Detection and management of nephrotoxicity during drug development

Loghman‐Adham, Mahmoud; Weber, Chek Ing Kiu; Ciorciaro, Cornelia; Mann, Jessica; Meier, Matthias

doi:10.1517/14740338.2012.691964

Cited by 34 publications

(30 citation statements)

References 37 publications

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“…Susceptibility of the kidneys to such insults is primarily due to their high degree of filtration and their metabolism by the kidneys to potentially toxic byproducts (1,2). Over the past several years, novel associations and descriptions of the nephrotoxic effects of common and emerging drugs of abuse have appeared.…”

Section: Introductionmentioning

confidence: 99%

Nephrotoxic Effects of Common and Emerging Drugs of Abuse

Pendergraft

Herlitz

Thornley‐Brown

et al. 2014

Clinical Journal of the American Society of Nephrology

111

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The kidneys can be injured in diverse ways by many drugs, both legal and illegal. Novel associations and descriptions of nephrotoxic effects of common and emerging drugs of abuse have appeared over the past several years. Anabolic androgenic steroids, illicitly used by athletes and others for decades to increase muscle mass and decrease body fat, are emerging as podocyte toxins given recent descriptions of severe forms of FSGS in long-term abusers. Synthetic cannabinoids, a new group of compounds with marijuana-like effects, recently became popular as recreational drugs and have been associated with an atypical form of AKI. 3,4-Methylenedioxymethamphetamine, commonly known as ecstasy, is a widely used synthetic recreational drug with mood-enhancing properties and a constellation of toxicities that can result in death. These toxic effects include hyperthermia, hypotonic hyponatremia due to its arginine vasopressin secretagogue-like effects, rhabdomyolysis, and cardiovascular collapse. Cocaine, a serotonin-norepinephrine-dopamine reuptake inhibitor that serves as an illegal stimulant, appetite suppressant, and anesthetic, also causes vasoconstriction and rhabdomyolysis. Recent adulteration of much of the world's supply of cocaine with levamisole, an antihelminthic agent with attributes similar to but distinct from those of cocaine, appears to have spawned a new type of ANCAassociated systemic vasculitis. This review discusses the nephrotoxic effects of these common and emerging drugs of abuse, of which both community and health care providers should become aware given their widespread abuse. Future investigation into pathogenetic mechanisms associated with these drugs is critical and may provide a window into ways to lessen and even prevent the nephrotoxic effects of these drugs of abuse and perhaps allow a deeper understanding of the nephrotoxicities themselves.

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Section: Introductionmentioning

confidence: 99%

Nephrotoxic Effects of Common and Emerging Drugs of Abuse

Pendergraft

Herlitz

Thornley‐Brown

et al. 2014

Clinical Journal of the American Society of Nephrology

111

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“…As such, a major challenge in bringing new drugs to market is the risk of nephrotoxicity, which is often detected late in drug development; attrition due to nephrotoxicity accounts for 2% of preclinical drug attrition but 19% of attrition during more costly phase 3 clinical trials (Redfern, 2010). Post-approval, drug-induced nephrotoxicity accounts for as much as 18–27% of cases of acute kidney injury (AKI) (Loghman-Adham et al, 2012), with up to 36% of these injuries related to commonly used antibiotics such as aminoglycosides (Kleinknecht et al, 1987). While many of these AKI cases are reversible, some drugs can induce chronic renal injury resulting in tubular necrosis, tubulointerstitial inflammation, and fibrosis (Kleinknecht et al, 1987; Choudhury and Ahmed, 2006).…”

