Relevance of leukaemia inhibitory factor to anti-melanoma differentiation-associated gene 5 antibody-positive interstitial lung disease.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive rapidly progressive interstitial lung disease (RP-ILD) is a life-threatening disease, the aetiology of which remains unclear. To detect potential diagnostic markers, a transcriptome analysis of the lung sample from a patient with anti-MDA5 antibody-positive RP-ILD was performed. METHODS: RNA sequencing analyses of an autopsy lung sample from a 74-year-old woman with anti-MDA5 antibody-positive RP-ILD was performed and compared with an age- and sex-matched normal lung sample. Genes with changes of gene expression ≥5-fold were considered differentially expressed genes and analysed by Metascape. The levels of leukaemia inhibitory factor (LIF) were measured in the serum samples from 12 cases of anti-MDA5 antibody-positive ILD, 12 cases of anti-aminoacyl tRNA synthetase (ARS) antibody-positive ILD, 10 cases of anti-transcription intermediary factor 1γ/anti-Mi-2 antibody DM and 12 healthy volunteers. RESULTS: Gene ontology enrichment analysis on the RNA sequencing data showed a strong association with antigen binding. Upregulated expressions of IL-1ß, IL-6 and LIF were also detected. Serum LIF levels were significantly elevated in anti-MDA5 antibody-positive ILD patients {median 32.4 pg/ml [interquartile range (IQR) 13.2-125.7]} when compared with anti-ARS antibody-positive ILD patients [4.9 pg/ml (IQR 3.1-19.7), P < 0.05] and DM patients [5.3 pg/ml (IQR 3.9-9.7), P < 0.05]. CONCLUSION: Our present study suggested that upregulation of LIF might be a new potential disease marker specific for anti-MDA5 antibody-positive ILD.

Bevacizumab-induced immunoglobulin A vasculitis with nephritis: A case report.

RATIONALE: Bevacizumab-an inhibitor of vascular endothelial growth factor-is effective against various advanced cancers. However, it is associated with the development of hypertension and high-grade proteinuria during thrombotic microangiopathy of the kidney. In addition, there are several reports of immunoglobulin A deposition in the glomeruli, but the etiology is unclear. PATIENT CONCERNS: A 67-year-old Japanese man with metastatic rectal cancer underwent low anterior rectal resection, followed by treatment with bevacizumab and SOX (S-1 plus oxaliplatin). Six months later, the patient developed hematuria, nephrotic syndrome, and purpura. DIAGNOSES: Renal biopsy revealed endocapillary proliferative glomerulonephritis. Immunofluorescence analyses showed granular mesangial deposition of galactose-deficient immunoglobulin A1. Skin biopsy revealed leukocytoclastic vasculitis. INTERVENTIONS: We ceased bevacizumab treatment, while continuing the remaining chemotherapy regimen, as we suspected bevacizumab-induced nephropathy. OUTCOMES: Proteinuria and purpura improved immediately after cessation of bevacizumab. We identified this as a case of bevacizumab-induced immunoglobulin A vasculitis with nephritis. LESSONS: To our knowledge, this is the first case of bevacizumab-related immunoglobulin A vasculitis with nephritis, as evidenced by galactose-deficient immunoglobulin A1. When a patient's urine tests are abnormal during bevacizumab treatment, clinicians should consider not only thrombotic microangiopathy but also vasculitis.

Extended Sessions of Polymyxin-B Immobilized Fiber Column Hemoperfusion Ameliorate Renal Outcome and Mortality in Septic Shock with Acute Kidney Injury.

BACKGROUND/AIMS: Polymyxin-B (PMX) treatment has been reported to decrease mortality in patients with septic shock and acute kidney injury (AKI). In this study, we aimed to evaluate whether extended sessions of PMX (Ext-PMX) immobilized fiber column hemoperfusion ameliorate clinical outcomes in patients complicated with septic shock and AKI without surgical control. METHODS: Twenty-two patients with nonsurgical septic shock and AKI who received PMX were included. They were divided according to the duration of PMX treatment: Ext-PMX and standard PMX (Std-PMX). RESULTS: The mean blood pressure increased and inotrope requirement decreased within 24 h after PMX initiation. The median value of predicted mortality was 52.5%, and the -28-day mortalities in the Ext-PMX and Std-PMX groups were 44.4 and 75% respectively. Renal replacement therapy (RRT) was also initiated in 17 patients, and renal insufficiency was recovered. CONCLUSION: Ext-PMX combined with RRT improved clinical outcomes in patients with nonsurgical septic shock and AKI.

Interstitial renal fibrosis due to multiple cisplatin treatments is ameliorated by semicarbazide-sensitive amine oxidase inhibition.

Elucidation of acute kidney diseases and disorders (AKD), including acute kidney injury (AKI), is important to prevent their progression to chronic kidney disease. Current animal AKI models are often too severe for use in evaluating human AKI. Therefore, new animal models of mild kidney injury are needed. Here a new clinically relevant animal model using multiple low doses of cisplatin (CP) was used to evaluate AKD. When 10 mg/kg CP was administered intraperitoneally once weekly for three times to L-type fatty acid-binding protein (L-FABP) transgenic mice, moderate renal interstitial fibrosis and tubule dilatation occurred, accompanied by brush-border loss. Urinary L-FABP, a promising biomarker of AKI, changed more drastically than blood urea nitrogen or creatinine. Preventing fibrosis in organs was also studied. Oral administration of a recently reported selective semicarbazide-sensitive amine oxidase inhibitor, PXS-4728A, for 1 week attenuated kidney injury and interstitial fibrosis compared with vehicle. Inhibition of renal lipid accumulation in semicarbazide-sensitive amine oxidase inhibitor-treated mice, together with reduced oxidative stress and L-FABP suppression in proximal tubules, suggested an antifibrotic effect of semicarbazide-sensitive amine oxidase inhibition in this CP-AKD model, a representative onco-nephrology. Thus, semicarbazide-sensitive amine oxidase inhibitors may be promising candidates for the prevention of chronic kidney disease in patients using CP to treat malignancy.

Protection of glucagon-like peptide-1 in cisplatin-induced renal injury elucidates gut-kidney connection.

Accumulating evidence of the beyond-glucose lowering effects of a gut-released hormone, glucagon-like peptide-1 (GLP-1), has been reported in the context of remote organ connections of the cardiovascular system. Specifically, GLP-1 appears to prevent apoptosis, and inhibition of dipeptidyl peptidase-4 (DPP-4), which cleaves GLP-1, is renoprotective in rodent ischemia-reperfusion injury models. Whether this renoprotection involves enhanced GLP-1 signaling is unclear, however, because DPP-4 cleaves other molecules as well. Thus, we investigated whether modulation of GLP-1 signaling attenuates cisplatin (CP)-induced AKI. Mice injected with 15 mg/kg CP had increased BUN and serum creatinine and CP caused remarkable pathologic renal injury, including tubular necrosis. Apoptosis was also detected in the tubular epithelial cells of CP-treated mice using immunoassays for single-stranded DNA and activated caspase-3. Treatment with a DPP-4 inhibitor, alogliptin (AG), significantly reduced CP-induced renal injury and reduced the renal mRNA expression ratios of Bax/Bcl-2 and Bim/Bcl-2. AG treatment increased the blood levels of GLP-1, but reversed the CP-induced increase in the levels of other DPP-4 substrates such as stromal cell-derived factor-1 and neuropeptide Y. Furthermore, the GLP-1 receptor agonist exendin-4 reduced CP-induced renal injury and apoptosis, and suppression of renal GLP-1 receptor expression in vivo by small interfering RNA reversed the renoprotective effects of AG. These data suggest that enhancing GLP-1 signaling ameliorates CP-induced AKI via antiapoptotic effects and that this gut-kidney axis could be a new therapeutic target in AKI.

Efficacy of vitamin E-bonded polysulfone dialyzer and polysulfone dialyzer on a series of non-anticoagulant hemodialysis.

Non-anticoagulant hemodialysis is conducted occasionally at limited numbers of hospitals on an empirical basis. This study examines the efficacy of polysulfone and vitamin E-bonded polysulfone dialyzer for non-anticoagulant hemodialysis. These dialyzers were assigned one after the other for a vintage hemodialysis patient complicated with uncontrollable bleeding. The patient's vital and console data throughout non-anticoagulant hemodialysis were monitored serially. Both dialyzers were reasonably applicable to hemodialysis without major clotting. The scheduled treatment period was completed. Vitamin E-bonded polysulfone dialyzer was superior to non-anticoagulant hemodialysis based on venous pressure observed during treatment.

New biomarker panel of plasma neutrophil gelatinase-associated lipocalin and endotoxin activity assay for detecting sepsis in acute kidney injury.

