Liver-type Fatty Acid-binding Protein Levels Research Articles

Abstract 3460: Liver-type Fatty Acid-binding Protein Is A Promising Predictive Marker Of Contrast-induced Nephropathy

Contrast-induced nephropathy (CIN), a well-known complication of contrast media exposure for the patients with chronic kidney disease (CKD), may results from acute tubular necrosis. Although 4 to 11 percent with mild to moderate renal insufficiency develop CIN, there were no biological markers to more accurately predict the occurrence of CIN than the existing makers such as serum creatinine (sCr). Liver-type fatty acid-binding protein (L-FABP) as a novel maker, is an intracellular carrier protein of free fatty acids that marked upregulated and expressed abundantly in proximal tubules after renal ischemia.We prospectively investigated whether urinary L-FABP is an alternative maker of predicting CIN. Methods: We enrolled sixty-five patients (46 male, 71.8 ± 8.2years) undergoing scheduled coronary angiography who had mild kidney disease with CKD stage3 (glomelurar filtration ratio (GFR) <60 ml/1.73 m 2 or albuminuria (u-Alb)≥ 300 mg/gCRE), treated with one-half isotonic (0.45 percent) saline between 12 hours before and after the procedure. We measured urinary L-FABP, u-Alb,β 2 -microglobulin, α 1 -microglobulin, sCr and NAG( N -acetyl-β-d-glucosaminidase). CIN was defined as an increase of sCr of >25% or 0.5 mg/dl (44.2micromol/l) within 2 days of contrast. The cohort was divided into two groups according to occurrence of CIN; CIN-G and nonCIN-G. Results: CIN occurred in 4 of 65 patients (6%). Demographics, the pre-procedural level of makers (β 2 -microglobulin, α 1 -microglobulin, sCr, NAG) and used contrast volume are no significant differences between the two groups. Pre-procedural urinary L-FABP levels were significantly greater in CIN-G than in nonCIN-G(112.5 ± 81.4μg/g Cr;19.7 ± 43μg/g Cr; P< 0.01) as well as u-Alb (CIN-G;1711.3 31386.6 mg/gCRE nonCIN-G; 192.3 3482.3 mg/gCRE Cr; P < 0.01). On the basis of ROC curve of urinary parameters , u-Alb and urinary L-FABP had the significantly high predictive value than other markers(p<0.05). Conclusion: Urinary L-FABP combined with u-Alb can be more accurate markers to predict the risk of CIN than other existing urinary parameters.

Azelnidipine Reduces Urinary Protein Excretion and Urinary Liver-Type Fatty Acid Binding Protein in Patients with Hypertensive Chronic Kidney Disease

Hypoxia plays a significant role in the pathogenesis and progression of chronic renal disease. Urinary liver-type fatty acid binding protein (L-FABP) levels reflect the clinical prognosis of chronic renal disease. The calcium channel blocker azelnidipine has anti-oxidative properties and these may contribute to the beneficial effects of this drug. The aim of the present study was to determine whether azelnidipine and/or amlodipine affected urinary protein excretion or the urinary levels of 8-OHdG and L-FABP in hypertensive patients with mild chronic kidney disease (CKD). Thirty moderately hypertensive chronic kidney disease patients were randomly assigned to 2 treatment groups: azelnidipine 16 mg once daily or amlodipine 5 mg once daily. Treatment was continued for 6 months. Urinary protein excretion and urinary levels of 8-OHdG and urinary L-FABP were measured before 3 and 6 months after the treatment period. Both drugs exhibited comparable and significant effects on the systolic and diastolic blood pressure. Azelnidipine decreased heart rate significantly after 3 and 6 months whereas amlodipine increased it significantly after 3 and 6 months. Urinary protein excretion, urinary 8-OHdG and urinary L-FABP levels decreased significantly after 3 months (p < 0.05) and 6 months (p < 0.05) in the azelnidipine group. In contrast, amlodipine showed little effect on urinary protein excretion or the urinary levels of 8-OHdG and L-FABP throughout the experimental period. Azelnidipine is renoprotective in hypertensive patients with mild CKD and this action is, at least in part, due to the anti-oxidative effect.

