Thanukrishnan, Harisudhan
(2019)
PHARMACOLOGICAL APPROACHES TO PRESERVE RENAL GRAFTS AND TO OPTIMIZE IMMUNOSUPPRESSION IN RENAL TRANSPLANTATION.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
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
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| 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 2020 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/37281 |
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