Staff View
Novel cisplatin kidney injury biomarkers and transporter interactions

Descriptive

TitleInfo
Title
Novel cisplatin kidney injury biomarkers and transporter interactions
Name (type = personal)
NamePart (type = family)
George
NamePart (type = given)
Blessy
NamePart (type = date)
1990-
DisplayForm
Blessy George
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Reuhl
NamePart (type = given)
Kenneth
DisplayForm
Kenneth Reuhl
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = personal)
NamePart (type = family)
Aleksunes
NamePart (type = given)
Lauren
DisplayForm
Lauren Aleksunes
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
co-chair
Name (type = personal)
NamePart (type = family)
Buckley
NamePart (type = given)
Brian
DisplayForm
Brian Buckley
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Guo
NamePart (type = given)
Grace
DisplayForm
Grace Guo
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Bridgeman
NamePart (type = given)
Mary
DisplayForm
Mary Bridgeman
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Joy
NamePart (type = given)
Melanie
DisplayForm
Melanie Joy
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
outside member
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
School of Graduate Studies
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2018
DateOther (type = degree); (qualifier = exact)
2018-01
CopyrightDate (encoding = w3cdtf); (qualifier = exact)
2018
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
Despite the recent development of new immunotherapies and anticancer drugs, cisplatin remains an important component of chemotherapeutic regimens for the treatment of solid tumors. However, use of cisplatin is limited by nephrotoxicity, which occurs in about one-third of patients and leads to small but permanent changes in kidney function over the long-term. Current clinical markers, such as serum creatinine and estimated glomerular filtration rate, are limited in their ability to detect acute kidney injury (AKI). Additionally, a recent study reported a potential interaction in vivo between concurrently administered antiemetic drug, ondansetron, and cisplatin that may exacerbate cisplatin-induced nephrotoxicity. One mechanism of cisplatin kidney injury is the ability of renal transporters to mediate its urinary secretion. Presently, the degree of interaction between antiemetic drugs and cisplatin renal transporters is unknown. The purposes of this dissertation research were to assess time-dependent changes in urinary protein biomarkers in cisplatin treated oncology patients with subclinical nephrotoxicity, characterize the renal expression and regulation of the novel urinary biomarker calbindin in cisplatin-mediated acute kidney injury, and determine the extent of antiemetic drug inhibition of renal transporters involved in cisplatin secretion. In 57 patients with solid tumors receiving outpatient cisplatin therapy (≥25 mg/m2), mean serum creatinine was unchanged following cisplatin infusion. Compared to baseline values, several novel biomarkers were significantly increased in the urine. B2M was increased 3-fold by day 3, while KIM-1, TFF3, and calbindin were elevated 2-fold, 2-fold, and 8-fold by day 10, respectively. In a subset of 27 patients, time-dependent changes in KIM-1, calbindin, and TFF3 were assessed during early and subsequent cycles of cisplatin-containing chemotherapy. Although significant increases were seen during the early cycle, baseline biomarker levels remained elevated for KIM-1 and TFF3 and for all three biomarkers (KIM-1, TFF3, and calbindin), time-dependent changes were modest during subsequent cycles. Subsequent mechanistic studies were performed to better understand the intrarenal regulation of one biomarker, calbindin, during cisplatin AKI in mice as well as identify potential cisplatin-drug interactions due to alterations in cisplatin transporter activity in vitro. In mice treated with cisplatin, calbindin protein was robustly elevated in urine prior to elevations in serum creatinine and blood urea nitrogen. A time-dependent decrease in renal calbindin protein was observed on day 4 with concurrent up-regulation of calbindin mRNA. Finally, in vitro models revealed that 5-HT3 antagonists used to treat cisplatin-induced emesis dose-dependently inhibited the activity of OCT2 and MATE1, two transporters responsible for cisplatin secretion. Importantly, the most potent inhibitor was ondansetron, which inhibited transport of a probe substrate ASP+ in MATE1 overexpressing HEK293 cells at concentrations that are pharmacologically relevant (IC50: 0.1 μM) and also caused accumulation and inhibition of ASP+ transport in polarized MDCK tubule cells that overexpress OCT2 and MATE1. These data suggest that potent inhibition of MATE1-mediated efflux of cisplatin from human proximal tubules by antiemetic drugs may increase intratubular concentrations of cisplatin. This research demonstrates that novel urinary protein biomarkers are responsive to cisplatin therapy in the absence of clinically detectable AKI during early cycles, but are not reflective of progressive kidney damage during subsequent cycles of cisplatin therapy. Additionally, this research provides new mechanistic understanding of urinary calbindin release as well as the potential for antiemetic drug inhibition of renal cisplatin transporters.
Subject (authority = RUETD)
Topic
Toxicology
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_8634
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (xviii, 309 p. : ill.)
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Subject (authority = ETD-LCSH)
Topic
Kidneys--Wounds and injuries
Note (type = statement of responsibility)
by Blessy George
RelatedItem (type = host)
TitleInfo
Title
School of Graduate Studies Electronic Theses and Dissertations
Identifier (type = local)
rucore10001600001
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier (type = doi)
doi:10.7282/T3JH3QC0
Back to the top

Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
George
GivenName
Blessy
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2018-01-09 21:49:16
AssociatedEntity
Name
Blessy George
Role
Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
AssociatedObject
Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
RightsEvent
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2018-01-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2020-01-31
Type
Embargo
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after January 31st, 2020.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
Back to the top

Technical

RULTechMD (ID = TECHNICAL1)
ContentModel
ETD
OperatingSystem (VERSION = 5.1)
windows xp
CreatingApplication
Version
1.4
ApplicationName
Mac OS X 10.10 Quartz PDFContext
DateCreated (point = end); (encoding = w3cdtf); (qualifier = exact)
2018-01-10T02:45:41
DateCreated (point = end); (encoding = w3cdtf); (qualifier = exact)
2018-01-10T02:45:41
Back to the top
Version 8.3.10
Rutgers University Libraries - Copyright ©2019