Urinary fatty acid binding protein in renal disease

Clinica Chimica Acta 374 (2006) 1 – 7 www.elsevier.com/locate/clinchim

Invited critical review

Urinary fatty acid binding protein in renal disease Atsuko Kamijo-Ikemori a,b , Takeshi Sugaya a,c , Kenjiro Kimura a,⁎ a

Division of Nephrology and Hypertension, Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, 216-8511, Tokyo, Japan b Department of Anatomy, St. Marianna University School of Medicine, Kawasaki, Tokyo, Japan c CMIC CO. Ltd., Tokyo, Japan Received 12 April 2006; received in revised form 19 May 2006; accepted 27 May 2006 Available online 3 June 2006

Abstract The number of patients with end stage renal failure has been increasing throughout the world. The importance of measuring clinical parameters in renal injury has been emphasized for administering appropriate treatment and preventing a worsening of the disease. However, there are no clinically useful markers in predicting and monitoring the progression of renal disease. Liver type fatty acid binding protein (L-FABP) of 14.4 kDa is expressed in human proximal tubules. In order to evaluate the clinical significance of urinary L-FABP as a biomarker in renal disease, a monoclonal antibody against human L-FABP was developed and a two step sandwich enzyme linked immunosorbent assay (ELISA) method was established for determining human L-FABP in urine. In some clinical studies, urinary excretion of L-FABP was shown to be an excellent clinical marker that can help predict and monitor the progression of renal disease. The dynamics of renal L-FABP in pathophysiological settings has been revealed in experimental studies using transgenic mice with the human L-FABP gene. This review presents recent findings on the function and pathophysiological role of L-FABP, and summarizes the clinical importance of measuring urinary L-FABP in renal disease. © 2006 Elsevier B.V. All rights reserved. Keywords: Liver type fatty acid binding protein; Renal disease; Fatty acid; Tubulointerstitial damage; ELISA; Biomarker

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Function of L-FABP . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiological role of L-FABP. . . . . . . . . . . . . . . . . . . Clinical significance of measuring urinary L-FABP . . . . . . . . . . 4.1. Assays for urinary human L-FABP . . . . . . . . . . . . . . . 4.2. Reference values of urinary L-FABP . . . . . . . . . . . . . . 4.3. Clinical significance of urinary L-FABP . . . . . . . . . . . . 4.4. Mechanism by which urinary excretion of L-FABP increases in 4.5. Urinary other type FABP . . . . . . . . . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

⁎ Corresponding author. Tel.: +81 44 977 8111; fax: +81 44 977 7873. E-mail address: [email protected] (K. Kimura). 0009-8981/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2006.05.038

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1. Introduction Renal disease is a worldwide public health problem. The progression of renal disease leads to end stage renal failure, which requires renal replacement therapy, such as hemodialysis, peritoneal dialysis or kidney transplantation to maintain life. In many countries, there is a rising incidence and prevalence of renal failure with poor outcomes and high cost. Furthermore, individuals with renal disease are more likely to die of cardiovascular disease (CVD) than those without renal disease, and thus renal disease is considered to be an independent risk factor for the development and progression of CVD [1]. Therefore, the detection of the progression factors of renal disease is important for decreasing the number of patients with end stage renal failure, for reducing the associated cardiovascular risk in these patients, for promoting the welfare of the patients with renal disease, and for suppressing the increase in medical expenses. Accumulating evidence has suggested that the progression to end stage renal failure is correlated more with the extent of tubulointerstitial damage than with glomerular injury [2– 5]. Although there are many factors causing tubulointerstitial injury, such as urinary protein [6–10], complement components [11], transferin [12] and oxidized low density lipoprotein filtered through the glomeruli [13], and tubular hypoxia induced by loss of peritubular capillaries [14], urinary protein is the particularly noteworthy factor to play a deleterious role in the progression of renal damage. In massive-scale clinical studies including the Modification of Diet in Renal Disease (MDRD) [15] and Reduction in Endpoints in Noninsulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonists Losartan (RENAAL), it was revealed that reduction in urinary protein was associated with a proportional effect on renal protection [16–18]. However, the mechanisms by which urinary protein provokes tubulointerstitial damage are not clear. Free fatty acids (FFA) are bound to albumin [19], filtered through the glomeruli, and reabsorbed into the proximal tubules [20]. In massive proteinuria, FFAs are overloaded in the proximal tubules and induce inflammatory (including macrophage chemotactic) factors [21,22], which in turn aggravate urinary protein-related tubulointerstitial damage [23–28]. Moreover, FFAs were reported to be overloaded to the proximal tubule not only in massive proteinuria, but also in other stress conditions that contribute to the progression of renal disease such as ischemia [29] and toxic insults [30]. FFAs are, thus, considered to be responsible for a common mechanism leading to tubulointerstitial damage seen in various renal diseases. FFAs loaded to the proximal tubules are bound to cytoplasmic fatty acid binding protein (FABP) and transported to mitochondria or peroxisomes, where they are metabolized by way of β-oxidation [31,32]. In the human kidney, 2 types of FABPs have been identified [33]: livertype FABP (L-FABP) of 14.4 kDa, which is expressed in the proximal tubule; and a heart-type FABP (H-FABP), which is

