Development of an Immunoassay for the Kidney-Specific Protein myo-Inositol Oxygenase, a Potential Biomarker of Acute Kidney Injury

Abstract

Background Acute kidney injury (AKI) affects 45% of critically ill patients resulting in increased morbidity and mortality. The diagnostic standard, serum creatinine (SCr), is non-specific 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 Gene expression data was analyzed from normal mouse tissues to identify kidney specific genes, one of which was Miox. Monoclonal antibodies were generated to recombinant myo-inositol oxygenase (MIOX), and an immunoassay was developed 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. Plasma MIOX, undetectable at baseline, increased 24 hours following AKI in mice. Plasma MIOX was increased in critically ill patients with AKI (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 hours before the increase in SCr. Conclusions MIOX is a renal specific, proximal tubule protein that is increased in plasma of animals and critically ill patients with AKI. MIOX preceded the elevation in SCr by approximately two days in human patients. Large-scale studies are warranted to further investigate MIOX as an AKI biomarker.

The Kidney Specific Protein myo-Inositol Oxygenase, a Potential Biomarker for Diabetic Nephropathy

“…Current researches have shown that MIOX not only regulates MI metabolism but also participates in the pathogenesis of DN tubular injury through non-MI metabolic pathways, such as by stimulating the release of TGF β [15], disrupting the redox status [16] and regulating mitochondrial dynamics [17]. Interestingly, Gaut et al found that an increase in serum MIOX preceded the elevation of serum creatinine in patients with acute kidney injury (AKI), which was closely associated with the degree of tubular damage [18], indicating that serum MIOX can be used as an AKI biomarker. Despite the evident importance of MIOX in streptozotocin-induced diabetic mice tubular injury, little is known about its role and diagnostic value in DN patients.…”

Ischemic modified albumin increases in acute kidney injury

“…New studies are carried out to search more specific new markers in AKI diagnosis, serum creatinine falling short to meet the criterion of being a specific marker prior to full blown AKI (7). Despite the fact that NGAL, KIM-1, IL-18, IGFBP7, liver-type fatty acid-binding protein 1 and N-acetyl-β-D-glucosaminidase are relevant in the diagnose of AKI, these parameters were not used routinely to show AKI because of difficulties related to reliability and accuracy in the measurement methods (7,(10)(11)(12).…”

“…It takes many days to rise until the loss of ca. 50% of glomerular functions (6,7). It is, therefore, inevitable to search new markers pinpointing a possible AKI in advance (8,9).…”

myo-Inositol Oxygenase: A Novel Kidney-Specific Biomarker of Acute Kidney Injury?

“…In this issue of Clinical Chemistry, Gaut and colleagues report on a potential novel structural biomarker of AKI, myo-inositol oxygenase (MIOX) (14 ). These researchers used an innovative approach to discover a kidney-specific protein that could be released from PTECs during AKI.…”