Nephrotoxicity of hexachloro‐1:3‐butadiene in the male Hanover Wistar rat; correlation of minimal histopathological changes with biomarkers of renal injury

Swain, Aubrey; Turton, John; Scudamore, Cheryl L.; Maguire, David; Pereira, Inês; Freitas, Sofia; Smyth, Rosemary; Munday, Michael R.; Stamp, Clare; Gandhi, Mitul; Sondh, Surjit; Ashall, Holly; Francis, Ian; Woodfine, Jennifer; Bowles, John; York, Malcolm

doi:10.1002/jat.1727

Cited by 17 publications

(25 citation statements)

References 36 publications

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“…Although urinary B2M and protein may also increase in the case of glomerular injury owing to increased filtration (Hoffmann et al, 2010), the reversible nature of the changes in our study suggest interference with tubular reabsorption. This is supported by the observed elevated levels of KIM1, aGST, and NAG, all markers known in animal models to increase in response to different tubulo-toxic agents (Feinfeld et al, 1986;Hoffmann et al, 2010;Vaidya et al, 2010;Ouchi et al, 2012;Swain et al, 2012 ). Accumulation of antisense oligonucleotides occurs in proximal tubular cells as basophilic granules (Monteith et al, 1999;Henry et al, 2012), and this was indeed seen also in animal studies with ISIS 388626 .…”

Section: Discussionmentioning

confidence: 54%

Renal Effects of Antisense-Mediated Inhibition of SGLT2

Meer

Moerland

Dongen

et al. 2016

J Pharmacol Exp Ther

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ISIS 388626 is an antisense sodium-glucose cotransporter 2 (SGLT2) inhibitor designed to treat type 2 diabetes mellitus by induction of glucosuria. ISIS 388626 was demonstrated to be safe and effective in preclinical trails in several species. We undertook the present study to evaluate the safety and efficacy of 13 weekly doses of 50, 100, and 200 mg of ISIS 388626 in humans. ISIS 388626 increased 24-hour urinary glucose excretion dose dependently with 508.9 6 781.45 mg/day in the 100-mg and 1299.8 6 1833.4 mg/day in the 200-mg cohort, versus 88.7 6 259.29 mg/day in the placebo group. ISIS 388626 induced a reversible increase in serum creatinine, with the largest effect after eight doses of ISIS 388626 (200 mg; 0.38 6 0.089 mg/dl; 44% increase over baseline). Three subjects were discontinued as a result of creatinine increases. The renal clearance test revealed no indications for impairment of glomerular filtration or renal perfusion. The creatinine increases were accompanied by a rise in the levels of urinary renal damage markers [b-2-microglobulin (B2M), total protein, kidney injury molecule (KIM1), a-glutathione S-transferase (aGST),Other treatmentrelated adverse events included mild injection site reactions occurring in 8-19% of the subjects. In conclusion, ISIS 388626 treatment induced glucosuria at a dose level of 200 mg/week. This intended pharmacological effect was small, amounting to approximately 1% of the total amount of filtered glucose. Changes in serum and urinary markers were indicative of transient renal dysfunction, most probably of tubular origin. Whether the glucosuria is caused by specific SGLT2 inhibition or general tubular dysfunction or a combination remains uncertain.

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Section: Discussionmentioning

confidence: 54%

Renal Effects of Antisense-Mediated Inhibition of SGLT2

Meer

Moerland

Dongen

et al. 2016

J Pharmacol Exp Ther

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“…a-GST is known to cross react with the GST Yb1 assay (by 7.22%, MSD, Argutus AKI Test, Assay Qualified Kit, 2011). Swain et al (2012) considered that apparent elevations of urinary GST Yb1 output could be compromised in the presence of markedly elevated a-GST excretion, and results for GST Yb1 in the present study should therefore be treated with some caution. Furthermore, no evidence of histopathologic injury was noted in the distal tubules.…”

Section: Discussionmentioning

confidence: 96%

“…Significance was set at three levels: *p < .05, **p < .01, and ***p < .001. Where used, the ''fold increase'' or ''fold decrease'' in a parameter is the ratio of the mean value of the HCBD-treated group in relation to the mean value of the concurrent control group (Swain et al 2011(Swain et al , 2012.…”

Section: Discussionmentioning

confidence: 99%

“…At 10.00 hr, 6 animals from each treatment group (rat numbers 1 to 6) were weighed and treated with corn oil (vehicle-treated controls); the remaining 6 animals (rat numbers 7 to 12) were weighed and treated with HCBD at 45 mg/kg. The administered dose of HCBD was chosen based on the work from preliminary studies (Swain et al 2011(Swain et al , 2012, in which 45 mg/kg of HCBD produced consistent and acute evidence of histopathologic proximal tubular degeneration. After treatment, rats were replaced in their communal cages, with diet and water ad libitum.…”

