an oxidative stress marker in the kidney increased in a histone dose-dependent manner before increased serum creatinine. Upon further investigation, fibrin deposition in the glomerulus was observed and it tended to be remarkable in the high dose administrated groups. The levels of coagulation factor were significantly changed after the administration of histone, and these were significantly correlated with the levels of urinary L-FABP. CONCLUSIONS: Firstly, it was suggested that histone is one of the causative agents for the urinary L-FABP increase at an early stage of the disease with a risk of acute kidney injury. Secondly, urinary L-FABP could be a marker reflecting the changes of coagulation system and microthrombus caused by histone in the early stage of acute kidney injury before becoming severely ill and maybe a guide to early treatment initiation.

Endurance Exercise Training-Attenuated Diabetic Kidney Disease with Muscle Weakness in Spontaneously Diabetic Torii Fatty Rats.

BACKGROUND: The aim of this study was to evaluate protective effects of endurance exercise training against diabetic kidney disease (DKD) with muscle weakness by using male spontaneously diabetic Torii (SDT) fatty rats as type 2 diabetic animal models with obesity, hypertension, and hyperlipidemia. METHODS: Eight-week-old SDT fatty rats (n = 12) and Sprague-Dawley (SD) rats (n = 10) were randomly divided into exercise (Ex; SDT-Ex: n = 6, SD-Ex: n = 5) and sedentary groups (SDT-Cont: n = 6, SD-Cont: n = 5), respectively. Each group underwent regular treadmill exercise 4 times a week from ages 8-16 weeks. RESULTS: The exercise attenuated hypertension and hyperlipidemia and prevented increases in renal parameter levels without affecting blood glucose levels. In the SDT fatty rats, it prevented induction of renal morphological abnormalities in the interstitium of the superficial and intermediate layers of the cortex. Downregulated expression of endothelial nitric oxide synthase in the glomerulus of the SDT fatty rats was significantly upregulated by the exercise. The exercise upregulated the renal expressions of both medium-chain acyl-CoA dehydrogenase and peroxisome proliferator-activated receptor γ coactivator-1α related to fatty acid metabolism. It increased muscle strength and both muscle weight and cross-sectional area of type IIb muscle fibers in the extensor digitorum longus muscle in the SDT fatty rats. CONCLUSION: Endurance exercise training in type 2 diabetes ameliorates DKD by improving endothelial abnormality and enhancing fatty acid metabolism in addition to attenuated hypertension, hyperlipidemia, and muscle weakness independently of blood glucose levels.

Glucagon-like peptide-1 receptor agonist, liraglutide, attenuated retinal thickening in spontaneously diabetic Torii fatty rats.

BACKGROUND: This study aims to investigate the effect of the glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) liraglutide on retinal pathological findings as compared with insulin and hydralazine using an animal model of type 2 diabetes with obesity, hypertension, and hyperlipidemia. METHODS: Male spontaneously diabetic Torii (SDT) fatty rats at 8 weeks of age were randomly assigned to three groups: the liraglutide group (SDT-lira, n = 6) received a subcutaneous injection of liraglutide from the age of 8 to 16 weeks, the SDT-ins-hyd group (n = 6) was provided both insulin against hyperglycemia and hydralazine against hypertension to match levels of both blood glucose and blood pressure to those of the liraglutide group, and the control group of SDT fatty rats (SDT-vehicle, n = 7) and a nondiabetic control group of Sprague-Dawley rats (SD, n = 7) were injected with vehicle only. Both eyeballs of all groups were collected at the age of 16 weeks. RESULTS: Retinal thickness, which was found in the SDT-vehicle group, was significantly prevented to similar levels in both the SDT-lira and SDT-ins-hyd groups. Immunohistological analysis revealed that GLP-1 receptor was not expressed in the retina of all rats. The ocular protein expression of monocyte chemoattractant protein-1, which causes a proinflammatory situation, was significantly upregulated in all SDT fatty rats as compared to SD rats, but the expression levels were similar between all SDT fatty rats. With regard to neovascularization in the eyes, there were no significant differences in protein expressions of vascular endothelial growth factor, CD31, or endothelial nitric oxide synthase in all rats. CONCLUSIONS: The present study indicates that liraglutide prevents retinal thickening, dependent on blood glucose and blood pressure levels in SDT fatty rats without ocular neovascularization. However, the effects did not improve the ocular proinflammatory state.

