The Utility of Novel Urinary Biomarkers in Mice for Drug Development Studies

Novel urinary protein biomarkers have recently been identified and qualified in rats for the early detection of renal injury in drug development studies. However, there are few reports on the utility of these renal biomarkers in mice, another important and widely used preclinical animal species for drug development studies. The purpose of this study was to assess the value of these recently qualified biomarkers for the early detection of drug-induced kidney injury (DIKI) in different strains of mice using multiple assay panels. To this end, we evaluated biomarker response to kidney injury induced by several nephrotoxic agents including amphotericin B, compound X, and compound Y. Several of the biomarkers were shown to be sensitive to DIKI in mice. When measured, urinary albumin and neutrophil gelatinase-associated lipocalin were highly sensitive to renal tubular injury, regardless of the assay platforms, mouse strain, and nephrotoxic agents. Depending on the type of renal tubular injury, kidney injury molecule-1 was also highly sensitive, regardless of the assay platforms and mouse strain. Osteopontin and cystatin C were modestly to highly sensitive to renal tubular injury, but the assay type and/or the mouse strain should be considered before using these biomarkers. Calbindin D28 was highly sensitive to injury to the distal nephron in mice. To our knowledge, this is the first report that demonstrates the utility of novel urinary biomarkers evaluated across multiple assay platforms and nephrotoxicants in different mice strains with DIKI. These results will help drug developers make informed decisions when selecting urinary biomarkers for monitoring DIKI in mice for toxicology studies.

Download Full-text

Faculty Opinions recommendation of Urinary biomarkers in the early detection of acute kidney injury after cardiac surgery.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1162033.622590 ◽

2010 ◽

Author(s):

John Augoustides ◽

Tygh Wyckoff

Keyword(s):

Acute Kidney Injury ◽

Cardiac Surgery ◽

Early Detection ◽

Kidney Injury ◽

Urinary Biomarkers

Download Full-text

An Immunohistochemical Investigation of Renal Phospholipidosis and Toxicity in Rats

International Journal of Toxicology ◽

10.1177/1091581817726040 ◽

2017 ◽

Vol 36 (5) ◽

pp. 386-394 ◽

Cited By ~ 1

Author(s):

Jing Ying Ma ◽

Sandra Snook ◽

Sheryl Garrovillo ◽

Charles Johnson ◽

David La

Keyword(s):

Electron Microscopy ◽

Membrane Protein ◽

Kidney Injury ◽

Tubular Epithelial Cell ◽

Vehicle Group ◽

Tubular Injury ◽

Histamine H4 Receptor ◽

Outer Stripe ◽

H4 Receptor ◽

Renal Tubular

Immunohistochemical staining for the lysosome-associated membrane protein 2 (LAMP-2) has been proposed previously as an alternative to electron microscopy to identify hepatic phospholipidosis. This study used LAMP-2 immunohistochemistry (IHC) to diagnose phospholipidosis in rats exhibiting renal tubular injury. Rats were administered toreforant, a histamine H4 receptor antagonist by oral gavage at a dose of 3, 10, or 100 mg/kg/d for 6 months. Hematoxylin and eosin staining revealed renal tubular epithelial cell vacuolation, hypertrophy, degeneration, and luminal dilation in the 100 mg/kg/d group animals. Renal tubular injury was confirmed using kidney injury marker 1 (KIM-1) IHC. The involvement of phosopholipidosis in the renal injury was investigated by LAMP-2. Adipophilin IHC was included to differentiate phospholipidosis from lipidosis. Increased LAMP-2 staining was observed in the 100 mg/kg/d group animals when compared to vehicle group animals. Lysosome-associated membrane protein-2 staining was most prominent in the outer stripe of the outer medulla where KIM-1 staining was also most prominent. By contrast, adipophilin staining was not increased. Phospholipidosis was also confirmed by electron microscopy. These data support the use of LAMP-2 IHC as a diagnostic tool and suggest an association between phospholipidosis and the renal tubular injury caused by toreforant.