Possible Role of Fatty Acids in Milk as the Regulator of the Expression of Cytosolic Binding Proteins for Fatty Acids and Vitamin A through PPAR.ALPHA. in Developing Rats

Fatty acids in milk are thought to play an important role in intestinal maturation and gene expression in the postnatal small intestine. In this study, we determined the jejunal mRNA levels, in rats, of peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARdelta which are nuclear receptors for fatty acids. We also measured expression of their target genes during the postnatal period, namely liver type fatty acid-binding protein (L-FABP) and cellular retinol-binding protein, type II (CRBPII). The mRNA levels of PPARalpha, L-FABP and CRBPII, but not PPARdelta, gradually increased during the suckling period and then sharply declined to a low level at the end of the weaning period. Rat pups at 17 d of age, weaned to a high-fat diet, showed significantly greater mRNA levels of PPARalpha, L-FABP and CRBPII than those weaned to a low-fat diet. Oral administration of PPARalpha ligand, WY14,643 during four consecutive days of the weanling period caused a parallel increase in the mRNA levels of PPARalpha, L-FABP and CRBPII genes. Furthermore, caprylic acid and oleic acid, which are major components of fatty acids in milk, induced jejunal PPARalpha, L-FABP and CRBPII gene expression. Our results suggest that fatty acids in milk may play a pivotal role in maintaining an enhanced level of expression of L-FABP and CRBPII genes in the small intestine, presumably by acting as inducers of PPARalpha gene expression.

Angiotensin II receptor antagonist reduces urinary liver-type fatty acid-binding protein levels in patients with diabetic nephropathy and chronic renal failure

To the Editor: The incidence of end-stage renal failure due to diabetic nephropathy has increased dramatically over the past 20 years. It is widely accepted that the rate of functional decline correlates with the severity of renal tubulointerstitial lesions. Previous studies have shown that renal function in patients with type 2 diabetes correlates better with tubulointerstitial changes than with glomerular pathology [1]. Further studies on tubulointerstitial injury in patients with diabetic nephropathy may provide additional insight into the pathogenesis of diabetic nephropathy and lead to the identification of therapeutic targets. Several factors play an important role in the progression of renal injury. Oxidative stress is both a cause and consequence of interstitial inflammation [2]. Tissue hypoxia resulting from angiotensin-induced vasoconstriction or from structural disruption of peritubular capillaries is a final common pathway in the development of tubulointerstitial fibrosis. Liver-type fatty acid-binding protein (L-FABP) is produced in the proximal tubules, where it plays a key role in fatty acid metabolism. Stresses to the proximal tubules tend to overload fatty acids in the cytoplasm and thereby damage tubules with the release of inflammatory factors. In this way, tubulointerstitial inflammation is provoked, and renal function deteriorates over time. Urinary excretion of L-FABP increases with the deterioration of kidney function and is a useful clinical marker for monitoring chronic kidney disease [3]. We have reported that urinary L-FABP may be a useful clinical marker for type 2 diabetic nephropathy [4].

Effect of Erythropoietin on Urinary Liver-Type Fatty-Acid-Binding Protein in Patients with Chronic Renal Failure and Anemia

Background/Aim: The urinary liver-type fatty-acid-binding protein (L-FABP) level reflects the clinical progression of chronic kidney disease. We conducted a study to determine whether administration of erythropoietin (EPO), which is produced in response to hypoxic stress, affects urinary protein excretion and L-FABP levels in patients with chronic renal failure (CRF) and anemia. Methods: The study was an interventional trial that included 20 anemic CRF patients (median serum creatinine level 2.0 mg/dl, range 1.3–2.9 mg/dl; median hemoglobin concentration 9.2 g/dl, range 8.2–9.8 g/dl; median estimated glomerular filtration rate 20.5 ml/min, range 15.0–28.0 ml/min; group A). Recombinant EPO (12,000 U twice/month) was given to these patients for 6 months. Urinary protein, L-FABP, 8-hydroxy-2′-deoxyguanosine, and hemoglobin levels were measured before and 3 and 6 months after treatment. Twenty nonanemic CRF patients were enrolled as controls (group B). Results: After 6 months, the hemoglobin level was increased as compared with the baseline level in group A treated with EPO (median 11.3 g/dl, range 9.3–13.8 g/dl, vs. median 9.2 g/dl, range 8.2–9.8 g/dl; p < 0.01) but not in the untreated group B (median 11.8 g/dl, range 10.2–13.0 g/dl, vs. median 12.1 g/dl, range 10.8–13.4 g/dl; not significant). The urinary protein excretion was decreased as compared with the baseline level in group A (median 1.2 g/day, range 0.6–1.9 g/day, vs. median 1.9 g/day, range 1.1–2.6 g/day; p < 0.01) but not in group B (median 1.4 g/day, range 0.7–2.2 g/day, vs. median 1.6 g/day, range 0.7–2.3 g/day; not significant). The urinary L-FABP level was also decreased as compared with the baseline level in group A (median 50.0 µg/g creatinine, range 7.5–90.0 µg/g creatinine, vs. median 115.0 µg/g creatinine, range 20.0–225.0 µg/g creatinine; p < 0.01) but not in group B (median 82.0 µg/g creatinine, range 15.5–158.0 µg/g creatinine, vs. median 76.0 µg/g creatinine, range 25.0–138.5 µg/g creatinine; not significant). The glomerular filtration rate changed little throughout the study period in either group. The urinary 8-hydroxy-2′-deoxyguanosine level was decreased as compared with the baseline level in group A (median 22.0 ng/mg creatinine, range 8.0–30.0 ng/mg creatinine, vs. median 38.5 ng/mg creatinine, range 14.0–68.0 ng/mg creatinine; p < 0.01) but not in group B (median 33.0 ng/mg creatinine, range 9.0–56.0 ng/mg creatinine, vs. median 30.0 ng/mg creatinine, range 10.0–54.0 ng/mg creatinine; not significant). Conclusion: EPO supplementation may ameliorate renal tubular damage, in part, due to a reduction of oxidative stress in CRF patients with anemia.

Effect of Pitavastatin on Urinary Liver-Type Fatty-Acid-Binding Protein in Patients with Nondiabetic Mild Chronic Kidney Disease

Background/Aim: Urinary liver-type fatty-acid-binding protein (L-FABP) is a useful clinical marker in the monitoring of chronic kidney disease (CKD) associated with tubulointerstitial damage. Statins have been shown to be effective in the treatment of renal disease. The aim of the present study was to determine whether pitavastatin, a newly developed statin, modulates the urinary L-FABP levels in normolipidemic patients with CKD. Methods: Thirty normolipidemic mild CKD patients (18 males and 12 females, mean age 40 years, mean serum creatinine level 1.0 mg/dl) were randomly assigned to two groups: (1) pitavastatin (1 mg/day, n = 15) and (2) placebo (n = 15). Urinary protein and urinary L-FABP levels were measured before the initiation of treatment and 3 and 6 months thereafter. Twenty age-matched healthy subjects were also studied as controls. Results: Before treatment, the urinary L-FABP levels in 30 CKD patients (84.0 ± 68.5 µg/g creatinine) were significantly higher than those of healthy subjects (6.4 ± 4.2 µg/g creatinine; p < 0.001). Pitavastatin slightly reduced serum total cholesterol and triglyceride levels, but this was not statistically significant. However, pitavastatin reduced the urinary protein excretion from 1.8 to 1.0 g/day (p < 0.01), while the urinary L-FABP levels fell from 88.5 ± 70.5 to 28.0 ± 16.5 µg/g creatinine (p < 0.01). Conclusion: The present data suggest that pitavastatin ameliorates tubulointerstitial damage in CKD patients independent of the lipid-lowering effect.

