Other Complication of Kidney Transplant, Renal Transplant Rejection
Conditions
Keywords
Kidney transplant, Immunosuppression, Steroid withdrawal, Donor specific antibodies
Brief summary
Steroids are one of the pillars of immunosuppression for kidney transplant patients but their use is associated with a high rate of complications. Withdrawal of steroids reduces some metabolic and cardiovascular complications, but it may increase the risk of acute rejection. However, little is known about whether steroid withdrawal is associated with the generation of anti-HLA donor-specific antibodies (DSA) and the relation between DSA and clinical and histological data. The aim of this study is to compare the incidence of de novo anti-HLA DSA in stable kidney transplant patients after withdrawing the steroids 3 months after the transplantation as compared with patients who continue with steroids. The hypothesis is that steroid withdrawal will increase the presence of de novo anti-HLA DSA in stable kidney transplant patients
Interventions
DRUGPrednisone withdrawal
Withdrawal of steroids
DRUGPrednisone continuation
Continuation of steroids
Sponsors
Sociedad Andaluza de Trasplantes de Organos y Tejidos
Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male and female patients aged over 18 years with no immunological risk (PRA \<25% and no DSA) who are receiving their first cadaveric or living kidney transplant. 2. Patients who, three months after the transplantation, are receiving tacrolimus in combination with mycophenolic acid (MPA) or mycophenolate mofetil (MMF) plus steroids, with stable plasma levels of tacrolimus. 3. No clinical or histological immunological dysfunction before randomization 4. No de novo anti-HLA DSA at the time of randomization. 5. Patients who wish to and are able to give written informed consent to participate in the study. 6. For women, agreeing to use efficient contraception during the study.
Exclusion criteria
1. Patients who receive a multiorgan transplant. 2. Retransplants. 3. Presence of DSA before the transplant or at the time of randomization. 4. Cold ischemia time \>30 hours 5. Patients with serum creatinine \>2 mg/dL or proteinuria \>1g/day at the time of randomization 6. Prior episode of severe rejection (II-B-III in the Banff/13 classification) prior to randomization. 7. Presence of subclinical rejection on the protocol biopsy prior to randomization 8. Patients with BK-polyomavirus nephropathy at the time of randomization. 9. Patients with recurrent or de novo glomerulonephritis. 10. Patients who are being treated with immunosuppressive drugs other than those in the randomized clinical trial in question. 11. Patients who are positive for the human immunodeficiency virus (HIV) or those who have a severe systemic infection that, in the investigator's judgment, will require continued treatment. 12. Patients with any present or prior (during the previous 5 years) malignant disease, except basal or squamous cell carcinoma that has been excised.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cases of Kidney Transplant Patients With DSA | 24 months | Measurements of DSA at baseline, and at 3, 6, 12, 18 and 24 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Score on the Protocol Biopsies in the Two Treatment Groups | 24 months | Measurement at 24 months according to the Banff classification. The Banff Classification of Allograft Pathology is an international consensus classification for the reporting of biopsies from solid organ transplant. The scale ranges from 0 to 3, 3 being the worst. |
| Number of Participants With Acute Rejection Lesions | 24 months | Patients with acute rejection lesions (including subclinical rejection) at 24 months according to Banff classification |
| Incidence of Diabetes Mellitus | 24 months | Incidence of diabetes mellitus after kidney transplant in both groups at 1, 2, 3, 4, 6, 9, 12, 18 and 24 months |
| Lipid Profile | 24 months | Lipid profile after kidney transplant in both groups at 24 months |
| Blood Pressure | 24 months | Blood pressure after kidney transplant in both groups at 24 months |
| Assess the Adherence to Immunosuppressive Therapy in the Two Treatment Groups | At 24 months | The Basle scale was used to assess adherence (BAASIS questionnaire) to immunosuppressive therapy. |
| Patient Survival | 24 months | Patient survival after kidney transplant in both groups |
| Graft Survival | 24 months | Graft survival after kidney transplant in both groups |
| Renal Function | 24 months | Renal function after kidney transplant in both groups at 24 months measured according to the creatinine (mg/dL) concentrations |
Countries
Spain
Participant flow
Pre-assignment details
Of the 230 patients, 125 were not randomized because of: screening failure 74; patient wishes 16; acute rejection 9; graft loss 9; died 3; lost to follow-up 1 and other causes 13. The main causes of screening failure were: creatinine \>2 mg/dl and subclinical rejection in the protocol biopsy at the third month. 105 patients were finally included
Participants by arm
| Arm | Count |
|---|---|
| Steroids, Tacrolimus and Mycophenolate Normal treatment arm
Prednisone continuation: Continuation of steroids | 52 |
