ABSTRACT
BACKGROUND: Acute kidney injury (AKI) affects 45% of critically ill patients, resulting in increased morbidity and mortality. The diagnostic standard, plasma creatinine, is nonspecific and may not increase until days after injury. There is significant need for a renal-specific AKI biomarker detectable early enough that there would be a potential window for therapeutic intervention. In this study, we sought to identify a renal-specific biomarker of AKI. METHODS: We analyzed gene expression data from normal mouse tissues to identify kidney-specific genes, one of which was Miox. We generated monoclonal antibodies to recombinant myo-inositol oxygenase (MIOX) and developed an immunoassay to quantify MIOX in plasma. The immunoassay was tested in animals and retrospectively in patients with and without AKI. RESULTS: Kidney tissue specificity of MIOX was supported by Western blot. Immunohistochemistry localized MIOX to the proximal renal tubule. Serum MIOX, undetectable at baseline, increased 24 h following AKI in mice. Plasma MIOX was increased in critically ill patients with AKI [mean (SD) 12.4 (4.3) ng/mL, n = 42] compared with patients without AKI [0.5 (0.3) ng/mL, n = 17] and was highest in patients with oliguric AKI [20.2 (7.5) ng/mL, n = 23]. Plasma MIOX increased 54.3 (3.8) h before the increase in creatinine. CONCLUSIONS: MIOX is a renal-specific, proximal tubule protein that is increased in serum of animals and plasma of critically ill patients with AKI. MIOX preceded the increases in creatinine concentration by approximately 2 days in human patients. Large-scale studies are warranted to further investigate MIOX as an AKI biomarker.
Subject(s)
Acute Kidney Injury/blood , Immunoassay/methods , Oxygenases/blood , Acute Kidney Injury/enzymology , Animals , Antibodies, Monoclonal/immunology , Biomarkers/blood , Blotting, Western , Critical Illness , Female , Humans , Immunohistochemistry , Inositol Oxygenase , Male , Mice , Oxygenases/genetics , Oxygenases/immunology , RNA, Messenger/geneticsABSTRACT
BACKGROUND: Definitive diagnosis of Alzheimer disease (AD) can be made only by histopathological examination of brain tissue, prompting the search for premortem disease biomarkers. We sought to determine if the novel brain injury biomarker, visinin-like protein 1 (VLP-1), is altered in the CSF of AD patients compared with controls, and to compare its values to the other well-studied CSF biomarkers 42-amino acid amyloid-beta peptide (Abeta(1-42)), total Tau (tTau), and hyperphosphorylated Tau (pTau). METHODS: Using ELISA, we measured concentrations of Abeta(1-42), tTau, pTau, and VLP-1 in CSF samples from 33 AD patients and 24 controls. We compared the diagnostic performance of these biomarkers using ROC curves. RESULTS: CSF VLP-1 concentrations were significantly higher in AD patients [median (interquartile range) 365 (166) ng/L] compared with controls [244 (142.5) ng/L]. Although the diagnostic performance of VLP-1 alone was comparable to that of Abeta, tTau, or pTau alone, the combination of the 4 biomarkers demonstrated better performance than each individually. VLP-1 concentrations were higher in AD subjects with APOE epsilon4/epsilon4 genotype [599 (240) ng/L] compared with epsilon3/epsilon4 [376 (127) ng/L] and epsilon3/epsilon3 [280 (115.5) ng/L] genotypes. Furthermore, VLP-1 values demonstrated a high degree of correlation with pTau (r = 0.809) and tTau (r = 0.635) but not Abeta(1-42) (r = -0.233). VLP-1 was the only biomarker that correlated with MMSE score (r = -0.384, P = 0.030). CONCLUSIONS: These results suggest that neuronal injury markers such as VLP-1 may have utility as biomarkers for AD.
