Browsing by Subject "Nephrotoxicity"

Now showing 1 - 5 of 5
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    Chemotherapy-related complications in the kidneys and collecting system: an imaging perspective
    (Springer Berlin Heidelberg, 2015-08) Jia, Jemianne Bautista; Lall, Chandana; Tirkes, Temel; Gulati, Rajesh; Lamba, Ramit; Goodwin, Scott C.; Department of Radiology and Imaging Sciences, IU School of Medicine
    Nephrotoxicity is a common adverse effect of many chemotherapeutic agents. The agents most commonly associated with chemotherapy-associated nephrotoxicity are methotrexate, semustine, streptozocin, mithramycin, and cisplatin. Certain chemotherapeutic agents have adverse effects on the kidneys and urothelium that can be visualized radiographically, including cystic change, interstitial nephritis, papillary necrosis, urothelial changes, haemorrhagic cystitis, acute tubular necrosis, and infarction. This review focuses on imaging features identifying complications of chemotherapy in the kidneys and collecting system and provides didactic cases to alert referring clinicians.
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    Genetic and Modifiable Risk Factors Contributing to Cisplatin-Induced Toxicities
    (American Association for Cancer Research, 2019-02-15) Trendowski, Matthew R.; El Charif, Omar; Dinh, Paul C. Jr.; Travis, Lois B.; Dolan, M.; Medicine, School of Medicine
    Effective administration of traditional cytotoxic chemotherapy is often limited by off-target toxicities. This clinical dilemma is epitomized by cisplatin, a platinating agent that has potent antineoplastic activity due to its affinity for DNA and other intracellular nucleophiles. Despite its efficacy against many adult-onset and pediatric malignancies, cisplatin elicits multiple off-target toxicities that can not only severely impact a patient’s quality of life, but also lead to dose reductions or the selection of alternative therapies that can ultimately affect outcomes. Without an effective therapeutic measure by which to successfully mitigate many of these symptoms, there have been attempts to identify a priori those individuals who are more susceptible to developing these sequelae through studies of genetic and nongenetic risk factors. Older age is associated with cisplatin induced ototoxicity, neurotoxicity and nephrotoxicity. Traditional genome-wide association studies have identified single nucleotide polymorphisms in ACYP2 and WFS1 associated with cisplatin-induced hearing loss. However, validating associations between specific genotypes and cisplatin-induced toxicities with enough stringency to warrant clinical application remains challenging. This review summarizes the current state of knowledge with regard to specific adverse sequelae following cisplatin-based therapy with a focus on ototoxicity, neurotoxicity, nephrotoxicity, myelosuppression and nausea/emesis. We discuss variables (genetic and nongenetic) contributing to these detrimental toxicities, and currently available means to prevent or treat their occurrence.
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    IL-6-mediated hepatocyte production is the primary source of plasma and urine neutrophil gelatinase associated lipocalin during acute kidney injury
    (Elsevier, 2020-05) Skrypnyk, Nataliya I.; Gist, Katja M.; Okamura, Kayo; Montford, John R.; You, Zhiying; Yang, Haichun; Moldovan, Radu; Bodoni, Evelyn; Blaine, Judith T.; Edelstein, Charles L.; Soranno, Danielle E.; Kirkbride-Romeo, Lara A.; Griffin, Benjamin R.; Altmann, Chris; Faubel, Sarah; Pediatrics, School of Medicine
    Neutrophil gelatinase associated lipocalin (NGAL, Lcn2) is the most widely studied biomarker of acute kidney injury (AKI). Previous studies have demonstrated that NGAL is produced by the kidney and released into the urine and plasma. Consequently, NGAL is currently considered a tubule specific injury marker of AKI. However, the utility of NGAL to predict AKI has been variable suggesting that other mechanisms of production are present. IL-6 is a proinflammatory cytokine increased in plasma by two hours of AKI and mediates distant organ effects. Herein, we investigated the role of IL-6 in renal and extra-renal NGAL production. Wild type mice with ischemic AKI had increased plasma IL-6, increased hepatic NGAL mRNA, increased plasma NGAL, and increased urine NGAL; all reduced in IL-6 knockout mice. Intravenous IL-6 in normal mice increased hepatic NGAL mRNA, plasma NGAL and urine NGAL. In mice with hepatocyte specific NGAL deletion (Lcn2hep-/-) and ischemic AKI, hepatic NGAL mRNA was absent, and plasma and urine NGAL were reduced. Since urine NGAL levels appear to be dependent on plasma levels, the renal handling of circulating NGAL was examined using recombinant human NGAL. After intravenous recombinant human NGAL administration to mice, human NGAL in mouse urine was detected by ELISA during proximal tubular dysfunction, but not in pre-renal azotemia. Thus, during AKI, IL-6 mediates hepatic NGAL production, hepatocytes are the primary source of plasma and urine NGAL, and plasma NGAL appears in the urine during proximal tubule dysfunction. Hence, our data change the paradigm by which NGAL should be interpreted as a biomarker of AKI.