Download Full-text

Genetic Polymorphisms of MnSOD Modify the Impacts of Environmental Melamine on Oxidative Stress and Early Kidney Injury in Calcium Urolithiasis Patients

Antioxidants ◽

10.3390/antiox11010152 ◽

2022 ◽

Vol 11 (1) ◽

pp. 152

Author(s):

Chia-Chu Liu ◽

Chia-Fang Wu ◽

Yung-Chin Lee ◽

Tsung-Yi Huang ◽

Shih-Ting Huang ◽

...

Keyword(s):

Oxidative Stress ◽

Manganese Superoxide Dismutase ◽

Kidney Injury ◽

Normal Function ◽

Nucleotide Polymorphisms ◽

Tubular Injury ◽

Single Nucleotide ◽

Manganese Superoxide ◽

Calcium Urolithiasis ◽

Renal Tubular

Environmental melamine exposure increases the risks of oxidative stress and early kidney injury. Manganese superoxide dismutase (MnSOD), glutathione peroxidase, and catalase can protect the kidneys against oxidative stress and maintain normal function. We evaluated whether their single-nucleotide polymorphisms (SNPs) could modify melamine’s effects. A total of 302 patients diagnosed with calcium urolithiasis were enrolled. All patients provided one-spot overnight urine samples to measure their melamine levels, urinary biomarkers of oxidative stress and renal tubular injury. Median values were used to dichotomize levels into high and low. Subjects carrying the T allele of rs4880 and high melamine levels had 3.60 times greater risk of high malondialdehyde levels than those carrying the C allele of rs4880 and low melamine levels after adjustment. Subjects carrying the G allele of rs5746136 and high melamine levels had 1.73 times greater risk of high N-Acetyl-β-d-glucosaminidase levels than those carrying the A allele of rs5746136 and low melamine levels. In conclusion, the SNPs of MnSOD, rs4880 and rs5746136, influence the risk of oxidative stress and renal tubular injury, respectively, in calcium urolithiasis patients. In the context of high urinary melamine levels, their effects on oxidative stress and renal tubular injury were further increased.

Download Full-text

Use of the kidney injury molecule-1 as a biomarker for early detection of renal tubular dysfunction in a population chronically exposed to cadmium in the environment

SpringerPlus ◽

10.1186/2193-1801-2-533 ◽

2013 ◽

Vol 2 (1) ◽

pp. 533 ◽

Cited By ~ 24

Author(s):

Werawan Ruangyuttikarn ◽

Amnart Panyamoon ◽

Kowit Nambunmee ◽

Ryumon Honda ◽

Witaya Swaddiwudhipong ◽

...

Keyword(s):

Early Detection ◽

Kidney Injury ◽

Tubular Dysfunction ◽

Renal Tubular Dysfunction ◽

Renal Tubular ◽

Kidney Injury Molecule 1

Download Full-text

Renal tubular injury exacerbated by vasohibin-1 deficiency in a murine cisplatin-induced acute kidney injury model

AJP Renal Physiology ◽

10.1152/ajprenal.00045.2019 ◽

2019 ◽

Vol 317 (2) ◽

pp. F264-F274 ◽

Cited By ~ 6

Author(s):

Satoshi Tanimura ◽

Katsuyuki Tanabe ◽

Hiromasa Miyake ◽

Kana Masuda ◽

Keigo Tsushida ◽

...

Keyword(s):

