Donor-derived Cell-free DNA for Early Diagnosis of Antibody-mediated Rejection

Study Overview
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Brief Summary
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Patients after kidney transplantation who develop donor-specific antibodies (DSA) are at high risk for antibody-mediated rejection (ABMR). Donor-derived cell-free DNA (dd-cfDNA) levels have been shown to be increased in patients with active or chronic active ABMR. This study aims to evaluate if repeated analysis of dd-cfDNA in patients with DSA and kidney allograft biopsy which is triggered by increased levels of dd-cfDNA can lead to early diagnosis of active or chronic active ABMR among these patients.

Official Title
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Donor-derived Cell-free DNA for Early Diagnosis of Antibody-mediated Rejection in Kidney Transplant Recipient With Donor-specific Antibodies

Conditions
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Kidney Transplant Rejection, Antibody-mediated Rejection, Kidney Transplant Failure

Intervention / Treatment
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* Procedure: Kidney allograft biopsy depending on donor-derived cell-free DNA levels


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients 18 years or older patients provided written informed consent patients after kidney transplantation functioning kidney allograft, at least after 180 days after last transplantation estimated glomerular filtration rate above 20 ml/min/1.73m^2 detection of DSA Exclusion Criteria: patients younger than 18 years patients unable or did not provide written informed consent pregnant or breastfeeding persons patients with increased bleeding risk patients with multi-organ transplantation patients who underwent kidney allograft biopsy after first detection of DSA biopsy-proven antibody-mediated rejection participation in another interventional clinical trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>Additionally to standard of care, measurements for donor-derived cell-free DNA (dd-cfDNA) are performed at months 0, 1, 3, 6, 9, and 12. If absolute levels of dd-cfDNA are > 50 copies/ml, the patients receive a kidney allograft biopsy. Additionally, kidney allograft biopsies are performed according to standard of care as determined by the treating physicians. | Procedure: Kidney allograft biopsy depending on donor-derived cell-free DNA levels<br>* Kidney allograft biopsy is performed, when absolute levels of donor-derived cell-free DNA are above 50 copies/ml<br>|
| No Intervention: Control<br>Additionally to standard of care, measurements for donor-derived cell-free DNA (dd-cfDNA) are performed at months 0, 1, 3, 6, 9, and 12. These measurements are not used to guide kidney allograft biopsies. Those are performed according to standard of care as determined by the treating physicians. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time from study inclusion to diagnosis of antibody-mediated rejection | Time from study inclusion date to biopsy-proven diagnosis of active or chronic active antibody-mediated rejection | 12 months after inclusion | 
| Time from DSA detection to diagnosis of antibody-mediated rejection | Time from first detection of donor-specific antibodies to biopsy-proven diagnosis of active or chronic active antibody-mediated rejection | 12 months after inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensitivity of absolute dd-cfDNA for detection of ABMR | Sensitivity of dd-cfDNA > 50 copies/ml to predict the occurence of active or chronic active ABMR in patients with DSA. | 12 Months | 
| Specificity of absolute dd-cfDNA for detection of ABMR | Specificity of dd-cfDNA > 50 copies/ml to predict the occurence of active or chronic active ABMR in patients with DSA. | 12 Months | 
| Receiver operating characteristics (ROC) analysis of absolute dd-cfDNA for detection of ABMR | ROC analysis for dd-cfDNA to predict the occurence of active or chronic active ABMR in patients with DSA. | 12 Months | 
| Sensitivity of intraindividual dd-cfDNA changes for detection of ABMR | Sensitivity of dd-cfDNA increase of > 25% to predict the occurence of active or chronic active ABMR in patients with DSA. | 12 Months | 
| Sensitivity of combined dd-cfDNA criterion for detection of ABMR | Sensitivity of the combination of dd-cfDNA increase of > 25% OR absolute dd-cfDNA > 50 copies/ml to predict the occurence of active or chronic active ABMR in patients with DSA. | 12 Months | 
| Clinical Outcome - estimated glomerular filtration rate (eGFR) 12 Months | Difference between eGFR decline after 12 months between control group and intervention group. | 12 Months | 
| Clinical Outcome - eGFR 24 Months | Difference between eGFR decline after 24 months between control group and intervention group. | 24 Months | 
| Clinical Outcome - albuminuria 12 Months | Difference between albuminuria after 12 months between control group and intervention group. | 12 Months | 
| Clinical Outcome - albuminuria 24 Months | Difference between albuminuria after 24 months between control group and intervention group. | 24 Months | 
| Clinical Outcome - Death-censored Graft Failure 12 Months | Difference in Death-censored Graft Failure after 12 months between control group and intervention group. | 12 Months | 
| Clinical Outcome - Death-censored Graft Failure 24 Months | Difference in Death-censored Graft Failure after 24 months between control group and intervention group. | 24 Months | 
| Clinical Outcome - Mortality 12 Months | Difference in Mortality after 12 months between control group and intervention group. | 12 Months | 
| Clinical Outcome - Mortality 24 Months | Difference in Mortality after 24 months between control group and intervention group. | 24 Months | 
| Clinical Outcome - Severe Infection 12 Months | Difference in occurence of severe infections (hospitalization, organ failure, death) during 12 months between control group and intervention group. | 12 Months | 
| Clinical Outcome - Severe Infection 24 Months | Difference in occurence of severe infections (hospitalization, organ failure, death) during 24 months between control group and intervention group. | 24 Months | 
| Adverse Events of Kidney Transplant Biopsy | Occurence of Complications from Kidney Transplant Biopsies, including Duration and potential therapy to treat the adverse event. | 12 Months | 
| Rate of ABMR | Number of biopsy proven active or chronic active ABMR in the cohort. | 12 Months | 
| DSA Levels 0 Months | Mean fluorescence intensity of immunodominant DSA | at inclusion | 
| DSA Levels 12 Months | Mean fluorescence intensity of immunodominant DSA at 12 months | 12 months | 
| DSA Levels 24 Months | Mean fluorescence intensity of immunodominant DSA at 24 months | 24 months | 
| Immunosuppressive Regimen | Report of immunosuppressive medication at the following time points: 0,1,3,6,9,12,24 months, changes of medication, additional therapies such as plasmapheresis, or experimental therapies. | 24 months |