expressed in the distal tubule. Expression of the L-FABP gene is induced by FFAs; L-FABP may regulate the metabolism of FFAs and may be a key regulator of FFA homeostasis in the cytoplasm. However, renal L-FABP has not yet been investigated under pathological conditions of renal diseases. Various types of FABP, such as heart-type FABP (H-FABP) [34–38], brain-type FABP (B-FABP) [39], intestinal-type FABP (I-FABP) [40–42] and liver-type FABP (L-FABP) [42– 46] are known as early and sensitive plasma markers of tissue injury. H-FABP is especially warranted as the most sensitive plasma marker for myocardial injury [47,48]. However, to our knowledge, there have been no clinical observations showing that urinary FABP is a novel marker for various diseases. This review is focused on L-FABP as a useful urinary marker in renal disease. The current knowledge relating to the function and pathophysiological role of L-FABP is discussed, and the importance of measuring urinary L-FABP in renal disease is emphasized. 2. Function of L-FABP Fatty acid-binding proteins (FABPs) belong to the family of lipid-binding proteins. The many different types of FABPs can be divided into two main groups: those associated with the plasma membrane and the intracellular or cytoplasmic proteins [45]. Approximately 9 tissue-specific cytoplasmic FABPs, which are 14- to 15-kDa proteins of 126–134 amino acids, have been identified and named after the tissue in which they were first isolated or first identified. L-FABP is expressed not only in the liver, but also in the proximal tubules of kidney, pancreas and small intestine [49]. L-FABP is capable of binding long chain and very long chain FAs (saturated, unsaturated and branched FAs) and other hydrophobic ligands, such as lysophosphatidic acids, eicosanoids, cholesterol, fatty acyl-CoAs, bile salts heme and hypolipidaemic drugs such as fibrates known as peroxisome proliferators [50, 51]. Richieri et al. found that in contrast to other FABPs, L-FABP had two FA-binding sites/monomer [52]. Moreover, Nemecz et al. revealed that L-FABP bound 2 mol of ligand/mol of protein [53,54]. Although the function of L-FABP in the proximal tubules of the kidney is not known, it is presumed to be the same as in the liver. The function of L-FABP in liver has been widely researched in vitro using cells expressing L-FABP or in vivo using L-FABP gene-ablated mice. The various roles ascribed to L-FABP are: •

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Cellular uptake of FAs from the plasma and utilization through rapid incorporation into triacylglycerols and phospholipids [43,55–58]: L-FABP deficient mice showed marked reduction in FA uptake and a decrease in intracellular triacylglycerol level [55,58]. Promotion of FA metabolism in mitochondria or peroxisomes [59–62]: In vitro study using isolated hepatocytes from LFABP knock-out mice showed that the intracellular level of L-FABP might directly affect the rate of FA β-oxidation in

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•

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mitochondria or peroxisomes [60,62], or microsomal esterification of FA [60]. Regulation of intracellular cholesterol metabolism [56,63]: In L-FABP null female mice fed a cholesterol-rich diet, hepatic cholesterol and neutral lipid (triacylglycerol, cholesterol ester) accumulation were shown to be increased [56,63]. Regulation of gene expression involved in lipid metabolism [64–67]: L-FABP is observed not only in the cytosol, but also in the nucleus [64,65]. In localization studies using laserscanning microscopy, it was found that L-FABP and peroxisome proliferator-activated receptor α (PPARα), of which the latter is a key regulator of lipid homeostasis and target for FAs, colocalized in the nucleus of mouse primary hepatocytes [67]. Furthermore, a strict correlation of PPARα transactivation with intracellular concentration of L-FABP was also observed [67]. Modulation of cell growth and proliferation [68]: L-FABP was reported to be a specific mediator of mitogenesis induced by two classes of carcinogenic peroxisome proliferators in hepatocytes [68].

3. Pathophysiological role of L-FABP FFAs are widely known to be easily oxidized and to exert oxidative stress on cells. Because the cellular oxidative stress is one of the factors responsible for the promotion of various diseases, an antioxidant defense system plays an important role in preventing the toxic effect of oxidative stress. There is a possibility that L-FABP inhibits the accumulation of intracellular FAs by promoting FA metabolism [43,55–63] and by regulating gene expression involved in FA metabolism [64–67], thereby preventing the oxidation of FFAs. Furthermore L-FABP has a high affinity and capacity to bind long-chain fatty acid oxidation products. L-FABP is therefore likely to be an effective endogenous antioxidant [69,70]. Under oxidative stress conditions induced by hydrogen peroxide and hypoxia/reoxygenation, L-FABP stably transfected Chang liver cells had a reduced reactive oxygen species level versus controls in an inverse proportion to the level of L-FABP expression [71]. This result suggested that L-FABP was an important cellular antioxidant during oxidative stress [71]. In regard to the pathological role of renal L-FABP, no significant differences in the effects of chemical anoxia or high extracellular oleate were observed between non-transfected and L-FABP-cDNA-transfected Madin-Darby canine kidney (MDCK) cells [51]. Although MDCK cells were known to be derived from distal tubules, the role of renal LFABP in the proximal tubules had not been investigated. Because L-FABP is not expressed in murine kidneys [72], we established transgenic mice with the human L-FABP gene [73]. In the nephropathy model with these Tg mice, we found that the expression of L-FABP in the proximal tubules mildly inhibited the tubulointerstitial damage via reducing the tubulointerstitial inflammation [73]. At present, the putative cytoprotective effect of L-FABP in renal disease is being examined.

