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Biomarkers in Drug-Induced Organ Injury

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 January 2017) | Viewed by 59436

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Prof. Dr. Satohiro Masuda

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Division of Clinical Pharmaceutics, Department of Pharmaceutical Health Care, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji 670-0896, Japan
Interests: biomarker; nephrology; pharmacogenomics; immunosuppressive drugs; drug transporter; liver transplantation; kidney transplantation; inflammatory bowel disease; antiinfective agent; therapeutic drug monitoring
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Dear Colleagues,

Biomarkers, reflecting pharmacological effects and/or toxicological disorders, have been widely examined. For example, serum creatinine is usually examined to utilized as conventional marker for the renal damage in the clinical treatment, however, this biochemical parameter is acknowledged to be non-specific to cover the drug-induced kidney injury. Similar to kidney, drug-induced liver, lung and bone marrow injury are often observed in pharmacotherapy and chemotherapy. Therefore, some organ-specific and/or drug-specific biological markers including protein, peptides, nucleic acids, and so on are required to make accurate diagnosis of patients’ situation. Recently, research area of biomarkers in pharmacology and toxicology has been expanded to find the physiological significance of biomarkers in molecular-biological processes. With these exciting findings, this Special issue focuses on “Biomarkers in Drug-Induced Organ Injury”.

Researchers are invited to submit both original research and review articles that explore the understandings of organ-specific biomarkers reflecting and/or predicting drug-induced organ injury. Potential topics include, but are not limited to:

Biomarkers in drug-induced liver disease
Biomarkers in drug-induced kidney injury
Biomarkers in drug-induced lung injury
Biomarkers in drug-induced bone marrow disorder
Biomarkers in cancer chemotherapy
Biomarkers in immunosuppressive treatment
Biomarkers in treatment against infection

Prof. Dr. Satohiro Masuda
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Related Special Issues

Molecular Mechanisms and Biomarkers in Drug-Associated Organ Injury in International Journal of Molecular Sciences (1 article)
Molecular Mechanisms and Biomarkers in Drug-Induced Organ Injury in International Journal of Molecular Sciences (14 articles)

Published Papers (10 papers)

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Research

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1338 KiB

Open AccessArticle

Elevated Soluble Urokinase Plasminogen Activator Receptor and Proenkephalin Serum Levels Predict the Development of Acute Kidney Injury after Cardiac Surgery

by Jana C. Mossanen, Jessica Pracht, Tobias U. Jansen, Lukas Buendgens, Christian Stoppe, Andreas Goetzenich, Joachim Struck, Rüdiger Autschbach, Gernot Marx and Frank Tacke

Int. J. Mol. Sci. 2017, 18(8), 1662; https://doi.org/10.3390/ijms18081662 - 31 Jul 2017

Cited by 48 | Viewed by 4840

Abstract

Acute kidney injury (AKI) develops in up to 40% of patients after cardiac surgery. The soluble urokinase plasminogen activator receptor (suPAR) has been identified as a biomarker for incident chronic kidney disease (CKD). Proenkephalin (proENK) also has been shown to be a biomarker for renal dysfunction. We hypothesized that pre-surgery suPAR and proENK levels might predict AKI in patients undergoing cardiac surgery. Consecutive patients (n = 107) undergoing elective cardiac surgery were studied prospectively. Clinical data, laboratory parameters, suPAR and proENK serum levels were assessed before operation, after operation and days one and four post-operatively. A total of 21 (19.6%) patients developed AKI within the first four days after elective surgery. Serum levels of suPAR and proENK, but not of creatinine, were significantly higher before surgery in these patients compared to those patients without AKI. This difference remained significant for suPAR, if patients with or without AKI were matched for risk factors (hypertension, diabetes, CKD). If cardiac surgery patients with pre-existing CKD (n = 10) were excluded, only pre-operative suPAR but not proENK serum levels remained significantly elevated in patients with subsequent AKI. Thus, our findings indicate that suPAR may be a predictive biomarker for AKI in the context of cardiac surgery, even in patients without underlying CKD. Full article

(This article belongs to the Special Issue Biomarkers in Drug-Induced Organ Injury)

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Open AccessArticle

Inferring Genes and Biological Functions That Are Sensitive to the Severity of Toxicity Symptoms

by Jinwoo Kim and Miyoung Shin

Int. J. Mol. Sci. 2017, 18(4), 755; https://doi.org/10.3390/ijms18040755 - 02 Apr 2017

