Delayed Graft Function, Kidney Transplant
Conditions
Keywords
kidney transplant, tacrolimus, sirolimus, delayed graft function, Graft survival, Acute rejection, Chronic allograft nephropathy
Brief summary
The objective of this study is to evaluate the safety and efficacy of conversion from tacrolimus to sirolimus early after kidney transplantation in patients with delayed graft function (DGF)and slow graft function (SGF) in improving graft function and delaying chronic allograft nephropathy. The investigators hypothesize that conversion from tacrolimus to sirolimus in renal transplant recipients with DGF/SGF in early months after surgery will improve graft function and decrease the progression of graft fibrosis.
Detailed description
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.
Interventions
DRUGTacrolimus
3-10 mg, PO, BID based on 12 hour trough on serum blood levels, adjusted according to protocol
DRUGSirolimus
5 mg, PO, daily based on 24 hour serum blood levels, adjusted according to protocol
Sponsors
Wyeth is now a wholly owned subsidiary of Pfizer
University of Maryland, Baltimore
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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 (Banff05 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The Composite Endpoint of Reduction of e eGFR at One Year by More Than 15% & the Progression in Fibrosis Score at One Year by >=20% Compared With the Baseline Values | One year |
Secondary
| Measure | Time frame |
|---|---|
| Change in eGFR From Baseline to 1-year | 1 year |
| Graft Survival (Actual, Actuarial) | 1 year |
| Incidence of Acute Rejection (Actual, Actuarial) | 1 year |
| eGFR | One year |
| Change in Inflammatory Marker : CRP From Baseline | 1 year |
| Change in Inflammatory Marker, IL-6 From Baseline | 1 Year |
| Change in Inflammatory Marker, MCP, From Baseline | 1 year |
| Incidence of BK Nephropathy (Cumulative) | 1 year |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tacrolimus Tacrolimus will be continued with target 12-hour trough level 7-10 ng/ml (tandem mass spectrometry) during the first year and 5-8 during second year.
Tacrolimus: 3-10 mg, PO, BID based on 12 hour trough on serum blood levels, adjusted according to protocol | 17 |
| Sirolimus 5 mg, PO , daily
Sirolimus: 5 mg, PO, daily based on 24 hour serum blood levels, adjusted according to protocol | 15 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Follow up biopsy not done | 2 | 3 |
Baseline characteristics
| Characteristic | Tacrolimus | Sirolimus | Total |
|---|---|---|---|
| Age, Continuous | 53.4 years STANDARD_DEVIATION 9.7 | 49.9 years STANDARD_DEVIATION 10.1 | 51.7 years STANDARD_DEVIATION 9.9 |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 9 Participants |
| Sex: Female, Male Male | 13 Participants | 10 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 17 | 0 / 15 |
| serious Total, serious adverse events | 0 / 17 | 0 / 15 |
Outcome results
Primary
The Composite Endpoint of Reduction of e eGFR at One Year by More Than 15% & the Progression in Fibrosis Score at One Year by >=20% Compared With the Baseline Values
Time frame: One year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus | The Composite Endpoint of Reduction of e eGFR at One Year by More Than 15% & the Progression in Fibrosis Score at One Year by >=20% Compared With the Baseline Values | 6 participants |
| Sirolimus | The Composite Endpoint of Reduction of e eGFR at One Year by More Than 15% & the Progression in Fibrosis Score at One Year by >=20% Compared With the Baseline Values | 9 participants |
Secondary
Change in eGFR From Baseline to 1-year
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tacrolimus | Change in eGFR From Baseline to 1-year | 7.45 mL/min per 1.73 m^2 | Standard Deviation 11.5 |
| Sirolimus | Change in eGFR From Baseline to 1-year | 1.57 mL/min per 1.73 m^2 | Standard Deviation 10.7 |
Secondary
Change in Inflammatory Marker : CRP From Baseline
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tacrolimus | Change in Inflammatory Marker : CRP From Baseline | -1668 mg/L | Standard Deviation 9403 |
| Sirolimus | Change in Inflammatory Marker : CRP From Baseline | 4510 mg/L | Standard Deviation 14495 |
Secondary
Change in Inflammatory Marker, IL-6 From Baseline
Time frame: 1 Year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tacrolimus | Change in Inflammatory Marker, IL-6 From Baseline | -0.7 pg/mL | Standard Deviation 8.53 |
| Sirolimus | Change in Inflammatory Marker, IL-6 From Baseline | 6.2 pg/mL | Standard Deviation 14.1 |
Secondary
Change in Inflammatory Marker, MCP, From Baseline
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tacrolimus | Change in Inflammatory Marker, MCP, From Baseline | -787.5 pg/mL | Standard Deviation 693.9 |
| Sirolimus | Change in Inflammatory Marker, MCP, From Baseline | -965.2 pg/mL | Standard Deviation 753.6 |
Secondary
eGFR
Time frame: One year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tacrolimus | eGFR | 56.4 mL/min per 1.73 m^2 | Standard Deviation 15.2 |
| Sirolimus | eGFR | 53.7 mL/min per 1.73 m^2 | Standard Deviation 19.2 |
Secondary
Graft Survival (Actual, Actuarial)
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus | Graft Survival (Actual, Actuarial) | 16 participants |
| Sirolimus | Graft Survival (Actual, Actuarial) | 14 participants |
Secondary
Incidence of Acute Rejection (Actual, Actuarial)
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus | Incidence of Acute Rejection (Actual, Actuarial) | 1 participants |
| Sirolimus | Incidence of Acute Rejection (Actual, Actuarial) | 1 participants |
Secondary
Incidence of BK Nephropathy (Cumulative)
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus | Incidence of BK Nephropathy (Cumulative) | 1 participants |
| Sirolimus | Incidence of BK Nephropathy (Cumulative) | 0 participants |