PURPOSE: Septic acute kidney injury (AKI) shows an unacceptably high mortality rate. Detection of sepsis is important for the clinical management of AKI patients. This study was undertaken to evaluate 2 biomarkers of neutrophil gelatinase-associated lipocalin (NGAL) and endotoxin activity (EA) assay and their combination for detecting sepsis in AKI. MATERIALS AND METHODS: Adult intensive care unit patients consisting of 40 non-AKI, 65 AKI without sepsis, 10 non-AKI with sepsis, and 24 septic AKI were examined in a cross-sectional manner. Plasma NGAL and EA values in whole blood were measured at recruitment. We evaluated whether combining 2 different biomarkers would improve the performance of each biomarker using receiver operating characteristic analysis. RESULTS: Plasma NGAL was significantly higher in septic AKI patients than in the other AKI patients and non-AKI patients, whereas EA values were higher in septic patients than nonseptic patients irrespective of AKI complication. Combination of plasma NGAL and EA value increased the area under the curve of the receiver operating characteristic curve and showed better performance compared with a clinical model consisting of clinically available variables. CONCLUSION: Combinations of plasma NGAL and EA, which are operating via different pathological pathways, significantly improved their detection performance in complicated conditions of septic AKI.

Mild elevation of urinary biomarkers in prerenal acute kidney injury.

Prerenal acute kidney injury (AKI) is thought to be a reversible loss of renal function without structural damage. Although prerenal and intrinsic AKI frequently coexist in clinical situations, serum creatinine and urine output provide no information to support their differentiation. Recently developed biomarkers reflect tubular epithelial injury; therefore, we evaluated urinary biomarker levels in an adult mixed intensive care unit (ICU) cohort of patients who had been clinically evaluated as having prerenal AKI. Urinary L-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), N-acetyl-ß-D-glucosaminidase (NAG), and albumin in patients with prerenal AKI showed modest but significantly higher concentrations than in patients with non-AKI. We also conducted a proof-of-concept experiment to measure urinary biomarker excretion in prerenal AKI caused by volume depletion. Compared with cisplatinum and ischemia-reperfusion models in mice, volume depletion in mice caused a modest secretion of L-FABP and NGAL into urine with more sensitive response of L-FABP than that of NGAL. Although no histological evidence of structural damage was identified by light microscopy, partial kidney hypoxia was found by pimonidazole incorporation in the volume depletion model. Thus, our study suggests that new AKI biomarkers can detect mild renal tubular damage in prerenal acute kidney injury.

High-throughput screening identified disease-causing mutants and functional variants of α-galactosidase A gene in Japanese male hemodialysis patients.

Fabry disease is a genetic disorder caused by deficient activity of lysosomal enzyme α-galactosidase A (GLA) and end-stage renal disease (ESRD) will be present after accumulation of glycosphingolipids within the kidney. Undiagnosed atypical variants of Fabry disease, which are limited to renal involvement, were found in several ESRD patient populations. On the other hand, unexpectedly high frequencies of male subjects having the c.196G>C nucleotide change (p.E66Q) showing low α-GLA activity have been reported on Japanese and Korean screening for Fabry disease. However, several evidences indicate the c.196G>C is not a pathogenic mutation but is a functional polymorphism. In the present study, high-throughput screening of serum GLA could successfully indentify two Fabry disease patients in a cohort consisted of 1080 male hemodialysis patients. Moreover, our serum assay was able to distinguish two patients with disease-causing genetic mutations (p.G195V and p.M296I) from eight functional variants that showed relatively decreased enzyme activity (p.E66Q). In conclusion, high-throughput serum enzyme assay distinctly identified disease-causing mutants and functional variants of GLA gene in Japanese male hemodialysis patients. In addition, our results underscore the high prevalence of not only undiagnosed Fabry patients but functional variants of p.E66Q among the ESRD population.

Combination of two urinary biomarkers predicts acute kidney injury after adult cardiac surgery.

