Evaluation of a urinary kidney biomarker panel in rat models of acute and subchronic nephrotoxicity

Hoffmann, Dana; Fuchs, T; Henzler, Tanja; Matheis, Katja; Herget, Thomas; Dekant, W.; Hewitt, Philip; Mally, Angela

doi:10.1016/j.tox.2010.08.013

Cited by 164 publications

(134 citation statements)

References 59 publications

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“…As previously described (Hoffmann et al 2010), VEGF also showed low diagnostic potential to detect nephrotoxicity induced by gentamycin, BI-3, or ochratoxinA after 7, 14, or 90 days. The inability of a-GST to predict nephrotoxicity at later times could be explained by the fact that any increase of a-GST in urine is caused by its release from necrotic cells.…”

Section: Discussionmentioning

confidence: 52%

Evaluation of Novel Acute Urinary Rat Kidney Toxicity Biomarker for Subacute Toxicity Studies in Preclinical Trials

et al. 2012

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Novel urinary protein biomarkers for the detection of acute renal damage, recently accepted by the U.S. Food and Drug Administration, European Medicines Agency, and Pharmaceuticals and Medical Devices Agency (Japan), now have to be validated in practice. Limited data regarding the performance of these acute markers after subacute or subchronic treatment are publicly available. To increase the area of applicability of these markers, it is important to evaluate the ability to detect them after 28 days of treatment or even longer. Wistar rats were treated with three doses of cisplatin, vancomycin, or puromycin to induce renal damage. Twelve candidate proteins were measured by Luminex xMAPbased WideScreen assays, MesoScale Discovery-based MULTI-SPOT technology, or RENA-strip dipstick assay after 28 days. Treatment with all three model compounds resulted in a dose-dependent increase in urinary biomarkers, specific for the observed areas within the nephron, determined histopathologically. The most promising biomarkers in this study were NGAL, Kim-1, osteopontin, clusterin, RPA-1, and GSTYb1, detected by multiplexing technologies. The RENA-strip dipstick assay delivered good diagnostic results for vancomycin-treated but not for cisplatin-or puromycin-treated rats. Taken together, the data show that these new biomarkers are robust and measurable for longer term studies to predict different types of kidney toxicities.

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Section: Discussionmentioning

confidence: 52%

Evaluation of Novel Acute Urinary Rat Kidney Toxicity Biomarker for Subacute Toxicity Studies in Preclinical Trials

et al. 2012

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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: 50%

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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“…Subsequently, the measured values of the gentamicin study (where clear histopathological findings were observable) delivered similar classification scores for the affected and nonaffected animals. 15 This result highlights the benefit of transcriptional biomarkers, especially in the early stages of developing kidney damage. In this investigation, changes in gene expression were observed much earlier than any increase in urinary marker proteins.…”

Section: Discussionmentioning

confidence: 83%

“…Similar results were reported for the developmental pharmaceutical compound BI-3 (3- (3S-trans)). 15 Currently, the involvement of Ca 2þ in the development of renal damage is not yet completely understood. However, a decrease was observed in all animals, independent of the treatment time.…”

Section: Discussionmentioning

confidence: 99%

An Exploratory Evaluation of the Utility of Transcriptional and Urinary Kidney Injury Biomarkers for the Prediction of Aristolochic Acid–Induced Renal Injury in Male Rats

et al. 2013

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The predictive value of different urinary and transcriptional biomarkers was evaluated in a proof-of-principle toxicology study in rats using aristolochic acid (AA), a known nephrotoxic agent. Male Wistar rats were orally dosed with 0.1, 1, or 10 mg/kg for 12 days. Urine was collected on days 1, 5, and 12 over 24 hours. Gene expression analysis was also conducted using quantitative realtime polymerase chain reaction and Illumina whole-genome chips. Protein biomarkers (Kim-1, Timp-1, vascular endothelial growth factor, osteopontin, clusterin, cystatin C, calbindin D-28K, b2-microglobulin, a-glutathione S-transferase, GSTY1b, RPA-1, and neutrophil gelatinase-associated lipocalin) were measured in these urine samples. Treatment with AA resulted in a slight dose-and/or time-dependent increase in urinary b2-microglobulin, lipocalin 2, and osteopontin before an increase in serum creatinine or serum urea nitrogen was observed. A strong decrease in urinary calbindin D-28K was also detected. The Compugen Ltd. prediction model scored both the 1-and 10-mg/kg AA dose groups as positive for nephrotoxicity despite the absence of renal histopathological changes. In addition, several previously described transcriptional biomarkers were identified as early predictors of renal toxicity as they were detected before morphological alterations had occurred. Altogether, these findings demonstrated the predictive values of renal biomarkers approved by the Food and Drug Administration, European Medicines Agency, and Pharmaceuticals & Medical Devices Agency in AA-induced renal injury in rats and confirmed the utility of renal transcriptional biomarkers for detecting progression of compound-induced renal injury in rats. In addition, several transcriptional biomarkers identified in this exploratory study could present early predictors of renal tubular epithelium injury in rats.Keywords aristolochic acid, nephrotoxicity biomarker, lipocalin 2/NGAL, osteopontin, prediction model, Nrf-2 signalingThe early detection of renal damage has been an important challenge in pharmaceutical drug development. Serum creatinine or serum urea nitrogen (SUN), the major clinicopathological markers currently employed to identify changes in kidney function, are not suitable for the early detection of acute kidney injury (AKI). Due to the functional reserve of the kidney, changes in these clinical markers appear late, when as much as two-thirds of the renal biomass has been lost. 33In the past few decades, intensive research has been conducted to identify additional more accurate biomarkers for clinical and preclinical safety assessment. 8,12 This whole process has been driven by the Predictive Safety Testing Consortium and the International Life Science Institute/Health and Environmental Sciences Institute. In the study reported here, our objective was to evaluate the predictive (observation of adverse events on a molecular basis before morphological and/or physiological alterations are established) performance of several novel urinary and transcription...

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Evaluation of a urinary kidney biomarker panel in rat models of acute and subchronic nephrotoxicity

Cited by 164 publications

References 59 publications

Evaluation of Novel Acute Urinary Rat Kidney Toxicity Biomarker for Subacute Toxicity Studies in Preclinical Trials

Evaluation of Novel Acute Urinary Rat Kidney Toxicity Biomarker for Subacute Toxicity Studies in Preclinical Trials

Renal Effects of Antisense-Mediated Inhibition of SGLT2

An Exploratory Evaluation of the Utility of Transcriptional and Urinary Kidney Injury Biomarkers for the Prediction of Aristolochic Acid–Induced Renal Injury in Male Rats

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