Cited by 2 | Viewed by 3623

Abstract

The effective development of new drugs relies on the identification of genes that are related to the symptoms of toxicity. Although many researchers have inferred toxicity markers, most have focused on discovering toxicity occurrence markers rather than toxicity severity markers. In this study, we aimed to identify gene markers that are relevant to both the occurrence and severity of toxicity symptoms. To identify gene markers for each of four targeted liver toxicity symptoms, we used microarray expression profiles and pathology data from 14,143 in vivo rat samples. The gene markers were found using sparse linear discriminant analysis (sLDA) in which symptom severity is used as a class label. To evaluate the inferred gene markers, we constructed regression models that predicted the severity of toxicity symptoms from gene expression profiles. Our cross-validated results revealed that our approach was more successful at finding gene markers sensitive to the aggravation of toxicity symptoms than conventional methods. Moreover, these markers were closely involved in some of the biological functions significantly related to toxicity severity in the four targeted symptoms. Full article

(This article belongs to the Special Issue Biomarkers in Drug-Induced Organ Injury)

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Open AccessArticle

Liver Effects of Clinical Drugs Differentiated in Human Liver Slices

by Alison E. M. Vickers, Anatoly V. Ulyanov and Robyn L. Fisher

Int. J. Mol. Sci. 2017, 18(3), 574; https://doi.org/10.3390/ijms18030574 - 07 Mar 2017

Cited by 12 | Viewed by 5124

Abstract

Drugs with clinical adverse effects are compared in an ex vivo 3-dimensional multi-cellular human liver slice model. Functional markers of oxidative stress and mitochondrial function, glutathione GSH and ATP levels, were affected by acetaminophen (APAP, 1 mM), diclofenac (DCF, 1 mM) and etomoxir (ETM, 100 μM). Drugs targeting mitochondria more than GSH were dantrolene (DTL, 10 μM) and cyclosporin A (CSA, 10 μM), while GSH was affected more than ATP by methimazole (MMI, 500 μM), terbinafine (TBF, 100 μM), and carbamazepine (CBZ 100 μM). Oxidative stress genes were affected by TBF (18%), CBZ, APAP, and ETM (12%–11%), and mitochondrial genes were altered by CBZ, APAP, MMI, and ETM (8%–6%). Apoptosis genes were affected by DCF (14%), while apoptosis plus necrosis were altered by APAP and ETM (15%). Activation of oxidative stress, mitochondrial energy, heat shock, ER stress, apoptosis, necrosis, DNA damage, immune and inflammation genes ranked CSA (75%), ETM (66%), DCF, TBF, MMI (61%–60%), APAP, CBZ (57%–56%), and DTL (48%). Gene changes in fatty acid metabolism, cholestasis, immune and inflammation were affected by DTL (51%), CBZ and ETM (44%–43%), APAP and DCF (40%–38%), MMI, TBF and CSA (37%–35%). This model advances multiple dosing in a human ex vivo model, plus functional markers and gene profile markers of drug induced human liver side-effects. Full article

(This article belongs to the Special Issue Biomarkers in Drug-Induced Organ Injury)

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210 KiB

Open AccessCommunication

Sensitivity of Quantitative Signal Detection in Regards to Pharmacological Neuroenhancement

by Maximilian Gahr, Bernhard J. Connemann, Carlos Schönfeldt-Lecuona and René Zeiss

Int. J. Mol. Sci. 2017, 18(1), 101; https://doi.org/10.3390/ijms18010101 - 05 Jan 2017