Urinary Excretion of Liver-Type Fatty Acid–Binding Protein in Contrast Medium–Induced Nephropathy

Administration of contrast agents can cause a decrease in renal function and, occasionally, end-stage renal disease. Liver-type fatty acid-binding protein (L-FABP) is an intracellular carrier protein of free fatty acids that is expressed in proximal tubules of the human kidney. Whether urinary excretion of L-FABP can predict the occurrence of contrast medium-induced nephropathy was studied. Sixty-six patients (46 men, 20 women; mean age, 60.0 years) undergoing nonemergency coronary angiography or intervention at 1 of our institutions who had a serum creatinine (Cr) level greater than 1.2 mg/dL (> 106 micromol/L) and less than 2.5 mg/dL (< 221 micromol/L) and 30 healthy volunteers (21 men, 9 women; mean age, 56.5 years) were included. Urinary L-FABP levels were measured before and after coronary angiography with the use of monoclonal antibodies. Contrast medium-induced nephropathy is defined as an increase in serum Cr level of greater than 0.5 mg/dL (> 44 micromol/L) or a relative increase of more than 25% at 2 to 5 days after the procedure. Contrast medium-induced nephropathy occurred in 13 of 66 patients (19.7%). Before angiography, urinary L-FABP levels were significantly greater in these 13 patients (contrast medium-induced nephropathy group; 18.5 +/- 12.8 microg/g Cr; range, 5.8 to 33.6 microg/g Cr) than in the remaining 53 patients (non-contrast medium-induced nephropathy group; 7.4 +/- 4.4 microg/g Cr; range, 2.8 to 13.8 microg/g Cr; P < 0.01) or healthy volunteers (5.4 +/- 4.4 microg/g Cr; range, 1.0 to 10.0 microg/g Cr; P < 0.01). The next day and 2 days after angiography, urinary L-FABP levels increased significantly to 46.8 +/- 30.5 microg/g Cr (range, 12.0 to 84.5 microg/g Cr; P < 0.01) and 38.5 +/- 28.5 microg/g Cr (range, 9.5 to 70.5 microg/g Cr; P < 0.01) in the contrast medium-induced nephropathy group, respectively. After 14 days, serum Cr returned to the baseline level, but urinary L-FABP level remained high (34.5 +/- 30.0 microg/g Cr; range, 4.0 to 68.0 microg/g Cr). However, urinary L-FABP levels in the non-contrast medium-induced nephropathy group changed little throughout the experimental period. Urinary L-FABP level can serve clinically as a predictive marker for contrast medium-induced nephropathy.

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.

Urinary liver-type fatty acid-binding protein levels for differential diagnosis of idiopathic focal glomerulosclerosis and minor glomerular abnormalities and effect of low-density lipoprotein apheresis