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4. Clinical significance of measuring urinary L-FABP 4.1. Assays for urinary human L-FABP Although a sandwich ELISA kit for detection of L-FABP in serum or plasma has been developed [43,44], no ELISA kits have been approved for measuring urinary excretion of LFABP. Therefore, we developed monoclonal antibodies FABP-2 and FABP-L from BALB/c mice immunized with the purified recombinant human L-FABP, prepared by using a fusion plasmid system (pMAL-cRI) [73,74]. These antibodies had no cross-reaction with the other family proteins, such as human intestine FABP (hI-FABP), human ileal bile acid-binding protein (hI-BABP), human epithelial FABP (hE-FABP) and human heart FABP (hH-FABP) [73]. The monoclonal antibody, FABP-2, was conjugated to horseradish peroxidase with the use of succinimidyl 4-(N-maleim-idomethyl) cyclohexane-1carboxylate. Ninety-six-well microtiter plates were coated with monoclonal antibody, FABP-L. In the first step, L-FABP in urine binds to the antibody, FABP-L. This then binds in the second step to the horseradish peroxidase-conjugated monoclonal antibody, FABP-2. Such a two-step sandwich ELISA kit developed in collaboration with CMIC Co. Ltd. (Human LFABP ELISA kit) enabled us to measure correctly and specifically urinary L-FABP. Although the calibration range for the previously developed ELISA kit for serum or plasma LFABP was reported to be from 0.0 ng/ml to 4.0 ng/ml [43,44], our ELISA procedure for urinary L-FABP established a range from 4.0 ng/ml to 400 ng/ml [74]. 4.2. Reference values of urinary L-FABP The mean value of urinary L-FABP in normal subjects (n = 150) determined from the log-transformed L-FABP values was 2.6 μg/g creatinine (cr.), and it ranged from 0.4 μg/g cr. (mean − 2S.D.) to 17.0 μg/g cr. (mean + 2S.D.). The logtransformed L-FABP values showed a log-normal distribution across the 150 control subjects [75]. 4.3. Clinical significance of urinary L-FABP Because chronic renal disease deteriorates slowly over a long period, and progresses to end stage renal failure, the measurement of clinical parameters, which enables one to predict or monitor the progression of the disease, is required for preventing the progression of the disease. We found that urinary L-FABP was correlated with the severity of the tubulointerstitial damage which was evaluated in the tissue obtained from renal biopsies [73]. In the patients from outpatient clinics with non-diabetic chronic renal disease (n = 120), the level of urinary L-FABP was significantly higher in patients whose kidney function deteriorated than in those whose kidney function was stable. Therefore urinary L-FABP may be a new and unique clinical marker for predicting the progression of chronic renal disease [74].

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Fig. 1. Urinary L-FABP levels in normal controls and in the non-progression and progression groups. On the basis of Scheffe's multiple-comparison procedure, urinary L-FABP at the start of follow-up was significantly higher in the progression group than in the non-progression group or the normal controls (p < 0.0001). The urinary L-FABP concentration was also significantly greater in the non-progression group than in normal controls. ⁎p < 0.0001 vs normal controls; $p < 0.005 vs normal controls; #p < 0.01 vs non-progression group. The cut off value of urinary L-FABP, 17.4 μg/g cr., and the mean value of urinary L-FABP in normal subjects, 2.6 μg/g cr., are indicated on the vertical axis.

Furthermore, in order to validate the clinical usefulness of urinary L-FABP as a marker of chronic renal disease, we carried out a multicenter trial in patients with non-diabetic chronic renal disease (n = 48) [75]. Clinical markers were measured in patients every 1 to 2 months for a year. The patients were then retrospectively divided into progression (n = 32) and nonprogression (n = 16) groups on the basis of the rate of disease progression, and several clinical markers were assessed. 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 μg/g cr.) (Fig. 1). This multicenter trial also supported urinary L-FABP as a predictor for the progression of chronic renal disease [75]. The sensitivity and specificity of predicting the progression of chronic renal disease, were established by using the cutoff values determined on the basis of a receiver operating characteristic (ROC) curve [75]. By setting the cut off values for urinary L-FABP and urinary protein at 17.4 μg/g cr. and 1.0 g/g cr., respectively, urinary L-FABP was found to be more sensitive than urinary protein which was generally known to be a predictor for the progression of chronic renal disease (93.8% and 68.8%, respectively). However, urinary protein was more specific than urinary L-FABP (93.8% and 62.5%, respectively). Urinary L-FABP may be a useful marker for the screening of kidney function to identify patients who are likely to experience deterioration of renal function in the future. The combined use of urinary L-FABP and urinary protein may allow us to precisely determine the state of chronic renal disease and therefore administer more appropriate treatments to patients affected with chronic renal disease. We also found that urinary L-FABP was useful as a monitoring marker of chronic renal disease [75]. With the progression of renal dysfunction, the level of urinary L-FABP increased significantly while the levels of urinary protein or