Acute Kidney Injury ◽

Endothelial Cells ◽

Kidney Injury ◽

Protective Effects ◽

Tubular Injury ◽

Injury Model ◽

Peritubular Capillaries ◽

Renal Tubular ◽

And Function ◽

Hospital Acquired

Acute kidney injury (AKI) is frequently encountered in clinical practice, particularly secondarily to cardiovascular surgery and administration of nephrotoxic agents, and is increasingly recognized for initiating a transition to chronic kidney disease. Clarifying the pathogenesis of AKI could facilitate the development of novel preventive strategies, because the occurrence of hospital-acquired AKI is often anticipated. Vasohibin-1 (VASH1) was initially identified as an antiangiogenic factor derived from endothelial cells. VASH1 expression in endothelial cells has subsequently been reported to enhance cellular stress tolerance. Considering the importance of maintaining peritubular capillaries in preventing the progression of AKI, the present study aimed to examine whether VASH1 deletion is involved in the pathogenesis of cisplatin-induced AKI. For this, we injected male C57BL/6J wild-type (WT) and VASH1 heterozygous knockout (VASH1+/−) mice intraperitoneally with either 20 mg/kg cisplatin or vehicle solution. Seventy-two hours after cisplatin injection, increased serum creatinine concentrations and renal tubular injury accompanied by apoptosis and oxidative stress were more prominent in VASH1+/− mice than in WT mice. Cisplatin-induced peritubular capillary loss was also accelerated by VASH1 deficiency. Moreover, the increased expression of ICAM-1 in the peritubular capillaries of cisplatin-treated VASH1+/− mice was associated with a more marked infiltration of macrophages into the kidney. Taken together, VASH1 expression could have protective effects on cisplatin-induced AKI probably by maintaining the number and function of peritubular capillaries.

Download Full-text

Urinary biomarkers in the early detection and follow-up of tubular injury in childhood urolithiasis

Clinical and Experimental Nephrology ◽

10.1007/s10157-017-1436-3 ◽

2017 ◽

Vol 22 (1) ◽

pp. 133-141 ◽

Cited By ~ 3

Author(s):

Mehmet Taşdemir ◽

Dilara Fuçucuoğlu ◽

Suat Hayri Küçük ◽

Meltem Erol ◽

Özgül Yiğit ◽

...

Keyword(s):

Early Detection ◽

Urinary Biomarkers ◽

Tubular Injury ◽

Childhood Urolithiasis

Download Full-text

Correlation between Neutrophil Gelatinase‐associated Lipocalin and highly sensitive C reactive protein as markers for early detection of acute kidney injury in neonatal sepsis.

GEGET ◽

10.21608/geget.2019.67031 ◽

2019 ◽

Vol 14 (2) ◽

pp. 1-6

Author(s):

Moftah Rabeea ◽

Mohamed Abdelkerim ◽

Ibrahim Metwaly ◽

Sayed Elsisi

Keyword(s):

Acute Kidney Injury ◽

Early Detection ◽

Neonatal Sepsis ◽

Kidney Injury ◽

C Reactive Protein ◽

Neutrophil Gelatinase Associated Lipocalin ◽

Reactive Protein ◽

Highly Sensitive ◽

Neutrophil Gelatinase

Download Full-text

Inhibition of Mitochondrial Complex I Aggravates Folic Acid-Induced Acute Kidney Injury

Kidney & Blood Pressure Research ◽

10.1159/000501934 ◽

2019 ◽

Vol 44 (5) ◽

pp. 1002-1013 ◽

Cited By ~ 2

Author(s):

Wen Zhang ◽

Yunwen Yang ◽

Huiping Gao ◽

Yue Zhang ◽

Zhanjun Jia ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Folic Acid ◽

Mitochondrial Dysfunction ◽

Complex I ◽

Kidney Injury ◽

Mitochondrial Complex I ◽

Tubular Injury ◽

Mitochondrial Complex ◽

Renal Tubular

Background: Some researches revealed that mitochondrial dysfunction is associated with various kidney injury. However, the role of mitochondrial dysfunction in the pathogenesis of acute kidney injury (AKI) still needs evidence. Methods: We evaluated the effect of mitochondrial complex I inhibitor rotenone on folic acid (FA)-induced AKI in mice. Results: Strikingly, the mice pretreated with rotenone at a dose of 200 ppm in food showed exacerbated kidney injury as shown by higher levels of blood urea nitrogen and creatinine compared with FA alone group. Meanwhile, both renal tubular injury score and the expression of renal tubular injury marker neutrophil gelatinase-associated lipocalin were further elevated in rotenone-pretreated mice, suggesting the deteriorated renal tubular injury. Moreover, the decrements of mitochondrial DNA copy number and the expressions of mitochondrial Cytochrome c oxidase subunit 1, mitochondrial NADH dehydrogenase subunit 1, and mitochondria-specific superoxide dismutase (SOD2) in the kidneys of FA-treated mice were further reduced in rotenone-pretreated mice, indicating the aggravated mitochondrial damage. In parallel with the SOD2 reduction, the oxidative stress markers of malondialdehyde and HO-1 displayed greater increment in AKI mice with rotenone pretreatment in line with the deteriorated apoptotic response and inflammation. Conclusion: Our results suggested that the inhibition of mitochondrial complex I activity aggravated renal tubular injury, mitochondrial damage, oxidative stress, cell apoptosis, and inflammation in FA-induced AKI.