| Tacrolimus and Mycophenolate Normal treatment for first 90 days, then steroid withdrawal carrying on with the other drugs
Prednisone withdrawal: Withdrawal of steroids | 53 |
| Total | 105 |
Baseline characteristics
| Characteristic | Steroids, Tacrolimus and Mycophenolate | Tacrolimus and Mycophenolate | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 9 Participants | 18 Participants |
| Age, Categorical Between 18 and 65 years | 43 Participants | 44 Participants | 87 Participants |
| Age, Continuous | 54.8 years STANDARD_DEVIATION 10 | 52.1 years STANDARD_DEVIATION 14 | 53.4 years STANDARD_DEVIATION 12.4 |
| Race/Ethnicity, Customized Race / Ethnicity Black | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Race / Ethnicity Caucasian | 47 Participants | 51 Participants | 98 Participants |
| Race/Ethnicity, Customized Race / Ethnicity Hispanic | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race / Ethnicity North African | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Spain | 52 participants | 53 participants | 105 participants |
| Sex: Female, Male Female | 13 Participants | 15 Participants | 28 Participants |
| Sex: Female, Male Male | 39 Participants | 38 Participants | 77 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 52 | 0 / 53 |
| other Total, other adverse events | 0 / 52 | 0 / 53 |
| serious Total, serious adverse events | 10 / 52 | 15 / 53 |
Outcome results
Primary
Cases of Kidney Transplant Patients With DSA
Measurements of DSA at baseline, and at 3, 6, 12, 18 and 24 months
Time frame: 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Steroids, Tacrolimus and Mycophenolate | Cases of Kidney Transplant Patients With DSA | 0 Participants |
| Tacrolimus and Mycophenolate | Cases of Kidney Transplant Patients With DSA | 0 Participants |
Secondary
Assess the Adherence to Immunosuppressive Therapy in the Two Treatment Groups
The Basle scale was used to assess adherence (BAASIS questionnaire) to immunosuppressive therapy.
Time frame: At 24 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Steroids, Tacrolimus and Mycophenolate | Assess the Adherence to Immunosuppressive Therapy in the Two Treatment Groups | Dose taken 2 hours or more before or after time | 3 Participants |
| Steroids, Tacrolimus and Mycophenolate | Assess the Adherence to Immunosuppressive Therapy in the Two Treatment Groups | Forgot at least one dose during last 4 weeks | 0 Participants |
| Tacrolimus and Mycophenolate | Assess the Adherence to Immunosuppressive Therapy in the Two Treatment Groups | Dose taken 2 hours or more before or after time | 11 Participants |
| Tacrolimus and Mycophenolate | Assess the Adherence to Immunosuppressive Therapy in the Two Treatment Groups | Forgot at least one dose during last 4 weeks | 1 Participants |
Secondary
Blood Pressure
Blood pressure after kidney transplant in both groups at 24 months
Time frame: 24 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Steroids, Tacrolimus and Mycophenolate | Blood Pressure | Systolic BP | 133 mmHg | Standard Deviation 16 |
| Steroids, Tacrolimus and Mycophenolate | Blood Pressure | Diastolic BP | 74.9 mmHg | Standard Deviation 11 |
| Tacrolimus and Mycophenolate | Blood Pressure | Systolic BP | 125 mmHg | Standard Deviation 15 |
| Tacrolimus and Mycophenolate | Blood Pressure | Diastolic BP | 76 mmHg | Standard Deviation 9.7 |
Secondary
Graft Survival
Graft survival after kidney transplant in both groups
Time frame: 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Steroids, Tacrolimus and Mycophenolate | Graft Survival | 39 Participants |
| Tacrolimus and Mycophenolate | Graft Survival | 36 Participants |
Secondary
Incidence of Diabetes Mellitus
Incidence of diabetes mellitus after kidney transplant in both groups at 1, 2, 3, 4, 6, 9, 12, 18 and 24 months
Time frame: 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Steroids, Tacrolimus and Mycophenolate | Incidence of Diabetes Mellitus | 10 Participants |
| Tacrolimus and Mycophenolate | Incidence of Diabetes Mellitus | 6 Participants |
Secondary
Lipid Profile
Lipid profile after kidney transplant in both groups at 24 months
Time frame: 24 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Steroids, Tacrolimus and Mycophenolate | Lipid Profile | Cholesterol | 164 mg/dl | Standard Deviation 28 |
| Steroids, Tacrolimus and Mycophenolate | Lipid Profile | HDL | 51 mg/dl | Standard Deviation 14 |
| Steroids, Tacrolimus and Mycophenolate | Lipid Profile | LDL | 86 mg/dl | Standard Deviation 21 |
| Steroids, Tacrolimus and Mycophenolate | Lipid Profile | Triglycerides | 140 mg/dl | Standard Deviation 54 |
| Tacrolimus and Mycophenolate | Lipid Profile | Triglycerides | 127 mg/dl | Standard Deviation 7.8 |
| Tacrolimus and Mycophenolate | Lipid Profile | Cholesterol | 161 mg/dl | Standard Deviation 27 |
| Tacrolimus and Mycophenolate | Lipid Profile | LDL | 92 mg/dl | Standard Deviation 18 |
| Tacrolimus and Mycophenolate | Lipid Profile | HDL | 44.7 mg/dl | Standard Deviation 10 |
Secondary
Mean Score on the Protocol Biopsies in the Two Treatment Groups
Measurement at 24 months according to the Banff classification. The Banff Classification of Allograft Pathology is an international consensus classification for the reporting of biopsies from solid organ transplant. The scale ranges from 0 to 3, 3 being the worst.