urinary N-acetyl-β- D -glucosaminidase (NAG) remained unchanged. The dynamics of other markers differed from that of urinary L-FABP, which increased as Ccr declined. Urinary parameters, which are generally available at present, increase after the occurrence of cellular structural damage: the level of urinary protein or albumin increased after the occurrence of glomerular structural injury and that of urinary NAG after the occurrence of proximal tubular structural injury (Fig. 2). However L-FABP expression in the proximal tubules may be up-regulated in renal disease and urinary excretion of LFABP from the proximal tubules may increase before the occurrence of cellular structural damage (Fig. 2). Therefore, urinary L-FABP may reflect the future course of chronic renal disease. Recently, the level of urinary L-FABP was reported to be correlated with various kinds of renal disease, and the importance of measuring urinary L-FABP was supported by some clinical studies. In focal glomerulosclerosis (FGS) with nephrotic syndrome, the level of urinary L-FABP was significantly higher in the drug-resistant FGS patients than in the drug-sensitive FGS patients [76]. In diabetic nephropathy, the level of urinary L-FABP was reported to increase following the progression of the disease [77,78]. Concerning acute tubular injury, the significance of measuring urinary L-FABP in contrast medium-induced nephropathy was studied in the patients undergoing nonemergency coronary angiography or intervention who had moderate renal dysfunction [79]. Before angiography, renal function was similar between the contrast medium-induced nephropathy (CMN) and non-contrast medium-induced nephropathy (non-CMN) groups. However, the urinary L-FABP level was significantly higher in the former group than in the latter (18.5 vs 7.4 μg/g cr.). Also, in the CMN group, the levels of urinary L-FABP were significantly higher at 24 and 48 h after angiography than before angiography. After 14 days, renal function returned to

Fig. 2. Urinary clinical markers in renal disease. The level of urinary protein increased after the occurrence of glomerular structural injury and that of urinary NAG after the occurrence of proximal tubular structural injury. However LFABP expression in the proximal tubules may be upregulated in renal disease and urinary excretion of L-FABP from the proximal tubules may increase before the occurrence of cellular structural damage.

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the baseline level, but urinary L-FABP level still remained high. In the non-CMN group, urinary L-FABP levels showed little change throughout the experimental period. In both the CMN and non-CMN groups, urinary NAG and urinary β2-microglobulin levels showed little change throughout the experimental period. Urinary L-FABP was thus reported to serve as a predictive marker for CMN [79]. Furthermore, the concentration of urinary L-FABP changed in accordance with the effect of various treatments, such as: low-density lipoprotein apheresis performed in drug-resistant FGS patients [76], peroxisome proliferator-activated receptor gamma agonists used in diabetic nephropathy patients [80], angiotensin II receptor blocker given in autosomal dominant polycystic kidney disease [81] and statins given in diabetic [77] or non-diabetic nephropathy patients [82]. These treatments suppressed the progression of renal injury and significantly reduced the degree of urinary L-FABP. As L-FABP is expressed not only in the kidney, but also in the liver, urinary L-FABP might also have been influenced by serum L-FABP. We evaluated the influence of serum L-FABP derived from the liver upon urinary L-FABP in patients with chronic renal disease. This was motivated by a report in an experimental model which showed that, under normal physiological conditions, L-FABP derived from liver is released into the circulation, filtered through glomeruli and re-absorbed into the proximal tubule. In renal disease however, tubulointerstitial damage reduces proximal tubular re-absorption of L-FABP, and leads to an increased level of urinary L-FABP [83]. Serum LFABP was not correlated with urinary L-FABP in patients with chronic renal disease [84]. These results suggested that serum L-FABP levels do not influence urinary L-FABP levels. 4.4. Mechanism by which urinary excretion of L-FABP increases in renal disease Various stresses such as massive proteinuria, ischemia and toxic insults which cause a progression of tubulointerstitial damage, finally cause an overload of FFAs in the proximal tubules and thereby exacerbate tubulointerstitial damage. The results of an experimental study indicated that renal L-FABP expression was up-regulated and urinary excretion of renal LFABP was accelerated by the accumulation of FFAs [73]. There is a possibility that such a performance of renal L-FABP also occurs in clinical pathophysiological conditions. Therefore, it is conceivable that L-FABP may help maintain a low level of FFAs in the cytoplasm not only by carrying them into mitochondria or peroxisomes for accelerating fatty-acid metabolism, but also by being excreted from the proximal tubules into urine together with FFAs. This potential mechanism, by which urinary excretion of renal L-FABP is accelerated in renal disease, should be clarified in a future study. 4.5. Urinary other type FABP Besides L-FABP, H-FABP expressed in the distal tubules was reported to be associated with early release following tissue injury to the kidneys [85]. In an experimental model, in which

