Estrogen in Kidney Study

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.

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