Intravenous Estrogen in Kidney Transplant Study

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Ischemia Reperfusion Injury

Intervention / Treatment
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* Drug: Conjugated Estrogen
* Drug: Normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female gender Age > 21 years at time of transplant Pre-existing dialysis dependence of at least 1-months duration at the time of transplant Receiving a deceased donor renal transplant with KDPI >40 Written informed consent obtained from subject and ability for subject to comply with the requirements of the study Exclusion Criteria: History of solid organ transplant Receiving a combined heart-kidney transplant, liver-kidney transplant, or other multi- visceral organ transplant Personal history of deep vein thrombosis (DVT) or pulmonary embolism (PE) 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 Personal history of an estrogen sensitive cancer (breast, endometrial, ovarian) Personal history of arterial thromboembolic disease such as stroke or myocardial infarction in the 6 months prior to transplantation Patient already on estrogen (including oral contraceptive pills) or anti-estrogen therapy for other indications 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 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 Pregnant and breast feeding patients will be excluded from the study due to the small risk of radiation associated with the DTPA renal scan Patient body mass index (BMI) > 40 Known anaphylactic reaction and/or angioedema to Premarin Intravenous therapy 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

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel: Participants are assigned to one of two or more groups in parallel for the duration of the study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Arm<br>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<br>* Dosing of conjugated estrogen will be given pre kidney transplant procedure and twice after reperfusion of the transplanted kidney.<br>* Other names: Premarin;|
| Placebo Comparator: Placebo Arm<br>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<br>* Dosing of normal saline will be given pre kidney transplant procedure and twice after reperfusion of the transplanted kidney.<br>* Other names: 0.9% sodium chloride;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glomerular filtration rate (GFR) | 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) | Measurement of urine creatinine clearance and serum creatinine. | Immediately post-operative |