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CHARACTERIZATION OF RENAL SECRETION IN RENAL TRANSPLANT PATIENTS

Kalluri, Hari Varun (2018) CHARACTERIZATION OF RENAL SECRETION IN RENAL TRANSPLANT PATIENTS. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The kidney is a vital organ in the human body. It conserves essential nutrients and eliminates endogenous and exogenous waste products by filtration and tubular secretion processes. Organic anionic and cationic transport systems expressed in the proximal tubular cells drive active renal secretion. Slow recovery and progressive graft function loss following renal transplantation due to prolonged cold ischemia (CI), calcineurin inhibitor (CNI) nephrotoxicity, BK virus nephropathy (BKVN) and varying grades of acute T-cell mediated rejection (TCMR) are hypothesized to affect the secretory function of renal allografts. This body of work is one of the first attempts to understand changes in expression and activity of renal transporters after renal transplantation. Pre-clinical studies in rats showed significant changes in gene expression of important transporters following prolonged-CI and renal transplantation, both in the presence and absence of tacrolimus treatment. Quantitative human gene expression studies showed significant differences in the expression of various transporters in kidney allografts that underwent prolonged-CI (CIT: 15.8±4.80 hrs) and in allografts with BKVN; allografts with acute TCMR and fibrosis had significantly compromised renal anionic transporter expression. Renal anionic secretory capacity was estimated in transplant patients using low-dose cefoxitin as a probe drug in 15 de-novo renal transplant recipients at two time-points post-transplantation. Results of this study suggest that anionic secretory capacity in living and deceased donor renal transplant recipients with no serious clinical complications is similar in the early post-transplant time-points. Renal transplant recipients, however, had a significantly higher cefoxitin exposure when compared to historical healthy controls (AUC0 ∞: 2.6 fold higher), indicating decreased (~60%) renal anionic secretory capacity. A robust physiologically based pharmacokinetic (PBPK) model of cefoxitin was built and validated in healthy subjects and renal transplant recipients. This PBPK model was used to predict the impact of changes in renal anionic transporter expression on anionic drug exposure. Overall this work shows that renal transplant recipients have altered expression of various renal transporters and altered activity of anionic transporters. Systematic characterization of changes in the activity of other transport systems and clinical monitoring of renal secretion is necessary to optimize pharmacotherapy of renally secreted drugs in renal transplant recipients.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Kalluri, Hari Varunhvk1@pitt.eduhvk10000-0002-5863-2452
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorVenkataramanan, Ramanrv@pitt.edurv
Committee MemberNolin, Thomas D.nolin@pitt.edunolin
Committee MemberEmpey, Philip E.pempey@pitt.edupempey
Committee MemberRandhawa, Parmjeet S.randhawapa@upmc.edu
Committee MemberHariharan, Sundaramhariharans@upmc.edu
Date: 19 April 2018
Date Type: Publication
Defense Date: 28 November 2017
Approval Date: 19 April 2018
Submission Date: 17 April 2018
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 256
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Renal Transporters, Kidney Transplantation, Renal Secretion, Prolonged Cold Ischemia, Tacrolimus, Pharmacokinetics
Date Deposited: 19 Apr 2018 16:08
Last Modified: 19 Apr 2018 16:08
URI: http://d-scholarship.pitt.edu/id/eprint/34320

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