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PHARMACOLOGICAL APPROACHES TO PRESERVE RENAL GRAFTS AND TO OPTIMIZE IMMUNOSUPPRESSION IN RENAL TRANSPLANTATION

Thanukrishnan, Harisudhan (2019) PHARMACOLOGICAL APPROACHES TO PRESERVE RENAL GRAFTS AND TO OPTIMIZE IMMUNOSUPPRESSION IN RENAL TRANSPLANTATION. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Renal transplantation has evolved as the best therapeutic option for patients with end stage renal diseases. Several risk factors such as ischemia reperfusion injury (IRI), delayed graft function, under or over-immunosuppression and drug toxicity can affect the renal graft function and survival. This work focused on pharmacological approaches to address two of the modifiable risk factors associated with early post-transplant graft survival, namely IRI and optimization of immunosuppression. The first part of work evaluated supplementation of the renal cold preservation solution with treprostinil to attenuate IRI injuries due to its vasodilatory, anti-platelet aggregatory and cytoprotective properties. Isolated rat kidneys were stored at 4°C for 24 h with or without treprostinil and reperfused in vitro to mimic post-transplant conditions. Cold stored kidneys showed a significant loss in renal function and treprostinil addition (20 ng/mL) to preservation significantly improved the filtration fraction, urine flow and showed a trend to increase the anionic and cationic tubular secretion. Treprostinil addition to storage and reperfusion attenuated the IR induced changes in certain gene expression, indicating protection against the IR induced effects and the need for a follow-up of its effects in an in vivo transplant setting. The second part of this work examined early (week 1) post-transplant pharmacologic measures in association with incidence of rejections (clinical and subclinical) at week-13 and infections at month-12 in renal transplant patients. The pharmacologic measures for exposure and efficacy to mycophenolic acid (MPA) and exposure to tacrolimus were obtained by sparse sampling. Patients with lower exposure to both drugs tended to have higher incidence and odds of rejection, when compared to patients who had optimal exposure to both tacrolimus and MPA (46 vs 23 %, NS, odds ratio of 3.0; p =0.3414 for rejections). A composite scoring using pharmacologic measures such as the total 12 h exposure to MPA, tacrolimus, IMPDH activity and genotype of p-glycoprotein on peripheral blood mononuclear cells revealed an increasing incidence of rejections in patients with higher scores. This observation emphasizes potential role for early post-transplant monitoring using sparse sampling in individualized therapy of kidney transplant patients, in order to further improve overall outcomes.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Thanukrishnan, Harisudhanhat36@pitt.eduhat360000-0001-5283-0733
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorVenkataramanan, Ramanrv@pitt.edurv
Committee MemberPoloyac, Samuelpoloyac@pitt.edupoloyac
Committee MemberBeumer, Janbeumerjh@upmc.edujhb11
Committee MemberSchonder, Kristineschonderks@upmc.edukss28
Committee MemberSood, Puneetsoodp2@upmc.edupus7
Date: 6 August 2019
Date Type: Publication
Defense Date: 10 June 2019
Approval Date: 6 August 2019
Submission Date: 5 August 2019
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 285
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: Clinical Pharmacology IMPDH activity Isolated kidney perfusion Mycophenolic acid Renal transplantation Tacrolimus
Date Deposited: 06 Aug 2019 12:15
Last Modified: 06 Aug 2019 12:15
URI: http://d-scholarship.pitt.edu/id/eprint/37281

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