PERT: Intravenous Estrogen in Kidney Transplant Study

University of Pennsylvania (Other)
Overall Status
Recruiting ID

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: Conjugated Estrogen
  • Drug: Normal saline
Phase 1/Phase 2

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 Design

Study Type:
Anticipated Enrollment :
30 participants
Intervention Model:
Parallel Assignment
Intervention Model Description:
Parallel: Participants are assigned to one of two or more groups in parallel for the duration of the studyParallel: Participants are assigned to one of two or more groups in parallel for the duration of the study
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Official Title:
The Use of Peri-Operative Intravenous Estrogen for the Mitigation of Ischemia Reperfusion Injury in the Setting of Renal Transplantation
Actual Study Start Date :
Aug 26, 2016
Anticipated Primary Completion Date :
Jan 31, 2022
Anticipated Study Completion Date :
Jan 31, 2022

Arms and Interventions

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
  • Outcome Measures

    Primary Outcome Measures

    1. Glomerular filtration rate (GFR) [Post-operative day three]

      GFR (glomerular filtration rate) as calculated from a DTPA (Diethylenetriamine Pentaacetic Acid, a medication) renal scan.

    Secondary Outcome Measures

    1. Delayed graft function (DGF) [Immediately post-operative]

      Measurement of urine creatinine clearance and serum creatinine.

    Other Outcome Measures

    1. Graft Failure [Post-operative day three and day ninety]

      Measurement of serum creatinine.

    Eligibility Criteria


    Ages Eligible for Study:
    21 Years and Older
    Sexes Eligible for Study:
    Accepts Healthy Volunteers:
    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

    5. Receiving their first (primary) kidney transplant

    6. Subjects must receive between 500-5000U intravenous systemic heparin during their kidney transplant

    7. Subjects must receive between 2500-7500U subcutaneous heparin prophylaxis three times daily during hospital stay

    8. Written informed consent obtained from subject and ability for subject to comply with the requirements of the study

    Exclusion Criteria:
    1. Receiving a non-primary (second, third, fourth, etc.) kidney transplant

    2. Receiving a combined heart-kidney transplant, liver-kidney transplant, or other multi-visceral organ transplant

    3. Receiving a live donor kidney transplant

    4. Personal history of deep vein thrombosis (DVT) or pulmonary embolism (PE)

    5. 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) to warrant exclusion from the study

    6. Personal history of an estrogen sensitive cancer (breast, endometrial, ovarian)

    7. Personal history of arterial thromboembolic disease such as stroke or myocardial infarction in the 6 months prior to transplantation

    8. Patient already on estrogen (including oral contraceptive pills) or anti-estrogen therapy for other indications

    9. 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

    10. 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

    11. Pregnant and breast feeding patients will be excluded from the study due to the small risk of radiation associated with the DTPA renal scan

    12. Patient body mass index (BMI) > 40Kidney donor profile index (KDPI) < 40

    13. Known anaphylactic reaction and angioedema to Premarin Intravenous therapy

    14. 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

    Contacts and Locations


    Site City State Country Postal Code
    1 University of Pennsylvania Philadelphia Pennsylvania United States 19104

    Sponsors and Collaborators

    • University of Pennsylvania


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

    Study Documents (Full-Text)

    None provided.

    More Information


    Responsible Party:
    University of Pennsylvania Identifier:
    Other Study ID Numbers:
    • 82378
    First Posted:
    Sep 10, 2018
    Last Update Posted:
    Sep 5, 2021
    Last Verified:
    Aug 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Plan to Share IPD:
    Studies a U.S. FDA-regulated Drug Product:
    Studies a U.S. FDA-regulated Device Product:
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Sep 5, 2021