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.

The Role of Elevated Liver-Type Fatty Acid-Binding Proteins in Liver Diseases.

Liver-type fatty acid-binding protein (L-FABP) is mainly expressed in the liver as well as the proximal tubular epithelial cells in the kidney. In general, the proteins and enzymes existing within the hepatocytes have the potential to become biomarkers, for instance alanine aminotransferase, which reflects hepatocellular damage. However, due to reduced hepatocellular function in late stage of chronic liver diseases (e.g. cirrhosis), proteins and enzymes relating to hepatocellular damage are not always accurate measures of disease progression. Recently, several publications have demonstrated elevated serum L-FABP levels during the progression of human liver diseases, including hepatocellular carcinoma (HCC), and were a prognostic factor for survival in acute and chronic liver disease patients. However, the study regarding serum L-FABP levels and hepatic L-FABP expression in liver diseases is not sufficient to understand the molecular mechanism of L-FABP during the progression of these disease states. In this review, we focus on the use of serum and/or hepatic L-FABP expression as a biomarker in human liver diseases, including mechanistic potential in HCC.

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.

Urine Biomarkers and Perioperative Acute Kidney Injury: The Impact of Preoperative Estimated GFR.

BACKGROUND: The interaction between baseline kidney function and the performance of biomarkers of acute kidney injury (AKI) on the development of AKI is unclear. STUDY DESIGN: Post hoc analysis of prospective cohort study. SETTING & PARTICIPANTS: The 1,219 TRIBE-AKI Consortium adult cardiac surgery cohort participants. PREDICTOR: Unadjusted postoperative urinary biomarkers of AKI measured within 6 hours of surgery. OUTCOME: AKI was defined as AKI Network stage 1 (any AKI) or higher, as well as a doubling of serum creatinine level from the preoperative value or the need for post-operative dialysis (severe AKI). MEASUREMENTS: Stratified analyses by preoperative estimated glomerular filtration rate (eGFR) ≤ 60 versus > 60mL/min/1.73m(2). RESULTS: 180 (42%) patients with preoperative eGFRs≤60mL/min/1.73m(2) developed clinical AKI compared with 246 (31%) of those with eGFRs>60mL/min/1.73m(2) (P<0.001). For log2-transformed biomarker concentrations, there was a significant interaction between any AKI and baseline eGFR for interleukin 18 (P=0.007) and borderline significance for liver-type fatty acid binding protein (P=0.06). For all biomarkers, the adjusted relative risk (RR) point estimates for the risk for any AKI were higher in those with elevated baseline eGFRs compared with those with eGFRs≤60mL/min/1.73m(2). However, the difference in magnitude of these risks was low (adjusted RRs were 1.04 [95% CI, 0.99-1.09] and 1.11 [95% CI, 1.07-1.15] for those with preoperative eGFRs≤60mL/min/1.73m(2) and those with higher eGFRs, respectively). Although no biomarker displayed an interaction for baseline eGFR and severe AKI, log2-transformed interleukin 18 and kidney injury molecule 1 had significant adjusted RRs for severe AKI in those with and without baseline eGFRs≤60mL/min/1.73m(2). LIMITATIONS: Limited numbers of patients with severe AKI and post-operative dialysis. CONCLUSIONS: The association between early postoperative AKI urinary biomarkers and AKI is modified by preoperative eGFR. The degree of this modification and its impact on the biomarker-AKI association is small across biomarkers. Our findings suggest that distinct biomarker cutoffs for those with and without a preoperative eGFR≤60mL/min/1.73m(2) is not necessary.

Urinary, Plasma, and Serum Biomarkers' Utility for Predicting Acute Kidney Injury Associated With Cardiac Surgery in Adults: A Meta-analysis.

