ApolipoproteinL1 Genotypes and Biomarkers of Immune Activation and Tubular Injury - PROJECT SUMMARY Chronic Kidney Disease (CKD) can effectively be a death sentence in sub-Saharan Africa where <2% of patients with kidney failure have access to dialysis or transplantation. Biomarkers of immune activation (soluble tumor necrosis factor receptor 1 [sTNFR1], tumor necrosis factor alpha [TNFα], soluble urokinase plasminogen activator receptor [suPAR]), and biomarkers of tubular injury (kidney injury molecule 1 [KIM-1]), have been associated with CKD progression. However, few studies have investigated CKD biomarkers in relation to APOL1 genotypes, and the findings in existing studies have been inconsistent. We do not know whether there is subclinical evidence of tubular injury prior to decline in kidney function and how this differs for high- vs low-risk APOL1 genotype carriers. Furthermore, we lack a clear understanding of how biomarkers of immune activation may modify CKD progression in high-risk genotype carriers. We propose an R03 application leveraging the Diet, CKD, and ApolipoproteinL1 (DCA) study which is an ancillary study to the Human Hereditary and Health in Africa (H3Africa) kidney disease study. The DCA study has enrolled 738 individuals with CKD in Nigeria and Ghana. DCA participants are being genotyped for APOL1 and have stored plasma and 24hr-urine aliquots along with follow-up serum creatinine for estimated glomerular filtration rate (eGFR) and CKD progression. Our overall hypothesis is that inflammation and tubular injury are key factors in the development and progression of APOL1-mediated kidney disease; to test this hypothesis, we will measure biomarkers of inflammation and tubular injury in Africans with CKD and compare across low-and high-risk APOL1 genotypes. Our specific aims are to: 1) Determine the cross-sectional associations of KIM-1, a biomarker of tubular injury, with APOL1 high- compared to low-risk genotypes; 2) Determine the prognostic significance of inflammation biomarkers in Africans with CKD across high- and low-risk APOL1 genotypes. The R03 project will add critical elements to the DCA cohort and provide the PI, Dr. Ilori, with preliminary data for future R01 applications focused on validating findings in larger cohorts and in new studies recruiting Africans with high-risk genotypes without CKD. Using genomic data and biomarker data to phenotype individuals with subclinical and overt kidney disease will advance precision medicine in CKD and will add to the evidence base on mechanisms of APOL1-mediated kidney disease.