Quantitative and qualitative analyses of urinary L-FABP for predicting acute kidney injury after emergency laparotomy.

PURPOSE: The aim of this study was to explore the clinical utility of urinary L-FABP for earlier prediction of acute kidney injury (AKI) after emergency laparotomy, and to assess the clinical utility of a point-of-care (POC) kit for urinary L-FABP. METHODS: Forty-eight patients undergoing emergency laparotomy were divided into AKI and non-AKI groups by the kidney diseases: improving global outcome (KDIGO) criteria. Ten patients were included in the AKI group. Urinary L-FABP, albumin, N-acetyl-ß-D-glucosaminidase (NAG), TIMP-2, IGFBP7, serum creatinine (SCr), and blood presepsin were measured perioperatively and compared between groups. Perioperative urinary L-FABP was also evaluated qualitatively using a POC kit. RESULTS: L-FABP and albumin levels were significantly higher in the AKI group at all measurement points. NAG was significantly higher only postoperatively in the AKI group. There were no inter-group differences in [TIMP-2] × [IGFBP7] at any measuring point. The area under the receiver operating characteristic curve of urinary L-FABP was greater than 0.8 perioperatively, which was larger than that of other biomarkers throughout the study period. The correlation coefficient at 2 h after entering the operating room between quantitative and qualitative tests for urinary L-FABP was 0.714, which was the maximum. The sensitivity, specificity, and negative predictive value of the urinary L-FABP POC kit at 2 h after entry were 55.6%, 91.9%, and 89.5%, respectively. CONCLUSION: Quantitative L-FABP analyses is suitable for predicting postoperative AKI earlier in the perioperative period of emergency laparotomy. Conversely, the higher specificity of qualitative L-FABP analysis suggests that it may be useful for excluding the risk of AKI but its overall clinical validity should be further investigated.

Renoprotective effect of GLP-1 receptor agonist, liraglutide, in early-phase diabetic kidney disease in spontaneously diabetic Torii fatty rats.

BACKGROUND: The aim of this study is to investigate the renoprotective effect of the GLP-1 receptor agonist, liraglutide, in early-phase diabetic kidney disease (DKD) using an animal model of type 2 diabetes with several metabolic disorders. METHODS: Male 8-week-old spontaneously diabetic Torii (SDT) fatty rats (n = 19) were randomly assigned to three groups. The liraglutide group (n = 6) was injected subcutaneously with liraglutide. Another treatment group (n = 6) received subcutaneous insulin against hyperglycemia and hydralazine against hypertension for matching blood glucose levels and blood pressure with the liraglutide group. The control groups of SDT fatty (n = 7) and non-diabetic Sprague-Dawley rats (n = 7) were injected only with a vehicle. RESULTS: The control group of SDT fatty rats exhibited hyperglycemia, obesity, hypertension, hyperlipidemia, glomerular sclerosis, and tubulointerstitial injury with high urinary albumin and L-FABP levels. Liraglutide treatment reduced body weight, food intake, blood glucose and blood pressure levels, as well as ameliorated renal pathologic findings with lower urinary albumin and L-FABP levels. Liraglutide increased expressions of phosphorylated (p)-eNOS and p-AMPK in glomeruli, downregulated renal expression of p-mTOR, and increased renal expressions of LC3B-II, suggesting activation of autophagy. However, these effects were not caused by the treatments with insulin and hydralazine, despite comparable levels of hyperglycemia and hypertension to those achieved with liraglutide treatment. CONCLUSIONS: Liraglutide may exert a renoprotective effect via prevention of glomerular endothelial abnormality and preservation of autophagy in early-phase DKD, independent of blood glucose, and blood pressure levels.

Incremental short maximal exercise increases urinary liver-type fatty acid-binding protein in adults without CKD.