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acute tubulointerstitial damage was mainly induced by injection of the renal toxic agents, the level of urinary H-FABP increased markedly, indicating distal tubular injury and showing the sensitivity of H-FABP compared to other generally used markers [48]. Clinical studies are needed to confirm the usefulness of measuring urinary H-FABP in renal disease. 5. Conclusion Although various FABPs are recognized as plasma markers of various tissue injuries [48], the clinical utility of urinary FABP has not been investigated. An ELISA kit for measuring urinary excretion of L-FABP expressed in the proximal tubules was newly established [73–75,84]. Because the performance of urinary L-FABP may be different from that of other markers, urinary L-FABP has been shown to be a useful marker for early detection or monitoring the progression of renal disease. When used in combination with the usual markers, the measurement of urinary L-FABP enables the precise assessment of the state of the renal disease and therefore the administration of more appropriate treatments to the patients. In the future, the development of automated and rapid analyzers is envisioned for the clinical and practical applications on a large number of the patients with renal disease. Acknowledgements We acknowledge Grants-in-Aid for scientific Research from the Japan Society for the Promotion of Science (13671099). We are grateful to Mr. Akihisa Hikawa (Eiken Chemical Co. Ltd., Tochigi), Mr. Masaya Yamanouchi, Mr. Fumikazu Okumura and Mr. Mitsuhiro Okada (Tanabe Seiyaku Company Limited, Osaka), Ms. Sanae Ogawa (Internal Medicine, University of Tokyo), Ms. Yasuko Ishii and Ms. Ayako Obama (Internal Medicine, St. Marianna University School of Medicine), Drs. Masao Omata and Yasunobu Hirata (Internal Medicine, University of Tokyo), Drs. Toshihiko Ishimitsu (Internal Medicine, Dokyo University School of Medicine, Tochigi), Drs. Atsushi Numabe and Masao Takagi (Tokyo Police Hospital, Tokyo), Drs. Fumiko Tabei and Hirochi Hayakawa (Internal Medicine, Kanto Central Hospital, Tokyo), Drs. Naobumi Mise and Tokuichiro Sugimoto (Internal Medicine, Mitsui Memorial Hospital, Tokyo), Drs. Hiroshi Miura, Hiroyo Sasaki, Tomoya Fujino, Takeo Sato, Takashi Yasuda (Internal Medicine, St. Marianna University School of Medicine) and our many other colleagues. References [1] Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 2003;108:2154–69. [2] Mackensen-Haen S, Bader R, Grund KE, Bohle A. Correlations between renal cortical interstitial fibrosis, atrophy of the proximal tubules and impairment of the glomerular filtration rate. Clin Nephrol 1981; 15:167–71.

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A. Kamijo-Ikemori et al. / Clinica Chimica Acta 374 (2006) 1–7

[3] Risdon RA, Sloper JC, De Wardener HE. Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis. Lancet 1968; 2:363–6. [4] Schainuck LI, Striker GE, Cutler RE, Benditt EP. Structural–functional correlations in renal disease: II. The correlations. Hum Pathol 1970;1:631–41. [5] Striker GE, Schainuck LI, Cutler RE, Benditt EP. Structural– functional correlations in renal disease: I. A method for assaying and classifying histopathologic changes in renal disease. Hum Pathol 1970;1:615–30. [6] Remuzzi G, Benigni A, Remuzzi A. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest 2006;116:288–96. [7] Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies. N Engl J Med 1998;339:1448–56. [8] Remuzzi G, Ruggenenti P, Benigni A. Understanding the nature of renal disease progression. Kidney Int 1997;51:2–15. [9] Ruggenenti P, Schieppati A, Remuzzi G. Progression, remission, regression of chronic renal diseases. Lancet 2001;357:1601–8. [10] Zoja C, Benigni A, Remuzzi G. Cellular responses to protein overload: key event in renal disease progression. Curr Opin Nephrol Hypertens 2004;13:31–7. [11] Rangan GK, Pippin JW, Couser WG. C5b-9 regulates peritubular myofibroblast accumulation in experimental focal segmental glomerulosclerosis. Kidney Int 2004;66:1838–48. [12] Chen L, Boadle RA, Harris DC. Toxicity of holotransferrin but not albumin in proximal tubule cells in primary culture. J Am Soc Nephrol 1998;9:77–84. [13] Ong AC, Moorhead JF. Tubular lipidosis: epiphenomenon or pathogenetic lesion in human renal disease? Kidney Int 1994;45:753–62. [14] Fine LG, Bandyopadhay D, Norman JT. Is there a common mechanism for the progression of different types of renal diseases other than proteinuria? Towards the unifying theme of chronic hypoxia. Kidney Int Suppl 2000;75:S22–6. [15] Peterson JC, Adler S, Burkart JM, et al. Blood pressure control, proteinuria, and the progression of renal disease. The modification of diet in renal disease study. Ann Intern Med 1995;123:754–62. [16] Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2000;345:861–9. [17] Chan JC, Wat NM, So WY, et al. Renin angiotensin aldosterone system blockade and renal disease in patients with type 2 diabetes. An Asian perspective from the RENAAL Study. Diabetes Care 2004;27:874–9. [18] de Zeeuw D, Remuzzi G, Parving HH, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 2004;65:2309–20. [19] Hamilton JA, Era S, Bhamidipati SP, Reed RG. Locations of the three primary binding sites for long-chain fatty acids on bovine serum albumin. Proc Natl Acad Sci U S A 1991;88:2051–4. [20] Barac-Nieto M, Cohen JJ. The metabolic fates of palmitate in the dog kidney in vivo. Evidence for incomplete oxidation. Nephron 1971;8:488–99. [21] Kees-Folts D, Sadow JL, Schreiner GF. Tubular catabolism of albumin is associated with the release of an inflammatory lipid. Kidney Int 1994;45:1697–709. [22] Lindner A, Hinds TR, Joly A, Schreiner GF. Neutral lipid from proteinuric rat urine is a novel inhibitor of the red blood cell calcium pump. J Am Soc Nephrol 1999;10:1170–8. [23] Arici M, Brown J, Williams M, et al. Fatty acids carried on albumin modulate proximal tubular cell fibronectin production: a role for protein kinase C. Nephrol Dial Transplant 2002;17:1751–7. [24] Arici M, Chana R, Lewington A, et al. Stimulation of proximal tubular cell apoptosis by albumin-bound fatty acids mediated by peroxisome proliferator activated receptor-gamma. J Am Soc Nephrol 2003;14:17–27. [25] Kamijo A, Kimura K, Sugaya T, et al. Urinary free fatty acids bound to albumin aggravate tubulointerstitial damage. Kidney Int 2002; 62:1628–37.