Cited by 4 | Viewed by 4421

Abstract

Pharmacological neuroenhancement (PNE) is a form of abuse and has not yet been addressed by methods of pharmacovigilance. In the present study, we tested if quantitative signal detection may be sensitive in regards to PNE. We evaluated the risk of drug abuse and dependence (DAAD) related to substances that are known to be used for PNE and divided this group into agents with (methylphenidate) and without a known abuse potential outside the field of PNE (atomoxetine, modafinil, acetylcholine esterase inhibitors, and memantine). Reporting odds ratios (RORs) were calculated using a case/non-case approach based on global and country-specific drug safety data from the Uppsala Monitoring Centre (UMC). Both control substances (diazepam and lorazepam) and methylphenidate were statistically associated with DAAD in all datasets (except methylphenidate in Italy). Modafinil was associated with DAAD in the total dataset (ROR, 2.7 (95% confidence interval (CI), 2.2–3.3)), Germany (ROR, 4.6 (95% CI, 1.8–11.5)), and the USA (ROR, 2.0 (95% CI, 1.6–2.5)). Atomoxetine was associated with DAAD in the total dataset (ROR, 1.3 (95% CI, 1.2–1.5)) and in the UK (ROR, 3.3 (95% CI, 1.8–6.1)). Apart from memantine, which was associated with DAAD in Germany (ROR, 1.8 (95% CI, 1.0–3.2)), no other antidementia drug was associated with DAAD. Quantitative signal detection is suitable to detect agents with a risk for DAAD. Its sensitivity regarding PNE is limited, although atomoxetine and modafinil, which do not have a known abuse potential outside PNE, and no antidementia drugs, whose use in PNE is presumably low, were associated with DAAD in our analysis. Full article

(This article belongs to the Special Issue Biomarkers in Drug-Induced Organ Injury)

1476 KiB

Open AccessArticle

Indoxyl Sulfate as a Mediator Involved in Dysregulation of Pulmonary Aquaporin-5 in Acute Lung Injury Caused by Acute Kidney Injury

by Nozomi Yabuuchi, Masataka Sagata, Chika Saigo, Go Yoneda, Yuko Yamamoto, Yui Nomura, Kazuhiko Nishi, Rika Fujino, Hirofumi Jono and Hideyuki Saito

Int. J. Mol. Sci. 2017, 18(1), 11; https://doi.org/10.3390/ijms18010011 - 23 Dec 2016

Cited by 30 | Viewed by 5902

Abstract

High mortality of acute kidney injury (AKI) is associated with acute lung injury (ALI), which is a typical complication of AKI. Although it is suggested that dysregulation of lung salt and water channels following AKI plays a pivotal role in ALI, the mechanism of its dysregulation has not been elucidated. Here, we examined the involvement of a typical oxidative stress-inducing uremic toxin, indoxyl sulfate (IS), in the dysregulation of the pulmonary predominant water channel, aquaporin 5 (AQP-5), in bilateral nephrectomy (BNx)-induced AKI model rats. BNx evoked AKI with the increases in serum creatinine (SCr), blood urea nitrogen (BUN) and serum IS levels and exhibited thickening of interstitial tissue in the lung. Administration of AST-120, clinically-used oral spherical adsorptive carbon beads, resulted in a significant decrease in serum IS level and thickening of interstitial tissue, which was accompanied with the decreases in IS accumulation in various tissues, especially lung. Interestingly, a significant decrease in AQP-5 expression of lung was observed in BNx rats. Moreover, the BNx-induced decrease in pulmonary AQP-5 protein expression was markedly restored by oral administration of AST-120. These results suggest that BNx-induced AKI causes dysregulation of pulmonary AQP-5 expression, in which IS could play a toxico-physiological role as a mediator involved in renopulmonary crosstalk. Full article

(This article belongs to the Special Issue Biomarkers in Drug-Induced Organ Injury)

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Open AccessArticle

Urine Levels of Defensin α1 Reflect Kidney Injury in Leptospirosis Patients

by Haorile Chagan-Yasutan, Yue Chen, Talitha Lea Lacuesta, Prisca Susan A. Leano, Hiroko Iwasaki, Firmanto Hanan, Delsi Taurustiati, Yasukazu Ohmoto, Yugo Ashino, Hiroki Saitoh, Hideyasu Kiyomoto, Yasuhiko Suzuki, Freda O. Elizabeth Telan and Toshio Hattori

Int. J. Mol. Sci. 2016, 17(10), 1637; https://doi.org/10.3390/ijms17101637 - 27 Sep 2016

