The discovery of certain APOL1 gene variations in African Americans (AA) showed that these variants are a major reason for the development of chronic kidney disease (CKD). Indeed, certain APOL1 gene variants account for much of the striking increase in end-stage renal disease (ESRD) in AA compare to European Americans (EA). In addition, kidney transplants that have these same APOL1 gene variants have a two-fold increase for failure. Thus, it is important to understand how these APOL1 genes contribute to kidney transplant failure and find other factors that can increase or decrease the occurrence of such kidney failure. There is also a need to understand if certain APOL1 genes will affect the health of living AA kidney donors. The NIDDK APOLLO network is a critical step in generating the data needed to answer these important questions. We have assembled a network of multiple transplant programs in the Mid-Atlantic and a multidisciplinary team of investigators that will gather a large group of AA kidney donors and recipients to follow their health and kidney function over time, as well as build a kidney tissue, serum and urine biobank to provide a platform for promising additional future research. The mechanisms of how certain APOL1 gene variants affect kidney function are not known. Accordingly, we propose to utilize state of the art ?omics? technologies such as RNA sequencing, exome sequencing metabolomics and epigenetics on the kidney biopsies, sera and urine samples to help discover how APOL1 gene variants cause kidney diseases. We will correlate the results of these tests with the health of the donors and recipients and the function of their kidneys. We propose to test three primary hypotheses: 1.) Certain APOL1 gene variants in AA can activate pathways that lead to abnormal responses in kidneys, resulting in increased susceptibility to CKD in kidney donors; 2.) In kidney recipients, certain APOL1 gene variants can activate responses that lead to kidney injury and increased CKD and/or kidney transplant failure; and 3.) Certain APOL1 gene variants can stimulate abnormal kidney responses, leading to increased blood pressure and cardiac disease in donors or recipients. To test these hypotheses we propose three aims:
Aim 1 : (a) Establish a large group of AA live kidney donors; (b) Establish a serum and urine biobank; and (c) Examine the relationship between APOL1 genes and kidney diseases.
Aim 2 : (a) Establish a large group of recipients of AA kidneys; (b) Establish kidney biopsy, serum and urine biobank; (c) Determine the relationship between APOL1 genes and transplant outcomes; (d) Examine the relationship of APOL1 genes and the pathology of the kidney biopsies; and (e) Use omics based methods to identify how APOL1 gene variants affect kidney outcomes.
Aim 3 : (a) Assess the relationship between of APOL1 gene variants and cardiac disease.
We will assemble a network of multiple transplant programs and a multidisciplinary team of investigators to establish a large cohort of African American (AA) kidney donors and recipients, and a tissue, serum and urine biobank. These resources will then allow us to: 1) follow a group of African American (AA) kidney donors; 2) follow a group of recipients of AA kidney transplants; 3) use the biobank to perform state of the art pathology and gene studies; and 4) show how the APOL1 gene regulates kidney responses and metabolism. The results from these studies will help to improve the kidney function and lives of kidney donors and recipients.