BACKGROUND: Urinary L-type fatty acid-binding protein (L-FABP) has not been evaluated for adult post-cardiac surgery acute kidney injury (AKI) to date. This study was undertaken to evaluate a biomarker panel consisting of urinary L-FABP and N-acetyl-ß-D-glucosaminidase (NAG), a more established urinary marker of kidney injury, for AKI diagnosis in adult post-cardiac surgery patients. METHODS: This study prospectively evaluated 77 adult patients who underwent cardiac surgery at 2 general hospitals. Urinary L-FABP and NAG were measured before surgery, at intensive care unit arrival after surgery (0 hours), 4, and 12 hours after arrival. The AKI was diagnosed by the Acute Kidney Injury Network criteria. RESULTS: Of 77 patients, 28 patients (36.4%) developed AKI after surgery. Urinary L-FABP and NAG were significantly increased. However, receiver operating characteristic (ROC) analysis revealed that the biomarkers' performance was statistically significant but limited for clinical translation (area under the curve of ROC [AUC-ROC] for L-FABP at 4 hours 0.72 and NAG 0.75). Urinary L-FABP showed high sensitivity and NAG detected AKI with high specificity. Therefore, we combined these 2 biomarkers, which revealed that this combination panel can detect AKI with higher accuracy than either biomarker measurement alone (AUC-ROC 0.81). Moreover, this biomarker panel improved AKI risk prediction significantly compared with predictions made using the clinical model alone. CONCLUSIONS: When urinary L-FABP and NAG are combined, they can detect AKI adequately, even in a heterogeneous population of adult post-cardiac surgery AKI. Combining 2 markers with different sensitivity and specificity presents a reasonable strategy to improve the diagnostic performance of biomarkers.

Evaluation of new acute kidney injury biomarkers in a mixed intensive care unit.

OBJECTIVE: Biomarkers for detection of acute kidney injury and prediction of mortality will be useful to improve the outcomes of critically ill patients. Although several promising acute kidney injury biomarkers have been reported, evaluation in heterogeneous disease-oriented populations is necessary to confirm their reliability before their translation to clinical use. This study was undertaken to evaluate the reliability of new acute kidney injury biomarkers including urinary L-type fatty acid-binding protein with heterogeneous intensive care unit populations. DESIGN: Prospective observational cohort study. SETTING: Single-center study, 15-bed medical-surgical mixed intensive care unit at a university hospital. PATIENTS: Three hundred thirty-nine adult critically ill patients who had been admitted to the intensive care unit were studied prospectively. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Five urinary biomarkers (L-type fatty acid-binding protein, neutrophil gelatinase-associated lipocalin, interleukin-18, N-acetyl-ß-D-glucosaminidase, and albumin) were measured at intensive care unit admission. By the RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) criteria, 131 patients (39%) were diagnosed as acute kidney injury. Urinary L-type fatty acid-binding protein detected acute kidney injury better than the other biomarkers did (the area under the receiver operating characteristic curves for L-type fatty acid-binding protein 0.75, neutrophil gelatinase-associated lipocalin 0.70, interleukin-18 0.69, N-acetyl-ß-D-glucosaminidase 0.62, albumin 0.69). Urinary L-type fatty acid-binding protein predicted later-onset acute kidney injury after intensive care unit admission with the highest area under the receiver operating characteristic curve value of 0.70. Furthermore, L-type fatty acid-binding protein, neutrophil gelatinase-associated lipocalin, and interleukin-18 were able to predict 14-day mortality with higher area under the receiver operating characteristic curves than acute kidney injury detection (area under the receiver operating characteristic curve for L-type fatty acid-binding protein 0.90, neutrophil gelatinase-associated lipocalin 0.83, interleukin-18 0.83). The combination of L-type fatty acid-binding protein and neutrophil gelatinase-associated lipocalin improved mortality prediction (area under the receiver operating characteristic curve 0.93). CONCLUSION: This prospective observational study with a cohort of heterogeneous patients treated in a mixed intensive care unit revealed that new acute kidney injury biomarkers have a significantly and moderately predictive use for acute kidney injury diagnosis and that urinary L-type fatty acid-binding protein and neutrophil gelatinase-associated lipocalin can serve as new biomarkers of mortality prediction in critical care.

Urinary L-type fatty acid-binding protein as a new biomarker of sepsis complicated with acute kidney injury.