Exercise-induced redistribution of tissue blood flow decreases the renal blood flow in an exercise intensity-dependent manner. However, the acute effects of incremental short maximal exercise on renal tubular conditions remain unknown. The purpose of this study was to investigate the acute effects of incremental short maximal exercise on the urinary liver-type fatty acid-binding protein, which is a highly sensitive tubular biomarker that correlates excellently with peritubular capillary blood flow. A total of 116 adults (aged 24-83 years) without chronic kidney disease performed the incremental short maximal exercise using a cycling ergometer, wherein the exercise sequence consisted of commencing with a 2-min workout period at 20 W (as a warm-up period) and then followed by a 10-20 W increase every 1 minute until termination criteria were reached. Urinary samples were gathered before and immediately after the exercise to evaluate the concentrations of urinary creatinine, albumin, and liver-type fatty acid-binding protein. Urinary excretion levels of albumin and liver-type fatty acid-binding protein were significantly increased post-exercise (P < .001 and P = .008, respectively). Furthermore, the % change in urinary liver-type fatty acid-binding protein levels after exercise was found to correlate independently with age, estimated glomerular filtration rate at baseline, and the % change in urinary albumin (Model R2  = 0.451, P < .001). Our findings suggest that incremental short maximal exercise may lead to acute slightly adverse effects on tubular conditions, especially in young adults or adults with lower renal function, even without chronic kidney disease.

The Possibility of Urinary Liver-Type Fatty Acid-Binding Protein as a Biomarker of Renal Hypoxia in Spontaneously Diabetic Torii Fatty Rats.

BACKGROUND: Renal hypoxia is an aggravating factor for tubulointerstitial damage, which is strongly associated with renal prognosis in diabetic kidney disease (DKD). Therefore, urinary markers that can detect renal hypoxia are useful for monitoring DKD. OBJECTIVE: To determine the correlation between urinary liver-type fatty acid-binding protein (L-FABP) and renal hypoxia using a novel animal model of type 2 diabetes. METHODS: Male spontaneously diabetic Torii (SDT) fatty rats (n = 6) were used as an animal model of type 2 diabetes. Age- and sex-matched Sprague-Dawley (SD) rats (n = 8) were used as controls. Body weight, systolic blood pressure, and blood glucose levels were measured at 8, 12, 16, and 24 weeks of age. Urine samples and serum and kidney tissues were collected at 24 weeks of age. Microvascular blood flow index (BFI) was measured using diffuse correlation spectroscopy before sampling both the serum and kidneys for the evaluation of renal microcirculation at the corticomedullary junction. RESULTS: Obesity, hyperglycemia, and hypertension were observed in the SDT fatty rats. Focal glomerular sclerosis, moderate interstitial inflammation, and fibrosis were significantly more frequent in SDT fatty rats than in SD rats. While the frequency of peritubular endothelial cells and phosphoendothelial nitric oxide synthase levels were similar in both types of rats, the degree of renal hypoxia-inducible factor-1α (HIF-1α) expression was significantly higher (and with no change in renal vascular endothelial growth factor expression levels) in the SDT fatty rats. Urinary L-FABP levels were significantly higher and renal microvascular BFI was significantly lower in the SDT fatty rats than in the SD rats. Urinary L-FABP levels exhibited a significant positive correlation with renal HIF-1α expression and a significant negative correlation with renal microvascular BFI. CONCLUSIONS: Urinary L-FABP levels reflect the degree of renal hypoxia in DKD in a type 2 diabetic animal model. Urinary L-FABP may thus prove useful as a renal hypoxia marker for monitoring DKD in patients with type 2 diabetes in clinical practice.

Role of angiotensin II type 1a receptor in renal injury induced by deoxycorticosterone acetate-salt hypertension.

The aim of this study was to investigate the in vivo role of angiotensin II type 1a (AT1a) receptor in renal damage as a result of hypertension by using transgenic mice with AT1a receptor gene disruption. Transgenic mice that express human liver-type fatty acid binding protein (L-FABP) with or without disruption of the AT1a receptor gene (L-FABP+/- AT1a-/-, and L-FABP+/- AT1a+/+, respectively) were used with urinary L-FABP as an indicator of tubulointerstitial damage. Those female mice were administered subcutaneously deoxycorticosterone acetate (DOCA)-salt tablets plus drinking water that contained 1% saline for 28 d after uninephrectomy. In L-FABP+/- AT1a+/+ mice that received DOCA-salt treatment, hypertension was induced and slight expansion of glomerular area, glomerular sclerosis, and tubulointerstitial damage were observed. In L-FABP+/- AT1a-/- mice that received DOCA-salt treatment, hypertension was similarly induced and the degree of glomerular damage was significantly more severe than in L-FABP+/- AT1a+/+-DOCA mice. Urinary L-FABP levels were significantly higher in L-FABP+/- AT1a-/--DOCA mice compared with those in L-FABP+/- AT1a+/+-DOCA mice. Hydralazine treatment significantly attenuated renal damage that was found in L-FABP+/- AT1a-/--DOCA mice along with a reduction in blood pressure. In summary, activation of the AT1a receptor may contribute to maintenance of the glomerular structure against hypertensive renal damage.-Hisamichi, M., Kamijo-Ikemori, A., Sugaya, T., Ichikawa, D., Natsuki, T., Hoshino, S., Kimura, K., Shibagaki, Y. Role of angiotensin II type 1a receptor in renal injury induced by deoxycorticosterone acetate-salt hypertension.

