Background Compared to European, Asian and Native Americans, African Americans have a 3-fold higher risk of developing end-stage kidney disease (ESKD) and are more likely to develop severe lupus nephritis (LN).

Methods Strong genetic association is observed between the apolipoprotein L1 gene (APOL1) and a spectrum of non-diabetic chronic kidney diseases (CKD) in African Americans, including LN, focal segmental glomerulosclerosis, solidified glomerulosclerosis (hypertension-attributed nephropathy), HIV-associated nephropathy, sickle cell nephropathy, and premature failure of transplanted kidneys from APOL1 high-risk donors. APOL1 risk variants arose in sub-Saharan Africa and are present only in those who possess recent African ancestry. These variants account for much of the excess risk for LN and CKD in African Americans. Studies in transgenic mice prove that APOL1 risk variants cause CKD. Kidney disease is due to locally produced APOL1 protein in kidney cells, not circulating APOL1 protein in the blood.

Results Patients with systemic lupus erythematosus who inherit two APOL1 risk variants are more likely to progress to ESKD and often display focal and diffuse proliferative or membranous glomerular lesions. Kidney disease often progresses despite cytotoxic therapy. In contrast, APOL1 is not associated with mild LN. Therefore, APOL1 risk variants are nephropathy progression factors. Not all individuals with two APOL1 risk variants develop CKD; modifying factors are required. HIV infection, SARS-CoV-2 infection, and interferon are powerful second hits that initiate nephropathy in genetically susceptible hosts.

Conclusions Conventional treatments for kidney disease often fail to halt the progression of non-diabetic CKD. Novel small molecule inhibitors of APOL1 protein and APOL1 anti-sense oligonucleotides hold great promise for slowing progression of APOL1-associated nephropathy, including LN. Treatments have the potential to reduce disparities in CKD risk among individuals with African ancestry. In addition, the NIH ‘APOL1 Long-term Kidney Transplant Outcomes’ (APOLLO) Consortium is considering the role of APOL1 genotyping in deceased African American kidney donors to improve organ allocation. Discovery of the APOL1 genetic association with nephropathy in the lab has moved to the bedside and will improve patient outcomes.