Genomics of Kidney Transplantation

Abstract: 

Genomics of Kidney Transplantation

End stage renal disease (ESRD) is a growing and expensive problem in the United States costing in excess of $25 billion in 2002 alone. For treating ESRD, kidney transplantation is more cost-effective than long-term dialysis. Despite improvements in one-year kidney allograft survival, late graft loss (LGL) persists as a major clinical problem. Almost 4,500 kidney transplant recipients returned to dialysis in 2003; most of them were greater than one year post-transplantation.

Both immune and non-immune mechanisms contribute to chronic allograft dysfunction (CGD) and subsequent LGL. Immunological injury can operate early or late. Non-immunological factors are also important mediators and “accelerants” of LGL. Although many correlates of allograft function are now known, there remains extensive unexplained variation in occurrence of LGL. Kidney biopsy findings in CGD also highlight the important role of fibrosis. Fibrosis is a prominent feature of LGL and also plays a key role in the clinical relevant pathological evaluation of kidney biopsies. This leads to the hypothesis that variation in important genetic factors involved in the regulation of the fibrosis are responsible for the variation in occurrence of LGL.

With the completion of the Human Genome Project, it is clear that there is considerable genetic variation among the human population with SNPs accounting for over 90% of the genetic variation in the human genome. Unlike somatic mutations, SNPs are stable and heritable. Individual patient outcomes are dependent on heritable variations in a wide variety of genes and pathways affecting fibrosis. Therefore the study of SNPs and haplotypes of candidate genes that control these intermediates of LGL could provide important clues in unraveling the pathogenesis of LGL.

This study uses a genetic epidemiology approach, using an ongoing, large, prospective cohort of kidney transplant recipients enrolled in an NIH-funded study, called DeKAF. All subjects in the DeKAF study will undergo kidney allograft biopsies for a deterioration of renal function defined by greater than 25% persistent increase in serum creatinine from a baseline established at three months post-transplant or new onset proteinuria. The DeKAF study is designed to classify causes of CGD, using clinical information and biopsy findings. The Israni group will determine how genetic predisposition may help to explain the outcomes defined in the DeKAF study. Although many correlates of CGD, as well as renal allograft and patient survival, have been defined, there remain extensive unexplained variations in these outcomes. This leads to the hypothesis that variation in important genetic factors involved in the regulation of fibrosis are responsible for some of the currently unexplained variation in renal allograft function and survival. This project's specific aim is to study the associations of allelic variants of donor and recipient genes with CGD defined as persistent 25% increase in serum creatinine (Scr) from a baseline established at three months post-transplantation and a persistent persistent 25% decline in eGFR, in a racially diverse transplant population. The group uses MSI resources to analyze the genetic data.

A bibliography of this group’s publications is attached.

Return to this PI's main page.

Group name: 
isrania
Attachment: