Identification of metabolomic biomarkers for drug‐induced acute kidney injury in rats

Abstract

Nephrotoxicity is a common side effect observed during both nonclinical and clinical drug development investigations. The present study aimed to identify metabolomic biomarkers that could provide early and sensitive indication of nephrotoxicity in rats. Metabolomic analyses were performed using capillary electrophoresis-time-of-flight mass spectrometry on rat plasma collected at 9 and 24 h after a single dose of 2-bromoethylamine or n-phenylanthranilic acid and at 24 h after 7 days of repeated doses of gentamicin, cyclosporine A or cisplatin. Among a total of 169 metabolites identified, 3-methylhistidine (3-MH), 3-indoxyl sulfate (3-IS) and guanidoacetate (GAA) were selected as candidate biomarkers. The biological significance and reproducibility of the observed changes were monitored over time in acute nephrotoxicity model rats treated with a single dose of cisplatin, with the glomerular filtration rate monitored by determination of creatinine clearance. Increased plasma levels of 3-MH and 3-IS were related to a decline in glomerular filtration due to a renal failure. In contrast, the decrease in plasma GAA, which is synthesized from arginine and glycine in the kidneys, was considered to reflect decreased production due to renal malfunction. Although definitive validation studies are required to confirm their usefulness and reliability, 3-MH, 3-IS and GAA may prove to be valuable plasma biomarkers for monitoring nephrotoxicity in rats.

The potential use of biomarkers in predicting contrast-induced acute kidney injury

“…The last few years has seen a number of studies investigating changes in metabolites accompanying AKI, especially with respect to the use of nephrotoxins such as cisplatin. 175,176 A recent study investigated changes in the metabolic profiles in a mouse model of IRI, in which a period of renal ischemia was followed by 2 hours to 7 days of reperfusion, 177 using gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry analysis. There were changes in metabolites related to energy and purine metabolism as well as osmotic regulation and inflammation.…”

“…178 Of note, an increase in the metabolite 3-indoxyl sulfate was observed early on during reperfusion, and it could serve as a potential biomarker, given that it has also been reported as increasing in other models of toxin-induced renal failure. 176 In another study, changes were noted in urinary metabolites of patients undergoing computerized tomography scan scan and administered with the LOCM iohexol, 179 but the study did not set out to associate any of these changes with CI-AKI.…”

Early lipid changes in acute kidney injury using SWATH lipidomics coupled with MALDI tissue imaging

“…Since the kidney is the major organ for excreting metabolic end products, its injury can cause changes in the renal metabolic profile, and understanding its influence on kidney function will shed light on new potential diagnostic markers and therapeutic targets in AKI (17,21,34,43). Advances in functional genomics and proteomics have fostered progress in our understanding of the pathogenic mechanisms involved and identified some novel protein biomarkers and candidate therapeutic targets in plasma, urine, and tissues which precede changes in commonly used clinical markers of renal dysfunction like plasma creatinine (6,14,18,29,41). Comparatively little, however, is known regarding the role of lipids in pathogenic mechanisms of AKI (1,5,39).…”

Evaluation of onion as a functional ingredient in the prevention of metabolic impairments associated to diet-induced hypercholesterolaemia using a multiplatform approach based on LC-MS, CE-MS and GC-MS

“…Furthermore, the preventive effects of onion could not exclusively rely on the inhibition of specific negative vascular events and the potential enhancement of the immune system, since the levels of 3-methylhistidine (3-MH), creatinine, carnitine and glycerophospholipids, among others (Table 2), were also affected. The circulating levels of 3-MH have been recently proposed as valuable plasma biomarkers for monitoring nephrotoxicity in rats (Uehara et al, 2014). However, it has to be considered that 3-MH may also increase in response to changes in skeletal muscle metabolism, and therefore its changes might be also indicative of muscular injury.…”