Cited by 7 | Viewed by 4787

Abstract

Leptospirosis is a zoonotic disease whose severe forms are often accompanied by kidney dysfunction. In the present study, urinary markers were studied for potential prediction of disease severity. Urine samples from 135 patients with or without leptospirosis at San Lazaro Hospital, the Philippines, were analyzed. Urine levels of defensin α1 (uDA1) were compared with those of neutrophil gelatinase-associated lipocalin (uNGAL) and N-acetyl-β-d-glucosidase (uNAG). Serum creatinine (Cr) was used as a marker of kidney injury. The levels of uDA1/Cr, uNGAL/Cr, and uNAG/Cr were positive in 46%, 90%, and 80% of leptospirosis patients, and 69%, 70%, and 70% of non-leptospirosis patients, respectively. In leptospirosis patients, the correlation of uDA1/Cr, uNGAL/Cr and uNAG/Cr levels with serum Cr were r = 0.3 (p < 0.01), r = 0.29 (p < 0.01), and r = 0.02 (p = 0.81), respectively. uDA1/Cr levels were correlated with uNGAL/Cr levels (r = 0.49, p < 0.01) and uNAG/Cr levels (r = 0.47, p < 0.0001) in leptospirosis patients. These findings suggest that uDA1, uNGAL, and uNAG were elevated in leptospirosis patients and reflected various types of kidney damage. uDA1 and uNGAL can be used to track kidney injury in leptospirosis patients because of their correlation with the serum Cr level. Full article

(This article belongs to the Special Issue Biomarkers in Drug-Induced Organ Injury)

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5127 KiB

Open AccessArticle

Urinary Dopamine as a Potential Index of the Transport Activity of Multidrug and Toxin Extrusion in the Kidney

by Moto Kajiwara, Tsuyoshi Ban, Kazuo Matsubara, Yoichi Nakanishi and Satohiro Masuda

Int. J. Mol. Sci. 2016, 17(8), 1228; https://doi.org/10.3390/ijms17081228 - 30 Jul 2016

Cited by 9 | Viewed by 6805

Abstract

Dopamine is a cationic natriuretic catecholamine synthesized in proximal tubular cells (PTCs) of the kidney before secretion into the lumen, a key site of its action. However, the molecular mechanisms underlying dopamine secretion into the lumen remain unclear. Multidrug and toxin extrusion (MATE) is a H⁺/organic cation antiporter that is highly expressed in the brush border membrane of PTCs and mediates the efflux of organic cations, including metformin and cisplatin, from the epithelial cells into the urine. Therefore, we hypothesized that MATE mediates dopamine secretion, a cationic catecholamine, into the tubule lumen, thereby regulating natriuresis. Here, we show that [³H]dopamine uptake in human (h) MATE1-, hMATE-2K- and mouse (m) MATE-expressing cells exhibited saturable kinetics. Fluid retention and decreased urinary excretion of dopamine and Na⁺ were observed in Mate1-knockout mice compared to that in wild-type mice. Imatinib, a MATE inhibitor, inhibited [³H]dopamine uptake by hMATE1-, hMATE2-K- and mMATE1-expressing cells in a concentration-dependent manner. At clinically-relevant concentrations, imatinib inhibited [³H]dopamine uptake by hMATE1- and hMATE2-K-expressing cells. The urinary excretion of dopamine and Na⁺ decreased and fluid retention occurred in imatinib-treated mice. In conclusion, MATE transporters secrete renally-synthesized dopamine, and therefore, urinary dopamine has the potential to be an index of the MATE transporter activity. Full article

(This article belongs to the Special Issue Biomarkers in Drug-Induced Organ Injury)

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Open AccessCommunication

Active and Repressive Chromatin-Associated Proteome after MPA Treatment and the Role of Midkine in Epithelial Monolayer Permeability

by Niamat Khan, Christof Lenz, Lutz Binder, Dasaradha Venkata Krishna Pantakani and Abdul R. Asif

Int. J. Mol. Sci. 2016, 17(4), 597; https://doi.org/10.3390/ijms17040597 - 20 Apr 2016

