Delayed Renal Allograft Function and Furosemide Treatment

1. Background/ Rationale Kidney Transplantation is a lifesaving modality in patients with
end-stage renal disease (ESRD), and the numbers of transplants have been skyrocketing
since the first successful trials. In 2013 alone, there were over 18,000 kidney
transplants done in the United States of America. Of those, 11,161 were from a deceased
donor (NKUDIC 2011, One Legacy 2014, USRDS 2013). One common complication of renal
transplants is Delayed Graft Function (DGF). DGF is a serious complication, which is
best defined as the need for renal replacement therapy, such as dialysis, within the
first week after renal transplant (Mallon et al. 2013). DGF greatly increases the risk
of acute and chronic transplant rejection, which decreases patient survival and quality
of life, for those patients who do survive (Perico et al. 2004, Weber et al. 2014).
Additionally, the rate of DGF is highest in patients who have received deceased donor
transplants (One Legacy 2014). Therefore, it is crucial to the well-being of this large
population to reduce the incidence of DGF. Our approach is to investigate current
treatment modalities for patients post-deceased donor renal transplant, to understand
how best to prevent DGF before it even starts. Currently, administration of loop
diuretics such as furosemide is a common practice in order to prevent and treat
oliguria in renal transplant patients. However, only animal models have been able to
show a benefit in treating acute kidney injury (AKI), which occurs in the transplant
kidney due to cold ischemia time, with furosemide. There is a lack of evidence that
furosemide use leads to improved patient outcomes in patients with AKI (Nadeau-Fredette
et al. 2013). Given that side effects of furosemide administration include ototoxicity,
hypotension, electrolyte abnormalities, and hypersensitivity reactions, and the
investigators hypothesize, may not significantly reduce the incidence of DGF from
placebo, it is important to investigate if the benefits of furosemide administration
truly outweigh the harms (Strom et al. 2003). The investigators intend to achieve this
by way of a randomized, double-blinded, pilot clinical trial in adult oliguric
patients, post-deceased donor renal transplant.

2. Objectives

I.Primary Objective:

i.To test the hypothesis that DGF rate is the same in adult oliguric post-deceased donor
renal transplant patients administered furosemide vs. placebo.

II.Secondary Objectives:

i.To compare the following within the two treatment groups:

- 30-day, 90-day and 12-month creatinine levels and estimated glomerular filtration rate
(eGFR)

- The need for RRT (Hemodialysis or Peritoneal dialysis) 30 days, 90 days and 12 months
post-transplant

- The time from transplant to DGF development

- The incidence of DGF

- The incidence of primary graft non-function

- Overall hospital length of stay

- The KDPI score in relation to primary graft non-function

ii. To quantify the association between furosemide administration and relevant patient
centered outcomes, such as hospital length of stay and acquired complications, in order to
decrease patient morbidity and mortality.

c. Study Outline

All patients that have been admitted for a deceased donor kidney transplant will be seen by
the Nephrology service for pre-transplant evaluation. The Nephrology Fellow/Attending
physician will go over a checklist that determines if the patient will be eligible for the
study and will obtain the informed consent if the patient is eligible. Informed consent will
be obtained from all eligible patients. All eligible patients' urine output will be
monitored as soon as they return to the unit from the operating room. If the patient remains
oliguric or anuric for 6 hours, the bedside nurse will alert the on-call study coordinator
for randomization and enrollment per protocol.

Study Intervention Patients assigned to the furosemide infusion group will receive
furosemide infusions, as outlined in figure 2. This has been adapted from Ostermann et al.
(2007) and the SPARK study protocol (Bagshaw et al. 2010).

Furosemide will be prepared in bags that contain 1000 mg of furosemide per 250 mL of saline
reaching a concentration of 4 mg/mL. All medication and placebo bags will have no
identifiers that show what type of drug is being administered, for blinding purposes.
Medication and placebo bags will have randomly generated study identifier numbers. The
protocol in figure 2 will be followed to achieve a total urine output of 1mL/kg/h. The
furosemide infusion rate will not exceed 4mg/min IV as this is the maximum set by the
manufacturer.

Inclusion Criteria:

- Age ≥ 18 years

- Patient with ESRD who has been on RRT (Hemodialysis or Peritoneal dialysis)

- Recipient of deceased donor kidney transplant

- Urine output less than 0.5 mL/kg/h before transplant

- Patient consents to the study

- Patient is not allergic to furosemide or sulfa

- English or Spanish speaking patient

- Patient is oliguric (urine output less than 0.5mL/kg/h, as per AKIN criteria) or
anuric (urine output less than 10 mL in 6 hours post-transplant or 2 mL/h) in the
first 6 hours post kidney transplant

Exclusion Criteria:

- Recipients of a living donor kidney transplant

- Patients who do not consent for the study

- Patients age <18 years

- Patients who are allergic to furosemide or sulfa containing medications

- Non-oliguric patients

- Patients who require immediate dialysis within 6 hours of the transplant (before
enrollment)

- Patients with renal ischemia due to vascular compromise that has been confirmed with
Doppler Ultrasound right after transplant as per standard of care

- Patients who return to the operating room due to complications within 24 hours

- Simultaneous multi-organ transplant recipients

- Hypotensive patients with BP <90/60 or MAP <60 mmHg

- Patients who are on vasopressors at any time during study period

- Non-English or Spanish speaking patient