Role of Donor Genetics and Recipient Genetics in Kidney Transplant Outcomes
Condition: Kidney Disease; Kidney Transplantation; Kidney Failure, Chronic
MeSH terms: Kidney Diseases; Renal Insufficiency; Kidney Failure, Chronic
Study type: Observational

Summary: 
      Background:

      - Genetic variation in a particular chromosome is a major contributor to the increased risk
      for kidney disease that is common in people of African descent, although the specific gene,
      mutations, and other aspects of the variations remain to be determined. By studying the
      outcomes of kidney transplant in donors and recipients of African descent, researchers hope
      to better understand the effects of this genetic variation on the success of kidney
      transplants.

      Objectives:

      - To examine possible connections between genetic variations and kidney transplant outcomes
      for donors and recipients.

      Eligibility:

        -  Participants in kidney transplant where both donor and recipient were of black African
           descent.

        -  Eligible transplants include both living donor and deceased donor.

      Design:

        -  The study will involve one visit of up to 8 hours.

        -  All participants will provide a detailed personal and family medical history.

        -  All participants will provide blood and urine samples, including a 24-hour urine
           collection, to test kidney function and collect material for genetic testing.

        -  Donor participants will also have a magnetic resonance imaging (MRI) scan of their
           remaining kidney.
    

Detailed description: 
      Genetic variation in the region of MYH9 and APOL1, located on chromosome 22, is a major
      contributor to the increased risk for kidney disease that characterizes African descent
      populations, although the specific gene, causative mutations, and the molecular and cellular
      mechanisms remain to be determined. We propose to study the role of MYH9 and APOL1 genetic
      variation, as well as other genes, in renal transplant, including the effect of donor
      genotype on recipient outcomes and on donor outcomes. Additional exploratory studies will
      address 1) whether variation in other donor genes might contribute to donor and recipient
      outcomes, which we may address with candidate gene studies or a genome-wide association study
      and 2) whether recipient genotype contributes to recipient outcomes, which we will address in
      similar ways.

      MULTICENTER STUDY. We will identify 300 kidney transplant dyads (donor/recipient pairs), in
      which both individuals were of African descent and the kidney transplants were performed
      between 1995 and 2006. We will include 150 living donor transplants (selected on the basis of
      the ability to locate the surviving living donor and their willingness to participate) and
      150 deceased donor transplants (selected at random, to minimize survival bias of the
      allograft). All subjects sign consents that are identical or similar to the NIH consent.

      RECIPIENT OUTCOMES. We hypothesize that genetic variants in the kidney donor genome and
      secondarily in recipient genome might contribute to kidney recipient outcomes. We will obtain
      kidney donor genotypes using blood from surviving living donors or using transplant kidney
      biopsy DNA from now-deceased living donors, and we will obtain deceased donor genotypes by
      using transplant kidney biopsies. We will obtain recipient DNA, when available, from
      surviving recipients or from tissues obtained from deceased recipients. We will carry out Cox
      proportional hazards analysis to test the primary hypothesis, that donor MYH9 and APOL1
      genotype influences allograft survival. We will also develop a multivariable model to predict
      last follow-up glomerular filtration rate, incorporating factors known to influence
      transplant outcomes and examining the effect of donor MYH9 and APOL1 genotype. In exploratory
      studies, we determine whether recipient genetic variants influence recipient outcomes.

      DONOR OUTCOMES. We hypothesize that genetic variants in the kidney donor affect kidney donor
      outcomes. While kidney donors do not have an increased risk of chronic kidney disease
      compared to the general population, they do have an increased prevalence of microalbuminuria.
      Furthermore, the extent of compensatory renal hypertrophy appears to differ among
      individuals. We wish to determine whether MYH9 and APOL1 genotype affects these outcomes, as
      well as the uncommon occurrence of overt kidney disease after kidney donation. CLINICAL
      IMPLICATIONS. We believe that that these studies will expand our knowledge of how donor
      genotypes influence kidney transplant outcomes for both donors and recipients.

      COLLABORATIVE STUDY. In separate but related studies, we will work with various collaborators
      who pursuing similar question under research protocols that they have generated and for which
      they have local IRB approvals. We will receive from these collaborators materials for
      preparation of DNA, from which we will genotype APOL1 and other genes known or hypothesized
      to be related to donor and recipient transplant outcomes.
    

Observational model: Cohort
Time perspective: Other
Sampling method: Probability Sample
Study population: 
        Will identify 300 kidney transplant dyads (donor/recipient pairs), which both individuals
        were of African descent and the kidney transplants were performed between 1995-2006. We
        hypothesize that genetic variants in the kidney donor affect kidney donor outcomes. Kidney
        donors have an increased prevalence of microalbuminuria.
      
Keywords: African-Americans; MYH9; Chronic Allograft Nephropathy; Chronic Kidney Disease; Proteinuria; Natural History; Kidney Disease; Kidney Transplant; African-American