BACKGROUND: Early accurate detection of acute kidney injury (AKI) occurring after cardiac surgery may improve morbidity and mortality. Although several novel biomarkers have been developed for the early detection of AKI, their clinical utility in the critical intraoperative and immediate postoperative period remains unclear. STUDY DESIGN: Systematic review and meta-analysis. SETTING & POPULATION: Adult patients having cardiac surgery. SELECTION CRITERIA FOR STUDIES: EMBASE, CINAHL, Cochrane Library, Scopus, and PubMed from January 1990 until January 2015 were systematically searched for cohort studies reporting the utility of novel biomarkers for the early diagnosis of AKI after adult cardiac surgery. Reviewers extracted data for study design, population, timing of biomarker measurement and AKI occurrence, biomarker performance (area under the receiver operating characteristic curve [AUROC]), and risk of bias. INDEX TESTS: Novel urine, plasma, and serum AKI biomarkers, measured intraoperatively and in the early postoperative period (<24 hours). REFERENCE TESTS: AKI was defined according to the RIFLE, AKIN, or 2012 KDIGO criteria. RESULTS: We found 28 studies reporting intraoperative and/or early postoperative measurement of urine (n=23 studies) or plasma or serum (n=12 studies) biomarkers. Only 4 of these studies measured biomarkers intraoperatively. Overall, intraoperative discrimination by the urine biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury marker 1 (KIM-1) demonstrated AUROCs<0.70, whereas N-acetyl-ß-d-glucosaminidase (NAG) and cystatin C had AUROCs<0.75. In the immediate 24-hour postoperative period, the urine biomarkers NGAL (16 studies), KIM-1 (6 studies), and liver-type fatty acid binding protein (6 studies) exhibited composite AUROCs of 0.69 to 0.72. The composite AUROCs for postoperative urine cystatin C, NAG, and interleukin 18 were ≤0.70. Similarly, the composite AUROCs for postoperative plasma NGAL (6 studies) and cystatin-C (5 studies) were <0.70. LIMITATIONS: Heterogeneous AKI definitions. CONCLUSIONS: In adults, known urinary, plasma, and serum biomarkers of AKI possess modest discrimination at best when measured within 24 hours of cardiac surgery.

Renoprotective effects of febuxostat in hyperuricemic patients with chronic kidney disease: a parallel-group, randomized, controlled trial.

BACKGROUND: Hyperuricemia is associated with the onset of chronic kidney disease (CKD) and renal disease progression. Febuxostat, a novel, non-purine, selective xanthine oxidase inhibitor, has been reported to have a stronger effect on hyperuricemia than conventional therapy with allopurinol. However, few data are available regarding the clinical effect of febuxostat in patients with CKD. METHODS: A prospective, randomized, open-label, parallel-group trial was conducted in hyperuricemic patients with stage 3 CKD. Patients were randomly assigned to treatment with febuxostat (n = 21) or to continue conventional therapy (n = 19). Treatment was continued for 12 weeks. The efficacy of febuxostat was determined by monitoring serum uric acid (UA) levels, blood pressures, renal function, and urinary protein levels. In addition, urinary liver-type fatty acid-binding protein (L-FABP), urinary albumin, urinary beta 2 microglobulin (ß2MG), and serum high sensitivity C-reactive protein were measured before and 12 weeks after febuxostat was added to the treatment. RESULTS: Febuxostat resulted in a significantly greater reduction in serum UA (-2.2 mg/dL) than conventional therapy (-0.3 mg/dL, P < 0.001). Serum creatinine and estimated glomerular filtration rate changed little during the study period in each group. However, treatment with febuxostat for 12 weeks reduced the urinary levels of L-FABP, albumin, and ß2MG, whereas the levels of these markers did not change in the control group. CONCLUSION: Febuxostat reduced serum UA levels more effectively than conventional therapy and might have a renoprotective effect in hyperuricemic patients with CKD. Further studies should clarify whether febuxostat prevents the progression of renal disease and improves the prognosis of CKD.

Assessment of Cardiopulmonary Bypass Duration Improves Novel Biomarker Detection for Predicting Postoperative Acute Kidney Injury after Cardiovascular Surgery.

