Evaluation of Novel Biomarkers of Nephrotoxicity in Two Strains of Rat Treated with Cisplatin

Gautier, Jean‐Charles; Riefke, Bjoern; Walter, Jakob; Kurth, Petra; Mylecraine, Lou; Guilpin, Valerie B.; Barlow, Norman J.; Gury, Thierry; Hoffman, David; Ennulat, Daniela; Schuster, Kerstin; Harpur, Ernest S.; Pettit, Syril

doi:10.1177/0192623310379139

Cited by 80 publications

(66 citation statements)

References 29 publications

(36 reference statements)

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“…Detection of alpha-GST in urine is a sensitive method for detection of early kidney damage in humans (Sundberg et al 1994) and in rats (Gautier et al 2010). In dogs and rats, this antibody was developed by Argustus, to design ELISA tests to detect alpha-GST in urine (Kilty et al 1998).…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical Identification of Kidney Nephron Segments in the Dog, Rat, Mouse, and Cynomolgus Monkey

et al. 2011

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Kidney is a major target organ in preclinical studies. In recent years, intense research has been undertaken to characterize novel renal toxicity biomarkers. In this context, we studied nephron segment specific antibodies against aquaporin-1 (AQP-1), a-glutathione-S-transferase (alpha-GST), Tamm-Horsfall protein (TH), calbindin-D 28K (CalD), and aquaporin-2 (AQP-2), using an immunoperoxidase method on formalin-fixed paraffinembedded kidney tissues of dogs, rats, mice, and Cynomolgus monkeys. AQP-1 was specific for proximal tubules and thin descending limbs of Henle's loops and AQP-2 for connecting and collecting ducts in dogs, rats, mice, and Cynomolgus monkeys. Alpha-GST stained the straight part of proximal tubules in dogs and proximal convoluted tubule and straight part of proximal tubules in rats. TH was specific for thick ascending limbs of Henle's loops in mice, rats, dogs, and Cynomolgus monkeys and stained additionally scattered cells in cortical connecting/collecting ducts of dogs. CalD was found in distal convoluted tubules and cortical connecting and collecting ducts of dogs, rats, and mice and in distal convoluted tubules, connecting ducts, and cortical and medullary collecting ducts of Cynomolgus monkey. This panel of antibodies may be a helpful tool to identify renal tubules by light microscopy in preclinical studies and to validate new biomarkers of renal toxicity.

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Section: Discussionmentioning

confidence: 99%

Immunohistochemical Identification of Kidney Nephron Segments in the Dog, Rat, Mouse, and Cynomolgus Monkey

et al. 2011

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“…Therefore 7 urinary biomarkers ; i.e., Kim-1, albumin, total protein, β 2 -microglobulin, cystatin C, clusterin, and trefoil factor-3, were subsequently proposed to and approved by the Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Pharmaceuticals and Medical Devices Agency (PMDA) as biomarkers to sensitively identify AKI in preclinical toxicity studies. Commercial tools to measure these urinary biomarkers were mainly validated in rats Gautier et al, 2010;Hoffmann et al, 2010;Tonomura et al, 2010;Fuchs et al, 2012). In addition to these biomarkers, neutrophil gelatinase-associated lipocal (NGAL), a member of the lipocalin superfamily, has been proposed as a candidate for a sensitive urinary biomarker to detect AKI Mori, 2005;Mori and Nakao, 2007).…”

Section: Introductionmentioning

confidence: 99%

Neutrophil gelatinase-associated lipocalin, a sensitive urinary biomarker of acute kidney injury in dogs receiving gentamicin