OBJECTIVE: This study is aimed to examine whether urinary L-type fatty acid-binding protein can detect the severity of sepsis with animal sepsis models and septic shock patients complicated with established acute kidney injury. DESIGN: Experimental animal models and a clinical, prospective observational study. SETTING: University laboratory and tertiary hospital. SUBJECTS AND PATIENTS: One hundred fourteen human L-type fatty acid-binding protein transgenic mice and 145 septic shock patients with established acute kidney injury. INTERVENTIONS: Animals were challenged by abdominal (cecal ligation and puncture) and pulmonary (intratracheal lipopolysaccharide injection) sepsis models with different severities that were confirmed by survival analysis (n = 24) and bronchoalveolar lavage fluid analysis (n = 38). MEASUREMENTS AND MAIN RESULTS: In animal experiments, significant increases of urinary L-type fatty acid-binding protein levels were induced by sepsis (severe cecal ligation and puncture 399.0 ± 226.8 µg/g creatinine [n = 12], less-severe cecal ligation and puncture 89.1 ± 25.3 [n = 11], sham 13.4 ± 3.4 [n = 10] at 6 hrs, p < .05 vs. sham; 200 µg of lipopolysaccharide 190.6 ± 77.4 µg/g creatinine [n = 6], 50 µg of lipopolysaccharide 145.4 ± 32.6 [n = 8], and saline 29.9 ± 14.9 [n = 5] at 6 hrs, p < .05 vs. saline). Urinary L-type fatty acid-binding protein predicted severity more accurately than blood urea nitrogen, serum creatinine, and urinary N-acetyl-d-glucosaminidase levels. In clinical evaluation, urinary L-type fatty acid-binding protein measured at admission was significantly higher in the nonsurvivors of septic shock with established acute kidney injury than in the survivors (4366 ± 192 µg/g creatinine [n = 68] vs. 483 ± 71 [n = 77], p < .05). Urinary L-type fatty acid-binding protein showed the higher value of area under the receiver operating characteristic curve for mortality compared with Acute Physiology and Chronic Health Evaluation (APACHE) II and Sepsis-related Organ Failure Assessment (SOFA) scores (L-type fatty acid-binding protein 0.994 [0.956-0.999], APACHE II 0.927 [0.873-0.959], and SOFA 0.813 [0.733-0.873], p < .05). CONCLUSIONS: Our results suggest that urinary L-type fatty acid-binding protein can be a useful biomarker for sepsis complicated with acute kidney injury for detecting its severity.

Monitoring of urinary L-type fatty acid-binding protein predicts histological severity of acute kidney injury.

The present study aimed to evaluate whether levels of urinary L-type fatty acid-binding protein (L-FABP) could be used to monitor histological injury in acute kidney injury (AKI) induced by cis-platinum (CP) injection and ischemia reperfusion (IR). Different degrees of AKI severity were induced by several renal insults (CP dose and ischemia time) in human L-FABP transgenic mice. Renal histological injury scores increased with both CP dose and ischemic time. In CP-induced AKI, urinary L-FABP levels increased exponentially even in the lowest dose group as early as 2 hours, whereas blood urea nitrogen (BUN) levels increased at 48 hours. In IR-induced AKI, BUN levels increased only in the 30-minute ischemia group 24 hours after reperfusion; however, urinary L-FABP levels increased more than 100-fold, even in the 5-minute ischemia group after 1 hour. In both AKI models, urinary L-FABP levels showed a better correlation with final histological injury scores and glomerular filtration rates measured by fluorescein isothiocyanate-labeled inulin injection than with levels of BUN and urinary N-acetyl-D-glucosaminidase, especially at earlier time points. Receiver operating characteristic curve analysis demonstrated that urinary L-FABP was superior to other biomarkers for the detection of significant histological injuries and functional declines. In conclusion, urinary L-FABP levels are better suited to allow the accurate and earlier detection of both histological and functional insults in ischemic and nephrotoxin-induced AKI compared with conventional renal markers.

Urinary L-type fatty acid-binding protein can reflect renal tubulointerstitial injury.

This study aimed to elucidate the role of L-type fatty acid-binding protein (L-FABP) in renal tubulointerstitial injury using a mouse adenine-induced renal injury model. C57BL/6 mice fed excess dietary adenine for 6 weeks showed a gradual increase in levels of blood urea nitrogen (BUN). They also showed severe tubulointerstitial pathological findings, such as fibrosis and macrophage infiltration without glomerular damage, which were attenuated by treatment with either allopurinol or Y-700, a new xanthine dehydroxygenase inhibitor. Because renal expression of L-FABP is defective in C57BL/6 mice, human L-FABP transgenic mice were fed an adenine-containing diet. Transgenic mice showed lower BUN levels and lower levels of pathological injury compared with wild-type mice. On the other hand, urinary levels and renal expression of L-FABP in the adenine group was significantly increased and attenuated by treatment with either allopurinol or Y-700. Urinary L-FABP was positively correlated with BUN levels and pathological damages in the tubulointerstitium. No increases in urinary protein, albumin, or N-acetyl-beta-D-glucosaminidase levels were found for 6 weeks in any group. In conclusion, we demonstrated that urinary L-FABP levels can be used to monitor both dynamics and drug responses in a mouse adenine-induced tubulointerstitial injury model.