Urinary liver-type fatty acid binding protein (L-FABP) is a novel biomarker with promising performance in detecting kidney injury. Previous studies reported that L-FABP showed moderate discrimination in patients that underwent cardiac surgery, and other studies revealed that longer duration of cardiopulmonary bypass (CPB) was associated with a higher risk of postoperative acute kidney injury (AKI). This study aims to examine assessing CPB duration first, then examining L-FABP can improve the discriminatory ability of L-FABP in postoperative AKI. A total of 144 patients who received cardiovascular surgery were enrolled. Urinary L-FABP levels were examined at 4 to 6 and 16 to 18 h postoperatively. In the whole study population, the AUROC of urinary L-FABP in predicting postoperative AKI within 7 days was 0.720 at 16 to 18 h postoperatively. By assessing patients according to CPB duration, the urinary L-FABP at 16 to 18 h showed more favorable discriminating ability with AUROC of 0.742. Urinary L-FABP exhibited good performance in discriminating the onset of AKI within 7 days after cardiovascular surgery. Assessing postoperative risk of AKI through CPB duration first and then using urinary L-FABP examination can provide more accurate and satisfactory performance in predicting postoperative AKI.

Temporal changes in urinary excretion of liver-type fatty acid binding protein (L-FABP) in acute kidney injury model of domestic cats: a preliminary study.

Liver-type fatty acid-binding protein (L-FABP) is a biomarker for the early detection of renal diseases in humans. It is secreted along with cytotoxic oxidation products from proximal tubular epithelial cells under conditions of ischemia and/or oxidative stress. This study examined urinary L-FABP excretion under renal ischemia in feline acute kidney injury (AKI) model. L-FABP excretion increased immediately after renal ischemia/reperfusion, despite the absence of obvious structural damage to the kidneys, in the two AKI model cats studied. L-FABP was detected in the renal tubular lumen immediately after renal ischemia/reperfusion in the two cats, but not in a sham surgery cat. These results suggested that high L-FABP excretion is a pathophysiological response associated with antioxidant defense in proximal tubules with renal ischemia and/or oxidative stress in a feline model.

Clinical application of biomarkers in DCD donor kidney perfusate for predicting delayed graft function after renal transplantation / 器官移植

Objective To explore the feasibility of biomarkers in static cold storage (SCS) perfusate of donor kidney from donation after cardiac death (DCD) for predicting delayed graft function (DGF) after renal transplantation. Methods Clinical data of 64 recipients and 47 donors undergoing DCD renal transplantation were retrospectively analyzed. All recipients were divided into the DGF group (n=7) and immediate graft function (IGF) group (n=57) according to the incidence of postoperative DGF in the recipients. The levels of neutrophil gelatinase-associated lipocalin (NGAL), liver-type fatty acid-binding protein (L-FABP), interleukin -18(IL-18) and kidney injury molecule-1 (KIM-1) in the SCS perfusate were statistically compared between two groups, and the correlation with DGF was analyzed. The predictive value of each biomarker in the occurrence of DGF in recipients after renal transplantation was analyzed. Results The incidence of DGF in the recipients undergoing DCD renal transplantation was 11% (7/64). The NGAL level in the donor kidney perfusate of the DGF group was significantly higher than that in the IGF group (P=0.009). The NGAL level in the donor kidney perfusate was positively correlated with the incidence of DGF in recipients after renal transplantation (r=0.430, P < 0.001). The receiver operating characteristic (ROC) curve analysis showed that the increased levels of NGAL and KIM-1 in the perfusate yielded certain predictive value for DGF in recipients after renal transplantation (both P < 0.05). The area under the curve (AUC) of combined detection of NGAL and KIM-1 for predicting DGF in recipients after renal transplantation was 0.932 [95% confidence interval (CI) 0.850-1.000]. The sensitivity was calculated as 1.000 and 0.754 for the specificity (P < 0.05). Conclusions The NGAL level in the SCS perfusate of DCD donor kidney is associated with the occurrence of DGF in recipients after renal transplantation. Combined detection of NGAL and KIM-1 levels in the perfusate may accurately predict the occurrence of DGF in recipients after renal transplantation.

Urinary liver-type fatty acid-binding protein change in gestational diabetes mellitus.

We compared urinary liver-type fatty acid-binding protein (L-FABP) among non-pregnant and pregnant women with and without gestational diabetes mellitus (GDM). Higher urinary L-FABP was found in pregnant with and without GDM, and considerably higher urinary L-FABP was found in the GDM group compared with the non-GDM group. Hyperglycemia and anemia were related with high urinary L-FABP expression.

Epoetin beta pegol alleviates oxidative stress and exacerbation of renal damage from iron deposition, thereby delaying CKD progression in progressive glomerulonephritis rats.

The increased deposition of iron in the kidneys that occurs with glomerulopathy hinders the functional and structural recovery of the tubules and promotes progression of chronic kidney disease (CKD). Here, we evaluated whether epoetin beta pegol (continuous erythropoietin receptor activator: CERA), which has a long half-life in blood and strongly suppresses hepcidin-25, exerts renoprotection in a rat model of chronic progressive glomerulonephritis (cGN). cGN rats showed elevated urinary total protein excretion (uTP) and plasma urea nitrogen (UN) from day 14 after the induction of kidney disease (day 0) and finally declined into end-stage kidney disease (ESKD), showing reduced creatinine clearance with glomerulosclerosis, tubular dilation, and tubulointerstitial fibrosis. A single dose of CERA given on day 1, but not on day 16, alleviated increasing uTP and UN, thereby delaying ESKD. In the initial disease phase, CERA significantly suppressed urinary 8-OHdG and liver-type fatty acid-binding protein (L-FABP), a tubular damage marker. CERA also inhibited elevated plasma hepcidin-25 levels and alleviated subsequent iron accumulation in kidneys in association with elevated urinary iron excretion and resulted in alleviation of growth of Ki67-positive tubular and glomerular cells. In addition, at day 28 when the exacerbation of uTP occurs, a significant correlation was observed between iron deposition in the kidney and urinary L-FABP. In our study, CERA mitigated increasing kidney damage, thereby delaying CKD progression in this glomerulonephritis rat model. Alleviation by CERA of the exacerbation of kidney damage could be attributable to mitigation of tubular damage that might occur with lowered iron deposition in tubules.

Urinary liver type fatty acid binding protein in diabetic nephropathy.

Deterioration of diabetic nephropathy (DN) is largely determined by the degree of tubulointerstitial changes rather than the extent of histological changes in the glomeruli. Therefore, a tubular marker that accurately reflects tubulointerstitial damage may be an excellent biomarker for early detection or prediction of DN. Liver-type fatty-acid binding protein (L-FABP) is a 14 kDa small molecule that is expressed in the cytoplasm of human proximal tubules. In vivo experimental studies revealed that renal L-FABP gene expression was up-regulated by various stresses that cause tubulointerstitial damage, such as massive proteinuria, hyperglycemia, hypertension, ischemia and toxins, and that urinary excretion of L-FABP was increased. Recent clinical studies of patients with type 1 or type 2 diabetes demonstrated that urinary excretion of L-FABP derived from proximal tubules is a suitable biomarker for predicting and monitoring deterioration of renal function in DN. Moreover, therapeutic interventions with renoprotective effects reduced urinary L-FABP concentrations. Therefore, urinary L-FABP measured using the Human L-FABP ELISA Kit developed by CMIC Co., Ltd. (Tokyo, Japan) was confirmed as a newly established tubular biomarker by the Ministry of Health, Labour and Welfare in Japan in 2010. This review article summarizes the clinical significance of urinary L-FABP in DN.