Focal glomerulosclerosis (FGS) and minor glomerular abnormalities are kidney diseases characterized by massive proteinuria. Urinary liver-type fatty acid-binding protein (L-FABP), an intracellular carrier protein of free fatty acids, is expressed in proximal tubules of the human kidney. Patients with FGS show significant improvement with low-density lipoprotein (LDL) apheresis. The aim of the present study was to determine whether urinary L-FABP levels differ between patients with FGS and those with minor glomerular abnormalities and whether levels are altered by LDL apheresis. There were 24 patients with minor glomerular abnormalities (nephrotic stage, n = 14, remission stage, n = 10), 17 patients with FGS, and 20 healthy age-matched subjects were included in the present study. Urinary L-FABP levels were measured by enzyme-linked immunosorbent assay and compared. All patients with minor glomerular abnormalities at the nephrotic stage received prednisolone for 6 months, and all FGS patients received some form of immunosuppression therapy with prednisolone, cyclophosphamide or mizoribine for 12 months. LDL apheresis was performed in eight FGS patients with drug-resistant nephrotic syndrome. Urinary L-FABP levels were significantly higher in the 17 FGS patients (82.0 +/- 44.4 microg/g.Cr) than in the 24 patients with minor glomerular abnormalities (10.2 +/- 8.4 microg/g.Cr) (p < 0.01) and in the 20 healthy subjects (7.4 +/- 4.2 microg/g.Cr) (p < 0.01). Urinary L-FABP levels differed little between nephrotic stage and remission stage in patients with minor glomerular abnormalities. Urinary L-FABP levels were significantly higher in the eight drug-resistant FGS patients (122.6 +/- 78.4 microg/g.Cr) than in the nine drug-sensitive FGS patients (45.9 +/- 32.0 microg/g.Cr). Urinary L-FABP levels did not correlate with levels of other clinical markers including serum creatinine, urinary protein, and urinary N-acetyl-beta-D- glucosaminidase. In the eight drug-resistant FGS patients, LDL-apheresis significantly reduced urinary protein excretion (p < 0.01) and urinary L-FABP levels (p < 0.01). Urinary L-FABP may be a useful diagnostic indicator for differentiation between FGS and minor glomerular abnormalities. LDL apheresis may be effective in ameliorating tubulointerstitial lesions associated with FGS.

Effect of Pitavastatin on Urinary Liver-Type Fatty Acid–Binding Protein Levels in Patients With Early Diabetic Nephropathy

Liver-type fatty acid-binding protein (l-FABP) is expressed in renal proximal tubules and is reported to be a useful marker for progression of chronic glomerulonephritis. The aim of this study was to determine whether urinary l-FABP levels are altered at various stages of diabetic nephropathy and whether pitavastatin affects urinary l-FABP levels in early diabetic nephropathy. Fifty-eight patients with type 2 diabetes (34 men and 24 women, median age 52 years) and 20 healthy, age-matched subjects (group E) were recruited for the study. The diabetic patients included 12 patients without nephropathy (group A), 20 patients with microalbuminuria (group B), 14 patients with macroalbuminuria and normal renal function (group C), and 12 patients with chronic renal failure but not undergoing hemodialysis (blood creatinine >1.2 mg/dl; mean 2.5 mg/dl, group D). Twenty group B patients were randomly assigned to receive 1 mg/day pitavastatin (10 patients, group B1) or placebo (10 patients, group B2). Treatment was continued for 12 months. Urinary l-FABP levels were measured by enzyme-linked immunosorbent assay. Urinary 8-hydroxydeoxyguanosine and serum free fatty acids (FFAs) were also measured in group B. Urinary l-FABP levels in groups A-D were 6.2 +/- 4.6 microg/g creatinine, 19.6 +/- 13.5 microg/g creatinine, 26.8 +/- 20.4 microg/g creatinine, and 52.4 +/- 46.8 microg/g creatinine, respectively. Urinary l-FABP levels in groups B-D were significantly higher than those in healthy subjects (group E, 5.8 +/- 4.0 microg/g creatinine) (group B, P < 0.05; group C, P < 0.01; group D, P < 0.01). In group B1, urinary albumin excretion (UAE) and urinary l-FABP levels were decreased after pitavastatin treatment (UAE before, 110 +/- 74 microg/min; 6 months, 88 +/- 60 microg/min, P < 0.05; 12 months, 58 +/- 32 microg/min, P < 0.01; l-FABP before, 18.6 +/- 12.5 microg/g creatinine; 6 months, 12.2 +/- 8.8 microg/g creatinine, P < 0.05; 12 months, 8.8 +/- 6.4 microg/g creatinine, P < 0.01). In group B2, UAE and l-FABP levels showed little change during the experimental period. In group B1, urinary 8-hydroxydeoxyguanosine was decreased 12 months after pitavastatin treatment (before 32.5 +/- 19.5 ng/mg creatinine, after 18.8 +/- 14.5 ng/mg creatinine, P < 0.01), but in group B2, these showed little difference during the experimental period. In both groups B1 and B2, serum FFAs showed little difference during the experimental period. Urinary l-FABP levels appear to be associated with the progression of diabetic nephropathy, and pitavastatin may be effective in ameliorating tubulointerstitial damage in early diabetic nephropathy.