Cited by 4 | Viewed by 6235

Abstract

Mycophenolic acid (MPA) is prescribed to maintain allografts in organ-transplanted patients. However, gastrointestinal (GI) complications, particularly diarrhea, are frequently observed as a side effect following MPA therapy. We recently reported that MPA altered the tight junction (TJ)-mediated barrier function in a Caco-2 cell monolayer model system. This study investigates whether MPA induces epigenetic changes which lead to GI complications, especially diarrhea. Methods: We employed a Chromatin Immunoprecipitation-O-Proteomics (ChIP-O-Proteomics) approach to identify proteins associated with active (H3K4me3) as well as repressive (H3K27me3) chromatin histone modifications in MPA-treated cells, and further characterized the role of midkine, a H3K4me3-associated protein, in the context of epithelial monolayer permeability. Results: We identified a total of 333 and 306 proteins associated with active and repressive histone modification marks, respectively. Among them, 241 proteins were common both in active and repressive chromatin, 92 proteins were associated exclusively with the active histone modification mark, while 65 proteins remained specific to repressive chromatin. Our results show that 45 proteins which bind to the active and seven proteins which bind to the repressive chromatin region exhibited significantly altered abundance in MPA-treated cells as compared to DMSO control cells. A number of novel proteins whose function is not known in bowel barrier regulation were among the identified proteins, including midkine. Our functional integrity assays on the Caco-2 cell monolayer showed that the inhibition of midkine expression prior to MPA treatment could completely block the MPA-mediated increase in barrier permeability. Conclusions: The ChIP-O-Proteomics approach delivered a number of novel proteins with potential implications in MPA toxicity. Consequently, it can be proposed that midkine inhibition could be a potent therapeutic approach to prevent the MPA-mediated increase in TJ permeability and leak flux diarrhea in organ transplant patients. Full article

(This article belongs to the Special Issue Biomarkers in Drug-Induced Organ Injury)

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Review

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715 KiB

Open AccessReview

Role of Oxidative Stress in Drug-Induced Kidney Injury

by Keiko Hosohata

Int. J. Mol. Sci. 2016, 17(11), 1826; https://doi.org/10.3390/ijms17111826 - 01 Nov 2016

Cited by 134 | Viewed by 9579

Abstract

The kidney plays a primary role in maintaining homeostasis and detoxification of numerous hydrophilic xenobiotics as well as endogenous compounds. Because the kidney is exposed to a larger proportion and higher concentration of drugs and toxins than other organs through the secretion of ionic drugs by tubular organic ion transporters across the luminal membranes of renal tubular epithelial cells, and through the reabsorption of filtered toxins into the lumen of the tubule, these cells are at greater risk for injury. In fact, drug-induced kidney injury is a serious problem in clinical practice and accounts for roughly 20% of cases of acute kidney injury (AKI) among hospitalized patients. Therefore, its early detection is becoming more important. Usually, drug-induced AKI consists of two patterns of renal injury: acute tubular necrosis (ATN) and acute interstitial nephritis (AIN). Whereas AIN develops from medications that incite an allergic reaction, ATN develops from direct toxicity on tubular epithelial cells. Among several cellular mechanisms underlying ATN, oxidative stress plays an important role in progression to ATN by activation of inflammatory response via proinflammatory cytokine release and inflammatory cell accumulation in tissues. This review provides an overview of drugs associated with AKI, the role of oxidative stress in drug-induced AKI, and a biomarker for drug-induced AKI focusing on oxidative stress. Full article

(This article belongs to the Special Issue Biomarkers in Drug-Induced Organ Injury)

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1284 KiB

Open AccessReview

Circulating Organ-Specific MicroRNAs Serve as Biomarkers in Organ-Specific Diseases: Implications for Organ Allo- and Xeno-Transplantation

by Ming Zhou, Hidetaka Hara, Yifan Dai, Lisha Mou, David K. C. Cooper, Changyou Wu and Zhiming Cai

Int. J. Mol. Sci. 2016, 17(8), 1232; https://doi.org/10.3390/ijms17081232 - 01 Aug 2016

Cited by 41 | Viewed by 7461

Abstract

Different cell types possess different miRNA expression profiles, and cell/tissue/organ-specific miRNAs (or profiles) indicate different diseases. Circulating miRNA is either actively secreted by living cells or passively released during cell death. Circulating cell/tissue/organ-specific miRNA may serve as a non-invasive biomarker for allo- or xeno-transplantation to monitor organ survival and immune rejection. In this review, we summarize the proof of concept that circulating organ-specific miRNAs serve as non-invasive biomarkers for a wide spectrum of clinical organ-specific manifestations such as liver-related disease, heart-related disease, kidney-related disease, and lung-related disease. Furthermore, we summarize how circulating organ-specific miRNAs may have advantages over conventional methods for monitoring immune rejection in organ transplantation. Finally, we discuss the implications and challenges of applying miRNA to monitor organ survival and immune rejection in allo- or xeno-transplantation. Full article

(This article belongs to the Special Issue Biomarkers in Drug-Induced Organ Injury)

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