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-β-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-β-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.

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-β-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.

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.

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.