Proteinuria
Conditions
Keywords
Proteinuria, Kidney transplantation, Allograft dysfunction, B7-1, Belatacept
Brief summary
Background: Proteinuria develops in about 30% of kidney transplant recipients and is a strong predictor of graft loss. The amount of proteinuria has a direct correlation with the risk of graft failure. Novel therapies are urgently needed to reduce proteinuria and prevent graft loss in transplant recipients, since ACE inhibitors carry a number of limitations in the transplant setting, including significant reduction in renal function, anemia and hyperkalemia. Preliminary data: B7-1 is expressed at significant levels in about 10% of kidney allograft biopsies with predominance in patients with proteinuria. Hypothesis: We hypothesize that B7-1 targeting therapy may reduce proteinuria and improve graft survival in proteinuric transplant recipients that have B7-1 staining on allografts. In addition, the absence of CNI nephrotoxicity and the potential protective effect of Belatacept on DSA production may be of benefit in this subset of transplant patients. Objectives: Primary: Determine the effect of Belatacept conversion in reducing proteinuria by 25% at 12 months in renal transplant recipients (≥1gram/d) that are either B7-1-positive or negative on kidney biopsy. Secondary: Assess the effect of Belatacept conversion in the percent change of renal function from baseline to 12 months; donor-specific anti-HLA antibodies presence and intensity (MFI); correlation of B7-1 positivity on immunofluorescence on biopsy with B7-1-expression in urine extracellular vesicles; adverse events; acute rejection episodes; blood pressure control; new onset diabetes; hyperlipidemia; graft survival; and patient survival.
Detailed description
A total of 36 patients will be recruited.
Interventions
DRUGBelatacept
Conversion from calcineurin-inhibitor to Belatacept maintenance immunosuppression.
Sponsors
Bristol-Myers Squibb
Brigham and Women's Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female adult kidney transplant recipients older than 18 years old 2. eGFR ≥30 ml/min 3. ≥6 months after transplantation 4. Proteinuria ≥1 gram/day in spot urine protein/creatinine ratio 5. Ability to provide written informed consent for the study. 6. Maintenance immunosuppression of CNI (cyclosporine or tacrolimus), antiproliferative agent (azathioprine, MMF or MPA) with either steroids or not.
Exclusion criteria
1. Age \<18 years 2. eGFR\<30 ml/min 3. active acute cellular rejection (ACR; higher than borderline) or ACR in the previous 6 months; active acute antibody-mediated rejection 4. recurrent FSGS 5. EBV IgG negative 6. patient on mTOR inhibitor (e.g. Everolimus, Sirolimus) 7. patient only on CNI (cyclosporine or tacrolimus) and steroids
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Proteinuria by 25% | 12 months | Change in proteinuria by 25%: daily proteinuria is estimated by spot urine protein (mg/dL) to creatinine (mg/dL) ratio at baseline (before the belatacept conversion) and post-conversion 12 months; and interval % change was calculated by getting the ratio of difference between the two time points to the baseline value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Acute Rejection Episodes | 12 months | Acute rejection episodes \[Time Frame: 12 months\]: Number of biopsy-proven rejection episodes from belatacept conversion to post-conversion 12 months. |
| Change in Blood Pressure Measurement (mm Hg) | 12 months | Change in Blood pressure measurement (mm Hg) \[Time Frame: 12 months\]: The mmHg difference in systolic and diastolic blood pressures between the baseline (pre-belatacept conversion) and post-conversion 12 months is assessed. Blood pressure measurement done at the office visits at baseline and 12 months after at least 5 minutes of resting. |
| Change in Fasting Glucose | 12 months | New onset diabetes \[Time Frame: 12 months\]: Number of new onset diabetes per American Diabetes Association 2015 Criteria from belatacept conversion to post-conversion 12 months |
| Change in Renal Function (eGFR in mL/Min/1.73 m^2) | from baseline to 12 months | — |
| Graft Survival | 12 months | Graft survival \[Time Frame: 12 months\]: Number of patients who developed end stage kidney disease and required kidney replacement therapy within 12 months post-belatacept conversion. |
| Patient Survival | 12 months | — |