Section: Experimental Designmentioning

confidence: 99%

“…Indeed, one limitation identified in the initial renal biomarker qualification submission process concerned the need for recovery studies to demonstrate that reversibility of histopathologic renal lesions could be similarly monitored by biomarker changes . Following on from the preliminary dose-response and time course studies (Swain et al 2011), and the dose-response investigations (Swain et al 2012), the aim of the present work was to characterize the temporal responses in several traditionally used and more recently proposed urinary biomarkers, employing HCBD-induced proximal tubule damage and to correlate the patterns of change in urinary biomarker levels with tubular histopathology and gene expression.…”

Section: Introductionmentioning

confidence: 99%

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Correlation of Histopathology, Urinary Biomarkers, and Gene Expression Responses Following Hexachloro-1:3-Butadiene–induced Acute Nephrotoxicity in Male Hanover Wistar Rats

et al. 2012

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Hexachloro-1:3-butadiene (HCBD) causes segment-specific injury to the proximal renal tubule. A time course study of traditional and more recently proposed urinary biomarkers was performed in male Hanover Wistar rats receiving a single intraperitoneal (ip) injection of 45 mg/kg HCBD. Animals were killed on days 1, 2, 3, 4, 5, 6, 7, 10, 14, and 28 postdosing and the temporal response of renal biomarkers was characterized using kidney histopathology, urinary and serum biochemistry, and gene expression. Histopathologic evidence of tubular degeneration was seen from day 1 until day 3 postdosing and correlated with increased urinary levels of a-glutathione S-transferase (a-GST), albumin, glucose, and kidney injury molecule-1 (KIM-1), and increased gene expression of KIM-1, NAD(P)H dehydrogenase, quinone 1, and heme oxygenase (decycling) 1. Histopathologic evidence of tubular regeneration was seen from day 2 postdosing and correlated with raised levels of urinary KIM-1 and osteopontin and increased gene expression of KIM-1 and annexin A7. Traditional renal biomarkers generally demonstrated low sensitivity. It is concluded that in rat proximal tubular injury, measurement of a range of renal biomarkers, in conjunction with gene expression analysis, provides an understanding of the extent of degenerative changes induced in the kidney and the process of regeneration.

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Usefulness of urinary kidney injury molecule‐1 (Kim‐1) as a biomarker for cisplatin‐induced sub‐chronic kidney injury

Nan-ya

Kajihara

Kojima

et al. 2014

J of Applied Toxicology

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We explored biomarkers suitable for monitoring sub-chronic kidney injury using the three rat models of cisplatin (CDDP)-induced kidney injury, which were designed to extend the current knowledge beyond the sub-acute exposure period. In the pilot study, a single intravenous administration of 1.5 mg kg(-1) CDDP to rats was confirmed to result in no histopathological changes. Subsequently, CDDP was intravenously administered to rats at a dose of 1.5 mg kg(-1) for 4 days at 24-h intervals (Experimental model 1) and for up to 10 weeks at weekly intervals (Experimental models 2 and 3), and the changes in blood and urine components, such as recently recommended urinary biomarkers (Kim-1, clusterin and so on) and traditional blood biomarkers (blood urea nitrogen and serum creatinine), were examined together with the histopathological changes in renal tissues during the development of the kidney injury in each model. In these experimental models, a significant increase in urinary Kim-1 was observed prior to the histopathological changes in renal tissues, and these changes were retained after the adverse histopathological changes. Significant changes in all of the other urinary biomarkers examined occurred along with the histopathological changes. In addition, the increase in urinary Kim-1 after weekly treatment with CDDP for 4 weeks was reduced in a time-dependent manner after cessation of the drug. The present findings indicate that urinary Kim-1 is the most useful biomarker for CDDP-induced rat sub-chronic kidney injury among the biomarkers examined.

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Nephrotoxicity of hexachloro‐1:3‐butadiene in the male Hanover Wistar rat; correlation of minimal histopathological changes with biomarkers of renal injury

Cited by 17 publications

References 36 publications

Renal Effects of Antisense-Mediated Inhibition of SGLT2

Renal Effects of Antisense-Mediated Inhibition of SGLT2

Correlation of Histopathology, Urinary Biomarkers, and Gene Expression Responses Following Hexachloro-1:3-Butadiene–induced Acute Nephrotoxicity in Male Hanover Wistar Rats

Usefulness of urinary kidney injury molecule‐1 (Kim‐1) as a biomarker for cisplatin‐induced sub‐chronic kidney injury

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