Candesartan Reduces Urinary Fatty Acid-Binding Protein Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease

Free fatty acids (FFAs) bound to albumin are overloaded in renal proximal tubules and exacerbate tubulointerstitial damage. Liver-type fatty acid-binding protein (L-FABP) is an intracellular carrier protein of FFAs that is expressed in renal proximal tubules in humans. Urinary L-FABP reflects the clinical prognosis of chronic glomerulonephritis. The aim of the present study was to determine whether urinary L-FABP excretion is altered in patients with autosomal dominant polycystic kidney disease (ADPKD) and whether candesartan cilexetil, an angiotensin II receptor antagonist, affects these levels. Subjects comprised 20 normotensive ADPKD patients (8 men and 12 women, mean age 42.6 years) and 20 age-matched healthy volunteers (8 men and 12 women, mean age 44.0 years). The 20 ADPKD patients participated in a randomized double-blind placebo-controlled study of candesartan cilexetil for 6 months. Urinary L-FABP levels were measured by a newly established ELISA method. Urinary L-FABP levels were significantly higher in ADPKD patients (154.5 +/- 110.6 microg/g Cr) than in healthy subjects (5.5 +/- 3.8 microg/g Cr) (P < 0.001). Candesartan cilexetil reduced urinary L-FABP levels from 168.5 +/- 104.5 microg/g Cr to 98.5 +/- 68.5 microg/g Cr after 3 months (P < 0.01) and to 44.6 +/- 30.8 microg/g Cr after 6 months (P < 0.001). Placebo had no effect on L-FABP levels (before, 140.5 +/- 100.5 microg/g Cr; at 3 months, 148.5 +/- 108.5 microg/g Cr; at 6 months, 150.5 +/- 110.8 microg/g Cr). During the 6 months, serum creatinine, blood urea nitrogen, 24-hour creatinine clearance and blood pressure showed little change in either group. Increased urinary L-FABP levels may be associated with the development of ADPKD, and candesartan cilexetil has a beneficial effect on reducing these levels.

Urinary Liver-Type Fatty Acid-Binding Protein: Discrimination between IgA Nephropathy and Thin Basement Membrane Nephropathy

Background: Microscopic hematuria without proteinuria is a common clinical finding in cases of immunoglobulin A (IgA) nephropathy and of thin basement membrane nephropathy. Liver-type fatty acid-binding protein (L-FABP) is expressed in renal proximal tubules and is reported to be a useful marker of the progression of chronic glomerulonephritis. Aim: To assess urinary L-FABP levels for differential diagnosis in patients with microscopic hematuria but without proteinuria. Methods: This was a multi-center retrospective study. Thirty adult patients who underwent renal biopsy for microscopic hematuria and 20 healthy adult volunteers were included in this study. Urinary L-FABP levels were measured by enzyme-linked immunosorbent assay and compared, particularly between those diagnosed with IgA nephropathy and those diagnosed with thin basement membrane nephropathy. Results: Twelve (40%) patients had IgA nephropathy, 6 (20%) had thin basement membrane nephropathy and 12 (40%) had normal biopsy findings. The urinary L-FABP level was significantly higher in patients with IgA nephropathy (38.4 ± 26.8 µg/g Cr) than in healthy subjects (5.8 ± 4.0 µg/g Cr) (p < 0.01); however, the level in patients with thin basement membrane nephropathy or normal biopsy results was comparable to that in healthy subjects. Follow-up data were available for 11 of the 12 patients with IgA nephropathy who initially had no proteinuria. After 24 months, 4 of the 11 were found to have proteinuria, and the urinary L-FABP level had increased from 40.6 ± 30.5 µg/g Cr to 58.8 ± 40.5 µg/g Cr (p < 0.01). Conclusions: Our data suggest that the urinary L-FABP level can be used to discriminate between IgA nephropathy and thin basement membrane nephropathy in patients with microscopic hematuria.