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    Lrpap1 (RAP) Inhibits Proximal Tubule Clathrin Mediated and Clathrin Independent Endocytosis, Ameliorating Renal Aminoglycoside Nephrotoxicity
    (Wolters Kluwer, 2023) Wagner, Mark C.; Sandoval, Ruben M.; Yadav, Shiv Pratap S.; Campos, Silvia B.; Rhodes, George J.; Phillips, Carrie L.; Molitoris, Bruce A.; Medicine, School of Medicine
    Background: Proximal tubules (PTs) are exposed to many exogenous and endogenous nephrotoxins that pass through the glomerular filter. This includes many small molecules, such as aminoglycoside and myeloma light chains. These filtered molecules are rapidly endocytosed by the PTs and lead to nephrotoxicity. Methods: To investigate whether inhibition of PT uptake of filtered toxins can reduce toxicity, we evaluated the ability of Lrpap1 or receptor-associated protein (RAP) to prevent PT endocytosis. Munich Wistar Frömter rats were used since both glomerular filtration and PT uptake can be visualized and quantified. The injury model chosen was the well-established gentamicin-induced toxicity, which leads to significant reductions in GFR and serum creatinine increases. CKD was induced with a right uninephrectomy and left 40-minute pedicle clamp. Rats had 8 weeks to recover and to stabilize GFR and proteinuria. Multiphoton microscopy was used to evaluate endocytosis in vivo and serum creatinine, and 24-hour creatinine clearances were used to evaluate kidney functional changes. Results: Studies showed that preadministration of RAP significantly inhibited both albumin and dextran endocytosis in outer cortical PTs. Importantly, this inhibition was found to be rapidly reversible with time. RAP was also found to be an excellent inhibitor of PT gentamicin endocytosis. Finally, gentamicin administration for 6 days resulted in significant elevation of serum creatinine in vehicle-treated rats, but not in those receiving daily infusion of RAP before gentamicin. Conclusions: This study provides a model for the potential use of RAP to prevent, in a reversible manner, PT endocytosis of potential nephrotoxins, thus protecting the kidney from damage.
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    Protein Kinase Cδ Suppresses Autophagy to Induce Kidney Cell Apoptosis in Cisplatin Nephrotoxicity
    (American Society of Nephrology, 2017-04) Zhang, Dongshan; Pan, Jian; Xiang, Xudong; Li, Yu; Dong, Guie; Livingston, Man J.; Chen, Jian-Kang; Yin, Xiao-Ming; Dong, Zheng; Pathology and Laboratory Medicine, School of Medicine
    Nephrotoxicity is a major adverse effect in cisplatin chemotherapy, and renoprotective approaches are unavailable. Recent work unveiled a critical role of protein kinase Cδ (PKCδ) in cisplatin nephrotoxicity and further demonstrated that inhibition of PKCδ not only protects kidneys but enhances the chemotherapeutic effect of cisplatin in tumors; however, the underlying mechanisms remain elusive. Here, we show that cisplatin induced rapid activation of autophagy in cultured kidney tubular cells and in the kidneys of injected mice. Cisplatin also induced the phosphorylation of mammalian target of rapamycin (mTOR), p70S6 kinase downstream of mTOR, and serine/threonine-protein kinase ULK1, a component of the autophagy initiating complex. In vitro, pharmacologic inhibition of mTOR, directly or through inhibition of AKT, enhanced autophagy after cisplatin treatment. Notably, in both cells and kidneys, blockade of PKCδ suppressed the cisplatin-induced phosphorylation of AKT, mTOR, p70S6 kinase, and ULK1 resulting in upregulation of autophagy. Furthermore, constitutively active and inactive forms of PKCδ respectively enhanced and suppressed cisplatin-induced apoptosis in cultured cells. In mechanistic studies, we showed coimmunoprecipitation of PKCδ and AKT from lysates of cisplatin-treated cells and direct phosphorylation of AKT at serine-473 by PKCδin vitro Finally, administration of the PKCδ inhibitor rottlerin with cisplatin protected against cisplatin nephrotoxicity in wild-type mice, but not in renal autophagy-deficient mice. Together, these results reveal a pathway consisting of PKCδ, AKT, mTOR, and ULK1 that inhibits autophagy in cisplatin nephrotoxicity. PKCδ mediates cisplatin nephrotoxicity at least in part by suppressing autophagy, and accordingly, PKCδ inhibition protects kidneys by upregulating autophagy.