[26] Thomas ME, Harris KP, Walls J, et al. Fatty acids exacerbate tubulointerstitial injury in protein-overload proteinuria. Am J Physiol Renal Physiol 2002;283:F640–7. [27] Thomas ME, Morrison AR, Schreiner GF. Metabolic effects of fatty acidbearing albumin on a proximal tubule cell line. Am J Physiol 1995;268: F1177–84. [28] Thomas ME, Schreiner GF. Contribution of proteinuria to progressive renal injury: consequences of tubular uptake of fatty acid bearing albumin. Am J Nephrol 1993;13:385–98. [29] Portilla D, Shah SV, Lehman PA, Creer MH. Role of cytosolic calciumindependent plasmalogen-selective phospholipase A2 in hypoxic injury to rabbit proximal tubules. J Clin Invest 1994;93:1609–15. [30] Walker PD, Shah SV. Evidence suggesting a role for hydroxyl radical in gentamicin-induced acute renal failure in rats. J Clin Invest 1988;81:334–41. [31] Sweetser DA, Heuckeroth RO, Gordon JI. The metabolic significance of mammalian fatty-acid-binding proteins: abundant proteins in search of a function. Annu Rev Nutr 1987;7:337–59. [32] Veerkamp JH, Peeters RA, Maatman RG. Structural and functional features of different types of cytoplasmic fatty acid-binding proteins. Biochim Biophys Acta 1991;1081:1–24. [33] Maatman RG, van de Westerlo EM, van Kuppevelt TH, Veerkamp JH. Molecular identification of the liver- and the heart-type fatty acid-binding proteins in human and rat kidney. Use of the reverse transcriptase polymerase chain reaction. Biochem J 1992;288(Pt 1):285–90. [34] Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined—a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000;36:959–69. [35] Glatz JF, van Bilsen M, Paulussen RJ, et al. Release of fatty acid-binding protein from isolated rat heart subjected to ischemia and reperfusion or to the calcium paradox. Biochim Biophys Acta 1988;961:148–52. [36] Haastrup B, Gill S, Kristensen SR, et al. Biochemical markers of ischaemia for the early identification of acute myocardial infarction without St segment elevation. Cardiology 2000;94:254–61. [37] Okamoto F, Sohmiya K, Ohkaru Y, et al. Human heart-type cytoplasmic fatty acid-binding protein (H-FABP) for the diagnosis of acute myocardial infarction. Clinical evaluation of H-FABP in comparison with myoglobin and creatine kinase isoenzyme MB. Clin Chem Lab Med 2000;38:231–8. [38] Seino Y, Tomita Y, Takano T, Ohbayashi K. Office cardiologists cooperative study on whole blood rapid panel tests in patients with suspicious acute myocardial infarction: comparison between heart-type fatty acid-binding protein and troponin T tests. Circ J 2004;68:144–8. [39] Pelsers MM, Hanhoff T, Van der Voort D, et al. Brain- and heart-type fatty acid-binding proteins in the brain: tissue distribution and clinical utility. Clin Chem 2004;50:1568–75. [40] Guthmann F, Borchers T, Wolfrum C, et al. Plasma concentration of intestinal- and liver-FABP in neonates suffering from necrotizing enterocolitis and in healthy preterm neonates. Mol Cell Biochem 2002;239:227–34. [41] Morrissey PE, Gollin G, Marks WH. Small bowel allograft rejection detected by serum intestinal fatty acid-binding protein is reversible. Transplantation 1996;61:1451–5. [42] Pelsers MM, Namiot Z, Kisielewski W, et al. Intestinal-type and liver-type fatty acid-binding protein in the intestine. Tissue distribution and clinical utility. Clin Biochem 2003;36:529–35. [43] Wolfrum C, Buhlmann C, Rolf B, et al. Variation of liver-type fatty acid binding protein content in the human hepatoma cell line HepG2 by peroxisome proliferators and antisense RNA affects the rate of fatty acid uptake. Biochim Biophys Acta 1999;1437:194–201. [44] Pelsers MM, Morovat A, Alexander GJ, et al. Liver fatty acid-binding protein as a sensitive serum marker of acute hepatocellular damage in liver transplant recipients. Clin Chem 2002;48:2055–7. [45] Glatz JF, van der Vusse GJ. Cellular fatty acid-binding proteins: their function and physiological significance. Prog Lipid Res 1996;35:243–82. [46] Bass NM, Barker ME, Manning JA, et al. Acinar heterogeneity of fatty acid binding protein expression in the livers of male, female and clofibratetreated rats. Hepatology 1989;9:12–21.