Urinary fatty acid-binding protein 1: an early predictive biomarker of kidney injury.

In the development of novel therapeutic strategies for kidney disease, new renal biomarkers for early detection and accurate evaluation of renal injury are urgently required for both acute kidney injury (AKI) and chronic kidney disease (CKD). Fatty acid-binding protein 1 (FABP1) is expressed in renal proximal tubule cells and shed into urine in response to hypoxia caused by decreased peritubular capillary blood flow. To clarify the role of urinary FABP1 in kidney disease, we established human FABP1 transgenic mice and evaluated the responses of FABP1 to several AKI and CKD models. Moreover, there are accumulating clinical data that urinary FABP1 can detect human AKI earlier than serum creatinine and can distinguish the risk population for AKI. Investigation with "humanized" FABP1 transgenic mice and measurement of clinical samples allowed us to develop urinary FABP1 as a new renal biomarker. Further clinical studies are necessary to confirm the potential of urinary FABP1 for clinical application.

A water-soluble fullerene vesicle alleviates angiotensin II-induced oxidative stress in human umbilical venous endothelial cells.

A water-soluble fullerene vesicle based on the Buckminsterfullerene molecule (Ph(5)C(60)K, denoted as PhK) was explored to determine its effects on anti-oxidation of human umbilical endothelial cells (HUVEC) exposed to exogenous and endogenous reactive oxygen species (ROS). Hydrogen peroxide 0.05-0.25 mmol/L remarkably reduced the cellular viability of HUVEC. This reduction in viability was markedly improved when PhK 0.01-1 micromol/L was added simultaneously to the culture medium. The reduction of viability in HUVEC induced by angiotensin II (AII) 10(-9) to 10(-7) mol/L was improved by pretreatment with PhK 0.1 or 10 micromol/L 12 h before AII stimulation. The ROS indicator CM-H(2)DCFDA demonstrated the efficacy of PhK 1 or 10 micromol/L in decreasing AII-induced ROS production to the level induced by the AII receptor blocker RNH-6470 20 micromol/L. The AII-induced peroxynitrite formation, as gauged using hydroxyphenyl fluorescein as a probe, was alleviated significantly by either pretreatment with PhK 0.1 or 1 micromol/L. Electron microscopy revealed intracellular localization of PhK in HUVEC after 12 h incubation. The PhK decreased the AII-induced apoptosis and lipid peroxidation processes as revealed by hexanoyl-lysine adduct formation. These observations show that the PhK water-soluble fullerene vesicle is promising as a compound controlling not only exogenous ROS, but also endogenous AII-mediated pathophysiological conditions.

Urinary human L-FABP is a potential biomarker to predict COX-inhibitor-induced renal injury.

BACKGROUND/AIM: A strong demand exists for the development of sensitive biomarkers in the nephrology field. We propose urinary human L-type fatty acid binding protein (L-FABP) as an earlier biomarker to detect the outcome of chronic renal injury induced by cyclooxygenase (COX) inhibitors using human L-FABP transgenic mice. METHODS: After consuming a low-sodium diet for 2 weeks, transgenic mice were administered meloxicam or celecoxib with the low-sodium diet. Mice were sacrificed 2 days and 4 weeks after starting COX inhibitors, and urine was collected 24 and 48 h and 1, 2, 3, and 4 weeks after starting COX inhibitors. Celecoxib-treated mice were divided into responders or nonresponders according to urinary L-FABP levels, and histology, urinary L-FABP and peritubular capillary blood flow were evaluated. RESULTS: Meloxicam-treated mice showed a higher blood pressure than control mice. Urinary L-FABP was significantly increased in COX inhibitor-treated mice. Peritubular capillary blood flow in all meloxicam-treated mice and in some celecoxib-treated mice was significantly decreased. Although blood urea nitrogen was not increased, interstitial fibrosis and macrophage infiltration were revealed, especially in meloxicam-treated mice. Responders showed an increase of fibrotic areas and correlations between urinary L-FABP and peritubular capillary blood flow. CONCLUSION: Urinary L-FABP is capable of revealing chronic renal injury induced by COX inhibitors.

Renal L-type fatty acid--binding protein in acute ischemic injury.

Fatty acid-binding proteins (FABPs) bind unsaturated fatty acids and lipid peroxidation products during tissue injury from hypoxia. We evaluated the potential role of L-type FABP (L-FABP) as a biomarker of renal ischemia in both human kidney transplant patients and animal models. Urinary L-FABP levels were measured in the first urine produced from 12 living-related kidney transplant patients immediately after reperfusion of their transplanted organs, and intravital video analysis of peritubular capillary blood flow was performed simultaneously. A significant direct correlation was found between urinary L-FABP level and both peritubular capillary blood flow and the ischemic time of the transplanted kidney (both P < 0.0001), as well as hospital stay (P < 0.05). In human-L-FABP transgenic mice subjected to ischemia-reperfusion injury, immunohistological analyses demonstrated the transition of L-FABP from the cytoplasm of proximal tubular cells to the tubular lumen. In addition, after injury, these transgenic mice demonstrated lower blood urea nitrogen levels and less histological injury than injured wild-type mice, likely due to a reduction of tissue hypoxia. In vitro experiments using a stable cell line of mouse proximal tubule cells transfected with h-L-FABP cDNA showed reduction of oxidative stress during hypoxia compared to untransfected cells. Taken together, these data show that increased urinary L-FABP after ischemic-reperfusion injury may find future use as a biomarker of acute ischemic injury.

High incidence of renal failure in patients with aortic aneurysms.

BACKGROUND: Renal failure (RF) is a well-recognized complication of aortic aneurysms (AA) although its incidence has been poorly documented previously. The purpose of this study is to examine the incidence of RF in patients with AA and prognosis of AA patients with RF. METHODS: Renal function, complications and prognosis of AA patients with RF were retrospectively reviewed in 350 AA patients (median age 69.8+/-10.7 years) in the International Medical Center of Japan from 1989 to 1999. RESULTS: Among 350 patients with AA, 90 patients (25.7%) had chronic renal failure (CRF) at the initiation of follow-up. The number of CRF patients increased to 117 (33.4%) at 30 months of follow-up. Forty-four out of 160 patients (27.5%) who had aortic surgery developed postoperative acute renal failure (ARF). Stepwise logistic regression analysis revealed that age (>or=65 years), hypertension and multiple aneurysms were independent risk factors for CRF, whereas dissecting aneurysms, preoperative serum creatinine (sCr) levels and duration of surgery were independent risk factors for postoperative ARF in AA patients. In the 5-year follow-up of AA patients with CRF, the mean slopes of 1/serum-creatinine did not significantly differ between conservative treatment and surgical treatment. The survival rates were 49.5% in the conservative treatment group and 67.3% in the surgical treatment group. CONCLUSION: Our data suggest that the management of renal function including blood pressure from an early stage in AA patients is important since CRF is highly prevalent in AA patients and affects their prognosis and mortality.

Attenuation of folic acid-induced renal inflammatory injury in platelet-activating factor receptor-deficient mice.

Platelet-activating factor (PAF), a potent lipid mediator with various biological activities, plays an important role in inflammation by recruiting leukocytes. In this study we used platelet-activating factor receptor (PAFR)-deficient mice to elucidate the role of PAF in inflammatory renal injury induced by folic acid administration. PAFR-deficient mice showed significant amelioration of renal dysfunction and pathological findings such as acute tubular damage with neutrophil infiltration, lipid peroxidation observed with antibody to 4-hydroxy-2-hexenal (day 2), and interstitial fibrosis with macrophage infiltration associated with expression of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha in the kidney (day 14). Acute tubular damage was attenuated by neutrophil depletion using a monoclonal antibody (RB6-8C5), demonstrating the contribution of neutrophils to acute phase injury. Macrophage infiltration was also decreased when treatment with a PAF antagonist (WEB2086) was started after acute phase. In vitro chemotaxis assay using a Boyden chamber demonstrated that PAF exhibits a strong chemotactic activity for macrophages. These results indicate that PAF is involved in pathogenesis of folic acid-induced renal injury by activating neutrophils in acute phase and macrophages in chronic interstitial fibrosis. Inhibiting the PAF pathway might be therapeutic to kidney injury from inflammatory cells.