APOL1 Kidney Disease Risk Variants: An Evolving Landscape

Semin Nephrol. 2015 May;35(3):222-36. doi: 10.1016/j.semnephrol.2015.04.008.


Apolipoprotein L1 (APOL1) genetic variants account for much of the excess risk of chronic and end-stage kidney disease, which results in a significant global health disparity for persons of African ancestry. We estimate the lifetime risk of kidney disease in APOL1 dual-risk allele individuals to be at least 15%. Experimental evidence suggests a direct role of APOL1 in pore formation, cellular injury, and programmed cell death in renal injury. The APOL1 BH3 motif, often associated with cell death, is unlikely to play a role in APOL1-induced cytotoxicity because it is not conserved within the APOL family and is dispensable for cell death in vitro. We discuss two models for APOL1 trypanolytic activity: one involving lysosome permeabilization and another involving colloid-osmotic swelling of the cell body, as well as their relevance to human pathophysiology. Experimental evidence from human cell culture models suggests that both mechanisms may be operative. A systems biology approach whereby APOL1-associated perturbations in gene and protein expression in affected individuals are correlated with molecular pathways may be productive to elucidate APOL1 function in vivo.

Keywords: APOL1; Health disparities; chronic kidney disease; focal segmental glomerulosclerosis; innate immunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Apolipoprotein L1
  • Apolipoproteins / genetics*
  • Apolipoproteins / metabolism
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Kidney Diseases / genetics*
  • Kidney Diseases / metabolism
  • Lipoproteins, HDL / genetics*
  • Lipoproteins, HDL / metabolism
  • Risk Factors


  • APOL1 protein, human
  • Apolipoprotein L1
  • Apolipoproteins
  • Lipoproteins, HDL