A. Kamijo-Ikemori et al. / Clinica Chimica Acta 374 (2006) 1–7 [47] Azzazy HM, Pelsers MM, Christenson RH. Unbound free fatty acids and heart-type fatty acid-binding protein: diagnostic assays and clinical applications. Clin Chem 2006;52:19–29. [48] Pelsers MM, Hermens WT, Glatz JF. Fatty acid-binding proteins as plasma markers of tissue injury. Clin Chim Acta 2005;352:15–35. [49] Su AI, Wiltshire T, Batalov S, et al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci U S A 2004;101:6062–7. [50] Haunerland NH, Spener F. Fatty acid-binding proteins—insights from genetic manipulations. Prog Lipid Res 2004;43:328–49. [51] Zimmerman AW, Veerkamp JH. Fatty-acid-binding proteins do not protect against induced cytotoxicity in a kidney cell model. Biochem J 2001;360:159–65. [52] Richieri GV, Ogata RT, Kleinfeld AM. Equilibrium constants for the binding of fatty acids with fatty acid-binding proteins from adipocyte, intestine, heart, and liver measured with the fluorescent probe ADIFAB. J Biol Chem 1994;269:23918–30. [53] Nemecz G, Hubbell T, Jefferson JR, et al. Interaction of fatty acids with recombinant rat intestinal and liver fatty acid-binding proteins. Arch Biochem Biophys 1991;286:300–9. [54] Nemecz G, Jefferson JR, Schroeder F. Polyene fatty acid interactions with recombinant intestinal and liver fatty acid-binding proteins. Spectroscopic studies. J Biol Chem 1991;266:17112–23. [55] Akiyama TE, Ward JM, Gonzalez FJ. Regulation of the liver fatty acidbinding protein gene by hepatocyte nuclear factor 1alpha (HNF1alpha). Alterations in fatty acid homeostasis in HNF1alpha-deficient mice. J Biol Chem 2000;275:27117–22. [56] Martin GG, Danneberg H, Kumar LS, et al. Decreased liver fatty acid binding capacity and altered liver lipid distribution in mice lacking the liver fatty acid-binding protein gene. J Biol Chem 2003;278:21429–38. [57] Murphy EJ, Prows DR, Jefferson JR, Schroeder F. Liver fatty acid-binding protein expression in transfected fibroblasts stimulates fatty acid uptake and metabolism. Biochim Biophys Acta 1996;1301:191–8. [58] Newberry EP, Xie Y, Kennedy S, et al. Decreased hepatic triglyceride accumulation and altered fatty acid uptake in mice with deletion of the liver fatty acid binding protein gene. J Biol Chem 2003;78:51664–72. [59] Atshaves BP, McIntosh AL, Payne HR, et al. Effect of branched-chain fatty acid on lipid dynamics in mice lacking liver fatty acid binding protein gene. Am J Physiol Cell Physiol 2005;288:C543–58. [60] Atshaves BP, McIntosh AM, Lyuksyutova OI, et al. Liver fatty acidbinding protein gene ablation inhibits branched-chain fatty acid metabolism in cultured primary hepatocytes. J Biol Chem 2004;279:30954–65. [61] Atshaves BP, Storey SM, Huang H, Schroeder F. Liver fatty acid binding protein expression enhances branched-chain fatty acid metabolism. Mol Cell Biochem 2004;259:115–29. [62] Erol E, Kumar LS, Cline GW, et al. Liver fatty acid binding protein is required for high rates of hepatic fatty acid oxidation but not for the action of PPARalpha in fasting mice. FASEB J 2004;18:347–9. [63] Martin GG, Atshaves BP, McIntosh AL, et al. Liver fatty acid binding protein gene ablation potentiates hepatic cholesterol accumulation in cholesterol-fed female mice. Am J Physiol Gastrointest Liver Physiol 2006;290:G36–48. [64] Huang H, Starodub O, McIntosh A, et al. Liver fatty acid-binding protein colocalizes with peroxisome proliferator activated receptor alpha and enhances ligand distribution to nuclei of living cells. Biochemistry 2004;43:2484–500. [65] Huang H, Starodub O, McIntosh A, et al. Liver fatty acid-binding protein targets fatty acids to the nucleus. Real time confocal and multiphoton fluorescence imaging in living cells. J Biol Chem 2002;277:29139–51. [66] Lawrence JW, Kroll DJ, Eacho PI. Ligand-dependent interaction of hepatic fatty acid-binding protein with the nucleus. J Lipid Res 2000;41:1390–401. [67] Wolfrum C, Borrmann CM, Borchers T, Spener F. Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors

[68]

[69]

[70]

[71] [72]

[73]

[74]

[75]

[76]

[77]

[78]

[79]

[80]

[81]

[82]

[83]

[84]

[85]

7

alpha- and gamma-mediated gene expression via liver fatty acid binding protein: a signaling path to the nucleus. Proc Natl Acad Sci U S A 2001;98:2323–8. Khan SH, Sorof S. Liver fatty acid-binding protein: specific mediator of the mitogenesis induced by two classes of carcinogenic peroxisome proliferators. Proc Natl Acad Sci U S A 1994;91:848–52. Ek-Von Mentzer BA, Zhang F, Hamilton JA. Binding of 13-HODE and 15HETE to phospholipid bilayers, albumin, and intracellular fatty acid binding proteins. Implications for transmembrane and intracellular transport and for protection from lipid peroxidation. J Biol Chem 2001;276:15575–80. Raza H, Pongubala JR, Sorof S. Specific high affinity binding of lipoxygenase metabolites of arachidonic acid by liver fatty acid binding protein. Biochem Biophys Res Commun 1989;161:448–55. Wang G, Gong Y, Anderson J, et al. Antioxidative function of L-FABP in L-FABP stably transfected Chang liver cells. Hepatology 2005;42:871–9. Simon TC, Roth KA, Gordon JI. Use of transgenic mice to map cis-acting elements in the liver fatty acid-binding protein gene (Fabpl) that regulate its cell lineage-specific, differentiation-dependent, and spatial patterns of expression in the gut epithelium and in the liver acinus. J Biol Chem 1993;268:18345–58. Kamijo A, Sugaya T, Hikawa A, et al. Urinary excretion of fatty acidbinding protein reflects stress overload on the proximal tubules. Am J Pathol 2004;165:1243–55. Kamijo A, Kimura K, Sugaya T, et al. Urinary fatty acid binding protein as a new clinical marker for the progression of chronic renal disease. J Lab Clin Med 2004;143:23–30. Kamijo A, Sugaya T, Hikawa A, et al. Clinical evaluation of urinary excretion of liver-type fatty acid binding protein as a marker for monitoring chronic kidney disease: a multi-center trial. J Lab Clin Med 2005;145:125–33. Nakamura T, Sugaya T, Kawagoe Y, et al. Urinary liver-type fatty acidbinding protein levels for differential diagnosis of idiopathic focal glomerulosclerosis and minor glomerular abnormalities and effect of low-density lipoprotein apheresis. Clin Nephrol 2006;65:1–6. Nakamura T, Sugaya T, Kawagoe Y, et al. Effect of pitavastatin on urinary liver-type fatty acid-binding protein levels in patients with early diabetic nephropathy. Diabetes Care 2005;28:2728–32. Suzuki K, Babazono T, Murata H, Iwamoto Y. Clinical significance of urinary liver-type fatty acid-binding protein in patients with diabetic nephropathy. Diabetes Care 2005;28:2038–9. Nakamura T, Sugaya T, Node K, et al. Urinary excretion of liver-type fatty acid-binding protein in contrast medium-induced nephropathy. Am J Kidney Dis 2006;47:439–44. Nakamura T, Sugaya T, Kawagoe Y, et al. Effect of pioglitazone on urinary liver-type fatty acid-binding protein concentrations in diabetes patients with microalbuminuria. Diabetes Metab Res Rev 2006;284:175–82. Nakamura T, Sugaya T, Kawagoe Y, et al. Candesartan reduces urinary fatty acid-binding protein excretion in patients with autosomal dominant polycystic kidney disease. Am J Med Sci 2005;330:161–5. Nakamura T, Sugaya T, Kawagoe Y, et al. Effect of pitavastatin on urinary liver-type fatty-acid-binding protein in patients with nondiabetic mild chronic kidney disease. Am J Nephrol 2006;26:82–6. Oyama Y, Takeda T, Hama H, et al. Evidence for megalin-mediated proximal tubular uptake of L-FABP, a carrier of potentially nephrotoxic molecules. Lab Invest 2005;85:522–31. Kamijo A, Sugaya T, Hikawa A, et al. Urinary liver-type fatty acid binding protein as a useful biomarker in chronic kidney disease. Mol Cell Biochem, in press. Lam KT, Borkan S, Claffey KP, et al. Properties and differential regulation of two fatty acid binding proteins in the rat kidney. J Biol Chem 1988;263:15762–8.