Evidence for megalin-mediated proximal tubular uptake of L-FABP, a carrier of potentially nephrotoxic molecules

Liver-type fatty acid binding protein (L-FABP) binds with high affinity to hydrophobic molecules including free fatty acid, bile acid and bilirubin, which are potentially nephrotoxic, and is involved in their metabolism mainly in hepatocytes. L-FABP is released into the circulation, and patients with liver damage have an elevated plasma L-FABP level. L-FABP is also present in renal tubules; however, the precise localization of L-FABP and its potential role in the renal tubules are not known. In this study, we examined the cellular and subcellular localization of L-FABP in the rat kidney and tried to determine from where the L-FABP in kidney tissues had originated. Immunohistochemical studies of kidney sections localized L-FABP in the lysosomes of proximal tubule cells (PTC). In rats with carbon tetrachloride (CCl4)-induced acute liver injury, we detected high levels of L-FABP in the circulation and in the kidney compared with those in the control rat by immunoblotting, while reverse transcription-polymerase chain reaction showed that the level of L-FABP mRNA expression in the kidney of CCl4-treated rats was low and did not differ from that in the control rat. When 35S-L-FABP was intravenously administered to rats, the kidneys took up 35S-L-FABP more preferentially than the liver and heart, and histoautoradiography of kidney sections revealed that 35S-L-FABP was internalized via the apical domains of PTC. Quartz-crystal microbalance analysis revealed that L-FABP bound to megalin, a multiligand endocytotic receptor on PTC, in a Ca2+-dependent manner. Degradation assays using megalin-expressing rat yolk sac tumor-derived L2 cells demonstrated that megalin mediated the cellular uptake and catabolism of 125I-L-FABP. In conclusion, circulatory L-FABP was found to be filtered by glomeruli and internalized by PTC probably via megalin-mediated endocytosis. These results suggest a novel renal uptake pathway for L-FABP, a carrier of hydrophobic molecules, some of which may exert nephrotoxic effects.

Clinical evaluation of urinary excretion of liver-type fatty acid-binding protein as a marker for the monitoring of chronic kidney disease: A multicenter trial

To confirm the clinical usefulness of the measurement of urinary liver-type fatty acid-binding protein (L-FABP) in chronic kidney disease (CKD), we carried out a multicenter trial. Clinical markers were measured in patients with nondiabetic CKD (n = 48) every 1 to 2 months for a year. We divided patients retrospectively into progression (n = 32) and nonprogression (n = 16) groups on the basis of the rate of disease progression, then assessed several clinical markers. Initially creatinine clearance (Ccr) was similar in the 2 groups; however, the urinary L-FABP level was significantly higher in the former group than in the latter (111.5 vs 53 microg/g creatinine, P < .001). For the monitoring CKD, we set the cutoff values for urinary L-FABP and urinary protein at 17.4 microg/g creatinine and 1.0 g/g creatinine, respectively. Urinary L-FABP was more sensitive than urinary protein in predicting the progression of CKD (93.8% and 68.8%, respectively). However, urinary protein showed greater specificity than did urinary L-FABP (93.8% and 62.5%, respectively). Over time, the progression of CKD tended to correlate with changes in urinary L-FABP (r = - .32, P < .05), but not in urinary protein (r = .18, not significant). The dynamics of urinary protein differed from that of urinary L-FABP, which increased as Ccr declined. Urinary L-FABP is more sensitive than urinary protein in predicting the progression of CKD. Urinary excretion of L-FABP increases with the deterioration of kidney function. Urinary L-FABP is therefore a useful clinical marker in the monitoring of CKD.