Clinical trial NCT00531921: Effects of Donor and Recipient Genetic Expression on Heart, Lung, Liver, or Kidney Transplant Survival
Official title: Correlation of Donor Proinflammatory mRNA Profiles With Early Outcomes of Thoracic and Abdominal Transplantation
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Heart Transplantation
Kidney Transplantation
Liver Transplantation
Lung Transplantation
Keywords: Heart Diseases
Kidney Diseases
Liver Diseases
Liver Failure
Lung Diseases
Transplant
Transplantation, Homologous
Rejection
Kidney Failure
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2007-09-19
Enrollment: 313
Sex: ALL
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Transplant patients evaluated for the association between proinflammatory mRNA expression from donor samples and subsequent development of early organ dysfunction

Brief summary: Activity of genes in donor tissues that are involved in inflammation are thought to be involved with early organ dysfunction, increased immune responses in transplant recipients, and organ rejection. The purpose of this study is to determine the relationship between genetic expression in donor and recipient tissue with transplant survival. Participants in this study will have received heart, lung, liver, or kidney transplants.

Detailed description: Inflammation and injuries to transplanted organs during the immediate post-operative period may be linked to early organ dysfunction and higher rates of transplant rejection in the recipient. Currently, mRNA expression of proinflammatory genes in donor tissues is thought to be a risk factor for early organ transplant dysfunction, increased expression of the recipients cell-mediated immunity genes, and organ rejection. The purpose of this study is to test the association between proinflammatory mRNA expression in donor samples and subsequent development of early organ dysfunction in kidney, lung, and liver transplant recipients. This study will also test the effects of proinflammatory mediators expressed in the transplanted organ pre- and post-reperfusion on organ rejection and genes expressed in cell mediated immune responses. This will be achieved by identifying the proinflammatory immune responses and their mechanisms.

This study will consist of up to 11 study visits over a period of 2 years. The baseline visit will occur 24 hours prior to organ transplantation. Follow-up visits will occur daily for Days 1 to 3 (for lung transplant recipients only) and on Day 7, Week 6, and Months 3, 6, 9, 12, 18, and 24 post-transplant. At the baseline visit, a physical exam, medical history, demographics, vital signs measurements, blood collection, and collection of donor tissue sample will occur. For most or all other study visits, medication and adverse events tracking and blood collection will occur. Depending on the transplant type, participants will undergo the following procedures:

* Heart: Participants will undergo a heart biopsy that is part of standard clinical care following a heart transplant. An echocardiogram and an electrocardiogram will occur at most visits.
* Kidney: Renal biopsies will be performed 1 hour after reperfusion at the time of surgery. Urine collection will occur at most visits.
* Liver: Liver biopsies will be performed at the time of procurement and within 1 hour of reperfusion.
* Lung: Participants will undergo bronchoalveolar lavage that is part of standard clinical care following a lung transplant. A chest x-ray, an arterial blood gas test, a pulmonary function test, and 6-minute walking test will occur at some visits.

Eligibility criteria: Inclusion Criteria for all participants:

* Received single lung, heart, kidney, or liver transplant
* Specimens of donor tissues have been collected
* Parent or guardian willing to provide informed consent, if applicable

Inclusion Criteria for Kidney or Liver Transplant Participants:

* 70 years old or younger

Inclusion Criteria for Heart or Lung Transplant Participants:

* Between 16 and 70 years old

Exclusion Criteria for All Participants:

* Previous solid organ transplant
* Need for combined organ transplant
* HIV or hepatitis C virus infection
* Recipient of an organ from a hepatitis C virus-infected donor
* Clinical evidence of systemic bacterial infection in the recipient at the time of transplantation
* Living donor transplant recipient of either a kidney, liver, or lung

Primary outcomes:
measure: Association between proinflammatory mRNA expression in donor samples and subsequent development of early organ dysfunction in the immediate period following transplantation
timeFrame: Within first 7 days after transplant
measure: Association of mRNA expression of proinflammatory mediatros in the transplanted organ in the immediate pre and post-reperfusion period with subsequent incidence of acute rejection and expression of genes involved in cell mediated immunity
timeFrame: 12 months after transplant
Secondary outcomes:
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern Memorial Hospital (kidney and liver)
state: Illinois
city: Ithaca
country: United States
facility: Cornell University Medical College (kidney)
state: New York
city: New York
country: United States
facility: Columbia University (lung and liver)
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania (heart, kidney, liver, lung)
state: Pennsylvania
city: Madison
country: United States
facility: University of Wisconsin (heart and lung)
state: Wisconsin
Study officials:
affiliation: University of Pennsylvania Medical Center
name: Abraham Shaked, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Fox-Marsh A, Harrison LC. Emerging evidence that molecules expressed by mammalian tissue grafts are recognized by the innate immune system. J Leukoc Biol. 2002 Mar;71(3):401-9.
citation: Isobe M, Suzuki J. New approaches to the management of acute and chronic cardiac allograft rejection. Jpn Circ J. 1998 May;62(5):315-27. doi: 10.1253/jcj.62.315.
citation: Jiang S, Lechler RI. CD4+CD25+ regulatory T-cell therapy for allergy, autoimmune disease and transplant rejection. Inflamm Allergy Drug Targets. 2006 Dec;5(4):239-42. doi: 10.2174/187152806779010981.
citation: Kaplan B, Srinivas TR, Meier-Kriesche HU. Factors associated with long-term renal allograft survival. Ther Drug Monit. 2002 Feb;24(1):36-9. doi: 10.1097/00007691-200202000-00007.
citation: Lande JD, Patil J, Li N, Berryman TR, King RA, Hertz MI. Novel insights into lung transplant rejection by microarray analysis. Proc Am Thorac Soc. 2007 Jan;4(1):44-51. doi: 10.1513/pats.200605-110JG.
citation: Reding R, Gras J, Truong DQ, Wieers G, Latinne D. The immunological monitoring of alloreactive responses in liver transplant recipients: a review. Liver Transpl. 2006 Mar;12(3):373-83. doi: 10.1002/lt.20704.
citation: Zheng XX, Sanchez-Fueyo A, Sho M, Domenig C, Sayegh MH, Strom TB. Favorably tipping the balance between cytopathic and regulatory T cells to create transplantation tolerance. Immunity. 2003 Oct;19(4):503-14. doi: 10.1016/s1074-7613(03)00259-0.
citation: Cantu E, Lederer DJ, Meyer K, Milewski K, Suzuki Y, Shah RJ, Diamond JM, Meyer NJ, Tobias JW, Baldwin DA, Van Deerlin VM, Olthoff KM, Shaked A, Christie JD; CTOT Investigators. Gene set enrichment analysis identifies key innate immune pathways in primary graft dysfunction after lung transplantation. Am J Transplant. 2013 Jul;13(7):1898-904. doi: 10.1111/ajt.12283. Epub 2013 May 24.
citation: Olthoff KM, Kulik L, Samstein B, Kaminski M, Abecassis M, Emond J, Shaked A, Christie JD. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl. 2010 Aug;16(8):943-9. doi: 10.1002/lt.22091.