Time frame: 24 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Steroids, Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Peritubular capillaritis | 0.24 score on a scale | Standard Deviation 0.6 |
| Steroids, Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Interstitial fibrosis and tubular atrophy | 1.18 score on a scale | Standard Deviation 1.14 |
| Steroids, Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Tubulitis | 0.5 score on a scale | Standard Deviation 0.7 |
| Steroids, Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Interstitial fibrosis | 0.6 score on a scale | Standard Deviation 0.62 |
| Steroids, Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Interstitial inflammation | 0.82 score on a scale | Standard Deviation 0.7 |
| Steroids, Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Chronic graft lesion | 1.96 score on a scale | Standard Deviation 1.5 |
| Steroids, Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Tubular atrophy | 0.6 score on a scale | Standard Deviation 0.56 |
| Steroids, Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Graft glomerulopathy | 0.14 score on a scale | Standard Deviation 0.45 |
| Steroids, Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Chronic vascular lesions | 0.58 score on a scale | Standard Deviation 0.9 |
| Steroids, Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Glomerulitis | 0.17 score on a scale | Standard Deviation 0.4 |
| Steroids, Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Arteriolar hyalinosis | 0.53 score on a scale | Standard Deviation 0.7 |
| Steroids, Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Arteritis | 0 score on a scale | Standard Deviation 0 |
| Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Arteriolar hyalinosis | 0.69 score on a scale | Standard Deviation 0.8 |
| Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Arteritis | 0 score on a scale | Standard Deviation 0 |
| Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Graft glomerulopathy | 0 score on a scale | Standard Deviation 0 |
| Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Interstitial fibrosis and tubular atrophy | 1.83 score on a scale | Standard Deviation 1.5 |
| Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Chronic graft lesion | 2.6 score on a scale | Standard Deviation 1.5 |
| Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Glomerulitis | 0.08 score on a scale | Standard Deviation 0.3 |
| Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Peritubular capillaritis | 0.20 score on a scale | Standard Deviation 0.5 |
| Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Tubulitis | 0.56 score on a scale | Standard Deviation 0.6 |
| Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Interstitial fibrosis | 0.88 score on a scale | Standard Deviation 0.78 |
| Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Tubular atrophy | 0.88 score on a scale | Standard Deviation 0.8 |
| Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Chronic vascular lesions | 0.64 score on a scale | Standard Deviation 0.7 |
| Tacrolimus and Mycophenolate | Mean Score on the Protocol Biopsies in the Two Treatment Groups | Interstitial inflammation | 0.68 score on a scale | Standard Deviation 0.7 |
Secondary
Number of Participants With Acute Rejection Lesions
Patients with acute rejection lesions (including subclinical rejection) at 24 months according to Banff classification
Time frame: 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Steroids, Tacrolimus and Mycophenolate | Number of Participants With Acute Rejection Lesions | 2 Participants |
| Tacrolimus and Mycophenolate | Number of Participants With Acute Rejection Lesions | 3 Participants |
Secondary
Patient Survival
Patient survival after kidney transplant in both groups
Time frame: 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Steroids, Tacrolimus and Mycophenolate | Patient Survival | 39 Participants |
| Tacrolimus and Mycophenolate | Patient Survival | 36 Participants |
Secondary
Renal Function
Renal function after kidney transplant in both groups at 24 months measured according to the creatinine (mg/dL) concentrations
Time frame: 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Steroids, Tacrolimus and Mycophenolate | Renal Function | 1.34 mg/dl | Standard Deviation 0.4 |
| Tacrolimus and Mycophenolate | Renal Function | 1.4 mg/dl | Standard Deviation 0.4 |
Secondary
Renal Function
Renal function after kidney transplant in both groups at 24 months measured according to the proteinuria (mg/24 h) concentrations
Time frame: 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Steroids, Tacrolimus and Mycophenolate | Renal Function | 209 mg/24h | Standard Deviation 185 |
| Tacrolimus and Mycophenolate | Renal Function | 148 mg/24h | Standard Deviation 82 |