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 Ͻ 0.0001), as well as hospital stay (P Ͻ 0.05). In human-L-FABP transgenic mice subjected to ischemiareperfusion 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.
The prevalence of coronary artery stenosis (CAS) at the initiation of renal replacement therapy (RRT) in patients with chronic kidney disease (CKD) and no previous history of angina and/or myocardial infarction (MI) has not been fully elucidated. The prevalence of significant CAS was evaluated in 30 asymptomatic stage 5 CKD patients without a history of angina and/or MI by coronary angiography at the initiation of RRT. The correlations of various parameters with the prevalence of CAS were also examined. Atherosclerotic surrogate markers, including intima-media thickness of carotid artery and ankle-brachial BP index (ABI), were also evaluated. Significant CAS (>50% stenosis) was seen in 16 (53.3%) of 30 asymptomatic CKD patients on coronary angiography at the start of RRT. Stress cardiac scintigraphy was not effective for detecting hidden cardiac ischemia among the CKD patients. Univariate analysis showed that diabetes (P ؍ 0.01), left ventricular mass index (P ؍ 0.04), hyperlipidemia (P ؍ 0.04), total cholesterol (P ؍ 0.02), LDL cholesterol (P < 0.01), intima-media thickness (P ؍ 0.04), and fibrinogen (P ؍ 0.01) were positively correlated with the presence of CAS, whereas ABI (P < 0.01) showed a negative correlation with CAS. Stepwise logistic regression analysis revealed that diabetes and fibrinogen were significant and independent risk factors for CAS in asymptomatic CKD patients who started RRT. The results clearly demonstrated that despite the absence of cardiac events, stage 5 CKD patients are already in a very high risk group for CAS at the initiation of RRT, which was also closely associated with a significant decrease in ABI.
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.
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.
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