Eliminating the Need for Pancreas Biopsy Using Peripheral Blood Cell-free DNA

Study Overview
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Brief Summary
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Donor-derived cell-free DNA (dd-cfDNA) has shown promise as an early marker for cellular injury caused by rejection. dd-cfDNA changes may also indicate other injuries that lead to progressive decline in transplant organ function associated with, in the case of kidney transplantation, the presence of interstitial fibrosis (IF) and tubular atrophy (TA) seen in biopsy specimens. Here, we will study the utility of dd-cfDNA to predict rejection in pancreas and pancreas-kidney recipients.

Detailed Description
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+Objective The objective of this prospective observational study is to correlate circulating dd-cfDNA to clinical and sub-clinical acute rejection in pancreas transplant alone (PTA), pancreas after kidney (PAK), and simultaneous pancreas kidney (SPK) allograft recipients. The secondary objective study is to correlate circulating dd-cfDNA to pancreas and kidney function, using Hgb1c, C-peptide and insulin requirement to assess pancreas function, and using serum creatinine and estimated glomerular filtration rate (eGFR) to assess kidney function. The clinical data and specimen collection will also enable future biomarker research. +Study endpoints Serial dd-cfDNA in individuals over time will be correlated with clinical status and outcomes, such as events of allograft dysfunction or biopsy proven rejection. The primary endpoints of the study are: Clinical T cell as well as antibody mediated acute rejection Sub-clinical T cell as well as antibody mediated acute rejection Composite of clinical and sub-clinical T cell as well as antibody mediated acute rejection. The secondary endpoints for the study are: eGFR (estimated Glomerular Filtration Rate [mL/min]): will be derived from serum creatinine level, corrected for variables, using the CKD-RPI (Chronic Kidney Disease Epidemiology Collaboration) equation. Renal allograft injury from BKV (Polyomaviridae polyomavirus) nephritis, CNI (calcineurin inhibitor) toxicity, acute pyelonephritis and recurrent disease confirmed by renal histology. Pancreas allograft function derived from hemoglobin A1c, insulin requirement, and serum c-peptide per SOC Pancreas allograft injury from pancreatitis (all causes, including gastrointestinal dysmotility or viral). Correlate cfDNA levels with presence or absence of delayed graft function (DGF) and subsequent outcomes in a subset of enrolled patients.

Official Title
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Non-invasive Blood Test to Diagnose Acute Rejection After Pancreas and Kidney Transplantation: Pancreas and Renal Rejection Diagnosis Using Circulating Donor-derived Cell-free DNA in Peripheral Blood

Conditions
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Transplant;Failure,Kidney, Transplant; Failure, Pancreas, Rejection Acute Renal, Rejection Acute Pancreas

Intervention / Treatment
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* Diagnostic Test: dd-cfDNA Blood Test


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult recipients (Age > 18 years ) All genders and all racial and ethnic groups Pancreas transplant alone (PTA) Simultaneous kidney-pancreas transplantation (SPK) Pancreas-after-kidney (PAK) 6. Simultaneous pancreas and living donor kidney (SPLK) 7. Primary or re-transplants 8. Ability to come for follow-up and undergo biopsy (Performed in accordance to SOC) 9. Provided consent Exclusion Criteria: Pediatric recipients (Age < 18 years) Pregnant women Patients undergoing multi-organ transplants not otherwise specified (e.g., pancreas-liver, multi-visceral, or pancreas-heart) Patients receiving donor kidney from an identical twin, as part of an SPLK (see above) Did not provide consent

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| University of Maryland<br>Pancreas and pancreas kidney patients enrolled at University of Maryland. Determine if dd-cfDNA exists in PTA, SPK, and PAK transplant recipient's blood by taking blood specimens at months 1-4, 6, 9, and 12 in the first year post transplant, and quarterly (month 15, 18, 21, 24) in the second year post transplant. | Diagnostic Test: dd-cfDNA Blood Test<br>* The cfDNA measurement isolated from the peripheral blood contains small amounts from the graft. The blood sample is collected in Cell-Free DNA BCT (blood collection) tubes. These are measured by their difference in SNP (single nucleotide polymorphisms) genotype to determine the ratio of donor to recipient through shotgun sequencing. Higher levels of dd-cfDNA in a patient experiencing rejection is measured as a higher percentage of the total cf-DNA.<br>|
| University of Wisconsin<br>Pancreas and pancreas kidney patients enrolled at University of Wisconsin. Determine if dd-cfDNA exists in PTA, SPK, and PAK transplant recipient's blood by taking blood specimens at months 1-4, 6, 9, and 12 in the first year post transplant, and quarterly (month 15, 18, 21, 24) in the second year post transplant. | Diagnostic Test: dd-cfDNA Blood Test<br>* The cfDNA measurement isolated from the peripheral blood contains small amounts from the graft. The blood sample is collected in Cell-Free DNA BCT (blood collection) tubes. These are measured by their difference in SNP (single nucleotide polymorphisms) genotype to determine the ratio of donor to recipient through shotgun sequencing. Higher levels of dd-cfDNA in a patient experiencing rejection is measured as a higher percentage of the total cf-DNA.<br>|
| Georgetown University<br>Pancreas and pancreas kidney patients enrolled at Georgetown University. Determine if dd-cfDNA exists in PTA, SPK, and PAK transplant recipient's blood by taking blood specimens at months 1-4, 6, 9, and 12 in the first year post transplant, and quarterly (month 15, 18, 21, 24) in the second year post transplant. | Diagnostic Test: dd-cfDNA Blood Test<br>* The cfDNA measurement isolated from the peripheral blood contains small amounts from the graft. The blood sample is collected in Cell-Free DNA BCT (blood collection) tubes. These are measured by their difference in SNP (single nucleotide polymorphisms) genotype to determine the ratio of donor to recipient through shotgun sequencing. Higher levels of dd-cfDNA in a patient experiencing rejection is measured as a higher percentage of the total cf-DNA.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| dd-cfDNA correlation to acute rejection | To correlate circulating dd-cfDNA to clinical and sub-clinical acute rejection in PTA, PAK, and SPK allograft recipients. Clinical T cell as well as antibody mediated acute rejection. Sub-clinical T cell as well as antibody mediated acute rejection. Composite of clinical and sub-clinical T cell as well as antibody mediated acute rejection. | August 1, 2019 to July 31, 2022 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| dd-cfDNA correlation to pancreas and kidney function | To correlate circulating dd-cfDNA to pancreas and kidney function, using Hgb1c, C-peptide and insulin requirement to assess pancreas function, and using serum creatinine and estimated glomerular filtration rate [eGFR] to assess kidney function. eGFR (estimated Glomerular Filtration Rate [mL/min]): will be derived from serum creatinine level, corrected for variables, using the CKD-RPI (Chronic Kidney Disease Epidemiology Collaboration) equation. Renal allograft injury from BKV (Polyomaviridae polyomavirus) nephritis, CNI (calcineurin inhibitor) toxicity, acute pyelonephritis and recurrent disease confirmed by renal histology. Pancreas allograft function derived from hemoglobin A1c, insulin requirement, and serum C-peptide per SOC 4. Pancreas allograft injury from pancreatitis (all causes, including gastrointestinal dysmotility or viral). | August 1, 2019 to July 31, 2022 |