Urinary Level of Liver-Type Fatty Acid Binding Protein Reflects the Degree of Tubulointerstitial Damage in Polycystic Kidney Disease.

BACKGROUND/AIMS: Polycystic kidney disease (PKD) is a common, progressive, and heritable type of kidney disease. Although certain imaging modalities are useful for the diagnosis and staging of PKD, they cannot adequately monitor the severity of interstitial inflammation and fibrosis. Therefore, the present study evaluated the urinary level of liver-type fatty acid binding protein (L-FABP) as a marker of interstitial inflammation and fibrosis in PKD. METHODS: Male PCK/CrljCrl-Pkhd1pck/Crl (PCK) rats (n = 34) were used as an animal model of the PKD. Age-and sex-matched Sprague-Dawley rats (SD) (n = 34) were used as controls. Urine samples were obtained from the rats at 8, 12, 16, 20, and 24 weeks of age, and the sera and kidney tissues were obtained at 8, 16, 20, and 24 weeks of age. RESULTS: All PCK rats developed cysts, and the degrees of tubular epithelial cell proliferation and interstitial inflammation increased linearly with age in these model rats relative to the controls. Interstitial fibrosis tended to increase in the PCK rats from 8 to 20 weeks of age, and revealed a peak level at 20 weeks. The urinary L-FABP levels increased linearly with age in the PCK rats, and the levels at 12, 16, 20, and 24 weeks were significantly higher than those in the controls. The urinary levels of L-FABP in the PCK rats correlated significantly with the severity of tubulointerstitial damage; specifically, we observed a significant correlation of the urinary levels at 16 weeks of age with the total kidney volume at 20 weeks. In contrast, both PCK and SD rats exhibited similar serum levels of L-FABP. CONCLUSION: Urinary L-FABP reflects the progression of tubulointerstitial damage, and therefore, may be a useful marker for monitoring the progression of PKD.

Utility of urinary tubular markers for monitoring chronic tubulointerstitial injury after ischemia-reperfusion.

AIM: The aim of this study was to elucidate whether urinary tubular markers during the chronic phase of acute kidney injury (AKI) are associated with chronic tubulointerstitial damage. METHODS: Male human L-type fatty acid binding protein (L-FABP) chromosomal transgenic (Tg) mice underwent ischaemic reperfusion (I/R) injury via renal pedicle clamping for either 10 min or 20 min. Contralateral nephrectomy was performed at the time of tissue reperfusion. The kidneys were analyzed 20 days after the last I/R. RESULTS: Serum creatinine levels 20 days post-I/R were significantly higher in the 20 min I/R than in the 10 min I/R and control groups and were similar between the 10 min I/R and control groups. The degree of tubulointerstitial damage 20 days post-I/R was significantly more severe in the 20 min I/R than in the 10 min I/R and control groups, as well as in the 10 min I/R than in the control group. Urinary levels of human L-FABP, albumin, and kidney injury molecule-1 (KIM-1) 20 days post-I/R were significantly higher in the 20 min I/R than in the control group, whereas urinary L-FABP was significantly higher in the 10 min I/R than in the control group. Conversely, urinary neutrophil gelatinase-associated lipocalin levels did not significantly differ between the three groups. Finally, the urinary levels of human L-FABP, albumin, and KIM-1 levels 20 days post-I/R were significantly correlated with the degree of renal damage. CONCLUSIONS: Urinary levels of human L-FABP, albumin and, KIM-1 may be useful for monitoring AKI-to-CKD transition in clinical practice.

Urinary liver-type fatty acid-binding protein is associated with subendocardial viability ratio in middle- and older-aged adults.

BACKGROUND: To identify one of the physiological underlying mechanisms of the predictive effects of urinary liver-type fatty acid-binding protein (L-FABP) for the onset of cardiovascular disease (CVD), we investigated the relationship between urinary L-FABP levels and subendocardial viability ratio (SEVR), a marker of myocardial perfusion, in middle- and older-aged adults. METHODS: This was a cross-sectional study of 249 middle- and older-aged adults (aged 46-83 years). We measured urinary L-FABP levels and central hemodynamic parameters, including SEVR, calculated by pulse wave analysis using an applanation tonometry. RESULTS: In the participants stratified in accordance with the tertiles of urinary L-FABP levels, SEVR decreased in a stepwise fashion with increasing tertiles (p < 0.001). Furthermore, this association remains significant after the consideration of various confounders. On the contrary, urinary albumin levels were not independently related with SEVR. CONCLUSION: Our results demonstrated that urinary L-FABP levels were independently associated with the SEVR of the middle- and older-aged adults. This result suggests that the increase in urinary L-FABP levels even within the normal range might be related to the decrease in myocardial perfusion (SEVR).

Habitual exercise decreases plasma xanthine oxidoreductase activity in middle-aged and older women.

The aim of present study was to investigate the association between plasma xanthine oxidoreductase activity, which has gained attention as a novel preventive target of cardiovascular disease, and various physiological parameters and was to determine the effects of habitual exercise on plasma xanthine oxidoreductase activity in middle-aged and older women. In the cross-sectional study, we investigated the association between plasma xanthine oxidoreductase activity and various physiological parameters in 94 middle-aged and older women. In the interventional study, subjects (n = 22) were divided into two groups: exercise (n = 12) or the control group (n = 10), whereby we examined the effect of 12-week aerobic exercise training on plasma xanthine oxidoreductase activity in middle-aged and older women. The cross-sectional study demonstrated that plasma xanthine oxidoreductase activity was significantly associated with various physiological parameters, including visceral fat and daily step counts. In the interventional study, the plasma xanthine oxidoreductase activity significantly decreased after the 12-week aerobic exercise training, its changes were inversely associated with the changes in daily step counts. Our results revealed that the plasma xanthine oxidoreductase activity was associated with visceral fat accumulation and lack of exercise, and it was decreased by the aerobic exercise training.

Increase in urinary markers during the acute phase reflects the degree of chronic tubulointerstitial injury after ischemia-reperfusion renal injury.

CONTEXT: Acute kidney injury (AKI) could lead to progressive chronic kidney disease (CKD). OBJECTIVES: To demonstrate that urinary markers in AKI are associated with the degree of persistent renal injury. MATERIAL AND METHODS: Human L-FABP chromosomal transgenic (Tg) mice were subjected to ischemia-reperfusion (I/R) clamping renal pedicle for 20 min or 30 min. Kidneys were obtained at one and 40 days after I/R. RESULTS: Urinary L-FABP, NGAL, Kim-1 and albumin levels increased during the acute phase and were significantly correlated with the degree of tubulointerstitial fibrosis during the chronic phase. DISCUSSION AND CONCLUSION: These markers could detect higher risk of progression to CKD.

Relationship between exercise capacity and urinary liver-type fatty acid-binding protein in middle-aged and older individuals.

BACKGROUND: The underlying mechanism linking the decline in exercise capacity with renal dysfunction remains unclear. Urinary liver-type fatty acid-binding protein (L-FABP) levels reflect the degree of peritubular capillary blood flow, an important factor for renal dysfunction with aging. The aim of this study was to examine the relationship between exercise capacity and urinary L-FABP levels. METHODS: This was a cross-sectional study of 187 middle-aged and older individuals (aged 50-83 years) without chronic kidney disease (CKD). We assessed urinary L-FABP levels, peak oxygen consumption ([Formula: see text]), and grip strength. RESULTS: Urinary L-FABP levels inversely correlated with both [Formula: see text] (r s = -0.349) and grip strength (r s = -0.485). When the participants were divided into four groups according to the median values of aerobic fitness and muscular strength ([Formula: see text] and grip strength), urinary L-FABP levels were the highest in participants with lower levels of aerobic fitness and muscular strength (2.95 ± 1.43 µg/g creatinine) and the lowest in the participants with higher levels of aerobic fitness and muscular strength (1.33 ± 0.76 µg/g creatinine). The difference between the two groups was significant (P < 0.001). CONCLUSION: Our results demonstrate that both [Formula: see text] and grip strength were inversely associated with urinary L-FABP levels in middle-aged and older individuals without CKD. This suggests that a decline in exercise capacity is associated with a reduction in peritubular capillary blood flow, providing a novel insight into the underlying mechanism linking the decline in exercise capacity to the development of renal dysfunction.