Section: Introductionmentioning

confidence: 99%

3D Proximal Tubule Tissues Recapitulate Key Aspects of Renal Physiology to Enable Nephrotoxicity Testing

et al. 2017

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Due to its exposure to high concentrations of xenobiotics, the kidney proximal tubule is a primary site of nephrotoxicity and resulting attrition in the drug development pipeline. Current pre-clinical methods using 2D cell cultures and animal models are unable to fully recapitulate clinical drug responses due to limited in vitro functional lifespan, or species-specific differences. Using Organovo's proprietary 3D bioprinting platform, we have developed a fully cellular human in vitro model of the proximal tubule interstitial interface comprising renal fibroblasts, endothelial cells, and primary human renal proximal tubule epithelial cells to enable more accurate prediction of tissue-level clinical outcomes. Histological characterization demonstrated formation of extensive microvascular networks supported by endogenous extracellular matrix deposition. The epithelial cells of the 3D proximal tubule tissues demonstrated tight junction formation and expression of renal uptake and efflux transporters; the polarized localization and function of P-gp and SGLT2 were confirmed. Treatment of 3D proximal tubule tissues with the nephrotoxin cisplatin induced loss of tissue viability and epithelial cells in a dose-dependent fashion, and cimetidine rescued these effects, confirming the role of the OCT2 transporter in cisplatin-induced nephrotoxicity. The tissues also demonstrated a fibrotic response to TGFβ as assessed by an increase in gene expression associated with human fibrosis and histological verification of excess extracellular matrix deposition. Together, these results suggest that the bioprinted 3D proximal tubule model can serve as a test bed for the mechanistic assessment of human nephrotoxicity and the development of pathogenic states involving epithelial-interstitial interactions, making them an important adjunct to animal studies.

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“…Of particular importance in drug development is the assessment of a new medicine's potential for causing drug-induced kidney injury (DIKI) (or drug-induced nephrotoxicity, DIN) [6]. Not only is the kidney a vital organ, but due to its elimination of the majority of drugs and their metabolites, and its concentration of these in the process of filtration, it is particularly sensitive to chemical insults.…”

Section: Introductionmentioning

confidence: 99%

“…Not only is the kidney a vital organ, but due to its elimination of the majority of drugs and their metabolites, and its concentration of these in the process of filtration, it is particularly sensitive to chemical insults. While measurements of serum creatinine (sCr) and blood urea nitrogen (BUN) are the most widely used monitors of kidney function, they are notoriously variable and sensitive only to late stages of kidney injury [6]. It is well established that in animal models histopathological changes are observed in response to nephrotoxic compounds at doses and time points much lower than those required to produce changes in sCr and BUN [7].…”

Section: Introductionmentioning

confidence: 99%

Prediction of Clinically Relevant Safety Signals of Nephrotoxicity through Plasma Metabolite Profiling

Mattes¹,

Kamp

Fabian

et al. 2013

BioMed Research International

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Addressing safety concerns such as drug-induced kidney injury (DIKI) early in the drug pharmaceutical development process ensures both patient safety and efficient clinical development. We describe a unique adjunct to standard safety assessment wherein the metabolite profile of treated animals is compared with the MetaMap Tox metabolomics database in order to predict the potential for a wide variety of adverse events, including DIKI. To examine this approach, a study of five compounds (phenytoin, cyclosporin A, doxorubicin, captopril, and lisinopril) was initiated by the Technology Evaluation Consortium under the auspices of the Drug Safety Executive Council (DSEC). The metabolite profiles for rats treated with these compounds matched established reference patterns in the MetaMap Tox metabolomics database indicative of each compound's well-described clinical toxicities. For example, the DIKI associated with cyclosporine A and doxorubicin was correctly predicted by metabolite profiling, while no evidence for DIKI was found for phenytoin, consistent with its clinical picture. In some cases the clinical toxicity (hepatotoxicity), not generally seen in animal studies, was detected with MetaMap Tox. Thus metabolite profiling coupled with the MetaMap Tox metabolomics database offers a unique and powerful approach for augmenting safety assessment and avoiding clinical adverse events such as DIKI.

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Detection and management of nephrotoxicity during drug development

Cited by 34 publications

References 37 publications

Nephrotoxic Effects of Common and Emerging Drugs of Abuse

Nephrotoxic Effects of Common and Emerging Drugs of Abuse

3D Proximal Tubule Tissues Recapitulate Key Aspects of Renal Physiology to Enable Nephrotoxicity Testing

Prediction of Clinically Relevant Safety Signals of Nephrotoxicity through Plasma Metabolite Profiling

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