| Hyperlipidemia | 12 months | Hyperlipidemia \[ Time Frame: 12 months\]: Changes (mg/dL) in serum total cholesterol, LDL, HDL, and triglyceride levels from pre-belatacept conversion to post-conversion 12 months. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Belatacept Conversion Belatacept: Conversion from calcineurin-inhibitor to Belatacept maintenance immunosuppression. | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | Belatacept Conversion |
|---|---|
| Age, Continuous | 57 years STANDARD_DEVIATION 12 |
| Race/Ethnicity, Customized Ethnicity Asian | 2 Participants |
| Race/Ethnicity, Customized Ethnicity Black | 3 Participants |
| Race/Ethnicity, Customized Ethnicity Hispanic | 3 Participants |
| Race/Ethnicity, Customized Ethnicity White | 7 Participants |
| Region of Enrollment United States | 15 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 15 |
| other Total, other adverse events | 9 / 15 |
| serious Total, serious adverse events | 1 / 15 |
Outcome results
Primary
Change in Proteinuria by 25%
Change in proteinuria by 25%: daily proteinuria is estimated by spot urine protein (mg/dL) to creatinine (mg/dL) ratio at baseline (before the belatacept conversion) and post-conversion 12 months; and interval % change was calculated by getting the ratio of difference between the two time points to the baseline value.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Belatacept Conversion | Change in Proteinuria by 25% | 8 Participants |
Secondary
Acute Rejection Episodes
Acute rejection episodes \[Time Frame: 12 months\]: Number of biopsy-proven rejection episodes from belatacept conversion to post-conversion 12 months.
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Belatacept Conversion | Acute Rejection Episodes | 0 episodes |
Secondary
Change in Blood Pressure Measurement (mm Hg)
Change in Blood pressure measurement (mm Hg) \[Time Frame: 12 months\]: The mmHg difference in systolic and diastolic blood pressures between the baseline (pre-belatacept conversion) and post-conversion 12 months is assessed. Blood pressure measurement done at the office visits at baseline and 12 months after at least 5 minutes of resting.
Time frame: 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Belatacept Conversion | Change in Blood Pressure Measurement (mm Hg) | Baseline (Systolic) | 140 mmHg | Standard Deviation 11 |
| Belatacept Conversion | Change in Blood Pressure Measurement (mm Hg) | Baseline (Diastolic) | 76 mmHg | Standard Deviation 6 |
| Belatacept Conversion | Change in Blood Pressure Measurement (mm Hg) | 12 Months (Systolic) | 129 mmHg | Standard Deviation 16 |
| Belatacept Conversion | Change in Blood Pressure Measurement (mm Hg) | 12 Months (Diastolic) | 72 mmHg | Standard Deviation 9 |
Secondary
Change in Fasting Glucose
New onset diabetes \[Time Frame: 12 months\]: Number of new onset diabetes per American Diabetes Association 2015 Criteria from belatacept conversion to post-conversion 12 months
Time frame: 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Belatacept Conversion | Change in Fasting Glucose | Baseline | 119 mg/dL | Standard Deviation 37 |
| Belatacept Conversion | Change in Fasting Glucose | 12 Months | 124 mg/dL | Standard Deviation 62 |
Secondary
Change in Renal Function (eGFR in mL/Min/1.73 m^2)
Time frame: from baseline to 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Belatacept Conversion | Change in Renal Function (eGFR in mL/Min/1.73 m^2) | Baseline | 45.8 mL/min/1.73m2 | Standard Deviation 13.3 |
| Belatacept Conversion | Change in Renal Function (eGFR in mL/Min/1.73 m^2) | 12 Months | 45.1 mL/min/1.73m2 | Standard Deviation 12.7 |
Secondary
Graft Survival
Graft survival \[Time Frame: 12 months\]: Number of patients who developed end stage kidney disease and required kidney replacement therapy within 12 months post-belatacept conversion.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Belatacept Conversion | Graft Survival | 13 Participants |
Secondary
Hyperlipidemia
Hyperlipidemia \[ Time Frame: 12 months\]: Changes (mg/dL) in serum total cholesterol, LDL, HDL, and triglyceride levels from pre-belatacept conversion to post-conversion 12 months.
Time frame: 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Belatacept Conversion | Hyperlipidemia | Baseline Total Cholesterol | 177 mg/dL | Standard Deviation 49 |
| Belatacept Conversion | Hyperlipidemia | 12 Month Total Cholesterol | 171 mg/dL | Standard Deviation 49 |
Secondary
Patient Survival
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Belatacept Conversion | Patient Survival | 14 Participants |