Intravenous Estrogen in Kidney Transplant Study (PERT)

August 21, 2023 updated by: University of Pennsylvania

The Use of Peri-Operative Intravenous Estrogen for the Mitigation of Ischemia Reperfusion Injury in the Setting of Renal Transplantation

Ischemia perfusion injury (IRI) is a major cause of organ injury during kidney transplantation. Currently there are no treatments for IRI other than dialysis. Preliminary studies in female mice have found protection from IRI when given short term estrogen supplements. This study will look at the effect of intravenous estrogen given peri-operatively to reduce the effect of IRI in female kidney transplant recipients.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Ischemia-reperfusion injury (IRI) is a major etiology of organ injury and dysfunction that occurs during transplantation. In renal transplantation, the clinical manifestation of IRI is delayed graft function (DGF), typically defined as a recipient requiring dialysis within the first week after transplant. At present, there are no directed treatments for IRI associated with kidney transplantation and resultant DGF, other than supportive care with dialysis. This represents an unmet clinical need. While dialysis enables the support of patients until DGF resolves, DGF is associated with increased medical costs, increased length of hospital stay, increased rates of readmission to the hospital after transplantation, increased rates of rejection, and decreased graft survival. Therapies to reduce IRI might alleviate clinical complications associated with DGF, reduce costs associated with transplantation, and ease organ shortages by facilitating use of more marginal organs.

Despite acceptance of gender disparities in IRI tolerance in animal systems, attempts to utilize hormonal manipulation in humans to achieve improved IRI tolerance have not been undertaken. In an effort to design such a translation, the investigators investigated if similar gender disparities exist in humans who have undergone kidney transplantation. After review of the United Network for Organ Sharing database, the investigators established that male recipient gender was highly associated with DGF. Then, the investigators demonstrated that manipulation of the pre-ischemic environment with short-term estrogen supplementation in female mice provides protection from renal IRI. As a logical next stop, the investigators propose hormonal manipulation with perioperative administration of intravenous conjugated estrogens as a novel therapeutic strategy to reduce the effect of IRI in female humans undergoing kidney transplantation. The investigators have designed an investigational new drug (IND) late phase I/early phase II prospective, single center, double blind, randomized, placebo-controlled trial to test the safety, feasibility, and efficacy of this therapy. If the administration of peri-operative intravenous administration has a positive impact on the rate of recovery of GFR after renal transplant and the inherent IRI, then this therapy would represent the first treatment for IRI and ultimately might reduce the incidence of DGF. Because DGF after kidney transplantation is associated with inferior transplant outcomes and increased costs,2 a therapy that mitigates the effect of IRI and consequently reduces the incidence of DGF not only might alleviate these complications but could also ease organ shortages by facilitating the use of more marginal organs. Moreover, if estrogen therapy does mitigate IRI in the setting of renal transplantation, it could be applied to other causes of renal IRI including supra-celiac clamping in trauma or vascular surgery or the use of cardiopulmonary bypass in cardiac surgery. Female adult subjects with a diagnosis of end stage renal disease who are dialysis dependent at the time of deceased donor renal transplantation and meet the inclusion and exclusion criteria will be eligible for participation in this study.

Study Type

Interventional

Enrollment (Estimated)

30

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • University of Pennsylvania

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

19 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Female gender
  2. Age > 21 years at time of transplant
  3. Pre-existing dialysis dependence of at least 1-months duration at the time of transplant
  4. Receiving a deceased donor renal transplant with KDPI >40
  5. Written informed consent obtained from subject and ability for subject to comply with the requirements of the study

Exclusion Criteria:

  1. History of solid organ transplant
  2. Receiving a combined heart-kidney transplant, liver-kidney transplant, or other multi- visceral organ transplant
  3. Personal history of deep vein thrombosis (DVT) or pulmonary embolism (PE)
  4. Personal history of hypercoagulable condition including but not limited to Lupus Anticoagulant, Leiden Factor V Mutation, Prothrombin Gene Mutation, Protein C or S deficiency, or any other hypercoagulable condition considered by the attending transplant surgeon on clinical service or Data and Safety Monitoring Board (DSMB) t to warrant exclusion from the study
  5. Personal history of an estrogen sensitive cancer (breast, endometrial, ovarian)
  6. Personal history of arterial thromboembolic disease such as stroke or myocardial infarction in the 6 months prior to transplantation
  7. Patient already on estrogen (including oral contraceptive pills) or anti-estrogen therapy for other indications
  8. Patient who is expected to not tolerate a dose of 500-5000U intravenous heparin at the time of transplant as determined by the transplant surgeon
  9. Patient who has a contraindication or allergy to or is expected to not tolerate a dose of 2500-7500U subcutaneous heparin prophylaxis three times daily during hospital stay as determined by the transplant surgeon
  10. Pregnant and breast feeding patients will be excluded from the study due to the small risk of radiation associated with the DTPA renal scan
  11. Patient body mass index (BMI) > 40
  12. Known anaphylactic reaction and/or angioedema to Premarin Intravenous therapy
  13. Presence of a condition or abnormality that in the opinion of the investigator or attending transplant surgeon primarily responsible for the patient's care would compromise the safety of the patient or the quality of the data

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Active Arm
Participants randomized to the active arm will receive a single infusion of conjugated estrogens at the time of admission if within 8 hours of the expected surgery time or at approximately 8 hours to the expected surgery time if admission is earlier than that. Participants will then receive two daily infusions of conjugated estrogens after transplant given at 8 hours after reperfusion of the transplanted kidney and 24 hours after the first post transplant dose (32 hours after reperfusion of the transplanted kidney).
Drug: Conjugated Estrogen
Dosing of conjugated estrogen will be given pre kidney transplant procedure and twice after reperfusion of the transplanted kidney.
Other Names:
  • Premarin
Placebo Comparator: Placebo Arm
Participants randomized to the placebo arm will receive normal saline (0.9% sodium chloride) at the same rate as the active arm.
Drug: Normal saline
Dosing of normal saline will be given pre kidney transplant procedure and twice after reperfusion of the transplanted kidney.
Other Names:
  • 0.9% sodium chloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Glomerular filtration rate (GFR)
Time Frame: Post-operative day three
GFR (glomerular filtration rate) as calculated from a DTPA (Diethylenetriamine Pentaacetic Acid, a medication) renal scan.
Post-operative day three

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Delayed graft function (DGF)
Time Frame: Immediately post-operative
Measurement of urine creatinine clearance and serum creatinine.
Immediately post-operative

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Graft Failure
Time Frame: Post-operative day three and day ninety
Measurement of serum creatinine.
Post-operative day three and day ninety
Post Op Day 3 Creatinine
Time Frame: Post-operative day 3
Measurement of serum creatinine and percent change from pre-transplant creatinine
Post-operative day 3
Nadir Post op Day 90 Creatinine
Time Frame: post transplant day 90
Measurement of serum creatinine and percent change from pre-transplant creatinine
post transplant day 90

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Pennsylvania

Investigators

  • Principal Investigator: Matthew Levine, MD, PhD, University of Pennsylvania Health System

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 26, 2016

Primary Completion (Estimated)

January 31, 2025

Study Completion (Estimated)

January 31, 2025

Study Registration Dates

First Submitted

August 27, 2018

First Submitted That Met QC Criteria

September 5, 2018

First Posted (Actual)

September 10, 2018

Study Record Updates

Last Update Posted (Actual)

August 22, 2023

Last Update Submitted That Met QC Criteria

August 21, 2023

Last Verified

August 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 82378

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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