Download Full-text

Abstract MP072: Association of Urinary Kidney Injury Biomarkers with Kidney Function Decline: A Case-Control Study from the Multi-Ethnic Study of Atherosclerosis (MESA)

Circulation ◽

10.1161/circ.125.suppl_10.amp072 ◽

2012 ◽

Vol 125 (suppl_10) ◽

Author(s):

Carmen A Peralta ◽

Ronit Katz ◽

Joseph V Bonventre ◽

Venkata Sabbisetti ◽

David Siscovick ◽

...

Keyword(s):

Kidney Disease ◽

Kidney Function ◽

Case Control Study ◽

Kidney Injury ◽

Case Control ◽

Urinary Biomarkers ◽

Tubular Injury ◽

Future Risk ◽

Kidney Function Decline ◽

Control Study

Background: The urinary biomarkers of tubular injury ((urine neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1)) can indicate acute kidney injury before reductions in estimated glomerular filtration rate (eGFR) are clinically detectable. Whether elevations of these markers are associated with future risk of kidney disease has not been investigated. Methods: We studied the association of urinary NGAL and KIM-1 with kidney function decline in a 1:1 ratio case-control study among 686 MESA participants. NGAL and KIM-1 were measured at baseline (standardized for urinary creatinine) and expressed both as continuous and in deciles. eGFR was estimated by cystatin C. Cases were defined as persons with eGFR>60 ml/min/1.73m 2 who subsequently developed incident CKD (defined as eGFR<60 plus eGFR decline > 1ml/min/year) and/or had rapid kidney function decline (RKFD, ≥3ml/min/1.73m 2 /year) by the MESA year 5 visit. Of the 343 cases, 145 had incident CKD, 141 had RKFD and 57 had both. Controls were matched for age, gender, race, diabetes, and baseline eGFR. We adjusted for age, hypertension and presence of albuminuria (ACR ≥30 mg/g). Results: Higher levels of KIM-1 were significantly associated with kidney function decline, and these associations were strongest for the top decile compared to lowest decile. Presence of albuminuria only minimally attenuated the findings. NGAL levels were not associated with kidney function decline. (Table) Model OR (95%CI) for Incident CKD and/or Rapid Kidney Function Decline KIM-1 (pg/ml) * KIM-1-Cr Ratio * (pg/mg) KIM-1 ≥ 927 pg/ml (Top Decile) NGAL (ng/ml) * NGAL-Cr Ratio * (ng/mg) NGAL ≥ 36 ng/ml (Top Decile) Age Adjusted 1.15 (1.02, 1.29) 1.17 (1.02, 1.34) 2.09 (1.21, 3.62) 1.04 (0.99, 1.10) 1.03 (0.98, 1.09) 1.63 (0.96, 2.78) Age + HTN Adjusted 1.15 (1.03, 1.29) 1.16 (1.01, 1.33) 2.13 (1.22, 3.70) 1.04 (0.99, 1.10) 1.03 (0.98, 1.09) 1.58 (0.93, 2.71) + ACR ≥ 30mg/g 1.15 (1.02, 1.29) 1.13 (0.98, 1.30) 2.02 (1.15, 3.56) 1.04 (0.99, 1.10) 1.03 (0.97, 1.08) 1.55 (0.89, 2.70) * Per doubling. Top decile is compared to lowest decile Conclusions: KIM-1, a marker of tubular injury, is associated with future risk of kidney disease independent of albuminuria. Our findings suggest that urinary biomarkers of tubular injury are a promising tool for identifying persons at risk for CKD.

Download Full-text