Deceased Donor Biomarkers and Recipient Outcomes (DDS)

Deceased Donor Urinary Biomarkers to Predict Kidney Transplant Outcomes

Compared to chronic dialysis, kidney transplantation provides recipients with longer survival and better quality of life at a lower cost. In order to meet increasing demands for kidney allografts, kidneys from older and sicker donors are being procured. This has led to greater discard rates of donated kidneys as well as more complications for recipients, including shorter allograft survival. Available clinical models to predict kidney allograft quality have poor prognostic ability and do not asses the degree of kidney allograft injury. However, allograft injury near the time of procurement can lead to major consequences for the transplant recipient: greater risks of delayed graft function, poor allograft function and premature loss of the transplant. Our proposal is based on the hypotheses that novel biomarkers measured in donor urine and transport media at the time of procurement can assess acute and chronic kidney injury and that distinct biomarker patterns will predict allograft survival. In collaboration with five organ procurement organizations, we will collect urine samples from consecutive deceased donors and samples of transport solution for every pumped kidney. We will measure markers of injury, repair, inflammation and fibrosis. We will determine mortality and allograft survival in all patients by linkage to the United Network for Organ Sharing (UNOS) database (Overall Cohort). Additionally, we will perform a detailed chart review of a subset of recipients (detailed cohort) and will also examine associations between biomarkers and longitudinal graft function over five years after transplant. Early, non-invasive and rapid assessment of donor kidney injury could drive better allocation decisions and potentially reduce the rates of post-transplant complications. Further, these new tools could provide a platform for clinical trials of therapies for allografts and kidney transplant recipients aimed at ameliorating allograft injury.

Study Overview

• Status: Completed
• Conditions: End Stage Renal Disease; Acute Kidney Injury; Graft Failure; Delayed Graft Function; Deceased Donor Kidney Transplant

Detailed Description

Our study has several key processes that we have developed and tested to address our scientific aims:

1. Enrollment

   We will collect urine samples from approximately 1600 deceased donors and approximately 600 perfusate samples from machine-pumped kidneys from participating organ procurement organizations (OPOs). We estimate that our final donor group will be comprised of 55% standard criteria donors, 25% expanded-criteria donors and 10% donors after cardiac death. Approximately, 20% of the kidneys will be discarded.

2. Donor Data

   Donor variables come from two sources: the United Network for Organ Sharing (UNOS) database and detailed data abstraction from each OPO. The UNOS database provides data on all donors with demographics and other important clinical characteristics. The additional data collected by the OPO staff captures granular information on events surrounding donor death, which are not included in the UNOS database. These data will be available on all enrolled donors and include variables such as serial serum creatinine, nadir blood pressures, medication and vasopressor use, and machine pump parameters.

3. Overall Recipient Cohort

   Over 2000 recipients will have received kidneys from the deceased donors in our study. The Overall Cohort will comprise all of these recipients General demographic and clinical characteristics about recipients in the Overall Cohort will come from the UNOS database. For the Overall Recipient Cohort, we will ascertain delayed graft function (DGF) through center reports to UNOS. We will ascertain allograft failure through center reports to UNOS and new episodes of wait-listing and re-transplant collected by UNOS, Recipient mortality will be ascertained through the center reports to UNOS/SRTR and through the Social Security Death Master File.

4. Detailed Recipient Cohort

   A subset of over 1100 recipients of the Overall Cohort who had transplantation at any of our collaborating transplant centers will comprise this cohort. For the Detailed Subcohort, on-site coordinators will perform manual chart review and abstract more extensive data about each recipient including dialysis indications post-transplant, comorbidities, and specific doses of immunosuppression. For the Detailed Subcohort, we will also collect data on clinical events for up to five years after transplantation, including acute rejection and estimated glomerular filtration rate at the time of transplantation and at months 1, 3, 6, 12, 18, 24, 30, 36, 48 and 60 months after transplant.