et al. 2013

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-A sensitive urinary biomarker for acute kidney injury (AKI) was investigated in beagle dogs with nephrotoxicity induced by gentamicin. Gentamicin sulphate at 25 or 50 mg/kg was injected (s.c.) for 9 days, and conventional urinalysis, ELISA assay of neutrophil gelatinase-associated lipocal (NGAL) in urine, blood chemistry, and pathological examinations were performed. The dog given gentamicin at 25 mg/kg only showed slight deposition of lysosomal granules in the proximal tubular epithelium of the kidneys without any other significant changes even though urinary NGAL was elevated on Day 10 (day of necropsy). In the dog receiving gentamicin at 50 mg/kg, increases in urinary NGAL were observed on Days 3 and 5, and absence of urination, marked increases in serum urea nitrogen and creatinine, enlargement and discoloration of the kidneys with marked necrosis, and swelling of proximal epithelium were observed. In conclusion, urinary NGAL is considered to be a candidate as a sensitive predictable biomarker of AKI in the gentamicin-induced nephrotoxicity model in dogs.Key words: NGAL, Dogs, Acute kidney injury, Urinary biomarker, Gentamicin Correspondence: Kiyonori Kai (E-mail: kai.kiyonori.xb@daiichisankyo.co.jp) LetterThe Journal of Toxicological Sciences (J. Toxicol. Sci.) Vol.38, No.2, 269-277, 2013 Vol. 38 No. 2 269 addition to these biomarkers, neutrophil gelatinase-associated lipocal (NGAL), a member of the lipocalin superfamily, has been proposed as a candidate for a sensitive urinary biomarker to detect AKI Mori, 2005;Mori and Nakao, 2007). Unfortunately, in part due to the lack of commercially available assays for non-rodents, limited data comparing the performance of the exploratory and approved markers are publicly available so far.In this study, we selected gentamicin, a well-known nephrotoxic agent that induces AKI in experimental animals and humans, and injected it subcutaneously to beagle dogs for 9 days and evaluated urinary NGAL using a commercial ELISA kit as a sensitive urinary biomarker in comparison with conventional blood and urinary toxicity makers and pathological examinations. MATERIALS AND METHODS Test articleELTACIN injection, an injectable product of gentamicin sulfate was purchased from FujiPharma (Shizuoka, Japan). Animals and housing conditionsTwo male beagle dogs were purchased from Narc Corporation (Chiba, Japan) for gentamicin treatment, and 6 males and 6 females were additionally obtained from Marshall BioResources, Japan (Ibaraki, Japan) for collection background data of urinalysis. The dogs were individually housed in stainless steel cages (W93.5 cm × W80 cm × H78.5 cm) in an air-conditioned room (temperature, 18 to 28°C; relative humidity, 30 to 70%). A light/dark cycle of 12 hr and ventilation rate of 10 to 20 air changes/ hr were used in the animal rooms. Two hundred and twenty grams of basal diet (Certified Canine Diet 5007, PMI Nutrition International, Inc., St. Louis, MO, USA) was given to each dog in the morning and tap water was available ad libitum. All experimen...

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“…Further, there are extensive structural differences among species that can affect vulnerability to kidney injury. For example, in the rat, cisplatin causes extensive necrosis of the pars recta of the PT in the outer stripe of the outer medulla (OSOM; Gautier et al 2010); yet humans and primates lack a defined OSOM. Also, in humans, cisplatin causes injury to the PT, distal tubule, and collecting duct (Tanaka et al 1986).…”

Section: Disconnect Between Human and Animal Akimentioning

confidence: 99%

Recent Successes in the Identification, Development, and Qualification of Translational Biomarkers

Ennulat

Adler

2014

Toxicol Pathol

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The development of novel safety or efficacy biomarkers has increasingly been used to improve safety monitoring and minimize attrition during drug development; however, for new biomarkers, the failure rate can equal or exceed that of new chemical entities. Drug-induced kidney injury is recognized to occur throughout the drug development process, with histopathology considered to be the gold standard for preclinical toxicologic screening. Renal biomarkers used clinically are primarily biomarkers of renal function and are considered insensitive for the detection of druginduced kidney injury during first-in-man studies, particularly for compounds known to induce renal injury in preclinical species. Recent efforts by public-private partnerships have led to unprecedented success in the identification, development, and qualification of several new translatable biomarkers of kidney injury in the rat. To optimize the chance of success in current and future biomarker efforts in preclinical species and man, selection and development of biomarkers should emphasize biological considerations including marker variability and biology in both health and disease. The research to support the qualification of novel renal safety markers for routine use in the clinical setting is currently underway, and results from this work are greatly anticipated.

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Evaluation of Novel Biomarkers of Nephrotoxicity in Two Strains of Rat Treated with Cisplatin

Cited by 80 publications

References 29 publications

Immunohistochemical Identification of Kidney Nephron Segments in the Dog, Rat, Mouse, and Cynomolgus Monkey

Immunohistochemical Identification of Kidney Nephron Segments in the Dog, Rat, Mouse, and Cynomolgus Monkey

Neutrophil gelatinase-associated lipocalin, a sensitive urinary biomarker of acute kidney injury in dogs receiving gentamicin

Recent Successes in the Identification, Development, and Qualification of Translational Biomarkers

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