Renoprotective effect of the xanthine oxidoreductase inhibitor topiroxostat on adenine-induced renal injury.

The aim of the present study was to reveal the effect of a xanthine oxidoreductase (XOR) inhibitor, topiroxostat (Top), compared with another inhibitor, febuxostat (Feb), in an adenine-induced renal injury model. We used human liver-type fatty acid-binding protein (L-FABP) chromosomal transgenic mice, and urinary L-FABP, a biomarker of tubulointerstitial damage, was used to evaluate tubulointerstitial damage. Male transgenic mice (n = 24) were fed a 0.2% (wt/wt) adenine-containing diet. Two weeks after the start of this diet, renal dysfunction was confirmed, and the mice were divided into the following four groups: the adenine group was given only the diet containing adenine, and the Feb, high-dose Top (Top-H), and low-dose Top (Top-L) groups were given diets containing Feb (3 mg/kg), Top-H (3 mg/kg), and Top-L (1 mg/kg) in addition to adenine for another 2 wk. After withdrawal of the adenine diet, each medication was continued for 2 wk. Serum creatinine levels, the degree of macrophage infiltration, tubulointerstitial damage, renal fibrosis, urinary 15-F2t-isoprostane levels, and renal XOR activity were significantly attenuated in the kidneys of the Feb, Top-L, and Top-H groups compared with the adenine group. Serum creatinine levels in the Top-L and Top-H groups as well as renal XOR in the Top-H group were significantly lower than those in the Feb group. Urinary excretion of L-FABP in both the Top-H and Top-L groups was significantly lower than in the adenine and Feb groups. In conclusion, Top attenuated renal damage in an adenine-induced renal injury model.

Clinical utility of urinary liver-type fatty acid binding protein measured by latex-enhanced turbidimetric immunoassay in chronic kidney disease.

BACKGROUND: Urinary liver-type fatty acid binding protein (L-FABP) measured by enzyme-linked immunosorbent assay method (ELISA) was approved as a clinical biomarker of tubular damage by the Japanese Ministry of Health, Labor and Welfare (MHLW) in 2011. We evaluated a new latex-enhanced immunoturbidimetric assay (LTIA) to evaluate the clinical utility of urinary L-FABP measured by LTIA versus an ELISA assay. METHODS: LTIA with anti-human L-FABP mouse monoclonal antibodies was performed using an automated clinical chemistry analyzer. Five positive samples with low, medium and high L-FABP concentrations were analyzed to determine the within-run precision. In patients with chronic kidney disease (CKD) (n=91), urinary L-FABP levels were measured by ELISA and LTIA. RESULTS: Measurement of urinary L-FABP revealed urinary L-FABP levels within 30 min. The within-run coefficient of variation was 10.0% for 1.4 ng/mL, 4.4% for 2.5 ng/mL, 3.2% for 9.8 ng/mL, 1.5% for 50.1 ng/mL, and 1.2% for 102.7 ng/mL. Concentrations of urinary L-FABP measured by LTIA were significantly correlated with those measured by ELISA (ρ=0.932). Proportional systematic error was almost within limits of agreement (LOA). Urinary L-FABP levels measured by LTIA were significantly correlated with urinary albumin (ρ=0.634), urinary NAG (ρ=0.688) and eGFR (ρ=-0.561). CONCLUSIONS: Measurement of urinary L-FABP by LITA was simple, speedy, and similar in quality to ELISA results. Therefore, this method was approved as external body diagnosing medicines by the Japanese MHLW in 2014. Urinary L-FABP is expected to be widely used in various pathophysiological conditions by measuring urinary L-FABP using LTIA.

Clinical significance of urinary liver-type fatty acid-binding protein as a predictor of ESRD and CVD in patients with CKD.