5. Novel biomarkers will be measured in urine and perfusate

• Study Type: Observational
• Enrollment (Actual): 1679

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale New Haven Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Massachusetts
    • Waltham, Massachusetts, United States, 02451
      • New England Organ Bank
  • Michigan
    • Ann Arbor, Michigan, United States, 48108
      • Gift of Life Michigan
    • Detroit, Michigan, United States, 48201
      • Harper University Hospital
  • New Jersey
    • Livingston, New Jersey, United States, 07039
      • St. Barnabas Medical Center
    • New Providence, New Jersey, United States, 07974
      • New Jersey Sharing Network
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
    • New York, New York, United States, 10467
      • Montefiore Medical Center
    • New York, New York, United States, 10001
      • New York Organ Donor Network
    • New York, New York, United States, 10032
      • NewYork-Presbyterian/ Columbia University Irving Medical Center
    • New York, New York, United States, 10065
      • The New York Hospital (Cornell)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University Hospital
    • Philadelphia, Pennsylvania, United States, 19102
      • Hahnemann University Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • Gift of Life Donor Program- Philadelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

The population from which our Deceased-Donor Cohort will be selected is all potential deceased organ donors located in the regions serviced by our participating organ procurement organizations (OPOs).

The recipient cohorts will be defined by the deceased donors enrolled in the study, and thus, the study population for this group is all recipients of kidneys from deceased organ donors procured in the regions serviced by our participating OPOs.

Description

Inclusion Criteria:

• Donor Cohort: Appropriate informed consent for research according to OPO policies
• Recipient Cohorts: Any recipient of at least one kidney from a deceased donor enrolled by our participating OPOs

Exclusion Criteria:

• Donor Cohort: Lack of adequate biospecimen quantity or quality as per protocol

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Deceased-Donor Cohort; We will collect urine samples from approximately 1600 deceased donors and approximately 600 perfusate samples from machine-pumped kidneys from participating organ procurement organizations (OPOs).
Recipient Cohort (Overall and Detailed); No samples will be collected from the recipients. Only clinical data and outcomes will be collected from the recipients.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Delayed Graft Function	Receipt of dialysis within the first seven days post renal transplant	Assessed within first week of receiving renal transplant
Death-Censored Graft Failure (Overall Cohort)	Requirement of chronic dialysis or retransplantation after renal transplant.	median of 4 years of follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Graft Function (detailed cohort)	Serum creatinine and estimated glomerular filtration rate at specified time points over a five year period.	median of 4 years of follow-up

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Johns Hopkins University; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Chirag R Parikh, MD PhD, Yale University

Publications and helpful links

General Publications

• Hall IE, Bhangoo RS, Reese PP, Doshi MD, Weng FL, Hong K, Lin H, Han G, Hasz RD, Goldstein MJ, Schroppel B, Parikh CR. Glutathione S-transferase iso-enzymes in perfusate from pumped kidneys are associated with delayed graft function. Am J Transplant. 2014 Apr;14(4):886-96. doi: 10.1111/ajt.12635. Epub 2014 Feb 24.
• Hall IE, Reese PP, Weng FL, Schroppel B, Doshi MD, Hasz RD, Reitsma W, Goldstein MJ, Hong K, Parikh CR. Preimplant histologic acute tubular necrosis and allograft outcomes. Clin J Am Soc Nephrol. 2014 Mar;9(3):573-82. doi: 10.2215/CJN.08270813. Epub 2014 Feb 20.
• Liu C, Hall IE, Mansour S, Thiessen Philbrook HR, Jia Y, Parikh CR. Association of Deceased Donor Acute Kidney Injury With Recipient Graft Survival. JAMA Netw Open. 2020 Jan 3;3(1):e1918634. doi: 10.1001/jamanetworkopen.2019.18634.
• Puthumana J, Hall IE, Reese PP, Schroppel B, Weng FL, Thiessen-Philbrook H, Doshi MD, Rao V, Lee CG, Elias JA, Cantley LG, Parikh CR. YKL-40 Associates with Renal Recovery in Deceased Donor Kidney Transplantation. J Am Soc Nephrol. 2017 Feb;28(2):661-670. doi: 10.1681/ASN.2016010091. Epub 2016 Jul 22.

Helpful Links

• Pubmed Link for Deceased Donor Study

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (Actual): December 1, 2019
• Study Completion (Actual): March 1, 2020

Study Registration Dates

• First Submitted: April 30, 2013
• First Submitted That Met QC Criteria: May 2, 2013
• First Posted (Estimate): May 7, 2013

Study Record Updates

• Last Update Posted (Actual): April 9, 2020
• Last Update Submitted That Met QC Criteria: April 8, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: biomarkers; kidney transplant; end stage renal disease; delayed graft function; kidney donor; deceased donors; transplant recipients; graft failure
• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Kidney Diseases; Death; Kidney Failure, Chronic; Acute Kidney Injury; Delayed Graft Function
• Other Study ID Numbers: 1206010465; R01DK093770-01A1 (U.S. NIH Grant/Contract)