Tacrolimus to Sirolimus Conversion for Delayed Graft Function

Eligible study subjects will be randomized into two groups 8-18 weeks after surgery. One
group will be maintained on tacrolimus according to the standard of care at our center. In
the second group tacrolimus will be converted to sirolimus, with one week overlap between
sirolimus therapy and tacrolimus taper. All the deceased donor kidney transplant recipients
transplanted at our center who experience DGF/SGF are eligible for inclusion in this study,
if they meet the inclusion/exclusion criteria as detailed later.

Data will be collected on patient demographics, duration on dialysis, history of diabetes and
chronic hepatitis C, previous transplantation, PRA, donor source, warm and cold ischemia
time, donor demographics and comorbidity such as diabetes and hypertension, serum creatinine
at the time of organ removal, early graft function, number of dialysis treatments after
transplantation, induction agent and immunosuppressive regimen including the dose or level of
the drugs at 3, 6, 9, 12, 18, and 24 months. Similar data regarding use of ACE
inhibitors/ARBs, erythropoietic agents, number of anti-hypertensives and lipid lowering
agents will be collected. In addition, the following tests and procedures will be obtained
for this study.

1. GFR measurement by cold iothalamate method at one year after transplantation.

2. Evaluation of routine surveillance graft biopsies for chronic changes at 3 and 12 months
posttransplant by morphometric analysis.

3. Spot urine protein, albumin, and creatinine measurement at 3 and 12 months.

4. Estimate GFR at 3, and 12 months using MDRD, CG, and Nankivell formulas

5. Examine the surveillance and indicated biopsies for acute rejection and BK nephropathy.

6. Fasting lipid profile at 3 and 12 months for all patients, and 24 months for those with
at least 2 years of follow up.

7. Office blood pressure measurements at 3 and 12 months for all patients, and 24 months
for those with at least 2 years of follow up.

8. Measurement of CRP, IL-6, and MCP at 3 and 12 months.

The safety measures will include:

Incidence of leukopenia (WBC < 3000) or thrombocytopenia (PLT < 100,000); hemoglobin level at
12 months; proteinuria at 12 months; incidence of oral aphthous ulcers; incidence of new
onset diabetes, incidence of CMV infection and rate of drug withdrawal due to side effects.

Inclusion Criteria:

1. Age => 18.

2. Recipient of a deceased donor kidney transplant.

3. Delayed graft function, defined as need for dialysis during first week after surgery
or slow graft function, defined as creatinine >=3.0 by post-op day 5 without requiring
dialysis

4. Stable serum creatinine for 2 weeks prior to enrollment.

5. Able to give informed consent.

6. Compliant with medical regimen and clinic visits.

Exclusion Criteria:

1. Episode of acute rejection within 4 weeks prior to enrollment.

2. Calculated GFR < 30 ml/min.

3. Interstitial fibrosis & tubular atrophy in transplant biopsy higher than grade II
(Banff"05 update).

4. Proteinuria > 500 mg/24 h or spot urine protein/creatinine > 0.5.

5. Total fasting cholesterol level > 300 mg/dl or triglyceride > 500 mg/dl despite
optimal lipid lowering therapy.

6. Recipient of pancreas or liver allografts.

7. Leukopenia (WBC < 3000 mm3) within 2 weeks prior to enrollment.

8. Leukopenia (WBC < 2000 mm3) within 4 weeks prior to enrollment.

9. Thrombocytopenia (platelets count < 100,000/mm3) within 2 weeks prior to enrollment.

10. Unwilling to comply with study protocol.

11. Enrollment in another drug trial that precludes use of sirolimus.

12. Diagnosis of malignancy within 2 years prior to enrollment, except adequately treated
non-melanoma skin cancer.

13. For women, pregnancy.

14. Allergy to iodine