BACKGROUND: To improve outcomes in patients with chronic kidney disease (CKD), it is important to identify prognostic factors for end-stage renal disease (ESRD) as well as cardiovascular disease (CVD). This study assessed urinary concentrations of albumin, N-acetyl-ß-D-glucosaminidase (NAG), and liver-type fatty acid-binding protein (L-FABP), as predictors of ESRD and CVD. METHODS: A prospective, observational, multicenter study, comprising 244 Japanese outpatients with CKD who had a follow-up period of at least 3 months. The primary endpoint was the first onset of a nonfatal or fatal CVD event and progression to ESRD, defined as myocardial infarction, stroke, or artery revascularization (coronary, carotid or peripheral), and initiation of dialysis. RESULTS: During a median follow-up of 3.8 years, the primary endpoint occurred in 39 (15.8 %) patients. Irrespective of diabetes, high urinary L-FABP correlated with the development of ESRD and CVD. The areas under the receiver-operator characteristic curves (AUCs) for predicting the primary endpoint for urinary concentrations of L-FABP, albumin, and NAG were 0.825, 0.797, and 0.722, respectively. Cox regression analyses, which were adjusted for factors known to influence the primary endpoint, including patient characteristics, and serum and urinary parameters, demonstrated that the primary outcome was associated with high urinary L-FABP and low eGFR [p = 0.049, hazard ratio = 1.341 (95 % CI 1.005-1.790); and p < 0.000, hazard ratio = 0.953 (95 % CI 0.930-0.976), respectively]. CONCLUSIONS: Urinary L-FABP may be a useful prognostic marker of progression to ESRD and the onset of CVD in patients with CKD.

Clinical usefulness of urinary liver-type fatty-acid-binding protein as a perioperative marker of acute kidney injury in patients undergoing endovascular or open-abdominal aortic aneurysm repair.

PURPOSE: Acute kidney injury (AKI) is common after cardiovascular surgery and is usually diagnosed on the basis of the serum creatinine (SCr) level and urinary output. However, SCr is of low sensitivity in patients with poor renal function. Because urinary liver-type fatty-acid-binding protein (L-FABP) reflects renal tubular injury, we evaluated whether perioperative changes in urinary L-FABP predict AKI in the context of abdominal aortic repair. METHODS: Study participants were 95 patients who underwent endovascular abdominal aortic aneurysm repair (EVAR) and 42 who underwent open repair. We obtained urine samples before surgery, after anesthesia induction, upon stent placement, before aortic cross-clamping (AXC), 1 and 2 h after AXC, at the end of surgery, 4 h after surgery, and on postoperative days (PODs) 1, 2, and 3, for measurement of L-FABP. We obtained serum samples before surgery, immediately after surgery, and on PODs 1, 2, and 3, for measurement of SCr. We also plotted receiver-operating characteristic (ROC) curves to identify cutoff laboratory values for predicting the onset of AKI. RESULTS: With EVAR, urinary L-FABP was significantly increased 4 h after the procedure (P = 0.014). With open repair, urinary L-FABP increased significantly to its maximum by 2 h after AXC (P = 0.007). With AKI, SCr significantly increased (P < 0.001, P = 0.001) by POD 2. ROC analysis showed urinary L-FABP to be more sensitive than SCr for early detection of AKI. CONCLUSION: Urinary L-FABP appears to be a sensitive biomarker of AKI in patients undergoing abdominal aortic repair.

Human liver-type fatty acid-binding protein protects against tubulointerstitial injury in aldosterone-induced renal injury.

To demonstrate the renoprotective function of human liver-type fatty acid-binding protein (hL-FABP) expressed in proximal tubules in aldosterone (Aldo)-induced renal injury, hL-FABP chromosomal transgenic (Tg) and wild-type (WT) mice received systemic Aldo infusions (Tg-Aldo and WT-Aldo, respectively) were given 1% NaCl water for 28 days. In this model, elevation of systolic blood pressure, monocyte chemoattractant protein-1 expression, macrophage infiltration in the interstitium, tubulointerstitial damage, and depositions of type I and III collagens were observed. Elevation of systolic blood pressure did not differ in WT-Aldo vs. Tg-Aldo animals, however, renal injury was suppressed in Tg-Aldo compared with WT-Aldo mice. Dihydroethidium fluorescence was used to evaluate reactive oxidative stress, which was suppressed in Tg-Aldo compared with WT-Aldo mice. Gene expression of angiotensinogen in the kidney was upregulated, and excretion of urinary angiotensinogen was increased in WT-Aldo mice. This exacerbation was suppressed in Tg-Aldo mice. Expression of hL-FABP was upregulated in proximal tubules of Tg-Aldo mice. Urinary excretion of hL-FABP was significantly greater in Tg-Aldo than in Tg-control mice. In conclusion, hL-FABP ameliorated the tubulointerstitial damage in Aldo-induced renal injury via reducing oxidative stress and suppressing activation of the intrarenal renin-angiotensin system.